Paget’s Disease of Bone

ABSTRACT

Sir James Paget described a skeletal disorder affecting one or more areas of the skeleton in 1876. It is most common in England and in countries to which the English migrated. In recent years the prevalence in most countries has decreased. A common feature is skeletal deformity which evolves over many years and is most visible in the skull and lower extremities. Pathological fractures are most likely to occur in the femurs. Pain is a common feature in patients with Paget’s disease and may be of skeletal, joint, neurologic, or muscle origin. The radiologic features begin with a localized area of osteolysis which advances very slowly in the absence of therapy. Over time the lesion becomes osteosclerotic and once an entire bone is affected the entire lesion is sclerotic with areas of osteolysis remaining. Bone scans utilizing technetium99m-labeled bisphosphonates exhibit markedly increased uptake in the untreated state. Histologic evaluation of early lesions reveals an increased number of osteoclasts advancing at the interface of normal bone. They are often larger than normal and contain many more nuclei than normal osteoclasts. Subsequently numerous osteoblasts are found to be producing a large amount of disorganized bone. Associated with the increase in osteoclasts and osteoblasts there is a highly vascular fibrocellular marrow replacing the hematopoietic marrow. The osteoclasts have an abnormal ultrastructure featuring nuclear inclusions, and sometimes, cytoplasmic inclusions resembling nucleocapsid-like structures of the Paramyxoviridae family. Measurement of serum or urine N- or C-telopeptides documents the degree of bone resorption and serum total alkaline phosphatase activity, serum bone specific alkaline phosphatase and serum procollagen type 1 amino-propeptide document bone formation. Serum total alkaline phosphatase activity is the least expensive and most widely used test. Patients may develop sarcomas or giant cell tumors in affected bone but this is rare. Metabolic complications include hypercalcemia associated with immobilization and hyperuricemia and gout in patients with more extensive disease. Increased cardiac output may occur in patients with extensive disease due to the vascularity of the lesions. The earliest effective treatment was calcitonin but with the increased efficacy of the more potent bisphosphonates calcitonin is seldom prescribed. The treatment of choice is presently an intravenous infusion of 5 mg zoledronate. This normalizes bone resorption and formation markers for up to six and a half years in most patients. Indications for treatment include bone pain, hypercalcemia, neurologic deficits with vertebral disease, congestive heart failure, preparation for orthopedic surgery, and prevention of complications such as hearing loss and deformity. Surgery most commonly is needed for lower extremity joint replacement and correction of deformities of the lower extremity. The etiology remains somewhat controversial with some studies indicating a role for measles virus. The observation that the prevalence of the disease has decreased could be explained by the introduction of measles vaccine in 1963. Clearly genetic factors also play a role. Mutations in the sequestosome 1 gene produce susceptibility to develop Paget’s disease but not all family members with the mutation develop Paget’s disease. Many other gene abnormalities may also increase disease susceptibility.

HISTORICAL ASPECTS

In 1876, Sir James Paget (Figure 1), a prominent English surgeon, described five men who had at least two deformed areas of the skeleton (1). His description of the disorder he called osteitis deformans included clinical features, and gross and histologic pathology. He believed he was describing a rare inflammatory disorder, but by the start of the new century, numerous publications describing similar patients appeared in England, France, and the United States. A small number of reports also came from Australia, Germany, Holland, Italy, and Sweden. By this time, the condition commonly became known as Paget's disease of bone.

Figure 1. The bust of Sir James Paget in the Museum of St. Bartholomew's Hospital.

Further realization that Paget's disease was not a rare disorder came about after the discovery of X-rays in 1895 by Roentgen. It was then possible to detect affected bones, which exhibited no external manifestations of the disease. The first X-ray report appeared in 1896 (2) and osteolytic disease was recognized by1901 (3).

The first biochemical marker of Paget's disease was recognized in 1929 by Kay (4). He reported elevated alkaline phosphatase activity in the patients' sera. Over time, it came to be appreciated that serum alkaline phosphatase activity could reach higher levels in Paget's disease than in any other disorder.

EPIDEMIOLOGY

The distribution of Paget's disease throughout the world is one of its most striking features. While commonly found in the population of England, the United States, Australia, New Zealand, Canada, South Africa, and France, it appears to be rare throughout Asia and Scandinavia. Estimates of the prevalence in individual British cities even suggest a striking variability within one country (5). Analysis of hospital radiographs indicated prevalence ranging from 2.3% in Aberdeen, Scotland to 8% in Lancaster, England. Recently analysis of 1000 CT scans of the abdomen revealed a striking decrease in prevalence to 0.8% in the Lancashire region (6). The most recent prevalence estimate in the United States is 1-2% (7), and in France is 1.1-1.8% (8). In many countries the prevalence of Paget’s disease appears to have decreased (9-13) although this has not been observed in Italy (14) or in the Salamanca province of Spain (15). It is particularly difficult to obtain a true estimate of prevalence in a population as serum alkaline phosphatase activity may be elevated in as few as 14% of individuals with x-ray evidence of Paget’s disease (16).

Paget's disease probably occurs equally often in men and women and clearly increases in prevalence with age (17). The diagnosis is nearly always determined in individuals over the age of 50 years. The prevalence in the past approached 10% by 90 years and affected individuals are rarely discovered before 20 years.

The occurrence of Paget's disease in more than one member of a family was first reported in 1883 (18). Analysis of numerous kindreds indicates an autosomal dominant mode of inheritance (19). A positive family history of Paget's disease was reported in nearly 15% of patients in two large studies (20,21). In a clinic in Spain, 40% of the patients had at least one first-degree relative with Paget's disease after screening with bone scans (22). Gene analysis of Paget's disease kindreds will be discussed subsequently.

CLINICAL FEATURES

Paget's disease is a localized disorder of the skeleton with a wide range of skeletal involvement. One bone was affected in 5% of patients whereas the average number of lesions was about 6.5 per patient in a series of 197 patients (23). In a more recent study younger patients had a 47% prevalence of monostotic disease while 28% of older patients had monostotic disease (24). In patients with familial disease there may be somewhat more bones affected than in patients with sporadic disease (25).

Deformity

A common feature of Paget's disease is skeletal deformity. This clearly evolves over a period of many years (probably decades) in most patients. The deformity is most visible in the skull and lower extremities.

Asymmetric enlargement of the cranium may first come to attention in those individuals who notice an increase in hat size. An increase in the size of superficial scalp veins, best appreciated over the frontal and temporal bones, is not uncommon. In patients with cranial enlargement, hearing loss is a common complication. Hearing loss correlates with loss of bone mineral density in the cochlear capsule (26). Inexplicably, despite the common skull involvement, Paget's disease is quite unusual in the facial bones. Facial disfigurement may be a consequence of enlargement of the maxilla and/or mandible and can be accompanied by spreading of the teeth, malocclusion, and loss of teeth (27).

One or, less often, two clavicles may become enlarged. An enlarged scapula is uncommonly appreciated perhaps because of its location.

The spine is a common source of morbidity from Paget's disease. The lumbar vertebrae and sacrum are most frequently affected. A single vertebra or multiple vertebrae may be involved. Over time, the vertebrae generally enlarge, but in some instances, vertebral compression may produce significant kyphosis.

Although Paget's disease is commonly found to affect the pelvis, only in its most severe form is it apparent on physical examination that the bone is thicker than normal. It is much easier to detect in the extremities, particularly when bowing of the femur and/or tibia is present (Figure 2). An increase in skin temperature is more readily detected over the tibia, a reflection of increased blood flow to the bone and surrounding soft tissue. Bowing of the upper extremity long bones is much less common than in the lower extremity, presumably because these are not weight-bearing bones.

Figure 2. Typical bowing of the leg due to Paget's disease involving the right tibia.

Pathological fractures in the lower extremity are most likely to occur in the femur and typically are transverse in nature (Figure 3). They are much more likely to result in nonunion than are tibial fractures (28).

Figure 3. Transverse fracture of the left femur.

Pain

Pain is a quite common symptom in patients with Paget's disease. It may be of skeletal, joint, neurologic, or muscle origin. Surprisingly, bone pain is usually absent even in patients with extensive disease or, when present, is mild to moderate in severity. The pain is usually dull in quality and often persists during the night. Weight bearing seldom produces a significant increase in bone pain.

Severe pain in a patient with Paget's disease is most likely to be due to osteoarthritis. This commonly occurs in the hip joint. Deterioration of the cartilage can occur when Paget's disease affects the acetabulum alone (Figure 4), but is likely to be more severe when both the acetabulum and head of the femur are affected by Paget's disease. If the femoral head is the only site of the disease, osteoarthritis is a less likely complication. A major feature of the pain in these patients is a significant increase in severity with weight bearing. In some patients, the combination of pain and impaired motion of the joint severely limits mobility. Knee pain and joint effusion may be prominent features in patients with bowing of the tibia. Back pain due to osteoarthritis also occurs in association with Paget's disease (Figure 5). Pain from osteoarthritis of the shoulder joint is relatively uncommon.

Figure 4. Paget's disease involving the left hemipelvis and right femur. There is severe osteoarthritis of the left hip but a relatively normal joint space in the right hip.

The most severe chronic pain in patients with Paget's disease is probably of neurologic origin. Pain from compression of the spinal cord or nerve roots may follow from enlargement of the vertebral bodies, pedicles, or laminae as well as from compression fractures. Pain from this source is more likely to arise from Paget's disease affecting the thoracic spine.

Figure 5. Patient with back pain who has multiple vertebrae affected by Paget's disease, large osteophytes, and narrowed disc spaces.

In a number of individuals, the weight of the skull may be so great that they have difficulty in keeping the head erect. This can produce neck pain and tension headaches due to muscle spasm. Deformity of the spine may also be associated with intermittent pain due to spasm of the paravertebral muscles.

RADIOLOGY

The radiologic features of Paget's disease include osteolytic, osteosclerotic, and mixed lesions.

The earliest lesions are osteolytic in character and are most readily appreciated in the skull (Figure 6). Circumscribed osteolytic skull lesions were called "osteoporosis circumscripta" by Schuller (29). These most often are seen in the frontal and occipital regions and with time may slowly coalesce. The other region where osteolytic lesions are commonly observed is the long bones of the lower extremity. The lesions usually arise at either end of the bone, seldom in the diaphysis. At the junction of the lesion with normal bone, the osteolytic lesion has the shape of a flame or inverted V (Figure 7). Such lesions have been noted to extend into normal bone at an average rate of about 1 cm per year (30).

Figure 6. Large osteolytic lesion in the skull of a woman with Paget's disease.

Figure 7. Osteolytic lesion of the distal left femur which is progressing proximally.

A heterogeneous region of osteosclerotic bone slowly develops in areas of the skeleton previously exhibiting a purely osteolytic character. This can be readily seen in long bones where the advancing front of osteolysis is trailed by patchy sclerosis superimposed on the earlier osteolytic process. With more time, the character of the bone may evolve into a dominant osteosclerotic appearance. This is often accompanied by periosteal new bone formation, which results in an increase in circumference of the bone. In the first observations reported by Paget, the thickness of the calvarium was fourfold greater than normal in one patient (1). The most severe skull involvement may be associated with basilar impression (Figure 8) which can produce compression of the structures in the posterior fossa resulting in ataxia, muscle weakness, and respiratory distress. With the evolution of the sclerotic phase of the disease, the lower extremity long bones often exhibit lateral and anterior bowing. Another radiologic feature in the long bones of the lower extremity is the presence of linear transverse radiolucencies in the cortex of the convex aspect of the bowed bone. These have been termed fissure fractures. Multiple fissure fractures may be seen. Although they usually remain stable, a small percent progress to complete transverse fractures.

Figure 8. Far advanced Paget's disease of the skull. Note the thickened inner and outer tables, the chaotic new bone deposition termed cotton-wool patch, and basilar impression.

It has been observed that after a dominant sclerotic lesion has developed, there may be secondary osteolytic lesions superimposed upon the sclerotic bone. These are most readily seen as clefts in the cortex of the long bones.

Computerized tomography (CT) and magnetic resonance imaging (MRI) are generally not needed in the evaluation of most patients (31). CT may be needed to detect subtle fractures, spinal stenosis and secondary neoplasms. MRI may be particularly useful in evaluating spinal complications.

The commercial availability of a technetium99m-labeled bisphosphonate in 1974 ushered in the era of routine use of bone scans in clinical medicine (32). In patients with Paget's disease, the affected bone has increased nuclide activity five minutes after intravenous administration of the bone-seeking tracer when compared with normal bone. The nuclide activity is 3-5 times higher than in normal bone. A bone scan is a very effective means of determining the extent of the disease and is clearly more sensitive than X-rays in determining the presence of small osteolytic areas of the disease (Figure 9). Since occult fractures and bone metastases may mimic some lesions of Paget's disease, it is necessary to do X-rays or CT scans of areas of increased nuclide uptake to distinguish the nature of the lesions. Very seldom is it necessary to do a bone biopsy to ascertain the diagnosis.

Figure 9. A technetium 99m-bisphosphonate bone scan of a patient with polyostotic Paget's disease.

In addition to the classical bone scan using a technetium-labeled bisphosphonate, gallium scans (33), fluorine-18-FDG PET scans (34), and Tl-201 scans (35) have been observed to delineate lesions of Paget's disease. In one study, the response to calcitonin treatment was more rapid with gallium scan than with a bone scan (33).

PATHOLOGY

Based on histological examinations of the interface of normal bone with an advancing osteolytic focus of Paget's disease, it has been concluded that the primary abnormality is a localized excess of osteoclastic bone resorption. An increased number of osteoclasts are present in Howship's lacunae in cortical and trabecular bone (Figure 10). They are frequently larger than normal and may have up to 100 nuclei in a single cross-section rather than the 3-10 found in normal osteoclasts (36). With progression of osteoclastic activity in the cortex, bone volume is reduced and individual osteons become confluent. The bone volume in trabecular bone of the medullary cavities is similarly reduced by osteoclastic activity. In association with the intense osteoclastic activity, the normal fatty or hematopoietic marrow is replaced by a fibrocellular stroma, which is highly vascular.

Figure 10. A bone biopsy of the iliac crest revealing an intense area of osteoclastic bone resorption. The osteoclasts are increased in size and have a greater number of nuclei than average.

In the mature lesion, there is a mixture of lamellar and woven bone, which transforms the matrix into a chaotic "mosaic" pattern of irregularly juxtaposed pieces of lamellar bone, interspersed with woven bone (Figure 11). The normal outer and inner circumferential lamellae and interstitial lamellae of the cortex are completely disrupted. Plump osteoblasts are found in large numbers on surfaces of new bone formation. There is an abundance of osteoid on bone surfaces but there is no increase in thickness of the osteoid seams (37). It has been noted that the size of the periosteocytic lacunae in the woven bone is greater than in the lamellar bone of Paget’s disease (37). Since this is also the finding in woven bone from non-pagetic individuals the relevance of this observation is unclear.

Figure 11. A bone biopsy demonstrating the "mosaic" pattern of bone matrix in Paget's disease. Note the chaotic lamellar pattern intermixed with woven bone as demonstrated with polarized light.

There is some evidence of a "burned out" phase of Paget's disease in which the abnormal matrix persists but cellular activity is nearly absent and the marrow space is mainly filled with fat. It is more likely that such a finding does not occur throughout an entire lesion, but is found with all stages of the disease in a single bone.

Studies of the ultrastructure of osteoclasts in Paget's disease have demonstrated that many of these cells harbor microfilaments in the nucleus and occasionally, in the cytoplasm (38,39) (Figure 12). The microfilaments have the same structural features as nucleocapsids of viruses of the Paramyxoviridae family, a family of RNA viruses known to cause childhood infections such as measles and pneumonia due to respiratory syncytial virus. The nucleocapsid-like structures have not been found in osteoblasts, osteocytes, or bone marrow cells in the same specimens containing the osteoclast microfilaments. Identical microfilaments have been found in a small percentage of the osteoclasts in giant cell tumors of bone and in the osteoclasts of some patients with osteopetrosis and pyknodysostosis (40).

Figure 12. Electron microscopic examination of an iliac crest biopsy revealing microfilaments within remnants of a degenerating osteoclast nucleus. The arrow indicates microfilaments in adjacent cytoplasm. Magn. x 25,800

In addition to the structural evidence for the presence of viral nucleocapsids in the osteoclasts of Paget's disease, evidence of paramyxoviridae nucleocapsid proteins (41,42), and mRNA (43) has been reported, although not by all investigators (44). In one study addressing the identity of the osteoclast microfilaments, the full-length sequence for the measles virus nucleocapsid gene was delineated from the bone marrow of one patient as were more than 700 base pairs of the nucleocapsid gene in three additional patients (45).

BIOCHEMICAL ASSESSMENT

The radiologic and histologic evidence of increased bone resorption and formation in patients with Paget's disease is readily assessed by measuring biochemical markers of bone turnover. In general, these tests reflect the extent and activity of the disease.

Bone Resorption

Since the underlying cellular abnormality in Paget's disease seems to be increased bone resorption, one might expect that serum calcium and/or urinary calcium levels would be increased in some individuals with active Paget's disease. In the absence of fractures, immobilization, primary hyperparathyroidism, or bone metastases, this is not the case (46). Presumably, this is explained by a concomitant increase in bone formation, which has been defined by histopathology and by kinetic analysis of plasma disappearance rates and skeletal uptake of radiocalcium (46). Evidence of increased bone matrix resorption was first provided by the demonstration of increased urinary hydroxyproline excretion, a component of all types of collagen. Subsequently, more specific indices of bone resorption have been developed including pyridinoline, deoxypyridinoline, type I collagen N-telopeptide, and C-telopeptide. The latter two collagen components are the most specific markers of bone collagen resorption (47); serum and urine assays of the telopeptides are widely available for clinical use.

Bone Formation

Measurement of total serum alkaline phosphatase activity has been a means of evaluating Paget's disease for 90 years (4). The enzyme activity, which is localized in the plasma membrane of osteoblasts before extracellular release, correlates with the extent of the disease on skeletal surveys (48) and with parameters of bone resorption (48). The circulating enzyme activity usually increases gradually or does not change during long-term follow up of patients who are untreated (49). In patients with liver disease or who might be pregnant, it would be preferable to measure bone-specific alkaline phosphatase levels by immunoassay (50). Several of these assays have been developed which have little cross-reactivity with non-skeletal alkaline phosphatase. Measurement of serum procollagen type1-N-terminal peptide has proven to be valuable in assessing the response to teriparatide in osteoporosis patients. While these assays may have an advantage over the nonspecific total alkaline phosphatase activity with respect to specificity, no study has been done which indicates that they should replace this inexpensive assay for routine clinical use (51).

Other markers of bone formation such as serum osteocalcin or type I procollagen carboxyl-terminal peptide are not as sensitive as total or bone-specific alkaline phosphatase levels in assessing the response to therapy (47).

Sclerostin is an important protein produced by osteocytes which inhibits bone formation. Serum sclerostin has been noted to be elevated in patients with Paget’s disease (52) but is not correlated with serum C-telopeptide or serum procollagen type1-N-terminal peptide levels. The relevance of this finding remains to be established.

Calciotropic Hormones

Serum parathyroid hormone levels are generally normal in patients with Paget's disease (23). Elevated levels are found in the presence of concomitant primary hyperparathyroidism (53) and would be expected to also be increased in the presence of renal failure or vitamin D deficiency. Serum calcitonin levels are normal in Paget's disease (54) although there was prior speculation that low levels might contribute to the pathogenesis of the disease. In the absence of vitamin D deficiency, serum 25-hydroxy-vitamin D and 1, 25 dihydroxyvitamin D levels are normal. Inexplicably, 24,25-dihydroxyvitamin D levels have been reported to be low (55).

NEOPLASTIC COMPLICATIONS

Sarcoma

Sarcomas develop in the lesions of Paget's disease more often than in an age-matched normal population, although the incidence is less than 1% overall (56). However, in patients with extensive disease, the incidence has been estimated at 10% (57), although a subsequent study suggests this is not so (58). Rarely, sarcomas have been known to develop in multiple members of a family.

A sarcoma should be suspected when new pain and swelling develop in a bone previously affected by Paget's disease. The most common sites are in the pelvis, femur, humerus, skull, and facial bones.

There is a variable histology of the sarcomas of Paget's disease including osteosarcoma, fibrosarcoma, chondrosarcoma, and anaplastic sarcoma (57). Several types of histology may be present in a single tumor. Multinucleated giant cells (probably osteoclasts) may be scattered throughout a tumor. They may contain the nuclear microfilaments seen in the osteoclasts and are not thought to be neoplastic in nature (59).

Because of the underlying distortion of the pagetic bone, it is difficult to detect an early stage of a sarcoma. Typically, a radiolucent focus with speckled regions of calcification will be observed to disrupt the cortex of the bone (Figure 13). The best means of delineating the extent of the tumor mass is by CT or MRI.

Figure 13. Multiple sites of osteogenic sarcoma in a patient with Paget's disease of the right hemipelvis. Note the extension of the tumor through the cortex of right ischium.

Perhaps because of a failure of early diagnosis in most patients with sarcoma arising in Paget's disease, survival is brief. Only 7.5%-10% of patients survive five years and despite the multiple modalities of therapy presently available, the prognosis remains poor (56,60).

Giant Cell Tumor

Giant cell tumors of bone may arise in lesions of Paget's disease, often in the skull and facial bones (61). They are nearly always benign and appear to be less common than sarcoma in Paget's disease. As is the case with sarcoma, they rarely may appear in multiple family members who have Paget's disease (62).

A prominent feature of the tumors is the presence of large numbers of multinucleated giant cells, a small percentage of which contain the nuclear microfilaments typical of the osteoclasts of Paget's disease (61). The neoplastic component of the giant cell tumor is a spindle-shaped cell with fusiform nuclei and clumped chromatin. These cells rarely have mitoses. There may be some difficulty in distinguishing these tumors from giant cell reparative granulomas, which commonly arise in the jaws (63).

Giant cell tumors in Paget's disease are usually successfully treated with surgery and radiation therapy. In a few patients, high doses of dexamethasone have been shown to shrink the tumors (64). Denosumab has been effective in treating patients with giant cell tumors (65) but has not been studied in patients with giant cell tumors arising in the lesions of Paget’s disease.

Other Neoplasia

Other neoplastic processes such as lymphoma (56), multiple myeloma (57), various carcinomas, and parathyroid tumors (53) have been reported in association with Paget's disease, but are probably chance occurrences. Metastatic cancers have been reported to metastasize to the highly vascular lesions of Paget's disease.

SYSTEMIC COMPLICATIONS AND ASSOCIATED DISEASES

Hypercalcemia

Hypercalcemia may occur as a consequence of immobilization in patients with Paget's disease (66), although this is an unusual clinical event. This is believed to occur because immobility results in increased bone resorption and decreased bone formation.

Hypercalcemia can also occur in association with a malignancy (67). More commonly hypercalcemia in Paget's disease occurs as a consequence of primary hyperparathyroidism (53). Correction of the hyperparathyroidism by surgery produced a decrease of 68% in plasma alkaline phosphatase in a series of 18 patients (53). The clinical features of these patients were quite similar to hyperparathyroid patients without Paget's disease, prompting the investigators to speculate that the two diseases were associated by chance.

Hyperuricemia and Gout

Hyperuricemia has been observed to be common in males with relatively severe Paget's disease (48). Clinical episodes of gouty arthritis occurred in almost half of these individuals. In a larger population of Paget's disease patients, hyperuricemia (20%) and gout (4%) were not felt to be increased in incidence (68). The differences in hyperuricemia and gout might be explained by the severity of the disease in the two study populations. With extensive skeletal involvement, a high turnover of nucleic acids in the lesions of Paget's disease could increase the urate pool enough to produce a clinical disturbance of urate metabolism (69).

Cardiovascular Dysfunction

A hallmark of the pathology of Paget's disease is the increased vascularity of affected bones. Further evidence for this has been documented by demonstration of an increase in blood flow to the extremities (70), although it has been suggested that this is mainly caused by cutaneous vasodilation (71). An echocardiographic study of cardiac function in Paget's disease found that patients with more severe disease had lower peripheral vascular resistance and higher stroke volume (72). These observations help account for the finding that patients with 15% or more of their skeleton affected by Paget's disease have increased cardiac output (73). High output congestive heart failure can occur.

It is possible that increased cardiac output in patients with Paget's disease accounts for an increased incidence in calcific aortic stenosis through causing turbulence across the valve. Patients with Paget's disease have a 4-6 times higher incidence of this lesion than control subjects (74,75). Calcification of the interventricular septum has also been reported in patients with Paget's disease and may be associated with complete heart block (75,76). It also has been reported that arterial calcification is more common in Paget’s disease than in control subjects in the aorta as well as in iliac, femoral, gluteal and pelvic arteries (77). The explanation for this is unknown.

A less certain consequence of an increase in vascularity of bone and surrounding soft tissues is a variety of vascular steal syndromes. Patients with marked enlargement of the skull have been noted to be withdrawn, somnolent, and weak. These findings might be explained by shunting of blood from brain vessels to the external carotid artery system (78). It has also been proposed that spinal cord dysfunction might be a consequence of shunting of blood flow from the spinal arteries to the bone (79).

TREATMENT

Prior to 1975, a number of nonspecific treatments were used to attempt to alleviate some of the manifestations of Paget's disease. With the exception of pain medications none were of value. With the development of salmon calcitonin, a new era of effective treatment began. Presently, there are a number of highly effective agents which make possible excellent control of the disease.

Pretreatment Evaluation

The initial goal of patient evaluation is to establish which bones are affected by Paget's disease and what symptoms the lesions produce. A search for skeletal deformity may indicate one or more bones are involved, but this should be confirmed by X-rays. The full extent of the disease would best be ascertained by full body bone scan followed by radiologic confirmation of the disease in areas of increased tracer uptake. The decision as to which patient requires a bone scan is an individual one. For example, a 90-year old asymptomatic patient who is found to have Paget's disease in the pelvis during an intravenous pyelogram probably does not need a scan.

There is now a considerable choice of bone resorption and bone formation parameters which could be used to determine the overall metabolic activity of the disease. For routine clinical purposes, in most patients, measurement of total serum alkaline phosphatase activity is an effective and inexpensive test.

Drug Therapy

Calcitonin

Calcitonin is a peptide hormone whose main pharmacologic effect is rapid inhibition of bone resorption. This is mediated by binding of the hormone to its receptor on the surface of osteoclasts.

Salmon calcitonin was the first calcitonin species approved by regulatory agencies for treatment of Paget's disease. A dose of 50 to 100 U given daily or three times a week produces relief of bone pain in most patients within 2-6 weeks. Following suppression of the metabolic activity of the disease cardiac output is reduced (80) as is the skin temperature over affected tibiae. In addition, some patients have had dramatic improvement of neurologic deficits (81). Stabilization of hearing loss has also been noted (82). Because the drug has been shown to reduce the vascularity of bone affected by Paget's disease, it has been given preoperatively to reduce the degree of hemorrhage in patients scheduled for orthopedic procedures (83).

A single injection results in an immediate decrease in urinary hydroxyproline reflecting an acute inhibition of bone resorption. A maximal effect occurs in several months. Serum alkaline phosphatase activity falls more slowly; a significant decrease is generally not seen for one month. Within 3-6 months, both hydroxyproline excretion and alkaline phosphatase activity decrease on average by 50%. If treatment is stopped, urinary hydroxyproline gradually increases over several months followed by an increase in alkaline phosphatase activity back to pretreatment levels. With chronic treatment osteolytic lesions generally are reversed (84). However, if treatment is not continuous, the osteolytic lesion will recur. Reduced uptake of radiolabeled bisphosphonate (85) and gallium (33) occurs during long term treatment. Bone biopsies exhibit a reduced number of bone cells, a decrease in marrow fibrosis, and a reduction of woven bone volume (86).

Since salmon calcitonin is a foreign protein, it is not surprising that more than half of patients on long-term treatment develop specific antibodies against the hormone in the circulation (87). High titers of these antibodies almost always impair the response to continuing treatment so that up to 26% of patients have become resistant to the drug. Although no longer available for clinical use, human calcitonin was effective in inducing remissions in salmon calcitonin-resistant patients. Presently, any of the bisphosphonates can be used to treat these patients.

Salmon calcitonin injections may cause nausea and facial flushing in 10-20% of patients. Vomiting, abdominal pain, diarrhea, and polyuria are much less common side effects. Rarely tetany and allergic reactions have been reported. Nasal spray salmon calcitonin is much less likely to cause side effects but has lower potency (88). At this time, salmon calcitonin is used much less frequently than in the past because of the development of potent bisphosphonates.

Bisphosphonates

The development of the bisphosphonates for the treatment of skeletal disorders associated with increased bone resorption has been a major advance in the management of Paget's disease (89). These drugs, initially known as diphosphonates, are analogues of inorganic pyrophosphonate, a factor believed to be a necessary component for the mineralization of bone. All bisphosphonates have a central P-C-P core, which was substituted for the naturally occurring P-O-P core of pyrophosphate, because unlike P-O-P, the P-C-P structure is impervious to metabolic degradation. The bisphosphonates have a profound influence on bone metabolism, in part, because they bind to hydroxyapatite. The primary effect of bisphosphonates is to inhibit osteoclastic bone resorption, which in vivo is followed by a secondary decrease in bone formation. The earliest bisphosphonates which were developed, etidronate and clodronate, appear to achieve their effects by generating nonhydrolyzable analogues of adenosine triphosphate, while the later generation of more potent aminobisphosphonates, such as pamidronate and risedronate, inhibit protein prenylation through inhibition of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. Although it is generally believed that bisphosphonates act directly on the differentiation and function of osteoclasts, evidence has accumulated which indicates that some bisphosphonates regulate cell proliferation, differentiation, and gene expression in human osteoblasts in vitro (90). How such observations translate into in vivo actions of bisphosphonates is unclear.

In table I, the bisphosphonates presently approved for treatment of Paget's disease in the United States are listed with their recommended regimes. There are four oral bisphosphonates available whose recommended daily treatment courses range from two months to six months and two intravenous bisphosphonates.

Table 1. Bisphosphonates Approved for Treatment of Paget's Disease

Bisphosphonates available in U.S.A.

Administration and Dosage

Etidronate

Trade Name: Didronel®

FDA approval: 1977

1. Tablet

2. 200 to 400 mg once daily for 6 months

200-400 mg dose is approved; 400 mg dose is preferred

3. Must be taken with 6-8 ounces of water on an empty stomach (no food, beverages, or medications for 2 hours before and after dose).

4. Course of Didronel® should not exceed 6 months.

5. Repeat courses can be given after rest periods of 3-6 months duration.

Pamidronate

Trade Name: Aredia®

FDA approval: 1994

Generic available

1. Intravenous

2. Approved regimen is 30 mg intravenous infusion over 4 hours on 3 consecutive days

3. A more commonly used regimen is a 60 mg or 90 mg intravenous infusion over 2-4 hours and repeated as clinically indicated.

4. A single infusion is sometimes effective in mild disease; 2-3 or more infusions may be required in more severe disease.

5. A course of Aredia® may be readministered at intervals as needed.

Alendronate

Trade Name: Fosamax®

FDA approval: 1995

Generic available

1. Tablet

2. 40 mg once daily for 6 months· Must be taken on an empty stomach, with 6-8 ounces of water, in the morning.

3. Wait at least 30 minutes after taking Fosamax® before eating any food, drinking anything other than tap water, or taking any medication.

4. Do not lie down for at least 30 minutes after taking Fosamax®. (Patient may sit.)

5. Available by mail order to the general public.

Tiludronate

Trade Name: Skelid®

FDA approval: 1997

1. Tablet

2. 400 mg (two 200 mg tablets) once daily for 3 months

3. Must be taken on an empty stomach with 6-8 ounces of water.

4. Skelid® may be taken any time of day, as long as there is a period of 2 hours before and after resuming food, beverages, and medications.

Risedronate

Trade Name: Actonel®

FDA approval: 1998

1. Tablet

2. 30 mg once daily for 2 months

3. Must be taken on an empty stomach, with 6-8 ounces of water in the morning.

4. Wait at least 30 minutes after taking Actonel® before eating any food, drinking anything other than tap water, or taking any medication.

5. Do not lie down for at least 30 minutes after taking Actonel®. (Patient may sit.)

Zoledronic Acid

Trade Name: Reclast®

FDA approval: 2007

1. Intravenous

2. A 15 minute infusion of 5mg

3. Creatinine clearance must be >35 ml/min

4. Correct vitamin D deficiency and/or hypocalcemia before infusion

5. To reduce the risk of hypocalcemia after infusion, patients should receive 1500mg calcium and 1000 units vitamin D3 daily for two weeks

*Adapted from Information for Patients about Bisphosphonates, A Publication of the Paget Foundation for Paget's Disease of Bone and Related Disorders (2007).

The least potent bisphosphonate, etidronate, is similar to salmon calcitonin with respect to suppression of the metabolic activity of Paget's disease. The more potent aminobisphosphonates, pamidronate, alendronate, risedronate, and zoledronic acid can induce biochemical remissions in the majority of patients. In the past patients with extensive disease and markedly elevated biochemical parameters may have impressive reductions in serum alkaline phosphatase activity yet not reach normal levels (91). However, patients treated with zoledronic acid, no matter how high the baseline serum alkaline phosphatase activity, nearly always reach the normal range of enzyme activity (92). Most of the clinical benefits attributed to salmon calcitonin are produced by the aminobisphosphonates, yet it remains to be demonstrated whether long term biochemical remissions with any agent can reduce the incidence of future complications such as hearing loss and deformity.

The oral bisphosphonates are poorly absorbed and must be taken with water only. In clinical trials, side effects involving the gastrointestinal tract were not greater in patients receiving the drug than in the placebo group. However, some individuals experience abdominal distress or diarrhea. Patients receiving an oral aminobisphosphonate are advised to remain upright for at least 30 minutes after taking the drug to reduce the chance of esophageal irritation. A small percentage of patients may experience a transient increase in bone pain. The first infusion of pamidronate (93) or zoledronic acid (92) may produce an acute phase reaction in 30-50% of patients manifested by fever, myalgia, and elevation of circulating interleukin 6 levels (93). Subsequent infusions produce little or no side effects. The mechanism responsible for the acute phase reaction appears to be release of cytokines from gamma delta T cells (94), which is worsened by vitamin D deficiency (95). Vitamin D supplementation in patients with low levels is very effective in preventing acute phase reactions and all patients who will be receiving pamidronate or zoledronic acid should have normal levels of serum 25OHD prior to the infusion (96). Allergic reactions to bisphosphonates are rare and most commonly manifest as inflammatory eye reactions due to pamidronate (97). If etidronate is used at a dose greater than 5 mg/kg body weight, osteomalacia may be a consequence (98). Another disadvantage of etidronate use is that osteolytic lesions may progress despite evidence of biochemical improvement (99).

Treatment with a potent bisphosphonate may produce long remissions. This is the most likely to be seen after treatment with zoledronic acid. A single infusion restores biochemical markers of bone turnover into the normal range and this is maintained for up to six and a half years in most patients (100). This response is largely independent of pretreatment disease activity. However, with the older bisphosphonates induction of a remission correlates well with the extent and activity (alkaline phosphatase) of the disease (101). Patients with less extensive disease and lower alkaline phosphatase activity are more likely to achieve remission. With respect to the duration of a remission, this appears to be dose-dependent as well as correlated with the nadir value of serum alkaline phosphatase activity, the number of affected bones, and the number of previous therapies (101). Intravenous ibandronate may produce a prolonged response but is not an FDA-approved therapy for Paget’s disease (102).

Resistance to etidronate therapy is commonly seen after two six-month courses of the drug (103). There is also evidence that resistance to intravenous pamidronate (101) or clodronate (104) can occur. In pamidronate-resistant patients, treatment with alendronate was effective (104). In the clodronate-resistant patients, either risedronate or pamidronate was effective (105). There is no information which explains the mechanism responsible for apparent decreased efficacy of these agents with time. It is possible that an increase in the disease activity is responsible for these observations rather than a change in efficacy of the drugs.

Considerable publicity has been given to the development of osteonecrosis of the jaw in patients treated with bisphosphonates (106). This mainly is seen in cancer patients given monthly infusions and is rare in patients with Paget’s disease.

Miscellaneous Agents

Other inhibitors of bone resorption such as plicamycin and gallium nitrate, approved for treatment of hypercalcemia of malignancy, are effective in treating Paget's disease (107,108). In view of the safety and efficacy of the aminobisphosphonates, there is very little present use of these agents. The most potent antiresorptive agent, denosumab, has been reported to decrease disease activity in two patients with Paget’s disease (109, 110). In 1971 glucagon infusions were reported to markedly reduce of bone turnover parameters in four patients with Paget’s disease (111) but large trials have not been reported.

Treatment and Posttreatment Evaluation

Assessment of total serum alkaline phosphatase activity is generally sufficient to determine the success of treatment. The frequency of evaluation does not need to be more frequently than every 3 months after the onset of the treatment and can be extended to every 6-12 months after a nadir has been reached. Serial nuclear scans of the skeleton are more sensitive in defining no residual disease activity than biochemical results as reported in one study (112). Minimal to significant disease activity was found in two-thirds of patients who had normal biochemical parameters after zoledronic acid infusions. A second infusion produced complete remission. It is uncertain how clinically important it is to produce complete suppression of radioisotope uptake in patients with normal biochemistry after treatment. If a patient has a well- defined osteolytic lesion on X-ray, it can be assessed annually to assure the disease is well-controlled.

Indications for Treatment

Effective drug treatment for Paget's disease has evolved over 45 years, but there have been no large, randomized, long-term clinical trials, which can provide definitive guidelines for treatment. Nevertheless, in table 2, indications for drug treatment of Paget's disease are listed. These are based on a review of the literature and a large personal experience.

Table 2. Indications for Drug Treatment of Paget's Disease
1. Bone pain 2. Hypercalcemia due to immobilization 3. Neurologic deficit associated with vertebral disease 4. High-output congestive heart failure 5. Preparation for orthopedic surgery 6. Prevention of complications including hearing loss, deformity

Table 2. Indications for Drug Treatment of Paget's Disease

1. Bone pain

2. Hypercalcemia due to immobilization

3. Neurologic deficit associated with vertebral disease

4. High-output congestive heart failure

5. Preparation for orthopedic surgery

6. Prevention of complications including hearing loss, deformity

Although bone pain is not a problem in the majority of patients, it is a clear indication for treatment. In patients in whom bone pain is difficult to distinguish from joint pain treatment of the Paget's disease will usually clarify the source of pain. Treatment should also correct hypercalcemia in an immobilized patient, a rare situation. Neurologic deficits may improve with treatment, also a very unusual complication. High output heart failure should respond favorably to a treatment which lowers the cardiac workload. Reducing the vascularity of the bone and surrounding soft tissue before elective orthopedic surgery should reduce perioperative bleeding.

A major indication for treatment could be the prevention of future complications. There is some evidence that progression of hearing loss is reduced by treating patients with cranial disease. Prevention of deformity of lower extremity long bones and secondary osteoarthritis is a reasonable possibility. Presumably, early treatment would reduce the incidence of future fractures. It would be more speculative as to whether the incidence of sarcoma or giant cell tumor formation would be influenced.

To achieve the long-term goals of therapy such as prevention of future complications, it may be necessary to maintain the serum alkaline phosphatase activity within the normal range. Future very long-term studies would be needed to determine if complications can be abolished.

Surgery

In table 3, the various surgical procedures which have been utilized in the management of Paget's disease are listed.

Table 3. Surgical Procedures for Management of Paget's Disease

1. Total hip replacement

2. Total knee replacement

3. Femoral osteotomy

4. Tibial osteotomy

5. Suboccipital craniectomy and upper cervical vertebral laminectomy for basilar impression

6. Ventricular shunting for hydrocephalus

7. Stapes mobilization or stapedectomy

8. Surgery for correction of spinal stenosis or nerve root compression

Total hip replacement is probably the most common elective orthopedic procedure in patients with Paget's disease (113,114). Pain relief and improved mobility occur in a high percentage of patients. Postoperatively, heterotopic ossification may be somewhat more common, but is seldom a significant problem. For patients with severe osteoarthritis of the knees, total knee replacement is an effective treatment (115). Knee pain and joint effusions associated with osteoarthritis and tibial bowing may be effectively treated by tibular and fibular osteotomy (83).

There is much less experience with neurosurgical procedures in treating Paget's disease. However, successful relief of symptoms is expected after surgery for spinal stenosis or nerve root compression (116). Percutaneous vertebroplasty might be considered in patients thought to have vertebral bone pain who do not respond to conservative therapy (117). Stapes mobilization or stapedectomy has not proven to be effective in improving hearing loss. One patient treated with cochlear implantation was reported to have improved speech perception (118).

ETIOLOGY

Slow Virus Infection

The possibility that Paget's disease fell into the category of a slow virus infection was suggested by the observation that the osteoclasts in this disorder harbored nuclear and cytoplasmic microfilaments which were essentially identical in structure to nucleocapsids of the Paramyxoviridae virus family (38,39). Immunochemical studies (40-42), and sequence analysis of nucleocapsid transcripts (43) have supported the initial hypothesis although not all studies have been positive with respect to a viral presence in the osteoclasts (44). Indirect support for the role of measles virus comes from a consideration of the availability of measles vaccine throughout the world (119). The vaccine was introduced in the United States in 1963, in Australia in 1967, in the United Kingdom and France in 1968, in New Zealand in 1969, in the Netherlands and Italy in 1976 and in Spain in 1978. Availability of the vaccine for more than 50 years in several countries might explain a decrease in prevalence whereas delayed availability might explain why other regions may not have had a decrease as yet.

Non-Viral Environmental Influences

A number of reports have suggested that toxins such as arsenic and lead and animal exposure to dogs and cattle may be factors in the pathogenesis of Paget’s disease (119). The most recent study indicates that exposure to woodburning during childhood, living near a mine, and hunting may be related to developing the disorder (120). Exactly how these factors might produce pagetic lesions is unknown.

Genetics

Since there is clearly a familial aggregation of Paget's disease in up to 40% of patients with Paget's disease (17,19), a search for a predisposition gene or genes has been undertaken by a number of investigators. The initial attempts to define genetic susceptibility in Paget's disease centered on chromosome 6 because of known associations between disease susceptibility and histocompatibility loci on this chromosome (121). Although there is some evidence for human leucocyte antigen linkage in families with Paget's disease no gene locus has yet been defined on chromosome 6.

The initial localization of a predisposition gene for Paget's disease came from linkage studies with chromosome 18 markers (122,123). Attention was given to chromosome 18 because of the discovery that mutations of receptor activator of nuclear factor kB (RANK), a critical osteoclastogenic factor, were responsible for the skeletal disorder, familial expansile osteolysis (124), a condition which bears some resemblance to Paget's disease (125). Although chromosome markers have indicated linkage to Paget's disease in the region of the RANK gene on chromosome 18, no RANK mutations have been found in families of typical Paget's disease.

A second susceptibility locus, not associated with RANK, has been identified on chromosome 18 in a large Australian kindred (126). A further finding of interest on chromosome 18 is that sarcomas arising in Paget's disease may harbor a tumor suppressor gene in the same region as the first locus to be described (127).

In 2002 Laurin and colleagues (128) reported that mutations in the sequestosome 1 gene on chromosome 5 were associated with Paget’s disease in 11/24 French Canadian families and in 18/112 apparently sporadic patients. Mutations of this gene were subsequently found in families in the United Kingdom, Australia, New Zealand, the United States, and The Netherlands. Mutations have also been found in a smaller percentage of patients with sporadic disease. More than 20 different mutations have been described, nearly all of which are clustered around the ubiquitin binding domain of the sequestosome 1 protein (128-131). This protein modulates activity of the NF-κβ pathway, an important mediator of osteoclast function, and has also been implicated in the process of autophagy in osteoclasts (132).

A second gene abnormality has been described in the rare syndrome of inclusion body myopathy, frontotemporal dementia, and Paget’s disease (133). More than 50 mutations have been identified in the VCP gene (134). Only about 50% of the individuals with a mutation have demonstrable Paget’s disease (135). VCP has a ubiquitin-binding domain as does sequestosome 1 and like sequestosome 1 is thought to play a role in autophagy (136). A search for VCP mutations in familial and sporadic Paget’s disease patients was negative in one study (137) and revealed a polymorphism associated with sporadic Paget’s disease in another study (138).

Further evidence of the heterogeneity of the genetics of Paget’s disease has come from studies reporting linkage of the disease with candidate loci at chromosome 5q31 and 5q35-qter (139), chromosome 2q36 (140), and chromosome 10p13 (140,141).

In a relatively small group of Paget’s disease patients, no mutations of the osteoprotegerin gene were found and a statistically significant increased frequency for the C allele in exon 2 was noted compared to control subjects (142). In a larger study a common polymorphism of the osteoprotegerin gene, G1181C, was found to predispose to the development of sporadic and familial Paget’s disease (143). Estrogen receptor-a and calcium-sensing receptor genotyping were significantly different in Paget’s disease versus control subjects in another study (144).

In the past 10 years 14 new susceptibility loci for Paget’s disease have been reported (145-158). Most of these are likely to influence bone metabolism (CSF1, TNFRSF11A, PML, TM7SF4, UCMA/GRP, DKK1, CTHRC1, OPTN, RIN3, hnRNPA2B7, FKBP5, ZNF687, BER, C9ORF72 hexanucleotide repeat expansion frequency). In one study single nucleotide polymorphisms were believed to amplify the effect of sequestosome 1 mutations and thereby magnify the severity of Paget’s disease (159).

In giant cell tumors arising in pagetic lesions H3F3A mutations have been detected and are associated with a higher number of osteoclast-like giant cells and an increased number of nuclei per cell (154) as compared with giant cell tumors occurring without Paget’s disease.

Clearly great progress has been made in studies of the genetics of Paget’s disease but the data suggest that an individual with a mutation has an increased susceptibility to develop particularly severe Paget’s disease but may not ever manifest evidence of the disorder. In a study of 84 offspring from 10 families whose Paget’s disease was associated with sequestosome 1 mutations, only 17% of the 23 offspring (mean age 45 years) who had mutations had evidence of the disease as indicated by bone scans (160). The offspring with normal scans had a mean age of 44 years and the mean age of the parents at the time of diagnosis was 48 years. There is incomplete penetrance of the Paget’s disease trait in these families although it is possible more offspring with aging will develop Paget’s disease in the future. In another study only 52% of patients with a VCP/p97 gene mutation were noted to have a lesion of Paget’s disease after extensive radiologic surveys (134). No assessment of viruses in the bone of these patients has been reported. In the most recent report from The Netherlands after 15.9 years of follow-up of sequestosome 1 mutation family members of pagetic patients only one individual (7.1%) was found to develop Paget’s disease (161). Fourteen individuals were followed and their ages ranged from 52 to 74 years.

Animal Models and In Vitro Models of Paget’s Disease

Transgenic mice have been utilized to investigate the potential roles of the measles virus nucleocapsid gene and the sequestosome1/p62 and VCP/p97 gene mutations in the pathogenesis of Paget’s disease. Targeting of the measles virus nucleocapsid gene into osteoclasts of transgenic mice produced lesions in some vertebrae which strongly resembled the lesions of Paget’s disease, increased osteoclastic activity with exuberant new bone formation often of woven character was observed (162). The same investigators targeted the most common sequestosome1/p62 mutation in familial Paget’s disease, P392L, into the osteoclasts of transgenic mice (163). They observed increased numbers of osteoclasts associated with bone loss but no increase in osteoblastic activity characteristic of Paget’s disease. Transduced osteoclast precursors isolated from the mice were hyperresponsive to receptor activator of NF-kappa B ligand (RANKL) and TNF-alpha but did not exhibit increased 1,25 (OH)2D3 responsivity, TAF(11)-17 expression, or increased number of nuclei per osteoclast, features found in osteoclast precursors isolated from individuals with Paget’s disease. In contrast to this study, Daroszewska and colleagues did find that targeting the P392L mutation into transgenic mice produced a Paget-like bone pathology predominantly in the lower limbs (164). They also found that osteoclast precursors had increased sensitivity to RANKL in vitro but did not examine 1,25(OH)2D3 sensitivity or TAF(11)-17 expression. They found nuclear inclusions also but it was not certain that they were identical to those found in patients. The explanation for the different results in these two studies is not apparent.

To examine the potential interaction of the measles virus nucleocapsid gene and the P392L mutation Kurihara and colleagues undertook studies of bone marrow specimens from patients with familial Paget’s disease who had the P392L mutation, utilizing specimens from pagetic and normal bone as well as from normal volunteers (165). The effects of antisense-measles virus nucleocapsid protein (MVNP) on osteoclast characteristics were different in marrow specimens from pagetic bone versus nonpagetic bone. The patient specimens which had MVNP expression responded to the antisense –MVNP with a reduction in osteoclast number, TATA box-binding protein associated factor 12 expression, 1,25 (OH)2D3 –stimulated IL-6 production and bone resorption, observations indicating a reversal of the usual features of osteoclasts generated from the marrow of sporadic or familial Paget’s disease patients. The results indicate an important role of measles virus in pagetic lesions. A contribution of the P392L mutation to the pathologic process was suggested by the fact that there was hyperresponsiveness to RANKL in both the pagetic and nonpagetic bone marrows obtained from the familial patients. These investigators then went on to carry out experiments in transgenic mice by cross breeding mice with MVNP and P392L mutations (165). The mice who harbored both MVNP and P392L had more severe Paget-like lesions than mice with MVNP alone. As expected zoledronic acid treatment of p62^P394Lmice with a high rate of bone resorption produced marked suppression of bone resorption (166).

Two groups have generated transgenic mice expressing mutant forms of the VCP/p97 gene (167,168). In both studies increased osteoclastic activity appeared to be the dominant histologic feature with a modest amount of sclerotic bone being present. No studies evaluating the characteristics of the osteoclast precursors were reported.

In a mouse study it was discovered that osteoclasts obtained from optineurin mutant mice have an increase in NF-kB activation and a reduction in response to RANKL as compared to wild-type mice (169). Bone histology revealed increased osteoclastic activity and increased bone formation but the overall histology was not typical of Paget’s disease.

A model to explain the coupling of bone resorption to bone formation in Paget’s disease has been developed utilizing osteoclasts from pagetic patients and transgenic mice harboring a knock-in of p62^P394L (170). It was concluded that in Paget’s disease, measles virus nucleocapsid protein upregulates IL-6 and IGF1 in osteoclasts to increase ephrinB2-EphB4 coupling and thereby promotes bone formation. This is the first hypothesis to explain the masked level of bone formation in Paget’s disease.

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The Epidemiology and Pathogenesis of Osteoporosis

ABSTRACT

Osteoporosis is a multifactorial disorder associated with low bone mass and enhanced skeletal fragility. Although most prevalent in older females, some men are also at high risk. Risk factors in men and women include smoking, family history of fracture, age greater than 65 years, and low but also high BMI particularly in men. Secondary causes of osteoporosis include chronic treatment with glucocorticoids, gastrointestinal disorders, diabetes mellitus (T1D, T2D), rheumatoid arthritis, liver disease, gluten enteropathy, multiple myeloma and other hematologic disorders. However, primary osteoporosis is most often related to either postmenopausal estrogen loss or age-related deterioration of skeletal microarchitecture; both are due to uncoupling in the bone remodeling unit. Reduced bone formation with age is almost certainly a function of impaired stem cell differentiation into the osteoblast lineage with a resultant increase in marrow adipogenesis. Increased bone resorption also characterizes most forms of osteoporosis but the etiology is multifactorial. Changes in local and systemic growth factors are often responsible for uncoupling between resorption and formation. However, alterations in peak bone acquisition contribute years later to low bone mass and enhanced skeletal fragility. Fracture risk assessment tools (e.g. FRAX) in handheld apps and computers which combine bone density score and risk factors, have provided rapid assessments of future osteoporotic fractures and can be performed at the bedside. Newer methods of measuring bone quality have led to insights into micro-architectural deterioration that contributes to skeletal fragility. Notwithstanding, low areal bone mineral density by DEXA remains the strongest predictor of subsequent fracture beyond age, and this is potentially measurable in everyone after age 65.

INTRODUCTION

Osteoporosis is a disorder characterized by reduced bone mass, impaired bone quality, and a propensity to fracture. For decades, this disease was considered a syndrome characterized by back pain, vertebral fractures, and osteopenia on plain films. Identifying secondary causes of low bone mass was the principle objective of most clinicians. However, osteoporosis is now classified as a primary disorder of the skeleton related to profound metabolic changes not only in bone but also related to changes in whole body homeostasis. Significant progress has been made in both defining this disorder and in understanding its complex pathogenesis. In addition, a consensus has emerged concerning the strength of the association between low bone mineral density and fracture risk, and the importance of qualitative aspects of the skeleton, as additional risk determinants.

Dual energy x-ray absorptiometry (subsequently referred to as DEXA) revolutionized our ability to predict fractures in large numbers of subjects by measuring areal bone mineral density (subsequently referred to as BMD). Virtually all population studies have confirmed that for every one standard deviation below young normal mean bone mineral density (at virtually any skeletal site) there is a nearly two-fold greater risk of a subsequent hip fracture (1). Some clinicians, as well as the WHO and the National Osteoporosis Foundation define osteoporosis purely on a bone mineral density (BMD) T-score more than 2.5 standard deviations below young normal reference ranges for the spine, hip or radius (2). Although this "bar" has been used to establish prevalence estimates and to define high risk individuals who should be considered for treatment, it is also evident that even this definition demands a better understanding of the pathophysiologic processes that result in low bone mass, and a more thorough review of 'bone quality'. Indeed, despite the strength of the association between BMD and fracture risk, qualitative measurements of the skeleton, such as bone turnover, mineralization, and trabecular connectivity also contribute to risk. In this chapter, the mechanisms responsible for altering bone microarchitecture and strength in such a way as to enhance the likelihood of fragility fractures will be reviewed. Irrespective of the epidemiology and pathogenesis of osteoporosis, the stark fact remains that this disease has significant morbidity, mortality, and economic costs. Just as importantly, understanding how this disorder develops and progresses, has important socio- economic as well as medical consequences.

EPIDEMIOLOGY OF OSTEOPOROSIS

Estimating exactly how many women have osteoporosis depends on the working definition of this disease and the appropriate diagnostic criteria (3). Prior to the widespread application of DEXA, osteoporosis was rarely diagnosed and then only in women with symptomatic vertebral fractures or osteopenia noted by x-ray for other reasons. Indeed, for too long, hip fractures, the end point of this metabolic syndrome, were either written off as a consequence of aging, or ignored in respect to treatment. BMD measurements by DEXA and CT changed all that, especially when it became clear that a single BMD measurement at any site was a very strong predictor of future spine and hip fractures (1,2,4). As such, the definition of osteoporosis began to evolve, and estimates of how many people were affected also changed. When the World Health Organization (WHO) set a cut off point of 2.5 standard deviations below a young normal mean value for BMD in the spine or hip of postmenopausal women, as an indicator of osteoporotic risk, estimates of disease prevalence increased (5). These were confirmed by publication of larger epidemiologic studies in women such as The Study of Osteoporotic Fractures (SOF) and MrOs, a large international cohort of men which provided better estimates of disease prevalence, onset and clinical course (4,6).

Currently most estimates suggest that there are approximately 0.3 million hip fractures per annum in the U.S. and 1.7 million hip fractures in Europe (7,8). With the introduction of readily available treatments, and clear prevention messaging annual hip fracture rates in the early 2000s started to decline. However, by 2015 those rates had flattened out and were trending upwards, following widespread reporting of atypical femoral fractures in patients treated with bisphosphonates and denosumab. Virtually all hip fractures can be attributed to osteoporosis, whether primary or secondary. Moreover, in most if not all cases, falls are a primary event leading to the fracture. The female to male ratio of hip fractures is approximately 2:1.0 (6,9). Not surprisingly, the occurrence of these fractures increases exponentially with age. In contrast, the incidence of wrist fractures in the UK and the US ranges from about 400- 800 per 100,000 women but is relatively stable over several decades of older life (9). Women are far more likely to suffer a Colle's fracture than a man (i.e. a ratio upwards of 10:1 by age 75) (9). Compression fractures of the vertebrae are much more difficult to estimate because often these can be asymptomatic. Best estimates are that more than a million American postmenopausal women will suffer a spine fracture in the course of a single year (9-11). The female to male ratio of occurrence is approximately 2:1. Moreover, both symptomatic, and radiographic (morphometric) fractures are associated with significant morbidity and disability (10). Finally, estimates about disease prevalence in women and men without fractures, but with low BMD (-2.5 or lower) vary greatly, but place the overall number at close to 25 million Americans and many more world-wide (9,12).

Bone loss as a result of aging/and or estrogen deficiency is the predominant pathophysiologic disorder of primary osteoporosis. However, the frequent use of glucocorticoids in both men and women, contribute dramatically to the total number of individuals with very low BMD and/or osteoporotic fractures (11). It is estimated that more than 5 million American men are afflicted with osteoporosis, based on either the presence of osteoporotic fractures (i.e. vertebral compressions, wrist fractures, hip fractures, or humerus/tibial fractures) or low BMD (11). However, the number of cohort studies in men with this disease is somewhat limited, and a more complete epidemiologic picture of male osteoporosis is becoming clearer with the MrOS study. Importantly, and somewhat surprisingly, in this cohort of more than 5000 men over the age of 65, obesity was associated with a significantly increased risk of fracture (11-13).

More frightening than estimates of the extent of low bone mass is the concern about the lower frequency of diagnosing osteoporosis and the poor adherence to therapy. It is now estimated that more than 70% of individuals who are at risk for osteoporosis, and who are receiving therapy, will not continue beyond the first year (14). Moreover, prescribing rates for bisphosphonates have fallen significantly due to the perceived risk of atypical femoral fractures (15,16). Whereas, osteoporosis was once considered a disorder of old Northern European women, it is now clear that this disease can occur in postmenopausal African Americans, that it is much more common in men than previously appreciated, and that the use of glucocorticoids and/or immunosuppressive therapies for transplant patients, markedly enhances that risk. Interestingly, and somewhat alarmingly although the prevalence of hip fractures has increased slightly, (possibly due to poor compliance from the perceived adverse events with anti-osteoporosis therapy) the diagnosis of osteoporosis by primary physicians has dropped.

FACTORS THAT AFFECT BONE QUANTITY AND QUALITY

Several risk factors predispose individuals to osteoporotic fractures. For a hip fracture, these include age greater than 65 years, a previous spine or hip fracture, maternal history of a hip fracture, poor neuromuscular function, weight loss after the age of 50, and low body mass index (1,18) (See Table 1). Falls are a major cause of fractures, and in all clinical situations, some degree of trauma can be linked to the injury (19). But many osteoporotic patients suffer fractures with minimal trauma, and this feature is pathognomonic of the skeletal fragility which accompanies low bone mass. It is for this reason that the most significant risk factor for fractures of the spine, hip or wrist remains low BMD (20). This association has been confirmed by use of the FRAX score (www.shef.ac.uk/frax) that includes areal BMD plus clinical risk factors including family history, BMI, smoking and use of glucocorticoids (21). The continuous but inverse relationship between BMD and fracture is consistent at all points below the mean suggesting there is no threshold effect (18,19). And, it is applicable at virtually every skeletal site by multiple types of measurements from the spine to finger to the calcaneus. Moreover, the advent of newer technology to measure bone mass has allowed widespread screening for risk as well as defining risk reduction with therapy. Notwithstanding the strength of the inverse relationship of BMD to fracture risk, it is important to note that the presence of a previous fracture is also an extremely important, BMD-independent risk for subsequent fracture. This is relevant clinically since the recognition of fracture at any BMD defines a skeleton that has poor bone quality, and hence is likely to fracture again.

Table 1. Phenotypic Characteristics that Adversely Affect Bone Strength
Bone Mineral Density (areal)	Yes	Yes (DXA)
Bone Mineral Density (volumetric)	Yes	Yes (QCT)
Microcracks	No	No (Histology)
Trabecular Connectivity	Yes	TBS (DXA)
Periosteal Circumference	No	Yes (pQCT/DXA)
Cortical Thickness	+/-	Yes (pQCT/DXA)
Bone Turnover	Yes	Yes (markers)
Previous Osteoporotic Fracture	Yes	Yes (radiograms or IVA)
Mineralization and cortical porosity	?	No/yes (back scatter EM) and sometimes with high resolution microCT

Table 1. Phenotypic Characteristics that Adversely Affect Bone Strength

Characteristic

Recognized Risk Factor for Fracture

Clinically Measurable

Bone Mineral Density (areal)

Yes

Yes (DXA)

Bone Mineral Density (volumetric)

Yes

Yes (QCT)

Microcracks

No (Histology)

Trabecular Connectivity

Yes

TBS (DXA)

Periosteal Circumference

Yes (pQCT/DXA)

Cortical Thickness

+/-

Yes (pQCT/DXA)

Bone Turnover

Yes

Yes (markers)

Previous Osteoporotic Fracture

Yes

Yes (radiograms or IVA)

Mineralization and cortical porosity

No/yes (back scatter EM) and sometimes with high resolution microCT

See references 22-26 for more discussion about bone quality and its relationship to fracture risk. uCT- micro CT, pQCT- peripheral quantitative CT, DXA- dual energy X-ray absorptiometry, TBS-trabecular bone score.

IVA- instant vertebral assessment- DXA scan for morphometric changes in the thoracic and lumbar spine.

Bone mass measurement defines mineral content per area of bone. In the laboratory, bone density by DEXA is a very strong predictor of bone strength and accounts for about 80% of the variability in the breaking strength of a single femur. Thus, a very low BMD can be linked to increased skeletal fragility with a great degree of confidence. Indeed, the FRAX tool has been independently validated as the most accurate tool to measure fracture risk and includes bone mineral density as a major component (21). But there are other determinants of bone strength, often referred to as qualitative measures, including the rate of bone turnover, the extent of trabecular connectivity, cortical and periosteal bone size, and skeletal morphometry (See Figure 1 and Table 1). Indeed, much progress has been made in quantifying several aspects of bone 'quality' utilizing tools such as single energy QCT of the spine/hip, ‘extreme’ CT (i.e. high resolution hr pQCT) of the radius or tibia (See Figure 1), TBS (i.e. trabecular bone score), histomorphometry and magnetic resonance imaging of the radius (22-26). However, more work still needs to be done to ascertain their role in clinical medicine. Still, BMD represents the most accurate, cost effective, and easiest parameter for risk assessment (21). In part, two-dimensional DEXA measurements integrate actual bone mineral content in both trabecular and cortical compartments with bone size. Due to the strong association between bone mineral density and future fractures, this phenotype remains an excellent surrogate for defining both the genetic and acquired components of the disease process. TBS, (trabecular bone score) in the vertebrae, which can be measured from DXA, provides a relatively rapid way of assessing bone quality, although its role in providing additional risk assessment remains to be determined (24).

Figure 1. This is a high resolution QCT image of the distal radius of an individual patient. One can image the trabecular bone of the peripheral skeleton and define measures of bone “quality” by specific measurements. It is still not clear whether these measurements provide a better insight into fracture risk than DXA.

BONE REMODELING AND ITS RELATIONSHIP TO BONE QUANTITY

Adult bone mineral density represents the end result of two processes; acquisition of peak bone mass during adolescence and maintenance of bone mass during the middle and later years. Changes in bone mass result from physiologic and pathophysiologic processes in the bone remodeling cycle (25). This can occur during the stage of accelerated linear growth in adolescence, or much later in life, usually after menopause in women. The bone remodeling cycle is a tightly coupled process whereby bone is resorbed at approximately the same rate as new bone is formed. Basic multicellular units (BMUs) compose the remodeling unit of bone and include: osteoclasts which stimulate bone resorption, osteoblasts, which are responsible for new bone formation, and osteocytes, older osteoblasts surrounded by bone and present in a reduced state of activity (26) (See Figure 2). Activation of the remodeling cycle serves two functions in the adult skeleton: 1) to produce a supply rapidly, as well as chronically, of calcium to the extracellular space; 2) to provide elasticity and strength to the skeleton. When the remodeling process is uncoupled so that resorption exceeds formation, bone is lost. On the other hand, during peak bone acquisition, formation exceeds resorption resulting in a net gain of bone. Remodeling is more pronounced in the trabecular skeleton (e.g. spine, calcaneus and proximal femur) due to much greater surface area, and is the most metabolically active component of bone, in part because of its proximity to the marrow space. However, trabecular bone is also extremely vulnerable to perturbations by local or systemic factors that can cause significant imbalances in bone turnover.

Figure 2. The bone remodeling cycle. The osteoblast (OB) orchestrates the orderly process of bone remodeling through activation signals from systemic factors including growth hormone (GH), interleukins (IL-1,IL-6), parathyroid hormone (PTH), and withdrawal of estrogen (-E2). M-CSF and RANKL are the two major OB mediated factors which regulate the recruitment and differentiation of the osteoclast (OC). Osteoprotogerin (OPG) is also synthesized by OBs and serves as a soluble decoy receptor blocking activation of RANK. Inhibition or knockout of these signals from OB-OC results in reduction in bone resorption. Other cells including activated T lymphocytes may contribute to the marrow milieu. Not pictured are IGFs which are released during bone resorption and serve as coupling factors to recruit new OBs to the surface. These peptides may also be important for osteoclast activity. Also sclerostin, a peptide produced by osteocytes reduces new bone formation by blocking Wnt signaling.

The initiation of the bone remodeling cycle remains unclear. The long-standing dogma was that activation of resting osteoblasts on the surface of bone and marrow stromal cells began the process (27-33). This would mean that there were initiating signals, either paracrine or endocrine that would stimulate osteogenesis. One possibility is that osteocytes, which can sense fluid shifts and microcracks, and are imbedded deep within the matrix of the skeleton, induce the remodeling sequence, by paracrine signaling to the osteoblast (27-29). But those same cells secrete factors that can initiate osteoclast differentiation as well as alter osteoblast mediated bone formation. Osteocytes, for those reasons, are now considered the ‘command and control’ system for remodeling. More recently, investigators believe that RANKL, released from osteocytes as well as stromal cells, drives osteoclast differentiation, beginning the process of active resorption prior to osteoblast differentiation. This can occur as a result of hormonal signals or mechanical loading. Resting lining cells or osteoblast progenitors as well as mesenchymal stromal cells can become activated at the same time when osteoclast differentiation is ongoing. Those progenitors also signal to osteoclast precursors to induce further differentiation and induction of hematopoietic cells (29). Osteoclasts, once differentiated, may also elaborate growth factors, such as the Wnts and sphingosine to signal back to osteoblast progenitors. After osteoclast- induced bone resorption, matrix components such as TGF-beta and IGF-I, as well as collagen, osteocalcin, and other protein and mineral components, are released into the micro environment of the niche. Growth factors released by resorption contribute to the recruitment of new osteoblasts to the bone surface, which begin the process of collagen synthesis and mineralization. But, in addition stromal factors such as the Wnts can induce further osteoblast differentiation via the LRP5/6 signaling pathway. In healthy adults as many as two million remodeling sites may be active at any given time, and it is estimated that nearly one fourth of all trabecular bone is remodeled each year. In general resorption takes only 10-13 days, while formation is much more deliberate and can take upwards of three months (Figure 2). Under ideal circumstances, by the end of the cycle, the amount of bone resorbed equals the amount reformed. Cessation of bone formation almost certainly occurs via osteocyte mediated sclerostin (see below) which blocks further Wnt signaling. In sum, remodeling begins at the surface of the trabecular and cortical bone via signals from the osteocytes, probably starting with osteoclast differentiation and then signaling backwards to osteoblasts, and vice versa.

In contrast to normal remodeling, osteoporosis has been classically defined in a pathogenic manner as an uncoupling in which resorption exceeds formation resulting in a net loss of bone. However, it is also apparent that some individuals have impaired peak bone acquisition. This scenario may be more common than previously appreciated and almost certainly represents inherited or acquired alterations in the rate of either bone formation or bone resorption during a critical period when several hormones in synchrony orchestrate a marked increase in bone mass (see later).

There are several key components of the remodeling cycle which are susceptible to systemic and local alterations and when perturbed, can lead to deleterious changes in bone mass. In particular, activation of remodeling via the osteoblast, and recruitment of osteoclasts, represent the two most vulnerable sites in the cycle. A third cell, altered by disease states is the osteocyte, an entombed fully differentiated osteoblast that connects to the surface osteoblasts, and likely senses mechanical stimulation. Osteocyte apoptosis may contribute to age-related osteoporosis either directly or through the elaboration of systemic peptides. Interestingly, remodeling may end with the osteocyte as well, since it produces a protein, sclerostin, which inhibits osteoblast activity by antagonizing the Wnt and BMP pathways (see below) (34). Monoclonal antibodies that bind to sclerostin have been developed and one (e.g. romosozumab) has been approved for the treatment of postmenopausal osteoporosis (35-36). That monoclonal antibody enhanced bone formation, increased bone mineral density by 13-15% at one year, suppressed bone resorption (via Wnt mediated RANKL), and reduced overall fractures of the spine (32). Finally, one could consider macrophages to have an important role in remodeling, since these cells are present in the bone marrow niche and respond to injury with inflammatory cytokines and immune modulators (37). On the other hand, the bone marrow niche may be protected against macrophage induced cytokine release due to a protective ‘canopy’ of lining cells, although recent evidence suggests that there is a pro-inflammatory response in the marrow with certain perturbations such as diet induced obesity or aging (29).

Uncoupled remodeling occurs during menopause, with estrogen deprivation or antagonists, or in response to endogenous parathyroid hormone fluxes, cytokine stimulation, growth hormone surges, glucocorticoid excess, or changes in serum calcium. For the most part, estrogen deprivation remains one of the most common and critical elements in shifting resorption rates to a higher set point (38-42). Although bone formation initially can "catch up", the length of time for each component of the remodeling cycle clearly favor resorption over formation as the process of laying down new bone requires the interaction of several processes (see Figure 2). But, it is still unclear why falling estrogen levels, which is a universal event during the menopausal years, causes such rapid bone loss in a relatively small percentage of women (43). Clearly, factors such as peripheral conversion of testosterone to estradiol, adrenal androgen production, FSH levels, and genetic determinants, as well as other local signals may also be important. In regards to FSH, SWAN (Studies of Women Across the Ages) reported that higher FSH precedes estrogen loss and this is associated with longitudinal bone loss more closely than circulating estrogen. Although not identified in humans, mice have strong heritable determinants that affect the rate of age-related bone loss and in one mouse model high FSH levels drove significant bone loss independent of estrogen.

The nature of the osteocyte-osteoblast-osteoclast interaction has been one of the most active areas of recent investigation (see Figure 2). External signals (such as PTH, growth hormone, interleukin-1, estrogen deprivation) to resting osteoblasts and stromal cells cause these cells to release a potpourri of cytokines (i.e. interleukins such as IL-1, -6, -11 as well as m-CSF, tumor necrosis factor (TNF), and TGF-beta) that enhance the recruitment and differentiative function of multinucleated giant cells destined to become bone resorbing cells (38). However, one of the most critical pathways in the osteoblast-osteoclast interaction scheme is the RANKL- Osteoprotogerin (OPG) relationship. OPG is a soluble peptide originally described as a factor which markedly inhibited bone resorption and osteoclast differentiation in vitro (42). This protein is a member of the TNF receptor super-family and its role in bone remodeling is to act as a decoy receptor for the peptide known as osteoprotegerin ligand i.e. OPGL (or RANKL) (42). In fact, RANKL is a surface peptide which when expressed on the osteoblast, binds to the true OPGL receptor (also called RANK-receptor activator of NFkB Ligand) on osteoclasts, and initiates cell-cell contact necessary for osteoclast activation and subsequent bone resorption (42). More recently RANKL has been shown to be produced by osteocytes and can result in osteocytic osteolysis during states of high calcium demand such as lactation, estrogen deficiency, and even acute exercise (43).

The OPG, OPGL and RANK system that affects osteoclast differentiation, in addition to the effects of m-CSF on osteoclast proliferation, provides the critical link among osteocytes, osteoclasts and osteoblasts. It has also led to the synthesis of RANKL antibodies. Denosumab, (brand name Prolia) was the first approved monoclonal antibody against RANKL for the treatment of postmenopausal osteoporosis due to its strong efficacy in reducing spine and hip fractures (44-46). It is administered once every six months and it suppresses bone resorption by 80-90%. Unlike the bisphosphonates, denosumab’s anti-resorptive effect wanes in 4-6 months, thereby providing a margin of safety in terms of total suppression in remodeling (46). On the other hand, because the anti-resorptive effect wanes rapidly, there is concern about post treatment rebound and fractures, particularly of the vertebral spine (47).

The osteoblast functions not only to signal osteoclasts during remodeling as well as receive signals from them, but also to lay down collagen and orchestrate mineralization of previously resorbed lacunae in the skeletal matrix. These complex functions are tied to differentiation of mesenchymal stromal cells which become terminally differentiated osteoblasts and rest on the surface of the remodeling space (29). Recruitment of stromal cells or lining cells into osteoblasts, rather than adipocytes is a critical step in bone formation and requires a series of transcription factors that enhance differentiation. This is particularly important since one of the features of estrogen deficiency and age-related osteoporosis is the development of increased bone marrow adiposity (48,49). Indeed, the presence of excess bone marrow fat may be a major risk factor for osteoporotic fractures (50).

One of the most important components driving osteogenesis is Runx2, a unique transcription factor which is essential in the early differentiation pathway of osteoprogenitors (51). Regulation of Runx2 has become a major focus of work in as investigators have begun to consider novel ways to enhance bone formation and reduce marrow adipogenesis (50). Also, it should be noted that there are metabolic programs activated by transcription factors that are essential for fueling the work of the osteoblast. Conditions of substrate insufficiency; e.g. anorexia nervosa, diabetes mellitus etc. also impair bone formation by altering their metabolic programs.

With activation of resting osteoblasts and lining cells, osteoblasts synthesize several types of collagen as well as elaborating a series of growth factors such as IGF-I, IGF-II, TGF-b. These, in turn, are necessary for further recruitment of bone forming cells (52). In addition, osteoblasts deposit growth factors in the skeletal matrix where they are stored in latent forms, and released during subsequent remodeling cycles. After deposition of new bone, some osteoblasts are encased by matrix. These osteocytes, are still viable, although less metabolic and, can, through newly developed caniculi, provide signals to other bone cells. Indeed, most evidence suggests that osteocytic signals are important in the so-called "mechanostat", the gravitary sensing device which modulates bone formation, as well as initiating normal remodeling sequences. As noted earlier, osteocytes may participate in bone resorption of the cortex by secreting RANKL. This is termed ‘osteocytic osteolysis’ and may occur during lactation and other states of high calcium demand.

In the last half-decade, the Wnt/b catenin signaling pathway has emerged as a major regulator of bone formation and a potential mediator of the mechanostat. Wnts belong to a large family of peptides that bind to two membrane bound receptors, Lrp5 or 6 and Frizzled (see Figure 3) (53). Once these ligands bind, activation occurs through a complex intracellular signaling pathway mediated by /b catenin which translocates to the nucleus and stimulates the transcription of several genes through the TCF/Lef network. Sclerostin (SOST), the osteocyte specific protein that inhibits bone formation does so by binding to Lrp5 and blocking Wnt signaling (54). The anti-sclerostin antibody, romosozumab, was shown to markedly increase bone mass and reduce fractures in postmenopausal women after only 1 year of treatment (55,56). It was approved by the FDA and European Regulatory Agencies for the treatment of postmenopausal osteoporosis.

Figure 3. The Wnt/-catenin signaling pathway that is critical for osteoblast differentiation (53).

In summary, the bone remodeling cycle is complex and redundant. The three major cells, osteocytes, osteoblasts and osteoclasts, arise from different stem cells (mesenchymal for osteoblasts and osteocytes, and hematopoietic for osteoclasts) and are under the control of various factors which in harmony orchestrate an orderly remodeling sequence. Their birth and death (i.e. the cycle of recruitment, proliferation and programmed cell death) and the regulatory factors which control those events, are also complex, yet vitally important for understanding the pathogenesis of osteoporosis. Alterations at any stage along the process of recruitment, activation, differentiation, or cell death can lead to imbalances in remodeling which eventually would result in bone loss, reduced bone mass and ultimately fractures. Some of those perturbations are noted below.

SYSTEMIC AND LOCAL ALTERATIONS IN THE BONE REMODELING SEQUENCE LEAD TO BONE LOSS

The importance of estrogen in maintaining calcium homeostasis for the postmenopausal woman was first established by Fuller Albright, more than 70 years ago (57). Since that time more evidence has accumulated from randomized intervention trials demonstrating that hormone replacement (estrogen with or without progesterone) reduces bone turnover and increases bone mass (58). However, these data provide only indirect evidence that estrogen levels are important as pathogenic components of the osteoporosis syndrome. More recent studies provide stronger evidence of the association between low estradiol concentrations and low bone mass. Several investigators have demonstrated that the lowest estradiol levels in postmenopausal women (i.e. <5 pg/ml) are associated with the lowest bone mineral density and the greatest likelihood of fracture (59). In addition, at least one study has shown that males with osteoporosis have lower serum levels of estradiol then do age-matched men who do not have low bone mass (60). Moreover, there are now two case reports describing mutations in either aromatase activity or the estrogen receptor, which produced a phenotype of severe osteoporosis in men (61,62). In the former case, estrogen replacement therapy for this young man, resulted in a marked increase in spine and hip bone mineral density. In both situations the lack of functional estrogen, despite normal to high levels of testosterone, resulted in very low BMD (63).

Although declining estradiol levels contribute to the osteoporosis syndrome, the precise molecular events or sequences that result from changes in ambient hormonal concentrations are not clear. In some animal models, estrogen deprivation is associated with a marked increase in IL-6 synthesis from stromal and osteoblastic cells. This is consistent with experimental findings which demonstrate that estrogen regulates the transcriptional activity of the IL-6 promoter (39,41). However, results in other studies are conflicting. In other experimental paradigms, changes in TNF, IL-11 and IL-1 can all be associated with increased bone resorption (40). Recently RANKL has been identified as a major regulator of osteoclast differentiation. Thus, it seems likely that several cytokines, working in concert, are active during estrogen deprivation, and each can accelerate the process of bone resorption. RANKL, however may be the most critical and necessary for full activation of remodeling. Enhanced bone resorption eventually leads to bone loss from estrogen deprivation since bone formation rates cannot keep up with rates of bone resorption (31,42, 43). Moreover, the faster the resorption, the greater the loss resulting in more damage to the structure integrity of the skeleton.

In contrast to the plethora of studies on bone loss and estrogen, there are few good studies relating androgen deprivation to bone loss in women. Androgen receptors are present on osteoblasts. However, both in vitro and in vivo studies in men have yielded conflicting results. Like estrogen, androgens can regulate the IL-6 promoter and in experimental animals, orchiectomy has been associated with increased IL-6 production and bone loss (64). In men, chronically low androgen levels have been associated with low bone mass, and testosterone replacement can enhance bone mineral density (65). However, estradiol levels in men may be a more important risk factor for fracture than androgen levels and correlate more closely with trabecular bone volume as measured by QCT. At the present time it is not clear precisely what role androgens play in the maintenance of bone mass in both men and women except in deficiency syndromes, particularly hypogonadism.

Other more common causes of male osteoporosis include alcoholism, glucocorticoid excess, and hypercalciuria (see Table 2). In the first two cases, hypogonadism remains a pathogenic feature of that osteoporosis syndrome. Less frequently, men with gluten enteropathy or an endocrinopathy such as thyrotoxicosis or primary hyperparathyroidism can present with multiple fractures and low bone mass (see Table 2).

Table 2. Etiology of Osteoporosis in Men
Hypogonadism	30-80	low Test, low E2, increased resorption
Alcoholism	40-80	low test, E2+/-, +/- turnover
Glucocorticoids	20-80	+/- test, E2 +/-, increased resorption, Decreased formation
Multiple myeloma	40-80	Hypercalcemia, ESR
Hypercalcuria	30-80	Test, E2 nl; increased resorption Hypercalcuria, inc PTH, kidney stones
Idiopathic Osteoporosis-	40-80	fractures, low formation, low IGF-I
Gluten enteropathy	20-80	low 25OHD, turnover increased
Endocrine Disorders	15-90	Cushing’s ±
PHPT	15-90	PTH increased in all cases; increased resorption
Thyrotoxicosis	15-90	Decreased PTH

Table 2. Etiology of Osteoporosis in Men

Etiology

Age-years

Clinical Features

Hypogonadism

30-80

low Test, low E2, increased resorption

Alcoholism

40-80

low test, E2+/-, +/- turnover

Glucocorticoids

20-80

+/- test, E2 +/-, increased resorption, Decreased formation

Multiple myeloma

40-80

Hypercalcemia, ESR

Hypercalcuria

30-80

Test, E2 nl; increased resorption Hypercalcuria, inc PTH, kidney stones

Idiopathic Osteoporosis-

40-80

fractures, low formation, low IGF-I

Gluten enteropathy

20-80

low 25OHD, turnover increased

Endocrine Disorders

15-90

Cushing’s ±

PHPT

15-90

PTH increased in all cases; increased resorption

Thyrotoxicosis

15-90

Decreased PTH

E2- estradiol; Test-testosterone; PTH-parathyroid hormone; PHPT-primary hyperparathyroidism; Inc- increased

In women, bone loss is accelerated immediately after menopause. However, recent studies demonstrate that markers of bone resorption are also very high later in life. In particular, women in their 80s and 90s have been noted to lose bone at a rate of greater than 1% per year from the spine and hip (65), Contrary to earlier studies, it is now evident that the older woman who is not as physically active, and is not on estrogen, is at extremely high risk of bone loss and subsequent fractures. The pathogenesis of this process is multifactorial although dietary calcium deficiency, leading to secondary hyperparathyroidism, certainly plays a central role. The average calcium intake of women in their 8th and 9th decades of life is now estimated to be between 800-1000 mg/day (66). If vitamin D intake is also sub-optimal, and serum levels of 25 OH vitamin D <20 ng/ml, or 50nmol/l, secondary hyperparathyroidism may occur, although there are other causes for increases in PTH, including chronic renal insufficiency and low calcium diet (67). PTH stimulates osteoblasts and provokes the remodeling sequence including the elaboration of several cytokines that accelerate bone resorption. Unfortunately, in most elders, bone formation is not enhanced although the reasons for this are not entirely clear beyond the simplistic notion that stem cell recruitment is impaired in the elderly. Nonetheless, this leads to further uncoupling in the bone remodeling cycle, and significant bone loss. Among elders with poor calcium intake who live in northern latitudes, seasonal changes in vitamin D lowering levels below 20 ng/ml might aggravate bone loss (68,69). Whether increased bone loss from vitamin D deficiency is an independent risk factor for future fractures in the elderly remains somewhat controversial necessitating further studies to define such a risk. Overall, there is evidence that vitamin D deficiency is associated with a greater risk of fracture in frail elderly institutionalized men and women (<20 ng/ml; 50 nmol/l), whereas it is unlikely that those individuals with 25 OHD levels between 20-30 ng/ml are at a greater risk (70). The recently completed VITAL trial demonstrated that 2000 IU of vitamin D to healthy men and women did not prevent bone loss or alter bone turnover (LeBoff, personal communication and abstract ASBMR,2019).

There is growing evidence that low serum levels of vitamin D, through impaired calcium absorption, can stimulate PTH release and increase bone turnover in the elderly. Increased PTH enhances 1,25 dihydroxyvitamin D, and this in turn could suppress further bone formation and mineralization (71). Thus, bone loss is associated with uncoupled remodeling. Many older individuals already have established osteoporosis. Coincidental vitamin D deficiency due to poor intake, absent sunlight exposure, or impaired conversion of vitamin D to its active metabolite, can result in osteomalacia as well as aggravating pre-existent osteoporosis (70). LeBoff et al reported that more than 50% of elders who presented with a hip fracture were frankly vitamin D deficient (71). Therefore, the combination of vitamin D deficiency with inadequate calcium intake enhances the likelihood of rapid bone loss in the very susceptible elderly population. Still, it is unclear how secondary hyperparathyroidism causes bone loss. Chronic elevations in PTH secretion due to primary or tertiary hyperparathyroidism, have been associated with low bone mass at several skeletal sites including the radius. Elevated PTH levels in older women have been associated with bone loss in some studies but not in others. In elderly individuals, it has been reported that PTH levels are closely correlated with increased synthesis of an insulin-like growth factor binding protein (IGFBP-4) which suppresses IGF action on bone cells and may increase sclerostin secretion (72, 34). Since IGF-I is an important growth factor for osteoblasts, it is conceivable that PTH down regulates IGF activity during states of relative calcium/and or vitamin D deficiency. This would shift the remodeling balance towards preserving intravascular calcium concentrations, while inhibiting new calcium incorporation into the skeletal matrix. In sum, there is little doubt that calcium and vitamin D insufficiency are prominent causes of accelerated bone loss in the elderly (73). However, in the healthy postmenopausal population, there is little evidence that vitamin D supplementation prevents bone loss or fractures.

As noted previously, high circulating levels of glucocorticoids have a significant impact on bone acquisition and maintenance. In 1932 Harvey Cushing recognized the syndrome of endogenous steroid excess which included marked osteopenia and fractures (74). Long term exposure to pharmacologic doses of glucocorticoids results in significant bone loss and enhanced marrow adipogenesis as marrow stromal cells differentiate down the fat lineage. In addition to having direct effects on the osteoclast and osteoblast, glucocorticoids also induce secondary hypogonadism and hyperparathyroidism, impaired vitamin D metabolism, muscle atrophy, and hypercalciuria (See Table 3). All these factors contribute to a rapid and sustained loss of bone during the first few months of steroid therapy (75). The addition of other immunosuppressants such as cyclosporine has been shown to aggravate bone loss by further increasing bone resorption. As the number of organ transplants have increased exponentially over the last decade, the prevalence of post-transplantation osteoporosis has risen substantially. Steroid induced osteoporosis is now considered the second most common cause of low bone mass in the general population and one of the most common causes of osteoporotic fractures (75). It is listed in the FRAX data set as one critical risk factor to assess in determining 10-year fracture likelihood.

Table 3. Effects of Glucocorticoids on Bone Mass
Increased PTH secretion	Increased bone resorption ? decreased bone formation	rapid loss of bone
Decreased LH/FSH secretion	Increased bone resorption due loss of estrogen	loss of bone
Impaired calcium absorption due to decreased 1,25 D	Increased PTH, increased bone resorption	loss of bone
Increased calcium loss in urine	Secondary increase in PTH, Increased bone resorption	loss of bone
Acute suppression of osteoblasts and apoptosis	Reduced bone formation	gradual bone loss
Stimulation of osteoclastogenesis	Increased bone resorption rapid	loss of bone

Table 3. Effects of Glucocorticoids on Bone Mass

Response to Glucocorticoids

Effects on Bone Remodeling

Effects on Bone Mass

Increased PTH secretion

Increased bone resorption

? decreased bone formation

rapid loss of bone

Decreased LH/FSH secretion

Increased bone resorption due loss of estrogen

loss of bone

Impaired calcium absorption due to decreased 1,25 D

Increased PTH, increased bone resorption

loss of bone

Increased calcium loss in urine

Secondary increase in PTH, Increased bone resorption

loss of bone

Acute suppression of osteoblasts and apoptosis

Reduced bone formation

gradual bone loss

Stimulation of osteoclastogenesis

Increased bone resorption rapid

loss of bone

PATHOGENIC FACTORS WHICH IMPAIR PEAK BONE MASS

Peak bone mass is acquired between the ages of 10-16 years. It is the zenith of bone acquisition and represents the sum of several processes including a marked increase in bone formation (76,77). Boys tend to reach peak 2 years later than girls and their bone mineral density is higher than women at all skeletal sites. In part this relates to a greater cross-sectional bone area in males than females (78). Peak bone mass results from linear growth and consolidation of cortical and trabecular components. Acquisition is most rapid during the latter stages of puberty and coincides with maximum growth hormone secretion, high serum IGF-I levels, and rising levels of estradiol and testosterone. In addition, calcium absorption is maximal and skeletal accretion is optimal. All these processes combine over a relatively short period of time to produce a bone mass that subsequently plateaus and then falls during later life. It is estimated that more than 60% of adult bone mass can be related to peak acquisition. Hence understanding the mechanisms responsible for low bone mass must include perturbations in peak bone acquisition.

There are several hormonal, environmental, nutritional and heritable determinants of peak bone mass. These include estrogen/testosterone, growth hormone/IGF-I, adequate nutrition, calcium/vitamin D, and unknown genetic factors. If each is perturbed, dramatic alterations in peak bone mass may occur, setting the stage for low bone density throughout life. Gonadal steroids are important not only to bone maintenance but also to its acquisition. During puberty, estrogen and testosterone levels rise and contribute to consolidation of bone mass. Estrogen is also necessary for epiphysial closure. Studies of a male with an estrogen receptor mutation and men with an aromatase deficiency established that estradiol is critical for bone acquisition (61,62). These young men share several phenotypic characteristics including tall stature unfused epiphysis, and very low bone mass. Hence, there must be a threshold effect for estradiol in men, and this effect must be time dependent. Similar conclusions can be drawn from studies in women. Acquired deficiencies in estrogen, such as anorexia nervosa, or chemotherapy induced ovarian dysfunction, result in low peak bone mass and lead to subsequent risk for osteoporosis (79,80,81). Nearly identical findings have been noted in patients with untreated Turner's syndrome and in men with Klinefelter's syndrome, although the high FSH levels could also contribute to bone loss.

The timing of gonadal steroid surges is critical for bone acquisition since there is a relatively short window of time in which bone formation is favored and matrix synthesis is markedly enhanced. That window is likely to be less than three years and earlier in girls than boys. Probably the best study which addressed this issue comes from a retrospective analysis of men in their thirties who underwent late onset of puberty (i.e. at the age of 17 or 18) but were otherwise normal by full endocrine testing. These men had significantly lower bone mineral density in their thirties than age matched men who went through puberty at a normal time. These data suggest that timing as well as quantity of gonadal steroids is critical for bone acquisition.

Pubertal surges of estrogen and androgens are also important for priming the growth hormone/ IGF-I axis. Rising levels of both contribute to growth hormone surges that lead to increases in circulating and tissue expression of IGF-I, an essential growth factor for chondrocyte hypertrophy and expansion. IGF-I may also be critical in defining the cross-sectional size of bone, a potentially important determinant of bone strength. Once again, studies in growth hormone deficient, or growth hormone resistant individuals have established that low levels of circulating IGF-I, especially during puberty, are associated with reduced bone mass (82). In addition, rhGH replacement has been shown to restore linear growth and improve peak bone mass acquisition. Several studies in experimental animals, including inbred strains of mice, have established that IGF-I is important for bone acquisition and the timing of IGF-I peaks coincide with maximal rates of bone formation. Impairment in production of IGF-I due to acquired disorders such as anorexia nervosa, malnutrition, and delayed puberty can also impede peak bone acquisition (80). Recently, it has become apparent that Type I IDDM can impact the bone marrow niche and suppress bone formation and increase resorption. This uncoupling can lead to an impairment in peak bone mass, although there are other determinants of glucose intolerance that can impact the skeleton; e.g. increased advanced glycation end products, glucose toxicity, material property changes in the matrix.

Hormonal abnormalities not only enhance bone resorption in older individuals, but may blunt the capacity of bone cells to maximize bone formation during adolescence. Clearly, hypogonadal boys and girls have impaired peak bone mass, resulting in low adult bone mineral density. Even one form of contraception, Depo-provera, may reduce estrogen concentrations enough in the teen girl, to reduce her capacity to acquire peak bone mass. Similarly, it seems likely although not proven that smoking during the teen years could impair osteoblast activity and flatten projected trajectories for peak bone acquisition.

More recently diabetes mellitus has been established as a secondary cause of osteoporosis. TIDM, particularly at early onset (e.g. childhood or adolescence) is associated with low bone mass and fractures (83). Both hip and vertebral fractures are more common in adult T1DM, whereas in T2D, in which areal BMD is normal, fracture risk is increased by 20%, but the type of fractures are usually peripheral in nature (84). Importantly use of rosiglitazone, a TZD is also associated with an increased risk of fracture whereas DPP4 inhibitors and GLP1 agonists are bone neutral or favor a slight increase in bone mass. The newer SGLT-2 inhibitors are associated with a greater risk of fracture as a class. Despite the greater risk with glucose intolerance, the pathophysiology of these disorders is not well defined, although changes in advanced glycation end products, enhanced reactive oxygen species, and glucose toxicity are all considered likely contributors.

In order to mineralize newly synthesized bone, calcium must become bioavailable to the skeletal matrix. In experimental studies in rodents and humans, it is clear that the several pools of available calcium are markedly enhanced during puberty. These include calcium efflux from the gastrointestinal tract, and the calcium pool available for incorporation in the matrix. It is no coincidence that growth hormone surges not only increases IGF-I, (thereby enhancing skeletal growth and matrix biosynthesis) but also result in increases in 1,25 dihydroxyvitamin D (possibly via IGF-I induction of 1, alpha hydroxylase activity), the active metabolite of vitamin D which markedly enhances calcium absorption from the gut. Although there are no longitudinal studies in pubertal individuals with prolonged calcium deficiency, several randomized placebo-controlled trials in pubertal and pre-pubertal girls and boys have established that supplemental calcium can enhance bone mineral density. In a twin study, in which one twin receives 1200 mg of calcium supplementation, and one receives placebo, radial BMD increases by as much as 5% after three years compared to placebo (81). This study suggests that there is significant gene-environmental interaction, and that even in those individuals with heritable determinants of low peak bone mass, calcium supplementation may provide an important and relatively simple means of protecting individuals from future osteoporotic fractures.

GENETIC DETERMINANTS OF PEAK BONE MASS

Probably the most important determinant of peak bone mass, but one that has lacked clear definition is the genetic contribution. In part this is due to the complex nature of bone mineral density as a trait. Nevertheless, low peak bone mass may be the most important pathogenic factor in the osteoporosis syndrome of later life. And, it appears that at least 50% of peak bone mass is determined by genetic factors (85). What are these determinants and how are they modified by environmental factors?

Efforts to define heritable determinants of peak bone mass have been complicated by a number of issues which are also common to analyses of other complex traits. These include the following:

A quantifiable phenotype;
Heterogeneity within a given population under study;
The polygenic nature of the disorder;
Epistasis (gene-gene interaction)
Pleiotropy- phenotypic differences with identical genotypes, and
Gene by environmental interactions.

Notwithstanding these complexities it is clear that BMD is an acceptable phenotype for defining heritable determinants of future risk. Bone mineral density in the population is distributed in a gaussian manner, thereby allowing analyses at the extremes (<-2.0 SD or > 2.0 SD) of the density distribution. Large homogeneous and heterogeneous populations are now being studied as part of the GEFOS consortium, to ascertain genetic determinants of BMD and fractures in humans (86-91). Candidate genes are those associated previously by biologic determinants or previous studies as being important for skeletal maintenance. Indeed, many of these have been identified by whole genome studies (GWAS) include RANKL, OPG, the vitamin D receptor, collagen IA1, the estrogen receptor, interleukin-1, and IGF-I. Additionally several other candidate genes that have not been previously associated with osteoporosis have been identified. These studies have been reviewed in depth elsewhere (86-89). Depending on the cohort, the phenotype, and the number of individuals studied, it is predicted there will be hundreds of genes that contribute to individual variation in bone mass (90,91). Twin studies examining discordant or concordant phenotypes are also helpful, as are sib-pair studies, although the results have been less generalizable.

One example of a candidate gene that has also been shown to have strong heritability and predictive value for osteoporosis from GWAS studies is Lrp5 (92). Originally Recker and colleagues identified an extended family with very high bone density and fine mapped the locus to a region in chromosome 11. After several years of intense high through put analysis, that group identified a 'high bone density' gene, LDL receptor related protein 5 (LRP-5) that was mutated in this family (92). The low affinity lipoprotein receptor is important in binding Wnts, ligands critical for cell differentiation in several organisms. At the same time, Warman and colleagues identified several children with osteoporosis pseudoganglioma syndrome and subsequently mapped the gene which resulted in 'loss of function' in these individuals (93). This turned out to also be Lrp5. The potential pathways that direct osteoblast function and mineralization through Lrp5, and its co-receptor frizzled, have opened up new areas of investigation (See Figure 3 and discussion above). Moreover, natural antagonists to the Wnt/Lrp5 signaling system including sclerostin and DKK-1 have been studied using genetic engineering in mice. This pathway continues to show great promise for therapeutic interventions such as romosozumab, recently approved by the FDA for the treatment of postmenopausal osteoporosis (54, 99).

In the past five years, Lrp5 has been studied extensively both in its function and its allelic effects through genome wide association studies as well as in translational bench work. Hence this pathway is important in regulating peak bone mass. But it is also clear that since BMD is a polygenic trait, other genes are now being discovered. Moreover, gene environmental interactions must play a major role in defining heritable risk for low BMD and fracture. In addition to the search for osteoporosis genes, intervention studies in adolescents have provided insight into at least one of the environmental impacts on genetic determinants (94-97). A twin study in Indiana revealed that as long as calcium supplementation continued during puberty, young boys could enhance their peak bone mass. In a Swiss study, younger pre-pubertal girls supplemented with a protein product had a significant increase in spine bone density, as did a cohort of pubertal girls receiving a milk powder in England (96,97). Remarkably, in the latter cohort, serum IGF-I levels also rose dramatically, providing further indirect evidence of a link between pubertal status, bone mass, and the growth hormone/IGF-I axis. Thus, there is strong evidence that nutritional, hormonal and environmental factors play a major role in regulating peak bone mass.

SUMMARY

The epidemiology of osteoporosis is well established and risk factors have been defined. On the other hand, the pathogenesis of osteoporosis is complex and multifactorial (41,98). Alterations in bone mineral density almost certainly represent the final common pathway by which pathologic factors affect risk of future osteoporotic fracture. The interplay of various physiologic processes which result in peak bone mass, and maintenance of adult bone mass are key to understanding the pathogenesis of this disease. Changes in hormonal status, and in particular estradiol, clearly are important factors in regulating both bone formation and bone resorption in men and women. Perturbations in growth hormone activity, musculoskeletal function, dietary intake of calcium and vitamin D, and genetic determinants are also important pathogenic factors. Defining the role of genetic factors and their interaction with many of the environmental and hormonal determinants that have been established as potential etiologic agents responsible for low bone mineral density and fracture will certainly be the most difficult challenge facing basic and clinical researchers. On, the other hand, the strength of data from basic and clinical studies over the last decade, now allows practitioners to confidently diagnose osteoporosis. New treatment strategies offer greater hope for patients suffering from this disease.

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Gastrinoma

ABSTRACT

Gastrinomas are neuroendocrine neoplasms (NENs), that occur primarily in the duodenum and pancreas, which ectopically secrete gastrin, resulting in the Zollinger-Ellison syndrome (ZES), which is due to marked hypersecretion of gastric acid causing severe gastro-esophageal peptic disease. ZES patients have two management problems that must be dealt with: control of the acid hypersecretion and control of the gastrinoma, which is malignant in 60-90% of cases. Most gastrinomas are sporadic, but 20-25% of patients have it as part of the Multiple Endocrine Neoplasia-type 1 syndrome (MEN1), an autosomal dominant disorder characterized by endocrine tumors/hyperplasia of multiple endocrine organs (parathyroid> pancreatic islets>pituitary>adrenal). It is important to identify those with ZES/MEN1 as their management differs from those with sporadic disease. Acid hypersecretion is now controlled medically both acutely and long term, with proton pump inhibitors (PPI) the drugs of choice. In patients with sporadic ZES, after detailed imaging with cross-sectional imaging and somatostatin receptor imaging (SRI), resection of the gastrinomas should be considered whenever possible, with cures reported in 20-45% of patients. The role of surgical resection of the gastrinomas in MEN1/ZES is controversial and it is generally recommended it be reserved for patients with tumors>1.5/2 cm because of the multiplicity of small gastrinomas resulting in very low cure rates. The diagnosis of ZES requires demonstrating fasting hypergastrinemia in the presence of inappropriate acid secretion (pH<2), however, because of the widespread use of PPIs and the lack of gastric acid testing, the diagnosis of ZES is becoming more difficult and referral to a specialty group is frequently required. Patients with advanced metastatic disease are treated as other patients with advanced NENs including with somatostatin analogues, chemotherapy, everolimus, sunitinib, liver directed therapies, and peptide radio-receptor therapy (PRRT) with radiolabeled somatostatin analogues.

GENERAL/DEFINITIONS

ZES was first described in 1955 by two surgeons, RM Zollinger and EH Ellison, in two patients with intractable peptic ulcer disease (1). Although previous cases had been described (2,3), including one well described case by Roar Strom in 1952 (3-5), in Zollinger/Ellison’s two patients the authors were the first to propose the important association between the gastric hypersecretion and the presence of a pancreatic neuroendocrine neoplasm (PNEN) (1-3,6). Presently, the term gastrinoma and ZES are often used synonymous, however, in the past the term gastrinoma was also used to refer to a neoplasm synthesizing gastrin and ZES to the clinical manifestations (7). Numerous NENs and non-NENs can synthesize gastrin precursors which are not processed to the biologically active gastrin-17 or gastrin-34 as in ZES, and thus are generally not called gastrinomas by clinicians or in most current classification systems of pNEN (7-9). In addition to being well-described in humans, Zollinger-Ellison syndrome due to a gastrinoma have also been reported in dogs (10-17), cats (10,18-22), and a Mexican gray wolf (23).

Like most other functional pNEN syndromes (F-pNEN) (insulinomas, glucagonomas, VIPomas, etc.), in ZES the functional syndrome due to the ectopic hormone secretion requires immediate treatment because it was the most frequent cause of morbidity/death prior to effective treatments (24-38). In addition, treatment must be directed at the gastrinomas itself, because similar to all other pNEN, except insulinomas, the majority (60-90%) are malignant (9,26,27,39-42). Whereas effective surgical resection would cure both problems, in <50% of ZES patients is curative resection possible because of advanced disease or the patients have MEN1/ZES, which can only be cured with Whipple resections, which are not generally recommended (discussed below) (6,9,43-49). Therefore, treatment of patients with ZES requires management of two different treatment problems: the acid hypersecretion and the malignant nature of the gastrinoma.

This chapter will review important aspects of the management of patients with ZES and important treatment issues at present, including the most recent studies up to 2023. It will concentrate on the most current important aspects and not cover comprehensively all areas of ZES or numerous areas in depth. For more in depth considerations the reader is referred to recent papers/reviews which cover ZES generally (6,33,38,40,46,49-54); its diagnosis (29,51,55-61), clinical features (24,25,41,62-69); acid hypersecretion (24,50,70-72); gastrin provocative testing and the diagnosis of hypergastrinemia (36,50,51,55,57,73-86); MEN1/ZES (30,44,47,57,64,85-96,96-102); medical treatment of acid hypersecretion (50,51,69,72,78,80,103-108);clinical course and prognosis (41,65,87,93,109-117); surgical treatment of the gastrinoma (6,44,50-52,80,92,95,96,99,100,102,103,118-128); imaging and tumor localization (37,50,90,112,124,125,129-141); treatment of advanced disease in ZES and other NENs (42,48,50,51,58,135,142-156); diagnosis and treatment of all/functional pNEN (24-26,34-36,36,48,48-50,54,58,148,156-165) and pathology, pathogenesis and classification of gastrinomas/NENs (9,50,58,86,96,117,158,166-174).

Before considering the diagnosis and management of ZES in more detail it is important to realize that there are a number of misconceptions about ZES, often because of comparison with other pNEN and these need to be kept in mind. They are listed in the Table 1 below and briefly discussed in the following sections.

Table 1. Widely Held Misconceptions About ZES

1) Gastrinomas, similar to a number of other pNEN (insulinomas, gastrinomas, PPomas), primarily occur in the pancreas. FACT: In recent studies, 60-100% of gastrinomas in both sporadic ZES and MEN1/ZES occur in the duodenum, with only 0-15% in the pancreas (6,43,50,95,102,127,175-179) (Table 2).

2) MEN1 is uncommon in ZES, similar to other pNEN such as insulinomas (3-5%), glucagonomas (<5%), PPomas/nonfunctional pNEN (<3%). FACT: MEN1 is found in the highest frequency of all pNEN syndromes in ZES patients occurring in 20-25% and is important to diagnose because of its different treatment aspects (30,50,64,72,87,89,95,102).

3) With the increased awareness of ZES and widespread availability of gastrin assays and sensitive imaging modalities, similar to some other pNEN, gastrinomas are being diagnosed earlier. FACT: The time of onset of symptoms to diagnosis of ZES remains 4-7 years (24,26,48,60,62,89,134) and a number of factors are contributing to make the diagnosis even more difficult (See point #4 below).

4) As recommended in all guidelines (9,72,80,152,157,180-182), similar to other functional pNEN syndromes (F-pNENs), ZES is currently diagnosed by demonstrating excess hormone production (fasting hypergastrinemia) in the presence of an unphysiological effect of the hormone hypersecretion (i.e., inappropriate acid hypersecretion (elevated basal acid output>15 mEq/hr., pH<2)) (9,50,51,55,56,59,70,72,73,79,181,183,184). FACT: In contrast to, for example, insulinomas, which are uniformly diagnosed by demonstrating fasting hyperinsulinemia with accompanying hypoglycemia (frequently during a fasting study) (29,50,185-188), in a recent review of the last 20 cases of ZES reported in the literature in 2018 (55), 95% of the diagnoses were reported without performing a gastric analysis or gastric pH assessment (55) and thus not using classical established criteria. This approach has complicated the diagnosis of ZES and the factors leading to this confusion will be discussed below in detail in the ZES diagnosis section.

5) In MEN1 patients, similar to other MEN1 patients with F-pNEN such as insulinomas and glucagonomas, most gastrinomas can be cured by nonaggressive surgical resections in MEN1/ZES patients. FACT: In contrast to other F-pNEN (29,157,189), the 5-year surgical cure rate of MEN1/ZES is <5% (6,30,43,44,88,190) without aggressive surgical resections such as Whipple resection, which are not recommended (6,9,88,92,93,118,123,157,180,182). However, without these resections, most patients with small tumors and adequate acid secretory control have an excellent prognosis, which has led to controversy in their treatment, and will be discussed in the surgical section later (30,43,47,92,93,95,102,118,157,180,182,191).

The misconceptions listed in Table 1 above as well as the factors specific to ZES that led to these misconceptions have led to controversies that are complicating numerous aspects of the management of ZES patients. These extend particularly to the current diagnosis of ZES, the management of both gastrinomas and nonfunctional pNENs in MEN1/ZES patients, and various aspects of the surgical management of these patients. Each of these will be discussed in more detail in the specific later sections in this chapter.

EPIDEMIOLOGY: ZES

PNEN account in different series for 1-10% of all pancreatic tumors with a prevalence of 1/100,000 and annual incidence of 1-4/million, which is increasing in frequency (192-194). In older series, insulinomas, gastrinomas, and NF-pNEN were reported with similar frequencies, however, in recent series of pNEN patients NF-pNEN make up 60-80% of all cases (24,48). Currently, for F-pNENs, insulinomas and gastrinomas are the most frequent, with incidences of 0.5-3/million in different series (26,50). Generally, insulinomas/gastrinomas are 8-10-fold more frequent than VIPomas, 17-fold more than glucagonomas, and >20 fold more the other F-pNENs (GRFomas, pancreatic ACTHomas, etc.) (26,50). Gastrinomas are the most frequent malignant F-pNEN, because 60-90% are malignant, like the other less common F-PNEN, in contrast to insulinomas, which are malignant in only 5-10% in most series (26,50,158,188).

Gastrinoma, as well as other pNENs, can occur both sporadically or as part of an inherited syndrome (30,158,195-197). Gastrinomas occur more frequently with an associated inherited pNEN syndrome than other F-pNEN, particularly in the case of MEN1, where 20-25% of all ZES patients have MEN1/ZES, compared to <3-5% of other F-pNEN syndromes (30,50,65,86,87,89). ZES is also rarely reported in other inherited syndromes associated with pNEN including the autosomal dominant syndromes, von Hippel –Lindau Disease (30,196,198,199), tuberous sclerosis (30,200), and neurofibromatosis type 1 and type 2 (30,199,201-204).

PATHOPHYSIOLOGY: CLINICAL FEATURES

In the majority of patients with ZES (>90%), the presenting symptoms are due to the marked gastric acid hypersecretion (24,28,62,64,70,205,206). Generally, only in patients with advanced disease late in the disease course are the prominent symptoms due to the tumor per se (abdominal pain, weight loss, anorexia, etc.) (24,28,40,62,205,206). The acid dependency of the above symptoms is shown by numerous studies reporting in a typical ZES patient, all of the presenting symptoms (including the PUD, pain, diarrhea, GERD symptoms, weight loss) disappear if the gastric acid hypersecretion is adequately controlled by any means (surgical, medical, acid aspiration) (7,27,28,40,103,106,207).

The ectopic release of gastrin by the gastrinoma is the direct cause of the gastric hypersecretion (49,170,208). In a typical ZES patient the fasting hypergastrinemia results in a markedly increased basal acid output (BAO) of approximately 4-fold (42-mEq/hr.) (70) and in some patients the BAO is increased more than >10-fold (27,28,70,206,209-212). Chronic hypergastrinemia also has trophic effects on the gastric mucosa, stimulating an increase in number of parietal cells and gastric enterochromaffin-like cells (ECL cells) (7,76,213-217) with the result the parietal cell mass is increased up to 4-6-times normal (27,76,218,219). This contributes to both the elevated BAO and increased maximal capacity to secrete acid, as shown by ZES patients having increased maximal acid outputs (MAOs) (27,70,76,212,219-221). Diarrhea which is seen in >70% of ZES patients (Table 3) in recent prospective studies is due to the effects of the gastric acid hypersecretion by causing structural damage to the small intestine, it interferes with fat transport; inactivates pancreatic lipase; can precipitate bile acids; and if prolonged, leads to steatorrhea (27,158,222).

Long-standing hypergastrinemia stimulates proliferation of the gastric enterochromaffin-like cells (ECL cells), which show such a response in ZES-patients (223). Gastric ECL cells are increased a mean of twofold in ZES (76,212,223-225). ZES patients can develop advanced ECL-proliferative responses, similar to the findings in animal studies of chronic hypergastrinemia induced by various methods, and which, in some cases, results in neoplastic changes (7,76,213,217,226,227). It has been proposed that with chronic hypergastrinemia, the ECL cells undergo a progressive hyperplasia-neoplasia sequence of events beginning with simple hyperplasia, followed by linear hyperplasia, micronodular hyperplasia, adenomatoid hyperplasia, dysplasia (pre-carcinoid) and finally the development of carcinoids (7,76,217,226,228). In the prospective NIH studies greater than 98% of ZES patients demonstrated ECL hyperplasia (217,227), with 50% having advanced changes with sporadic ZES (7% dysplasia) (217) and 53% with MEN1/ZES (2%-dysplasia) (227). In ZES, there is a close correlation between the degree of ECL hyperplasia and the fasting serum gastrin level (76,217,227). Even though advanced ECL proliferative changes are seen in both sporadic and MEN1/ZES-patients, they have a marked difference in the rate of occurrence of gastric carcinoids. Gastric carcinoids occur in 0-33% of MEN1/ZES-patients (76,227), and in the one perspective NIH study were found in 23% (87,224,227,229-231). However, gastric carcinoids rarely occur (<1%) in sporadic-ZES patients (212,217,232-234), and it has been estimated they occur at least with 70-fold greater frequency in MEN1/ZES-patients (227). An important finding of the prospective NIH studies of ZES patients is there was no threshold effect of fasting gastrin on ECL growth, as had been previously proposed, with any increase in FSG being associated with increased ECL proliferation (76,217,227).

PATHOLOGY AND TUMOR CLASSFICATION

In the past, gastrinomas were frequently reported as nonbeta islet cell tumors (1), because they were originally thought to originate in the pancreas from the islets and to generally be pancreatic in location, similar to insulinomas (1,51,185,205,235,236). They were reported to occur in the pancreas with a distribution of pancreatic head: body: tail of 4:1:4 (27,40,63,205,237,238). Later studies described a small percentage of duodenal gastrinomas (239,240). Currently, duodenal gastrinomas are found 2-10 times more frequently than pancreatic (Table 2) (43,64,95,102,175-177,241-245). Therefore, prior to the mid-1980s, 80-95% of gastrinomas were reported in the pancreas, whereas now 45-100% are duodenal, and 0-45% pancreatic (40,175-177,236,241-244). Even as late as 1998, in Soga’s review of 359 cases of ZES, only 11% of the patients had a duodenal gastrinoma (7,27,43,63,235).This likely occurred because of the analogies to insulinomas which are almost always in the pancreas, as well as the fact that duodenal tumors were being missed on preoperative localization studies or with a standard laparotomy because of their small size (Table 2) (27,43,175-177,241) and in many series no gastrinoma was found in a significant percentage of patients (7,27,28,40,63,235). Furthermore, a number of the early cases were patients with MEN1/ZES, and intra-pancreatic tumors were found (which were generally NF-pNEN) and these were attributed to be the source of the gastrin, with the true source being in a duodenal gastrinoma, which was not explored for or detected. Recent studies show that when careful attention is paid to the duodenum at surgery (duodenotomy, intraduodenal palpation, transillumination on occasion), more duodenal tumors were found (6,45,95,102,175,176,241-244,246-248). Primary gastrinomas are rarely found in other intra-abdominal sites: (particularly the ovary and liver/bile duct, as well as very uncommonly in the pylorus, spleen, mesentery, stomach, kidney) and in a few cases(<5 total) (<0.5%) in extra-abdominal locations, including the cardiac intraventricular spectrum and due to nonsmall cell lung cancer (Table 2) (40,45,109,110,121,126,176,236,249-265). A number of studies provide strong evidence that gastrinomas can arise in lymph nodes as the primary site, however, this is not universally accepted and some have proposed that they represent metastases from occult primaries (27,40,43,258,259,266-274). The possibility that a lymph node primary tumor may occur is supported by studies demonstrating long-term cure after resection of only a lymph node gastrinoma (40,258,259,267). Furthermore, in 3-25% of patients without pNEN, chromogranin-positive rests occur in abdominal lymph-nodes (266,275). In the NIH prospective series, 11% of patients are classified as having primary lymph node gastrinomas (Table 2).

At surgery, it has been recently emphasized that 60-90% of gastrinomas occur within the “gastrinoma-triangle”, which is an area formed by the junction of the cystic/common bile ducts posteriorly, the junction of the second/third parts of the duodenum inferiorly, and the junction of the pancreatic neck/body medially (40,176,177,244,276). This occurs primarily because of the high frequency of duodenal gastrinomas which are now found that fall into this area. Duodenal gastrinomas do not occur in equal proportion in all parts of the duodenum, but instead demonstrate a decreasing occurrence distally, with almost 90% of duodenal gastrinomas occurring in the 1^st/2^nd part of the duodenum (Table 2) (175,277,278).

In early studies, 60-90% of gastrinomas were associated with metastases (primarily lymph-node/liver) and therefore they should all be considered potentially malignant (9,39,205,236,257,279). The presence of metastases or gross invasion of normal tissue remains the only generally accepted criterion for the diagnosis of malignancy (27,40,280). Gastrinomas metastasize initially primarily to regional lymph nodes and the liver (27,109,236). Duodenal gastrinomas are characteristically small in size (Table 2), frequently <1 cm in diameter; however, they are associated with lymph node metastases in 47% of the cases in the NIH prospective studies (20-80%-literature), which is a similar percentage seen with the larger pancreatic gastrinomas (mean size 3.8 cm) (Table 2). From this data it has been proposed that gastrinomas in these two sites are equally malignant (109,110,175,281). However, from the NIH prospective studies it is also proposed that duodenal and pancreatic gastrinomas are not equally aggressive, because liver metastases occur in 52% of the NIH patients with a pancreatic gastrinoma (15-45%-literature) (Table 2), whereas liver metastases occur in only 5% of duodenal gastrinomas (10%-literature) (Table 2) (109,110,281). This is a similar rate to a recent collective series of 24 ZES cases with a duodenal gastrinoma in which 4 of the patients (16%) had liver metastases but 75% had lymph node metastases (282).Similarly in a recent review of 52 ZES patients(33-sporadic/19-MEN1/ZES) the rate of liver metastases was significantly lower in those with MEN1/ZES (21% vs 51%, p=0.031) (64). At presence the basis for this difference in aggressive behavior of pancreatic and duodenal gastrinomas is unclear. A genomic analysis (172) identified a number of molecular similarities and differences between duodenal gastrinomas and pNENs. In a comparison of RNA-seq data, duodenal gastrinomas and pancreatic pNENs shared 1233 common co-expressed transcripts, however duodenal gastrinomas expressed 909 distinct transcripts not seen in either normal duodenum or pancreatic pNENs and pancreatic pNENs had 588 unique transcripts not shared in normal pancreas or duodenal gastrinomas (172).The duodenal gastrinomas strongly expressed two inflammatory mediators (IL-17 and TGF-alpha), enrichment of mesenchymal, cytoskeletal, neuroactive-ligand receptor interaction, and calcium signaling pathway genes (64). In both duodenal and pancreatic neuroendocrine tumors alterations in expression of genes were found that were involved in cellular signaling cascades as well as in associated immune cells, and presence of proinflammatory cytokines, however it is unclear how these are related to the differences in biologic behavior of these two groups of NENs.

Duodenal gastrinomas in sporadic cases (75-80%) differ from those in MEN1/ZES patients in that they are usually solitary tumors, whereas in MEN1/ZES they are multicentric, smaller and multiple (64,178,283,284).

Duodenal gastrinomas account for 44-66% of all duodenal NENs (285,286), however only 58 % are associated with the development of ZES (286). In a recent study (286) the characteristics of sporadic duodenal gastrinomas associated with ZES (n=24) or not associated with ZES (n=17) were compared. The duodenal gastrinomas associated with ZES had a higher mean Ki-67(1.74 vs 0.85, p=0.012), more frequently had associated lymph node metastases (75 vs 6%, p=0.012), more frequently were associated with liver metastases and presented more frequently with TNM stage ≥III (75 vs 6%, p<0.0010). In a recent collective study of 108 sporadic ZES patients (127) in which 68 had duodenal gastrinomas and 19 pancreatic tumors, the overall 5-yr survival was 94% and not affected by gastrinoma location. However, pancreatic location was associated with higher recurrence rate (p=0.0001) (127).

In the past literature, approximately one-third of ZES patients presented with metastatic liver disease, approximately one-third with no tumor found and one-third with localized disease (Table 2) (27,40). Some recent studies suggest an increasing proportion are being seen with earlier disease stages, without advanced disease (40) (Table 2). For example, in the last 221 patients seen at the NIH, the majority (65%) at presentation had localized disease, and in the remaining 35% of the patients, they were divided between those with hepatic metastases and those with no primary tumor found (40,109,110) (Table 2). This distribution of gastrinoma extent differs from that reported in various surgical series, because not all ZES patients are included in these series with exclusion of all non-operated patients including those with patients with diffuse liver metastases, most with MEN1/ZES and those with contra-indications to surgery (9,43,181,287,288). In the last 155 patients undergoing surgical exploration at NIH, 85% had limited disease and the remaining 15% either had limited hepatic metastases (8%) or no tumor was found (7%) (40). In older studies, up to 50% of patients had no tumor found (Table 2), whereas at present, gastrinomas are more frequently found, as evidenced by the recent NIH data in which in the last 81 patients explored for possible cure at NIH, a gastrinoma was found in all (43). As pointed out above this difference is almost entirely due to the careful exploration of the duodenal area with a Kocher maneuver, duodenotomy, intraluminal palpation, and transillumination, (43,63,175,176,244,247,289). It is likely the detection rate of primary gastrinomas will increase even further with the recent development and widespread use of somatostatin receptor imaging (SRI), which has superior sensitivity to conventional cross-sectional imaging (129,133,134,136,137,139,153). SRI was initially performed with ¹¹¹Indium (diethylenediamine penta-acetic-D-phenylalanine-1) octreotide with single photon emission CT (SPECT) detection, but has now been replaced by⁶⁸Gallium DOTA (9,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid) labeled somatostatin analogues (generally ⁶⁸Ga-DOTATOC PET/CT) with positron-emission tomography detection because of its even greater sensitivity (129,134-137,139,153,290-293).

Distant, extrahepatic, metastases can occur with advanced gastrinomas (112,294-299). Metastases to bone are reported in 31% of ZES patients with advanced disease which occur primarily in the axial skeleton initially, however, they are uncommonly seen in ZES patients that do not have liver metastases (112,294,297,300). Their identification is important, because their detection frequently alters management (109,112,294,296,298,299).

Histologically, gastrinomas show the typical features of NENs, with cubical cells generally with few mitoses and having a granular, eosinophilic cytoplasm (236,280). They can demonstrate trabecular, gyriform or glandular morphology; however, no specific pattern is predictive of biologic behavior (27,235,280). Duodenal gastrinomas occur in the submucosa, frequently infiltrate the mucosa and in the case of tumors >1 cm, the muscular layer (236). Duodenal gastrinomas usually have proliferative rates <10%, whereas pancreatic gastrinomas frequently have higher proliferative rates (236,286). Both duodenal and pancreatic gastrinomas may demonstrate blood vessel invasion (236,280). Gastrinomas are usually identified as a NEN by their histological appearance and positivity with immunohistochemistry for the NEN markers (chromogranin A, synaptophysin) (27,236,280,301). Gastrin immunoreactivity (Gastrin-IR) can be detected in most gastrinomas (27,236,302,303) and approximately one-half produce multiple hormones (27,236,302,303).

Recently, it has been proposed that gastrinomas, as well as all pNEN/GI-NENs (carcinoid tumors), should have a common classification as NENs (166,168,304-306). Several classification systems (International Union for Cancer Control/American Joint Cancer Committee (UICC/AJCC), World Health Organization (WHO), European Neuroendocrine tumor Society (ENENs)) for both staging and grading NENs have been proposed recently, validated for pNEN, GI-NENs (carcinoids) and NENs (carcinoids) in other locations and recently updated (158,166,168,306-308). The use of these classification systems is essential to the management of NEN patients because they not only have overall prognostic significance, they also have predictive value for different treatment approaches and thus can dictate the treatment approach in some cases (115,115,116,116,158,166,167,306,308). These classification systems use primarily tumor size, extent, differentiation of the tumor and invasion for determination of stage (306). The grade of the tumor is determined by evaluating proliferative indices (Ki-67 and mitotic index (MI)) and the degree of differentiation of the tumor (well vs poor). NENs are divided into three grades based on the proliferative indices with Grade 1(G1) or low grade, having a Ki67<3%(MI <2 mitoses/10-HPF; Grade 2(G2) or intermediate grade having a Ki67>3-20%(MI-2-20/10 HPF), and high grade or Grade 3(G3) having a Ki67>20%(MI>20 mitosis/10 HPF) (115,116,158,166,167,306-309). Recently (WHO2017, 2019) Grade 3 was divided into two different groups depending on tumor differentiation with G3NEN having well differentiated tumor cells, and G3NEC (neuroendocrine cancer) having poorly differentiated tumor cells (115,116,158,166,167,306,308,310). Recent studies show G3NENs and G3NECs not only vary markedly in survival, but they also vary in their molecular pathogenesis and their treatment approaches (115,116,158,166,167,306,310,311). Proper classification of gastrinomas is essential, because recent studies demonstrate it has prognostic value and may affect the type of treatment recommended (115,116,304-306,312). Most gastrinomas are well-differentiated, pNEN Grade 1 or grade 2 (38,64,236,286). In one recent retrospective cohort study (64) (n=52), the grades of gastrinomas in patients with MEN1/ZES differed from those with sporadic ZES in having lower grade (G1: 83 % vs 39%; G2 (11% vs 54%) G3: (5.6% vs 6.1%), as well as being smaller in size (1.7 cm vs 3.1 cm). A review of 171 gastrinomas in various papers published up to 10/2020 in which tumor grade was reported, shows that 74% of the gastrinomas were grade 1, 22% were Grade 2 and only 4% were Grade 3(313). There is limited data on the correlation of tumor grade in ZES patients with survival. In one study (65)on univariate analysis in MEN1/ZES and sporadic ZES patients(n=37) the presence of grade 3 gastrinomas correlated with decreased survival (p=0.008), however not on multivariate analysis. In a recent review (127) of 108 patients with sporadic ZES, no predictive factors for survival, including tumor grade, were identified, however, for recurrence post- surgical resection, only tumor size (p=0.005) and tumor grade (p=0.01) were independent predictors of tumor recurrence. Two recent analyses (115,116) of prognostic factors in patients with any pNEN demonstrate that grade of the tumor was the most frequent significant prognostic factor cited in the studies analyzed both for overall survival and for disease free survival post-surgery (116) and in treatment of advanced resistant disease (115). These data would strongly suggest that the tumor grade of the gastrinoma in ZES patients will likely be a very important prognostic factor for assessing various aspects of long-term tumor behavior (survival/recurrence/aggressive growth).

Table 2. Characteristics of Gastrinomas (NIH Prospective Studies and Literature)

Characteristic

NIH Data (n=221)

Mean (range) Percent

Literature

Mean (range) Percent

Primary Location

Pancreas

Duodenum

Lymph node

Other ⁽¹⁾

Unknown

42 (0 – 70%)

15 (0 – 100%)

<1%

2 (0 – 18%)

30 (7 – 48%)

Duodenal Location

D-1

D-2

D-3

D-4

Percent Extent of Disease

No tumor found

Localized disease

Metastatic disease to liver

30 (7 – 50%)

36 (23 – 52%)

34 (13 – 54%)

Extent Metastases

Primary only

Primary + lymph nodes

Primary + liver metastases

Liver metastases only

Lymph node metastases only

32 (23 – 50%)

23 (8 – 61%)

32 (15 – 40%)

10 (4 – 15%)

11 (4 – 24)

Gastrinoma Size (cm)

Mean (largest)

Duodenal

Pancreatic

2 ± 0.2(0.1-4.8)

0.9 ±0.1(0.1-5)

4 ± 0.3 (0.5-7)

(1-6)

(0.2-5.5)

(0.5-10)

Metastases: Duo vs Pancreatic

Lymph node Metastases (%)

Duodenal

Pancreas

Liver Metastases (%)

Duodenal

Pancreas

(20-80%)

(up to 48% of patients had no primary 0-60%)

(15-45%)

Abbreviations: Duo-duodenal; D1-4-duodenal regions, 1,2,3,4;

Data are from (2,109,110,175,177,178,243,244,246,281,314-317).

(1) Other tumor locations include additional intra-abdominal sites (liver, bile duct, spleen pylorus, mesentery, ovary, lymph nodes) and very rarely extra-abdominal sites (heart, nonsmall cell lung cancer.

Tumors in a given patient in multiple locations can be monoclonal or polyclonal. In MEN1, multiple gastrinomas were reported to arise by independent clonal events in one study (318). A more recent study (114) which include 137 microscopic and macroscopic duodeno-pancreatic NENs and 36 matched metastases in 10 patients with MEN1 assessed tumoral ARX, PDX1, Ki67, gastrin expression and alternative lengthening of telomere. Most metastases (91%) originated from a single NET of origin, however, a few patients had likely multiple, metastatic primary NETS. In 6 patients with hypergastrinemia with MEN1, periduodeno-pancreatic lymph node metastases expressed gastrin and clustered with minute duodenal gastrinomas, not with larger pNEN. The pNEN frequently clustered with high grade or alternative lengthening of telomere positive primary tumors. It was concluded that in MEN-1 patients with ZES and pNEN a duodenal origin of the periduodeno-pancreatic lymph node metastases is likely even if preoperative localization studies do not reveal a duodenal tumor (114). Clonality (319) was analyzed in 20 sporadic gastrinomas from eight patients in whom the tumor was present in at least two separate sites. A combination of methods was used to assess clonality, including MEN1 gene mutation analysis, loss of heterozygosity analysis of the MEN1 locus, and analysis of X-chromosome inactivation at the human androgen receptor locus (human androgen receptor analysis). In three patients, a somatic MEN1 gene mutation was detected in the tumor. Identical mutations were found in other tumors at different sites within the same patients. Human androgen receptor analysis in three informative patients and loss of heterozygosity analysis in five patients revealed identical clonal patterns in the tumors from multiple sites in each patient. This study (319) concluded that sporadic gastrinomas at multiple sites are monoclonal and that MEN1 gene alterations in gastrinomas occur before the development of tumor metastases.

TUMOR BIOLOGY

Similar to other NENs, gastrinomas frequently synthesize (pancreatic polypeptide, insulin, glucagon, somatostatin) and also secrete multiple, gastrointestinal peptides as well as chromogranins, alpha-subunits of the glycoprotein hormones, and neuron-specific enolase (27,280,303,320-322). In one study (303) plasma levels of hormones other than gastrin are elevated in 62% of ZES-patients, with one additional hormone elevated in 44% and two in 18%. Motilin is the most common plasma hormone also elevated (30%), followed by human pancreatic polypeptide (27%), neurotensin (20%) and gastrin-releasing peptide (10%) (303). The occurrence of a second F-pNEN syndrome does occur in ZES patients (27,303,323,324) with cases of concomitant ZES and insulinoma (87,303,324-331),GRFomas (326,332,333), ectopic Cushing’s syndrome (66-68,113,325,334-345), glucagonomas (87,324,328,342,343,346-348), VIPoma (324,325), somatostatinomas (339,349), carcinoid syndrome (87,325,327,343,350) and PTHrPomas (351) all described. Even though secondary F-pNEN syndromes have been described in ZES, in general they are relatively infrequent, except for the development of Cushing’s syndrome in patients with advanced metastatic gastrinomas (66,68,109,113,325,336). In a prospective study from NIH of 45 ZES patients with a mean follow-up of 146 mos. from ZES, only one patient (2%) developed a second F-pNEN syndrome onset for a rate of 0.16%/yr (1% of patients every 6 yrs. of follow-up). This rate was considerably less than that reported in another study (352) of 353 patients with all pNEN(169=gastrinomas) in which 6.8% of all patients developed a secondary pNEN syndrome over a 19-mo. mean follow-up(rate=4.3%/yr.). Ectopic Cushing's syndrome has been more frequently reported in patients with ZES (27,113,334,336,345,353) as well as other pancreatic endocrine tumors (353-356). In a prospective study from the NIH (109) ectopic Cushing's syndrome developed in 4% of all patients with ZES studied (9/212), 17% (9/54) with liver metastases, 21% (7/33) dying of ZES-related causes and 25% (5/20) with bone metastases. It was an independent predictor of poor survival (p <0.005) with patients having a 10-year survival of 0%. Ectopic Cushing's syndrome only developed in patients with metastatic liver disease. Similar to bone metastases, development of ectopic Cushing's syndrome was a strong predictor of poor prognosis with patients only surviving a mean of 1.7+0.4 years after its onset (109).

The gastrin-gene covers a 4 kilobase area and consists of 3 exons and 2 introns, with the coding region translating into a 101-amino acid peptide, pre-progastrin (7,7,8,170,357,358). In normal antral G-cells, pre-progastrin undergoes a number of post-translational processing steps including dibasic cleavages, removal of the glycine extended COOH-terminal amino acids and sulfation, leading to the formation of progastrin, then COOH-terminal glycine-extended forms and finally the biologically active forms consisting of 2 COOH-amidated gastrins, gastrin-17 (G-17) and gastrin-34 (G-34), existing in sulfated and non-sulfated forms (7,8,170,357,358). Normally, >90% of antral gastrin is G-17, while in the duodenum only 40-50% is G-17(7,8,357,358). In the circulation, normal G34 is the predominant form (>60%) and sulfated/non-sulfated forms occur equally (7,8,357,358). In contrast, in patients with gastrinomas the relative concentrations of G-17 are higher (74-80%), and increased concentrations of partially processed forms are found (progastrin, NH₂- and COOH- terminal fragments, COOH-glycine extended fragments, incompletely amidated fragments) (7,8,27,357-360). Alterations in post-translational processing have been correlated with the presence of metastatic disease (7,8,27,359,360); however, no prospective studies have established their usefulness in an individual case (7) and they are currently rarely measured.

Chromogranin A (CgA) is a 48-kilodalton protein stored in secretory granules of neuroendocrine cells and is widely used as an immunocytochemical marker to identify tumors as NENs (27,236,280,301,322,361-364). CgA is released simultaneously with the release of polypeptides and thus can be used as a general plasma tumor marker for NENs (322,361-363,365-368). Plasma CgA levels are elevated in 80-100% of ZES patients, as is the case in patients with other pNEN/GI-NENs (carcinoids) (322,365-370). Changes in plasma CgA levels are reported to be useful for assessing changes in tumor mass in some studies; however, in other studies, including in patients with gastrinomas, it has been found to be a relatively insensitive marker for tumor progression and/or NEN identification (115,116,364-369,371-375). One major problem with using plasma CgA as a tumor marker in ZES patients is that the chronic hypergastrinemia causes gastric ECL cell proliferation which increases plasma CgA (24,362-364,368,376). Thus, in ZES, elevated plasma CgA can come from the gastrinoma or from hyperplastic ECL cells (24,377-379). Unfortunately, plasma CgA is also increased by inflammatory disorders, other endocrine diseases, the use of proton pump inhibitors, gastrointestinal disorders, cardiovascular disorders and altered renal function, and therefore minimally or moderately elevated plasma CgA levels in the range frequently seen with small gastrinomas/pNEN overlap with values found in these other disorders (361-364,368).

In patients with gastrinoma, a number of agents stimulate the release of gastrin including secretin (61,74,75,84,380-384), glucagon (385-387), bombesin/GRP (380,388), muscarinic cholinergic agonists (380), beta-adrenergic agonists(389), calcium (74,75,380,383,384,390) and a standard meal (74,384,391,392); in addition, native and synthetic somatostatin analogues (octreotide, lanreotide) can decrease serum gastrin (7,103,393-396). Studies demonstrate that gastrinomas possess secretin receptors, somatostatin receptors, bombesin/GRP receptors, and calcium-sensing receptors (380,388,397-401). These findings have been used clinically for ZES diagnosis with the development of secretin, calcium, glucagon and standard meal provocative tests and the use of somatostatin analogues to control acid hypersecretion (7,56,74,75,103,391,394). The clinical aspects of gastrin provocative testing will be discussed in a later section on ZES diagnosis. Currently, somatostatin analogues are uncommonly used to control acid hypersecretion in ZES patient, because they must be given parenterally, whereas effective long-acting, oral antisecretory agents such as PPIs are available and are the drugs of choice (29,103,142,151,181,182,396). Somatostatin analogues are used for their anti-growth effects or to control ectopic secretion of other hormones in gastrinoma patients, as in other F-pNEN (25,58,142,148,152,155,402,403), and this will be discussed in later sections. Furthermore, the presence of somatostatin receptors on gastrinomas, as well as on other pNEN/NENs, is used for tumor localization, as well as to deliver cytotoxic radiotherapy to patients with advanced tumors (51,129,133,134,136,137,139,142,185,404), both of which will be discussed later in the treatment sections.

The exact mechanisms by which secretin, calcium, glucagon, or a meal stimulate an increase, and somatostatin analogues a decrease, in serum gastrin in ZES patients is not completely clear (27,74,397). The most likely explanation is a direct effect on gastrin release from the gastrinoma through activation of specific receptors which are known to be present on these cells, although others have proposed (in the case of the secretin-test) that it is an exaggerated physiological response (397,405,406). The evidence for a direct effect is that presence of receptors for these agents which have been shown on gastrinomas. Furthermore, in dispersed/cultured gastrinoma cells, calcium and secretin stimulate gastrin release, and secretin activates adenylate-cyclase in these cells which stimulates gastrin release (380,393,397,399,407-409). whereas somatostatin causes inhibition (393,409). Also, a direct relationship has been shown between the magnitude of expression of secretin receptors on gastrinomas and the magnitude of the secretin-stimulated response in ZES patients (397).

The exact pathogenesis or cell-of-origin of pancreatic or duodenal gastrinomas remains unclear. As mentioned above, gastrinomas and other pNEN were frequently called islet cell tumors, however it is still controversial that those arising in the pancreas actually originate from pancreatic islets (410,411). Numerous older studies have reported that gastrin is found only in the fetal/developing pancreas in islet cells so if pancreatic gastrinomas arose from islets, the possible cell of origin was unclear (8,27,412-414). Passaro and colleagues proposed two different subpopulations of gastrinomas existed (414-416). One group occurred in the gastrinoma triangle (duodenum, pancreatic head, peri-duodenal lymph nodes), which were to the right of the superior mesenteric artery, which originated form the ventral pancreatic bud and were relatively more benign with frequent positive lymph nodes, low rate of liver metastases and high cure rate (414-417). In contrast, the second group occurred outside the gastrinoma triangle, were entirely within the pancreas, were to the left of the superior mesenteric artery, arose from the dorsal pancreatic bud, and were more aggressive with lower cure rates and liver frequency of liver metastases (414-417). Numerous studies support the conclusion that duodenal and pancreatic gastrinomas differ in biologic behavior (109,110,127,170,172,281,415,418-420). Furthermore, in numerous studies gastrin-producing G cells were found in the adult duodenum, but not in the adult pancreas; therefore, supporting the proposal that different cells-of-origin were likely for duodenal and pancreatic gastrinomas (27,40,412,413,418,419). This proposal is further supported by a study (420) which demonstrates that all 15 duodenal gastrinomas show sonic hedgehog expression with none showing expression of pancreatic-duodenal homeobox 1, whereas the reverse pattern was seen in 11 pancreatic gastrinomas. It has been suggested that gastrinomas in the gastrinoma triangle area originate from stem cells in the ventral pancreatic bud, and that these cells become dispersed in lymphoid and duodenal tissue and give rise to the gastrinomas in this area (414) Others have proposed that gastrinomas originate from multi-potential, endocrine- programmed stem cells that undergo inappropriate and incomplete differentiation toward the G-cell in the islets/pancreas (27,413,418). Although some recent studies propose that cancer stem cells, which have been described in a number of solid tumors, could also be important in the pathogenesis of pNEN or GI-NENs, at present they have not been convincingly identified and isolated in GEP-NEN pathologic samples (421). A recent detailed lineage tracing study of gastrin expressing cells in pancreas provides some of the strongest evidence that pancreatic gastrinomas in sporadic ZES cases may originate from the islets (412). In this study (412) during fetal stages up to postnatal day 7 gastrin expressing cells were abundant, whereas a small population of gastrin expressing cells existed in adult islets which co-expressed glucagon or insulin and the pancreatic gastrin positive cells were found to originate from PTF1a+ and neurogenin 3 expressing progenitors that were a subpopulation of alpha and beta cells. Furthermore, disruption of the MEN1 gene in the progenitor cells, resulted in the development of pancreatic gastrin-expressing tumors, but no animals developed ZES (412). Recent studies provide evidence that gastrinomas in MEN1/ZES may have different pathogenesis than sporadic gastrinomas and also the development of the duodenal gastrinomas and pancreatic tumors differ in these patients. In MEN1/ZES patients, it has been proposed that the duodenal gastrinomas arise from the G cells by a process of hyperplasia similar to proposed for the response of ECL cells to gastrin in the stomach (422,423). In MEN1/ZES patients, it is proposed that the pivotal event in the development of the multifocal gastrin neoplasms is the allelic deletion of the second MEN1 allele (422,424). However, this sequence was not seen in sporadic duodenal gastrinomas (422,424). Previous studies (424) have reported that in MEN1 gastrinomas only 46% of the tumors exhibited LOH at the MEN1 locus with the remaining 55% not exhibiting allelic loss of the MEN1 gene locus, despite having precursor lesions such as hyperplastic G cells in the crypt base or in Brunner’s glands, suggesting that mechanisms besides loss of the wild type MEN1 allele may be involved in the transition from G-cell hyperplasia to duodenal gastrinoma (425). Recent studies (170,173,174,426,427) using mice with targeted MEN1 deletion bred onto a somatostatin null background and treated with omeprazole to induce hypergastrinemia developed gastric carcinoids as well as hyperplastic gastrin-expressing cells in the lamina propria of the proximal duodenum expressing markers for enteric glial cells such as glial fibrillary acidic protein. Because in these experiments, the MEN1gene had been deleted from the epithelial cells, this suggested a possible non-cell autonomous mechanism was involved. This conclusion was supported by a study (427) reporting duodenal gastrinomas as well as their metastatic lymph nodes showed immunohistochemical staining for enteric glial cell markers, whereas it was not seen in pancreatic gastrinomas (170,174,427). From these findings the authors (170,174) proposed that duodenal gastrinomas in these patients may arise from a neural crest-derived cell and /or an endodermally derived epithelial cell.

For pancreatic pNEN in MEN1 patients, two studies have come to different conclusions, with one concluding that PETs arise from duct cells (411) and the other concluding that they arise from islet cells (422,428).

Important insights into the natural history and prognosis of the gastrinoma per se have been provide by a number of long-term studies of patients with or without MEN1 (64,87,89,93,109-111,258,314,315,429-434). In ZES patients without MEN1(sporadic ZES), 25% of their gastrinomas show aggressive growth behavior (109,110). Aggressive growth is associated with a decreased ten-year survival (30%) compared to the excellent survival in those with nonaggressive disease (10 yr.-survival=96%) (110). A similar aggressive growth pattern has been described in patients with MEN1/ZES; however, the percentages are different, with only 14% demonstrating aggressive growth (111). In the sporadic ZES patients, those with aggressive growth are characterized by more frequently having liver metastases, a pancreatic primary, a large primary (>3 cm), a short disease history, higher gastrin levels, female gender, and sporadic ZES (109,110). In general, patients with MEN1/ZES have a better prognosis than patients with sporadic ZES (110). Finally, long-term studies demonstrate that even in patients with liver metastases, their rate of tumor growth may markedly vary with 42% demonstrating rapid growth, 26% having no tumor growth and 32% demonstrating a slow growth over a three-year period (429). Deaths only occurred in the subgroup with rapid tumor growth (62% died during follow-up) (429). This result has important implications for treatment in gastrinomas as well as other NENs with a number of studies demonstrating the rate of tumor growth prior to treatment is an important prognostic predictor of patient’s survival, outcome and even response to different therapies (402,429,435-440).

MOLECULAR PATHOGENESIS

The molecular pathogenesis of gastrinomas, similar to other pNEN /NENs, differs from more common adenocarcinomas, but has remained largely unknown until recently (29,170,172,174,427,441-443,443-448). In contrast to many adenocarcinomas, mutations of common tumor suppressor genes (p53, retinoblastoma, etc.) and oncogenes (Ras, myc, jun, Src, etc.), are infrequent in gastrinomas and other pNEN (29,158,308,310,311,441,443,443,446,448-453). This is not the case with G3NECs, which are uncommon in gastrinomas (<5%), which have a higher mutation rate for p53, Rb and p16(158,310). Whereas mutations of common oncogenes or tumor suppressor genes are uncommon in pNEN, recent studies provide evidence that both the p53 pathway and the retinoblastoma (RB) pathway are frequently altered in pNEN (454-457). The Rb pathway is inactivated in most pNEN (including gastrinomas) (455) by amplification of genes encoding the cyclin-dependent kinases Cdk4/Cdk6. A second study (454) found a low rate of p53 mutations in pNEN (<3%); however, the p53 pathway was altered in 70% of pNEN through aberrant activation of its negative regulators- MDM2 (22%), MDDM4 (320%), and WIPI (15%). A third study found the p53 target gene PHLDA3 is frequently inactivated in pNEN and this correlates with tumor progression and poor prognosis (456,457)

As discussed above, gastrinomas, as well as other pNEN not only occur sporadically (75%-gastrinomas), but can also occur as part of various inherited syndromes (30,114,158,195,197,458,458-462), including MEN1, tuberous sclerosis, neurofibromatosis, von Recklinghausen’s disease and von Hippel-Lindau disease (VHL), and investigations of the altered genes in these diseases have provided insights into the molecular pathogenesis of pNEN (30,195,196,442,449). Approximately 20-25% of patients (Table 3) (27,30,87,89,463) with ZES have Multiple Endocrine Neoplasia type 1 syndrome (Wermer’s syndrome) (MEN1/ZES). MEN1 is an autosomal dominant disorder due to mutations in the MEN1 gene on the long arm of chromosome 11 (11q13). The MEN1 gene has 10-exons encoding for a 610 amino acid protein, MENIN (30,87,97,317,448,464). A recent sequencing study (446) showed in sporadic pNEN, MENIN is also important with 44% having an inactivating mutations of the Multiple Endocrine Neoplasia-type 1(MEN1) gene. Mutations in the MEN1 gene occur in one-third of sporadic gastrinomas (30,441,449,450,465). Furthermore, 5-95% of patients with sporadic pNEN have loss of heterozygosity (LOH) at the MEN1 locus(11q13) including in 44% of sporadic gastrinomas (30,318,463). These results strongly suggest alterations in MENIN are important in the pathogenesis of sporadic gastrinomas and in the inherited syndrome, MEN1. The exact molecular alteration that occurs with MENIN mutations that results in pNEN, including gastrinomas, is not clear. However, it is known that MENIN is a nuclear protein that interacts with a large number of proteins (30,98,463,464,466,467). MENIN interacts with SMAD3; RPA2(a DNA-processing-factor); the AP1-transcription factor, JunD; nuclear factor-B(NF-B), Pem, FANCD2 (a DNA-repair-factor), nucleoside diphosphate kinase, NM23 cytoskeletal-associated proteins and various histone-modifying enzymes (30,463,464,466,467). A recent large WGS study (443) of pNENs found an MEN1 mutation in 41% of the pNENs and altered copy number in 70% and concluded that MEN1 played a central core pathway role in pNENs molecular pathogenesis interacting with each of the key cascades found to be altered in these tumors. This included MEN1(443) interacting with altered key genes involved in DNA damage repair (MLH1-4, MSH5, etc.), chromatin modification (SETD2, MLL3, etc.), altered telomere length (DAXX, ATRX, etc.), mTOR signaling (PTEN, TSC1-2,etc), homologous recombination and double break repair(CHEK2, BRAC1,TP53, etc.) and cell cycle regulation(CDK2C, JNK, etc.).

In recent sequence studies(446) of pNENs was carried out, and it was found that in addition to alterations in the MEN1 gene in 21-100%% (443,446,448), mutations were found in frequently in genes encoding for two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated-protein) (25-40%) and ATRX (alpha-thalassemia/mental retardation syndrome X-linked) (18-35%), followed by mutations in mTor pathway genes (15-54%) (443,446,448). MEN1/DAXX/ATRX are important in the epigenetic landscape including DNA methylation, histone modifications, posttranscriptional regulation, and are thought to play important roles in the pathogenesis of pNEN (308,443,446,448,452). Recent studies provide evidence that pNEN are heterogeneous (308,447,452,468,469). The presence of the MEN1/DAXX/ATRX mutant phenotype, which is present in 60% of pNEN, has been reported to correlate with a worse prognosis (448,452,470-474). The MEN1/DAXX/ATRX mutant profile of pNEN is associated with an islet alpha-cell lineage pattern (high ARX, low PDX1, high HNF1A expression) and has a much worse recurrence free survival (470). Numerous recent studies in pNENs (114,444,445,475,476) including gastrinomas support the importance of the cell lineage (alpha cell, beta cell, intermediate pattern), as well as alterations in DAXX, ATRX, alternative lengthening of telomeres and MEN1 mutations as determinants and prognostic factors for identify patients with pNENs showing aggressive growth and cohorts associated with decreased survival.

The VHL locus occurs at 3p25, and chromosome 3 alterations are reported in 21-50% of sporadic pNEN (449,477). However, these chromosome 3 alterations are rarely associated with a mutation at the VHL locus, suggesting that it is not involved in pNEN development; however, a locus telomeric to the VHL locus may be involved. Recent studies provide evidence for the importance in pNEN/gastrinomas of alterations in the DPC4/SMAD gene (20% in pNEN), the p16/MTS1 tumor suppressor gene (50-90%), mTor/Akt/PI3K pathway, amplification of the HER-2/neu proto-oncogene, as well as increased expression of a number of growth factors and/or their receptors (platelet-derived growth factor, hepatocyte growth-factor, epidermal growth factor, insulin-like growth-factor 1) (441,442,449,450,478,479). Numerous recent studies provide evidence that the mTor/Akt/PI3K pathway is particularly important for mediating the growth of pNEN (478,479). This evidence includes the success of the mTOR inhibitor, everolimus, in extending disease-free survival in patients with advanced pNEN (480), but also studies showing the mTor/Akt/PI3K/ signaling cascade plays a central role in pNEN cell growth and proliferation (442,478,479,481). Additional evidence for the importance of the mTor/Akt/PI3K pathway comes from a study showing mutations in mTor pathway genes (15%) in sporadic pNEN (443,446) as well as from a study (482) reporting the effects of a single nucleotide polymorphism. Replacing arginine by glycine in codon 388 (R388)) of the fibroblast growth factor receptor 4 (FGF4) (482) diminishes the responsiveness to mTor inhibitors in pNEN, and its presence in pNEN is associated with advanced tumor stage and liver metastases.

Numerous chromosomal alterations have been identified in sporadic pNEN and accumulate with advancing stage and tumor progression (158,308,452). Comparative genomic hybridization (CGH) and genomic-wide allelotyping studies report that chromosomal gains/losses occur frequently in pNEN, including in gastrinomas, and that the distribution of these changes differs between GI-NENs (carcinoids) and pNEN, supporting the conclusion that they have a different pathogenesis (29,48,449-451). In pNEN, allelic losses occur most frequently at chromosomal locus 1p (25-75%), 1q (20-90%), 3p (40-95%), 11p (30-50%), 11q (30-70%) and 22q (40-95%) (441,449,450,478). With pNEN, chromosomal gains occur most frequently at 17q (10-55%), 7q (15-70%), and 4 q (33%) (441,449,450,478). A number of these alterations are associated with malignant behavior including deletions at chromosome 1, 3p, 6, 11q, 17p and 22p, and gains on chromosome 4, 7, 14q, Xp (441,449,450,478). Deletions are more frequently seen in the primary tumor and gains in the metastases (452). The commonly mutated genes in pancreatic cancer such as KRAS, TP53, p16/cdk2A and SMAD4 and not commonly mutated in pNEN (446,469).

Results have been reported from a number of studies in which pNEN were studied using microarrays to perform gene expression profiling (449,450,478,483-485). Results from 8 studies in pNEN have been summarized (478) and they demonstrate a wide variation in the number of genes up-regulated (45-668) or down-regulated (25-323). These studies and others (483,484,486) describe a number of gene alterations that correlate with prognosis, survival, and relapse, but it is not clear presently which gene changes are of most important in the molecular pathogenesis of the pNEN.

CLINICAL FEATURES AND PRESENTATION: ZES

ZES most frequently occurs between the ages of 35-65 with a mean age of 41 yrs. (range-41-53) (7,27,62,235) but is reported in both children (487,488,488-491) and the elderly (27,62,63,235). There is a slight male predominance and in most series 20-35% of cases occur as part of the MEN1 syndrome (Table 3) (30,62,87,88). The main presenting symptoms are summarized in Table 3. Abdominal pain remains the most prominent symptom (>70%), and it is most frequently due to the presence of a duodenal ulcer, with a lesser subset presenting with pain due to gastro-esophageal reflux disease (GERD 20-44%%) (62). Whereas, in the older literature the ulcer was frequently described as occurring in abnormal locations outside the duodenum or as multiple ulcers, at present, most ZES patients present with a typical duodenal ulcer that is indistinguishable form that seen in idiopathic peptic ulcer disease (27,28,62). Similarly, the pain at presentation is similar to that seen in patients with idiopathic gastro-esophageal peptic disease (28,62). Diarrhea was uncommonly reported in older series, however in more recent series it is present in more than one-half the patients, and in 9-20% of patients it is the principal or a prominent presenting feature (Table 3) (51,55,60,62,87,490,492-495). The diarrhea differs from that seen with VIPomas in that it is characteristically not large volume (<1 L/day) and is more characterized by increased frequency and mild steatorrhea, if it is present (28,62,222). The presence of the diarrhea is an important clinical clue that when associated with peptic ulcer disease, should suggest the diagnosis of ZES (9,24,28,51,55,59,62,181), and this will be discussed in more detail in a later section on diagnosis of ZES.

Table 3. Clinical Features of Patients with ZES
Feature	NIH data (n= 261)	Literature data (range)
INITIAL SYMPTOM (percentage)
Abdominal pain	75	26–98
Diarrhea	73	17–89
Heartburn	44	0–56
Nausea	30	8–37
Vomiting	25	26–51
Bleeding	24	8–75
Pain and bleeding	19	19–44
Pain and diarrhea	55	28–56
FINDINGS AT PRESENTATION
Prominent gastric folds	94%	(10-30%)
OTHER CLINICAL FEATURES
Gender (percentage male)	56	44–70
Mean age onset (years)	41	41–53
MEN1 present (percentage)	22	10–48
PAST CLINICAL FEATURES
History-confirmed peptic ulcer (percentage)	71	71–93
History of Esophageal stricture (percentage)	4	4–6
History of Abdominal perforation (percentage)	5	5–18

Note. NIH data are from 261 patients with ZES prospectively studied (62). Literature data are from 11 series (50,64). Abbreviations: ZES-Zollinger-Ellison syndrome, MEN1-Multiple Endocrine Neoplasia type 1, ND-no data

In the past before effective nonsurgical methods to control acid hypersecretion was available, many ZES patients with ZES developed severe complications of the gastric acid hypersecretion (1,28,205,235). These included severe peptic ulcer disease (with perforation or penetration, with or without fistula formation), bleeding (22-45%), strictures leading to gastric outlet obstruction) (up to 20%) or GERD complications (esophageal ulcers, strictures, ulcers, bleeding, Barrett’s, rarely perforation) (up to 20) (1,28,62,205,235,496,497). At present, because of the widespread off label antisecretory drug use, it is uncommon to have patients present with symptoms due to complications from advanced peptic ulcer disease /GERD (62,498-501). In the NIH prospective study (62), only 4% of the 261 ZES patients had a perforation due to a peptic ulcer disease and 5% had esophageal strictures, although 10% had duodenal scarring due to chronic peptic ulcer disease (Table 3). At present, while a duodenal ulcer is usually present at diagnosis, it is not advanced, with 18-65% having no ulcer present (27,62,205), although up to 91% have a history of peptic ulcer disease (Table 3).

The diarrhea is a consequence of the acid hypersecretion and not due directly to the hypergastrinemia per se, as shown in numerous studies which report any method that controls the acid hypersecretion (nasogastric section, medications, surgery), without changing the level of hypergastrinemia, all lead to a decrease or cessation of the diarrhea (9,28,55,62,222,502).

In early studies of ZES patients, gastroesophageal reflux disease (GERD) symptoms (i.e., heartburn, pain) were either uncommon or not reported, so that 7 early series of ZES patients reported before 1986, the GERD symptoms were reported to occur in only at 0-2% of all patients (62). More recent GERD symptoms are increasingly reported in series of ZES patients, with 44% of 261 ZES patients having GERD symptoms at presentation in the prospective NIH series(62), and 49-61% in other series in the recent literature (Table 3) (62,498,503). Other gastrointestinal symptoms such as nausea (30%) and vomiting (25%) as well as weight loss (17%) are not infrequent in ZES patients at presentation (Table 3). The cause of the weight loss can be multifactorial, including from effect of the gastric acid hypersecretion on intestinal absorption causing malabsorption, decreased appetite, or from advanced metastatic disease resulting in anorexia, pain or other symptoms (62). In most patients early in their disease course or without widespread metastatic disease, the weight loss is due to maldigestion and malabsorption (28,62,222).

Approximately 20-25% of patients (Table 3) (27,30,87,89,190,463) with ZES have Multiple Endocrine Neoplasia type 1 syndrome (Wermer’s syndrome) (MEN1/ZES) and these patients have a number of important differences including clinical presentation and disease course from patients with ZES without MEN1(sporadic ZES) (27,30,64,87,89,190,463). These aspects will be discussed in the next section.

MEN1/ZES-GENERAL AND CLINCIAL FEATURES

MEN1/ZES-General

As discussed above, MEN1 is an autosomal dominant disorder resulting from mutations in the MEN1 gene located on the long arm of chromosome 11 (11q13) (30,87,317,464). The MEN1 gene has 10-exons with 9-exons encoding for a 610 amino acid protein, MENIN (30,87,317,464). The exact molecular alteration that occurs with MENIN mutations that results in pNEN, including gastrinomas, is not clear.

MEN1 causes NENs and hyperplasia in multiple endocrine organs (Table 4) that classically includes: hyperparathyroidism due to multi-gland parathyroid hyperplasia; pancreatic NENs (nonfunctional pNEN>gastrinoma> insulinoma>>other) (Table 4); and pituitary adenomas (prolactinomas>ACTH-secreting>growth hormone-secreting) (Table 4) (30,87,463,504,505). Each may be associated with a functional syndrome. The most frequent pNEN is a nonfunctional pNEN (NF-pNEN) with 80-100% developing microscopic NF-pNEN; however, NF-pNEN cause symptoms in only 0-13% (30,87). Gastrinomas are the most frequent functional pNEN (mean 54%, range 20-61%) (62,87,463,505,506) (Table 3). In addition, classically, adrenal tumors (rarely functional) and thyroid disease can occur in <50%, and these patients have an increased incidence of carcinoid (stomach, lung, thymus) (Table 4). Recently it has become recognized that these patients can develop a number of other tumors including smooth muscle tumors (leiomyomas, leiomyosarcomas), CNS tumors (meningiomas, schwannomas, ependymomas); and skin tumors (angiofibromas> collagenomas >lipomas >melanoma) (Table 4).

As will be discussed in the separate sections below the presence of MEN1 in ZES patients is important to recognize because it affects all aspects of the disease including: the pathogenesis, the pathologic findings; the clinical presentation; the treatment approaches; the prognosis and the role of surgery; and the need for genetic counseling (9,30,64,87-89,93,181,190,463,505,507-509).

Table 4. Clinical Features of Multiple Endocrine Neoplasia - Type I (MEN1)
	Average Frequency (range) % of all patients
Hyperparathyroidism	97 (78-100)
Pancreatic Endocrine Tumors
Pancreatic endocrine tumors (panNENs)	81-100
Nonfunctional or PPomas	80-100 (microscopic) 0-13 (symptomatic)
Gastrinomas	54 (20-60)
Insulinomas	18 (7-30)
Glucagonomas	3 (1-8)
VIPomas	1 (1-15)
Somatostatinomas	0-1
GRFoma	<1
Pituitary Tumors	54-65 (15-100)
Prolactin-secreting	15-45
Growth-hormone secreting	6-20
Cushing's syndrome	16
Adrenal Tumors Cortical adenomas Hyperplasia, carcinoma (uncommon)	27-36 (symptoms<2%)
Thyroid Tumors- adenomas	0-10 (0-30) (<1% symptomatic)
Carcinoid Tumors
Gastric (ECLoma)	7-35 (symptomatic<5%)
Lung	0-8
Thymic	0-8
Skin Tumors	40-100
Angiofibromas> collagenomas> café-au-lai> macules> lipomas	88%>72>38>34(symptomatic<1%)
Smooth muscle tumors- Leiomyomas, leiomyosarcomas	1-8% (symptomatic<1%)
CNS tumors- Meningiomas>ependymomas, schwanomas	0-8%>0-1% (symptomatic<1%)

Data from references (27,30,87,89,257,463,505).

MEN1/ZES-Clinical Features

For the 20-25% of patients (Tables 4 and 5) (27,30,87,89,463) with ZES with the Multiple Endocrine Neoplasia type 1 syndrome (MEN1/ZES), the presentation of mild hyperparathyroidism is best detected by an assessment of plasma ionized calcium levels, combined with assessment of plasma parathormone levels using a more sensitive assay such as intact PTH-IRMA assays (87,510). In general, the clinical manifestations of ZES are largely similar to those of patients with sporadic and MEN1/ZES, although patients with MEN1/ZES tend to have diarrhea less frequently as one of the presenting symptoms (26% vs 53%) (511). A carefully taken clinical, personal, and family history of endocrinopathies can be particularly important in suspecting MEN1/ZES, because up to 75% have a family history of MEN1 (Table 4) and 24-42% have a personal history compatible with renal colic (30,87,89). The presence of the MEN1 can affect the manifestations of ZES and aspects of its presentation, which will be discussed in a later section dealing with the diagnosis of ZES. In one study (64) the delay in diagnosis of ZES was greater in MEN1/ZES patients than in sporadic cases (7.4 ± 4.9 yrs. vs 3.9 ± 0.2 yrs, p=0.022).

Table 5. Features of Patients with MEN1/ ZES
Feature	NIH Data (n=106) Mean (range)	Literature (range)
I. MEN1 Tumor/hyperplasia
Hyperparathyroidism	100 (94%)	88% (78-100%)
Pituitary disease	60%	31% (28-60%)
Adrenal abnormality	45%	13% (13-35%)
Other functional pNEN)	6%	15.7%
Smooth muscle tumor	7%	0.2%
Thyroid disease	6%	5% (3-25%)
CNS tumor (meningioma, etc.)	8%	<1%
Carcinoid Gastric Bronchial Thymic	30% 20% 8% 6%	6% 4% 2% 2%
Skin tumor Lipoma Melanoma Collagenoma Angiofibroma	5% 2% 72% 88%	3% <1% <1% <1%
II. Age/duration
Age (yrs. Age at study Age at onset ZES Age onset MEN1	51.2 ± 1.2 (23.8 – 80) 29.8 ± 1.1 (10.2 – 61) 34.7 ± 1.0 (12.1 – 61)	43.5 ± 0.5 (43-51) 36.6 ± 0.6 34.1 ± 0.5
Duration (yrs.) Of ZES Of MEN1	16.6 ± 0.9 (1.4 – 43) 21.5 ± 1.1 (1.4 – 58)	ND ND
III. Other MEN1 feature
Family History of MEN1	70%	76%
First MEN1 symptom Asymptomatic (screening) HPT ZES Pituitary other	5% 38% 45% 8% 2%	1.3% 38% 41% 12% 8%

Abbreviations: MEN1 = multiple endocrine neoplasia type-1; ZES = Zollinger-Ellison syndrome; HPT = hyperparathyroidism; NIH = National Institutes of Health; ND=no data

NIH data are from (27,62,87,227,512-514)

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Differential Diagnosis: When Should You Suspect ZES

Despite many articles on the diagnosis of ZES, the diagnosis is continuing to be delayed by 4-7 years from disease onset with no shortening occurring over the last few years (27,29,56,59,62,184,511), and in fact, numerous studies support the conclusion the diagnosis is becoming more difficult and may be delayed even further in the future (24,51,55,56,59,77,78,515-517). The diagnosis of ZES has historically been frequently missed and delayed, because ZES is an uncommon cause of PUD (1-3 new cases/million population/year), whereas idiopathic PUD is 1000-fold more frequent (2300 cases/ year /million) and their initial clinical manifestations can closely resemble each other (27,40,55,56,511,515). In the past when there was ineffective gastric antisecretory medications, ZES would often present with advanced, refractory peptic disease suggesting the diagnosis, however, at present, most patients present with a typical appearing duodenal ulcer, without complicated disease, as seen in patients with idiopathic PUD (28,40,511). This is occurring primarily because of the widespread available of potent gastric acid suppressant drugs (i.e., PPIs), which in conventional doses used to treat idiopathic GERD/PUD, also generally control the acid hypersecretion occurring in most ZES patients (70,105,518,519). The result of this change and others, are making the diagnosis more difficult primarily for two reasons: first, the widespread use of PPIs can both lead to a false negative diagnosis of ZES because the symptoms and acid secretion are well controlled on the PPI, as well as lead to a false-positive diagnosis of ZES because it can induce fasting hypergastrinemia (24,51,55,56,76-78,515,517). Secondly, there is an increasing unreliability of serum gastrin assays which are essential for the diagnosis of ZES (55,56,516,520-522). Each of these points will be discussed in detail later in this section.

A number of clinical/laboratory findings should suggest the diagnosis of ZES, and these are summarized in Table 6.

The presence of diarrhea with PUD is a particularly important clue to the possible presence of ZES, because in recent series when a history for diarrhea is careful sought it is present in >60% of ZES patients (Table 3,4,6). Conversely, in patients with idiopathic PUD/GERD, the occurrence of diarrhea is now uncommon, because the use of high doses of Mg containing antacids is now rare, which were a frequent cause of diarrhea in the past in patients with PUD/GERD (523,524).

Table 6. Findings That Should Suggest Possible Diagnosis of ZES

I. SYMPTOMS

A. Peptic ulcer disease or gastro-esophageal reflux disease (GERD) with:

diarrhea (>60%)

without H. pylori or use of NSAIDs (PUD) (10-50%)

with a long history of persistent or severe symptoms (i.e., >3 yrs.) (>50%)

with refractoriness to treatment

with a PUD complication (bleeding, perforation, penetration) (10-15%)

with a GERD complication (esophageal stricture, perforation, ulcer) (<5%)

with weight loss (15-20%)

with family history of PUD or GERD

with family history of endocrinopathy (esp. renal lithiasis, hyperparathyroidism)

B. Persistent diarrhea (50-80%) which is:

responsive to gastric acid antisecretory drug treatment (H₂-R, PPIs)

secretory

associated with abdominal pain (50-70%)

associated with malabsorption that is unexplained

unexplained

with esophageal disease/symptoms (40-70%)

not responding to specific treatments of diarrheal diseases

with weight loss (15%)

with history of endocrinopathies or peptic ulcer disease (25%)

with family history of endocrinopathies (esp. renal lithiasis, hyperparathyroidism)

II. SIGNS

Multiple peptic ulcers in unusual locations (<10%)

Gastric outlet obstruction due to peptic ulcer disease (PUD) (3-10%)

Esophageal stricture due to peptic ulcer disease (3-5%)

PUD/GERD with findings of endocrinopathy or with MEN1-related tumors

Prominent gastric folds on UGI endoscopy/Imaging (94%)

III. LABORATORY/RADIOLOGY FINDINGS

PUD/GERD/unexplained diarrhea with:

Hypergastrinemia

Hypercalcemia

Positive somatostatin receptor imaging

Positive pancreatic mass

Numbers in parenthesis refer to percentage of ZES patients with these features. Table prepared from data in ref. (56,62,73,87,89,133,512,525).

Furthermore, in any patient with chronic diarrhea without an evident cause, especially if it is fasting in nature, ZES should be suspected (Tables 3,4,6) (60,62,63,87,183,222,490,492-494,498).

In idiopathic PUD, H. pylori infection (>80%) or the widespread use of NSAID/aspirin are a frequent contributing factor, whereas they are frequently not present in ZES patients with a duodenal ulcer (approximately 50%), thus the lack of their presence should raise the possibility of ZES (60,80,526-531). Although less common than in the past, any patient with severe PUD/GERD or with a PUD/GERD complication (stricture, obstruction, perforation, bleeding, penetration), ZES should be suspected (Tables 3,5,6). Because of the frequent occurrence of MEN1 in ZES patients (20-25%) (Table 5), any patient with PUD/GERD/unexplained diarrhea with a personal or family history of an endocrinopathy or a laboratory finding suggesting an endocrinopathy (especially hyperparathyroidism, renal stones, pituitary disease) should lead to suspicion of ZES (Tables 4,5,6). An unappreciated finding that was not emphasized in the past, but which recent studies show is present in up to 94% of ZES patients is the presence of prominent gastric folds on upper gastrointestinal endoscopy or imaging studies (Table 3) (62).

Establishing ZES Diagnosis

If ZES is suspected, a fasting serum gastrin level (FSG) is generally the initial study performed (9,29,55,56,59,182,184). FSG levels are elevated in almost all patients with ZES (>99%), except in some unusual circumstances, such as post-parathyroidectomy in MEN1/ZES or post-noncurative gastrinoma resection (73,74,190,498,508,509,511,532-534). Because of its high sensitivity, the assessment of FSG is an excellent screening test (40,56,498). However, an elevation of FSG alone has a low specificity for establishing the diagnosis of ZES, and no matter how high the FSG level, is not sufficient for a ZES diagnosis (29,40,51,55,56,59,184,498). Many physicians assume that a very high level of FSG (>10-100-fold elevated) is indicative of ZES; however, similar magnitudes of elevation in FSG levels can occur in patients with chronic atrophic gastritis/pernicious anemia, renal failure or those taking PPIs (55,56). For example, FSG levels 10-20-fold elevated are not uncommon in patients with chronic atrophic gastritis (367,535-537). Furthermore, in patients without ZES taking PPIs, although hypergastrinemia is frequent seen (see next paragraph) (80-100%), the FSG is usually increased<3-fold, although in some patients it is increased >10-fold (55,56,59,76,78,376,515,538-543).

Hypergastrinemia can either be physiological which develops as a physiological response to anything causing chronic hypo-/achlorhydria or it may be pathological or inappropriate which occurs in the presence of normal or even elevated gastric acid secretion, which would physiologically suppress gastrin release (Table 7). In humans the disorders causing physiological hypergastrinemia are due to CAG/pernicious anemia, use of PPIs, or H. pylori infections, which are much more frequent than ZES, and thus need to be excluded as a cause of the hypergastrinemia to establish a firm diagnosis of ZES.

Table 7. Causes of Chronic Hypergastrinemia

A. Associated with gastric acid hyposecretion/achlorhydria

Chronic atrophic gastritis (CAG)

Pernicious anemia

Treatment with potent gastric acid antisecretory agents (especially PPIs/uncommonly-H₂-R)

H. pylori infections

Chronic renal failure

Post acid-reducing surgery/vagotomy

Inherited inactivating mutations in H⁺K⁺ATPase (1)

B. Associated with gastric acid hypersecretion

H. pylori infections

Antral G cell hyperfunction/hyperplasia

Gastric outlet obstruction

Chronic renal failure

Short bowel syndrome (rare)

Retained gastric antrum syndrome (rare)

ZES

1)-includes ATP4R mutations encoding for the alpha subunit of H⁺K⁺ATPase (544-547)

Therefore, historically, the next study generally recommended in a patient in whom fasting hypergastrinemia was detected and the possibility of ZES was being considered, was an assessment of gastric pH or fasting basal gastric secretory output (9,27,29,55,56,59,72,76,181,182,185,548). Gastric secretory rates are now rarely measured (55,70,72,105) and are available in only a few specialty centers and thus will be discussed briefly below for completeness. If the patient has fasting hypergastrinemia with a gastric pH≤2, ZES should be strongly suspected (55,59,70,73), as summarized in Table 8, because an NIH ZES study found that all ZES patients off of any antisecretory drug had a fasting gastric pH≤2 (70). As shown in Table 8 the diagnosis is established in the group with FSG increased>10-fold combined with gastric pH≤2. However, in the 60% of patients with FSG<10 fold elevated, the diagnosis is strongly suspected but not proven, because there are a number of other diseases (majority=rare) which can also cause these findings that are not ZES which are listed in Table 7 (51,55,56,59,73,74,76).

Table 8. Established and Recently Proposed (untested) Criteria for the Diagnosis of ZES

I. Established Criteria for diagnosis of ZES

Required all: Fasting serum hypergastrinemia (FSG) and gastric fluid pH≤2.

1. If FSG> 10 times elevated (over ULN) and gastric pH≤2, the diagnosis of ZES is established (exclude retained antrum almost always by history) (40% of ZES patients)

2. If FSG is <10 fold elevated and gastric pH≤2, need to perform additional testing to exclude other causes of FSG/ hyperchlorhydria) (60%)

a. Secretin test positive (≥120 pg/ml increase)

b. Elevated basal acid output (>15 mEq/Hr)

II. Possible new criteria for diagnosing ZES in patients with Fasting Hypergastrinemia in the absence of PPI therapy (gastric pH data not available) (Proposed; not evaluated or/and should not be routinely used)

A. Strongly supportive of ZES diagnosis

1. Active peptic ulcer disease (PUD) or a history compatible with recent PUD or improvement in diarrhea with PPIs combined with:

a. a positive somatostatin receptor scintigraphy imaging (SRI) with either 68Ga-DOTATATE PET/CT or 111In-DTPA-octreotide with SPECT/CT imaging.

b. a positive biopsy or cytology for a neuroendocrine tumor (NEN) (stronger support if a gastrinoma is found)

c. a positive secretin test.

d. known or strongly suspected MEN1 syndrome (i.e., a positive family history, hyperparathyroidism, or pituitary disease)

2. A patient with known MEN1 or strongly suspected MEN1 (i.e., a positive family history, hyperparathyroidism, or pituitary disease) with a positive gastrinoma by cytology/biopsy

B. Moderately supportive of ZES diagnosis (consider this a tentative diagnosis)

1. Positive somatostatin receptor scintigraphy imaging (SRI) with either 68Ga-DOTATATE PET/CT or 111In-DTPA-octreotide with SPECT/CT imaging (sporadic disease only) or positive cytology or biopsy for a NEN, ideally a gastrinoma, (sporadic disease or MEN1 syndrome present) with a biopsy-proven absence of atrophic gastritis and negative autoimmune markers. (1,2)

C. Weakly supportive of ZES diagnosis (insufficient alone for even a tentative diagnosis)

1. A patient with known MEN1 or strongly suspected MEN1 (i.e., a positive family history, hyperparathyroidism, or pituitary disease) with positive imaging or an SRI (1)

2. MEN1 syndrome absent but positive SRI or imaging for possible tumor (3).

III. Possible new criteria supporting the diagnosis of ZES in patients with Fasting Hypergastrinemia taking PPIs (4) (gastric pH data not available) (Proposed; not evaluated or and should not be routinely used)

A. Moderately supportive of ZES diagnosis (ZES is likely)

1. In a patient with or without MEN1 with active peptic ulcer disease (PUD) or a history compatible with recent PUD or improvement in diarrhea with PPIs combined with a positive biopsy or cytology for a neuroendocrine tumor (NEN) (stronger support if a gastrinoma is found.

2. In a patient without MEN1 with active peptic ulcer disease (PUD) or a history compatible with recent PUD or improvement in diarrhea with PPIs combined with

a positive somatostatin receptor scintigraphy imaging (SRI) with either 68Ga-DOTATATE PET/CT or 111In-DTPA-octreotide with SPECT/CT imaging. (5)

B. Weakly supportive of ZES diagnosis (consider this a tentative diagnosis)

1. In a patient without active PUD or history of diarrhea responding to PPIs without MEN1 with a biopsy-proven absence of atrophic gastritis and negative autoimmune markers with a positive SRI (6,7)

2. In a patient without active PUD or history of diarrhea responding to PPIs with known MEN1 or strongly suspected MEN1 (i.e., a positive family history, hyperparathyroidism, or pituitary disease) with a biopsy-proven absence of atrophic gastritis. (6) and negative autoimmune markers. (7)

C. Minimally supportive of ZES diagnosis (consider this a possible diagnosis only)

1. In a patient without active PUD or history of diarrhea responding to PPIs without MEN1 with a positive SRI

2. A patient with known MEN1 or strongly suspected MEN1 (i.e., a positive family history, hyperparathyroidism, or pituitary disease) without active PUD or history of diarrhea responding to PPIs with prominent gastric folds (8).

Part II and part III are from (55), Part I data from (55,73,74)

⁽¹⁾ Under such conditions a NEN is confirmed but since MEN1 patients develop multiple NENs in various locations NEN(s) identified on SRI may not be a gastrinoma(s) (30,89,90,549).

⁽²⁾ Five biopsies (2-antrum, 2-corpus,1- incisura angularis) of the stomach are recommended to diagnose atrophic gastritis) (550,551).

⁽³⁾ SRI can be positive in nonngastrinoma NENs, numerous other tumors and both physiological and pharmacologic processes, so alone is not specific for gastrinoma (134,401,552).

⁽⁴⁾ The potential for a false-positive secretin test in patients with hypo-/achlorhydria limits the usefulness of the secretin test in patients taking PPIs unless the gastric pH≤2.

⁽⁵⁾ Under these conditions a NEN is likely but since MEN1 patients develop multiple NENs in various locations NEN(s) a positive SRI or biopsy may not be a gastrinoma(s) (30,89,90,549)

⁽⁶⁾ Five biopsies (2-antrum, 2-corpus,1- incisura angularis) of the stomach are recommended to diagnose atrophic gastritis) (550,551).

⁽⁷⁾ Biopsy and autoimmune markers can both be negative in confirmed autoimmune gastropathy (550,551).

⁽⁸⁾ Prominent gastric folds are present in 94% of ZES patients when initially seen, however they are not specific for ZES (62)

Abbreviations: ULN-upper limit of normal; FSG-fasting serum gastrin level; CAG-chronic atrophic gastritis, PPI-proton pump inhibitor; PUD-peptic ulcer disease; SRI-somatostatin imaging

The increased widespread use of PPIs has made the diagnosis of ZES more difficult (51,55,56,59,78,185). PPIs are potent gastric acid suppressants and because of their long durations of action (up to one week) (40,55,553-556) they induce hypergastrinemia in 80-100% of normal (55,56,59,78,184,376,515,538-543). The hypergastrinemia with PPIs develops rapidly (within 5 days); is a common finding among patients even without gastroesophageal disease since these agents are widely prescribed; are now available as over-the-counter medications; and are one of the most over-prescribed medications (185). The degree of hypergastrinemia is variable among PPI users, however in >20% of those taking PPIs in some studies the FSG increased >4-fold, and FSG levels>5-fold are not infrequent, with FSG levels even exceeding >10-fold increased have been reported (55,56,59,78,376,515,538-543). Furthermore, in contrast to H₂R antagonists (cimetidine, ranitidine, nizatidine, famotidine), PPIs control symptoms in most ZES patients at conventional doses used in the treatment of idiopathic PUD/GERD (103,518,519,557-559), whereas with H₂R antagonists, higher doses and/or more frequent dosing are usually needed than used to treat the typical patient with idiopathic GERD/PUD (40,72,103-106,559-562). In the past, ZES patients treated with conventional doses of H₂R antagonists continued to have symptoms suggesting the diagnosis, whereas this is not the case with PPIs (56,56,59,515). Therefore, PPIs both mask and delay the diagnosis of ZES because of their effective symptom control at conventional doses and they also complicate the diagnosis of ZES by their ability to cause a false suspicion for ZES by inducing hypergastrinemia in normal subjects (56,515). However, the characteristic of PPIs which has most complicated the ability to diagnose ZES is their long duration of action which makes it difficult to take patients off the PPI, especially if ZES is present and can lead to complications (25,51,55,57,59,77,78,563) as will be discussed below.

If the gastric fluid is sampled in a patient with an elevated FSG while the patient is being treated with a PPI, and the gastric pH is >2 it is not possible with this information alone, to determine whether the hypergastrinemia is physiological or pathological. To resolve this problem, both historically and in the more recent American NANETs and European ENETs guidelines, as well as recommendation by experts for the diagnosis of ZES, it was recommended to stop the PPI for up to one week and then determining gastric pH and FSG (7,9,27,55,78,79,103,181,182,235,517,564). This approach should be performed with caution (25,55-57,59,77,520). In each of the above guidelines, it is pointed that this must be performed only after taking a careful history of the prior effects of stopping the PPIs, that high-dose H₂R antagonists be substituted for the PPI (equivalent to ranitidine-300-600-every 4-6 hours), and this only be performed after it is established that acute PUD/GERD lesions are healed and the patient can be carefully followed during this time (55,56,59,77,520). After 5-7 days, the H₂R can be stopped, antacids used and on the following day the repeat testing performed. A recent study (77) reported two patients with ZES who developed severe PUD/GERD complications when PPIs were suddenly stopped and recommended the diagnosis of ZES should be established by not stopping the PPI. A number of subsequently papers (55,56,59) have pointed out that it may be possible in some patients to decrease the dose/frequency of PPI to obtain gastric pH≤2 or use other findings (presence of gastrinoma) to establish the diagnosis; however, in most cases this will not be possible. The only established criteria, which usually require discontinuation of PPIs, are listed in Table 8 (Part I). Because of the potential risk in a patient who does have ZES, it has been recommended that in a patient suspected of having ZES on PPIs, that the trial off PPIs in such a patient is best performed at experienced centers (9,55,56,181,565).

In the past, gastric acid secretory studies were performed in most centers and the results used for ZES diagnosis. A study of gastric acid secretory results in 234 NIH ZES patients and 984 ZES patients from the literature reported study found that most ZES patients without previous gastric acid-reducing surgery have elevated basal and maximal acid outputs (BAO, MAO) with a mean BAO=42mEq/hr (normal<10 mEq/hr) and mean MAO=62.7 mEq/hr. (normal 48 mEq/hr. (men)/ 30 mEq/hr. (women) (70). In this study various levels of BAO, MAO, BAO/MAO ratios as well as basal gastric fluid volume and basal/maximal acid concentration or pH were proposed to identify ZES patients (70). A number of these secretory criteria had high sensitivity for identifying ZES patients with the commonly used BAO criteria of ≥15 mEq/hr. (no previous gastric surgery) or ≥5 mEq/hr (with previous gastric surgery) having a sensitivity of 87-90% and 81-100%, respectively (70). However, gastric acid secretion studies are now performed by very few centers, and thus not generally available, so these secretory criteria are no longer used. However, the above NIH study (70) demonstrated that >99% of ZES had a fasting gastric pH ≤2 off antisecretory drugs; therefore, this is a useful criterion that can be applied widely today. A recent study (566) described the validity of measuring gastric pH at the time of gastrointestinal endoscopy in ZES patients, so this criterion can be generally applied (70).

In a patient suspected of having ZES, who is found to have a FSG level >10-fold elevated and a gastric pH≤2 (which in 40% of ZES patients), the diagnosis is established without further testing (Table 8 (part I)), if the possibility of a retained antrum syndrome, which can mimic ZES (Table 7), has been ruled out by previous history/records (27,552,567). Unfortunately, most ZES patients (60%) present with a FSG<10-fold elevated (27,73,75,212) and are found to have a gastric-pH ≤2, which overlaps with a number of other disorders that can cause hyperchlorhydria with hypergastrinemia (Table 7, 8 (part b)) (7,28,81,105,134,183,184,527). The most frequent of this group are patients with H. pylori infection, which is most frequently thought to be associated with acid hyposecretion, but which can also result in hyperchlorhydria with hypergastrinemia (485,527,568,569), and may thus be particularly confusing. To exclude these other disorders (Table 7,8 (part b)) it is now recommended that a BAO and a secretin provocative test be performed (Table 8 (part b)). In the past, a number of gastrin provocative tests were reported to help identity the patients with ZES, which included tests using secretin (27,28,74,75,381,384,570), calcium (28,40,74,75,384,390,390,570) or a standard meal (27,28,74,384,391). The secretin/calcium tests were based on the finding that these agents stimulated an increase in serum gastrin in ZES patients compared to normal subjects (381,390), while with the standard meal test, ZES patients generally show <100%-increase in serum gastrin (74,384,391), whereas patients with antral G-cell hyperfunction/hyperplasia have an augmented and much larger response (74,384,391,571). At present, only the secretin test is widely used because of its convenience, sensitivity, specificity, and lack of side effects (33,61,74,83). A NIH study of 293 ZES patients (NIH) and 537 ZES cases(literature) (74) demonstrated that a value of 120 pg/mL increase with secretin had a sensitivity of 94% and specificity of 100% for ZES (74), and was more sensitive than previously proposed criteria of increases of 200 pg/ml, 50% over basal or 110 pg./ml (75,382,384,570), and therefore is the criterion recommended today (29,84,181,182). In some countries, secretin is not available, and a glucagon stimulation test has been proposed as an alternative (572); however, there is much less experience with the glucagon stimulation test. Unfortunately, the secretin tests results can be affected by PPI-inducted hypo/achlorhydria or by the presence of hypo/achlorhydria for other reasons; therefore, it cannot be reliably performed while the patient is taking PPIs or is hypo- or achlorhydric (573,574).

The availability of a reliable serum/plasma gastrin-assay is essential in all phases of the diagnostic evaluation of a patient with possible ZES. Unfortunately, a recent study (516) examined the accuracy of 12 widely used commercial assays for FSG assessment used by laboratories in both the US and Europe demonstrated and reported that only 5 assays reliably measured gastrin concentrations, with the others either overestimating or under-estimating the true value. Hence, 7 assays produced FSG values that could lead to false diagnoses or missed diagnoses (56,516,521). The inaccuracy occurred because inadequately characterized antibodies were used that either recognized precursor/inactive fragments or did not interact with all biologically active forms. The lack of a reliable FSG assay invalidates both the assessment of the FSG levels and the results of the secretin test. This is a potential major problem, and the best approach is to check to see if the laboratory performing the FSG assay for your patients uses one of the 5 reliable gastrin-assays listed in this paper or to obtain advice from a center that routinely performs FSG studies in your area for the assay they recommend. A recent study (82) reports a rapid method to measure serum G17 an G34 using liquid chromatography-tandem mass spectroscopy which might prove useful to circumvent the above problems using RIA’s.

A recent study (55) pointed out in regular practice the criteria that most physicians are using to make the diagnosis of ZES are not those outlined above. This report (55) for the first time proposing new criteria which would support the diagnosis of ZES that did not involve the assessment of gastric pH, because it was found that in the last 20 cases of ZES reported in the literature, in only 5% (1/20) was an assessment of gastric acidity used in establishing the proposed ZES diagnosis of the cases reported in these studies. This has occurred primarily because of the difficulty physicians are having in assessing the gastric fluid acidity in these patients. The failure to measure gastric acidity in newly selected patients is due to a number of different contributing factors. First, ln almost all community as well as many university hospitals, the assessment of gastric acid acidity is complicated by the general lack of its availability and the widespread use of PPIs. Secondly the vast majority of newly diagnosed ZES patients when the diagnosis is first suspected, the patients are almost all being treated with PPIs. As discussed above, these drugs have a long duration of action (up to 1 week), making it is difficult to assess the unsuppressed gastric acidity which can only be done by stopping the PPI for up to one week (40,55,70,74,75,254,553,555,556) which makes it difficult to take patients off the PPI. Third, because in a patient who has ZES, this approach is not without potential risk (51,55-57,59,77) and must be performed under control conditions, often using high doses of histamine H₂ receptor antagonists, hence it is uncommonly performed. Although many current reports use the presence of an elevated FSG in combination with a positive SRI study to make the diagnosis of ZES (55), unfortunately, this is not specific for ZES, as patients can be achlorhydric/hypochlorhydria and have a non-gastrinoma neuroendocrine tumor that will be positive on SRI, and thus not have ZES. Furthermore, some propose the use of provocative test on PPIs to circumvent the need to stop the PPI to assess gastric pH (55), however a number of studies (573,574), but not all (61)conclude this is not a reliable alternative as the secretin test results are not reliable in a patient taking PPIs which frequently cause achlorhydria/marked hypochlorhydria which causes unreliable results (573,574). In a recent study (61) this conclusion has been challenged, because in 28 patients taking PPIs, no false positive or false negative secretin tests occurred and the sensitivity, specificity and positive predictive values for the secretin test were the same in patients taking or not taking PPIs.

It is important to remember that the new criteria (55) have been proposed to support the diagnosis of ZES, have not been widely evaluated and are not as strong as the classical criteria requiring increased FSG and gastric pH<2. These criteria were only proposed because 95% of physicians are not using the established criteria for the diagnosis of ZES (Table 8 (Part I)), and it is not apparent this practice will be reversed in the future. At present, it is best to refer these patients to a center that has expertise in the diagnosis of ZES to firmly establish the diagnosis by the established criteria. This is importance because it will dictate the course of management acutely and long term in the patient if ZES is present or not present (9,50,55).

TUMOR LOCALIZATION: ASSESSMENT OF PRIMARY LOCATION AND DISEASE

An assessment of both the primary tumor location and the tumor extent by various tumor localization modalities is needed at all steps in the management of ZES patients, similar to patients with other malignant NENS (9,27,29,33,53,135,140,140,142,181,575-582). It is initial needed in ZES patients to determine whether surgery should be considered and if so, to determine the extent of surgery; to determine the location, extent and in some cases the rate of growth of metastatic disease prior to any anti-tumor treatment; to assess in MEN1 patients the possible presence of extra-duodenal-pancreatic NENs, such as carcinoid tumors (especially of the lung/thymus); to assess post-resection status; and to assess changes in tumor load with antitumor therapies or extent of recurrence, with time (9,27,29,33,53,129,135,140,140,142,142,181,291,575-578,578,579,579-582). Generally, more than one imaging modalities is used in different patients with the most frequent cross-sectional imaging study being a being a triphasic CT scan with intravenous contrast. In the case of SRI, in the past primarily somatostatin receptor scintigraphy (SRS) using ¹¹¹Indium-labeled somatostatin analogues with SPECT imaging was used (141,582). But now in most centers it is replaced by the use of SRI with ⁶⁸Gallium-labeled somatostatin analogues with positron emission tomographic imaging (PET-scanning) (45,129,134-137,139,141,157,291,293,578,582).

A wide range of different imaging modalities have been used in the evaluation of ZES patients (Table 9) (9,130,134,135,141,291,293,576,582,583). These include cross-sectional imaging (CT scanning, magnetic-resonance imaging (MRI), transabdominal ultrasound); selective angiography; somatostatin receptor scintigraphy (SRS) using ¹¹¹Indium-labeled somatostatin analogues with SPECT imaging or ⁶⁸Gallium-labeled somatostatin analogues with positron emission tomographic imaging (PET-scanning); endoscopic ultrasound (EUS); and the assessment of serum gastrin gradients either determined in the portal venous drainage through transhepatic venous sampling or in hepatic veins after selective, intra-arterial secretin injections (9,27,29,37,130-132,135,138,142,153,181,291,293,323,577,583-592) vary in sensitivities for detection of the primary tumor, as well as metastatic tumor (Table 9).

Table 9. Tumor Localization Results in Patients with ZES
	NIH studies Mean(range)	Literature Mean(range)	Literature Mean(range)
Extra-hepatic lesions
Ultrasound	13 (9-16)	24 (0-28)	92 (92-93)
MRI	40 (30-57)	22 (20-25)	100 (99-100)
CT scan	38 (31-51)	38 (0-59)	90 (83-100)
Angiography	43 (28-57)	68 (35-68)	89 (84-94)
SRS	69 (58-78)	72 (57-77)	86 (86-100)
PVS	71	68 (60-94)	ND
Intra-arterial Secretin test	86	89 (40-100)	ND
EUS	ND	70 (28-86)	85 (80-93)
IOUS	83	83 (75-100)
Liver Metastases
Ultrasound	46	40 (15-77)	100 (99-100)
MRI	71	63 (60-75)	92 (88-100)
CT scan	42	48 (37-56)	99 (99-100)
Angiography	65	62 (33-86)	98 96-100
SRS	92	97 (92-100)	95 (90-100)
Intra-art. Secretin test	40	ND	ND

Data are from (9,27,40,119,129,133,142,295,525,591,593).

ND-no data.

At present, most patients when initially evaluated have performed a cross-sectional imaging study (CT, MRI. Ultrasound) and an SRI study to determine whether surgical resection should be considered (6,9,44,88,181,182,584). Gastrinomas, similar to other pNEN, are hypervascular and are thus their detection on imaging studies can be enhanced by the of administration of contrast; hence, in most patients, either a triphasic CT with intravenous contrast or an MRI with intravenous contrast (gadolinium (129,291,576,577,583). With the cross-sectional imaging modalities, the detection of lesions is influenced by their (40,141,525,577,591). In patients with gastrinoma lesions <1 cm in diameter, only <10-20% are detected, with 1-3 cm in diameter it increases to 15-40%, and with tumor lesions >3 cm, >80-90% are detected (40,525,577,591). Therefore, cross-sectional imaging studies will miss most primary duodenal gastrinomas, which are characteristically <1 cm in diameter; however, they detect most pancreatic primaries which are frequently > 3 cm in diameter (43,45,109,110,175,176,577). As summarized in Table 9, the sensitivity of cross-sectional imaging for detection of primary gastrinomas varies markedly among different series, with generally excellent specificity. In general, they detect <50% of the primaries, with lower yields in series with a high percentage of duodenal gastrinomas. For detection of a patient with liver metastases, cross-sectional CT/ultrasound identify approximately one-half the patients, whereas MRI detects nearly three-quarters (Table 9).

Selective angiography was widely used in the past, but is infrequently used now, however it is a sensitive method to image gastrinomas, (27,43,241,525,591,593). In most studies angiography was more sensitive than cross-sectional imaging studies for localizing primary gastrinomas, but it still did not localized approximately half of all primary gastrinomas, particularly missing small duodenal gastrinomas (40,43,175,241,525,591) (Table 9). However, angiography is increasingly not used, because it is an invasive procedure, but more importantly because of the increasing sensitivity of both cross-sectional imaging, and the increased availability of SRI which has a significantly higher sensitivity of SRS (Table 9). In the past frequently at the time of angiography, selective hormonal sampling was also used, and still used today in some centers for patients with ZES who have negative cross-sectional imaging and negative SRI studies (138,323,585,588,589,593-597) Two different methods for gastrin hormonal sampling have been used, with the first being the transhepatic catheterization of portal venous tributaries draining the pancreas (portal venous sampling (PVS)) (323,593,595) and the second, which is more frequently used, is the assessment of hepatic venous gastrin concentrations performed after secretin injection into selective arteries to various pancreatic/duodenal regions (585,588,589,593,594,596,597). This method is not dependent on tumor size and involves functional localization which can be very sensitive (Table 9), however, it is now rarely used being replaced by cross sectional imaging and SRI (588,589).

Greater than 90% of NENs/NTs including gastrinomas are well differentiated tumors which overexpress or ectopically express one of the subtypes of somatostatin receptors (sst1-5) in >90% of cases (primarily sst2) with the result that somatostatin receptor imaging (SRI) with various radiolabeled various somatostatin analogues is now widely used (90,134-137,139,141,153,291,292,582,598,599). This method is particularly sensitive method to identify both the primary and metastatic gastrinoma location (181,401,525,576,600-602). Of the five classes of somatostatin receptors (sst1-5), all can be detected in various gastrinomas; however, sst2(80-100%) and sst5 (30-60%) are the most often overexpressed (603). Whereas native somatostatin (som14) interacts with all 5 receptor subtypes with high affinity; it is rapidly degraded in the circulation, hence is not useful therapeutically or for radio-imaging studies (601,603). Two synthetic analogues of somatostatin, octreotide and lanreotide, which have high affinity only for sst2 and sst5, are metabolically stable, and are now widely used for both SRI, for their anti-tumor effects both alone or coupled to radiolabels that are cytotoxic to the tumor and will be discussed in the treatment section later (see PRRT) (90,129,292,601,603-609). Specifically in gastrinomas, in the NIH ZES prospective studies (Table 9), SRS using ¹¹¹In-labeled somatostatin analogues (Octreoscan) and single photon emission computed tomographic scanning (SPECT) imaging detected primaries in 69% of patients and in one prospective study of 80 consecutive ZES patients (133), SRS was more sensitive than any single cross-sectional imaging study or angiography, and was equal in sensitivity to the combination of all three cross-sectional imaging studies (US, CT, MRI) and angiography together (58% vs 48%)(133). The sensitivity of SRS, similar to cross-sectional imaging, is influence by the size of the gastrinoma, with SRS using ¹¹¹In-labeled somatostatin analogues (Octreoscan) and SPECT imaging visualizing only 20% of gastrinomas <0.5 cm in diameter, 30-40% <1 cm in diameter (610). Because the mean size of duodenal gastrinomas is <1 cm, SRS detects only 32% of duodenal gastrinomas (175,610). The use of ⁶⁸Ga-labelled somatostatin analogues with positron emission tomography (PET-scanning) has greater resolution with increased sensitivity (129,134,141,290-292,582) and thus is an important recent advance. In the US and in many countries, the most commonly used ligand for SRI is now ⁶⁸Gallium DOTA (9,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid) labeled somatostatin analogue (generally ⁶⁸Ga-DOTATOC PET/CT) with positron-emission tomography detection (129,134,141,290,582). This SRI method has generally replaced the use of ¹¹¹Indium (diethylenediamine penta-acetic-D-phenylalanine-1) octreotide with single photon emission CT (SPECT) detection, because of it greater sensitivity (129,134,290-292). SRI at present is the most sensitive method for assessing whole body localization of advanced NENs (129,134,290,292).

SRI is of particularly valuable for detecting distant metastases both to the liver and more distant, especially to bone, with a detection rate of 97% for identifying a patient with metastatic disease in the liver (Table 9). Studies demonstrate that bone metastases are relatively common in patients with advanced NENs including gastrinomas, in which they occur in up to 31% of ZES patients with liver metastases (58,112,294,611,612). The detection of bone metastases in ZES patient has been shown to have a high clinical importance, because they may not only require specific treatment, they also have important prognostic significance) (109,294,299,612,613). In one prospective study from NIH (112), SRS had greater sensitivity than bone scans for detecting bone metastases, and for imaging metastases in the spine was equal in sensitivity to MRI (112). Because 15-25% of the initial metastases occur outside the axial skeleton, SRI is recommended as the initial study over MRI to detect bone metastases (112).

Whereas endoscopic ultrasound (EUS) has proven to be one of the most sensitive modalities for detecting insulinomas/NF-pNEN and is reported to be sensitive for localizing gastrinomas in some studies, its use is controversial in gastrinomas (40,119,245,614-616). EUS detected a mean of 70% of gastrinomas in different studies (Table 9) and has the advantage of allowing histological verification of the presence of a NEN as well as obtaining samples for determining the grade of the NEN which is particularly important for prognosis (617,618). However, EUS’s result is operator-dependent and false positives can occur (119,133,245,615). An important issue in patients with ZES is EUS’s sensitivity for detecting gastrinomas in different locations such as the duodenum, which is the source of controversy in is use in ZES as opposed to its general use in patients with entirely intra-pancreatic NENs (insulinoma, NF-pNEN, etc.). In one review of EUS in ZES patients, EUS detected a pancreatic gastrinoma in 83%, whereas it detected a duodenal gastrinoma in only 43 % (119). This is a major problem for EUS in patients with ZES because in recent studies 3-10 times more gastrinomas are found duodenal than pancreatic (9,181,182). Because of this difference, many experts do not recommend EUS as a routine preoperative imaging study in patients with ZES, especially in the 75-85% of patients with sporadic ZES (119). As will be discussed further in a later section, serial EUS studies may be used in patients with MEN1/ZES to evaluate the possible growth of the pNETs in patients who do not undergo routine exploration (30,44,88,90,619,620). At present it is recommended that a cross-sectional imaging study and SRS with SPECT imaging be performed in all ZES patients to evaluate tumor location/extent (9,42,50,181,182). If negative, but where the diagnosis of ZES has otherwise been confirmed, MEN1/ZES is not present and surgery is being considered, there is not complete agreement on which if any localization procedure should be performed prior to surgery (45,119,254). This issue will be discussed further under the section on surgical management.

Recently, there has been increased interest in pNENs, including gastrinomas, as well as NENs in other locations of the use of ¹⁸F-Fluordeoxyglucose (¹⁸F-FDG) PET imaging particularly as a prognostic marker (42,90,115,116,129,134,291,621-623). ¹⁸F-FDG PET/CT assesses tumor metabolic activity by determining the glucose uptake and therefore measures a different tumor parameter than SRI which is assessing somatostatin receptor expression. Although ¹⁸F-FDG PET/CT is widely used in oncology, until recently, it was generally not thought helpful in patients with pNENs/NETs (134,624). However, numerous recent studies report high uptake by a proportion of NETs (291,625-627). In a number of studies, the high uptake/SUV of ¹⁸F-FDG PET/CT was reported to be associated with higher Ki67 values and was a predictor of overall survival as well as PFS (42,115,116,134,291,621-623). Lately there have been an increasing number of papers advocating either the use of FDG either alone or combined in dual imaging with ⁶⁸Ga-DOTA-SSA PET/CT (42,622,623,625-631). Similar to its increasing use in other pNENs/NENs the use of ¹⁸F-FDG PET/CT in patients with gastrinomas may help in identifying those with aggressive disease, particular as a postoperative tool to stratify patients that may benefit by more aggressive postoperative treatments.

TREATMENT (ACID SECRETION/LOCALIZED DISEASE)

General Aspects (Not Advanced Metastatic Disease)

Like patients with other F-NEN syndrome, patients with ZES have two different aspects that require treatment and often can’t be controlled by a single treatment strategy (25,48,54,158,632-634): control of the hormone excess state and treatment directed at the NEN per se, because, except for insulinomas, but similar for gastrinomas and the other F-NEN, these NENs are malignant in 50-100% of cases and require treatment. Specifically, in the case of ZES treatment needs to be directed at two different problems: the control of the marked acid hypersecretion and the gastrinoma itself. Whereas a curative resection would solve both problems; unfortunately, it is possible in <30% of patients. Furthermore, in patients with MEN1/ZES which comprise 20-25%, treatment must be also directed at the other endocrinopathies these patients frequently develop, as well as genetic family counseling (30,65,96,99,100,203,463,505). The first section will discuss management of the acid hypersecretion, followed by the surgical management of the gastrinoma in patients without advanced metastatic disease. In the last section of treatment, the management of patients with advanced/metastatic disease will be discussed.

Management of Gastric Hypersecretion

GENERAL MANAGEMENT OF GASTRIC HYPERSECRETION

Numerous studies, especially older studies prior to adequate drug therapy to control the gastric acid hypersecretion in ZES patients, demonstrate that both the acute and long-term control of the acid hypersecretion is essential for long-term survival (9,46,72,89,103,181,184,205,313,635-637). Prior to the availability of effective acid antisecretory drugs, most ZES patients who did not have a total gastrectomy, eventually developed complications of the gastric acid hypersecretion, and the majority died from these complications rather than from tumor progression (1,27,28,46,72,89,103,184,205,235,313,635,638). This occurred largely because of the direct effect of the marked acid hypersecretion, with the mean basal-acid output (BAO) in ZES patients typically 4-times normal but reaching as high as 12-times the upper limit of normal in some patients (40,70). In a given patient it is not possible to predict when these elevated acid levels will overcome the defense mechanism (increased bicarbonate secretion, increased duodenal secretion, etc.), thus in all patients it is essential to acutely control the acid hypersecretion as soon as ZES is suspected and as the initial step in management (1,9,28,51,56,72,181,182,313,558,639).

SURGICAL TREATMENT OF GASTRIC HYPERSECRETION

While surgical management of the gastric acid hypersecretion in ZES patients is now rarely used, in the past (prior to the 1970’ s), the only effective means of adequately controlling gastric acid hypersecretion in these patients was by total gastrectomy (1,28,205,207,237,620,638,640-642). Lesser operations were almost invariably inadequate to prevent recurrence long-term (1,28,237,403,620,638,641). Because in ZES patients prior to any other means of controlling the acid hypersecretion, the total gastrectomy was often performed as an emergency procedure and was associated with considerable morbidity/mortality (1,40,205,638). However, later with the availability of histamine H₂receptor antagonists, starting in the 1970’s, allowing preoperatively control of the acid hypersecretion medically in most patients, the total gastrectomy could then be performed electively and was relatively safe, with an overall mortality of 5.8% in 248 cases since 1980, and 2.4% for elective cases (207). However, the long-term morbidity remained unclear, and in some studies up to 50% of patients have moderate or severe side-effects, including weight loss, pain, stenosis of the anastomoses, vomiting and early satiety (27,40,643). At present, because of the effectiveness of medical therapy especially the PPIs, total gastrectomy is rarely performed and reserved for patients (<0.2%) (9,27,51,71,103,108,644,645) who cannot or will not regularly take oral antisecretory drugs.

Both vagotomy, as well as medical treatment with anticholinergic agents, can reduce the levels of gastric acid hypersecretion in ZES patients and also, they can potentiate the effectiveness of histamine H₂R antagonists when added (27,40,646-648). After the availability of histamine H₂R antagonists (1970+), but prior to the availability of PPIs(mid-1980s), most ZES patients were not cured at surgery, and because many continued to require frequent histamine H₂R antagonists, it was proposed that parietal cell vagotomy, be performed at the time of surgery in ZES patients (211). In ZES patients that underwent selective vagotomy, (211,648), the BAO decreased by a mean of 50%, the histamine H₂R antagonist dosage could be reduced by 40%, and in 36% of patients all antisecretory drugs could be stopped postoperatively. Today, with the development and availability of PPIs, which are highly effective in ZES patients, a form of vagotomy is rarely necessary or used.

In patients with MEN1/ZES with hyperparathyroidism, an effective parathyroidectomy can markedly reduce fasting gastrin levels (FSG), the BAO and can increase the sensitivity to gastric antisecretory drugs (190,508,509,533), with a mean decrease in BAO of 56% and the FSG of 55% (40,190,508,509). Moreover, in some patients, the FSG levels can decrease to the normal range, as well as a positive secretin-test can become negative (40,190,508,509). MEN1 patients, with or without ZES, have parathyroid hyperplasia which involves all four parathyroid glands, if recurrent hyperparathyroidism is to be avoided post-parathyroidectomy, it is recommend that either a 3.5 parathyroid gland resection or a 4-gland resection, with a parathyroid implant, should be performed in these patients (463,508,509,649-653).

Long-term, curative gastrinoma resection is possible in < 40% of patients with sporadic ZES undergoing surgery with the recommended surgical approaches in most guidelines with no-aggressive resections (non-Whipple resection) (6,43,175,254); and even when curative, it does not completely correct the gastric acid hypersecretion in some patients (654-656). In the NIH prospective studies of acid hypersecretion post-curative resection, the MAO decreased 50%, BAO decreased 75% within 6-12 mos. and then remained unchanged for up to 4 years, and the histamine H₂R antagonists’ dose could be reduced by >60% (654-656). However, even though the BAO decreased by 75% after curative resection for up to 4 years, 60% of the patients remained acid hypersecretors (654,655). This group included 34% who were mild hypersecretors (BAO-15-24.9 mEq/hr.) and 28% who had marked to extreme hypersecretion (≥25 mEq/hr. (range-25-69 mEq/hr.)) (655). The mechanism of this continued hypersecretion post-curative resection is unclear (655). Practically, it means that all ZES patients should continue to be followed carefully post-curative resection and many will continue to need low doses of antisecretory drugs (655).

MEDICAL TREATMENT OF GASTRIC HYPERSECRETION

In all recent guidelines, medical treatment with oral gastric acid antisecretory drugs is the recommended method to control the gastric acid hypersecretion seen in ZES patients, both acutely and long-term (9,29,103,157,164,180,181). PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) are the recommended drug of choice because of their long durations of action and potency (7,9,25,29,40,72,103,157,164,180-182,657,658). Most ZES patients without complicated disease (MEN1/ZES, moderate-severe GERD, post-Billroth II surgery) require only once a day dosing and many are controlled on PPI doses equivalent to those used in idiopathic PUD disease (i.e., equivalent to 20 mg/day omeprazole) (103,184,518,519,557). In patients with complicated disease (MEN1/ZES (especially with active hyperparathyroidism), moderate-severe GERD, post-Billroth II surgery) higher doses/frequency are usually needed (72,184,518,519,557,659). For patients requiring higher doses, in general, increasing the dose frequency is more effective than increasing the dosage once-per-day (72,518,519). Most long-term studies were performed with omeprazole or lansoprazole as the PPI, however; other PPIs (pantoprazole, rabeprazole, esomeprazole) are effective in ZES, and it is not apparent anyone has an advantage over the others (103,184,660-662). There is no complete agreement on the starting dose of PPI to be recommended. This becomes an important point in patients with ZES because many of the PPI formulations are acid-labile and thus starting a patient on a low PPI-dose could delay its action, and in acutely ill ZES-patients with PUD this could result in complications (663). One study attempted to address this question (663) by starting patients with ZES on a low dose of omeprazole (20 mg/day) and found that in 32% acid secretion was not controlled and higher omeprazole doses were needed. This study proposed that ZES patients with uncomplicated ZES (no MEN1/ZES, moderate-severe-GERD, post-Billroth II surgery) be started on higher PPI doses (equivalent to omeprazole 60 mg/day) and then doses reduced during follow-up. Both the US NANETs guidelines (182) and the European ENETs guidelines (181) recommend that ZES patients with uncomplicated disease (no-MEN1/ZES, moderate-severe GERD, post-Billroth II surgery) be started on the equivalent of 60 mg/day of omeprazole and that patients with complicated disease be started on PPI doses equivalent to omeprazole 40-60 mg BID and then, with time, dose reduction be attempted. It is ideal to titrate the PPI dose to control the acid output (<10 mEq/hr for no gastric surgery, <5 mEq/hr for previous gastric surgery) (27,40,72,103,106,184,503,660), but few physicians now have access to units measuring gastric acid output. Symptom control (particularly diarrhea, pain, heartburn) can be used to guide management, and if mucosal disease is present, repeat UGI endoscopy should be performed after 6-8 weeks. Because of their potency, dose titration is less important with PPIs; however, it is essential with histamine H₂R antagonists (see comments below in this section).

Only a few studies have reported the long-term results of continuous treatment with PPIs in ZES patients for 9-15 years (72,76,518,557,661). Tachyphylaxis does not develop with long-term PPI treatment in ZES patients, and on average <20% of patients require a PPI-dose increase/year (rate-0.13/patient), whereas with long-term histamine H₂R antagonist treatment, an average of at least one dose increase/year was required (27,72,103,104,518,558-561). Long-term PPI use has proven safe; with fewer than 0.1% of patients stopping treatment because of a side-effect (103). A potential concern of long-term PPI-treatment is the drug-induced hypo-/achlorhydria, which may lead to effects on nutrient absorption (vitamin B₁₂, iron, calcium) as well as enhanced hypergastrinemia resulting in an increased risk of gastric carcinoid tumors (76,502,664-669). Low vitamin B₁₂ levels are frequent in ZES patients (666,667,670,671), are more frequent in ZES patients treated with PPIs, and correlate with the PPI-induced hypo/achlorhydria (670). While the PPI induced decrease in serum VB₁₂ levels in ZES patients in the above study (670) was established in a prospective study of these patients, the question of whether PPIs systematically decrease VB₁₂levels in the nonZES, general population and thus should be monitored for, remains controversial (76,667,672).

In another study of ZES patients (673), deficiencies in body iron stores were not found with long-term PPI treatment. Recently, epidemiological, and various correlative studies report in the general population that long-term PPI use may result in an increased incidence of bone fractures, particularly in the spine/ hip, but there are no specific studies in ZES patients (76,666,667,674). In addition, in similar correlative studies in the general population a number of other possible side effects of long-term PPI treatment have been proposed: these are controversial and except for malabsorption of vitamin B₁₂ have not been reported with increased occurrence in ZES patients (76,667). The proposed PPI-side-effects include an increased occurrence of such diverse problems as: dementia, chronic renal disease, hypomagnesemia, malabsorption of various nutrients (vitamin B₁₂, iron, etc.), well as increased growth of various other cancers including gastric, pancreatic, and colorectal tumors (76,502,667,668,675,676). Hypomagnesemia has been rarely reported (3 case reports) in ZES patients (76,645,672,677) and in the prospective NIH studies involving 250 ZES patients, only a single patient developed hypomagnesemia despite chronic, continuous PPI with many patients taking higher PPI doses and with a mean treatment time >10 years, for rate of 0.4% over the treatment period (76). On the basis of these studies, it has been proposed (76,181,673) that only the serum vitamin B₁₂-levels should be periodically assessed once a year in ZES patients with long-term PPI treatment, especially the group of patients who might have low vitamin B₁₂ level initially or a poorer nutritional status (elderly patients with a long history of malabsorption).

Recently, there have been an increasing number of reports of medical failure in ZES patients of the long-term use of H₂R (27,558,562,586,678) for maintenance acid control, and also even problems controlling acid with PPI therapy long-term (71,71,95,102,108,136,285,403,494,644,645,672,679-686). This is occurring in large part due to the lack of data from any extended long-term/ lifetime treatment studies (i.e., >10 yrs.-lifetime) of antisecretory acid control in ZES patients. This is in contrast to a number of studies of acute acid control and short-term (<5-6 yrs.) control with small number of ZES patients (225,518,519,554,561,661,662,677,687-693). This lack of information about the long-term efficacy of acid antisecretory drug’s in ZES is a particular problem because of the unique acid secretory condition in ZES. In ZES there is a constant hypersecretory drive due to constant ectopic secretion of gastrinoma from the gastrinoma, resulting in a constant acid hypersecretory state, which results in a constant requirement to inhibit the acid secretion, which because it is unique to ZES, its treatment can only be addressed by long-term/lifetime study data in these patients. In contrast to ZES, there are numerous long-term PPI studies in nonZES patients, particularly in patients with advanced idiopathic GERD, and these can provide evidence for safety issues that might occur with lifetime PPI treatment (76,667,694-696), which is applicable to chronic treatment of ZES patients, however, this is not the case with long-term/lifetime efficacy data in ZES. Another important variable contributing to the need to have data on long-term/lifelong antisecretory efficacy in ZES patients, occurs because of the marked variation of the dose requirement between individual ZES patients as well as in each patient, which has been well-examined in short-term ZES acid secretory studies (225,518,519,554,561,661,662,677,687-689,697). This issue was recently addressed (72)in an analysis of the results of acid antisecretory treatment in ZES patients, which examined in detailed the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients. This study included results from all 303 patients with established ZES who were prospectively followed and had acid antisecretory treatment with either H₂Rs or PPIs who had antisecretory doses individually titrated by the results of regular gastric acid testing. It includes both patients treated for short-term periods (<5 years), as well as patients treated long-term (>5 yrs.), and with lifetime treatment (30%), followed for up to 48 yrs. (mean-14 yrs.). Long-term/lifelong acid antisecretory treatment with H₂Rs/PPIs could be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). Successful treatment in this study was only possible because the drug doses were individually set by assessing acid secretory control by measuring the acid secretory rate and adjusting the various drug doses to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both up and down were needed; as well as regulation of dose-frequency and a primary reliance on the use of PPs. In this study (72) prognostic factors predicting patients who required PPI dose-changes were identified which need to be studied prospectively to develop a useful predictive algorithm which could be clinically useful for tailored long-term/lifetime therapy in these patients. These results clearly establish that long-term/lifelong medical control of the acid hypersecretion is possible in all ZES patients who can take acid antisecretory drugs, but requires it be performed in centers with the capability of titrating the drug dose over time by assessing the acid secretory rate, thus it is best if these patients are referred to centers with this capability.

Chronic hypergastrinemia in animals and man stimulates gastric enterochromaffin-like (ECL) cell proliferation and in animal models, gastric carcinoid tumors (ECLomas) can develop, some of which are malignant (76,217,224,227,502,665,666,698-701). In patients with ZES, ECL cell proliferative changes develop in >90% (76,217,227). However, patients with sporadic ZES (no MEN1) (75-80%), rarely develop gastric carcinoids (76,103,217,502), whereas MEN1/ZES patients have >70 greater risk of developing a gastric carcinoid (227). In one prospective study (227), 23% of MEN1/ZES patients had gastric carcinoids and other studies have indicated that these can be malignant in 10-30% of patients (76,227,502,666,702,703). In a similar prospective study of 106 patients (217) with sporadic ZES, none of the patients had a gastric carcinoid tumor, although 99% had ECL cell hyperplasia, and 50% had advanced ECL cell proliferative changes, including 7% with dysplasia. Even though there are a few case reports of gastric carcinoids found in sporadic ZES patients (76,212,228,229,232,233,704-709), the prospective NIH study discussed above(217), demonstrates that this is very uncommon, and differs markedly from the chronic atrophic gastritis patients in which 0.4-7% have gastric carcinoids on a routine endoscopy, and 5-35% in some series with long-term follow-up (76,710,711). There is no evidence the long-term use of PPIs accelerates gastric carcinoids development either in patients with sporadic ZES or with MEN1/ZES (76,103,502). However, because of the association of hypergastrinemia with gastric carcinoids, all patients with ZES should undergo an initial upper gastrointestinal endoscopy; those with MEN1/ZES should have a repeat UGI endoscopy yearly, while in those with sporadic ZES, if there are no upper GI symptoms, follow-up UGI endoscopy can be less frequent.

During the subsequent clinical course of many ZES patients after diagnosis, for their frequently occurs brief periods where they cannot take the oral antisecretory drugs (e.g., after surgery, chemotherapy, etc.) and during this period a parenterally administered gastric antisecretory drug may be necessary. Parental histamine H₂R antagonists can be used, however, continuous infusions of high doses are required (27,103,105,586,712,713). In contrast, with parenteral PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole, etc.), because of their long durations of action, intermittent parenteral administration (every 6-12 hours) can be used (103,555,714-716).

At present histamine H₂R antagonists are much less frequently used than in the past (76). Although histamine H₂R antagonists can be effective if properly administered, they usually have to be taken every 4-6 hours, and the oral dose needs to be titrated so that acid hypersecretion one hour prior to the next dose is decreased to <10 mEq/hr (no previous-gastric-surgery, <5 mEq/hr.-previous gastric-acid surgery) (28,103-105,558,560,562,717). In most patients at this level of control, symptoms will be controlled, and mucosal lesions heal (27,103,105,106,586). For patients with complicated ZES (MEN1/ZES, moderate-severe GERD, previous Billroth II surgery), acid hypersecretion may have to be reduced to <1 mEq/hr in order to achieve complete healing (27,105,503,519,659). Using dose-titration, the average daily doses needed of oral histamine H₂R antagonists in the prospective NIH studies were 4.9, 2.2 and 0.33 g/day for cimetidine, ranitidine, and famotidine, respectively (40,103). Despite these high doses, the drugs were generally free of dose related side effects, except for anti-androgen effects with cimetidine (gynecomastia, impotence) and were effective long-term, although approximately one dose-increase/ year was needed (27,40,103,104,558,561,718). Because of this need to titrate the histamine H₂R antagonist dose for each patient, the need for frequent, high dosing and the need to adjust of dosage with time, PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) have now largely replaced the use of histamine H₂R antagonists, and are currently the recommended drugs of choice, because of their long durations of action and potency (7,9,29,40,76,103,157,180-182,657,719). Most ZES patients without complicated disease (MEN1/ZES, moderate-severe GERD, post-Billroth II surgery) require only once a day dosing and many are controlled on PPI doses equivalent to those used in idiopathic PUD disease (i.e., equivalent to 20 mg/day omeprazole) (103,184,518,519,557). In patients with complicated disease (MEN1/ZES (especially with active hyperparathyroidism), moderate-severe GERD, post-Billroth II surgery) higher doses/frequency are usually needed (184,518,519,557).

Currently, somatostatin analogues are uncommonly used to control acid hypersecretion in ZES patient, because they must be given parenterally, whereas effective inexpensive long-acting, oral antisecretory agents such as PPIs are available and are the drugs of choice (29,103,142,151,181,182,396).

SURGICAL TREATMENT (NOT FOR ADVANCED METASTATIC DISEASE)

At presents most authorities, as well as all guidelines, agree that surgical resection for attempted cure should be performed in ZES patients whenever possible without undue risk, similar to the treatment of other potentially resectable pNENs (9,43,46,95,99,102,119,120,122,157,180,182,267,461,720-728). This approach is, in contrast to that in the recent past, wherein the role of routine surgery for cure was controversial, with some recommending that surgery not routinely be performed, because gastrinomas were frequently not found at surgery and cure was uncommon (729-731). In addition, many patients had negative preoperative imaging, and most patients with non-imaged or small gastrinomas had a good prognosis without surgery (729,731). The situation has changed because of results from a number of more systematic studies. In a NIH prospective surgical study (43) of sporadic ZES patients (n=123), the immediate postoperative cure rate was 51% and after 10-years was 34%. A number of other NIH surgical studies (45,175,176,241,254,258,732,733), as well as studies from other institutions (46,95,99,102,122,177,724) have provided additional support for routine surgery. This approach is further supported by two NIH studies on survival/disease course post-surgical resection of the primary gastrinoma, with the one study (732) demonstrating that patients who underwent routine exploration had a lower incidence of developing liver metastases post-resection (3% vs 23%, p<0.003). A subsequent NIH study (733) with more patients (n=160) and a longer follow-up (mean 12 yrs. postresection) demonstrated that patients undergoing surgery had a better overall survival (15 yrs., 98% vs 74%, p=0.0002); the survival advantage was disease-related (p=0.0012), due to less tumor progression, and fewer patients developed liver metastases (5% vs 29%, p=0.0002). This is a particularly important finding, because two NIH studies (109,110) in patients with gastrinomas, as well as a number of other studies both in patients with gastrinomas and other pNEN (115,116,235,276,433,639,734), have demonstrated that the development/presence of liver metastases is one of the most important prognostic markers of long-term survival in these patients. Neither of above NIH studies were randomized, but in each case the comparative groups were well matched (109,110,242,733).

In the past, imaging studies were not infrequently all negative on preoperative studies, and because these ZES patients had an excellent prognosis without surgery, and because surgery was often negative in these patients, this led a number of investigators to recommend against surgical exploration in this group (45,515,729-731,735-737). A subsequent NIH study (45) provided important information to challenge this approach by reporting the value of surgery in patients with preoperative negative imaging in an expert treatment center. In this study (45), in 58 ZES patients with negative preoperative imaging (40%=negative SRS), at surgical exploration, a gastrinoma was found in almost every patient (98%), and nearly 50% were cured. The postoperative cure rate was not different from ZES patients with positive preoperative imaging studies treated in a similar manner (45). This study demonstrated that if the diagnosis of ZES is appropriately established, that an experienced surgeon can find gastrinoma in almost every patient, even if imaging studies and negative, and almost one-half will be cured (45). This improvement in the surgical success of finding and curing gastrinomas in sporadic ZES patients has occurred because of a number of factors: particularly important is the appreciation that the majority of gastrinomas are not in the pancreas, as previously thought, and are, in fact, small duodenal tumors (often <1 cm) (6,109,110,175,177,236,286,738), which are frequently missed on even the most sensitive pre-operative imaging studies, including SRI (293); which will be missed at standard surgical operations if special duodenal gastrinoma localization procedures are not used, such as duodenotomy with or without duodenal-transillumination (175,176,244,247); the use of improved imaging including SRI (549); at surgical exploration the routine resection of pancreatic head area lymph nodes because of the possibility of lymph node primaries (258,259,268,269,269-272,739); and an understanding that patients with sporadic ZES have a different surgical outcome than those with MEN1/ZES (9,30,43,179,723).

The standard operation includes besides a careful inspection of the duodenum, pancreas and general abdominal inspection, a Kocher maneuver to explore the pancreatic/head; a duodenotomy with or without duodenal transillumination; routine resection of pancreatic/duodenal lymph nodes; careful inspection of biliary tract and liver, and an intra-operative ultrasound(IOUS) examination of the pancreas (43,95,120,175,176,247,249,258,288,738,740-743). This detailed examination is based on the fact that the relative order of occurrence of gastrinomas is duodenum>>pancreas>lymph node primary>primary liver/biliary tract> other (ovary, mesentery, gastric, etc.) (27,40,50,744). The most important procedure is a careful inspection of the duodenum. This requires the performance of a duodenotomy which is characteristically a 3-cm longitudinal duodenotomy centered on the anterolateral surface of the descending part (second portion) of the duodenum accompanied in the NIH protocol with transillumination of the duodenum (175,176,244,247). A duodenotomy is required to carefully inspect the duodenum because intraoperative ultrasound (IOUS) has been found to be relatively insensitive for duodenal wall tumors in patients with ZES (740). The use of a duodenotomy was proposed by Norman Thompson, University of Michigan in 1989 (246) at a time when most physicians though gastrinomas were primarily intrapancreatic, similar to insulinomas and its benefits and risks for detecting occult duodenal gastrinomas was debated (175,175,246,247,721). Its routine use was firmly established by a prospective study at NIH involving 35 patients with ZES in which all patients first had the standard exploration for a duodenal tumor involving careful palpation without a duodenotomy/or intraoperative transillumination of duodenum, followed IOUS, then duodenal transillumination and finally a duodenotomy (244). Standard palpation identified only 61% of all duodenal tumors found by any method, IOUS found only 26% and no new lesions; transillumination identified 64% of all duodenal tumors and 6 of these were new tumors, whereas duodenotomy identified all 31 duodenal tumors of which 5 were not identified by any other method.

This result was corroborated by another NIH study (176) which compared the surgical results from 36 patients (Group 1) who underwent the standard laparotomy (1980-1986) without duodenotomy (prior to its routine use) to a group receiving the same operation but with transillumination and a duodenotomy (19987-1990-37 patients) (Group 2). Gastrinomas were found in significantly more patients in Group 2(92% vs 64%, p<0.01); this increase was due to more duodenal gastrinomas detected in Group 2 (43% vs 11%, p<0.01) which resulted in an increased disease-free rate in group 2 (176). Most importantly, a NIH 2004 study (175) examined the long-term effects of adding a duodenotomy on the long-term cure rate. This study (176) compared results in 143 ZES patients, of which all had the standard exploration protocol, but 79 had a duodenotomy and the others had not had one. Gastrinomas were found in a higher percentage of patients who had underwent a duodenotomy (98 vs 76%, p<0.000011); as were duodenal gastrinomas (62 vs 18%, p<0.00001), whereas the detection rate of pancreatic tumors was similar; the duodenotomy group had a postoperative cure rate that was higher (62 vs 44%, p=0.010) as well as the long-term cure rate (52 vs 26%, p=0.0012). These results have established the need for all patients to have duodenotomy at exploration (9,157,181,182,745).

The routine resection of peri-duodena/peripancreatic lymph nodes is recommend for two reasons. First, as discussed earlier, a number of different groups have reported lymph node primary gastrinomas (27,40,43,258,259,266-274)which in the NIH series (258) was the third largest primary tumor group after pancreaticoduodenal tumors, comprising 10 % and their resection resulted in a disease-free state. Secondly, lymphadenopathy is reported to increase the disease-free rate postresection in ZES patients, as well as to increase overall survival in patients with sporadic ZES (746).

In contrast to the situation with sporadic ZES (no MEN1), the surgical management of MEN1/ZES patients remains controversial (9,30,87,92,93,95,95,96,99,120,122,123,128,157,181,182,745,747). This has occurred because almost all studies demonstrate that these patients are rarely cured by the standard ZES operation involving local tumor resection/enucleation even with a duodenotomy, and that cure only occurs if a Whipple resection is performed, which is not routinely recommended (9,43,44,88,89,92,122,181,182,747,748). Even though pancreaticoduodenectomy (Whipple resection) will cure the ZES in MEN1 patients (30,92,119,747,748), it is not routinely or generally recommended by most groups or in most guidelines in patients with MEN1/ZES, primarily because of the long-term potential complications (119,748,749). Also, in patients with NF-pNEN, because of the multiplicity of small adenomas, a total pancreatectomy would be required, which because of its morbidity, is not recommended (30,750). This low cure rate with nonaggressive resections occurs because MEN1/ZES patients almost invariably have multiple, duodenal gastrinomas which are microscopic to small in size (many <0.5 cm) and thus difficult to find at surgery, as well as >50% have metastatic lymph nodes at surgery (43,95,119,178,179,191,284). On preoperative imaging studies in MEN1/ZES patients, duodenal-pancreatic NENs are frequently visualized, however, the peripancreatic tumors are often not the primary but an adjacent positive metastatic lymph node, whereas the pancreatic NENs frequently visualized are usually not gastrinomas (0-<15%) (mostly-nonfunctional-pNEN) (88,191,284). Numerous studies report that if the preoperative imaging studies identify a tumor <1.5-2 cm in diameter, that these patients have an excellent long-term prognosis; in fact, survival is not different from MEN1 patients without a pNEN seen in some studies (9,27,191,751).

A number of other points complicate the decision for surgery and the management of the pancreatic-duodenal lesions in MEN1 patients and have particularly importance in recommending a more conserve approach than aggressive surgical resection in MEN1/ZES patients. First, pNEN present approximately 10-years earlier in MEN1 than sporadic cases (30,87), even occasionally occurring in patients < 20 years old (101,752). This has led to added controversy on whether such young patients should undergo surgery or have continued surveillance. Second, MEN1 patients have an increased incidence of glucose intolerance and diabetes (753,754). This could become an important consideration, particularly in younger patients if they underwent extensive pancreatic resections such as Whipple resection, because the occurrence of glucose intolerance/diabetes after such procedures is reported in different series as, 10% (749), 34 % (755),40% (102) and 86%(756) if MEN1 patients underwent a major pancreatic resection and in 8-27 % of any patients undergoing pancreaticoduodenectomy (102,757,758). Furthermore, pancreatic insufficiency develops in 41-50% after major resections or un 40% after Whipple resections (102) which can complicate the post-surgical clinical management. Third, is the potential importance of continued radiation exposure in MEN1 patients who require life-long monitoring (90). This could become an important issue if these patients are followed, and continued imaging surveillance is required. Some recommend endoscopic ultrasound (EUS) for this purpose (90), which is the most sensitive modality, however, it is an invasive procedure which is done under general anesthesia in many centers, and therefore other imaging modalities that allow serial assessment of changes in pNEN size, would be of value, such as repeated cross-sectional imaging studies (MRI, CT scanning), however they are less sensitive. These cross-sectional imaging modalities (CT, MRI) very frequently miss small pNEN<1.5-2 cm in diameter, a group that numerous studies shows do not have an increased mortality from pNEN (181,505,751,759,760). For the above reasons, there has been increased interest in MEN1 patients, especially younger patients, in imaging studies not involving radiation such as MRI, but because MRI does not detect a significant number of small pNEN in MEN1 patients, there also is increased interest in more sensitive imaging studies such as ⁶⁸Ga-DOTATOC positron emission tomographic/CT imaging (⁶⁸Ga-DOTATOC-PET/CT) which involve radiation. This interest has especially increased with recent studies reporting for the first time prospective (549,761,762) and non-prospective studies (763,764) demonstrating enhanced sensitivity/specificity for localizing NETs, including pNEN, in MEN1 patients, using ⁶⁸Ga-DOTATOC-PET/CT. Lifetime exposure to radiation may be a particular issue in MEN1 patients because basic science studies demonstrate that menin, the protein altered in patients with MEN1, is involved in DNA repair, cell cycle control and transcriptional regulation, and when there is a loss of menin activity, as occurs in MEN1 patients, cells become more sensitive to the effects of ionizing radiation as well as other cell damaging injuries (765-767). As a result, a number of studies have raised concerns about the use of imaging studies involving radiation in younger patients (without MEN1) (768-770), and whether younger MEN1 patients are at increased risk is unclear. These points raise controversies about when and how frequent these serial imaging studies should be used.

For these reasons, most current guidelines, and expert opinions (9,44,88,157,180-182) for the treatment of pNEN in MEN1 patients recommend that MEN1/ZES patients with preoperative imaging studies demonstrating pNETs <1.5-2 cm in diameter not undergo routine surgical exploration. These guidelines also recommend that when surgical exploration is performed that Whipple resections not be routinely performed.

There are however, increasing concerns raised by the number of recent studies with this general conservative approach. Important points being raised is that these patients have a markedly shortened life- expectancy (i.e., 55 yrs. in the large prospective NIH review (89) with the major cause of death being malignant NENs, although presumed pNEN in origin it is not proven at this point (89). A second major point reviewed above is the enhanced ability to localize the primary NENs and their extent preoperative with the availability of SLI, allowing an enhanced ability to plan the operation and extend of surgery needed and likely enhancing the probability of cure. A third major point is that there have been a number of series (95,99,102) from different institutions reporting high cure rates and excellent long term survival in these patients after Whipple resections (95,99,102,119,178,191,683,747,748,771-801) . Furthermore, in a number of these studies the rate of post operative diabetes is less than previous reported in some studies and even not higher than seen with the recommended more conservative resections (273).

Increasingly, both patients with sporadic ZES, as well as those with MEN1/ZES, who had undergone an initial surgical resection, are being reoperated with time for either a recurrence after being initial rendered disease-free or due to increasing tumor growth with persistent disease (92,127,254,747,802-805). In a recent prospective NIH study of 52 ZES patients (254) with recurrence who underwent reoperation, the reoperation occurred a mean of 6 years after the initial surgery. After the reoperation, 35% were disease-free immediately postoperative and on the last follow-up after the repeat surgery (mean-8 years), 25% remained disease free, which are lower percentages than seen with the initial operation in NIH studies (43,45,175,254,805). In this study (254), the 20-year survival was 84% and the presence or absence of MEN1/ZES did not affect survival, but the length of the disease-free interval postresection and presence of liver metastases did. A recent study (127) reported recurrence in 108 sporadic ZES patients who had underwent an initial elective surgery between 2000-2020 in 15 different European hospitals. In these patients (127) 68 had duodenal gastrinomas, 19 (18%) had pancreatic gastrinomas, and 21 (19%) had a primary lymph node gastrinoma in the original surgery. During the initial surgery 74% of the patients with duodenal gastrinomas had a pancreaticoduodenectomy (Whipple Resection). For all gastrinoma patients (127) their mean OS was 173 mos., 5-yr survival 94%, and no predictive factors were found. The median DF-survival was 93 mos., and the 5 yr DF survival rate was 63%. For recurrence, significant prognostic factors were tumor size> 2 cm, (P=0.00001), tumor grade (p=0.00001) and pancreatic gastrinoma location (p=0.0001), however on multivariate analysis only tumor size >2 cm (p=0.005) and grade (p-0.013) were significant. Specifically, not a significant prognostic factor was age, sex, preoperative gastrin level, lymphadenopathy <10 nodes or metastatic lymph nodes in resected nodes. Also, for duodenal gastrinoma the recurrence rate was similar in patients with a Whipple operation to that in patients with excisions of duodenal tumors and lymphadenectomy (127).

A recent study also reported the results of duodenopancreatic reoperations in patients with MEN1(12 patients), of whom 5 patients (42%) had MEN1/ZES (92,747). In this study (92,747) the mean time to reoperation was 5.5 yrs., and with a long-term mean follow-up of 18 years, 83% (10/12) remained alive. The authors (92,747) concluded reoperations in this group of patients are not uncommon, there is no increased perioperative morbidity with reoperation in a specialty center, the patients can have prolonged survival after reoperation and that organ-sparing resections are preferred in these patients.

TREATMENT OF ADVANCED METASTATIC DISEASE

General Points

With the increased ability to medically control the gastric acid hypersecretory state in ZES patients, the natural history/growth of the gastrinoma is becoming the major determinant of long-term survival in ZES patients (46,89,109,110,314,433). Natural history studies show that gastrinomas are malignant in 60-90% of patients, and at present, approximately one-third of ZES patients present with metastatic disease to the liver, and because most patients are not cured surgically, an increasing proportion develop advanced metastatic disease over time (40,46,89,109,110,254,314,433,639). Overall, in NIH prospective studies, 25% of patients with sporadic ZES (109,110) and 15% of MEN1/ZES patients (111) have tumors showing an aggressive growth pattern, and in 40% of patients with hepatic metastases, aggressive growth occurs (429). As a result, currently one-half of ZES patients have tumor-related deaths (109).

A number of clinical, laboratory, pathological and other tumoral features in ZES patients are associated with a poor prognosis and are summarized in Table 10. A number of studies report one of the most important prognostic factors is the presence of any liver metastases (initially or their development) (Table 10). For example, in the NIH studies, the 10-year survival of ZES patients with no liver metastases initially is 96%, with liver metastases limited to one hepatic lobe is 78%, and with diffuse liver metastases is 16% (109,110). If liver metastases develop for the first time during the follow-up period after an initial evaluation wherein no liver metastases were present, the ten-year survival is decreased to 85% (110). However, in different studies at different times in the NIH cohort of ZES patients, the presence of lymph node metastases alone was, at best, only a weak predictor of poor prognosis, and in fact, was not predictive in a number of early studies (Table 10) (109,110,314,806). In a detailed analysis (806) of 216 pNEN patients at NIH in which >90% were ZES, with a prolonged follow-up (mean 11 years), overall survival decreased not only in patients with any lymph node positive, but also the extent of decrease in survival correlated with the number of positive lymph nodes. This result is consistent with some general studies in patients with various pNEN (807-809), but differs from others, which found no effect of lymph node metastases on survival in patients with various pNEN (130,314,806,810-813).

Numerous characteristics of the gastrinoma itself correlate with decreased survival including (Table 10): pancreatic location over duodenal location; increasing primary size; rate of growth overtime; in addition to the presence of liver or lymph node metastases the development of bone metastases has a poor prognosis. The development of ectopic, Cushing’s syndrome or bone-metastases has a particularly poor prognosis with survival averaging only one year (109,113,294,611). The fact that duodenal and pancreatic gastrinomas are equally malignant (40-70%=lymph node metastases), but not equally aggressive, with liver metastases present in 25-40% of pancreatic gastrinomas, but in only 2% of duodenal gastrinomas; results in pancreatic gastrinomas having a worse prognosis (Table 10) (27,109,110,314,433). Other features of gastrinomas associated with a poor prognosis including advanced ENET/WHO classification, higher ENET/WHO grade, poor differentiation, other histological features, and rapid growth (Table 10) (65,142,301,814).

As mentioned earlier in the pathology section of this paper, both the recently developed TNM tumor classification systems (ENETs, UICC/AJCC/WHO) and the tumor grading systems have been shown to be the most important single factors in numerous multivariate analyses for predicting overall survival or disease-free survival in all NENs ( pNEN, GI-NENs (Carcinoids) (Table 10) (115,116,142,815-817). Most (>90%) of gastrinomas are well differentiated NENs (Grade G1 or G2), and at present there is only one study just including only gastrinomas showing the importance prognostic effect of grade on survival of ZES patients (65). However, because of the almost universal importance of these classification/grading systems in studies involving all pNEN, it is almost certain this will be true of gastrinomas also.

Table 10. Prognostic Factors in Patients with Gastrinomas (overall survival or associated with increased development liver metastases)
Prognostic factor for decreased survival	Reference(s)
I. GASTRINOMAS ONLY
I.A. Acid Control
Uncontrolled acid hypersecretion	(1,27,205,433,638)
I.B. Demographic Features
Female gender (p=0.024)	(109,110)
Diagnosis before 1980 (p=0.010)	(315)
Older age at diagnosis (p=0.001)	(65,315)
I.C. Disease Clinical/Lab Features
MEN1 absent (sporadic ZES) (p<0.03) (Fig.3.D)	(64,65,110,207,734,818)
Short disease history prior diagnosis (<3 yrs.) (p<0.001)	(109,110,819)
High gastrin (p=0.022)	(109,110,191,507,819)
I.D. Disease Course
Recurrence postop with short disease-free interval	(254)
Develop ectopic Cushing’s syndrome (p=0.0049)	(109,113)
Primary gastrinoma location
Pancreatic >duodenal (p<0.004)	(109,110,281,315,734,819)
I.E. Tumor size, Location, Extent, Growth Rate
Large primary tumor size (>2-3 cm)	(109,110,315,433,507,819)
Gastrinoma located to the Left of the SMA> right of SMA (gastrinoma triangle)	(415)
Presence of Lymph node metastases (p<0.004)	(109,734,806)
Extent/presence of liver metastases (p<0.0001)	(27,64,109,110,254,314,314,433,507,734)
Diffuse>localized (p<0.0001)
Diffuse>both lobes>single lobe>none
Rate of growth of liver metastases or tumor
Rapid> slow, none	(111,402,429)
Time liver metastases diagnosed
Present initially>develop on follow-up (p=0.02)	(109)
Develop bone or extrahepatic metastases (p<0.0001)	(65,109,112,433,611)
I.F. Specific Tumor Features
Flow cytometric results
High S phase, low % nontetraploid aneuploid, multiple stem line aneuploid frequent	(820)
Molecular changes	(821)
(Chromosome 1qLOH) (p=0.019))	(822)
(Chromosome XLOH) (p=0.042))
Tumor grade	(65)
II. ADDITIONAL FEATURES SHARED WITH OTHER pNEN
II.A. Classification
Advanced TNM classification (ENETs, UICC/AJCC/WHO)	(41,115,116,142,816,817,823)
IIB. Histological Features
Poorly differentiated	(41,115,116,142,824,825)
High Ki₆₇>low Ki₆₇ proliferative index	(115,116,142,815-817)
Cytokeratin 19-IR positivity	(115,116,826-828)
Vascular, neural invasion	(115,116,639,829)
Decreased expression of autophagic genes	(117)
Alternative lengthening of telomeres, ATRX/DAXX loss	(444)
Alpha cell origin over Beta cell origin	(444)
IIC. Other Features
Age	(41,825)
Gender	(825)
Poor symptom control post-resection	(32)
No surgical resection	(41,825)
NF-pNEN rather than F-pNEN	(825)
Tumor size	(825)

Abbreviations: SMA, superior mesenteric artery; LOH, loss of heterozygosity; IR, immunoreactivity; ENETs, European Neuroendocrine Tumor network; postop-postoperative

A wide range of different anti-tumor treatments is used in patients with advanced pNEN, which are similar to that used in all advanced NENs. These include: surgical resection including cytoreductive (debunking) surgery; liver-directed therapies including radio-frequency ablation (RFA)/other local ablative therapies; trans-arterial embolization (TAE) or chemo-embolization (TACE), radio-embolization or selective internal radiation therapy (SIRT); chemotherapy; biotherapy with somatostatin analogues or interferon-Alfa; molecular targeted therapy with mTOR (everolimus) or tyrosine kinase inhibitors; peptide radio-receptor therapy (PRRT), liver transplantation and immunotherapy (38,50,142,158,604,830-839). There are only a few small, specific studies including only patients with metastatic gastrinomas as they are usually included in series with other metastatic pNEN, and in some cases even with GI-NENs (Carcinoids). Thus, below the results will primarily be from series containing pNEN with some gastrinomas.

One of the main problems with all forms of anti-tumor treatment in patients with advanced pNENs and other NENs, is the development of resistant to the therapies with time. This occurs to varying degrees at different times with all of the current therapies except complete surgical removal without recurrence (840,841). Numerous experimental approaches have been tried after failure of the different primary therapies, with the most frequent approach used is to switch to another primary established approach (840,841). The development of resistant with treatment and approaches recommended to deal with it will be briefly covered in each of the following sections dealing with the various established specific primary anti-tumor therapies.

Cytoreductive Surgery

In patients with gastrinomas with advanced metastatic disease, similar to all malignant NENs, it is recommended that the possibility of surgical removal of all resectable tumor (cytoreductive surgery, debunking surgery) should be considered by many authorities although there are no controlled studies to support its value (9,41,128,142,143,157,171,181,191,258,288,831,842-862,862-864). Surgery is generally recommended if ≥90% of all imageable disease can be removed, although others, have recommended lower numbers. There are only a few reports containing primarily gastrinomas treated with this approach (122,258,288,403,842-844,865), with most studies reporting results from different malignant pNEN and in some cases combined with GI-NENs (carcinoids). In various studies using this approach five-year survivals of 75-80% are reported and increased survival over patients not undergoing such surgery (128,142,143,157,831,849-859,861,862,862,864,866). This approach is primarily used in patients with well differentiated NENs, which is the case in >90% of gastrinomas (G1, G2,G3NET). Unfortunately, this approach is possible in the minority of even patients with advanced well differentiated gastrinomas or other NENs (<15-20%), and because of lack of control studies establishing its efficacy, it is not uniformly used. In only a small minority of G3NEC patients, is such an approach considered and even then, it is controversial (857,867).

At the time of any abdominal surgery, it is generally recommended that prophylactic cholecystectomy be performed because of the widespread use of somatostatin analogues for their anti-tumor activity and the ability of long-term treatment with them to cause biliary stasis and gallstones (143,180,849,868). Lastly, recent non-controlled studies, report that removal of the primary tumor increases the survival rate with PRRT and suggest it routinely be performed, although this approach is not widely used at present (869).

Liver Directed Therapies

GENERAL

These approaches include the use of local ablative techniques (radiofrequency ablation (RFA), ethanol injections, cryotherapy), which are frequently used in combination with other anti-tumor treatments, as well as various more general hepatic cytotoxic approaches using trans-arterial embolization (TAE)/chemo-embolization (TACE) or radioembolization (42,142,143,831,834,851,859,870-872,872-877). The embolization approaches in gastrinoma patients are generally reserved for patients who have metastatic unresectable hepatic metastases either limited to the liver or with liver-predominant disease, particularly if locally symptomatic, whereas in patients with other F-NENs, they are also frequently used for patients in whom the symptoms due to F-NEN excess-state not controlled by other modalities (25,142,143,831,834,851,870-872,876,878,879).

RADIOFREQUENCY AND OTHER ABLATIVE THERAPIES

Of the all of the liver-directed therapies, RFA is the most widely used, which converts RF waves to heat resulting in cellular destruction (142,831,880-883). RFA and other ablative techniques (cryotherapy, ethanol injections) are administered either at the time of surgery (+/- laparoscopic) to ablate isolated metastases or by radiological techniques for guidance (25,142,844,847,881,882,884-887).In different studies, relative contra-indications to its use are the presence of large lesions (>3.5-5 cm), a large number of lesions (>5-15), and he presence of metastases near vital structures (831,848,880,880,881,883,885,887-889). RFA has response rates of 80-95% which last up to 3 years, has the lowest complication rate of all liver-directed therapies (<15%), and can be used alone for a palliative procedure or to supplement a surgical resection by removing additional isolated liver metastases (25,831,880,885,888).

Embolization and Chemoembolization

Embolization of advanced metastases in the liver in patients with metastatic gastrinomas or other NENs, can be used because the blood supply to the tumor is primarily arterial, whereas in normal liver only 20-25% is arterial, with the majority coming from the portal vein (42,142,831,870,872-876,880,882). Therefore, interrupting the tumoral area arterial supply preferentially affects metastases (142,870,880,882). At present, this procedure is usually performed radiological, rather than at surgery and can be done alone (trans-arterial embolization or TAE) or accompanied by administration of chemotherapeutic agents (trans-arterial chemoembolization or TACE) such as doxorubicin, cisplatin, 5-fluorouracil, mitomycin C or streptozotocin (42,142,837,870,872,872,873,875,876,880,882,888,890). TAE or TACE is performed using gel foam powder or polyvinyl alcohol particles. In various studies a response is seen in 55-100% of symptomatic patients, 25-85% have an objective tumor response, and responses last from 6-45 mos. (142,831,834,870,872,880,891). Five-year survival rates for TAE/TACE are 20-35% and the progression free survival is 1.5 years (142,870,892). Contra-indications are the presence of portal venous occlusion, liver failure, extensive liver involvement (>50-75%), poor performance score, and previous biliary surgical reconstruction (142,870,880,888,890-893). Both TAE and TACE are associated with side-effects including a mortality rate of <6%, complications in 10-80%, particularly post embolization syndrome (pain, fever, nausea/vomiting), and occasionally gallbladder necrosis, hepatic failure, abscess formation and liver/renal failure (831,834,870,880,882,888,890,891,894). TAE/TACE are generally considered for palliative therapy in patients with non-resectable liver metastases with hepatic predominant disease (142,143,180,834,872,891). There are no prospective studies that have established the value of TAE/TACE; however, both the NANETS and ENETs guidelines recommend TAE/TACE be considered for palliative treatment in an experienced center if the patient has hepatic-only or hepatic-predominant disease that is not surgically resectable (142,143,180,182,834,848,891).

Radioembolization or Selective Internal Radiation Therapy (SIRT)

Radio-embolization or selective internal radiation therapy (SIRT) utilizes ⁹⁰Yttrium-labeled microspheres (Sir-spheres-20-60 um diameter, load-50Bq/sphere or Theraspheres-glass sphere, 20-30um diameter, 2500 Bq/sphere), which are administered by selective intra-arterial injection after a pretreatment angiogram to allow correct catheter localization (9,142,181,182,831,848,871,872,876,876-878,895-905). Prior to their administration, the position of the catheter tip needs to be properly established so that microsphere administration does not enter the cystic or duodenal arteries, which can result in cholecystitis or ulceration, and the amount of lung shunting must be determined to avoid radiation pneumonitis (142,831,871,871,872). Contraindications include: the presence of excessive shunting to the lung/GI tract; inadequate liver reserve; and the inability to isolate the liver arterial tree from the gastric/small intestinal branches (142,831,871,872,905,906). The mean objective response rate from 12 studies in patients with advanced NENs was 55% (range-12-90%) with stable disease seen in 32% (range-10-60% (142,831,871,905,907) and the disease control rate was 91% in a recent multicenter international study (908). The mean survival is 30-months and 50% of patients have symptomatic improvement in quality-of-life indices (142,871,897-899). Side-effects include post-embolization (fever, nausea, vomiting, abdominal pain) (25-45%), \and rarely ulceration or cholecystitis (<1%) if the catheter is not properly positioned (142,831,871,905,907,909).

At present the exact embolization procedure that is preferable in which clinical situation is not clear because of lack of prospective comparative studies. There have been no randomized control trials comparing radioembolization to the other liver-directed therapies, so at present at is unclear which should be preferred.

Medical Treatment of Advanced Metastatic Disease

CHEMOTHERAPY

Chemotherapy has a poor response rate (<15%) in well-differentiated NENs outside the pancreas (lung/GI-NETs, carcinoids) and thus is uncommonly used for these tumors, it has higher response rates in different series of malignant, well-differentiated pNEN, varying from 25% to 70 % (9,147,181,182,832,848,893,904,910-920). Until recently the generally used chemotherapeutic regimen was streptozotocin (STZ) based for advanced pNEN (most frequently combined with doxorubicin, 5-FU or cyclophosphamide) (9,142,147,181,182,832,878,893,910,916-919,921). STZ is a glycosamine-nitrourea derivative which was found to have cytotoxic effect on pancreatic islets (28), and since 1968 has been used for the treatment of patients with metastatic pNEN/gastrinomas (9,142,181,182,878,893,916-918,921). However, recent studies report temozolomide and capecitabine may have at least similar if not better activity than STX based regimens (827,830,911-913,918-920,922-927). Recently, in a randomized, prospective trial (ECOG-ACRIN E2211) (928) the Eastern Cooperative Oncology group compared the combination of temozolomide (TMZ) and capecitabine (CAP)(CAPTEM) to TMZ alone in 144 patients with advanced G1/G2 pNENs. At the interim analysis the mean PFS was 14.4 mos. in the TMZ alone group and 22.7 MS FR CAPTEM (P=0.022). At the final analysis the mean S was 53,6 mos. for TMZ and 58.7. mos. with CAPTEM. MGMT deficiency was associated with the response in this study. The authors concluded that the CAPTEM combination was superior to TMZ alone and that MGMT deficiency correlated with a response (928). In a recent systematic review of CAPTEM treatment of patients with advanced NENs, involving 42 articles with 1818 patients the overall disease control rate was 77% (range 44-100%), the median PFS ranged from 4 to 38 mos., and the media OS ranged from 8 to 103 mos. In this review (920) the safety analysis showed an occurrence of G3-G4 toxicities in 16% of the patients treated. The most common toxicities were hematological (27%), gastrointestinal (8%) and cutaneous (3%). This systematic analysis (920) concluded CAPTEM was an effective and relatively safe treatment for patients with well-moderately differentiated NENs of pancreatic, GI, lung and unknown origin.

STZ-based regimens have considerable morbidity with 70-100% developing some side-effect including nausea/vomiting (70-100%), abnormalities in hepatic function, leukopenia, and thrombocytopenia in 6%, and 15-40% developing some degree of renal toxicity including proteinuria (40-60%) and decreased creatinine clearance (893,913,916,917). The combination of STZ/doxorubicin (±5-FU) has an objective response rate of 20-45%, but complete responses are rare, and the median-response duration is 5-20 months (9,142,181,182,830,878,893,914,916-919,921). In patients with advanced gastrinomas only, the response rate varied from 5 to 40% (147,929).

Poorly differentiated pNETs comprise only 2-6.5% of all pNETs; however, it is important that they be identified because they have an aggressive course and poor prognoses and are generally treated differently than well-differentiated pNEN (54,142,848,912,913,918,930-935). The recommended chemotherapeutic drug combinations for treatment of well differentiated pNEN differs from that for treatment of poorly differentiated NENs (Grade 3) in any location (142,143,180,912,913,932,935-937). In contrast to the combinations listed above to treat advanced well differentiated pNEN, in patients with poorly differentiated NENs, a cisplatin-based drug combination with etoposide is generally the initial treatment (142,143,180,848,912,913,918,919,931,932,936,938,939). This combination results in an objective response in 30-80% of patients with mean duration of <12 months (142,143,180,912,932,936). The median survival is 4-16 mos., and the 5-year survival is 11% (range 0-31%) (142,143,180,912,913,918,931,932,936,938). This chemotherapeutic regiment can be associated with significant toxicity including GI toxicity (nausea/vomiting), myeloid-suppression and renal toxicity (142,143,180,912,913,931,932,936,938,939). In a recent multicenter study promising results were reported with the use of temozolomide/capecitabine (92%/8%=TMZ alone) (CAPTEM) in patients with Gr3 GP-NENs (933). In this study (933) the results of treatment with CAPTEM were reported from 130 patients (67% pNENs) and a radiological response was seen in 36%, the median TTF was 3.6 mos., OS was 9.2 mos., with the TTF being longer in pNENs than patients with GI-NENs Gr 3 tumors (5.8 vs 1.8 m0s, p=0.04). The role of surgery in patients with high grade NENs is controversial (940), although it is reported to be associated with higher survival in those with Gr3 WDs in some studies (940).

Recently, some studies (926,928,941-948) report that the effectiveness of alkylating agents in NENs correlated with the expression of, but not all (489,945,949-951) the DNA repair enzyme, O⁶-methylguanine DNA methyl transferase (MGMT) in these tumors. MGMT, in its role as a DNA repair enzyme, specifically removes the methyl/alkyl group form the O⁶position of guanine, whereas alkylating agents induce methylation at this site which leads to DNA mismatch occurring and results in cell death/apoptosis. Some studies show that pNEN have a higher response rate to alkylating agents due to their low level of MGMT (926) compared to GI-NENs (carcinoids) having higher MGMT levels and lower response rate. Perspective studies are needed before recommending the routine determination of NEN tumoral MGMTs to help predict, for a given patient the subsequent response to an alkylating agent, and therefore its routine use is not generally recommended at this time (928,945-948).

BIOTHERAPY

Somatostatin Analogues

Similar to NENs in general, most well-differentiated G1, G2 pNEN, as well as a proportion of G3 pNEN, overexpress one of the 5 subtypes of somatostatin receptors (sst1-5) (most frequently sst2) (142,851,952-955). Numerous studies, including both non- controlled and randomized controlled studies (PROMID, CLARINET studies) on NENs and pNEN(including gastrinomas) (142,954,956,957), demonstrate that somatostatin agonist analogs (octreotide, lanreotide) are not only are effective for controlling the hormone-excess state in F-NENs(discussed in a previous section), but also have anti-tumor growth effects in NENs (25,142,155,402,603,609,848,851,952-955,958-965). The exact molecular basis for this antiproliferative-effect is not entirely clear, but somatostatin analogues inhibit the release of growth factors from NETs, have antiproliferative effects on neighboring cells (stromal, immune, vascular, etc.) and activate intracellular cascades that have antiproliferative effects (phosphatases, inhibition of adenylate -cyclase, etc.) (603,954,959,962-964). In these studies the anti-tumor effect of the somatostatin analogues is almost entirely a tumoristatic effect (only 10-15% show decreased tumor-size), resulting in disease stabilization with prolongation of progressive free survival, and because of study design and the multiple treatments the patients received, an effect on overall survival has not been established (155,402,603,609,848,956,958,961-964,966). However, these agents are very well tolerated, and are generally the first line treatment of patients with advanced well-differentiated gastrinomas and other pNEN as well as with lung/GI-NENs(carcinoids) (25,142,143,150,164,180,833,851,952-956). In a recent study of the use somatostatin analogs (SSAs) on tumor progression in 12 ZES patients (WD, G1, G2) (155), 67% had a sustained response to SSAs and 33% showed early progression. There was a significant difference in PFS between the early and late progression groups (84 vs 2 mos., p=0.004) (155). However, there was no difference OS or PFS between these 12 SSA treated ZES patients and 21 other ZES patients not treated with SSA analogues (155).

With time the tumor may become refractory to the antigrowth effect of the somatostatin analogue, and its efficacy may be restored by either increasing the dosage or shortening the time interval between doses (965). Side effects that result in somatostatin analogue therapy discontinuation are rare with any side-effect occurring in 50% of patients (including pain at injection site, GI symptoms), which may improve with continued treatment (25,29,142,848,954,955,958,961,964,967). Long-term more serious side-effects include the development of biliary sludge/gallstones which cause symptomatic disease in <1%, developing glucose intolerance/diabetes or developing steatorrhea which is usually mild (25,29,142,142,848,868,954,955,958,961,964,967).

Interferon

Interferon-alpha, similar to somatostatin analogues, is able to control symptoms of the hormone hypersecretory state and has anti-proliferative effects in pNEN/NENs which result in primarily disease stabilization, rather than a decrease in tumor size (<15%) (142,848,961,968-973). In the only study of interferon limited to gastrinoma patients (13 patients, advanced metastatic progressive disease) (972), 46% of patients showed disease stabilization, and in 23% it lasted almost 2 years. The antiproliferative effect on pNENs/NETs of interferon is partially mediated by blocking cell-cycle progression in G1, inhibiting DNA synthesis, stimulating an increase in Bcl-2, inhibiting protein synthesis, inhibiting angiogenesis, and induction of apoptosis (961,968,970,971). Side effects develop in the majority of patients (>70%) with the most frequent being flu-like symptoms (40-80%), weight loss/anorexia (60%), and fatigue (51%), which frequently decrease in severity with continued treatment or with decreased dose (848,961,970-972). More serious side effects include hepatotoxicity (31%), hyperlipemia (31%), and bone marrow toxicity; autoimmune disorders particularly thyroid disease and rarely CNS side effects such as depression or mental disorders (142,961,968,970-972). While interferon-alpha was frequently used in the past either alone or with somatostatin, at present it is uncommonly used because of the availability of other agents with fewer side effects.

MOLECULAR TARGETED THERAPIES

mTor-Inhibitors (Everolimus)

Both extensive in vitro and in vivo studies demonstrate that activation of the mTOR cascade, plays and important role in the proliferation, growth, and apoptosis of pNEN, as well as NENs in other locations (142,150,479,882,915,957,964,974-979). mTor is a serine-threonine kinase critically involved in a variety of cellular functions including apoptosis, cell-growth, and proliferation (150,957,974,977,978,980). A number of different mTOR antagonists have been developed and shown to have anti-proliferative effects in NENs in various in vitro and in vivo studies, however, only one, everolimus, has been approved by the FDA for patients with advanced NENs (pNEN (including gastrinomas) and GI-NENs (carcinoids) (142,150,480,974-976,978-981). The approval of everolimus for use in both advanced pNEN and GI-NENs(carcinoids) was based on the positive results of two randomized, double-blind, prospective, placebo-controlled studies, RADIANT-3 (pNEN) (480) and RADIANT-4 (lung/GI-NENs) (982), which each demonstrated almost a 3-fold increase in PFS (p<0.001). There are no specific studies on the effects of everolimus on gastrinomas only, and the only data comes from general trials of all pNEN.

Everolimus treatment was associated with a 2-fold increase in adverse events, the majority being grade 1 or 2, with grade 3 or 4 side effects occurring in 3-7% (primarily hematological, stomatitis, or hyperglycemia) which could be managed by dose-reduction or drug interruption (480). At present, it is not established whether everolimus’ ability to increase progression-free survival will result in an increase in overall survival (142,981).

Long-term treatment with everolimus is associated with primary and acquired resistance, which has frequently limited its long-term benefit for patients with advanced NEN (150,983-985). Numerous mechanisms for this have been described but none has been sufficiently successful to lead to its widespread use or its ability to function as a biomarker for the occurrence of resistance (983-985).

Numerous studies have provided information on the importance of angiogenesis in the pathogenesis of pNENs as well as other NENs (986). A recent randomized Phase II study compared the effectiveness of everolimus alone versus everolimus plus the anti-VEGF agent, bevacizumab in 150 patients with advanced pNENs (987). The combination resulted in improved PFS compared to everolimus alone (16.7 mos. vs 14 mos., complete tumor response in 31% with the combination compared to 12% with everolimus alone (p=0.0053), with similar median overall responses. Toxicities were more frequently seen in the combination group (987). The authors concluded that these results support the need for continued evaluation of VEGF pathway inhibitors for the treatment of advanced pNENs (987).

Tyrosine Kinase Receptor Inhibitors (Sunitinib and Surufatinib)

PNEN including gastrinomas, similar to other NENs, as well as other neoplasms and normal tissues, frequently possess multiple tyrosine kinase (TK) receptors, which are important in mediating growth, angiogenesis, differentiation, and apoptosis (26,142,848,895,957,964,988-995). TK receptors comprise >20 families of transmembrane receptors that mediate the actions of a number of different growth factors that include the receptors for insulin-like growth factor (IGF1R), epidermal growth factor family (EGFRs); hepatocyte growth factor (c-Met); platelet-derived growth factor family (PDGFRs); vascular endothelial growth factor family (VEGFRs); stem cell factor (c-Kit) and a number of others (142,957,992,994). A number to tyrosine kinase receptor antagonists (sunitinib, axitinib, cabozantinib, famitinib, nintedanib, pazopanib, sorafinib, sulfatinib, surufatinib) (979,994,996-998,998-1001) have been shown to have anti-growth/anti-angiogenic effects on pNEN/NENs in both in vitro and in vivo animal studies, however, at present the only two are approved for use in various countries which are sunitinib (US, Europe, other countries) which is an inhibitor of a number of tyrosine kinase receptors (PDGFR, VEGFR1/2,c-KIT, FLT-3) (142,914,989,991,994,996,1002-1004) and surufatinib (approved in China) which is an inhibitor of VEGFR, FGFR1, and colony stimulating factor 1 (CSF1R) (998,998-1001). In a Phase 3 double blind, randomized trial (1002) in 171 patients with progressive well-differentiated nonresectable pancreatic NENs (including 19 patients with ZES), sunitinib resulted in a doubling of PFS (11.4 vs. 4.5 mos., p<0.001), which lead to its approval for advanced pNEN. There are no specific studies on the effects of sunitinib on gastrinomas only, and the only data comes from general trials of all pNEN.

Sunitinib treatment is associated with frequent grade 1/2 side effects and some grade 3/4 side effects particularly neutropenia (12%) and hypertension (10%) (994,1002,1005). A quality-of -life analysis (1002) showed sunitinib did not have a significant effect, with most side-effects able to be managed by dose-reduction and/or temporary cessation of treatment.

Surufatinib was evaluated in two multicenter studies, one a randomized, double-blind, placebo controlled Phase III involving 172 patients with advanced pNENs in 21 different Chinese hospitals (999) and a second study (SANET-ep) involving 198 patients with advanced extra-pancreatic NENs 1in 24 hospitals in China (998), In the first study in patients with pNENs (999) the PFS was 19.3 mos. with surufatinib vs 3.7 with placebo (p=0.00110) with the most common Gr ¾ side-effects being hypertension (38% vs 7%), proteinuria (10% vs 1%) and hypertriglyceridemia (7% vs 0%). In the second study on patients with advanced extra-pancreatic NENs (998) the PFS was 9.2 mos. with surufatinib vs 3.8 with placebo (p<0.0001) with the most common Gr ¾ side-effects being hypertension (47% vs 13%) and proteinuria (19% vs 0%). Currently, surufatinib is not approved by either the FDA or European regulatory agencies.

Long-term treatment with sunitinib is associated with primary and acquired resistance, which has frequently limited their long-term benefit for patients with advanced NEN (840,841,983,984,994,995). Numerous mechanisms for this have been described but none has been sufficiently successful to lead to its widespread use or its ability to function as a biomarker for the occurrence of resistance (840,841,983,984,995).

Peptide Radioreceptor Therapy (PRRT) Using Radiolabeled Somatostatin Analogues

PRRT utilizes the fact that almost all well-differentiated NENs, as well as a proportion of G3NECs, overexpress somatostatin receptors (sst1-5) particularly sst2, which can bind radiolabeled somatostatin analogues resulting in the targeted delivery of cytotoxic radiation to the tumor cells (142,154,603-605,607,608,836,952,953,1006-1018). Two different isotopes have been used in most studies: ⁹⁰Yttrium(⁹⁰Y)- or ¹⁷⁷Lutetium(¹⁷⁷Lu)- labeled somatostatin analogues (142,154,836,1008-1016,1018). ¹⁷⁷Lu emits beta-particles and gamma rays, has a maximum tissue penetration of 2 mm, and a half-life of 6.7 days, whereas ⁹⁰Y strongly emits beta-particles, has a maximal tissue penetration of 12 mm, and a half-life of 2.7 days (1011-1015). A number of different synthetic somatostatin analogues have been used, with the most frequent being octreotide or octreotate coupled to the radiolabel by different chelators, including diethylene triamine penta-acetic acid (DTPA) and 1,4,7,10-tetraazaacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (142,1010,1011,1013,1014).

At present the only approved formulation for pNEN is ¹⁷⁷Lu-DOTATATE (604,605,607,608,1006-1010). The approval of this therapy is based on results of a double-blinded, control phase 3 trial (NETTER-1) (1019) in patients with advanced unresectable, midgut carcinoids which showed a marked prolongation of PFS (from 8.4 mos. to >40 mos., p<0.0001), with an increased overall survival from 3 to 18%, combined with the results of treatment of 510 patients with advanced pNEN and other NENs, in Rotterdam which showed complete response in 2%, partial response in 28%, and tumor stabilization in 35% (404,1015). Of 440 patients (10 studies) with various malignant pNEN/NETs, including gastrinomas, treated with ⁹⁰Y-labeled somatostatin analogues, complete tumor remission was rare (0-6%), partial remission occurred in 7-37%, and tumor stabilization in 40-86% (29,142,1011,1013,1014). In a recent meta-analysis of 22 studies (1758 patients) with advanced NENs treated with PRRT the pooled disease response rate (complete/partial tumor response) was 33% with RECIST criteria, and the pooled disease control rate (compete/partial response or stable disease) was 79% (1020). In a second recent meta-analysis of PRRT results (1018) involving 15 studies selected from 715 references in patients with advanced NENs, the pooled response rate was 27.6% by RECIST criteria, and 20.6 % by SWOG criteria, with respective DCR rates of 79.1% and 78.3% by the two criteria demonstrating excellent agreement with these two different criteria of response.

In two different studies there was no significant difference in the PFS overall survival rates between NEN patients treated with PRRT with advanced pNEN compared to NENs in other sites (869,1010).

Gastrinomas are one of the malignant pNEN/NETs that were most responsive to PRRT (42%-3mos); however, they also had one of the highest recurrence rates leading to a poorer prognosis (142,404,1011,1013-1015,1021). In one detailed study of 11 patients with metastatic ZES (1022) treated with either ⁹⁰Y-and/or ¹⁷⁷Lu-labeled somatostatin analogues, the mean serum gastrin decreased by 81%, compete response occurred in 9%, partial tumor response in 45%, tumor stabilization in 45%, and in 64% the antitumor effect persisted for a median period of 14 months. In a second study (1023) involving 30 gastrinoma patients treated with ⁹⁰Y- labeled somatostatin analogues the tumoral partial response rate was 33% with a mean overall survival time of 40 mos.

The treatment was well tolerated when given with renal protective amino acid infusions, with no Grade 3/4 nephrotoxicity. In various studies the most serious side effects are hematological (15%-transient, 0.8% developing a myeloproliferative disorder), liver toxicity (0.6%) and renal toxicity, with the latter occurring primarily in patients receiving ⁹⁰Y-labeled somatostatin analogues (154,404,604,605,607,608,1006,1007,1010,1015,1019).

Recent studies show that in patients with refractory hormonal symptoms due to a F-NEN, PRRT may be of great help in control the hormone excess state’s symptoms independent of its effect on tumor proliferation (25,148,350,860,1010,1024). Although this is almost never an issue in patients with gastrinoma because of the effectiveness of PPIs in controlling the symptoms of the gastric acid hypersecretion, numerous recent studies suggest that PRRT may be particularly helpful in patients with refractory advanced F-NEN syndromes in controlling the hormone excess state, particularly in patients with carcinoid syndrome, VIPomas and insulinomas (25,148,350,860,1010,1024).

With ¹⁷⁷Lu-(DOTA⁰, Tyr³) octreotate, a number of prognostic factors were identified which predicted a poor outcome after PRRT, which included; presence of progressive metastatic disease prior to treatment; Karnofsky performance score of ≤70; no tumor-response to PRRT; weight loss at the time of treatment; presence of bone metastases; extensive liver involvement; poor uptake of the radiolabeled analogue by the tumor; the presence of malignant gastrinoma, VIPoma, or insulinoma and the presence of positive lesions on ¹⁸F-FDG Pet scans(142,404,612,1011,1013-1015,1021,1025,1026).

Recent studies support the conclusion that retreatment of NEN patients with PRRT who develop progressive disease after an initial PRRT treatment, is a feasible option with good efficacy and acceptable toxicity (1027,1028). This conclusion was supported by two recent systematic reviews and met analyses (1027,1029). In the report by (1027) 9 articles with 426 patients were analyzed and the ORR after retreatment was 17.1%, DCR was 76.9%, PFS was 14.1 mos. and OS was 26.9 mos. Pooled proportions of hematologic and renal toxicities were 11% and 0.7%. In a subgroup allowing direct comparison to initial PRRT treatment data, the salvage PRRT had a lower therapeutic efficacy (ORR, DCR, p<0.001) and shorter PFS (P=0.03), despite similar hematologic and renal toxicity. In a second analysis (1029) 13 studies were identified containing retreatment data (¹⁷⁷Lu-PRRT, or ⁹⁰Y-PRRT) from 567 original studies. With ¹⁷⁷Lu-PRRT retreatment in 7 studies PFS was 12.5 mos., mean OS was 26.8 mos., and DCT was 71%. Grade ¾ toxicity occurred in 5% of 177Lu-PRRT retreated patients, with no Gr ¾ renal toxicity and no myelodysplastic and acute myeloid leukemia incidence.

Liver Transplantation

In contrast to many metastatic tumors, liver transplantation is both recommended for pNEN/NENs (including patients with advanced gastrinomas) and is selectively used in a small number of patients with metastatic advance metastatic pNEN/NENs, although it use remains controversial (142,143,1030-1038). In one recent systematic analysis of reported NEN series the 1-,3- and 5-yr survival rates were 89%, 69% and 63% with a recurrence rate after transplantation of 31-57% (1032). In another recent (2020) review of 206 patients with metastatic pNEN/NENs who underwent liver transplantation the overall survival rates at 1,3,5 and 10 years were 89%,75%, 65% and 46% respectively (1039). In this study (1039) the recurrence rate was 34% with a mean time to recurrence of 28 mos. Important prognostic factors in the systematic analysis (1032) were >50% liver involvement by tumor, high Ki₆₇, or the presence of a pancreatic primary over a GI-NEN. In other studies important other factors predict a poorer prognosis include: older age of patient(>50), older age of donor, cold ischemic time MELD score, tumor recurrence, presence of a symptomatic tumor, a primary tumor in the pancreas as opposed to an extra-pancreatic NEN (carcinoid), poor tumor differentiation, transplantation associated with a simultaneous and extensive digestive tract resection, presence of hepatomegaly, presence of extra-hepatic metastases and a patient with a primary tumor not resected (1034-1036,1039). Liver transplantation is generally reserved for patients with life-threatening hormonal disturbances refractory to other treatments (which is very rare in ZES) or to selected patients with pNEN/NENs with diffuse liver involvement refractory to all other treatments (26,142,1033-1040).

If liver transplantation is considered, important selection criteria include the presence of a well-differentiated NEN/pNEN; age <45-50; a Ki-67 index <10%; <50% liver involvement; the absence of extra-hepatic metastases as determined using the most sensitive methodology (⁶⁸Ga-labeled somatostatin-analogues and PET imaging) ; the absence of extra-hepatic disease(resected primary tumor); the absence of other resections at the time of liver-transplantation; and some groups consider various histological features such as E-cadherin-tumor staining characteristics (142,848,930,1032,1034-1039,1041,1042).

Immunotherapy

Since the recent widespread effectiveness of immune check point inhibitors in a number of tumors (melanomas, etc.), including in patients with poorly differentiated lung NENs with small cell neuroendocrine tumors, there have been several studies of the efficacy and safety in other tumors such as patients with advanced NENs including pNEN such as advanced gastrinomas (995,1043-1049).

A number of these studies suggest single agent (Anti-PDL1) immunotherapy may be a useful approach in only small subset of patients with advanced disease (12% in Keynote 02 study (1047) , 0-5% in other studies not selecting for PD-L1 activity (1049-1051) and this subset is primarily patients with high-grade poorly differentiated NENs (995,1043-1046). In various GEP-NENs the presence of high tumor-infiltrating lymphocyte (TILs) numbers and high PD-1 expression show a significant correlation with decreased survival and higher grading of the tumor supporting the finding that immunotherapy might be most promising in GEP-NENs with high TILs (1044). In other tumors particularly melanomas, renal cell carcinoma and non-small cell lung tumors, a combination of immunotherapies using anti-PD-L1 and CTLA-4 blockade resulted in increased efficacy, and a recent study in patients with various advanced NENs reported an objective response rate of 24 % with increased activity in patients with both atypical lung NENs and with high-grade pNEN (1046). Other studies report ORR of 14.7-25% almost entirely in patients with high grade NENs (995). Ongoing and future studies are in progress to exactly define the best combinations as well as define which specific NEN types will best respond (995,1043-1045).

Neoadjuvant Therapy

Because the large majority (>80%) of patients with advanced gastrinomas or other advanced NENs present with surgically unresectable disease, primarily with widespread liver metastases or unresectable locally invasive tumors, the possible benefit of surgical resection is not an option. Therefore, with the increasingly effectiveness of various anti-tumor modalities, there is increasing interest in a possible role of neoadjuvant treatments which could allow tumor downsizing to the point surgical resection can become an option (1052,1053). In one recent systematic review and meta-analysis of 9 studies from the literature (1052), involving 468 patients with advanced pNENs who had adjuvant therapies, there were no complete responders, 43.6% had a partial response; 51.3% had stable disease; and 4.3% had progressive disease. The estimated resection rate was 68.2%, and the RO resection rate was 60.2% (1052). There was no difference in the resection rate between different chemotherapy regimens (41% vs 34%), as well as the RO resection rate (62% to 68%) and the ORR was similar with CAPTEM and FAS (42% and 34%). PRRT showed a higher numerical ORR than chemotherapy although the difference did not reach statistical significance (49% vs 37%, p=0.154). The authors concluded these results were promising for some patients, however the best neoadjuvant regime to use remains unclear (1052).

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Diabetes, Cardiomyopathy, and Heart Failure

ABSTRACT

Heart failure (HF) is an underappreciated complication of diabetes. HF occurs in individuals with diabetes at higher rates, even in the absence of other HF risk factors such as coronary artery disease and hypertension. Comorbid ischemic heart disease and cardiovascular risk factors significantly contribute to the etiology of cardiomyopathy and HF in patients with diabetes. In addition, long-standing diabetes can independently cause subclinical alteration in cardiac structure and function, eventually leading to the development and progression of HF. A complex interplay between numerous mechanisms underlies the pathophysiologic links between diabetes and HF. Patients with concurrent diabetes and HF have impaired quality of life and a poor prognosis with a high risk of hospitalization and mortality. Despite the solid epidemiologic link between poor glycemic control and HF risk, the effects of intensified glycemic control in preventing HF remain controversial. Large-scale cardiovascular outcome trials published since 2015 have confirmed the efficacy and safety of sodium-glucose co-transporter-2 inhibitors (SGLT2) inhibitors in preventing HF among patients with type 2 diabetes mellitus. In addition, several dedicated major clinical trials confirmed the cardiovascular benefits of SGLT2 inhibitors in patients with established HF, regardless of left ventricular ejection fraction or diabetes status. Furthermore, high-quality data from these clinical trials transformed SGLT2 inhibitors from glucose-lowering agents to HF drugs. This chapter outlines the complex relationship between HF and diabetes, focusing on the epidemiology, pathophysiology, and prognostic implications. Additionally, we review the current knowledge on identifying subclinical cardiac remodeling, predicting HF risk, and preventing HF in diabetes. We also summarize the recent evidence and guideline recommendations for the pharmacological treatment of patients with coexisting HF and diabetes.

INTRODUCTION

Diabetes is a risk factor for cardiomyopathy and heart failure (HF) independent of traditional cardiovascular (CV) disease (CVD) risk factors such as hypertension and coronary artery disease (CAD) (1–4). The universal definition of HF recognizes patients with diabetes as “at risk for HF” (Stage A). Asymptomatic individuals with at least one of the following: 1) evidence of structural heart disease, 2) abnormal cardiac function, or 3) elevated cardiac natriuretic peptide or troponins are considered to have “pre-HF” (stage B). According to this classification, HF (stage C) is defined as a clinical syndrome with signs or symptoms of HF caused by an abnormality in cardiac structure and function and corroborated by elevated natriuretic peptide or objective evidence of cardiogenic congestion (pulmonary or systemic) (3,5).

The prevalence of diabetes is approximately 10.2% in the U.S. population, and HF affects 9 to 22% of patients with diabetes (6–10). In clinical trials of antidiabetic agents, HF was present in 4 to 30% of participants with diabetes (11). On the other hand, the prevalence of pre-diabetes or diabetes was 30 to 40% among individuals enrolled in HF trials (12,13).

Longstanding diabetes alters cardiac structure and function, resulting from the direct effects of abnormal myocardial metabolism and insulin resistance (IR) even without atherosclerotic CAD (14). The pathophysiologic link between diabetes and HF is complex and multifactorial, involving various abnormal biochemical pathways including but not limited to abnormal calcium signaling, deranged glucose/fatty acid metabolism, and inflammatory pathways contributing to myocardial fibrosis, stiffness, and hypertrophy (7,15,16). A complex interaction of these mechanisms can cause asymptomatic diastolic and systolic dysfunction, eventually leading to the clinical syndrome of HF. Conversely, HF is also associated with a higher prevalence of diabetes and is considered a predictor of future risk of type 2 diabetes mellitus (T2DM) (17).

Left ventricular (LV) dysfunction in patients with diabetes may present with three different HF phenotypes, such as HF with preserved LV ejection fraction (LVEF ≥ 50%; HFpEF), HF with mildly-reduced LVEF (HFmrEF; LVEF 40-49%), and HF with reduced LVEF (HFrEF; LVEF ≤40%) (3). Diagnosing HFpEF and HFmrEF is often challenging since the symptomatology of HF may overlap with other comorbidities such as obesity, lung disease, and chronic kidney disease (CKD). Therefore, the guidelines usually recommend incorporating additional objective diagnostic criteria such as elevated natriuretic peptides or imaging evidence of either structural heart disease or diastolic dysfunction (18).

The coexistence of diabetes and HF is a poor prognostic factor, posing a greater risk of HF hospitalization, all-cause mortality, and CVD mortality. For instance, epidemiologic studies indicated a 50-90% higher risk of CVD mortality in patients with HF and diabetes, regardless of HF phenotype (12,19). HF patients without DM are at increased risk of developing glycemic abnormalities. In addition, newly diagnosed pre-diabetes was associated with a significantly higher risk of all-cause and CV mortality in HF patients. These findings underscore the importance of screening for pre-diabetes or diabetes among patients with HF (17,20,21). Moreover, early assessment with echocardiography can be helpful for the detection of subclinical structural abnormalities and myocardial dysfunction in asymptomatic patients with diabetes.

The pathophysiology of diabetes-related HF is complex, and despite significant advances over the past decades, many areas are still poorly understood. Since 2015, several landmark clinical trials on sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have revolutionized our understanding of CVD risk reduction in patients with T2DM and have led to a paradigm shift in the clinical practice recommendations for the management of T2DM (22). Incredible evidence from the CVD outcome trials (CVOTs) has confirmed the significant improvement in HF outcomes with SGLT2 inhibitors in patients with or without diabetes. These findings increased medical communities' awareness and interest in the links between diabetes and HF.

The American Diabetes Association (ADA) now recommends using SGLT2 inhibitors as first-line agents in T2DM patients with a high risk of or established HF (23). In addition, several dedicated major randomized clinical trials (RCTs) confirmed the CVD benefits of SGLT2 inhibitors in patients with established HF, regardless of LVEF or diabetes status. Moreover, these RCTs transformed SGLT2 inhibitors from glucose-lowering agents to HF drugs. The 2022 American College of Cardiology (ACC) Foundation / American Heart Association (AHA) / Heart Failure Society of America (HFSA) guideline for the management of HF recommended the use of SGLT2 inhibitors for the treatment of HF, regardless of LVEF (3).

This chapter outlines the complex relationship between HF and diabetes, focusing on the epidemiology, pathophysiology, and prognostic implications. Additionally, we review the current knowledge on identifying subclinical cardiac remodeling, predicting HF risk, and preventing HF in diabetes. We also summarize the recent evidence and guideline recommendations for the pharmacological treatment of patients with coexisting HF and diabetes.

EPIDEMIOLOGY OF DIABETES AND HF

There is a bidirectional link between diabetes and HF (24). Diabetes, either type 1 or type 2, is a strong risk factor for developing HF (25–27). In addition, HF may contribute to the pathogenesis of IR and T2DM (28). The shared underlying risk factors and the overlap of the pathophysiological mechanisms play a critical role in the frequent coexistence of T2DM and HF.

Based on the data from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018, the prevalence of HF is 2.3% in the US general adult population (29). The prevalence of HF in individuals with diabetes ranges between 9% and 22%, depending on the characteristics of the population studied (6,8,9). Diabetes is also highly prevalent among patients with HF. In major contemporary drug trials of HF, 32% to 43% of patients with chronic HF had coexisting diabetes (12,30,31). A report from a nationwide US registry (NHANES 2005-2016) demonstrated that, among patients with HF, the prevalence rates of diagnosed and undiagnosed T2DM were 34.7% and 12.8%, respectively (32).

HF is a common but often neglected complication of diabetes (33). HF and cardiomyopathy have a heterogeneous etiology in patients with diabetes (Figure 1 and Figure 2). The strong link between diabetes and CAD, hypertension, and renal disease plays a significant role in the development of cardiomyopathy and HF in patients with diabetes (34). Moreover, HF occurs in individuals with diabetes at higher rates, even in the absence of other HF risk factors (16,35).

Diabetic Cardiomyopathy

Diabetic cardiomyopathy, which lacks a standardized clinical definition, generally refers to diabetes-related myocardial dysfunction without other potential causes (36). A report by Lundbæk in 1954 described the concept of diabetes directly causing myocardial dysfunction (37). In 1972, a landmark study by Rubler et al. described diabetic cardiomyopathy as a new clinical entity by reporting the post-mortem results of 4 patients with diabetes-related HF and dilated cardiomyopathy without other apparent causes of myocardial dysfunction (14). The initial reports of diabetic cardiomyopathy referred to a dilated LV with eccentric hypertrophy and LV systolic dysfunction (HFrEF). Nevertheless, more recent clinical studies described HFpEF with concentric LV hypertrophy and LV diastolic dysfunction as a distinct phenotype of cardiomyopathy rather than being an intermediate form between risk factors and HFrEF (38). The transition from HFpEF to HFrEF does not appear to occur as commonly as it was once presumed.

Epidemiologic Evidence

Evidence from large-scale epidemiologic studies has confirmed the strong link between diabetes and HF. For instance, reports from the prospective Framingham Heart Study in the 1970s indicated that individuals with diabetes had 2-fold (in men) to 5-fold (in women) higher risk of developing HF than individuals without diabetes after adjustment for other risk factors (2,39). Similarly, contemporary cohort studies suggested that diabetes is independently associated with a 1.7 to 2.5-fold greater risk of HF (6,40).

A recent nationwide cohort study from Sweden including >679.000 patients with T2DM and >2 million matched control subjects demonstrated that a diagnosis of T2DM was associated with HF risk even if CVD risk factors, such as glycated hemoglobin, systolic blood pressure (BP), estimated glomerular filtration rate, and lipids were within a target range (41). The study also demonstrated that CVD complications have significantly declined over the past 20 years in individuals with and without T2DM. However, the decline in the rate of HF in patients with T2DM has plateaued over recent years. One potential explanation for this finding is the obesity epidemic, as adiposity plays a major role in the development of HF in patients with diabetes. For instance, a recent analysis of 2 US cohort studies demonstrated that overall obesity, abdominal obesity, and fat mass were strongly associated with a greater risk of HF in participants with diabetes. Interestingly, a similar independent association was absent in those without T2DM (42).

Ischemic heart disease is more frequently seen in HF patients with coexistent T2DM than those without T2DM (63% vs. 47%). Moreover, ~90% of the patients with T2DM and HF of non-ischemic etiology have at least one comorbidity that can contribute to HF development, such as hypertension, atrial fibrillation, valvular disease, or pulmonary disease (43).

Figure 1. Heart failure with reduced ejection fraction due to ischemic cardiomyopathy in a patient with uncontrolled type 2 diabetes. 57-year-old female patient with a history of uncontrolled type 2 diabetes (HbA1c = 12.0) and active tobacco abuse presented with a 2-day history of intermittent midsternal chest pain. (A) Her ECG on presentation demonstrated findings of acute/recent anteroseptal myocardial infarct and old/age indeterminate inferior myocardial infarct, and her serum troponin I was markedly elevated. (B and C) Her echocardiography revealed a dilated left ventricle with severely reduced systolic function, an ejection fraction of 20-25%, and akinetic anterior and inferior wall segments. Her coronary angiography, which was performed emergently, demonstrated subacute occlusion of the proximal segment of the anterior descending artery (arrow in image D) and chronic total occlusion of the middle segment of the right coronary artery (arrow in image E).

Figure 2. Heart failure with reduced ejection fraction due to non-ischemic cardiomyopathy in a patient with uncontrolled type 2 diabetes. 59-year-old male patient with a history of hypertension (medically managed), class I obesity, hyperlipidemia, moderate alcohol consumption, and undiagnosed type 2 diabetes (HbA1c = 13.5) presented with dyspnea on exertion, orthopnea, and leg edema and he was admitted with the diagnoses of acute decompensated heart failure. (A) His ECG on presentation demonstrated left ventricular hypertrophy with repolarization abnormalities. (B and C) His echocardiography revealed a dilated left ventricle with severely reduced systolic function and diffuse hypokinesis, an ejection fraction of 25-30%, and eccentric left ventricular hypertrophy. (D and E) His coronary angiography, performed for ischemic evaluation, demonstrated no evidence of significant epicardial coronary artery disease. The patient’s non-ischemic cardiomyopathy was attributed to a mixed presentation of alcoholic and diabetic cardiomyopathy and hypertensive heart disease.

Diabetes is an independent predictor of progression from preclinical HF (stage A and stage B) to clinic HF (stage C) (44). A population-based analysis on the National Scottish Register found that HF hospitalization risk was ~2-fold higher among patients with diabetes than those without diabetes (45). A prospective cohort study, including individuals from the southeastern U.S., demonstrated that hypertension and diabetes were associated with the highest HF risk in white and black participants (46). The population-attributable risk of HF was highest for hypertension (31.8%), followed by diabetes (17%). A population-based case-control study also observed an attributable risk of HF at ~17% for diabetes, without any significant difference between HFpEF and HFrEF (47).

Epidemiologic studies have demonstrated a higher incidence of HF in men than in women with diabetes (27,40). This finding is consistent with the strong association between HF risk and male sex in the general population. However, interestingly, diabetes contributes to the future risk of HF more in women than in men, as supported by multiple epidemiologic studies (27,39). In a meta-analysis of 47 cohort studies including >12 million individuals, type 1 diabetes mellitus (T1DM) and T2DM were associated with a 47% and 9% greater excess risk of HF in women than men, respectively (48). The basis for the sex-specific disparity in HF risk attributable to diabetes remains unclear.

Prediabetes and HF Risk

Some epidemiologic studies have suggested that prediabetes may pose a risk for cardiomyopathy and HF(49). In a population-based cohort study, prediabetes was independently associated with HF with an odds ratio of 1.7 (9). A modest but significant association exists between fasting plasma glucose levels and the risk of HF independent of an individual’s diabetes status (50).

Glycemic Control and HF Risk

Glycemic exposure predicts HF risk in individuals with T1DM and T2DM (26,27,51). A population-based prospective case-control study from the Swedish National Diabetes Register evaluated the impact of glycemic control on the future risk of HF hospitalization over a mean follow-up of 7.9 years (26). Compared to a population-based control group without diabetes, patients with T1DM had a four times higher risk of HF hospitalization. Nevertheless, the risk markedly varied depending on glycemic control or comorbidities; hazard-ratio (HR) of 2.2 (1.5–3.0; p<0·0001) in patients with hemoglobin A1c (HbA1c) ≤6.9%, HR of 11.2 (8·4–14·9; p<0·0001) in patients with HbA1c ≥9.7%. Another report from the same dataset revealed that each 1% increase in HbA1c correlated with a 20% higher risk of HF in patients with myocardial infarction and T1DM (52). Among individuals with T2DM, the excess risk of HF attributable to glycemic control varies depending on the patient’s age. For instance, poor glycemic control correlates more strongly with excess risk of HF among middle-aged adults (<55 years old). In contrast, the correlation between HbA1c and the risk of HF markedly attenuates with advanced age (27).

Age at Diagnosis of Diabetes and HF Risk

Diagnosis of diabetes at a younger age correlates with a higher risk of HF (45,53,54). A report by Rawshani et al. using the data from the Swedish National Diabetes Register demonstrated that compared to a control group without diabetes, individuals with onset of T1DM before age ten years had 12 times and those with onset during young adulthood (20 to 29 years) had five times increased risk of HF. Sattar et al., using the same registry data, evaluated the association between age at diagnosis and future HF risk among participants with T2DM (54). Their analysis revealed that adults diagnosed with T2DM before 41 years of age had a five times higher risk of HF than their counterparts without diabetes. Interestingly, T2DM diagnosis after the age of 80 years did not increase the risk of HF and was associated with a lower risk of all-cause and CV mortality. Consistently, an analysis from a US cohort demonstrated that every 5-year increase in the duration of DM was independently associated with a 17% rise in the risk of incident HF (55). As expected, the association between diabetes duration and HF risk was more prominent in patients with elevated HbA1c.

The explanations behind the association of duration and age at diabetes diagnosis and future HF risk are likely multifaceted, with a variation between T1DM and T2DM. The total glycemic load, defined as the cumulative exposure to the effects of hyperglycemia, is a predictor of complications of diabetes. The main components of the total glycemic load are the glycemic variability and the duration of diabetes determined by the age of diabetes onset, more prominently in T1DM (53). Individuals who develop T2DM at a younger age are more likely to have other comorbidities such as obesity, dyslipidemia, hypertension, nephropathy, smoking, and lower socioeconomic status when compared to their counterparts without diabetes. Furthermore, this comorbidity burden likely contributes to the relative excess risk of HF observed in patients diagnosed with T2DM at a relatively young age (54). These findings highlight the significance of delaying diabetes onset as one focus of HF prevention efforts (55).

The Relationship Between Diabetes and Comorbidities

Traditional modifiable CVD risk factors, such as hypertension, obesity, dyslipidemia, and cigarette smoking, are prevalent among individuals with diabetes. Hypertension affects 66% to 76% of adults with diabetes in the US (56). According to the 2020 National Diabetes Statistics Report, 45.8% of adults with diabetes are obese (body-mass-index [BMI] of 30 to 39.9 kg/m²), and 15.5% are morbidly obese (BMI of ≥40 kg/m²) (10).

Coexisting CVD risk factors significantly contribute to the risk of HF in patients with diabetes. A large prospective cohort study, including >270,000 participants with T2DM in the Swedish National Diabetes Register, examined the relationship between five risk factors (elevated HbA1C, dyslipidemia, albuminuria, smoking, and high BP) and CVD outcomes after a median follow-up of 5.7 years (57), The analyses revealed that participants with T2DM who had no risk-factor variables outside the target ranges had a 45% higher risk of hospitalization for HF when compared to that of a control group without diabetes. However, the excess risk of hospitalization for HF was substantially higher (HR vs. control, 11.35; 95% CI, 7.16 to 18.01) when patients with T2DM had all five risk-factor variables outside the target range. These findings indicated the importance of controlling coexisting CV risk factors for preventing HF in diabetes.

Recent reports have indicated that comorbid mental disorders may increase HF risk in individuals with diabetes. A retrospective analysis of nationwide health claims data of Korean participants demonstrated an independent association between HF risk and the number of mental disorders in patients with diabetes (58).

HF as a Risk Factor for Diabetes

Patients with HF are at risk of developing incident DM over time. Data from clinical trials showed that the incidence of new-onset diabetes among patients with HF is 7 to 11% over a 3- to 5-year follow-up period (59,60). Even though the published data is sparse, some evidence has emerged over the past two decades supporting the possible independent role of HF as a risk factor for incident T2DM (61). Analyses of prospective cohort studies and clinical trial participants demonstrated that HF at baseline might predispose the future risk of new-onset diabetes (61–64). Significant predictors of incident diabetes among individuals with HF are elevated glucose and HbA1c, higher BMI and waist circumference, longer duration of HF, and higher functional class of HF (28,61–63).

IMPACT OF DIABETES ON CARDIAC STRUCTURE AND FUNCTION

The frequent coexistence of diabetes with other comorbidities, such as hypertension and obesity, makes it difficult to understand the relative contribution of each disease entity in cardiac remodeling and dysfunction in clinical practice (65). However, growing evidence has supported an independent association between diabetes and various alterations in cardiac structure and function. These asymptomatic subclinical alterations at earlier stages can be detrimental and increase the risk of developing HF and CVD morbidity and mortality in general (44). Recognizing these subclinical alterations is critical for the early identification of high-risk patients and preventing overt HF and diabetic cardiomyopathy.

Left Ventricular Hypertrophy

LV hypertrophy (LVH) is characterized by increased LV mass due to myocardial remodeling. LVH is usually caused by a complex interaction between several factors, including hypertension, diabetes, metabolic syndrome, obesity, gender, ethnicity, and genetic and neurohumoral factors (66). There are three distinct LV geometric abnormality patterns: concentric remodeling (normal LV mass with increased relative wall thickness), concentric LVH (increased LV mass and increased relative wall thickness), and eccentric LVH (increased LV mass and normal relative wall thickness) (Figure 3).

Figure 3. Based on linear measurements, relative wall thickness and left ventricular mass index determine left ventricular geometric patterns. LVH, left ventricular hypertrophy.

LVH has long been recognized as a target organ response and a strong independent risk factor for HF, CAD, stroke, and CVD mortality (66,67). LVH leads to LV diastolic dysfunction by reduced LV compliance, impaired diastolic filling, prolonged isovolumetric relaxation, and increased LV and left atrial filling pressures (16). The universal definition of HF recognizes asymptomatic LVH, LV systolic dysfunction, and LV diastolic dysfunction as “pre-HF” to emphasize the progressive nature of HF and the importance of HF prevention (5).

LVH is common among adults with diabetes, with an estimated prevalence as high as 70% (68). A pooled analysis of 3 epidemiological cohort studies, including 2900 individuals with T2DM and no known CVD, demonstrated that 67% of the participants had at least one of the following echocardiographic abnormalities: LVH, left atrial enlargement, or diastolic dysfunction (44). Coexistent hypertension appears to be the main contributor to LVH in patients with diabetes (69). However, several studies have also demonstrated an independent association between diabetes and LVH. In the Framingham Heart Study, serum glucose, insulin levels, and IR were significantly linked to concentric LV remodeling, a finding that was more striking in women than in men (70,71). Results from a prospective cohort study with a 25-year follow-up period indicated that long-standing glycemic abnormalities have a cumulative effect on LV remodeling, and patients with early-onset diabetes tend to have a worse degree of LVH (72).

Diabetic cardiomyopathy may present with distinct LVH features (34). Thickened and stiff LV walls with normal LV volume usually characterize diabetic cardiomyopathy with HFpEF phenotype. Furthermore, at the cellular level, cardiomyocytes appear hypertrophied with normal sarcomere structure and increased collagen deposition in the interstitial space. Contrarily, diabetic cardiomyopathy with HFrEF phenotype usually manifests with eccentric LVH with dilated LV volume. At the cellular level, cardiomyocytes appear to have damage with loss of sarcomeres and replacement of some cardiomyocytes with interstitial fibrosis (38).

LV Diastolic Dysfunction

Diastolic dysfunction is common among otherwise asymptomatic individuals with diabetes, and its prevalence varies between 20% and 60% depending on the diagnostic criteria used and the population studied (73–75). Prospective cohort studies have confirmed that diabetes and poor glycemic control can independently contribute to the development of diastolic dysfunction (72). Even though diastolic dysfunction is often linked to LVH, it can occur in patients with diabetes, even in the absence of LVH (34).

Mild diastolic dysfunction (delayed myocardial relaxation) has a weak prognostic significance. However, the progression of diastolic dysfunction and increased LV filling pressure findings on echocardiography predispose to the future risk of HF and mortality in patients with diabetes (73,75). Moreover, among asymptomatic individuals with baseline diastolic dysfunction, diabetes is an independent predictor of progression to HFpEF or HFrEF (76).

LV Systolic Dysfunction

Traditionally, impaired LVEF is the primary marker of cardiomyopathy and systolic dysfunction. LVEF is a simple measure commonly used in the CV risk evaluation and management of CVD. However, LVEF does not capture the full spectrum of myocardial function (77). Global longitudinal strain (GLS) evaluated by speckle-tracking echocardiography is a robust technique that measures tissue deformation in a longitudinal direction (Figure 4). Reduced GLS is a marker of reduced contractility (75). GLS is more sensitive than conventional LVEF as a measure of systolic function and has an additional prognostic value (77,78). Therefore, it is now commonly used to detect subclinical LV systolic dysfunction.

Figure 4. Global longitudinal strain by speckle tracking echocardiography. Assessment of global longitudinal strain (GLS) in a healthy, asymptomatic individual with a GLS of -25%. The top row displays a regional strain map superimposed on the grayscale two-dimensional echocardiographic images in apical four-chamber (A4C), apical two-chamber (A2C), and apical three-chamber (A3C) views. The bottom left bullseye displays regional longitudinal strain for each segment of a 16-segment left ventricle model. Bright red denotes the most negative normal values of GLS. The bottom right bullseye shows the time (ms) between aortic valve opening and peak longitudinal strain, a measure of desynchrony, for each segment.

Impaired GLS is highly prevalent in asymptomatic, normotensive patients with diabetes and normal LVEF (67,79,80). Diabetes is associated with reduced GLS, even in adolescents and young adults with T1DM or T2DM (81,82). Moreover, an inverse correlation exists between HbA1C and GLS regardless of diabetes status, race, and sex (83). Not surprisingly, impaired GLS is a robust independent predictor of new-onset HF and mortality in patients with diabetes (67).

Diabetes can lead to clinical HF syndrome in individuals with asymptomatic LV systolic dysfunction. An RCT that included adults with asymptomatic LV systolic dysfunction demonstrated that diabetes increased the risk of HF development by 53% and doubled the risk of HF hospitalization over a median follow-up of 3 years (84).

Better glycemic control in patients with diabetes can lead to improvements in LV systolic and diastolic function indices. In a prospective cohort study of subjects with uncontrolled T2DM, lowering of average HbA1c from 10.3% to 8.3% over 12 months was associated with a 21% increase in GLS and a 24% increase in septal e’ velocity, a marker of myocardial relaxation (85).

PATHOPHYSIOLOGIC LINKS BETWEEN DIABETES AND HF

A complex interplay between numerous mechanisms underlies the pathophysiologic links between diabetes and HF. These pathophysiologic mechanisms include but are not limited to impaired cardiac insulin signaling, glucotoxicity, lipotoxicity, mitochondrial dysfunction, myocardial fibrosis, oxidative stress, impaired myocardial calcium handling, CV autonomic dysfunction, endocardial dysfunction, overactivation of the renin-angiotensin-aldosterone system (7)(Figure 5). The relative contribution of each pathophysiologic mechanism and their relationship with the phenotype of diabetic cardiomyopathy are still poorly understood. The pathophysiology of cardiomyopathy and HF vary depending on the type of diabetes (T1DM vs. T2DM) and type of HF (HFrEF vs. HFpEF) (86).

Figure 5. Pathophysiological mechanisms, subclinical abnormalities, and clinical manifestations of diabetic cardiomyopathy. AGEs, advanced glycation end-products; CMP, cardiomyopathy; EF, ejection fraction; HF, heart failure; LV, left ventricular; RAAS, renin-angiotensin-aldosterone system. *In patients with type-1 diabetes mellitus.

Alterations in Myocardial Energy Substrate

Under normal circumstances, the heart predominantly consumes free fatty acids (FFA; ~70%) and glucose (~30%) and can adapt its choice of fuels depending on their availability (15). In T2DM, cardiomyocyte substrate utilization shifts towards FFA, and glucose utilization decreases in response to IR. As a result, the heart becomes metabolically less flexible and almost completely reliant on FFA. These alterations lead to inefficient energy metabolism since FFA oxidation requires more oxygen for energy production than glucose or ketone bodies (15,87). Moreover, the increased FFA uptake causes the accumulation of triglycerides in the cardiomyocytes and promotes lipotoxicity, mitochondrial dysfunction, oxidative stress, and apoptosis (34). A prospective study elegantly evaluated the impact of diabetes on lipid accumulation by analyzing endomyocardial biopsy samples from 158 adult heart transplant recipients (88). The investigators demonstrated that cardiomyocyte samples of transplanted healthy hearts begin to show evidence of lipid accumulation (triacylglycerol and ceramide) as early as three months after a transplant in diabetic recipients. In comparison, no lipid accumulation was present in cardiomyocyte samples of transplant recipients without diabetes. Not surprisingly, cardiomyocyte lipid accumulation was an independent predictor of early systolic and diastolic dysfunction in recipients with diabetes after 12 months of a transplant.

Hyperinsulinemia and Insulin Resistance

In broad terms, IR is defined as the inability of insulin to carry on its metabolic actions at the cellular level (34). IR is the central defect in the pathogenesis of metabolic syndrome and T2DM. Moreover, HF is a well-known insulin-resistant state, and HF risk and prognosis are markedly affected by IR (34,89).

IR increases lipolysis, hepatic lipogenesis, and hepatic gluconeogenesis. These changes lead to substrate overload and myocardial dysfunction through lipotoxicity and glucotoxicity (75). IR and related hyperinsulinemia can affect the signaling pathways involved in cardiomyocyte hypertrophy (38).

Oxidative Stress

Oxidative stress is the imbalance between the increased generation of reactive oxygen species and reduced antioxidant defense (75). Exposure to hyperglycemia induces oxidative stress by activating NADPH oxidase, promoting mitochondrial production of superoxides, and increasing the formation of advanced glycation end products (AGEs) due to nonenzymatic glycation and oxidation of proteins and lipids (34,87).

Oxidative stress contributes to increased cardiac remodeling, reduced cardiac contractility and relaxation, and impaired cardiomyocyte calcium handling (75). Moreover, oxidative stress contributes to myocardial dysfunction by causing protein and DNA damage, increasing myocardial inflammation, and impairing intracellular signaling pathways (34).

Endoplasmic Reticulum Stress and Impaired Calcium Handling

Myocardial intracellular calcium levels regulate myocardial contractility during a cardiac cycle. Alterations in the complex mechanism of calcium handling can impact myocardial contraction and relaxation (90). The endoplasmic reticulum has a major role in Ca²⁺ handling, lipid synthesis, and protein folding and modification (91). Moreover, cytosolic Ca²⁺ levels regulate cellular metabolism and cell signaling. Hyperglycemia and IR trigger endoplasmic reticulum stress, leading to unfolded proteins accumulating and impairing Ca²⁺ handling. In diabetic cardiomyopathy, impaired Ca²⁺ reuptake by the endoplasmic reticulum prolongs diastolic relaxation time (91). Studies on animal models have indicated that impaired cardiomyocyte Ca²⁺ handling plays a crucial role in the pathophysiology of diabetic cardiomyopathy (7,90).

Endothelial and Microvascular Dysfunction

Endothelial dysfunction, which disturbs endothelial-cardiomyocyte communication and vascular function, is common in patients with diabetes and CVD (15). Diabetes induces the deposition of AGEs in the endothelial and smooth muscle cells of the myocardial microvasculature (92). Furthermore, the deposition of AGEs triggers vascular inflammation, which reduces endothelial nitric oxide production. Low myocardial nitric oxide bioavailability levels predispose to concentric LV remodeling and diastolic dysfunction (38). Diabetes has also been linked to capillary rarefaction and pericyte loss. Microcirculatory rarefaction can impair myocardial perfusion, reduce coronary flow reserve, lead to tissue hypoxia, increase myocardial stiffness, and decrease contractility (38,93).

Inflammation

Systemic inflammation is a central component of the association between obesity, diabetes, CAD, and HF (34). In individuals with obesity, the expanding adipose tissue recruits immune cells and causes overproduction of proinflammatory cytokines, leading to obesity-mediated chronic inflammation (94). Chronic low-grade inflammation predisposes to IR and T2DM and contributes to diabetes-related complications (94). Similarly, systemic inflammation is highly prevalent in patients with HF, contributing to the development, progression, and poor prognosis of HF regardless of LVEF (95). Animal model studies have shown a complex interaction between various inflammatory pathways implicated in cardiac inflammation and the development of diabetic cardiomyopathy (96,97). One potential link between HF and diabetes is S100A12, an inflammatory protein that increases with hyperglycemic stress. A prospective cohort study including 1345 patients with T2DM demonstrated an independent association between increased A100A12 and risk of HF hospitalization (98).

Epicardial Adipose Tissue Expansion

Diabetes and obesity can independently contribute to the expansion and transformation of epicardial adipose tissue (86,99). Epicardial adipose tissue expansion has been associated with LV systolic and diastolic dysfunction in patients with T2DM (100). Epicardial fat volume correlates with myocardial fibrosis (101), vascular stiffness (102), and reduced coronary microcirculation (103). Epicardial adipose tissue expansion and transformation contribute to the alterations in the cardiac structure and function through several pathophysiological mechanisms such as proinflammatory effects of adipokines (i.e., leptin, tumor necrosis factor-a, interleukin-1b and interleukin-6) secreted from epicardial fat and oxidative stress induced by reactive oxygen species released from adipocytes (86,104).

Autoimmunity

Autoimmunity is implicated in the pathogenesis of CVD among patients with T1DM (38,105). A recent report from a prospective cohort study showed that participants with T1DM and uncontrolled glycemia (HbA1c 9.0%) have a high prevalence of cardiac autoantibodies with an antibody profile similar to that seen in patients with chronic Chagas cardiomyopathy (106). Moreover, cardiac autoantibody positivity predicted elevated high-sensitivity C-reactive protein and the future risk of CVD events. Interestingly, cardiac autoimmunity was lower in participants with controlled T1DM (HbA1c <7.0%) compared to those with uncontrolled (HbA1c 9.0%). The specific role of cardiac autoimmunity in the development and progression of diabetic cardiomyopathy remains to be further explored.

Overactivation of the Renin-Angiotensin-Aldosterone System

Overactivation of the renin-angiotensin-aldosterone system (RAAS) constitutes a robust pathophysiologic link between diabetes, obesity, hypertension, and HF (34). The typical features of RAAS overactivation are elevated serum angiotensin and aldosterone levels and the upregulation of angiotensin and mineralocorticoid receptors (91,107). There is a bidirectional relationship between RAAS activation and dysglycemia. Hyperglycemia and IR can activate the RAAS, and in return, RAAS induces systemic and cardiac IR and contributes to oxidative stress in cardiomyocytes by increasing the activity of NADPH oxidase (7).

Autonomic Dysfunction

Autonomic nervous system dysfunction is highly prevalent in patients with diabetes. CV autonomic neuropathy (CAN) differentially impacts the cardiac innervation's sympathetic and parasympathetic components, leading to sympathetic overactivation in the earlier stages (16). This imbalance is believed to contribute to the pathogenesis of CVD. CAN induces LV remodeling, LV systolic and diastolic dysfunction, and myocardial ischemia (108–110). CAN is usually asymptomatic at earlier stages, and at advanced stages, it may present with resting tachycardia, orthostatic hypotension, abnormal BP regulation, blunted heart rate response to exercise, and impaired heart rate variability (34,111).

Myocardial Fibrosis

Myocardial fibrosis, detected by histopathology or cardiac MRI, is a hallmark of diabetes-induced cardiac remodeling and related myocardial dysfunction. In patients with diabetes, the degree of myocardial fibrosis directly correlates with HbA1c levels (112). Diabetes-induced myocardial fibrosis is characterized by the remodeling of extracellular matrix with the deposition and crosslinking of stiff collagen, progressive elimination of muscular fibrils, perivascular fibrosis, basement membrane thickening, coronary microvascular sclerosis, and formation of microaneurysms (16). Myocardial fibrosis is often considered an end product of various pathophysiologic abnormalities such as hyperglycemia, hyperinsulinemia, oxidative stress, CAN, inflammation, and the overactivation of RAAS.

Apoptosis

Apoptosis, the process of programmed cell death, has been implicated in the development of diabetic cardiomyopathy and HF (113). Studies from animal models and human subjects have demonstrated a strong association between hyperglycemia and cardiomyocyte apoptosis (114,115). The primary drivers of cardiomyocyte apoptosis in diabetes are oxidative stress, endoplasmic reticulum stress, and dysregulation of autophagy, the lysosomal process that degrades and recycles cellular proteins and organelles (34,116).

PROGNOSTIC IMPLICATIONS OF DIABETES IN HF

Data from epidemiologic studies and clinical trials have consistently demonstrated that individuals with concurrent diabetes and HF have impaired quality of life, are at high risk of hospitalization and mortality, and have an overall poor prognosis (33,117). In addition, coexistent prediabetes also appears to increase the risk of morbidity and mortality in patients with HF as well (118).

A large meta-analysis including >380,000 subjects with acute and chronic HF from 43 registries and clinical trials revealed that diabetes was associated with a 28% increased risk of all-cause mortality and ~35% increased risk of both CV death and hospitalization (mostly from HF) over a three year follow up (119). Interestingly, the adverse impact of diabetes on the risk of hospitalization and mortality did not differ according to the LVEF group (≤35% vs. >35%) but was higher in patients with chronic HF than those with acute HF. Observational studies have suggested a U-shaped relationship between HbA1c and mortality in patients with coexisting HF and diabetes. Aguliar et al. reported that HbA1c of 7.1% to ≤7.8% was associated with the lowest risk of mortality when compared with the other quantiles of HbA1c in a cohort of ambulatory patients with HF who were receiving medical therapy for diabetes in the early 2000s (120).

Several potential mechanisms have been proposed to explain the prognostic impacts of diabetes in HF. Diabetes is linked to multimorbidity, which significantly alters HF outcomes. Moreover, diabetes induces myocardial fibrosis, inflammation, and endothelial dysfunction, leading to higher LV pressures, poor functional status, and impaired exercise capacity in patients with HF (121–125). Diabetes predisposes neurohumoral overactivation and alterations of renal sodium handling, which may lead to congestion, cardiorenal syndrome, and impaired diuretic responsiveness (121). Also, hyperglycemia in patients with diabetes upregulates SGLT2, which leads to increased renal sodium absorption and volume expansion (121). Moreover, the increased burden of ischemic heart disease and other diabetes-related comorbidities, such as CKD, contribute to the detrimental effects of HF (126).

Data from the Swedish Heart Failure Registry demonstrated that the diabetes-associated mortality risk is more pronounced in individuals with HF of ischemic etiology than those with nonischemic etiology (43). The 2-year survival rate was less than 50% among those with HF, T2DM, and ischemic heart disease.

The presence of preexisting microvascular disease is an independent risk factor for the risk of future HF events in patients with T2DM (44). In addition, microvascular disease portends an increased risk of mortality and morbidity in patients with HF. A post hoc analysis of a large RCT

demonstrated a significant association between a history of microvascular complications and future risk of adverse events among study subjects with diabetes and HFpEF (127).

PREVENTION OF HF IN PATIENTS WITH DIABETES

The critical importance of HF prevention is underscored by HF staging, where risk factors such as hypertension and diabetes are classified as stage A (at risk for HF) (3). Because of the detrimental prognostic impact of clinical HF, the prevention of asymptomatic cardiac remodeling and dysfunction (pre-HF, stage B) and symptomatic HF (stage C) are among the primary goals of the management of patients with diabetes (128).

Prevention of HF by Preventing Diabetes

Preventing the onset of diabetes during young adulthood or middle age is an effective strategy for reducing HF risk later in life. An analysis of a large pooled US cohort evaluated the cumulative and relative impact of the absence of five modifiable HF risk factors (diabetes, hypertension, obesity, dyslipidemia, smoking) in middle age (45 to 55 years of age) (129). The data showed that the absence of diabetes in middle age strongly predicted HF-free survival, with a more than 60% lower risk of incident HF than those with diabetes. In addition, subjects without diabetes, hypertension, and obesity at ages 45 to 55 years, compared to those with all 3 of these risk factors, had an average >10 years longer HF-free survival and 13 years longer overall survival (129).

Prediction of HF Risk in Patients with DM

HF risk stratification is essential for prevention in patients with DM or prediabetes who do not have ASCVD. Even though echocardiography can detect cardiac remodeling in patients with diabetes, its use is not routinely recommended for asymptomatic individuals because of concerns about cost-effectiveness (4). However, measuring natriuretic peptides or high-sensitivity cardiac troponin can help identify patients with pre-HF or those at risk of progression to HF. Therefore, patients with diabetes should have a measurement of natriuretic peptides or high-sensitivity cardiac troponin yearly to identify high-risk individuals and assist with HF prevention (4).

Several risk prediction tools and algorithms have been developed to predict incident HF in patients with dysglycemia. Pandey et al. described a simple biomarker-based risk score including high-sensitivity cardiac troponin T ≥6 ng/l, high-sensitivity C-reactive protein ≥3 mg/l, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥125 pg/ml, and LVH by ECG, with each abnormal parameter counting as 1 point. This risk score was tested in participants from 3 major US cohort studies. This risk score had good risk stratification for predicting 5-year incident HF risk in patients with both diabetes and prediabetes (130). More complex risk prediction tools (WATCH-DM and TRS-HF_DM) incorporating a more extensive list of clinical variables have also been developed. Validation studies on participants from different clinical trials demonstrated that these risk scores could stratify HF risk among patients with T2DM (131–133). However, prospective studies have not evaluated these risk scores, and their clinical utility remains uncertain.

Glycemic control, obesity management, and BP control are well-established therapeutic options to lower the risk of microvascular or macrovascular complications in patients with diabetes. The clinical implications of these therapeutic options in HF prevention will be reviewed here.

Impact of Blood Pressure Control on HF Prevention

Diabetes and hypertension commonly coexist because of the overlap of underlying risk factors and pathophysiological mechanisms (134,135). The coexistence of diabetes and hypertension synergistically contributes to the risk of microvascular and macrovascular complications and CVD. Therefore, BP control with lifestyle modifications and antihypertensive medications is a primary target for reducing the risk of complications due to coexisting diabetes and hypertension (134). The ACC/AHA guidelines recommend initiating an antihypertensive agent when patients with diabetes have an office BP of ≥140/90 mmHg. The recommended BP target is below 140/90 mmHg for low-risk patients and below 130/80 for individuals with established or high risk for atherosclerotic CVD (136).

BP lowering has strong benefits in preventing HF among individuals with diabetes (35). However, the magnitude of this benefit appears to be smaller in patients with diabetes than in those without diabetes. Large meta-analyses of RCTs of BP-lowering therapy demonstrated that every 10 mmHg reduction in systolic BP (SBP) was associated with a 16% to 25% lower risk of HF among individuals with diabetes and 25% to 43% risk reduction among those without diabetes (137,138). The landmark ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) trial compared the impact of intensive (SBP goal <120 mmHg) versus standard BP control (SBP <140 mmHg) on major adverse CV events (MACE) in hypertensive patients with diabetes (139). In this trial, intensive BP control did not improve the risk of MACE or HF but increased the risk of adverse events. Therefore, the 2018 European Society of Cardiology (ESC)/European Society of Hypertension guidelines for the management of arterial hypertension recommended avoiding a target SBP <120 mmHg in patients with diabetes (140).

The antihypertensive drug classes with strong CV risk reduction in individuals with diabetes are thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and dihydropyridine calcium channel blockers. Therefore, any of these agents can be considered a first-line therapy for lowering BP in individuals with diabetes. Because of their renal protection benefits, an ACE inhibitor or an ARB should be a part of the initial therapy for those with albuminuria (136,141). It should be noted that beta-blockers are not among the first-line antihypertensive agents for patients with or without diabetes. Because there is insufficient evidence on the mortality benefits of beta-blockers when used for the sole purpose of BP reduction in the absence of HF or CAD (136,141). The landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) has been the largest trial designed to assess the relative efficacy of different antihypertensive agents in protection against CVD. The results of this trial demonstrated that chlorthalidone (a thiazide diuretic) was superior to lisinopril (an ACE inhibitor) and amlodipine (a calcium-channel blocker) in the prevention of HF among patients with or without diabetes (142,143). A subsequent large meta-analysis of RCTs revealed that diuretics and renin-angiotensin system blockers were independently superior to other antihypertensive agents in the prevention of HF among patients with diabetes (138).

Loop diuretics are considered to have a neutral effect on glycemic control in patients with diabetes. Evidence from posthoc analysis and meta-analysis of antihypertensive drug trials has shown a small but significant association between thiazide diuretic use and higher fasting plasma glucose (144). A meta-analysis of 26 RCTs demonstrated that thiazide diuretic use was associated with a 4.6 mg/dL higher fasting plasma glucose than non-thiazide agents or placebo in patients with hypertension (145). A possible link between thiazide diuretic use and new-onset diabetes in patients with hypertension was supported by some studies (146) but not all (147). Overall, the CV benefits of thiazide diuretics outweigh the risk of new-onset diabetes in non-diabetic individuals and the risk of uncontrolled glycemia in patients with diabetes (144). Therefore, neither hypertension nor HF management guidelines recommend avoidance of thiazide diuretics in patients with or at risk for diabetes.

The ACC/AHA guidelines recommend the use of steroidal mineralocorticoid receptor antagonists (MRA, i.e., spironolactone and eplerenone) as an add-on therapy to the first-line antihypertensive agents in the treatment of resistant hypertension (136). Besides modest BP reduction, these agents can provide anti-fibrotic, anti-inflammatory, and anti-proteinuric benefits (148,149). The clinical CV benefits of these agents have been proven in patients with HFrEF. However, we lack large-scale RCTs demonstrating their CV benefits in primary prevention settings among patients with hypertension or diabetes. In a small RCT including 140 patients with T2DM and high CVD risk, adding high-dose eplerenone to standard treatment reduced LV mass and decreased NT-ProBNP and a circulating serum marker of myocardial fibrosis (150). Our knowledge of MRAs in patients with diabetes has expanded with two Phase III landmark RCTs evaluating the cardiorenal benefits of Fineranone, a recently discovered non-steroidal MRA with high affinity and specificity for the mineralocorticoid receptor (151). FIDELIO-DKD and FIGARO-DKD trials demonstrated that fineranone therapy on top of maximally tolerated RAAS inhibitor treatment was renally protective and reduced the risk of the primary endpoint of CVD outcomes in patients with T2DM and CKD (152,153). More specifically, fineranone therapy significantly reduced the risk of hospitalization for HF (HR; 0.71 [95% CI, 0.56-0.90]) in the FIGARO-DKD trial (153). Based on these results, the U.S. Food and Drug Administration (FDA) recently approved fineranone to reduce the risk of estimated glomerular filtration rate (eGFR) decline, end-stage renal disease, CVD death, non-fatal MI, and HF hospitalization in patients with CKD and T2DM (151).

Obesity Management and Lifestyle Modifications

Studies have consistently demonstrated that purposeful weight reduction, achieved via diet, exercise, or bariatric surgery, has favorable impacts on glycemic control, IR, BP, and lipid profiles and reduces the need for antidiabetics in obese individuals with T2DM (34,154,155). Moreover, weight reduction can delay the progression from prediabetes to T2DM (156). The ADA recommends lifestyle modification to achieve at least a 5% weight loss for all overweight or obese individuals with prediabetes or diabetes (157). Also, the guidelines emphasize the need for an individualized medical nutrition therapy program for individuals with diabetes to achieve treatment goals. The recommended exercise regimen for most individuals with T1DM and T2DM is at least 150 minutes of moderate to vigorous aerobic activity per week, spread over at least three days/week, and an additional 2-3 sessions/week of resistance exercise (157).

Despite the well-established favorable effects of weight loss in patients with diabetes, the role of lifestyle changes and weight loss in preventing HF among diabetic patients remains uncertain. A meta-analysis of 36 prospective cohort studies published before 2014 demonstrated that achieving recommended physical activity levels (150 minutes of moderate‐intensity aerobic activity per week) was associated with reduced risk of incident HF (relative risk; 0.81 [0.76, 0.86]) in patients with diabetes (112).

The Look AHEAD (Action for Health in Diabetes) has been the largest RCT evaluating the CV effects of an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity in overweight or obese participants with T2DM (154). The study subjects in the intensive lifestyle intervention group lost 8.6% of body weight at one year and, by the end of the 10-year follow-up, maintained a modest (6%) weight loss compared to 3.5% in the control group. Despite the achieved relative weight loss and improved physical fitness and HbA1c, the intensive lifestyle intervention did not reduce the risk of CVD mortality and morbidity, including HF risk, which was a secondary outcome. A post hoc analysis by Pandey et al. evaluated the impact of cardiorespiratory fitness and the degree of weight loss on the HF risk among the Look AHEAD trial participants with an extended follow-up period (158). The investigators observed a 20% reduction in incident HF risk as a response to a 10% reduction in BMI over a 4-year follow-up. Moreover, a higher baseline and improvement of cardiorespiratory fitness over time predicted a lower risk of incident HF. Interestingly, subgroup analysis revealed a more significant correlation between baseline fitness and incident HFpEF than incident HFrEF. Future dedicated studies are needed to explore the HF risk reduction effects of more intense weight loss and exercise training interventions to promote sustained improvements in body weight and cardiorespiratory fitness in patients with T2DM (158).

Metabolic surgeries, when performed as a part of a comprehensive weight management strategy, are effective treatment options for achieving more significant and durable weight loss in individuals with severe obesity (159). Individuals with T2DM and severe obesity who undergo metabolic surgeries experience improvement in glycemic control and insulin sensitivity and may have remission of diabetes (159). Evidence from RCTs and observational studies has demonstrated that metabolic surgery, as compared to conventional lifestyle modifications and medical therapy, can reduce overall CV risk and improve the quality of life in individuals with T2DM and severe obesity (160–162). The impact of metabolic surgeries on incident HF risk has not yet been evaluated in large-scale RCTs. In a large nationwide prospective observational study of obese individuals without a known history of HF, metabolic surgery was associated with a >50% reduction in the risk of incident HF (163). Another retrospective cohort study from the Cleveland Clinic Health System in the U.S. demonstrated that metabolic surgery among patients with T2DM and obesity was associated with approximately 40% relative reduction of major adverse CV event risk and more than 60% relative reduction of incident HF risk over a median follow-up of 3.9 years (164).

Impact of Glycemic Control

In patients with T1DM and T2DM, intensive glycemic control significantly reduces the risk and severity of microvascular complications (34). However, despite the solid epidemiologic link between poor glycemic control and HF risk, the effects of intensified glycemic control in preventing HF remain controversial. Early clinical trials that established the CV benefits and risks of intensive glycemic control did not include HF as a primary endpoint. However, post hoc or secondary outcome analyses of prospective trials have shed light on the relationship between glycemic control and HF prevention.

In the UK Prospective Study of Diabetes (UKPDS) published more than 20 years ago, intensive glycemic control with metformin, sulfonylureas, or insulin was compared to conventional therapy in adults with recently diagnosed T2DM. A post hoc analysis of the main trial demonstrated that each 1% reduction in mean HbA1c was associated with a 16% decrease in incident HF (165). However, similar results were not replicated by subsequent large-scale RCTs such as the ACCORD (166,167), the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (168), and the VADT (Veterans Affair Diabetes Trial) (169) which failed to show any reduction in HF risk with intensive glucose control in patients with T2DM. Consistently, a meta-analysis of all these trials showed no overall effect of intensive glucose control on HF risk despite a modest (9%) reduction in the risk of major CV outcomes (170). These observations confirmed that blood-glucose-lowering and improvement of HbA1c are insufficient targets for preventing HF in patients with diabetes.

The treatment section below discusses the impact of specific antidiabetic agents on the prevention of HF in high-risk patients.

TREATMENT OF HF IN PATIENTS WITH DIABETES

The primary objectives in managing HF are to reduce mortality, prevent HF hospitalization, and improve patients’ clinical status, quality of life, and functional capacity (18). The major components of managing HF are lifestyle changes, education and support for HF self-management, monitoring, control of the underlying causes and associated comorbidities, pharmacologic therapy, cardiac rehabilitation, device therapies, mechanical circulatory support, and cardiac transplantation (171). The major society guidelines for the management of patients with HF include the ACC/AHA/HFSA guidelines published in 2022 (3) and the European Society of Cardiology (ESC) guidelines published in 2021 (18).

The main components of lifestyle changes recommended for patients with HF are physical exercise, smoking cessation, restriction of or abstinence from alcohol consumption, dietary modifications, and avoidance of obesity (18). ACC/AHA/HFSA and ESC guidelines strongly recommend regular aerobic exercise and exercise training to improve functional capacity and symptoms in patients with HF who can participate. The ACC/AHA/HFSA guideline indicated that avoiding excessive dietary sodium intake is reasonable (class IIa) for patients with symptomatic HF to reduce congestive symptoms (3). However, because of a lack of affirmative evidence from clinical trials, the guidelines did not provide precise recommendations about the limit of daily sodium intake and whether it should vary depending on the type, stage, or severity of HF or comorbidities.

Diuretic Therapy in HF

Diuretics increase urinary sodium excretion and reduce physical signs and symptoms of congestion in HF patients by inhibiting sodium or chloride reabsorption in the renal tubules. Loop diuretics such as bumetanide, furosemide, and torsemide act in the loop of Henle, whereas thiazide diuretics such as hydrochlorothiazide, metolazone, chlorthalidone, and potassium-sparing diuretics such as spironolactone, eplerenone, and triamterene act in the distal position of the tubule (172). Loop diuretics, which produce a shorter and more intense diuresis than thiazides, are usually the preferred agents for achieving and maintaining euvolemia and reducing the risk of HF hospitalization in patients with HF. Large-scale RCTs have not evaluated the effects of the loop and thiazide diuretics on mortality and morbidity in patients with HF.

First-Line Pharmacological Treatment of HFrEF

Neurohumoral antagonists (RAAS inhibitors and beta-blockers) and SGLT2 inhibitors with proven morbidity and mortality benefits are the cornerstone of guideline-directed medical therapy for patients with chronic HFrEF (173). The guidelines generally do not recommend specific therapeutic approaches in patients with diabetes compared to those without diabetes.

RAAS AND NEPRILYSIN INHIBITORS

The guidelines from AHA/ACC/HFSA (3) and ESC (18) recommend (Class I) the use of angiotensin receptor-neprilysin inhibitor (ARNI; sacubitril/valsartan) as a first-line therapy for patients with HFrEF (New York Heart Association [NYHA] Class II or III). ACE inhibitors (Class I recommendation) are recommended to reduce the risk of morbidity and mortality in patients with HFrEF when using ARNI is not feasible. ARBs are considered acceptable vasodilator treatment options (class I recommendation) as a first-line alternative to ACE inhibitors for patients intolerant of ACE inhibitors because of cough or angioedema and when using ARNI is not feasible.

Subgroup analysis or meta-analysis of major HF trials demonstrated that the effectiveness of RAAS and neprilysin inhibitors in HF does not vary based on patients’ diabetes status. Therapy with ACE inhibitors, ARBs, or an ARNI reduces the risk of morbidity and mortality among HF patients without significant effect variation based on diabetesstatus (33,61,122,174). In addition, ARNI therapy provides a similar degree of natriuretic peptide improvement and cardiac reverse remodeling in patients with or without diabetes (175).

Post hoc analysis of RCTs revealed that ACE inhibitors and ARBs might reduce the risk of incident diabetes in patients with HFrEF (59,61,176). However, the data on the impact of these agents on glycemic control in patients with HF and preexisting diabetes remains limited. Neprilysin inhibition with sacubitril appears to have more favorable effects on glycemic control than ACE inhibitors (61). In the PARADIGM-HF trial, HFrEF patients enrolled in the enalapril and sacubitril-valsartan arms experienced an average of 0.16% and 0.26% HbA1c reduction after one year of treatment (177). In addition, sacubitril-valsartan use was associated with a 29% reduction in new insulin use compared to enalapril.

Diabetes confers a higher risk of diabetic nephropathy and CKD. Diabetic nephropathy can lead to increased renal sodium retention and a higher risk of hyperkalemia. Therefore, it is critical to monitor serum electrolytes and creatinine when starting or escalating the dose of RAAS inhibitors in patients with HF and diabetes (178). Of note, ARNI therapy may cause a higher rate of hypotension than ACE inhibitors or ARB (4).

BETA-BLOCKERS

Beta-blocker therapy is recommended (class I) for all patients with stable, symptomatic HFrEF (3,18). Beta-blocker therapy reduces the risk of death and hospitalization and improves LVEF and clinical status in patients with HFrEF. The ACC/AHA/HFSA guidelines recommend using one of the three beta-blockers with proven mortality benefits (e.g., metoprolol succinate, carvedilol, and bisoprolol).

Based on RCTs, the morbidity and mortality benefits of beta-blockers are similar in HFrEF patients with or without diabetes (174,179,180). A prospective cohort study from the UK suggested that increasing beta-blocker dose was associated with a more significant prognostic advantage in HF patients with diabetes than those without diabetes(181).

Data from some old observational studies and clinical trials raised concerns for a slight increase in the risk of new-onset diabetes associated with using propranolol, a first-generation non-selective beta-blocker, to treat hypertension (182,183). However, such an adverse effect concern is not present with newer-generation beta-blockers in HF populations (184). Compared to other beta-blockers, carvedilol use may even reduce HbA1c, fasting insulin levels, and risk of new-onset diabetes in patients with HFrEF (60,184).

Beta-blockers can potentially mask hypoglycemia symptoms by preventing palpitations and tremors and could prolong recovery from hypoglycemia by reducing glucose production in the liver (178). A post hoc analysis of the ACCORD trial demonstrated a significant association between beta-blocker use and severe hypoglycemia risk in patients with diabetes (185). However, a post hoc analysis of the MERIT-HF trial (Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure) did not show a similar association between beta-blocker use and hypoglycemia events in patients with HF and coexisting T2DM (186).

MINERALCORTICOID RECEPTOR INHIBITORS

MRAs (i.e., spironolactone or eplerenone) are recommended for all patients with HFrEF (LVEF ≤35%) and NYHA class II to IV symptoms if eGFR is >30 ml/min/1.73 m² and serum potassium is <5 mEq/L (3,18). Similar to other RAAS inhibitors, the clinical benefits of MRAs have been consistent in HF patients with or without diabetes (187). Based on limited data, MRAs appear to have a neutral effect on glycemic parameters and diabetes risk in individuals with HFrEF (64,188). MRAs can cause hyperkalemia; therefore, monitoring electrolytes while initiating or maintaining MRA therapy is crucial.

SGLT2 INHIBITORS

SGLT2 inhibitors are recommended (class I) to reduce CVD mortality and HF hospitalization in patients with symptomatic HFrEF, irrespective of the presence of T2DM (3,18). Empagliflozin, Dapagliflozin, and Sotagliflozin are the SGLT2 inhibitors approved by the U.S. FDA to reduce CVD death and HF hospitalization in patients with HF across the range of LVEF (HFrEF, HFpEF, HFmrEF).

Dedicated landmark trials proved the CV benefits of SGLT2 inhibitors in patients with HFrEF, regardless of T2DM status (Table 1). The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) (189) and EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) (190) trials enrolled symptomatic chronic HFrEF (LVEF ≤40%, NYHA class II to IV, and elevated natriuretic peptides) and were already on guideline-directed medical therapy. Patients with T1DM and advanced CKD were excluded. In these trials, compared to placebo, SGLT2 inhibitors reduced the composite of CVD death and HF hospitalization by ~25%. In addition, SGLT2 inhibitors slowed the progression of renal disease. The SGLT2 inhibitors' CV benefits are independent of their glucose-lowering effects (191). In addition, SGLT2 inhibitor therapy appears to improve the clinical stability and functional status of patients with HF. An analysis from the EMPEROR-Reduced trial demonstrated that empagliflozin therapy was associated with improvement in the NYHA class and requirement of diuretic intensification when compared to placebo (192).

Sotagliflozin is a dual SGLT1/SGLT2 inhibitor that increases urinary glucose excretion by SGLT2 inhibition and delays intestinal glucose absorption by SGLT1 inhibition. The SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes And Worsening Heart Failure) trial evaluated the efficacy and safety of sotagliflozin in patients with T2DM who were hospitalized with HF (HFpEF and HFrEF) (190). In this trial, Sotagliflozin therapy initiated before or shortly after hospital discharge reduced the combined endpoint of CVD death, HF hospitalization, or urgent HF visits by 33%.

Despite the guideline recommendations and strong clinical trial evidence supporting their benefits, SGLT2 inhibitor therapy utilization among patients with HF remains low. A recent nationwide retrospective cohort study analyzed the STLT2 inhibitor prescription patterns among patients hospitalized with HFrEF between July 2021 and July 2022 (193). Only 20% of eligible patients in this cohort were prescribed SGLT2 inhibitors at discharge. Moreover, the utilization was low even among patients with multiple indications, such as comorbid CKD and T2DM.

Table 1. Trials of SGLT2 Inhibitors in Patients with HF
Medication	Trial	Publication Year	Patient Characteristics	History of T2DM	Follow-up Period	Primary Outcome* (HR, 95% CI)
Empagliflozin	EMPEROR-REDUCED (190)	2020	Symptomatic stable HF (LVEF ≤40%)	50%	16 months	0.75 (0.65 – 0.86)
Empagliflozin	EMPEROR-PRESERVED (194)	2021	Symptomatic stable HF (LVEF > 40%)	49%	26 months	0.79 (0.69 – 0.90)
Dapagliflozin	DAPA-HF(189)	2019	Symptomatic stable HF (LVEF ≤40%)	42%	18 months	0.74 (0.0.65 - 0.85)
Dapagliflozin	DELIVER(118)	2022	Symptomatic stable HF (LVEF > 40%)	45%	2.3 years	0.82 (0.73 – 0.92)
Sotagliflozin	SOLOIST-WHF (195)	2021	Recently hospitalized HF (All LVEF groups)	100%	9 months	0.67 (0.52 – 0.85)

*Primary outcome was a composite of cardiovascular death or hospitalization for HF.

Device Therapies for HFrEF

Implantable cardioverter-defibrillator (ICD) is strongly recommended (Class I) for primary prevention of sudden cardiac death in patients with symptomatic HFrEF who have an LVEF ≤35% despite guideline-directed medical therapy for >3 months (3,18). HFrEF patients with diabetes carry a significantly higher risk of sudden cardiac death than those without diabetes (122). This observation highlights the importance of considering ICD in appropriately selected cases with HFrEF and diabetes. Strong evidence from major ICD trials has confirmed the sudden cardiac death risk reduction benefits of ICDs in individuals with coexisting HFrEF and diabetes (196,197).

Cardiac resynchronization therapy (CRT) is a well-established therapeutic modality in patients with HFrEF and prolonged QRS duration. In appropriately selected cases, CRT with biventricular pacing can improve LV systolic function and reduce the risk of morbidity and mortality through its ability to reverse the remodeling of LV (198). In major CRT trials, HFrEF patients with and without diabetes experienced similar overall effectiveness of CRT for reducing mortality and HF hospitalization (199–201). However, observational studies suggested that the magnitude of LV reverse remodeling and improvement of systolic and diastolic function may be less pronounced in individuals with diabetes than in those without diabetes (198,202,203).

Treatment of HFpEF

Until recently, the management of patients with HFpEF and HFmrEF lacked specific therapies shown to improve morbidity and mortality definitively. Clinical trials of pharmacologic agents with proven benefits in HFrEF have predominantly revealed neutral results in populations with HFpEF (30,31,204).

The guidelines focus on aggressive management of risk factors and comorbidities, exercise training, and symptom management with diuretics when volume overload findings are present in patients with HFpEF (3). The landscape of medical management of HFpEF has dramatically changed with the data from clinical trials evaluating the safety and efficacy of SGLT2 inhibitor therapy in patients with HFpEF (Table 1). The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) enrolled 5988 symptomatic patients with HF with LVEF >40% and elevated natriuretic peptides (194). In this trial, compared to placebo, empagliflozin therapy reduced the primary composite outcome of CVD death or HF hospitalization by 21%, primarily driven by a 29% reduction in HF hospitalization. SGLT2 inhibitor therapy was beneficial regardless of the presence or absence of T2DM. Based on the results of the EMPEROR-Preserved trial, the 2022 ACC/AHA/HFSA guidelines recommended (class IIa) SGLT2 inhibitor therapy to reduce CV death and HF hospitalization in patients with HFpEF and HFmrEF (3). Since the publication of these guidelines, the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial was completed (118). This trial demonstrated similar benefits of dapagliflozin therapy in patients with HF and LVEF >40%. Data from the PRESERVED-HF trial, a relatively small-size multicentric RCT, evaluated the impact of dapagliflozin on the quality of life and symptoms in patients with HFpEF. In this trial, 12 weeks of dapagliflozin treatment significantly improved patient-reported physical limitations and symptoms and objectively measured exercise tolerance (205).

The 2022 ACC/AHA/HFSA guidelines indicate that based on a subgroup analysis of RCTs, ARBs, MRAs, and ARNI (in appropriately selected patients) might be considered (Class IIb) in patients with HFpEF or HFmrEF to decrease hospitalizations (3).

PHARMACOLOGIC THERAPY OF T2DM IN PATIENTS WITH HF

Lifestyle therapy is essential to managing patients with diabetes and established or high risk for HF. We point the readers to documents from ADA and ACC/AHA for detailed review and recommendations on lifestyle therapy in this patient population (3,4,157).

In this chapter, we provide a focused review of the effects of glucose-lowering agents from a HF perspective. Glycemic control is essential in patients with diabetes who have additional CV risk factors or established CVD. The ADA Standards of Medical Care in Diabetes recommend a holistic, multifactorial, and patient-centered approach when choosing antidiabetic medications. As per the guidelines, antidiabetic therapy should be selected according to patient-specific goals such as cardiorenal protection or achieving and maintaining glycemic and weight management goals. Moreover, considering comorbidities, such as HF and CKD, is essential when determining management goals (23,141).

SGLT2 Inhibitors

In light of the evidence from CVOTs showing the benefits of CVD risk reduction and renal protection, the ADA recommends using GLP1-RAs or SGLT2 inhibitors as first-line agents in T2DM patients with high-risk or established ASCVD (23). In addition, SGLT2 inhibitors are the preferred first-line antidiabetic in patients with known HF or CKD (eGFR <60 ml/min/1.73 m² or albuminuria). This approach is a change from before, as the guidelines no longer require first-line metformin therapy before initiating SGLT2 inhibitors or GLP1-RAs when the therapy is started with the goal of cardiorenal risk reduction in high-risk patients with T2DM. (Table 2).

Table 2. Pharmacologic Therapy with a Goal of Cardiorenal Risk Reduction in High-Risk Patients with T2DM
Risk Profile	First-line Therapy	Second-line Therapy if A1C is Above the Target
ASCVD* Indicators of High Risk**	GLP1-RA with proven CVD benefit Or SGLT2 inhibitor with proven CVD benefit	GLP1-RA with proven CVD benefit Or SGLT2 inhibitor with proven CVD benefit
Heart Failure	SGLT2 inhibitor with proven HF benefit	Follow the algorithm for the achievement of glycemic and weight management goals.
CKD***	SGLT2 Inhibitor with proven CKD benefits	GLP1-RA with proven CVD benefit

*ASCVD, atherosclerotic cardiovascular disease: Individuals with established cardiovascular disease such as myocardial infarction, stroke, revascularization procedure, amputation, or symptomatic/asymptomatic coronary artery disease. **Indicators of high risk: ≥55 years of age with two or more additional risk factors such as obesity, hypertension, dyslipidemia, smoking, and albuminuria. ***CKD, chronic kidney disease: GFR <60 ml/min/1.73 m²or albuminuria (albumin-creatinine ratio ≥30 mg/g). GLP1-RA, glucagon-like peptide-1 receptor agonists; A1C, hemoglobin A1c, SGLT2, sodium-glucose co-transporter -2.

A wealth of high-quality data proves the HF benefits of SGLT2 inhibitors in patients with T2DM. Since the publication of EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial results in 2015, (206) several large-scale CVOTs have revolutionized our understanding of the prevention of CV events and HF in patients with T2DM (Table 1 and 3).

In the EMPA-REG OUTCOME, empagliflozin, in the CANVAS (Canagliflozin Cardiovascular Assessment Study), canagliflozin and in the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), dapagliflozin significantly reduced incident HF events as a secondary end-point in patients with established or high risk for CVD (206–208). The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, designed to assess renal outcomes of canagliflozin, also showed a reduction in hospitalization for HF (HR:0.69, p<0.001) (209). In the VERTIS-CV (Cardiovascular Outcomes Following Ertugliflozin Treatment in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease) trial, ertugliflozin was non-inferior to placebo in regards to major CVD events in 8264 patients with T2DM and established CVD. In this trial, Ertugliflozin reduced the risk of HF hospitalization (an exploratory secondary outcome) by 30% (hazard ratio 0.70 [95% CI, 0.54 to 0.90]) (210).

A meta-analysis of 6 RCTs (EMPAREG-OUTCOME, CANVAS, DECLARE-TIMI 58, and CREDENCE, VERTIS-CV) explored the CV benefits of 4 SGLT2 inhibitors in a combined sample size of 46969 patients with T2DM. In this meta-analysis, SGLT2 inhibitor therapy was associated with a reduced risk of MACE (HR, 0.90; 95% CI, 0.85-0.95), kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70), and a combined outcome of CVD death and HF hospitalization (HR, 0.78; 95% CI, 0.73-0.84) (118).

The SCORE trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) evaluated the CV benefits of sotagliflozin, a dual SGLT1/SGLT2 inhibitor, against placebo in 10584 patients with T2DM, CKD, and risk of CVD. In this trial, Sotagliflozin reduced the coprimary end-point of MACE (HR; 0.84 [95% CI, 0.72 to 0.99]) and secondary end-point of HF hospitalization (HR; 0.67 [0.55–0.82]) (210).

In Europe and Japan, SGLT-2 inhibitors are approved as adjunctive therapy for T1DM in patients with a BMI of at least 27 kg/m². This recommendation is primarily based on the assumption that CV and renal protective effects of SGLT2 inhibitors can be generalized to T1DM populations. However, we still lack large-scale RCTs assessing the cardiorenal benefits of SGLT2 inhibitors in T1DM (211). Considering the high risk of diabetic ketoacidosis and the lack of proven diabetic ketoacidosis risk mitigation strategies, the U.S. FDA denied the approval of SGLT2 inhibitors for T1DM in the U.S.

Table 3. Heart Failure Hospitalization Risk with SGLT-2 Inhibitors in Patients with T2DM
Medication	Trial	Publication Year	Patient Characteristics	History of HF	Follow-up Period	HF hospitalization (HR, 95% CI)
Empagliflozin	EMPA-REG OUTCOME (206)	2015	Established CVD	10%	3.1 years	0.65 (0.50 - 0.85)
Empagliflozin	EMPA-KIDNEY (212)	2023	CKD with or without albuminuria*	Not reported	2 years	0.84 (0.67 – 1.07) ** [p=0.15]
Canagliflozin	CANVAS Program (207)	2017	CV risk factors (34%) Established CVD (66%)	14%	3.2 years	0.67 (0.52 - 0.87)
Canagliflozin	CREDENCE (209)	2019	CKD with albuminuria	15%	2.6 years	0.61 (0.47 - 0.80)
Dapagliflozin	DECLARE-TIMI 58(208)	2019	CV risk factors (59%) Established CVD (41%)	10%	4.2 years	0.73 (0.61 - 0.88)
Dapagliflozin	DAPA-CKD (213)	2020	CKD with albuminuria	11%	2.4 years	0.71 (0.55 – 0.92) **
Ertugliflozin	VERTIS-CV (210)	2020	Established CVD	24%	3.5 years	0.70 (0.54 - 0.90)
Sotagliflozin	SCORED (214)	2020	CKD with a high risk for CVD	31%	16 months	0.67 (0.55 – 0.82)

*Estimated eGFR of 20 to 45 ml/min/1.73 m², or eGFR of 45 to 90 ml/min/1.73 m² with a urinary albumin-to-creatinine ratio of ≥ 200 mg/g. **Composite secondary outcome of cardiovascular death and heart failure hospitalization. CKD, chronic kidney disease; CVD, cardiovascular disease.

Glucagon-like Peptide-1 Receptor Agonists

As mentioned above, GLP1-RAs are among the first-line agents for glucose-lowering and cardiorenal risk reduction in T2DM patients with indicators of high-risk or established ASCVD (23). In addition, GLP1-RAs are recommended as second-line therapy in patients with CKD if SGLT2 inhibitor therapy is contraindicated or not tolerated or if the HbA1c remains above target despite using an SGLT2 inhibitor.

Landmark CVOTs have confirmed the favorable effects of GLP1-RAs on the risk of major CV events such as CV death, nonfatal myocardial infarction, or nonfatal stroke in patients with T2DM. However, individual trials revealed mostly neutral results regarding the effect of GLP1-RAs on HF outcomes in patients with T2DM and at risk for HF (Table 4) (215,216). Efpeglenatide was the only GLP-RA that significantly reduced HF hospitalization as a secondary end-point in a major CVOT, including T2DM patients with a history of CVD or CKD (217). U.S. FDA has not yet approved this agent.

Some early small-size trials raised concerns for increased risk of hospitalization or arrhythmia in response to GLP1-RA treatment in patients HFrEF (218). However, A recent meta-analysis of 7 RCTs, including 54,092 ambulatory patients with T2DM, revealed that GLP1-RAs reduced the composite of HF hospitalization and CVD death (HR 0.84, 95% CI: 0.76-0.92.) in patients without a prior history of HF. However, compared to placebo, GLP1-RAs did not reduce the same outcome in patients with a previous history of HF (219). Based on available data, GLP1-RAs may potentially prevent HF in patients with no history of HF. However, GLP1-RAs do not appear to reduce HF-related events in patients with a history of HF and coexisting diabetes (218).

GLP1-RAs (i.e., liraglutide and semaglutide) have also been approved as a medical therapy for weight loss in non-diabetic individuals with overweight or obesity. And in a landmark trial, treatment with tirzepatide, a novel combined glucose-dependent insulinotropic polypeptide and GLP1-RA, led to substantial and sustained weight loss and improvement of cardiometabolic parameters in individuals with obesity (220). Several ongoing CVOTs are expected to shed light on the CV-related efficacy and safety of semaglutide or tirzepatide therapy in people with obesity or overweight but without diabetes.

STEP-HFpEF (Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction) trial has been the first RCT demonstrating the benefits of weight loss with a GLP1-RA in non-diabetic patients with HFpEF and obesity (BMI kg/m²) (221). In this trial, semaglutide once-weekly therapy for one year led to 13.3% weight loss and was associated with significant reductions in HF-related symptoms and physical limitations. In addition, patients treated with semaglutide experienced significant improvement in 6-minute wall distance and reduction levels of natriuretic peptide and c-reactive protein. Interestingly, fewer serious adverse events were observed with semaglutide than placebo. This trial was not powered to evaluate mortality and HF hospitalization outcomes properly. Another ongoing trial is investigating the impact of semaglutide in patients with HFpEF, obesity, and T2DM.

Metformin

As per the recent guidelines, metformin remains the preferred initial pharmacologic agent for treating T2DM if the treatment goal is achieving and maintaining glycemic control and weight management (23). The efficacy and safety of metformin in patients with HF have not been evaluated in dedicated prospective CVOTs. Therefore, metformin is no longer considered the first-line agent for cardiorenal renal risk reduction in T2DM patients with established or increased risk of HF. However, metformin can be used for glucose lowering in patients with T2DM and stable HF if eGFR remains >30 ml/min/1.73 m². However, it should be avoided in hospitalized patients with HF (141).

Data from retrospective studies and post hoc analysis of prospective RCTs predominantly supported the benefits and safety of metformin in HF populations (222). A meta-analysis of 9 observational studies conducted in the 2000s and early 2010s showed reduced mortality and no change in safety outcomes with the use of metformin compared to sulfonylurea therapy (predominantly) in HF populations (223). It should be noted that the U.S. FDA removed HF from the contraindication list of metformin in 2006 since the lactic acidosis risk is rare, and the benefits of metformin use in patients with HF were supported by observational studies (61).

Table 4. Effect of Glucose-Lowering Drugs on Heart Failure Hospitalization Risk in Patients with T2DM
Drug Class	Medication	HF Hospitalization
SGLT-2 Inhibitors	Empagliflozin	35% reduced risk
	Canagliflozin	33% reduced risk
	Dapagliflozin	27% reduced risk
	Ertugliflozin	30% reduced risk*
Dual SGLT1/SGLT2 Inhibitor	Sotagliflozin	33% reduced risk
GLP-1 Receptor Agonists	Liraglutide	Neutral effect
	Lixisenatide	Neutral effect
	Semaglutide	Neutral effect
	Albiglutide	Neutral effect
	Exenatide	Neutral effect
	Efpeglenatide	39% reduced risk
DPP-4 Inhibitors	Saxagliptin	27% increased risk
	Alogliptin	Neutral effect**
	Sitagliptin	Neutral effect
	Vildagliptin	Neutral effect
	Linagliptin	Neutral effect
Thiazolidinediones	Rosiglitazone	Increased risk***
Thiazolidinediones	Pioglitazone	41% Increased risk

*Exploratory secondary outcome (primary outcome of MACE was similar to placebo). **Possible increase in the risk of HF hospitalization in patients without a history of HF at baseline (HR 1.76, 1·07–2·90). *** Increased risk of HF hospitalization and HF-related death (HR 2.10, 1.35-3.27).

DPP4 Inhibitors

CV safety and HF outcomes of DPP4 inhibitors have been examined in several large-scale CVOTs (Table 4). In the Savor-TIMI-53 trial, there was no significant difference between Saxagliptin and placebo regarding the primary outcome of CV events. However, saxagliptin use was associated with a 27% relative increase in the risk of HF hospitalizations (224). In the EXAMINE (Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome) trial, alogliptin use showed a non-significant trend towards (3.9% vs. 3.3%, p = 0.22) increased risk of HF hospitalizations in the entire study population with a history of T2DM and recent acute coronary syndrome (225). However, the subgroup analysis showed an unexpected increase (2.2% vs. 1.3%, p = 0.026) in the risk of HF hospitalizations among subjects without a previous history of HF at baseline. Contrarily, a similar increase in the risk of HF hospitalization was not observed with other DPP4 inhibitors in dedicated CVOTs (226,227). The mechanism of increased HF hospitalization risk with saxagliptin and alogliptin remains unknown.

A recent retrospective comparative-effectiveness study using a US health insurance data set compared the CVD outcomes among patients with T2DM who were prescribed a DPP4 inhibitor vs. an SGLT2 inhibitor (193). In this cohort, the DPP4 inhibitor therapy group experienced a higher risk of MACE and hospitalization for HF than those initiated on an SGLT2 inhibitor.

DPP4 inhibitors have become less popular due to their cost and limited effectiveness in CV risk reduction compared to SGLT2 inhibitors and GLP1-RAs. Therefore, they are not among the preferred first- or second-line agents for managing T2DM in patients with HF. Based on available data, saxagliptin should be avoided in patients with known or at risk for HF. Moreover, HF risk is listed in the prescribing precautions of alogliptin.

Insulin

No solid evidence exists to suggest that, in T2DM, improving glycemic control with insulin lowers HF risk in at-risk patients or improves outcomes in those with established HF. Even though some observational studies suggested an increased risk of CV mortality and HF in T2DM patients treated with insulin (228), limited prospective trial data did not support such an association. The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention) was a CVOT that examined the early use of basal insulin (glargine) versus standard care in patients with T2DM or prediabetes and a high risk of CVD. The study found that insulin glargine was neutral with regards to CV outcomes and HF events (229).

Sulfonylureas

Sulfonylureas (i.e., glipizide, glyburide, and glimepiride) are widely used glucose-lowering agents that promote weight gain and fluid retention (4). No dedicated RCTs evaluated the efficacy and safety of sulfonylureas in patients with HF. Data from post hoc analysis of prospective trials and observational studies have suggested either no change or worsening of HF outcomes with the use of sulfonylureas in patients with or without known HF. A recent population-based cohort study including older diabetic patients hospitalized for HF between 2006 and 2014 demonstrated that sulfonylurea initiation was associated with increased risk of future HF hospitalization (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) and mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) (193). Based on current evidence, SGLT2 inhibitors, GLP1-RAs, and metformin are strongly preferable; sulfonylurea use should be avoided in patients with established or high risk for HF (4,141).

Thiazolidinediones

Thiazolidinediones (rosiglitazone and pioglitazone) have been effective oral antidiabetics in treating T2DM, significantly reducing HbA1c. However, they carry a risk of HF exacerbation and thus should be avoided in patients with established or at risk for HF. (Table 4). Therefore, thiazolidinediones should not be used in patients with pre-HF or clinical HF (4).

European Medicines Agencies and the U.S. FDA restricted the use of rosiglitazone, citing concerns about increased HF exacerbation after the publication of the results of the RECORD trial (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) (230). Similarly, the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events) showed an improvement in MACE but an increased risk of HF events with pioglitazone therapy in high-risk patients with T2DM (231). The worsening HF outcomes with the treatment of thiazolidinediones have mainly been attributed to their effect on fluid retention. Some studies have raised concerns about the adverse impact of thiazolidinediones on myocardial metabolism and remodeling (61,222). Because of the availability of better options and their potential unfavorable side effect profile, the popularity of thiazolidinediones has significantly declined.

CONCLUSIONS

HF and cardiomyopathy have a heterogeneous etiology in patients with diabetes. Diabetes-related comorbidities, such as CAD and hypertension, contribute to the pathogenesis of HF in patients with diabetes. The pathophysiologic link between diabetes and HF is multifactorial, involving various abnormal biochemical pathways. A complex interaction of these mechanisms contributes to the development of asymptomatic diastolic and systolic dysfunction, eventually leading to the clinical syndrome of HF.

The coexistence of diabetes and HF is a poor prognostic factor, and it poses a higher risk of HF hospitalization, all-cause mortality, and CVD mortality. Therefore, the prevention of asymptomatic cardiac remodeling and progression into symptomatic HF are among the primary goals of the clinical management of patients with diabetes. BP lowering has substantial benefits in preventing HF among individuals with diabetes. Despite the well-established favorable effects of weight loss, the role of lifestyle changes and weight loss in preventing HF among diabetic patients remains uncertain. Observational data demonstrated a significant reduction in HF outcomes in response to metabolic surgeries among patients with diabetes and morbid obesity.

Guideline-directed medical therapy for HF has robust morbidity and mortality benefits in individuals with or without diabetes. Subgroup analysis or meta-analysis of major HF RCTs demonstrated that the effectiveness of HF therapies such as beta-blockers, RAAS inhibitors, ARNI, and MRAs do not vary based on patients’ diabetes status, and these therapies lead to similar reductions in morbidity and mortality among HF patients with or without diabetes.

Since 2015, several landmark clinical trials of SGLT2 inhibitors and GLP1-RA have revolutionized our understanding of CVD risk reduction in patients with T2DM and have led to a paradigm shift in the clinical practice recommendations for managing T2DM. SGLT-2 inhibitors are the preferred agents in the glucose-lowering regimen independent of baseline HbA1c in T2DM patients with known or at risk for HF.

Several dedicated major clinical trials confirmed the CVD benefits of SGLT2 inhibitors in patients with established HF, regardless of LVEF or diabetes status. High-quality data from these clinical trials transformed SGLT2 inhibitors from a glucose-lowering agent to a HF drug. Moreover, SGLT2 inhibitors are the only medication class with U.S. FDA approval and strong guideline indication (class I or IIa) for all HF patients across different LVEF groups.

ACKNOWLEDGMENT

We thank Halis Kaan Akturk for his contribution to the previous version of this chapter.

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Prevention of Obesity

ABSTRACT

Obesity has become a major public problem which is associated with increased risk to health and enhanced mortality along with increased medical costs. Prevention is obviously the first line of attack and this chapter outlines preventive strategies starting with a model which translates the energy imbalance which produces obesity into the social framework in which this occurs and where intervention must occur. Increased food intake is the major driver with reduced physical activity as a second component, modified by many other factors. Prevention begins with pregnant woman where maintaining a healthy weight gain improves the outcome for both infant and mother with diet and exercise both showing positive results. The early years of life are another important time for prevention. Studies of children have shown that exercise and nutritional quality can be improved by lifestyle intervention, but that impacting body weight change is more difficult. Reducing sugar-sweetened beverage intake and increasing water intake are two potentially useful strategies. Finally, there are many studies examining strategies for prevention of weight gain in adults as a group and in special subsets of adults with variable effect. One can conclude that prevention is the cornerstone for reducing the prevalence of obesity in pregnant women and their offspring, in children and adolescents, and in adults, but that the current strategies may need to be supplemented with additional successful modalities of implementation.

INTRODUCTION

Obesity is a worldwide problem (1) and affect more than 100 million Americans (2). In the 1980s the prevalence of obesity began to rise more rapidly than before and has now reached epidemic proportions worldwide. Since 1980 it has more than doubled and In the United States. Data provided by the US National Health and Nutrition Examination Survey (NHANES) in 2009-2010 showed that 35.5 % (95% CI, 31.9%─39.2%) of men were obese (BMI>30 kg/m²) and 35.8% (95% CI, 34.0%─37.7%) of adult women were obese (1, 2). The National Health and Nutrition Examination Surveys (NHANES) in 2014 noted a BMI of ≥25 was present in 71.3% of men 20 years or older and in 65.8% of women 20 years or older. The prevalence of obesity (BMI ≥30) was 33.5% for men and 36.1% for women. Females at any age are disproportionately at greater risk for obesity, and especially extreme obesity (BMI ≥40, 8.3% in females; 4.4% in males). The prevalence of obesity has risen dramatically since 1980, but may have slowed at current higher than desirable levels. The prevalence of obesity among children age 3-5 is alarmingly high at 12.4% in boys and 10% in girls with higher rates in Hispanic and Blacks (3). The increase has continued in extreme obesity in the United States and is rising worldwide. This increase in the prevalence of obesity carries with it increased risks for diabetes, metabolic syndrome, non-alcoholic fatty liver, heart disease and cancer among others (4). It also has significant costs to the individual and to society (5). Clearly the “brakes” that prevented a rapid increase in obesity before 1980 are not working well enough, and new preventive strategies are needed. To select papers for this chapter the words prevent, prevention, obesity, and overweight were screened in PubMed and additional references identified from the selected papers.

FRAMEWORK FOR DEVELOPMENT OF OBESITY

Figure 1 is a model with the “energy balance” equation at the center and social and environmental factors surrounding it (4). When an individual becomes obese it is a clear sign that the balance has tipped slightly towards positive energy intake (or reduced expenditure) and that this imbalance has been present for months to years. Primary prevention of obesity would occur if strategies similar to what were in place before 1970-1980 were re-introduced and obesity rates were reversed, or alternatively if equally effective new ones were implemented. Secondary prevention is the use of techniques to prevent regain of weight in an individual who has gained too much weight as fat and then lost it. These are often also called “maintenance” strategies.

Figure 1. Model of Energy Intake and Energy Expenditure on a Balance Influenced by Genetic and Epigenetic Factors and Environmental and Social Influences.

The development of obesity, that is moving the central pendulum in Fig 1 to the right in favor of a positive energy balance could occur because there is a small increase in energy expenditure, a small decrease in energy expenditure or a combination of both.

Food available for consumption and food intake, corrected for plate waste, began to increase in the US after 1970 and has continued to the present (6, 7). The extra amount of food is now estimated to be about 400 kcal/d which is enough to account for the calories needed to produce the documented weight gain (8). An alternative explanation would be a decrease in activity in the ordinary duties of the day (9). I tend to favor the rise in food intake as the major factor.

The rise in consumable food items from farms in the United States began after a change in food policy for reimbursing farmers in 1970 (10). There are several outlets for this growing surplus of food. First, it could be stored in warehouses against a future need. It could be destroyed. Or it could be transferred to storage depots on people – obesity (11). Since the growth of the population is less than 1-2% per year, the growth in food supplies was larger than needed to meet this growing population. Since we don’t see stores of food in warehouses, we have probably transferred it to the population producing obesity. As Tillotson has said “…certain of our agricultural and industrial policies have had the unintended and unforeseen consequences of increasing overweight and obesity”. Our current “preventive strategies” thus operate in a setting of agricultural and industrial policies that favor production of more food that is needed to feed the population. Surpluses of food operate in a socio-economic environment. In many groups of women this is reflected in an inverse relationship between the prevalence of obesity and the educational and income levels (10).

Several economic hypotheses related to “food security” have been proposed. These economic factors may need to be part of the preventive strategy if we are to develop a cohesive approach to dealing with obesity around the world.

The positive energy balance that we see leading to obesity can be influenced by a variety of factors which are controlled by the individual, by the family, and by society. We know that people can “consciously” control their weight by restrained eating. It is clear from the model that the individual is at the center of this system but their responses in terms of energy intake and energy expenditure are influenced by a myriad of factors over which they have little or no control. Genetics underpins obesity (11, 12, 13). There are some genes that have such potent effects on body weight that when defective obesity is almost certain. Leptin is one of the most potent (11). There are more than 90 other genes that contribute small amounts to differences in body weight accounting for less than 5% of the risk for obesity (11, 13).

Epigenetic factors, environmental influences on the fetus and early life also have important effects. For example, offspring of mothers who smoke during pregnancy or whose mother is a diabetic are at higher risk of obesity later in life and those who gain large amounts of weight (4). Duration of sleep time also affects body weight. Availability of food and its palatability are environmental factors that have significant effects that can override the controls systems for body weight. It is clear that although many of these environmental factors can be controlled by the individual, the genetic and epigenetic influences make it difficult for many people to maintain a stable body weight. Thus, preventive and therapeutic strategies are needed.

STRATEGIES FOR PREVENTING OBESITY

At least 4 preventive strategies are available to deal with the epidemic: Education, regulation, modification of the food supply, and changes in the cost of food energy. Education about good nutrition and healthy weight in the school curriculum would be beneficial in helping all children learn how to select appropriate foods and should be included in school curricula. Foods used in school breakfast and lunch programs should match these educational messages.

However, it is unwise to rely on educational strategies alone, since they have not, so far, prevented the epidemic of obesity. The program of knowing your BMI initially instituted on a state wide basis in Arkansas may have helped that State to reduce the upward trend in obesity. Regulation is a second strategy. Regulations to provide an improved food label would be one good idea. Better regulations on appropriate serving sizes and caloric value that would be easy for the public to use might be part of the information provided by restaurants on their menus. This is now required in New York City and if effective may spread around the country.

Modification in some components of the food system is a third and very important strategy. Since the energy we eat comes from the food we eat, we need to modify this system to provide smaller portions and less energy density. One approach is to use differentiated food taxes to promote healthy diets. This is the approach New York State is trying with its tax on soft drinks introduced in 2007, and has been urged by a group of prominent nutritional scientists (15). This strategy has been argued both at the academic level (16, 17, 18), and at the policy level. It may be that economic tools that will shift food choices using cost is the “fluoride” for treating the epidemic of overweight that is described below.

Some years ago, I proposed that the best strategy for prevention of obesity may be modeled after the use of fluoride for prevention of dental caries (19). The addition of fluoride to the water supply had a more profound effect on the incidence of dental caries than brushing and flossing teeth. Brushing and flossing are like diet and exercise. They both require commitment on the part of the individual. Adding something like fluoride to the water supply doesn't require any commitment. Increasing the price of oil may be one such strategy. Between 1940 and 2005, Pollan pointed out that the number of calories from petroleum (oil) used to produce food energy has risen dramatically. In 1940 it was 0.4 cal of oil for each calorie of food energy. In 2005 it had risen over 20-fold with 10 calories of oil needed for each calorie of food. These calories come from the petroleum products used to make fertilizers, to transport food, to process and package food, for pesticides, and so on. If oil prices rise significantly, this will shift the use of oil for food and shift our consumption patterns (20).

Strategies for Preventing Obesity in Pregnant Women

Women who gain more weight during pregnancy have increased risk of diabetes, hypertension, pre-eclampsia, and still birth. The offspring is at increased risk for macrosomia and later obesity (21). A lifestyle intervention program during pregnancy in Denmark (Lifestyle in Pregnancy = LiP), however, failed to alter the metabolic risk factors in the offspring. A systematic review of evidence relating weight gain during pregnancy and outcomes of pregnancy found that dietary interventions were the most effective type of intervention in pregnancy. They reduced gestational weight gain and the risks of pre-eclampsia, hypertension, and shoulder dystocia in the infant. There was no difference in the incidence of small-for-gestational-age infants as a result of treatments (22, 23). Another systematic review reached similar conclusions and showed that dietary interventions significantly reduced gestational weight gain by 1.92 kg (95% CI -3,65, -0,19), and the incidence of Caesarean section (24). The Cochrane review of this subject in 2015 found that diet, exercise or both reduced the gestational weight gain by an average of 20%. These interventions included low glycemic index diets, supervised or unsupervised exercise program, and diet combined with exercise which were all comparable in their effects. Hypertension was reduced but pre-eclampsia was not. They also found no differences between intervention and control groups in the risk of preterm births, or macrosomia overall. However, the subgroup of women who were overweight or obese did have a 15% reduction in macrosomia. Fetal distress syndrome of was also reduced in women with obesity in the intervention groups (25).

Strategies Aimed at Children

There is a great deal of concern for the plight of obese children. The pioneering work of the psychoanalyst, Dr. Hilde Bruch, a refugee from Nazi Germany working in the 1940’s did much to alert the public to this important issue (26).

Children of overweight parents are a high-risk group for development of overweight (27). In a long-term follow-up study, Berkowitz et al studied 32 high risk children whose maternal pre-pregnancy BMI was 30.4 kg/m² and compared them to 29 low risk children whose maternal BMI was low at 19.6 kg/m². At this age they consumed a test meal in which their eating behavior was assessed, including rate of caloric consumption, mouthfuls/min, and requests for food. Parental prompts for the child to eat also were measured. Parental feeding prompts were not different between high risk and low risk children, but the rate of eating measured by mouthfuls of food/min, and total caloric intake/min during the test meal predicted an increased risk of being overweight or obese at age 6. Thus, pre-school years are important in setting risks for future obesity

Schools have also changed. They were once a place where children could be very active. With security issues and concerns about safety when children walking home from school there is less opportunity for physical exercise. Providing safe pedestrian walk-ways to school could increase physical activity for children more easily than changing the built environment for adults. In a review of school-based programs, 18 studies involving 18,141 children were evaluated. They were primarily elementary school children and had programs that lasted from 6 months to 3 years. A meta-analysis showed that physical activity interventions did not improve BMI (28).

To examine the studies that have looked at prevention of childhood obesity, I have taken data from a Cochrane Collaboration review of preventive strategies for children divided studies into long and short term. Short-term studies were those with data for 12 weeks or more but less than 52 weeks. Long-term studies were those with data beyond 52 weeks. I will discuss only the long-term studies.

LONG-TERM STUDIES

One controlled trial that was deemed of good quality was conducted in the US randomized 26 children and their families to 2 conditions: 1) increasing fruit and vegetable and 2) decreasing fat and sugar (29). The children were 6-11 years old and at least one parent accompanied them. They received a comprehensive behavioral program. At the end of 12 months the decrease in percentage of overweight was decreased 1.10% in the fruit and vegetable group and 2.40% in the lower fat and sugar group. These differences were not statistically significant, but are nonetheless tantalizing and suggest the need for applying this to high-risk groups like the children of overweight parents.

A second study of good quality was conducted by James et al (30) where 644 children were randomized by school class into 15 intervention and 14 control classes in 6 schools. The baseline prevalence of overweight was comparable. The intervention focused on decreasing consumption of carbonated beverages. The intervention was delivered in 3 one-hour sessions by trained personnel with the assistance of teachers. At 12 months the change in BMI “Z” score was not significantly different between intervention and control classes (mean Z score 0.7 (SD 0.2). However, there was a reduction in the self-reported consumption of soft drinks.

Sugar-sweetened beverages have been incriminated in the development of obesity and cardio-metabolic risks in a number of studies (31). One outcome of this data were 2 randomized clinical trials to reduce the intake of sugar-sweetened beverages among adolescents (32, 33, 34). At the end of one year the weight gain in one study was significantly smaller in those provided with sugar-free beverages, but most of this benefit, except in the Hispanic children, was lost at 2 years after the treatment program had been discontinued. In the other trial lasting 18 months, the children receiving the artificially sweetened beverages gained less weight than those drinking the sugar-sweetened soft-drinks (33). In a follow-up of this study (34) it was shown that compensation for changing sugar content in beverages was sub-optimal in children in the upper half of the BMI spectrum. Thus, replacing the sugar-sweetened beverages associated with weight gain with lower calorie versions might be beneficial to most children and adolescents.

Another trial was conducted in Thailand randomized kindergarten children by class into an exercise group and a control group with 5 classes in each arm (35). The reduction in the prevalence of obesity tended toward significance (p=0.07).

A US trial including 549 children from 6 schools was stratified by percentage ethnicity (36). This intervention, called SPARK (Sports, Play and Active Recreation for Kids) was a physical education program with a self-management component. The results for boys showed that the control group had significantly lower BMIs at 6 and 12 months, but not at 18 months. In contrast, the girls in the control group had lower BMIs at each time point that reached statistical significance at 18 months.

The Pathways Study (37) is one of the largest studies for prevention of obesity in children. The participants included 1704 children from 41 American Indian schools. Children were age 8-11. Pathways was a school-based multi-component, multi-center intervention for reducing percentage body fat. There were 4 components: 1) changing dietary intake; 2) increasing physical activity; 3) A classroom curriculum focused on healthy eating and lifestyle; and 4) a family-involvement program. At the end of the 3-year study, knowledge improved and fat intake at lunch decreased, but there were no changes in either body composition or activity level measured by motion sensor.

The Planet Health study is a high quality randomized controlled trial (38) conducted among 1295 ethnically diverse children in 10 US schools in New England who were randomized by school. The children were 11-12 years old and in the 6-8^th grade. The program was a behavioral choice intervention and concentrated on the promotion of physical activity, modification of dietary intake, and reduction of sedentary behavior with an emphasis on reducing time watching television. At follow-up the percentage of obese girls in the intervention schools was reduced 53% compared with controls, [Odds Ratio 0.47 (95% CI 0.24 to 0.93)]. Each hour of reduction in television time predicted a 15% reduction in obesity [OR 0.85 (95% CI 0.75 to 0.97]. Among the boys there was a decline in BMI in both groups, but no significant difference between them. Time spent viewing television was reduced among both boys and girls and fruit and vegetable consumption increased significantly. Gortmaker et al (38) concluded that the decline in television watching was a major factor in preventing obesity.

In another clinical trial from Germany, Muller et al (39) randomized a group of 414 children from 6 schools into control or intervention groups in the Kiel Obesity Prevention Study or KOPS. The key messages in the intervention group were to eat more fruits and vegetables each day, to reduce high fat foods, to keep active for at least 1 hour a day, and to decrease television viewing to less than 1 hour a day. At the end of one year there was no significant difference in change of BMI between the intervention and control groups.

In a program called Active Program Promoting Lifestyle in School, or APPLES, 634 children in 10 schools were randomized to intervention or control groups (39). The intervention included teacher training and resources, modification of school meals, support for physical education, and playgroups activities. At one year there was no difference in change in BMI between the children in the two groups, nor was there any difference in dieting behavior. However, children reported a higher consumption of vegetables. Although APPLES was successful in changing the ethos in the schools and the attitudes of the children, the trial was ineffective in changing weight status.

The program “VERB™--It’s What you Do!” was developed by the US Centers for Disease Control and Prevention is another example of a social marketing strategy. It is designed to increase physical activity among ethnically diverse 9- to 13-year-olds (40). The question of whether it is really possible to get long term behavioral change in a society with a vibrant advertising industry remains to be seen.

Mind, Exercise, Nutrition – Do it (MEND) is a British program held at a sports center, twice-weekly, for 3 months which consists of behavior modification, physical activity, and nutrition education. In their pilot study, 11 obese children age 7-11 years and their families were recruited and attended a mean of 78% (range 63-88%) of the sessions. Waist circumference, cardiovascular fitness, and self-esteem were all significantly improved at 3 months and continued to improve at 6 months. BMI was significantly improved at 3 months but lost significance by 6 months. This program has now been expanded to many sites through the United Kingdom (41) and Australia (42). The Stockholm Obesity Prevention Program (STOPP) is another randomized trial parents who are overweight or obesity designed to prevent obesity in their children. (43)

A meta-analysis examining the impact of lifestyle interventions on body weight and cardio-metabolic outcomes in overweight children found 33 studies with complete data on weight change. Lifestyle interventions compared to either no treatment control or usual care resulted in significant weight loss of 1.25 to 1.30 kg/m2 (BMI units). In the 15 studies reporting cardio-metabolic outcomes, there were significant reductions in fasting insulin, triglycerides, blood pressure, and LDL-cholesterol, but no effect on HDL-cholesterol (44). The importance of prevention in childhood and adolescence has prompted 3 Cochrane Reviews of the effect of Lifestyle Interventions. One focused on improvements in school performance (45), another focused on improvements in physical activity and fitness from lifestyle interventions (46), and a third one on the effects on body weight (47). This latter report showed that lifestyle was effective in in age groups 0 to 5 years, age 6 to 12 and age 13 to 18 with the largest effects seen in the children under 12. Community wide interventions for Increasing population levels of physical activity are not very effective based on another Cochrane Database Review (48).

Systematic analyses have also been done for special groups of individuals with obesity in the United States. Two of these reviews have examined Latino children and find that lifestyle and physical activity interventions are promising (49, 50). In a review of studies on Latino and African-American children Robinson et al (51) found that 2 of 17 studies showed benefits for preschool and elementary schools on reducing obesity in African-American children. Parent-child participation has also been found to be valuable (52).

Strategies Aimed at Adults

A large number of trials have been conducted in adults and reviewed in detail by Kumanyika and Daniels (53). The Pound of Prevention study (54, 55) is probably the largest and most general study for prevention of overweight reported to date. It demonstrated the feasibility of reaching a large number of people and producing some positive behavioral changes. However, as with many of the studies in children, the interventions were not successful in preventing weight gain relative to the control condition. The decrease of fat intake and increased physical activity were the strongest predictors of weight maintenance (55). Again, behavioral changes were positive and perhaps a higher intensity might have produced different results, but at the present time there is a reasonable argument to be made that money spent on behavioral efforts at changing behavior is wasted.

The results of the 5-year trial from the Healthy Women’s Study is also worth noting (56, 57). Behavioral counseling at 6 months was effective in preventing weight gain during the transition to menopause. The intervention program appears to have been well received, judging from retention rates, but it seems to be labor and cost intensive to deliver.

Rural counties in the United States have higher rates of obesity, sedentary lifestyle, and associated chronic diseases than non-rural areas. To tackle this problem, Perri et al worked with the USDA Cooperative Extension Service. They recruited obese women from rural communities who had completed an initial 6-month weight-loss program at Cooperative Extension Service offices in 6 medically underserved rural counties in Florida (n = 234). The women were randomized to extended care program or to an education control group. The extended-care programs entailed problem-solving counseling delivered in 26 biweekly sessions via telephone or face to face. Control group participants received 26 biweekly newsletters containing weight-control advice. The body weight at entry was 96.4 kg, and the women in the intervention group lost 10 kg during the 6-month intervention. One year after randomization, participants in the telephone and face-to-face extended-care programs regained less weight [1.2± 0.7 and 1.2 ±0.6 kg, (mean± SEM) respectively] than those in the education control group (3.7 ±0.7 kg; P = .03 and .02, respectively). The beneficial effects of extended-care counseling were mediated by greater adherence to behavioral weight-management strategies. Cost analyses indicated that telephone counseling was less expensive than face-to-face intervention, thus offering a strategy of working with the Cooperative Extension service using behavioral weight strategies to modulate body weight (58).

Strategies for Preventing Obesity Aimed at the Entire Population

Population-based messages aimed at the public concerning food and exercise are cognitive in nature requiring individual commitment (53). If the “individual” follows the advice in the message this strategy would be sufficient to “overcome” the epidemic of obesity. However, positive preventive messages are delivered in an environment in which there are many alternative messages urging consumption of this or that kind of food or eating at one or another of many different kinds of restaurants. The Low-Fat message of the 1990’s is one example of a message that assumed obesity results from increased fat intake and that reducing fat intake would reverse it. Omitted from this was the realization that eating less fat did not necessarily mean eating fewer calories and thus redressing the energy imbalance. A test of the low-fat hypothesis as a public health message came from the Women’s Health Initiative. Women were randomly assigned to normal or low-fat diets, but without calorie goals. The women assigned to the low-fat diet lost more weight that the other group, but after the low point, weight was regained (59). Of particular interest, is that the weight change over 8 years had a strong relation to the level of fat that the women chose to eat. Those with the lower fat intake remained 2 kg or more lighter after 7 years than those in the highest fat intake group indicating that dietary fat is one component of the problem, but that it is not the “whole story”. If one believed that the current epidemic of obesity was due to limited activity, then a campaign like “America on the Move”, which enrolls individuals to use step counters as a way to increase their activity should be an effective strategy (60). The jury is still out on this strategy.

An alternative approach might be to re-engineer the built environment to make it both easier to walk and make it more likely that individuals would do so rather than getting into their car (61). The current housing model of the cluster of houses off a main street where the automobile is essential for mobility will make this strategy a long-term one. A systematic review by Papas et al (62) identified 20 studies, of which 18 were cross-sectional that examined the relation of obesity to the numbers of outlets for physical activity and food. Seventeen of these found significant relationship between built environment (food outlets or access physical activity) and risk of obesity. The number of recreational facilities and likelihood of overweight in adolescents were significantly related.

FOOD

Faith et al (63) reviewed research that used manipulations of the environment to produce weight change. They concluded that easy access to food may influence food purchases, consumption, and possibly weight change while restriction of food availability may accomplish the same goals although this requires further research.

The food industry, for obvious reasons, favors the hypothesis that obesity results from reduced levels of physical activity and strongly supports providing more places for people to exercise and providing them with more healthy alternatives in food stores as a strategy to help overcome the obesity problem (53, 64). However, since “healthy” food items are likely to be more expensive than the ones already on food shelves, and since newer technologies and marketing are needed, it is unclear whether a price-sensitive public can be moved in this direction.

Strategies for improving access to healthful foods often focus on fruits and vegetables. The value of a diet high in fruits, vegetables, and low-fat dairy products with a reduction in the level of fat and sugar containing products was found to lower blood pressure across the range of salt intake in individuals who were maintaining their body weight (65, 66). Regular farmers’ markets, subsidizing the availability of fresh fruits and vegetables to school children, lowering the cost of fruits and vegetables while increasing the price of high-fat or high sugar foods in school or worksite cafeterias, or changing marketing strategies in other ways might increase fruit and vegetable consumption (67, 68, 69, 70, 71, 72). Since we are all price sensitive, these might move choices of food from the lower cost less healthy ones to more healthy choices. However, as Drewnowski has pointed out, the high-fat, high sugar alternatives provide much more food energy for the money than the so-called healthier options (73).

Another strategy toward this end is to “limit” availability of higher energy foods by making them more expensive. A review of the use of price of food items by Smed et al (16) has shown that in Europe increasing the tax or reducing the subsidies on “unhealthy” items and reducing the tax on “healthy” items through the value added tax system could shift consumption toward healthier foods (15). Federally funded programs such as food stamps, school lunches, and meals on wheels could also be used toward this end. Pending the willingness of the public and the politicians to tackle some of the political implications of tax policy to combat the epidemic of obesity, this strategy is likely to remain on the back burner (13).

INCREASING PHYSICAL ACTIVITY AS A FOCUS FOR PREVENTION

An overall increase in physical activity would increase energy expenditure and is one strategy for prevention of obesity. One assumption of such a strategy is that activity may have decreased during the time that the epidemic of obesity developed. This is difficult to establish, but a recent publication used total daily energy expenditure in a small number of individuals (some 300) measured over years (74). This strategy would be appropriate, whether there has been a decrease in energy expenditure or not, and the data on this question is unclear. In contrast, Church et al (8) have presented data showing that leisure activity has declined as the obesity epidemic has moved ahead. Altering the “built environment” such as side-walks and shopping centers is one way to do encourage more physical activity (61). However, there is a 30–40-year lag between initiation of changes in architectural land use and real changes in configuration of sidewalks, making these approaches unlikely to impact this problem in the foreseeable future.

How much has our daily activity level changed? To examine this question Cutler et al (75) examined levels of activity in various tasks from 1965 to 1995, which covers the period before and to the peak of weight gain. They found that over the 30 years from 1965 to 1995 the major changes in activity have been a decrease in household work and an increase in recreation and communication. These are relatively small compared to the proportion of the daily routine which is spent in paid work and in personal needs and care. We thus think food intake is a more viable strategy for combating the obesity epidemic.

Work places are another place where prevention and intervention can occur. In a review of worksite nutrition and physical activity programs Anderson et al (76) noted modest improvements in employee weight status at the 6-12-month follow-up. Based on 9 randomized controlled trials, there was a loss of 2.8 pounds (-1.3 kg) (95% CI=-4.6, -1.0 weight loss) and a decrease of 0.5 (95% CI=-0.8, -0.2) BMI units based on six RCTs. The findings were applicable to both male and female employees, across a range of worksite settings. Most of the studies combined informational and behavioral strategies to influence diet and physical activity; fewer studies modified the work environment (e.g., cafeteria, exercise facilities) to promote healthy choices. This is an area of potential future advance.

The nutrition-transition in China provides an interesting example of how the modern way of life makes preservation of physical activity so difficult (77, 78). As recently as 20 years ago, the bicycle was a major mode of transport for Chinese. This is no longer the case. The automobile and public transport systems are relegating the bicycle to museums. Whether understanding the need for people to move can provide a rescue strategy for weight gain is doubtful.

One element in trying to combat the obesity epidemic is to focus on the needs of selected groups – so-called social marketing. The idea is to provide focused messages targeted at specific sub-groups. Another approach is to focus on specific food groups. The program by the National Cancer Institute to increase Fruits and Vegetable consumption through the “5 A Day for Better Health” program is an example of this idea. Although we would all agree that this is a desirable approach, its effectiveness in changing the consumption of fruits and vegetables has not been overwhelming (79).

SUMMARY AND CONCLUSION

Efforts to prevent obesity or to reverse components through changing lifestyle have focused on both adults and children and well as worksites. Although some changes can be documented in these studies, the net effects have been small and the epidemic has continued to move ahead. The role of economic incentives has received less exploration, but may be more promising as a way to halt this epidemic.

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Glanz K, Hoelscher D. 2004. Increasing fruit and vegetable intake by changing environments, policy and pricing: restaurant-based research, strategies, and recommendations. Prev Med. 39 Suppl 2:S88-93.
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TEST FOR TABLE DESIGN

WEBSITE TABLES TESTING

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Table 1. Widely Held Misconceptions About ZES
1) Gastrinomas, similar to a number of other pNEN (insulinomas, gastrinomas, PPomas), primarily occur in the pancreas. FACT: In recent studies, 60-100% of gastrinomas in both sporadic ZES and MEN1/ZES occur in the duodenum, with only 0-15% in the pancreas (6,43,50,95,102,127,175-179) (Table 2).
2) MEN1 is uncommon in ZES, similar to other pNEN such as insulinomas (3-5%), glucagonomas (<5%), PPomas/nonfunctional pNEN (<3%). FACT: MEN1 is found in the highest frequency of all pNEN syndromes in ZES patients occurring in 20-25% and is important to diagnose because of its different treatment aspects (30,50,64,72,87,89,95,102).
3) With the increased awareness of ZES and widespread availability of gastrin assays and sensitive imaging modalities, similar to some other pNEN, gastrinomas are being diagnosed earlier. FACT: The time of onset of symptoms to diagnosis of ZES remains 4-7 years (24,26,48,60,62,89,134) and a number of factors are contributing to make the diagnosis even more difficult (See point #4 below).
4) As recommended in all guidelines (9,72,80,152,157,180-182), similar to other functional pNEN syndromes (F-pNENs), ZES is currently diagnosed by demonstrating excess hormone production (fasting hypergastrinemia) in the presence of an unphysiological effect of the hormone hypersecretion (i.e., inappropriate acid hypersecretion (elevated basal acid output>15 mEq/hr., pH<2)) (9,50,51,55,56,59,70,72,73,79,181,183,184). FACT: In contrast to, for example, insulinomas, which are uniformly diagnosed by demonstrating fasting hyperinsulinemia with accompanying hypoglycemia (frequently during a fasting study) (29,50,185-188), in a recent review of the last 20 cases of ZES reported in the literature in 2018 (55), 95% of the diagnoses were reported without performing a gastric analysis or gastric pH assessment (55) and thus not using classical established criteria. This approach has complicated the diagnosis of ZES and the factors leading to this confusion will be discussed below in detail in the ZES diagnosis section.
5) In MEN1 patients, similar to other MEN1 patients with F-pNEN such as insulinomas and glucagonomas, most gastrinomas can be cured by nonaggressive surgical resections in MEN1/ZES patients. FACT: In contrast to other F-pNEN (29,157,189), the 5-year surgical cure rate of MEN1/ZES is <5% (6,30,43,44,88,190) without aggressive surgical resections such as Whipple resection, which are not recommended (6,9,88,92,93,118,123,157,180,182). However, without these resections, most patients with small tumors and adequate acid secretory control have an excellent prognosis, which has led to controversy in their treatment, and will be discussed in the surgical section later (30,43,47,92,93,95,102,118,157,180,182,191).

Table 1. Widely Held Misconceptions About ZES

Radiology of the Pituitary

ABSTRACT

MRI is the primary imaging modality for the pituitary gland. This chapter reviews and illustrates the normal anatomy and MRI appearances of the pituitary gland and hypothalamic region. The optimal MRI technique relies on thin section T1-weighted sequences in the sagittal and coronal planes before and after gadolinium contrast enhancement. T2-weighted sequences can add useful additional information in some cases but are not a substitute for T1-weighted sequences. Congenital abnormalities with characteristic imaging appearances including the ectopic posterior pituitary and hypothalamic hamartoma are illustrated, along with images of all the common primary pituitary pathologies: adenomas, Rathke’s cysts and hypophysitis (infundibular, lymphocytic, and immunotherapy drug-induced). Non-pituitary origin pathologies which may involve the pituitary or parasellar region are also illustrated, including meningioma, arachnoid cysts, germinoma, craniopharyngioma and chondrosarcoma; they all have distinct imaging appearances. Inflammatory processes such as sarcoid or Langerhans cell histiocytosis can also involve the pituitary stalk or hypothalamus and in these cases diabetes insipidus may be a clinical feature, correlating with stalk involvement on imaging. More recently, IgG4- and immune checkpoint inhibitor-associated hypophysitis have emerged as new diseases entities. Metastases or lymphoma can occasionally involve the pituitary gland and stalk. The granular cell tumor is a rare tumor arising in the pituitary stalk and has a typical appearance, distinct from other inflammatory or infiltrative stalk processes.

ANATOMY AND EMBRYOLOGY

The pituitary gland sits within the sella turcica which is a cup-shaped depression in the sphenoid bone. The sphenoid air sinus lies below and anterior to the sella turcica (Fig 1). Lying above the pituitary gland is a cerebrospinal fluid (CSF) space, the suprasellar system, which contains the optic chiasm (Figs 1 and 2). The lateral walls of the pituitary fossa are formed by the cavernous sinuses (Fig 1B) which contain the internal carotid arteries as well as a number of cranial nerves: the 3^rd, 4^th and 6^th cranial nerves as well as the first and second divisions of the 5^th cranial nerve. The pituitary gland is connected via the pituitary stalk to the hypothalamus, which is a thin plate of tissue making up the floor of the anterior part of the 3rd ventricle (Figs 1 and 3).

Figure 1. Sagittal T1 weighted unenhanced image of the pituitary fossa demonstrate normal anatomy. The anterior pituitary tissue, A, is visible within the sella and the posterior pituitary bright spot, P, is evident behind it. The stalk (arrow) is well seen with a small cleft of CSF visible within it superiorly –the infundibular recess of the third ventricle. The optic chiasm, C, and mamillary bodies, M, are seen in the suprasellar region. B - brainstem, S - sphenoid air sinus, CL - clivus.

Figure 2. Coronal T1 weighted unenhanced image of the pituitary fossa. The anterior pituitary gland, A, is within the fossa. The posterior pituitary bright spot is visible centrally, P. The stalk is seen extending up into the suprasellar region. The optic chiasm, C, is visible. The cavernous segments of the carotid arteries, I, are seen within the cavernous sinuses, which form the lateral boundaries of the pituitary fossa.

Figure 3. Sagittal T1 weighted enhanced image of the pituitary. The pituitary tissue has enhanced, as has the pituitary stalk.

The appearance and size of the pituitary gland changes during life. At birth, it is typically globular in shape and shows high signal on T1 weighted images (1). By approximately 6 weeks of age this high signal has diminished, and the anterior pituitary tissue has a similar signal to brain tissue. The posterior pituitary tissue, however, retains a bright signal on T1 weighted sequences. This so-called “posterior pituitary bright spot” is a normal appearance thought to be due to the high neurophysin content (which is not present in the anterior pituitary tissue) (Fig 1).

The size of the pituitary gland varies with age and sex. On average it is between 3 and 8mm in height but is generally larger in females than males. The height increases during adolescence due to normal physiological hypertrophy (2). There is also a slight increase in size seen during the sixth decade in females. The most striking physiological changes are seen during pregnancy when the gland progressively enlarges reaching a maximal height immediately after birth when it may reach 10mm in height (3).

Embryologically, the anterior and posterior pituitary lobes are distinct. The anterior lobe forms from an invagination of the oral ectoderm known as Rathke’s Pouch. The posterior pituitary forms from a protrusion of the neural ectoderm of the diencephalon. Between the anterior and posterior lobes lies an intermediate lobe which is vestigial and known as the pars intermedia. This is a potential site for small non-functional Rathke’s cysts (Fig 4).

Figure 4. Sagittal enhanced T1 weighted image demonstrating a small Rathke’s cyst. This is seen to lie just below the insertion of the pituitary stalk and centrally within the gland. Although it is possible that a small cystic adenoma could have these appearances, this is a very typical location for a Rathke’s cyst arising in the pars intermedia.

MR IMAGING

MR is the imaging of choice for the pituitary gland. In order to optimize the study, it is necessary to perform thin sections (2mm or 3mm) targeted to the pituitary fossa and performed in both the sagittal and coronal planes. T1 weighted sequences before and after intravenous contrast are the mainstay of pituitary imaging (Fig 1-3) (4). Coronal T2 weighted sequences can also give added information but are less sensitive in the detection of adenomas. Sequences before and after intravenous contrast are the main stay of pituitary imaging (Fig 1-3). Coronal T2 weighted sequences can also give added information but are less sensitive in the detection of adenomas. The higher field strength 3 Tesla MR scanners, which are now in more widespread clinical use, can provide higher resolution pituitary images, the T2 images being reliably improved at 3T. However, artefacts related to vascular flow and patient movement are more pronounced and may outweigh the benefits. CT does not provide such excellent soft tissue resolution as MR but can be a very useful investigation if MR is not possible, and also if it is important to identify the presence of calcification in or around the sella. A dedicated CT study should be performed with a 1mm slice thickness in the axial plane and then reconstructed in the sagittal and coronal planes.

There can be some benefit in performing the post-contrast MR sequences in a dynamic fashion (within the first 60 seconds) after contrast injection. This can maximize the conspicuity of adenomas within the pituitary gland, which typically enhance less than the normal pituitary tissue, and this differential enhancement is sometimes best appreciated within the first arterial phase of the contrast injection (Figs 4 and 5) (5). However, in the majority of cases the lesions are adequately demonstrated on a standard acquisition (non-dynamic) scan after the contrast administration (Fig 7) (5).

Figure 5. Coronal T1 weighted image of the pituitary gland before contrast. There is a microadenoma in the right side of the gland. On the unenhanced image there is evidence of depression of the floor of the sella on the right side but the microadenoma cannot be visualized within the gland.

Figure 6. Coronal T1 weighted image of the pituitary gland immediately after contrast. There is a microadenoma in the right side of the gland. After contrast a dynamic acquisition shows an area of lesser enhancement indicative of a microadenoma.

Figure 7. Coronal T1 weighted image of the pituitary gland that demonstrates a left sided microadenoma (arrow) which was best seen on this nondynamic post-contrast sequence.

The pituitary gland, pituitary stalk and cavernous sinuses are all vascular structures which are seen to enhance after gadolinium injection. The optic chiasm and hypothalamus, however, do not show enhancement if the blood brain barrier is intact (Figs 1-3).

PITUITARY ADENOMAS

Pituitary adenomas are by far the most common mass lesion seen in the sella and parasellar region. They are slow-growing benign neoplasms arising from the anterior pituitary tissue; radiologically they are simply classified by size: lesions smaller than 10mm transversely are termed microadenomas and those greater than 10mm are macroadenomas. The clinical classification separates adenomas into those that are hormonally activity, e.g., prolactinomas, and those that do not have measurable evidence of hormonal activity referred to as non-functioning adenomas. The histology of the so-called non-functioning adenoma suggests that these arise from gonadotroph cells. The imaging appearances of pituitary adenomas is similar whether they are hormonally functioning or not. Obviously, non-functioning adenomas are more likely to present when they have attained a significant size and are producing effects on local structures around the sella.

Pituitary Macroadenomas

Pituitary macroadenomas can extend superiorly into the suprasellar cistern (Figs 8-10) and impinge on the optic nerves and/or optic chiasm to produce visual field abnormalities (typically a bitemporal hemianopia). Pituitary macroadenomas with a large suprasellar component characteristically show the appearance of “waisting” (Figs 9 and 10) as they pass through the diaphragma sellae, the sheet of dura which normally lies above the pituitary gland. Lateral growth of a macroadenoma is initially seen to cause deformity of the cavernous sinus; however, adenomas can invade into the cavernous sinus. (Fig 11) This may be associated with symptoms or signs related to involvement of the cranial nerves that run in the cavernous sinus. The third, fourth and sixth cranial nerves run through the cavernous sinus, as do the first and second divisions of the fifth (trigeminal) nerve. If the MR imaging demonstrates adenoma tissue extending beyond the most lateral margin of the cavernous segment of the internal carotid artery, then it is very likely that there is tumor within the cavernous sinus (6). In many cases, however, tumor simply deforms the cavernous sinus flattening the medial wall but not extending more laterally, and in these cases the tumor is typically confined to the sella and has not invaded into the cavernous sinus at surgery. Adenomas can also extend inferiorly into the sphenoid producing remodeling of the bone. Occasionally, macroadenomas will show a very extensive involvement of the skull base (Fig 12) and, exceptionally, can extend out into the infratemporal fossa.

Figure 8. Sagittal T1 weighted unenhanced image of a macroadenoma. The sella is enlarged and the macroadenoma is seen to extend upwards into the suprasellar cistern with the optic chiasm stretched and deformed over the surface of the macroadenoma.

Figure 9. Coronal T1 weighted unenhanced image of a macroadenoma. The sella is enlarged and the macroadenoma is seen to extend upwards into the suprasellar cistern with the optic chiasm stretched and deformed over the surface of the macroadenoma.

Figure 10. A coronal T1 weighted enhanced image shows diffuse enhancement of the macroadenoma, no normal pituitary tissue can now be identified. The optic chiasm is easily identified, it does not enhance and is seen to be stretched over the superior aspect of the adenoma.

Figure 11. A coronal enhanced T1 weighted image shows a right-sided pituitary adenoma that has invaded laterally into the right cavernous sinus. A significant component of the tumor lies lateral to the cavernous carotid artery and must therefore be within the cavernous sinus.

Figure 12. A sagittal T1 weighted unenhanced image shows an invasive macroadenoma which has involved much of the central skull base. It has invaded the sphenoid air sinus which can no longer be identified and has also extended down the clivus. There is also a modest suprasellar extension with elevation of the optic chiasm.

When pituitary macroadenomas attain a certain size, it is no longer possible to identify any normal pituitary tissue within the sella. The posterior pituitary bright spot may also be difficult to identify but is often seen in the lower aspect of the pituitary stalk which itself may be markedly deformed by the adenoma. Despite these appearances it is very rare for patients with macroadenomas of the pituitary to have diabetes insipidus, which usually points to a different pathology within the pituitary gland or stalk. Macroadenomas may be homogeneous or heterogeneous in their MR signal characteristics. Areas of cystic change and focal areas of hemorrhage are not infrequently identified. It is not uncommon for areas of hemorrhage to be seen within macroadenomas without any correlating clinical event; however, significant hemorrhage with necrosis in an adenoma can produce the syndrome of pituitary apoplexy. The patient reports sudden onset of headache usually associated with visual disturbance. The MRI scan shows an enlarged sella containing a macroadenoma with areas of high T1 signal representing the hemorrhage (Figs 13 and 14). Often there is suprasellar extension and there may also be involvement of the cavernous sinus. Clinically, the patient may present with cranial nerve problems related to involvement of the cavernous sinus. Hemorrhage extending outside the tumor into the subarachnoid space is documented but is very rare.

Figure 13. Sagittal T1 non-contrast image showing hemorrhage into an existing pituitary macroadenoma. The area of high signal represents the recent hemorrhage. There is a component of the tumor extending into the left cavernous sinus which does not show hemorrhage. The suprasellar extension is compressing the chiasm particularly on the right side.

Figure 14. Coronal non-contrast image showing hemorrhage into an existing pituitary macroadenoma. The area of high signal represents the recent hemorrhage. There is a component of the tumor extending into the left cavernous sinus which does not show hemorrhage. The suprasellar extension is compressing the chiasm particularly on the right side.

Pituitary Microadenomas

Pituitary microadenomas are confined within the sella and are sometimes identified within the normal pituitary gland as an area of lower signal on T1 weighted sequences than the normal pituitary tissue (Fig 15). (7) Local remodeling of the floor of the sella (Fig 5) and remodeling of the dorsum are also useful features to identify the presence of a microadenoma. Although there may be displacement of the pituitary stalk by a lesion, this is not a very reliable indicator (8). Administration of intravenous gadolinium will improve the sensitivity of pituitary MR in identifying the presence of a microadenoma; typically, the microadenomas enhance less avidly than the normal anterior pituitary tissue (Figs 5-7) Acquiring sequences dynamically within the first minute after intravenous injection can slightly further improve the sensitivity of the study (5). This will demonstrate adenomas that appear less vascular on the initial arterial phase of contrast enhancement but then equilibrate to show similar vascularity to the normal gland in the next few minutes. The use of volumetric T1W sequences after contrast (as compared to standard T1W spin echo -SE) improves the detection rate for microadenomas (9), and so is of particular use in Cushing’s disease. A fluid attenuated Inversion recovery (FLAIR) sequence after contrast may further improve the detection of Cushing’s adenomas, if used with the volumetric sequence, which has the highest individual sensitivity (10). The signal characteristics of GH-secreting adenomas on T2 weighted sequences (whether they are of lower or higher signal than adjacent grey matter) can be an indicator of their histological composition: densely granulated GH secreting adenomas are typically hypointense whilst sparsely granulated GH secreting adenomas are hyperintense. The low T2 signal (densely granulated) adenomas seemingly respond better to somatostatin analogues (11) (Fig 16).

Figure 15. A coronal unenhanced T1 weighted image shows a small left sided microadenoma (arrow) as an area of lower signal than the rest of the anterior pituitary tissue.

Figure 16. A coronal T2 weighted image shows a low T2 signal adenoma in the left side of the gland (arrow) which represented a densely granulated GH secreting adenoma.

After pituitary surgery it takes around 3 to 4 months for the postoperative changes within the sella to regress to allow for assessment of the true volume of residual pituitary tissue (12).

RATHKE’S CLEFT CYSTS

These benign, non-functioning cysts arise from remnants of squamous epithelium from Rathke’s cleft. They typically arise close to the insertion of the stalk (Fig 17) They are a common incidental finding reported in up to 11% of pituitary glands at autopsy (13). On imaging they may appear proteinaceous rendering their signal higher to the point that they appear hyperintense on the T1 weighted sequence. It is not uncommon for these cysts to lie in the suprasellar region on the surface of the gland where they are usually found anterior to the pituitary stalk (Figs 18 and 19). If they are of significant size, then it may be hard to distinguish a Rathke’s cyst from a cystic craniopharyngioma. However, it is notable that the wall of a Rathke’s cyst shows no more than minimal enhancement. There are no solid enhancing areas and they do not calcify. Rathke’s cysts can be found in all age groups.

Figure 17. A coronal unenhanced T1 weighted image demonstrating a small Rathke’s cyst. This is seen to lie just below the insertion of the pituitary stalk and centrally within the gland. Although it is possible that a small cystic adenoma could have these appearances, this is a very typical location for a Rathke’s cyst.

Figure 18. Sagittal enhanced T1 weighted image of a large Rathke’s cyst. The cyst is seen to be sitting on the superior aspect of the pituitary tissue which appears flattened within the sella. The optic chiasm is stretched over the surface of the cyst. After contrast the cyst does not show enhancement. The cyst shows higher signal than the CSF indicating that it has a higher protein content.

Figure 19. Coronal unenhanced T1 weighted image of a large Rathke’s cyst. The cyst is seen to be sitting on the superior aspect of the pituitary tissue which appears flattened within the sella. The optic chiasm is stretched over the surface of the cyst. After contrast the cyst does not show enhancement. The cyst shows higher signal than the CSF indicating that it has a higher protein content.

MENINGIOMAS

Meningiomas are slow-growing neoplasms that arise from the dura and can arise from any of the dural surfaces around the sella. Suprasellar meningiomas appear as soft tissue mass lesions apparently sitting on the superior surface of the pituitary and often compressing or involving the optic chiasm and nerves (Fig 20) (14) A typical feature is a dural “tail” of enhancement seen extending forward along the planum sphenoidale (Fig 21). Meningiomas have very similar signal to both the brain parenchyma and the pituitary gland, but show prominent homogeneous enhancement after contrast. The dural tail is a helpful distinguishing feature to separate meningiomas from other sella tumors.

Figure 20. Coronal enhanced T1 weighted image There is a suprasellar meningioma which appears to be arising from the planum sphenoidale and is seen extending along the floor of the anterior cranial fossa where a dural tail (arrow) is visible. The pituitary gland itself appears normal and a cleft of CSF is visible between the meningioma and the pituitary tissue. The meningioma is displacing and possibly involving the optic nerves anterior to the chiasm.

Figure 21. Sagittal (B) enhanced T1 weighted image. There is a suprasellar meningioma which appears to be arising from the planum sphenoidale and is seen extending along the floor of the anterior cranial fossa where a dural tail (arrow) is visible. The pituitary gland itself appears normal and a cleft of CSF is visible between the meningioma and the pituitary tissue. The meningioma is displacing and possibly involving the optic nerves anterior to the chiasm.

Meningiomas can also arise from the cavernous sinus producing a soft tissue mass lying lateral to normal pituitary tissue. The meningioma may encase the cavernous carotid artery and can produce constriction of this vessel (Fig 22). This feature may be helpful in distinguishing between cavernous sinus extension of a pituitary tumor and a cavernous sinus meningioma. Pituitary tumors do not typically cause any vascular constriction. There may be hyperostosis (bony thickening) of any bony surface from which a meningioma has arisen, most typically the anterior clinoid process, though this may be more easily appreciated on CT than MR.

Figure 22. A Coronal T1 weighted enhanced image of a left cavernous sinus meningioma. There is expansion of the left cavernous sinus (arrows) and some concentric narrowing of the left cavernous carotid artery (compare to the right carotid).

CRANIOPHARYNGIOMAS

Craniopharyngiomas are rare epithelial tumors arising in the sella/suprasellar region from the remnants of the craniopharyngeal duct. They are most commonly seen in children between 5 and 10 years of age; however, they can also occur in late adulthood in the sixth decade. They are the commonest lesion to involve the hypothalamic/pituitary region in children. In children it is the adamantinomatous histological subtype that is the most common (15). These shows both cystic and solid components as well as calcification, best appreciated on CT. The fluid within the cysts contains a high content of cholesterol as well as protein and desquamated cells, and this accounts for the cyst fluid often having high signal on T1 weighted unenhanced images (Fig 23) The solid enhancing tumor components are most easily seen after contrast injection (Fig 24). Craniopharyngiomas presenting in adulthood are more likely to be of the papillary subtype. These may be exclusively solid lesions (Fig 25 and 26) or show a mixed solid and cystic morphology (15). They do not typically calcify, and they are less locally infiltrative. The adamantinomatous subtype is particularly adherent to surrounding brain tissue and is therefore difficult to surgically resect; however, imaging cannot distinguish accurately between the histological subtypes. The imaging characteristics are those of a complex suprasellar mass containing both cystic and solid components, the solid components show enhancement after contrast (14). Large lesions may be associated with hydrocephalus (more commonly in children) while the cystic components may show variable signal characteristics from low signal to high signal on the T1 weighted sequences. (Fig 23).

Figure 23. Sagittal T1 weighted unenhanced image showing a partially cystic craniopharyngioma. This is a large complex suprasellar mass which extends down into the pituitary fossa and up to deform the third ventricle. There are patchy areas of high signal before contrast which represent the cystic components with a high protein/ lipid content.

Figure 24. Coronal enhanced image showing a partially cystic craniopharyngioma. This is a large complex suprasellar mass which extends down into the pituitary fossa and up to deform the third ventricle. It is of mixed signal intensity and the solid components enhance after contrast.

Figure 25. Sagittal T1 weighted unenhanced image. This shows a solid suprasellar enhancing mass, a solid craniopharyngioma. This is elevating and deforming the chiasm but is not involving the pituitary gland itself which can be seen within the sella.

Figure 26. Sagittal T1 weighted enhanced image. This shows a solid suprasellar enhancing mass, a solid craniopharyngioma. This is elevating and deforming the chiasm but is not involving the pituitary gland itself which can be seen within the sella. The mass enhances after contrast indicating that it is solid, and no cystic areas are evident.

HYPOTHALAMIC/OPTIC CHIASM GLIOMAS

These tumors present as suprasellar mass lesions and are most commonly seen in children. It is very often hard to determine whether the tumor has arisen in the optic chiasm or the hypothalamus as typically both of these structures are involved. These tumors are often associated with neurofibromatosis type I, in which case there is often involvement of the optic nerves and very often a significant cystic component is evident (14). Otherwise, these tumors appear as well-defined suprasellar mass lesions which may show enhancement (Fig 27 and 28) and may also show reactive signal change in the brain along the optic radiation. Calcification is not seen in these lesions.

Figure 27. Sagittal T1 weighted enhanced image show a partially cystic and partially solid hypothalamic glioma in the suprasellar region. The mass is centered on the region of the optic chiasm and is flattening the pituitary stalk and hypothalamus. The pituitary gland is normal.

Figure 28. T1 weighted coronal enhanced image show a partially cystic and partially solid hypothalamic glioma in the suprasellar region. The mass is centered on the region of the optic chiasm and is flattening the pituitary stalk and hypothalamus. The pituitary gland is normal.

GERMINOMA

These are rare intracranial germ cell tumors which most typically arise in the suprasellar or pineal regions (16,14). They are usually seen in children or young adults. These patients commonly have diabetes insipidus as one of the presenting complaints, and this reflects the involvement of the hypothalamus and pituitary stalk. Characteristic imaging appearances are those of a homogeneous, solidly enhancing mass involving the hypothalamic region with involvement of the upper aspect of the pituitary stalk (Figs 29 and 30) If the lesions are large then the optic chiasm may be also involved. Involvement in both the suprasellar region and the pineal region at the time of presentation is well recognized (16) (Fig 29). Detection of tumor markers, either human chorionic gonadotrophin (HCG) or alpha fetoprotein (AFP) can be detected in the serum/CSF to confirm the diagnosis (16), and may obviate the need for biopsy. The absence of these markers does not exclude the diagnosis and biopsy may be necessary. Dramatic resolution of the imaging findings after treatment can be seen as these tumors are very sensitive to radiation. These tumors can disseminate through the CSF spaces producing enhancement around the ventricular margins.

Figure 29. Sagittal T1 weighted enhanced images of a germinoma. Figure demonstrates a large homogeneously enhancing soft tissue mass within the suprasellar region involving the upper aspect of the pituitary stalk and the hypothalamic region with a second separate mass visible in the region of the pineal gland - this is typical of a germinoma.

Figure 30. Sagittal T1 weighted enhanced images of a germinomas. Figure demonstrates a small lesion in the region of the upper aspect of the stalk and hypothalamus (arrow).

GRANULAR CELL TUMORS

Granular cell tumors are rare, benign WHO grade 1 lesions most typically seen in the suprasellar region. They arise from the neurohypophysis and/or the pituitary stalk. They have also been known as choristomas (17) .Histologically, they appear to arise from the pituicyte which is the main posterior pituitary cell. These are seen as well-defined suprasellar masses related to the pituitary stalk with homogeneous enhancement (Fig 31) (17). Despite their intimate relationship to the pituitary stalk, diabetes insipidus is not usually present although other endocrine disturbance may be present and these lesions may even be asymptomatic. If they have reached significant size, they may be associated with visual disturbance or headache. They are benign and slow growing with a low recurrence rate after surgery. Similar in appearance to the granular cell tumor, and equally rare, are the so called pituicytoma and the spindle cell oncocytoma. It seems that histologically these 3 entities show morphological overlap and may arise from a common lineage: they cannot be distinguished on imaging appearances (18).

Figure 31. Sagittal enhanced T1 weighted image shows a well-defined enhancing mass within the pituitary stalk. The pituitary gland is normal, as is the hypothalamus. This was a granular cell tumor.

LANGERHANS CELL HISTIOCYTOSIS

This is a rare disease of childhood due to a proliferative disorder of the Langerhans cell of the dendritic cell line; CNS involvement is common but it is rarely the only site involved, skeletal involvement being the most frequent (19). A common location for intracranial involvement is the hypothalamo-pituitary axis. The MRI appearances characteristically show thickening of the pituitary stalk with enhancement (Fig 32). The posterior pituitary bright spot is usually absent. These appearances correlate with the typical clinical presentation of diabetes insipidus. This is often an isolated intracranial abnormality but extra-axial/osseous intracranial mass lesions and degenerative changes in the cerebellum and basal ganglia are also recognized (19).

Figure 32. Sagittal T1 enhanced image shows diffuse thickening of the pituitary stalk in a patient with Langerhans cell histiocytosis.

HYPOPHYSITIS

Hypophysitis is an inflammatory disorder of the pituitary gland which can be primary or secondary to a known infection or systemic disease. Primary hypophysitis includes autoimmune hypophysitis and other inflammatory forms of unknown cause. Distinct histopathological types are recognized; lymphocytic hypophysitis, granulomatous hypophysitis and xanthomatous hypophysitis (20). Lymphocytic and granulomatous hypophysitis have similar indistinguishable MR imaging features: enlargement of the gland producing the appearance of a sellar mass lesion with suprasellar involvement of the stalk (Figs 33 and 34). The gland may appear heterogeneous after contrast and there may be distortion of the chiasm if the suprasellar component is sizeable, which is not uncommon. Lymphocytic hypophysitis is the most common form occurring more often in females and classically presenting at the end of pregnancy or in the post-partum period with endocrine dysfunction (20) There may be also be diabetes insipidus which may correlate with loss of the posterior pituitary bright spot.

A variant of this condition is the so-called lymphocytic infundibulo-neurohypophysitis where the inflammatory process selectively involves the pituitary stalk and the posterior pituitary tissue, and imaging reflects that showing enlargement of the posterior gland and stalk (21).

Figure 33. Sagittal T1 weighted enhanced image of lymphocytic hypophysitis. There is slight enlargement and heterogeneity of the gland with thickening of the lower part of the stalk. The fossa is not enlarged.

Figure 34. Coronal T1 weighted enhanced image of lymphocytic hypophysitis. There is slight enlargement and heterogeneity of the gland with thickening of the lower part of the stalk. The fossa is not enlarged.

Secondary hypophysitis can be a reaction to a local process (e.g., infection or cyst rupture) or due to systemic disease, neoplastic processes or drugs. IgG4 plasma cell hypophysitis (22) and hypophysitis caused by the immune checkpoint inhibitors (ICPi) used in oncology (23) are now well described.

The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents (e.g., ipilimumab) and the programmed death 1 (PD-1) agents (e.g., nivolumab) can both cause hypophysitis, but the CTLA-4 agents more frequently do so, and the combination of CTLA-4 and PD-1 carries the highest risk of hypophysitis (23). Ipilimumab-related hypophysitis has been reported in up to 11% of patients and is commoner in men (24). ICPi-related hypophysitis usually occurs within several weeks to months of starting therapy and manifests with headache, fatigue and anterior pituitary hormonal deficiency. Diabetes Insipidus is very rare (23).

MR typically shows a diffuse enlargement of the gland (more rarely the stalk or the gland plus stalk) which regresses after discontinuation of treatment. Enlargement that involves the chiasm is rare (21). Pituitary function may not recover despite the imaging normalization (Fig 35). As many as 23% of cases may have a normal MR despite clinical evidence of drug-induced hypophysitis (25).

Figure 35. Coronal T1 weighted enhanced image of ipilimumab-induced hypophysitis show diffuse enlargement of the gland with slightly heterogenous enhancement.

IgG4 related hypophysitis is one manifestation of IgG4 related disease. In around 40% of cases it may be an isolated manifestation, but in the majority of cases there is multi-organ involvement, most commonly lung or retroperitoneum (26). Clinical symptoms can relate to the sella mass effects, central diabetic insipidus, or anterior hypopituitarism. In distinction to drug-related hypophysitis, there is a high incidence of diabetes insipidus. A recent case series of 76 cases (26) identified a pituitary mass in 22.4%, a thickened stalk in 26.3%, while 51.3% had both a pituitary mass and a thickened stalk. As it is a fibro-inflammatory process the involved pituitary/ stalk may show low T2W signal (Figs 36 and 37).

A paraneoplastic syndrome with Anti-Pit 1 antibodies is a recognized cause of hypophysitis (with no specific radiological feature from other causes of hypophysitis). Systemic disease such as Granulomatosis with polyangiitis can occasionally involve the pituitary gland, the low T2 signal seen in IgG4 disease (Fig 37) would also be a feature of this type of granulomatous involvement

Figure 36. Sagittal enhanced T1 weighted image shows a diffusely enlarged gland and enlarged stalk, of low T2 signal -see Fig 37- due to IgG4 hypophysitis.

Figure 37. Coronal T2 weighted image shows a diffusely enlarged gland and enlarged stalk, of low T2 signal due to IgG4 hypophysitis.

All forms of hypophysitis can ultimately result in hypopituitarism with a small volume pituitary gland on imaging (Figs 38 and 39).

Figure 38. Sagittal enhanced T1 weighted images show a diffusely enlarged gland and enlarged stalk due to hypophysitis.

Figure 39. Sagittal enhanced T1 one year after hypophysitis has resulted in a small volume pituitary gland.

Granulomatous hypophysitis is less common and is found equally in males and females. MR appearances are the same as those described for lymphocytic hypophysitis (20).

Xanthomatous hypophysitis is the least common form and is characterized by a distinctly cystic appearance on imaging. An intrasellar cyst without suprasellar extension or involvement of the stalk is the most recognized appearance (20).

THE EMPTY SELLA

An empty sella contains only CSF without any visible pituitary tissue (anterior or posterior). The pituitary stalk will be visible and typically extends down to the floor of the sella (Figs 40 and 41). An empty sella may be the result of previously documented pituitary/hypothalamic pathology or treatment (e.g., surgery, radiotherapy, hypophysitis, Sheehan’s syndrome or pituitary apoplexy). However, it may also be discovered incidentally during MR scanning or in the course of investigating a new endocrine problem, then referred to as a “primary empty sella” (27). A partially empty sella implies that some residual pituitary tissue can still be seen along the floor of the fossa. In the case of a primary empty sella it is thought that a defect in the diaphragma sella (the sheet of dura over the surface of the sella through which the stalk passes) has allowed increased communication with the pulsatile CSF in the subarachnoid space. Primary empty sella is more common in women and has been associated with intracranial hypertension, obesity, visual disturbance, and spontaneous CSF leaks. Endocrine problems may be seen in up to 25% of cases with a primary empty sella (27), the majority within this group being specifically investigated for a suspected endocrine abnormality. However, a small proportion of patients found to have an empty sella unexpectedly may have endocrine abnormalities on detailed testing.

Figure 40. Sagittal enhanced T1 weighted image shows an empty sella. No pituitary tissue is visible, and the stalk extends down to the floor of the sella. The optic chiasm has prolapsed inferiorly, a not uncommon appearance after a large mass has been removed.

Figure 41. Coronal enhanced T1 weighted image shows an empty sella. No pituitary tissue is visible, and the stalk extends down to the floor of the sella. The optic chiasm has prolapsed inferiorly, a not uncommon appearance after a large mass has been removed.

ARACHNOID CYSTS

Arachnoid cysts are benign, congenital CSF-containing cysts that arise within the arachnoid membrane. They can be found in the suprasellar region where they may displace and distort the chiasm and stalk and/or flatten the pituitary tissue (Figs 42 and 43). They will always show the same signal as CSF on all MR imaging sequences, do not show any enhancement after contrast, and do not calcify.

Figure 42. Sagittal unenhanced T1 weighted image shows an arachnoid cyst in the suprasellar region. This is markedly elevating the hypothalamus and stretching the pituitary stalk.

Figure 43. Coronal unenhanced T1 weighted images show an arachnoid cyst in the suprasellar region with elevation of the right side of the chiasm by the cyst. No cyst wall is evident and the pituitary tissue itself is normal.

CONGENITAL PITUITARY ABNORMALITIES

Congenital hypopituitarism can manifest as isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), which can be related to anatomical abnormalities of the hypothalamic/pituitary structures on MR imaging. Imaging features include an ectopic location to the posterior pituitary which is seen to be undescended and is visible as a high signal area in the region of the median eminence (Fig 44). There may be absence of the pituitary stalk and/or hypoplasia of the anterior pituitary tissue. Other congenital abnormalities of midline structures may be associated with these hypothalamic/pituitary features: optic nerve hypoplasia, absence of the septum pellucidum, and corpus callosum abnormalities (28). CPHD is more often associated with callosal and stalk abnormalities than the milder forms of hypopituitarism such as IGHD (28). There are many genetic associations with both IGHD and CPHD, covered in detail in other sections.

Figure 44. Sagittal T1 weighted unenhanced image. This demonstrates a small pituitary fossa containing a reduced volume of anterior pituitary tissue. The stalk cannot be seen and the posterior pituitary bright spot (arrow) is lying in an ectopic location within the hypothalamus.

An incidental but uncommon imaging finding is that of a lipoma in the suprasellar cistern (Fig 45). This is identified as an entirely high T1 signal mass adjacent to normal hypothalamic and pituitary structures. The fatty nature of the mass can be confirmed with a fat-saturation sequence which will obliterate the signal from the mass.

Figure 45. Sagittal T1 weighted unenhanced image. There is a high signal mass lying just below the hypothalamus and behind the pituitary stalk in the suprasellar cistern. This is a lipoma. The pituitary tissue and stalk are normal.

HYPOTHALMIC HAMARTOMAS

These are benign developmental mass lesions that arise in the tuber cinereum of the hypothalamus and can be associated with central precocious puberty, gelastic (laughing) seizures, and sometimes developmental delay. The lesions are easily identified on MR imaging as they have a distinctive appearance as an almost pedunculated rounded mass hanging from the hypothalamus. They are of similar signal to the grey matter of the brain and do not show enhancement after contrast injection (Fig 46). Histologically, they are composed of well differentiated neurons and glial cells. They are sometimes approached surgically if the epilepsy is proving refractory to treatment.

Figure 46. Sagittal T1 weighted enhanced image of a hypothalamic hamartoma. There is a non-enhancing mass visible arising from the under surface of the hypothalamus and lying behind the pituitary stalk.

SARCOID

CNS involvement is seen in about 25% of cases of sarcoid (29) but many of these are subclinical. Neurosarcoid has a wide spectrum of intracranial imaging appearances including high T2 lesions in the white matter, meningioma-like dural masses, optic nerve lesions, and leptomeningeal enhancement (30). Involvement of the pituitary stalk/hypothalamus is one manifestation and may be part of more widespread leptomeningeal enhancement or may be isolated (Figs 47 and 48). If there is widespread leptomeningeal enhancement then appearances may be indistinguishable from TB meningitis (30)

Figure 47. Sagittal T1 weighted enhanced images show thickening of the pituitary stalk and nodular enhancement of the right side of the chiasm in a patient with neurosarcoid.

Figure 48. Coronal T1 weighted enhanced images show thickening of the pituitary stalk and nodular enhancement of the right side of the chiasm in a patient with neurosarcoid.

SKULL BASE TUMORS

Tumors of the central skull base may involve the sella or parasellar region and are in the differential diagnosis of any large mass around the sella which has significant bony involvement. Primary tumors occurring in this region are the chordoma and the chondrosarcoma (14) Chordomas arise from remnants of the primitive notochord and are seen as well-defined, centrally-located, expansile masses arising from the clivus. They show distinctive high signal on T2 weighted images and bony destruction on CT (Fig 49). Chondrosarcomas (malignant mesenchymal tumors) have a similar appearance but tend to arise just lateral to the clivus at the site of the petroclival synchondrosis (Fig 50 and 51); however, it is often not possible to distinguish between these two tumor types radiologically (31). Any destructive bony malignancy such as metastatic disease or plasmacytoma may involve the central skull base.

Figure 49. Sagittal CT reconstruction shows a destructive bony lesion in the clivus – a chordoma, the sella itself is preserved.

Figure 50. Axial T2 image of a chondrosarcoma. This shows the typical bubbly high T2 signal and involves the right side of the pituitary fossa, the right cavernous sinus and extends into the right middle cranial fossa.

Figure 51. Axial-enhanced T1 weighted image of a chondrosarcoma. This shows the typical bubbly high T2 signal and involves the right side of the pituitary fossa, the right cavernous sinus and extends into the right middle cranial fossa.

ECCHORDOSIS PHYSALIPHORA

Ecchordosis physaliphora is a benign, congenital, hamartomatous notochord remnant usually found in the retroclival region. They are typically small, asymptomatic and can be found in up to 2 % of autopsies.

They are histologically identical to chordomas, which are typically sizeable and present with brainstem or cranial nerve compression.

On MR imaging they lie in the retroclival, prepontine region, are similar signal to CSF, notably high signal on T2 sequences (Fig 52) and show variable (usually none to little) enhancement. CT classically shows a well-defined, non-aggressive clival bony defect. A bony stalk may be seen, and this is considered pathognomonic (Fig 53). Although previously considered a distinct clinical entity they are now considered to lie at the benign end of a pathological spectrum that extends to chordomas (32).

Fig 52. Axial T2 volumetric scan shows a small nodule of T2 hyperintense tissue extending through a well-defined midline bony defect in the clivus(arrow).

Fig 53. Axial CT of the skull base shows a well-defined cortical defect (arrow) in the clivus with a small bony spur just to the Rt of the defect (not the same case as image 51).

METASTASES

Metastatic spread of systemic tumors to the pituitary gland/stalk is relatively uncommon and is usually seen in the context of diffuse malignancy. Breast and lung are the commonest primary tumors to do this although other primary tumors have been reported in the literature (33,14). A clinical presentation with diabetes insipidus reflects the involvement of the stalk in many cases. Diffuse enlargement of the gland with thickening of the stalk (Fig 54) in a patient with known malignancy might suggest this diagnosis.

Figure 54. Coronal enhanced T1 weighted image shows a diffusely enlarged pituitary gland with bilateral enlargement of both cavernous sinuses and some thickening of the stalk, this was metastatic disease in a patient with breast carcinoma.

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Gastrointestinal Neuroendocrine Tumors and The Carcinoid Syndrome

ABSTRACT

Neuroendocrine neoplasms originating from the gut are increasingly diagnosed as a result of the rise in radiological and endoscopic procedures, improved pathological classification, and likely an increase in true incidence. The diffuse neuroendocrine gastrointestinal system can trigger cancer formation into a wide variety of neoplasm subtypes, ranging from well-differentiated tumors to poorly differentiated carcinomas. All gastrointestinal neuroendocrine neoplasms have the potential to metastasize and ultimately impair patient survival. In recent years, changes have occurred in the pathophysiological understanding, nomenclature, pathological grading, molecular imaging, and management options for these neuroendocrine neoplasms. This chapter will focus on well-differentiated neuroendocrine tumors of gastrointestinal origin, which find their origin at separate primary locations, all characterized by their specific clinical behavior. A minority of patients suffer from hormonal syndromes due to the secretion of peptides or amines from the neuroendocrine tumor. The carcinoid syndrome is the quintessential hormonal syndrome in gastrointestinal neuroendocrine tumors, particularly those of midgut origin. Patients suffering from the carcinoid syndrome have a reduced survival and quality of life, due to debilitating symptoms of flushing and diarrhea as well as fibrotic complications. We provide an overview of the background of gastrointestinal neuroendocrine tumors as well as the carcinoid syndrome and discuss the diagnostic pathways as well as treatment possibilities for patients presenting with this disease.

INTRODUCTION

Enteroendocrine cells constitute approximately 1-2% of all cells within the gastrointestinal tract. Quite similarly, neuroendocrine neoplasms (NEN) of the digestive tract form 1-2% of all malignancies in this organ system. When grouped together with pancreatic NEN (panNEN), gastroenteropancreatic (GEP) NEN are the second most common malignancy in the gut, surpassing esophagus, gastric, and pancreatic carcinomas in incidence rates (1). These tumors can arise anywhere along the primitive gut, but are most commonly detected in the small intestine or rectum. Based on histology, NENs are grouped into well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC) (2). The former group was previously termed carcinoid tumors, based on the original observation by Siegfried Obendorfer (1876-1944) in 1907 that NETs of the small bowel displayed “carcinoma-like” or “carcinoid” features (3). As this term has led to the common misconception that carcinoid tumors are benign or always indolent, current correct nomenclature of this gastrointestinal malignancy solely uses the term NEN.

This chapter focuses on the clinical features, diagnosis, and management of the different well-differentiated NET along the gastrointestinal tract. The reader is referred to chapter “Diffuse hormonal systems” for lung NEN (4), where well-differentiated tumors are still termed typical or atypical carcinoids, and to chapter “Pathophysiology and treatment of pancreatic neuroendocrine tumors” for panNEN (5).

EPIDEMIOLOGY

NEN are historically considered a rare cancer type with an incidence of all subtypes combined of 5-10 per 100,000 persons per year (6). Two registry studies have shown that the incidence of NEN is rising several fold over the last decades. In the United States of America, NEN incidence increased 6.4-fold from 1.09 to 6.98 per 100,000 population per year between 1973 and 2012 (7), while in the United Kingdom rates rose 3.7-fold from 2.35 to 8.61 per 100,000 population per year between 1995 and 2018 (8). Within the GEP subtypes, small intestinal, pancreatic, and rectal NEN are most prevalent and have seen the clearest rising incidence rates. Part of the increased detection rate is caused by the rise in the absolute number of endoscopy procedures and radiological imaging, shifting the diagnosis more often towards incidentalomas. On the other hand, increased awareness among pathologists and improved classification likely also plays a role. The striking rise of NEN incidence compared to the stable incidence of all other malignant neoplasms in recent decades (7, 8) might suggest that a currently unknown epigenetic or environmental risk factor could stimulate NEN carcinogenesis.

The combination of increased detection as well as improved survival leads to an overall increase in NEN prevalence. The recent epidemiological data in the United Kingdom (8) suggest that NEN should not be considered a rare form of cancer anymore, as it comprised the 10^th most prevalent cancer.

PATHOPHYSIOLOGY

Much is unknown about the pathogenesis of gastrointestinal NET (9). Besides the driver function of gastrin in two subtypes of gastric NET (see below), the causative factors for NET formation in the gut remain elusive. Genetic mutations have been identified as driving carcinogenesis across a wide array of malignancies, but – even in late, advanced stages of disease – NET remains among the tumor types with the lowest amount of tumor mutational burden or driver mutations (10). Contrarily, NEC show a high tumor mutational burden with gene mutations in well-known oncogenes or tumor suppressor genes, such as TP53, KRAS, RB1 (11). Dedicated studies of small intestinal NET genotypes with next generation sequencing have failed to detect prevalent mutations. The most commonly mutated gene in small intestinal NET, CDKN1B encoding cyclin-dependent kinase inhibitor p27, was found to be mutated in 10% of cases (12). Germline mutation in CDKN1B also cause the rare endocrine tumor syndrome multiple endocrine neoplasia type 4 (MEN4), which predisposes to the occurrence of gastric, duodenal, and pancreatic NET among other tumor types (13). Whole genome sequencing of synchronous multifocal small intestinal NET also failed to detect common genetic drivers, but instead observed clonal independency of tumors within individuals (14). No clear driver mutations have been identified for the other subtypes of gastrointestinal NET as well. Multiple endocrine neoplasia type 1 (MEN1) is besides primary hyperparathyroidism and pituitary NET primarily associated with the occurrence of pancreatic, bronchial, and thymic NET (15). However, duodenal NET can also arise within the context of MEN1 and these have a predilection to secrete gastrin, leading to gastrinoma or Zollinger-Ellison syndrome. This in turn stimulates secondary gastric NET formation (16). A genome-wide association study of 405 patients compared to more than 600,000 control subjects in two cohorts revealed an association between the occurrence of small intestinal NET and single nucleotide polymorphisms in 6 genes (17). The most interesting locus was of a missense mutation in the intestinal stem cell factor LGR5, suggesting a role for aberrant cellular differentiation in the development of small intestinal NET. Contrary to DNA mutations, chromosomal aberrations are prevalent in gastrointestinal NET. For small intestinal NET copy number variations have been frequently detected. The most prominent observed change is loss of chromosome 18 in up to 70% of cases, followed by losses in chromosomes 9, 11 and 16 and gains in chromosomes 4, 5, 14 and 20 (18). Whether these changes have a causative role in the development of small intestinal NET is currently unknown.

Due to the lack of obvious DNA changes contributing to NET pathogenesis, studies have investigated the role of epigenetics, e.g. changes to the chromatin that affect gene transcription without changing the DNA code (19). In the largest study to date in 97 patients with small intestinal NET, integrated genetic, epigenetic, and transcriptomic analysis detected 3 molecular subtypes, that differed in their survival outcome (20). DNA methylation analysis found that small intestinal NET were highly epigenetically dysregulated. The prognostically favorable molecular subgroup was associated with loss of chromosome 18, while another subgroup displayed no copy numbers alterations. NET in the molecular subgroup with inferior survival outcome displayed multiple copy number variations.

Because of the link between enteroendocrine cells and the bowel content, there have been speculations on carcinogenic factors in the bowel content. This could include but is not limited to dietary factors, microbial species, and microplastics. Further research is needed before a clear role can be identified for these factors.

COMMON FEATURES

NET of the gastrointestinal tract share many features owing to their collective origin from enteroendocrine cells. Originally described as APUD (amine precursor uptake and decarboxylation) tumors or APUDomas by Anthony Pearse (1916-2003) these neoplasms retain the potential to produce and secrete several hormonal substances in the form of amines and peptides (3, 21). These secretagogues are stored in intracellular dense-core secretory granules, which are released upon fusion with the plasma membrane. Gastrointestinal NET, like other types of NET, express markers specific for their neuroendocrine phenotype. The two most prevalent markers, synaptophysin and chromogranin A, form the basis for a immunohistochemical diagnosis of a NEN cell (22).

Stage

Similar to other cancers, NET are staged according to the TNM classification, which signifies key therapeutic and prognostic information (2), Table 1. Whereas stage I and II indicate local disease confined to the presence of the primary tumor (T1-4 N0 M0), stage III signifies the presence of regional spread to lymph node metastases (T1-4 N1 M0). Distant metastases (T1-4 N0-1 M1) are classified as stage IV disease.

Table 1. TNM staging of gastrointestinal neuroendocrine neoplasms according to the 8th edition of the AJCC Cancer Staging Manual (2018)
	Stomach	Duodenum	Small intestine	Appendix	Colon and rectum
Tx	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Invades the lamina propria or submucosa and is ≤ 1 cm in size	Invades the lamina propria or submucosa or confined within the sphincter of Oddi and is ≤ 1 cm in size	Invades the lamina propria or submucosa and is ≤ 1 cm in size	Tumor ≤ 2 cm in size	Invades the lamina propria or submucosa and is ≤ 2 cm in size
T1a					Tumor ≤ 1 cm in size
T1b					Tumor > 1 and ≤ 2 cm in size
T2	Invades the muscularis propria or is > 1 cm in size			Tumor > 2 but ≤ 4 cm in size	Invades the muscularis propria or is > 2 cm in size
T3	Invades into the subserosa	Growth into the pancreas or peripancreatic adipose tissue	Invades into the subserosa	Tumor > 4 cm in size or invades into the subserosa or mesoappendix	Invades into the subserosa
T4	Invades into the (visceral) peritoneum or adjacent organs or structures
Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis has occurred
N1	Regional lymph node metastasis		Regional lymph node metastasis in < 12 nodes	Regional lymph node metastasis
N2			Large mesenteric masses (> 2 cm) or extensive nodal deposits (≥ 12)
M0	No distant metastasis
M1	Distant metastasis
M1a	Metastasis confined to liver
M1b	Metastasis in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
M1c	Both hepatic and extrahepatic metastasis

Stage I	T1 N0 M0
Stage II	T2-3 N0 M0
Stage IIA					T2 N0 M0
Stage IIB					T3 N0 M0
Stage III	Any T N1 M0 or T4 N0 M0
Stage IIIA					T4 N0 M0
Stage IIIB					Any T N1 M0
Stage IV	Any T any N M1

Grade

The biological behavior of the individual NEN is classified according to the tumor grade. NEN can display a wide array of biological behavior from generally very indolent taking years to significantly grow (e.g., appendix NET) to very aggressive inevitably leading to death (small cell lung NEC) (23). In order to predict prognosis and guide management all gastrointestinal NEN should be examined histologically for differentiation (well versus poorly differentiated), mitotic index (per 10 HPF), and ki67 index. The latter encompasses staining of the nuclear proliferation marker ki67 by the MIB1 antibody. Different grading cut-offs have been used in the past (24), but the WHO 2019 classification of digestive system tumors and 2022 classification of (neuro)endocrine tumors separate well-differentiated NET from poorly differentiated NEC on the basis of the histological phenotype (2, 25). In cases of an ambiguous entity, molecular analysis or staining of Rb1 and p53 can point towards the presence of a NEC (26).

NET are divided into grade 1, 2 and 3, whereas NEC by definition are grade 3. NET grading is discerned through the combination of mitotic and ki67 index, with the highest value counted (Table 2) (2, 25). Due to the differences in biological behavior, tumor grading is key to management of GI NET, especially in cases of metastatic and consequently incurable disease.

Table 2. Classification of gastrointestinal neuroendocrine neoplasms, according to 2022 WHO classification of endocrine and neuroendocrine tumors and 2019 WHO classification of tumors of the digestive system
Well-differentiated NEN	Ki67 proliferation index	Mitotes per 2 mm²
NET Grade 1	<3%	<2
NET Grade 2	3–20%	2–20
NET Grade 3	>20%	>20
Poorly differentiated NEN Small cell NEC Large cell NEC	>20%	>20

HORMONAL SYNDROMES IN NET

Due to their endocrine heritage, gastrointestinal NET can produce and secrete excessive amounts of hormonal substances, that can elicit clinical syndromes in patients (22). All patients presenting with a gastrointestinal NET should be examined by history taking and physical exam for the presence of a hormonal syndrome, as this has important therapeutic and prognostic consequences. In case of a suspected hormonal syndrome, appropriate biochemical analysis should be performed for the elevation of the causative hormonal peptides or amines (27).

Carcinoid Syndrome

The carcinoid syndrome is the most common hormonal syndrome encountered in gastrointestinal NET and even NEN in general. Estimations fluctuate that around 20% of patients with stage IV midgut NET suffer from carcinoid syndrome (28). It is mainly characterized by symptoms of secretory diarrhea and vasodilatory flushes. Occasionally, bronchospasms can also occur (29). In severe and long-standing cases carcinoid heart disease (CHD) can arise, characterized by plaque-like depositions in mainly right-sided heart valves and endocardium (30). Following acute stressors, some NET associated with carcinoid syndrome are able to secrete massive amounts of vasoactive compounds, leading to hemodynamic instability. This type of vasodilatory shock, also known as carcinoid crisis, can be defined as an acute onset of stressor-induced hemodynamic instability in patients with carcinoid syndrome and can be observed during the induction of anesthesia and after tumor lysis following embolization or peptide receptor radionuclide therapy (31).

The principal effector of carcinoid syndrome is thought to be the amine serotonin (5-hydroxytryptamine) (32), which is also secreted physiologically by several subtypes of neuroendocrine cells in the gut and lungs. A variety of preclinical and clinical studies support a central role of serotonin in the pathophysiology of carcinoid syndrome-related diarrhea and CHD, while its role in flushing in carcinoid syndrome patients is still controversial. Other hormonal substances postulated to contribute to the carcinoid syndrome include tachykinins, catecholamines, kallikrein and histamine (33).

Carcinoid syndrome predominantly arises in NET of midgut origin, comprised of jejunum, ileum, cecum, and ascending colon. This location specificity is presumably due to carcinogenesis within the enterochromaffin (EC) cell, which uses serotonin as its main secretagogue to communicate with the autonomous nervous system and influence bowel motility (4). This hormonal syndrome can also be encountered in bronchial NET (typical or atypical carcinoid) or NET of other origin (e.g., ovarian, pancreatic, unknown primary). Importantly, tumor seeding beyond the portal circulation is a prerequisite for carcinoid syndrome, as its causative hormones are inactivated by hepatocytes (34). For midgut NET, carcinoid syndrome thus hallmarks spread beyond locoregional disease, with liver metastases being present in more than 90% of cases. Alternatively, the tumor sites may secrete through the retroperitoneal or ovarian/testicular venous drainage, effectively bypassing the portal circulation and drain directly on the inferior caval vein.

The presence of carcinoid syndrome is a negative prognostic indicator, which is likely caused by its association with tumor bulk (28, 35). Within this spectrum, CHD is also associated with decreased survival in patients in univariate analyses (36). Because of these features carcinoid syndrome should be diligently investigated in all patients with NET and actively managed alongside antiproliferative therapy (see management section below).

Other Functioning Syndromes

Besides carcinoid syndrome, other NEN-associated hormonal syndromes are predominantly encountered in patients with a panNEN. Duodenal NET can in rare cases elicit hormonal syndromes that are also seen in pancreatic NET, such as gastrinoma (16), VIPoma (37), and somatostatinoma (38). Ectopic hormonal production has also been described in gastrointestinal NET in limited case reports. However, these functioning syndromes are more frequented encountered in pancreatic (ACTH, PTHrP, GHRH) or lung NET (SIADH, ACTH), see the Endotext chapter on Paraneoplastic syndromes related to Neuroendocrine Tumors (39).

PRIMARY NET LOCATIONS

Esophagus

Well-differentiated NET of the upper alimentary tract are extremely rare. The esophagus is a predilection place for the occurrence of NEC (40). Alternatively, mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be encountered in the esophagus, similar to other gastrointestinal sites. Formerly these tumors were designated as Mixed adeno-neuroendocrine carcinoma (MANEC). This aggressive tumor entity is comprised of both a NEN component (NET or NEC) as well as an adenocarcinoma component, with the latter being responsible for the prognostic outcome (2).

Stomach

The neuroendocrine cells in the stomach can give rise to several NEN subtypes, depending on the underlying pathophysiology. Central to understanding gastric NEN is the dependency of the histamine-producing enterochromaffin-like (ECL) cells on gastrin stimulation. Chronic hypergastrinemia due to several causes can lead to ECL cell hyperplasia and gastric NET formation, so called ECLoma. When an ECLoma occurs during compensatory gastrin elevations this is termed a type I gastric NET (41), accounting for 75-80% of gastric NEN. This is most commonly caused by atrophic gastritis due to antibodies against intrinsic factor or parietal cells, which is also causative for pernicious anemia. Alternatively, type I gastric NET have been described following Helicobacter pylori infection, chronic use of proton pump inhibitors, or mutations in the proton pump gene (ATP4A) and resulting hypergastrinemia (42-45). When ECLoma arise due to a gastrin-producing NET in the pancreas or duodenum (Zollinger-Ellison syndrome), these are termed type 2 gastric NET, which is responsible for 5% of all gastric NET cases. This pathology is generally restricted to patients with MEN-I and a duodenal gastrinoma (46). A well-differentiated gastric NET arising in the presence of normal fasting gastrin levels is termed a type 3 NET and accounts for approximately 15-20% of gastric NET. Some authors have proposed the rare gastric NEC as the type 4 gastric NEN (9), Table 3.

Table 3. Subtypes of Gastric Neuroendocrine Neoplasm
	Hypergastrinemia, ECL cell hyperplasia	Growth	Features
Gastric NET type 1	Yes	Indolent	Secondary to atrophic gastritis, helicobacter pylori infection, proton pump inhibition or ATP4Amutation
Gastric NET type 2	Yes	Indolent	Secondary to gastrinoma (Zollinger Ellison syndrome)
Gastric NET type 3	No	Intermediate	Sporadic
Gastric NEC type 4	No	Aggressive	Sporadic

Biological behavior of the gastric NEN subtypes differs widely with generally indolent course for type 1 and 2 NET, which are predominantly grade 1 and can be characterized by multiplicity (47-49). Only a few metastatic cases have been reported in the literature, without clear evidence of impaired survival (50). Type 3 gastric NET and type 4 gastric NEC were previously considered as a single subtype, which was accompanied by a high rate of metastases and poor survival outcome. However, recent analyses show lower grade, metastatic potential, and better outcome of type 3 gastric NET than previously assumed (51, 52).

The vast majority of gastric NET is clinically non-functional, although ghrelin production has been described in NET presumably derived from gastric H cells, see Endotext chapter on Ghrelinoma (53).

Duodenum

A rare subtype of gastrointestinal NET, duodenal NET are often incidentally discovered during esophagogastroduodenoscopy (Figure 1A). They are characterized by intramural lesions which might sometimes only be visible on endoscopic ultrasound. Bleeding or ulceration is rare, but can be a presenting symptom (54). The majority of duodenal NET are localized and grade 1-2, particularly for tumors smaller than 1.0 cm. Metastatic potential increases with size and can be present at diagnosis or occur during follow-up (55, 56). Due to the nature of the neuroendocrine cells in the duodenum several hormonal syndromes can be encountered, such as gastrinoma or VIPoma. Somatostatin-expressing NET near the ampulla of Vater have been described as part of neurofibromatosis type 1 (57). Some of the larger duodenal NET cannot be effectively localized as originated from either duodenum or pancreas due to the overlapping anatomy.

Figure 1. Endoscopy in gastrointestinal NET. (A) Endoscopic image of a 5 mm submucosal lesion in the duodenal bulb. Fine needle aspiration confirmed a grade 1 duodenal NET, which was subsequently removed by endoscopic mucosal resection. (B) Endoscopic view of an 8 mm rectal NET, grade 1, which was successfully resected by endoscopic submucosal dissection.

Small Intestinal (Jejunum and Ileum)

The classic site for well-differentiated NET in the gastrointestinal tract is the small intestine, particularly the terminal ileum. NET are the most common malignancy in the small intestine, followed in incidence by adenocarcinoma and lymphoma (58). Almost all small intestinal NET are low to intermediate grade and can potentially show indolent growth (59). NEC of the small intestine are extremely rare. As EC cells are the predominant neuroendocrine cell in the small intestine, metastatic small intestinal NET are most often associated with the carcinoid syndrome (60).

At presentation, the majority of small intestinal NET are metastasized, with a predilection for lymph node and liver metastases (59). In some cases, the primary tumor cannot be visualized despite modern imaging techniques, such as PET/CT. Lymphogenic spread of small intestinal NET occurs locally within the mesentery. The finding of NET accompanied by a mesenteric mass hints towards a small bowel origin of the NET. Unique to small intestinal NET, mesenteric metastases can develop extensive fibrosis (Figure 2). This is seen on cross-sectional imaging as fibrotic strand radiating from a solid mesenteric mass, in a spoke-wheel pattern (61). This pathognomonic feature of small intestinal NET can lead to chronic bowel ischemia due to compression of venous drainage, leading to intermittent abdominal cramps or colicky pain, particularly after a large meal. Ultimately, ileus or bowel perforation can occur. In one study of 530 patients with small intestinal NET, mesenteric fibrosis was found to be progressive in 13.5% of cases with a median time to growth of 40 months, signifying slow progression (62). Although mesenteric fibrosis can lead to fatal complications and is associated with overall survival in univariate analysis, it was not associated with a worse overall survival in multivariate analysis (63).

Figure 2. Mesenteric fibrosis in midgut NET. (A) Transversal and (B) coronal plane contrast-enhanced CT images of a patient with a cecal NET and a mesenteric metastasis (arrow). A desmoplastic reaction consisting of fibrotic strands can be seen radiating from the mesenteric tumor mass, which can compromise venous blood flow from the bowel. The mass is partly calcified.

Hepatic metastases of small intestinal NET can be much larger than the primary tumor or lymph nodes. Even in the presence of extensive bilobar metastases, the function of the liver is often preserved, although isolated hyperammonemia due to shunting has been described in selected cases (64).

Appendix

In the majority of cases, appendix NET are incidentally encountered during appendectomy because of appendicitis. A contributory role of the potentially obstructive tumor has been attributed to the occurrence of appendicitis, but this has not been proven to date. Because of its association with appendicitis, appendix NET have a peak incidence in adolescents and young adults (65). Most appendix NET cases are confined to the appendix and have a favorable proliferation index (grade 1 or low 2). Development of lymph node metastases can be seen in up to 25% of appendix NET patients, whereas distant metastases are rare (66). Contrary to origin NET within the midgut, carcinoid syndrome is rarely encountered in appendix NET patients, potentially due to other cell of origin and limited metastatic spread and tumor bulk.

Colon

NET arising in the caecum and ascending colon generally show a biological behavior that is similar to that of small intestinal NET. Together these are termed midgut NET due to their common embryological origin and vascularization by the superior mesenteric artery and vein. Consequently, cecal and ascending colonic NET are often low-grade tumors, can be associated with carcinoid syndrome when metastasized beyond the portal circulation, and give rise to fibrotic complications (67).

Contrarily, NEN in the transverse and descending colon are more aggressive with a predilection for the occurrence of NEC. These NEC share common features with adenocarcinomas of the colon, like molecular background (11). Hormonal syndromes are seldomly encountered in these colon NEC.

Rectum

Unlike the distal colon, NEN in the rectum show a preference for well-differentiated NET (68). Most rectal NET are incidentally discovered during colonoscopy (Figure 1B). A rise in rectal NET incidence rates has been detected that coincided with the increased use of diagnostic colonoscopy (69). At the time of detection, tumor size is often small (< 1 cm) signifying indolent behavior and small risk of metastatic spread (70). However, a subset of rectal NET can present in locally advanced stages and be associated with metastatic spread. Although their venous drainage is not connected to the portal vein, rectal NET are rarely associated with hormonal syndromes, presumably due to their neuroendocrine cell type of origin.

DIAGNOSIS

Histopathology

Obtaining histology for evaluation and confirmation of diagnosis remains essential in the work-up of a gastrointestinal NEN, even in the setting of modern imaging techniques and circulating biomarkers. The diagnosis of a NEN can be suggested through histological findings on H&E staining, such as an organoid pattern, absence of necrosis, low nucleus to cytoplasm ratio, and salt and pepper chromatin. Ultimately, the histological diagnosis requires positive immunohistochemical staining of neuroendocrine markers (71). Most commonly used neuroendocrine markers include synaptophysin and chromogranin A, although N-CAM (CD56) has also been advocated as such in the past. Staining with either synaptophysin or chromogranin A should be positive, with the former having a higher positivity rate in gastrointestinal NEN (72). Expert pathological examination is advised in uncertain cases, for instance in neoplasms with overlap with other malignancies, such as carcinomas with neuroendocrine differentiation, amphicrine carcinoma and MiNEN (25, 73).

Besides for confirming the diagnosis, histopathological evaluation is required for tumor grading according to the WHO classification. First, the distinction between a poorly differentiated NEC and a well-differentiated NET is crucial as shown above. This distinction is made on the basis of cellular morphology (74). Second, each pathological evaluation of a NET specimen should include grading through evaluation of differentiation, ki67 (MIB1) proliferation index and mitotic index (Table 2). Importantly, tumor grade can be heterogenous within or between tumor lesions as well as change over time (75, 76). The disease course over many years in patients can be accompanied by an increase in proliferation indices and grade over time, providing rationale for repeat biopsies in selected patients with disease progression. Altogether, grading provides key information for clinical decision making across all stages and primary locations of gastrointestinal NET. The subclass of grade 3 well-differentiated gastrointestinal NET was only introduced as recent as 2019 (2), which limits the clinical studies and experience on the management of this rare subtype.

Immunohistochemical analysis can also helpful in cases of an unknown primary tumor. Although the prevalence of an unknown primary tumor has decreased due to contemporary PET imaging, up to 5% of NET can present with an unknown primary (77). Positive staining for the following immunohistochemical marker is specific for different primary origins of NET: TTF-1 for foregut tumor, ISL-1 or PAX8 for pancreatic tumor, CDX-2 for midgut tumor, and SATB2 for hindgut tumor (78-81).

Biochemistry – General

Historically, elevated levels of biochemical markers have been directly linked to the diagnosis of a NET. While this can be true for certain hormones eliciting clinical syndromes when taken under controlled conditions, the vast majority of NET cannot be diagnosed through the use of a circulating biomarker. At most, a biomarker can be used during follow-up when it is elevated in a particular patient as a marker of disease recurrence or activity (27, 82).

Chromogranin A (CgA) has been extensively studied since the 1990s as a diagnostic and prognostic biomarker for gastrointestinal and other NET. This acid glycoprotein is stored within the secretory vesicles of neuroendocrine cells and co-secreted with the hormones upon stimulation. In a meta-analysis of 13 studies including 1260 patients with a NET sensitivity of CgA was 73%. In healthy controls, CgA levels were elevated in less than 5%, securing an excellent specificity. However, when compared to subjects with other gastrointestinal, renal, or oncological disease the specificity can drop to ranges of 50-60% (83), making CgA a poor diagnostic marker in patients presenting with abdominal complaints or a tumor. Measurement of CgA for this indication has led to many unnecessary clinical investigations, e.g., endoscopy, cross-sectional and functional imaging, into the cause of an elevated CgA (84) and should be discouraged.

Circulating CgA levels are associated with tumor bulk and consequently are correlated to a worse prognostic outcome (85). Because of its link to tumor bulk, CgA can be used during follow-up to track disease activity, although it should never replace imaging due to insufficient sensitivity and specificity of detecting progressive disease.

Neuron-specific enolase (NSE) represents another circulating marker on neuroendocrine cells. Mostly studied in small cell lung cancer, NSE is also elevated in a subset of gastrointestinal NET patients. Its sensitivity and specificity for the diagnosis of NET is approximately 40% and 60%, respectively (85, 86), and thereby inferior to that of CgA. Importantly, NSE levels tend to be more increased in aggressive disease. Consequently, a sudden rise in NSE could herald the occurrence of dedifferentiation in a NET.

Other circulating neuroendocrine markers, like pancreatic polypeptide and neurokinin A, have been used as diagnostic biomarkers in the past, but due to their overall lack of sensitivity or specificity their use in clinical practice has disappeared (27).

Because of the inferior diagnostic characteristics of the peptides described above an mRNA transcript-based marker called the NETest was developed. Through multiplex PCR and a machine learning-based algorithm, the NETest provides a number on a 100-point scale, where an outcome above 20 has been used for optimal diagnostic cut-off (87). In a meta-analysis of 6 studies the sensitivity and specificity of the NETest was 89-94% and 95-98%, respectively (88). An independent study employing serial sampling in 132 patients with gastroenteropancreatic NET showed a high rate of fluctuation in the NETest despite stable disease during follow-up (89). This technique is of interest to the field, but as of yet there are restrictions regarding the availability in clinical practice, costs, and reimbursement. Hopefully, these developments will lead the way towards more superior multianalyte diagnostic biomarkers for gastrointestinal NET in the future.

Biochemistry – Specific

When patients present with features compatible with a NET-associated functioning syndrome dedicated analysis should be performed. The reader is referred to other Chapters in Endotext for hormonal analysis of Gastrinoma (16), Insulinoma (90), VIPoma (37), Glucagonoma (91), Somatostatinoma (38), Ghrelinoma (53), and Paraneoplastic Syndromes (39). The latter included the hormonal work-up of NET-associated hypercalcemia, hyponatremia, Cushing’s syndrome, acromegaly and hypoglycemia.

Although the majority of gastrointestinal NET are not accompanied by a hormonal syndrome, the carcinoid syndrome is the most common hormonal complication. Because patients can be asymptomatic but still at risk for complications such as carcinoid crisis or CHD, all patients with advanced gastrointestinal NET should undergo biochemical evaluation for the carcinoid syndrome at baseline and when clinical suspicion arises during follow-up (29).

Serotonin (5-hydroxytryptamine) is the main but not exclusive culprit in the carcinoid syndrome. Upon secretion it is mainly stored in platelets, but a proportion freely circulates in the blood. It is metabolized by hepatocytes to 5-hydroxyindolaceticacid (5-HIAA), which is more stable than serotonin and excreted in the urine. 24-hour urine 5-HIAA levels are the best-established biomarker for the carcinoid syndrome, with 50 µmol/24h used as the optimal diagnostic cut-off (29, 92). Urinary 5-HIAA levels correlate with tumor bulk and multiple studies have described an association in univariate analyses with survival in CS patients, which did not persist in multivariate analyses (93-95). 5-HIAA level associate with the risk of developing CHD, with levels above 300 µmol/24h conferring a 2.7-fold increased risk of the development of CHD (36). Alternatively, 5-HIAA can be measured in plasma or serum, resulting in a slightly lower sensitivity/specificity compared to 24h urine collection (96, 97). Venous sampling saves on the cumbersome collection of 24h urine, but its availability is currently limited. Similarly, platelet serotonin levels are associated with carcinoid syndrome, but few labs can perform the assay (98). Although several other peptides, including neurokinin A, bradykinin, and histamine, have been associated with the occurrence of carcinoid syndrome, these markers have no utility in the diagnostic workup in clinical practice.

NT-proBNP is u useful biomarker to screen for the presence of CHD in patients with established carcinoid syndrome (99). An NT-proBNP level below 260 ng/mL (31 pmol/L) has a negative predictive value of 97%, thereby effectively ruling out the presence of CHD (100). Patients with NT-proBNP levels above 260 mg/mL should be referred for echocardiography to confirm or exclude the presence of CHD.

Cross-Sectional Imaging

Despite the developments in biochemistry and functional imaging, cross-sectional imaging remains the cornerstone of follow-up of NET. Furthermore, as more NET are incidentally discovered on imaging, it is important to be aware of typical or even pathognomonic radiological features of NET. On contrast-enhanced computer tomography (CT) scan gastrointestinal NET typically present as hypervascular lesions in the bowel wall (101). The majority of NET have enhanced intravenous contrast uptake in arterial phase, making it relevant to include an early arterial scan phase next to a venous or portal phase in case of a suspicion of a NET (102). Primary NET lesions in the small intestine tend to be small and can easily be missed, whereas lymph node or distant metastases can be extensive. Fibrosis can occur in mesenteric NET metastases, leading to pathognomonic fibrotic strands radiating from the mesenteric mass (61)(Figure 2). Gastrointestinal NET predominantly metastasize to the liver, where single, multiple or extensive metastases can be found. Again, these are hypervascular and enhancing on arterial phase in the majority of cases (103) (Figure 3).

Figure 3. Cross-sectional imaging in gastrointestinal NET. Due to their hypervascular nature, NET primary lesions and metastases can be enhancing in early arterial phase. In case (A) diffuse hypervascular liver metastases of a small intestinal NET are visible. Not all NET (metastases) are hypervascular, as shown in case (B) with a single non-enhancing liver metastasis of small intestinal NET during arterial phase (arrow). The added value of including an early arterial phase after contrast injection (C) op top of venous phase imaging (D) is illustrated within a patient with a small intestinal NET, where visibility of a segment 3 NET metastasis is improved during arterial scan. MRI, particularly diffusion weighted imaging (DWI), can improve the detection rate of small liver NET metastases (E).

Magnetic resonance imaging (MRI) is superior to CT with regard to liver and bone metastases, particularly with contrast enhancement and diffusion-weighted imaging (DWI) (104, 105) (Figure 3). For small liver neuroendocrine metastases, MRI even has a higher lesion-based sensitivity than contemporary SSTR-based PET imaging (see below) (106). In rectal NET, MRI is also helpful to stage local growth and lymph node metastases (107). MRI has caveats in the detection of the primary tumor of the bowel, mesenteric, or peritoneal metastases.

Endoscopy

Endoscopy is often the modality used leading to the incidental detection of a gastrointestinal NET, particularly within primary locations in the stomach or rectum (Figure 1). Primary tumors of gastroduodenal or rectal origin can also be missed on cross-sectional imaging, providing rationale for performing endoscopy or endoscopic ultrasound (EUS) to stage locoregional disease (67, 108). The added value of endoscopy in advanced disease is generally of limited value, unless the aim is to obtain histology. Alternatively, obtaining histology from metastases could be more informative as these can have a higher grade than the primary tumor and ultimately determine the patient prognosis (76).

Nuclear Imaging

Over 90% of well-differentiated NET express somatostatin receptors, which can be used for functional imaging. Somatostatin is a hormone, whose physiological actions are to inhibit hormonal production and release from neuroendocrine cells, for instance in the pituitary, pancreas, and intestine (109). It binds to one or more of five somatostatin receptor subtypes expressed on the cell membrane. Radiolabeled somatostatin analogues (SSA) were developed in the 1980s to image gastrointestinal and pancreatic NET. First, Octreoscan® with gamma-emitter ¹¹¹In-pentreotide was shown superior to cross-sectional imaging in NET using planar and SPECT imaging (110). In the recent ten years, ⁶⁸Gallium-labeled SSA (⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTANOC) suitable for PET imaging have replaced ¹¹¹In-pentreotide as the preferred imaging modality. Importantly, ⁶⁸Ga-DOTA-SSA PET changes clinical management in 40-50% of cases, according to two meta-analyses (111, 112), and as such constitutes a key diagnostic modality in the NET armamentarium (Figure 4). The PET can be combined with diagnostic, contrast-enhanced CT (PET/CT) or MRI (PET/MRI) for hybrid imaging. Pitfalls include PET-positive granulomatous disease, meningioma, renal cell cancer, and lymphoma. Expression of the somatostatin receptors decreases with increasing proliferative capacity in NET, making it very useful in low-to-intermediate grade NET but less sensitive in higher grade NET or NEC. Recently, ⁶⁴Cu-DOTA-SSA PET/CT and ¹⁸F-AIF-NOTA-SSA have been introduced with similar or slighter superior diagnostic capability compared to ⁶⁸Ga-DOTA-SSA PET (113, 114).

Alternatively, ¹⁸F-DOPA PET has been advocated by several centers as superior to ⁶⁸Ga-DOTA-SSA PET, particularly for midgut NET (115). Although this may vary between patients and mostly pertain to tumor count rather than to change in management, ⁶⁸Ga-DOTA SSA also has therapeutic consequences for theranostics using unlabeled (‘cold’) SSA and peptide receptor radionuclide therapy (PRRT) with radiolabeled (‘hot’) SSA (see below).

Figure 4. 68Ga-DOTA-SSA PET imaging. 68Ga-DOTA-SSA PET staging is superior to anatomical imaging and 111In-pentreotide SPECT (Octreoscan). In this case of a patient with stage IV small intestinal NET, PET imaging detected more lesions than Octreoscan, scanned within 3-month timeframe without anatomical progression. In the same patient, multiple liver metastases are detected on hybrid PET/CT imaging (arrow), which were not visible on contrast-enhanced CT (CECT).

Similar to other malignancies, a subset of NET metabolize increased amounts of glucose, which makes them amenable to imaging with ¹⁸F-fluorodeoxyglucose (FDG) PET. Uptake of ¹⁸F-FDG PET in NET increases with aggressiveness, making it the preferred imaging modality in NEC and higher-grade NET (116, 117). Positive FDG uptake of NET is associated with growth potential and consequently several studies have established that FGD uptake constitutes a prognostic marker for a worse survival outcome (118).

MANAGEMENT

Surgery

Radical resection remains the cornerstone in the management of locoregional stages of gastrointestinal NET. Metastatic spread is dependent on the location and size of the primary tumor and adequate staging should be performed accordingly, preferably through hybrid cross-sectional and ⁶⁸Ga-DOTA-SSA PET imaging (102). If the disease is confined to the local tumor (stage I-II) or locoregional lymph nodes (stage III), the option of a surgical oncological resection should be evaluated. If the NET can be radically resected the outcome is very favorable with 10-years survival outcomes of >90% for all primary sites. A large registry series from Canada did find that recurrence rates can increase up to 60% for small intestinal NET and 40-50% for other NET in a 15-year postoperative period (119). Given the retrospective nature of this series and contemporary preoperative imaging it remains uncertain whether recurrence rates of current therapeutic interventions are still this high.

For stage I gastroduodenal NET, metastatic spread is limited and endoscopic resection of the NET can be considered (108). This pertains to gastric type I and type II NET up to 2 cm without muscle invasion and duodenal NET localized at safe distance from the Vater’s ampulla. Similarly, an endoscopic resection can be performed in stage I rectal NET, as the risk of lymph node metastases is limited to less than 3% (67). Resection from both tumor subtypes should be performed by endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), or endoscopic full thickness resection (eFTR) rather than snare polypectomy due to the submucosal growth pattern of NET. Successful removal of type I gastric NET or stage I rectal NET is are high (>85%) with slight superiority of ESD over EMR, while eFTR might approach 100% radical resection rates (120-122). In cases of an inadequate endoscopic resection further imaging should be performed and a step-up endoscopic approach or surgical resection should be considered.

Patients with oligometastatic disease might also benefit from an upfront surgical approach. As the liver is the predominant site for metastatic disease, concomitant surgical resection and/or interventional tumor ablation should be considered in patients with limited liver involvement (123). This can potentially cure the patient, but it should be noted that modern imaging techniques detect approximately one-third of liver metastases compared to histological evaluation (124, 125). The presence of micrometastases should be factored into the management process. Despite this, long-term outcomes can be excellent in cases of upfront surgery in oligometastatic disease. A potential advantage of tumor debulking in this setting could be the delay of the need to start systemic therapy. Several series have also described survival benefits of extensive liver metastases resection (126-129), but these concern mostly retrospective series, which might introduce selection bias, and data was often collected before the advent of currently available molecular therapies.

Resection of the primary tumor in the context of stage IV or metastatic disease is controversial. Whereas retrospective studies have supported a survival benefit in patients whose primary tumor was resected compared to those that were not operated (130-132), this was later refuted in other series or after propensity score-matched controls (63, 133). Importantly, the disease course locoregionally can be indolent, and in one series only 13% of mesenteric masses showing significant progression after a median follow-up time of 40 months (62). Patients with advanced midgut NET and recurrent complaints from the primary tumor or (fibrotic) mesenteric mass should undergo operation to explore the possibility of a palliative resection or alternatively, an intestinal bypass.

Palliative Management

Patients with unresectable or advanced gastrointestinal NET are in a palliative setting and the different treatment modalities should be weighed in terms of efficacy and toxicity. Given the wide range of gastrointestinal NET subtypes, the treatment chosen should align with the biological behavior of the tumor as well as the characteristics of the individual patient (Figure 5). Factors to consider in the management of gastrointestinal NET include: tumor grade, growth rate and location(s), symptoms, presence of a hormonal syndrome, performance score, comorbidities, previous therapies, availability of treatments and patient preference.

Figure 5. Stage IV gastrointestinal NET. There is a wide heterogeneity in clinical presentation of gastrointestinal NET in advanced or metastatic setting. On these maximal intensity projections of 68Ga-DOTATATE PET, there are 8 different clinical scenarios of stage IV gastrointestinal NET. Despite the similar disease stage, all these patients deserve personalized management of their disease according to several patient- and tumor-specific factors. For optimal management, choice of treatment should be discussed in an experienced multidisciplinary setting.

Active Surveillance

One potential option to consider is to perform active surveillance in asymptomatic patients with advanced, grade I or low-grade II NET with limited tumor bulk. Evidence for this strategy can be found in placebo-controlled trials. First, the median time to progression in placebo-treated patients was 6 months in the phase III randomized PROMID trial in midgut NET patients (134). Second, in the phase III randomized CLARINET trial in patients with nonfunctioning GEP NET, patients randomized to placebo had a median progression-free survival (PFS) of 18 months (135). Consequently, not all tumors show clear growth potential over time and selected patients can thus safely refrain from costly and potentially toxic medication. This strategy should not be adopted in patients with symptomatic, functioning, high-grade, quickly progressive, or high tumor volume disease. Follow-up cross-sectional imaging every 3-6 months is advised for gastrointestinal NET patients undergoing active surveillance.

Somatostatin Analogs

Before their role in imaging, SSA were developed for their potential antihormonal effects. The SSA octreotide was found to effectively reduce serotonin production in patients with carcinoid syndrome and other NEN-associated functioning syndromes (136). Following its long-term application in functioning NET, antitumoral efficacy was tested in the PROMID and CLARINET trials. The German multicenter PROMID study randomized 85 midgut NET patients to 4-weekly 30 mg octreotide long-acting release (LAR) injections or placebo injections (134). These patients were in the beginning of their disease course with a median time from diagnosis of 4 months and had on average limited liver tumor load and grade I. In an intention to treated (ITT) analysis median time to progression was 14.3 months in octreotide LAR-treated patients versus 6.0 months in the placebo group (P=0.000072). Overall survival (OS) was not different between the groups. The effect of SSA is predominantly stabilization of disease as only one patient in both treatment groups experienced a partial response. Overall, octreotide LAR treatment was well tolerated, although diarrhea, flatulence, and bile stones were more frequently observed in the SSA-treated group.

The international multicenter CLARINET trial randomized 204 patients with advanced nonfunctioning GEP NET to 4-weekly injections of 120 mg lanreotide autogel or placebo injections (135). Tumors were grade I and II with ki-67 index up to 10% and mostly from pancreas or midgut origin. Over 80% of patients had not received previous antitumoral treatment and tumor progression before randomization was only shown in 4-5% of patients. ITT analysis revealed that PFS was significantly longer in lanreotide-treated patients compared to placebo (median not reached versus 18.0 months, P<0.001). The benefit of lanreotide persisted in most predefined subgroups across primary origin, tumor grade, and liver involvement. Safety of lanreotide was good, with known side effects of gastrointestinal complaints, exocrine pancreas insufficiency, and hyperglycemia. Interestingly, the open label extension study of the CLARINET showed a median PFS of 33 months in those continuing lanreotide, while patients in the placebo group – with a median PFS of 14 months - who crossed over to lanreotide after progression had a median second PFS of 18 months (137). This again supports the possibility of considering active surveillance in a subset of patients with indolent disease. Overall survival (OS) in the core CLARINET study was not significantly different between treatment groups, but was also biased by crossover from placebo to lanreotide.

Together these landmark trials have positioned SSA as first-line antiproliferative treatment for well-differentiated gastrointestinal NET, particularly in patients without signs of high tumor volume or aggressive disease course. Injections with octreotide LAR or lanreotide are every 4 weeks in the gluteal area intramuscularly or deep subcutaneously, respectively. Overall tolerability is excellent, although patients should be counselled on the potential gastrointestinal adverse effects, e.g., diarrhea, flatulence, nausea, stool discoloration, after the first administration, which tend to dissipate after repeated injections. Long-term concerns include hyperglycemia and bile stones. Although preventive cholecystectomy has been advocated in the past, this practice has been abandoned in most expert centers (138).

Several retrospective series and clinical experience supported the use of SSA dose escalation in patients with mild progressive disease (139). These studies suggest that increasing the injected dose or injection frequency might be accompanied by improved antiproliferative control. First prospective evidence of this effect came from the NETTER-1 study designed to investigate the effect of peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lutetium-DOTA-octreotate (¹⁷⁷Lu-DOTATATE) (140). Patients enrolled in this study had advanced, progressive midgut NET on regular dose of SSA and were randomized between PRRT and an escalated dose of 60 mg of octreotide LAR every four weeks. Patients in the high-dose SSA control group had a medium PFS of 8.4 months, supporting some antiproliferative effect of SSA dose escalation after disease progression on a regular dose of SSA. The CLARINET forte single-arm, phase II trial was designed to study the efficacy of lanreotide dose escalation in midgut and pancreatic NET patients with disease progression on standard lanreotide dose in the previous 2 years (141). In the midgut NET cohort, 51 patients were included with grade 1-2 disease and 57% of patients had – generally limited - hepatic metastases. After dose escalation to lanreotide 120 mg every 2 weeks median PFS in this cohort was 8.3 months, while disease control rate (partial response or stable disease as best outcome) was 73%. Importantly, no deterioration of quality of life and no additional treatment-related safety concerns were observed in patients treated with high-dose lanreotide.

SSA treatment should be given lifelong in patients with carcinoid syndrome and other SSA-responsive functioning syndromes for which these drugs are registered and approved (29, 142). This includes continuation of treatment after radiological or clinical progression and initiation of a second-line of treatment. Whether SSA should be continued in nonfunctioning gastrointestinal NET disease is a matter of controversy and no prospective data is available to guide this. Intriguingly, 50% of panelists in the NANETS guideline supported continuing SSA treatment, while 50% supported stopping treatment upon progression (143).

The pan-somatostatin receptor agonist pasireotide has been investigated in NET based on the hypothesis that targeting more somatostatin receptor subtypes might have an additive antiproliferative effect compared to octreotide and lanreotide, which predominantly target the somatostatin receptor subtype 2 (144). However, early phase clinical trials provided insufficient grounds to pursue further clinical development of this drug in NET (145, 146).

Peptide Receptor Radionuclide Therapy

Similar to the diagnostics and therapeutics of thyroid disease with radioactive iodine, the discovery of molecular somatostatin receptor imaging also heralded the advent of targeted somatostatin receptor-based radionuclide therapy. Following initial developments with ¹¹¹In-pentreotide and ⁹⁰Yttrium-DOTATATE, the short-range beta-emitter ¹⁷⁷Lutetium coupled to DOTATATE (¹⁷⁷Lu-DOTATATE) was introduced in 2000 (147). This technique of targeting the somatostatin receptor on tumor cells with internal radiation was termed PRRT.

Individual phase II trials at several centers showed promising antitumoral effects on somatostatin receptor-positive NET, including gastrointestinal subtypes (148). The multinational phase III randomized NETTER-1 trial established PRRT with 4 cycles of ¹⁷⁷Lu-DOTATATE as an effective therapy for advanced, somatostatin receptor-positive midgut NET (140). In this trial, 229 patients were randomized between PRRT, including 30 mg octreotide LAR between cycles and 4-weekly after the fourth cycle, and 60 mg octreotide LAR every four weeks. Patients had a grade 1-2 midgut NET that was progressive on SSA before enrollment. The median PFS in the PRRT group was not reached compared to 8.4 months in the high-dose SSA group. Benefit in PFS prolongation was evident across all pre-specified subgroups. Risk of progression or death was 79% and decreased in the patients treated with PRRT. The study confirmed known side effects of ¹⁷⁷Lu-DOTATATE, including nausea, fatigue, abdominal pain, and diarrhea. Two percent of patients experienced grade 3 or higher thrombocytopenia, while 2 patients (1.8%) developed myelodysplastic syndrome following PRRT. In a meta-analysis of 28 studies comprising 7334 patients treated with ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE, the combined incidence of myelodysplastic syndrome and acute myeloid leukemia after PRRT was 2.6% (149). Final analysis of the NETTER-1 study revealed that the median OS in the PRRT group was 48.0 months compared to 36.3 months in the high-dose SSA group, which was not significantly different (150). Crossover of 37% of the patients randomized to high-dose SSA, long-term survival with multiple other treatment lines and insufficient statistical power could have contributed to the failure of reaching this secondary endpoint. Another key secondary endpoint was reached: time to deterioration of quality of life was significantly longer in patients treated with PRRT compared to those treated with high-dose SSA (151).

Although the NETTER-1 only included midgut NET patients, the phase II Erasmus MC Rotterdam data were used to obtain regulatory approval of ¹⁷⁷Lu-DOTATATE for all gastrointestinal (and pancreatic) NET subtypes (152). Importantly, PRRT also induced tumor response in 18% of midgut NET patients in the NETTER-1 study and 39% of various NET patients in the Rotterdam study, which makes it a potential cytoreductive therapy. Standard protocol of PRRT included four infusions of 7.4 GBq ¹⁷⁷Lu-DOTATATE spaced 8 (range 6-12) weeks apart. PRRT should preferably be administered in the absence of long-acting SSA (4-6 weeks) or short-acting SSA (24 hours) due to competition at the receptor level. An amino acid solution of 2.5% lysine and arginine is co-infused with ¹⁷⁷Lu-DOTATATE in order to saturate the renal reuptake of radioactive peptide and prevent radiation-induced nephrotoxicity. This limits the incidence of severe renal insufficiency after PRRT to less than 1% (152). Special considerations should be applied to patients with pre-existing cytopenia or clonal hematopoiesis, impaired renal function or hydronephrosis, massive liver tumor bulk, mesenteric fibrosis, or nervous system involvement (153). Patients with a severe functioning syndrome are at risk of an exacerbation of symptoms or hormonal crisis following temporary SSA withdrawal or tumor lysis with PRRT. Although the risk is minor at 1% incidence in retrospective series and limited to patients with severe hormonal hypersecretion (154, 155), adequate management through supportive measures and swift re-introduction of SSA should be employed to prevent a hormonal crisis.

There is a possibility for salvage PRRT when progressive disease (re-)occurs after a period of disease control following 4 cycles of PRRT. Several retrospective series have described renewed disease control or even response after additional cycles with ¹⁷⁷Lu-DOTATATE after progression. In the largest series to date of 181 patients with gastrointestinal, pancreatic, bronchopulmonary, or unknown origin NET, salvage PRRT with two cycles was administered if disease progression occurred after a period of at least 18 months after the first cycle of the initial PRRT (156). The median PFS after salvage PRRT was 14.6 months and thereby approximately 50% of the initial PRRT, while disease control was observed in 75% of patients. Salvage PRRT was not associated with increased rates of myelotoxicity or nephrotoxicity. In patients that respond favorably to salvage PRRT, future cycles can be considered when progressive disease once again arises, although clinical outcome data of additional treatments are scarce.

Targeted Therapy

The mammalian target of rapamycin (mTOR) protein is a central proliferative factor in many cancer cells. Inhibition of the mTOR pathway has been investigated for several malignancies, including NEN. The RADIANT-2 multicenter phase III trial investigated whether the oral mTOR inhibitor everolimus had efficacy in patients with advanced NET and carcinoid syndrome (157). In total, 429 patients with progressive and advanced grade 1-2 disease were randomized between everolimus 10 mg q.d. plus octreotide LAR 30 mg every 4 weeks or placebo plus octreotide 30 mg every 4 weeks. Primary sites included among others small intestine (52%), lung (10%), colon (6%), and pancreas (6%). Baseline characteristics between the groups were not well balanced with regard to WHO performance status, primary sites, and prior use of chemotherapy. The median PFS was 16.4 months in the everolimus combination group compared to 11.3 months in the placebo combination group (p=0.026). This analysis encompassing central review of radiological images did not reach the pre-specified cut-off for superiority. Median OS was 35.2 months in the placebo-octreotide LAR group compared to 29.2 months in the everolimus-octreotide LAR group, which was not a statistically significant difference, but more deaths related to respiratory or cardiac disease were observed in the everolimus arm.

In the RADIANT-4 phase III trial, patients with advanced, progressive, grade 1-2, nonfunctioning NET of gastrointestinal or lung origin were included (158). Here, 302 patients were randomized 2:1 to everolimus 10 mg q.d. or placebo. Approximately 60% of patients had a gastrointestinal NET, while 80% had liver metastases, generally with limited liver tumor bulk. Median PFS was longer in the everolimus-treated patients at 11.0 months versus 3.9 months in the placebo group. This difference was significant after central radiology review as well as after local review (P<0.00001). Despite a 36% reduction in the risk at death in the everolimus group, overall survival was not significantly improved. Partial response was obtained in 2% of patient treated with everolimus, while stable disease was observed in 81%. Given the outcomes of the RADIANT-2 and RADIANT-4 trials, everolimus appears to be better suited for nonfunctioning NET than functioning NET.

Everolimus use is associated with a high rate of side effects, such as stomatitis, rash, diarrhea, fatigue, diabetes, infections, and non-infectious pneumonitis. Dose reductions or interruptions are necessary in up to two-thirds of NET patients taking everolimus (158). No benefit in terms of quality of life has been proven for everolimus (159), with potentially a decrease in quality of life in patients with extrapancreatic NET (160).

Multitarget tyrosine kinase inhibitors (MTKI) are another form of targeted therapy that can exert potent anti-cancer effects. Sunitinib is an oral multireceptor MTKI which has been investigated in panNET patients. In a phase II study, suninitib showed encouraging antitumoral activity in 61 pancreatic NET with partial response observed in 17% (161). While the median time to progression of 10.2 months in 41 patients with gastrointestinal and lung NET treated with sunitinib exceeded the 7.7 months observed in panNET patients, further development of sunitinib in gastrointestinal NET was not pursued due to the low response rate of 2.4%. A subsequent phase III trial in panNET patients showed that sunitinib improved PFS and OS in panNET patients (162), which led to registration of this drug for NET of pancreatic origin only.

Another MTKI surufatinib was tested in two phase III studies in China in pancreatic and extrapancreatic NET, respectively (163, 164). In the multicenter, randomized SANET-ep trial 198 patients with advanced, grade 1-2, progressive NET of gastrointestinal (47%), thoracic (24%), or other origins were randomized 2:1 to oral surufatinib 300 mg or placebo once daily (164). The median PFS after central review in the surufatinib group was 7.4 months compared to 3.9 months in the placebo group (P=0.037), which appeared to be independent of the subgroups studied. There was a large difference with the local radiology review, which tended to overexaggerate the effect of surufatinib on PFS. OS was not different between the groups at the time of the interim analysis. Partial response and stable disease were observed in 10 (8%) and 88 (70%) out of 126 patients, respectively, in the surufatinib arm. Relevant treatment-related side effects included hypertension, proteinuria, anemia and elevated liver enzymes. Quality of life did not improve in the surufatinib arm, while surufatinib-treated patients experienced more diarrhea than those in the placebo arm (165). Based on the SANET-ep study and its partner SANET-p study in panNET patients, surufatinib is registered in China for the treatment of nonpancreatic and pancreatic NET. Surufatinib is thus far not registered for these indications by the FDA or EMA.

Several other MTKI have shown potential for antiproliferative activity in NET patients. These include pazopanib (166), lenvatinib (167), and axitinib (168). Further phase III data are necessary before these MTKI can be considered in gastrointestinal NET.

Immunotherapy: Interferon-Alpha and Immune Checkpoint Inhibitors

In the 1980s, the advent of interferon as a novel cancer drug was also investigated in NEN. Several uncontrolled series supported antiproliferative and antihormonal effects of interferon alpha in mostly small intestinal NET (169, 170). The proinflammatory effects of interferon alpha however led to side effects of flu-like symptoms, myalgia, asthenia, auto-immune diseases, and diarrhea, limiting its tolerability in patients. Compared to SSA, interferon alpha had comparable antiproliferative effects (171). Long-acting interferon alpha appears to be better tolerated and was shown to produce antitumor effect in a single retrospective series in 17 patients (172).

Immunotherapy with immune checkpoint inhibitors has revolutionized treatment of several malignancies, including melanoma and non-small cell lung cancer. However, infiltration of immune cells, like T-cells, is a rare occurrence in NET samples (173-175). In line with these preclinical findings, immune checkpoint inhibition in clinical (basket) trials have failed to show positive effects in well-differentiated NET (176-178).

Chemotherapy

In contrast to panNET there are no phase III clinical data to support the use of chemotherapy in gastrointestinal NET. Presumably in part through their well-differentiated nature, response rates to chemotherapy have been disappointing and further clinical development halted (179). Consequently, ENETS 2016 and NANETS 2017 guidelines do not support the use of chemotherapy in gastrointestinal NET (143, 180). The EMSO 2021 guideline does advocate the use of either FOLFOX (5-fluorourical, oxaliplatin) or TEMCAP (temozolomide, capecitabine) in selected cases with high grade 2 gastrointestinal NET in third-line or higher setting, although this is not supported by prospective clinical data (181).

Supportive Therapy

Due to the primary tumor and metastasis locations as well as the sequalae of hormonal overproduction and therapeutic interventions, patients with gastrointestinal NET can be in a poor clinical condition. Inadequate nutrient intake and uptake in these patients leads to increased incidence rates of weight loss, muscle atrophy, and decreased performance status (182). Consequently, all gastrointestinal NET patients should be screened on dietary intake and referred to dieticians if they are at risk of weight loss. High-protein, high-calorie supplements should be prescribed if regular dietary advice is insufficient to prevent weight loss. In cases of suspected reduced calorie uptake due to exocrine pancreatic insufficiency, often encountered during SSA treatment, or bile acid diarrhea, due to bowel resection, a trial of pancreatic enzyme supplements or bile acid sequestrants can be considered.

In some cases, patients can be refractory to these interventions and escalation should be considered. This is particularly true for patients with extensive bowel resections leading to short bowel syndrome and those with severe desmoplastic reaction surrounding mesenteric metastases of small bowel NET. Food intake in the latter group might also be compromised by intermittent venous ischemic pain precipitated by meals. Tube feeding through nasogastric tube should be considered in selected cases. In case enteral feeding fails to improve the clinical situation, total parenteral nutrition can serve as a last resort for these refractory cases. Treatment with total parenteral nutrition up to 5 years has been successfully implemented in severe cases of NET (183).

Besides nutritional support, physical therapy should also be offered to patients in order to improve their clinical performance status. Finally, given the impact of an incurable disease and its complaints psychosocial support should be discussed with patients and made accessible, if needed (184).

MANAGEMENT OF CARCINOID SYNDROME

Patient with gastrointestinal NET and the carcinoid syndrome require dedicated management of their hormonal symptoms. Quality of life in these patients is severely decreased, even when compared to patients with other – generally more aggressive – cancers (185). Prompt recognition of symptoms of flushing and diarrhea is key to specific management, while the complications of mesenteric fibrosis and CHD should also be screened and treated adequately (29).

The cornerstone of the management of the carcinoid syndrome is SSA. Since the 1980s octreotide and later lanreotide have been shown to lead to biochemical and clinical responses in patients with the carcinoid syndrome. In a meta-analysis comprising 1945 interventions in 33 studies, SSA significantly decreased 5-HIAA excretion in 45-46% of patients, while flushing and diarrhea were decreased in 69-72% and 65%, respectively (186). Also given its favorable tolerability, all patients should be started on SSA soon after a confirmed diagnosis of carcinoid syndrome.

Although patients with carcinoid syndrome in the majority of cases have widespread disease, the option of cytoreductive therapy by surgical resection or ablation or intra-arterial liver embolization can be considered in selected cases. If the vast majority of tumor bulk can be resected or embolized, this can lead to biochemical responses and clinical benefit for the patient (186). These options should be weighed also considering the level of serotonin overproduction, tumor growth rate, and efficacy of SSA. Importantly, SSA should be initiated before interventional therapy is commenced in order to reduce the risk of a carcinoid crisis (187).

Patients with persistent symptoms despite label doses of SSA are designated as having refractory carcinoid syndrome. Several systemic options are available for treatment and these should be weighed on an individual basis guided by tumor bulk, rate of progression, severity of symptoms, and availability. Dose escalation of SSA can be attempted and leads to symptomatic improvement in 72-84% of patients (186). Alternatively, a randomized controlled trial has proven efficacy of the oral drug telotristat ethyl in controlling diarrhea in patients with refractory carcinoid syndrome (188). This serotonin synthesis inhibitor, dosed at 250 mg t.i.d., decreased bowel movements in approximately half of the cases and with a mean reduction of 0.8 bowel movements per day, whilst having no significant effect on flushing. A drug trial of three months is generally advised with stopping of telotristat ethyl if no benefit has been obtained after this time. Clinical symptoms improved in patients treated with PRRT in the NETTER-1 trial (140), although no sub-analysis was performed for carcinoid syndrome patients. In a retrospective series of 24 patients with stable disease or severe, refractory carcinoid syndrome, PRRT with four cycles of ¹⁷⁷Lu-DOTATATE effectively reduced flushes and diarrhea in 67% and 47% of patients, respectively (155). Therefore, PRRT constitutes a viable option for refractory carcinoid syndrome patients with aggressive or progressive disease. In the past, interferon-alpha injections have been shown to diminish diarrhea and flushing resulting from carcinoid syndrome. Its antihormonal effect on top of SSA was limited (189), however, and given its poor tolerability interferon-alpha is reserved to selected cases, refractory to the above-mentioned options. Anecdotal reports support the use of serotonin receptor antagonists, like granisetron or ondansetron, and antihistamines (H1 and H2 receptor blockers) in refractory carcinoid syndrome.

Importantly, the patient should be counselled on supportive therapy, which could include the use of antidiarrheals, like loperamide or morphine, adaptation of dietary intake, including avoidance of alcohol, tryptophan-containing or spicy foods, and the avoidance of stressors (29). Patients with severe carcinoid syndrome are at a high risk of a catabolic state and vitamin deficiencies. Patients should be referred to a dietician and adequately monitored and supplemented for vitamin deficiencies, particularly for vitamin B3 or niacin and fat-soluble vitamins.

Patients suffering from CHD should be evaluated by cardiologists experienced in right-sided cardiac pathology. Dedicated echocardiographic evaluations should be performed, preferably through standardized protocols (190). Fluid and salt restriction comprise first-line treatment of right-sided heart failure due to tricuspid valve regurgitation or pulmonary valve regurgitation or stenosis in the context of CHD. Alternatively, loop diuretics can be prescribed to treat fluid overload and edema. Severe symptomatic patients should be discussed in a multidisciplinary team for evaluation of surgical valve replacement (191).

PROGNOSIS AND FOLLOW-UP

Resection is the only potential cure for gastrointestinal NET. Recurrence is however frequently observed in NET patients operated on with curative intent (119). Exceptions that are associated with excellent curation rates after local resection include T1-T2 appendiceal, gastric, duodenal, or rectal NET. Long-term imaging follow-up is mandated for the other subtypes of gastrointestinal NET after resection of localized, locoregional, or oligometastatic disease.

In a US registry study of almost 100,000 NET patients, median overall survival was 112 months and 62% of patients died of disease-related causes (192). All-cause mortality was 4.3-fold higher in all NET patients, compared to the general population, while patients with stage IV disease had 35-fold elevated risk of mortality. Whereas patients with localized disease still have an elevated standardized mortality ratio, the risk of non-cancer death is higher than cancer-related death in patients with non-metastatic gastrointestinal NET (193). Primary site, stage or grade are tumor-specific prognostic markers, while age, sex, comorbidities and socio-economic status constitute patient-specific factors that are associated with overall survival (7, 8, 192-194). Over the last few decades, NET management has improved considerably with the advent of superior classification, imaging, and biochemical diagnostics and treatment modalities. These developments, combined with expert multidisciplinary team care in dedicated NET centers, have likely contributed to the observed improvement in overall survival in patients with gastrointestinal NET (7, 8). However, survival of gastrointestinal NET patients is still limited, particularly in those with advanced disease, prompting the need for future innovation in the fields of early detection of disease (recurrence), novel druggable targets, and personalized management for NET.

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Hypoglycemia in Neonates, Infants, and Children

ABSTRACT

Hypoglycemia in neonates, infants and children should be considered a medical emergency that can cause seizures, permanent neurological injury, and in rare cases, death, if inadequately treated. Under normal conditions, glucose is the primary fuel for brain metabolism. Due to the metabolic demands of the developing brain, infants and children have increased rates of glucose utilization as compared to adults. Normal regulation of glucose during fasting requires integration of glycogenolysis, gluconeogenesis, and fatty acid oxidation coordinated by various hormones. In the first days of life, the time course of the physiologic transitional changes to autonomous glucose regulation may overlap with presentation of inherited and acquired pathologic forms of hypoglycemia, introducing inherent challenges and controversy in addressing neonatal hypoglycemia. Therefore, a careful approach to the neonate with hypoglycemia is critical to determine the precise etiology so that rapid and appropriate interventions can be implemented to avoid permanent neurological injury. After infancy, hypoglycemia is uncommon, but, up to 10% of children older than one year of age presenting to emergency rooms with previously undiagnosed hypoglycemia have a serious underlying condition requiring long-term treatment. An important caveat in the pediatric population is that the classical definition of hypoglycemia, Whipple’s triad, is of limited use as young children are unable to reliably communicate symptoms. At all ages, determining the cause of the hypoglycemia is paramount for establishing specific and effective treatment to prevent further episodes of hypoglycemia and long-term neurological sequelae. The majority of hypoglycemic events in infants and children with hypoglycemic disorders occur during periods of fasting. Evaluation of key metabolic fuels and hormones (the critical sample) during a supervised fast, or at the time of spontaneous hypoglycemia, thus permits classification and relevant treatment of hypoglycemia disorders.

INTRODUCTION

Hypoglycemia is the biochemical finding of a plasma glucose lower than normal for age. Hypoglycemia itself is not a diagnosis but rather reflects an underlying perturbation in metabolic adaptation, which may be as simple as prolonged fasting in a child with an intercurrent illness, or a complex genetic disorder. It is critical for the physician at all times to determine the etiology of hypoglycemia while at the same time treating critical low blood glucose and stabilizing the person with hypoglycemia.

In this chapter, we outline the basic physiology of glucose regulation, the change in glucose homeostasis in the immediate newborn period and describe the common diseases that cause hypoglycemia in childhood. We discuss the definitions of hypoglycemia, pitfalls in the measurement of blood glucose concentration, the critical importance of glucose as a fuel for energy in the brain, and the implications of hypoglycemia on brain damage. For information on hypoglycemia related to diabetes and its treatment see the chapter entitled “Hypoglycemia During Therapy of Diabetes” in the Diabetes Mellitus and Carbohydrate Metabolism---Diabetes Manager section of Endotext (1).

PHYSIOLOGY OF GLUCOSE REGULATION

An understanding of the physiology of glucose regulation is critical in order to understand the etiology of the different hypoglycemic disorders. By utilizing a fasting systems approach to diagnosis, one can rapidly pinpoint the general physiological system disrupted and with appropriate examination of blood and urine at the time of hypoglycemia (the critical sample) one can identify the diagnosis relatively quickly. This approach is particularly useful because apart from the newborn period (2), the vast majority of causes of hypoglycemia in children are caused by abnormalities of fasting adaptation. Rare exceptions to this rule include postprandial hypoglycemia typically related to gastrointestinal surgery such as Nissen fundoplication (3), or esophageal atresia repair (4), protein induced hypoglycemia of certain genetic forms of hyperinsulinism (5,6), and the hypoglycemia triggered by the ingestion of fructose in hereditary fructose intolerance (7).

The recognition and identification of the etiology of hypoglycemic disorders in the immediate newborn period may be more complicated due to the changes in glucose homeostasis that occur during the transition from intra uterine to extra uterine life, typically defined as the first 12-72 hours of life, and will be discussed separately (2).

The Physiology of Fasting

The key to diagnosing the etiology of hypoglycemia is a good understanding of the three key metabolic systems that regulate the physiological response to fasting and the hormonal control over these systems. The first, glycogenolysis, involves the breakdown of glycogen and conversion to glucose 6 phosphate (G-6-phos). G-6-phos may either undergo glycolysis and be converted to lactate (8), or converted to glucose by glucose-6-phosphatase (G-6-Pase), and then released from the liver and transported to the brain for fuel. The second, gluconeogenesis, is the pathway by which fuels such as lactate, alanine, fructose and glycerol are converted into glucose. The third, fatty acid oxidation and ketogenesis, are the processes by which ingested fat and fat stores are converted either to acetyl-CoA for entry into the citric acid cycle (Krebs cycle) and generation of energy, or to beta-hydroxybutyrate which is then transported to tissue such as the brain for energy production. An essential role of fatty acid oxidation is the production of an alternate fuel to glucose for energy production. This process conserves glucose for those tissues that can only metabolize glucose (such as red blood cells). Each of these mechanisms of fasting adaptation are finely regulated to maintain the plasma glucose between 70 and 110 mg/dL (3.9 to 6.1 mmol/L) by a combination of insulin to utilize or store glucose, and the counter regulatory hormones to mobilize and release glucose (Table 1). Insulin, the main hormone secreted in the fed state, suppresses glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. The counter regulatory hormones glucagon, cortisol, growth hormone, and epinephrine are the predominant hormones secreted in the fasting state and have overlapping effects on these processes. Because of the critical importance of these 3 processes (glycogenolysis, gluconeogenesis and fatty acid oxidation) in preventing hypoglycemia, there is overlap in hormonal control of the systems with both glucagon and epinephrine stimulating glycogenolysis, cortisol and glucagon stimulating gluconeogenesis, growth hormone and epinephrine stimulating lipolysis and finally glucagon and epinephrine stimulating ketogenesis.

Table 1. Hormonal Control of Fasting Adaptation
Hormones	Glycogenolysis	Gluconeogenesis	Lipolysis	Ketogenesis
Cortisol		stimulates
Growth Hormone			stimulates
Glucagon	stimulates	stimulates		stimulate
Epinephrine	stimulates		stimulates	stimulates

Hormonal Control of Fasting

Following a meal, insulin is the predominant secreted hormone as glucose, and other fuels, are absorbed, facilitating glucose entry into cells and its utilization for energy. Under the influence of insulin, excess glucose is stored as glycogen in the liver for use later in fasting. As the plasma glucose starts to fall below 85 mg/dL insulin secretion is reduced and then suppressed (Figure 1). As the blood sugar continues to fall to around 70 mg/dL, the rapidly acting counter regulatory hormones glucagon and epinephrine are secreted. This initially drives glycogenolysis which supplies glucose from the liver for up to 4-8 hours in infants and 8-12 hours in children and young adults. Cortisol and growth hormone secretion stimulate gluconeogenesis and lipolysis providing amino acids, glycerol, and free fatty acids for metabolism to ketones.

Figure 1. Relationship of hormone secretion to plasma glucose levels.

Brain Fuel Metabolism/Energy Production

As the plasma glucose levels approach 50 mg/dL the ability of the blood brain barrier to transport glucose into the brain for maximal usage, begins to become limited (9). The brain responds by utilizing alternative fuels for energy (lactate, beta-hydroxybutyrate) or in the absence of alternate fuels (as occurs in hyperinsulinism) cuts down nonessential functions in order to conserve energy. When the glucose levels drop below 30 mg/dl cerebral blood flow increases in an attempt to increase glucose delivery (10). In conditions of prolonged fasting, as beta-hydroxybutyrate levels rise, monocarboxylate transporter 1 (MCT1) transports the beta-hydroxybutyrate across the blood brain barrier, which presents the brain with an alternative fuel for energy production. With very prolonged fasting, the brain is able to switch from utilizing almost 100% glucose for energy production to utilizing almost all ketones (11). In disease conditions such as glycogen storage disease (GSD) type 1, glycogenolysis results in elevated lactate levels because of the inability to de-phosphorylate G-6-phos and generate glucose that can be transported out of the liver. As a result, the plasma glucose falls rapidly, and the plasma lactate levels rise to 5-10 mmol/L (4-5 times normal levels). Carriers such as MCT1 transport this lactate across the blood brain barrier where the brain can efficiently metabolize it in the presence of oxygen through the citric acid cycle and produce the energy needed for brain function. Indeed, animal studies have demonstrated that the cerebral metabolic rate of oxygen consumption does not fall significantly during the initial phase of hypoglycemia when either ketones or lactate are available as an alternate substrate. In patients with diabetes, lactate infusions can prevent insulin induced neuroglycopenia (12). In addition, humans undergoing a ketogenic diet were able to transition from utilizing primarily glucose as brain fuel to ketones providing 17% of whole brain energy requirements with no overall change in the cerebral metabolic rate (13). It is for this reason that that hypoglycemia itself does not cause brain damage, it is a lack of fuel (glucose, beta-hydroxybutyrate or lactate combined) that causes brain damage. In addition to a lack of fuels for energy production a lack of oxygen supply to the brain prevents the utilization of lactate which can dramatically worsen energy failure in the brain.

In non-physiological conditions when the plasma glucose continues to drop down to 30 mg/dL or lower, cerebral spinal fluid glucose levels become almost zero and in the absence of either ketones or lactate essential functions of the brain stop and cell death begins to occur (14). Breakdown of the phospholipids in the brain provides free fatty acids and breakdown of protein provides gluconeogenic substrates but also increases brain ammonia levels 10-15 fold (15). Whilst breakdown of tissues provides fuel for energy production, this process also damages vital cells and organelles causing permanent cellular destruction. Once the production of energy is insufficient to maintain adequate high energy phosphate compounds, the infant or child will become comatose and have an isoelectric electroencephalogram. It is not known exactly how long glucose and the alternate fuel levels need to be low to cause harm nor how low the total fuels need to be prior to the onset of permanent brain damage; however, it is likely to differ based on availability of alternative fuels, rates of brain metabolism (increased in seizures), and degree of plasma oxygenation. In conditions such as hyperinsulinism, where there are no alternate fuels available and when patients may have seizures which both increase brain energy needs and decreases the availability of oxygen in the blood stream, all these factors combine and may cause profound brain damage (16).

It is clear that not all hypoglycemia is equal, and the responsible physician must assess the etiology of the hypoglycemia, the likelihood of the presence of alternate fuels, and the presence of good blood flow and oxygenation in order to understand the danger of any given episode of hypoglycemia. The importance of correctly identifying the etiology of the hypoglycemia thus affects not just the long-term approach to management but also the immediate approach to the infant or child. This also explains why efforts to define a single blood glucose value that predicts brain damage is impossible and why efforts to define neurological outcome relative to glucose levels alone are not valid.

DEFINITION OF HYPOGLYCEMIA

For the reasons stated above, a single measurement of glucose does not reflect the total energy availability to the brain. Therefore, when one tries to define hypoglycemia, one should consider why a definition is required. We suggest that the definition of hypoglycemia needs to include three critical aspects.

Diagnostic hypoglycemia is the level of glucose required to make a diagnosis of the etiology of the hypoglycemia.
Therapeutic hypoglycemia is the level of glucose one should aim to stay above during treatment of hypoglycemic disorders.
The concentration of glucose at which hypoglycemia causes brain damage is unknown and practically there is no such value.

Diagnostic Hypoglycemia

Evaluation of a blood and urine sample when the plasma glucose is less than 50 mg/dL is essential in determining the etiology of hypoglycemia. This allows a determination of the metabolic profile at the time of hypoglycemia. This sample is often referred to as a “critical sample” and typically includes both blood (plasma) and urine samples, which are analyzed for the analytes in Table 2.

Table 2. The Critical Sample: Blood and urine samples to be drawn at a time of hypoglycemia (plasma glucose <50mg/dL) to guide the diagnosis of the etiology of hypoglycemia with additional testing for certain conditions.

Plasma

Glucose

Insulin

Cortisol

Growth hormone

Beta-hydroxybutyrate

Free fatty acids

Acylcarnitine profile

Ammonia

Liver function tests

Urine

Urine organic acids

In suspected insulin administration

C-peptide

Specific insulin assays to measure biological insulin only

Sulfonylurea screen

In suspected insulinoma

Proinsulin

C-peptide

Sulfonylurea screen

In suspected fatty acid oxidation defects

Free and total carnitine

The critical sample can be drawn either at a time of spontaneous hypoglycemia or at the end of a fasting study in which plasma glucose less than 50 mg/dL is deliberately induced. Once the plasma glucose is <50 mg/dL, the counter regulatory hormones should be elevated, and insulin suppressed. The metabolic systems of glycogenolysis, gluconeogenesis, fatty acid oxidation, and ketone utilization should be underway and with glucagon administration, there should be no glycemic response as the liver should have utilized all the glycogen stores. Interpretation of the critical sample is the key to making the correct diagnosis (Table 3). Figure 2 is a simple diagnostic algorithm to aid the provider.

Table 3. The Differential Diagnosis of Hypoglycemia in Neonates, Infants, and Children Based on the Results of the Critical Sample.
Disorder	Plasma Fuels when glucose <2.8 mmol/L			Plasma Hormones at End of Fast				Clinical Features
Disorder	Lactate mmol/L	FFA mmol/L	BOHB mmol/L	Insulin (µu/mL)	Cortisol (µg/dL)	GH (ng/mL)	ΔPG following glucagon (mg/dL)	Clinical Features
Normal infants	0.7-1.5	>1.7	2-4	<2	>18	>10	<30	Normal
Hyperinsulinism	N	<1.7	<1.8	>1	N	N	>30	LGA
Cortisol deficiency	N	N	N	N	<14*^†	N	N	Hyperpigmentation if primary
GH deficiency	N	N	N	N	N	<8^†	N	Short stature
Panhypopituitarism	N	Low-N	Low-N	N	Low	Low	N	Short stature, midline facial malformation, optic hypoplasia, micro/small penis
Epinephrine deficiency (beta-blocker)	N	<1.5	<2	N	N	N	N
Debrancher deficiency (GSD III)	N	N	N	N	N	N	N	Hepatomegaly 4+
Phosphorylase deficiency (GSD VI)	N	N	N	N	N	N	N	Hepatomegaly 2+
Phosphorylase kinase deficiency (GSD IX)	N	N	N	N	N	N	N	Hepatomegaly 2+
Glycogen synthase deficiency (GSD 0)	N	N	N	N	N	N	N
Glucose 6-phosphatase deficiency (GSD la and lb)	4-8 +	N	<2	N	N	N	Normal glucose elevated lactate	Hepatomegaly 4+
Fructose 1, 6-diphosphatase deficiency	4-8 +	N	N	N	N	N	N	Hepatomegaly 1+
Pyruvate carboxylase deficiency	4-8 +	N	N	N	N	N	N

*Depending on sensitivity of the assay used (17). ^†Note that findings of a single low growth hormone or cortisol level at the time of hypoglycemia has poor specificity for deficiency of either hormone (18,19). Stimulation testing may be needed to confirm the diagnosis. FFA, free fatty acids; GH, growth hormone; GSD, glycogen storage disease; LGA, large for gestational age; N, normal; PG, plasma glucose. Adapted from De Leon DD, Thornton P, Stanley CA, Sperling MA. Hypoglycemia in the Newborn and Infant. In: Sperling MA, Majzoub JA, Menon RK, Stratakis CA, eds. Sperling Pediatric Endocrinology. Fifth ed: Elsevier; 2021 (20).

Figure 2. Hypoglycemia diagnosis based on plasma metabolic fuel responses. Measurement of lactate as a gluconeogenic substrate, FFA from adipose tissue lipolysis, and BOHB at the time of hypoglycemia segregates major groups of hypoglycemia disorders. FFA, free fatty acids; GH, growth hormone; HCO3, bicarbonate; BOHB, beta-hydroxybutyrate. Adapted from Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, Sperling MA, Weinstein DA, White NH, Wolfsdorf JI, Pediatric Endocrine S. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015;167(2):238-245 (21).

Therapeutic Hypoglycemia

Generally, the target to treat infants and children with known hypoglycemic disorders is to keep the blood glucose above 70 mg/dL. There are certain conditions when the target maybe higher such as patients in acute decompensation with fatty acid oxidation defects where the goal is to stimulate insulin secretion which will prevent lipolysis and then fatty acid oxidation. In these circumstances it may require that the glucose levels are elevated to greater than 85 mg/dL. Thus, in this case, getting the blood sugar up to 70 mg/dL will prevent the consequences of hypoglycemia but will not rapidly reverse the breakdown of lipids to free fatty acids and glycerol and thus will not stop the accumulation the abnormal metabolites of fatty acid oxidation. In children with GSD 1 the provision of adequate glucose to get the blood sugar greater than 70 mg/dL will provide the brain with adequate glucose for energy, however raising the blood sugar too high will drive glucose to lactate and thus worsen lactate levels. So, for individuals with GSD 1 the goal is to maintain the glucose at a level that will maximally suppress lactate levels (70-85 mg/dL) without triggering insulin release.

A second reason to maintain the plasma glucose greater than 70 mg/dL is to prevent hypoglycemic unawareness. Recurrent episodes of glucose levels less than 70 mg/dL over time will blunt the release of epinephrine by the autonomic nervous system. The secretion of epinephrine triggers awareness by the child and young adult of impending neuroglycopenia and allows them to react by food seeking behavior to prevent further hypoglycemia. After every episode of hypoglycemia, this counter regulatory response is blunted for up to 5 days and if the hypoglycemia recurs inside this period, the response is blunted even more. This failure to secrete epinephrine in response to hypoglycemia is hypoglycemia associated autonomic failure (HAAF) (22).

NEONATAL TRANSITIONAL GLUCOSE REGULATION

The transition from intrauterine to extra uterine life is a critical time for the neonate. In utero, the fetus is exposed to seemingly limitless supplies of glucose, amino acids, and other fuels necessary for growth and development, through the maternal placenta unit. Because of the insulin resistance of pregnancy, maternal plasma glucose levels are higher than in the non-pregnant state. Glucose is transported across the placenta by facilitated diffusion and fetal plasma glucose levels are approximately 8-15 mg/dL lower than maternal levels. Fetal plasma glucose levels are determined by maternal plasma glucose levels, however fetal insulin secretion is regulated by fetal plasma glucose levels. Recent data have shown that the threshold for insulin secretion in the fetus is lower than the adult and that this is controlled at the level of the K_ATP channel by decreased trafficking of the channel to the beta cell plasma membrane (23). The function of insulin in the fetus is to act as the main anabolic hormone and drive fetal growth. At the time of birth and clamping of the umbilical cord this constant supply of glucose is interrupted. The now newborn has to suddenly adjust initially to no glucose and soon thereafter to limited glucose input via, intermittent feeding and a nutrition source that is primarily fat (colostrum). The recent glucose in well babies study (GLOW) has shown that this transition can last up to 72-96 hours in normal breast-fed babies and consists of two phases (24): initially a hypoketotic hypoglycemic phase, and then a ketotic euglycemic/hypoglycemic stage until the mother’s milk comes in (Figure 3).

Figure 3. Glucose and beta-hydroxybutyrate levels in healthy term newborns over the first 96 hours of life demonstrating the period of transitional hyperinsulinism during adaptation to extrauterine life followed by the period of hyperketotic euglycemic/hypoglycemic phase of starvation until breast milk has come in and the neonate has adequate caloric intake. Stanley CA, et al. Figure 1. From Stanley CA, Thornton PS, De Leon DD. New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia. Front Pediatr. 2023;11:1071206 (25) CC BY 4.0. Adapted from Harris DL, Weston PJ, Harding JE. Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in Well Babies (GLOW) Study. J Pediatr. 2021;231:81-86 e82 (26).

In healthy newborns with normal birth weight, the glycogen stores from the liver built up during pregnancy, provide the initial glucose support. In the healthy newborn, liver glycogen concentration is the highest of all times in life and can supply the newborn with glucose for up to 12 hours. In preterm infants and infants born small for gestational age (SGA) or with intra-uterine growth retardation (IUGR), this supply is dramatically diminished thus increasing the risk of hypoglycemia in these babies. In addition, in the immediate newborn period, lactate levels are elevated (24), and gluconeogenesis from lactate rapidly increases over the first few hours of life, as the rate limiting enzyme of gluconeogenesis, phosphoenolpyruvate carboxy-kinase (PEPCK) increases to adult level by 24 hours of life. In the immediate post-natal hours, ketone levels are inappropriately low for the plasma glucose due to the lower threshold for insulin secretion but over the first 48 hours as the threshold for glucose stimulated insulin release rises, plasma ketone concentration begins to increase. In addition, medium chain fatty acids from colostrum are directly absorbed and transported to the liver through the portal circulation and undergo beta oxidation to generate ketones. In starved breastfed infants, ketones can reach 2 mmol/L by 48-72 hours of life (26).

The newborn rapidly adjusts from living in a steady anabolic state to an intermittent catabolic state until nutrition becomes adequate to supply sufficient energy to grow. In the relatively hypoxemic environment of in-utero life, insulin has a lower threshold for secretion to ensure the fetus remains in an anabolic state. After birth the newborn must adjust rapidly from the steady secretion of insulin associated with consistent fetal glucose availability to rapidly changing plasma glucose levels with feeding and to be able to deal with intermittent fasting. Over the first 12-24 hours of life the threshold for insulin secretion rises to the more typical 80-85 mg/dL seen in older infants, children and adults. All of this occurs while awaiting maturation of all the enzymes needed for gluconeogenesis and fatty acid oxidation. The consequences of these changes are that in the first 1-2 hours of life the blood glucose concentration falls to a mean of approximately 55 mg/dL (Figure 3). Gradually over the next 12-48 hours the plasma glucose concentration starts to rise to levels (60 mg/dL) approaching normal adult levels and by 72-84 hours of life, transition is complete and plasma glucose levels are in essence similar to adults (70 to 110 mg/dL) (2,24). During the first 24-48 hours of life upwards of 35-45% of normal healthy term babies may have occasional plasma glucose levels less than 50 mg/dL, however by 72-84 hours of life persistent plasma glucose levels less than 60 mg/dL reflect an underlying pathological problem (21).

Approach to Neonatal Glucose Screening and Treatment

The dilemma for physicians caring for newborns is how to differentiate babies having normal transitional glucose regulation with transient hypoglycemia from those with pathological hypoglycemia due to conditions such as perinatal stress-induced hyperinsulinism (PSHI). The 2015 Pediatric Endocrine Society (PES) recommendations (21) guide the physician on how to differentiate physiological plasma glucose levels less than 50 mg/dL from pathological causes of hypoglycemia in the first days of life. They recommend that normal healthy term babies with no symptoms of hypoglycemia do not require glucose monitoring. Babies at risk for hypoglycemia such as those with IUGR, those born large for gestational age (LGA) or SGA, those born late pre-term, and those in whom maternal factors increase the risk of hypoglycemia such as maternal hypertension, preeclampsia, and eclampsia should be monitored. In addition, babies who have symptoms consistent with hypoglycemia (Table 4) should also be screened for hypoglycemia.

Table 4. Symptoms and Signs of Hypoglycemia

Neurogenic symptoms appear when glucose <70 mg/dL (<2.8mmol/L)

Jitteriness (neonates), shakiness

Tachycardia

Pallor

Hypothermia

Hunger

Sweating

Weakness

Neuroglycopenic symptoms appear when glucose <45-50 mg/dL (2.5-2.8 mmol/L)

Poor feeding (neonates)

Apnea (neonates)

Floppiness (neonates)

Weak/high-pitched cry (neonates)

Lip smacking and eye twitching (neonates)

Headache

Confusion

Irritability, outbursts of temper

Bizarre neurological signs

Motor and sensory disturbances

Lethargy

Decreased muscle tone

Unconsciousness

Seizure

The PES guidelines recommend that the target to treat these infants be 50 mg/dL but if intravenous glucose is required indicating a more serious problem, the target should be 60-70 mg/dL. After 48 hours of life the target for treatment is 60 mg/dL. The recommendations also state that if a known hypoglycemic disorder is identified then the target for treatment is to maintain the blood glucose greater than 70 mg/dL. These goals should be achieved initially by appropriate resuscitation in the newborn period with the avoidance of cold stress to the baby, early skin to skin contact, early breast feeding or if chosen by mothers, bottle feeding (27). Supplemental glucose can be given with dextrose gel (28). In neonates with symptomatic hypoglycemia or those in whom the above measures fail to maintain the plasma glucose above 50 mg/dL intravenous glucose therapy should be initiated at a glucose infusion rate (GIR) of 4-6 mg/kg/min with or without a 200 mg/kg bolus of IV dextrose. As shown. in Figure 4, within 10 minutes following an IV dextrose bolus of 200 mg/kg followed by a GIR of 8 mg/kg/min, plasma glucose levels reach close to 90% of the glucose concentration measured at 60 minutes. Thus, in patients with dangerously low glucose levels (<30 mg/dL) plasma glucose levels should be rechecked in 10-15 minutes to demonstrate correction of the hypoglycemia and if the glucose has not achieved the target level, then a repeat bolus and increase in the IV infusion rate of glucose should be implemented. In this manner, severe hypoglycemia can be rapidly corrected without significant overcorrection. At all times during treatment of hypoglycemia, the newborn infant should be encouraged to continue to feed orally, unless the patient is seizing or has significant respiratory distress in which case feeding should be withheld temporarily.

Figure 4. The effect of a 200 mg/kg IV mini-bolus in addition to starting a glucose infusion rate of 8 mg/kg/minute compared to just starting 8 mg/kg/minute infusion rate alone. Reprinted from J. Pediatr, 97(2), Lilien LD, Pildes RS, Srinivasan G, Voora S, Yeh TF., Treatment of neonatal hypoglycemia with minibolus and intravenous glucose infusion, 295-298, 1980, with permission from Elsevier (29).

The single most important clinical differentiators of pathological hypoglycemia from transitional hypoglycemia in the newborn period are the presence of neuroglycopenic signs of hypoglycemia (apnea, lethargy, seizures) and the need for intravenous glucose treatment to correct low glucose levels. In both these circumstances the newborn should undergo a fasting study of 6-9 hours to demonstrate that normal glucose regulation has returned (ability to keep glucose >60-70 mg/dL for 6-9 hours) prior to discharge from the hospital. In babies who have hypoglycemia within 6-9 hours of commencing fasting an underlying pathological cause should be sought prior to discharge and appropriate therapy implemented. For babies with persistent glucose <60 mg/dL after 48 hours of life the use of point of care ketone screening may assist in detecting those babies with failed breast feeding from those with the more serious hypoketotic forms of hypoglycemia such as hyperinsulinism, hypopituitarism, or the fatty acid oxidation defects. In the case of persistent hypoglycemia with hypoketosis, further investigations need to be done to determine the etiology.

CLINICAL SYMPTOMS AND SIGNS OF HYPOGLYCEMIA

Classical symptoms and signs of hypoglycemia are outlined in Table 4. It is important to note that children <5 years of age will generally have hypoglycemic unawareness and not be able to recognize the neurogenic symptoms of hypoglycemia. Neonatal hypoglycemia, by virtue of neonates being unable to communicate in a complex way, may be difficult to detect as many of the signs of hypoglycemia occur in normal neonates (30). Subtle signs such as poor feeding, sleepiness, and jitteriness occur in many non-hypoglycemic babies and clinical judgement as to when to check glucose is required. However, if in doubt it is better to check blood glucose (21). For more serious symptoms, such as lethargy, seizures, apnea and coma, screening point of care glucose should be performed and hypoglycemia simultaneously confirmed by laboratory measured plasma glucose. Older children with acquired hypoglycemia such as that caused by insulinoma, often have hypoglycemic unawareness due to the frequency of hypoglycemia and only demonstrate neuroglycopenic signs. All neonates, infants, and children with neuroglycopenic symptoms or signs must have a plasma glucose concentration checked and if <60-70 mg/dL serious consideration of hypoglycemia as a cause should be entertained.

HORMONAL CAUSES OF HYPOGLYCEMIA

Hyperinsulinism

Hyperinsulinism refers to the group of hypoglycemic disorders caused by dysregulated, excessive insulin secretion or action via signaling. Insulin secretion from pancreatic beta-cells is tightly regulated and predominantly controlled by the plasma glucose concentration (Figure 5). In normal circumstances glucose enters the beta-cell via insulin-independent glucose transporters and is phosphorylated by glucokinase to G-6-phos. Glucokinase acts as the “glucose sensor” setting the threshold for insulin secretion; normally, insulin secretion is triggered when plasma glucose levels are above 85 mg/dL. Metabolism of G-6-phos leads to an increase in the intracellular adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio which regulates subsequent closure of the ATP-sensitive plasma membrane K_ATP channels, membrane depolarization, activation of voltage-gated calcium channels, calcium influx, and release of insulin from stored granules. Amino acid metabolism also influences insulin secretion. Leucine allosterically activates glutamate dehydrogenase, increasing oxidation of glutamate to alpha-ketoglutarate, thereby increasing the ATP-to-ADP ratio, triggering the insulin secretion cascade. Glutamine mediates glucagon-like peptide 1 (GLP-1) receptor signaling, which acts as an “amplification pathway” for insulin secretion.

Figure 5. Diagram of the pathways stimulating beta-cell insulin secretion. Glucose enters the beta-cell via glucose transporters and is phosphorylated by GCK to G-6-phos. Oxidation of G-6-phos in mitochondria increases the ATP-to-ADP ratio, leading to closure of plasma membrane ATP-sensitive KATP channels (comprised of SUR1 and Kir6.2 subunits), inhibition of K+ efflux, membrane depolarization, opening of voltage-dependent Ca++ channels, Ca++ influx, and release of insulin from storage granules. Amino acids stimulate insulin secretion through glutamine-mediated amplification of GLP-1 receptor signaling. Leucine stimulates insulin secretion by increasing the oxidation of glutamate via activation of GDH, thereby increasing the ATP-to-ADP ratio and triggering the insulin secretion cascade. HK1 and MCT1 are not normally present in the beta-cell. Diazoxide suppresses insulin secretion by activating the KATP channel to remain open. Somatostatin suppresses insulin secretion downstream of Ca++ signaling. Known sites of defects associated with congenital hyperinsulinism are indicated by bold and underlined font and include GCK (glucokinase), HK1 (hexokinase 1), PGM1 (phosphoglucomutase 1), MCT1 (monocarboxylate transporter 1), UCP2 (uncoupling protein 2), SCHAD (short-chain 3-hydroxyacyl-coenzyme A dehydrogenase), GDH (glutamate dehydrogenase), HNF1A (hepatocyte nuclear factor 1A), HNFA (hepatocyte nuclear factor 4A), SUR1 (sulfonylurea receptor 1), Kir6.2 (inwardly rectifying potassium channel 6.2). Other abbreviations: OAA, oxaloacetate; PEP, phosphoenolpyruvate; α-KG, α-ketoglutarate; GAD, glutamic acid decarboxylase; GABA, γ-aminobutyrate, GHB, γ-hydroxybutyrate; SSA, succinic semialdehyde; Ins, insulin. Reprinted from Stanley CA, Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders, J Clin Endocrinol Metab, 2016, 101(3):815-826 by permission of Oxford University Press and Endocrine Society (31).

In neonates, hyperinsulinism may occur as a transient issue due to intrauterine factors, in association with recognized clinical syndromes, or may reflect genetic mutations in the pathway of insulin secretion (Figure 5). In older children, acquired forms of hyperinsulinism, including insulinoma, autoimmune causes, and medications are more common. However, late presentation of monogenic forms of hyperinsulinism remain possible (Table 5).

Table 5. Classification of Hyperinsulinism Disorders in Infants and Children.
Acquired neonatal HI	Risk Factors	Clinical features
	Maternal diabetes, including gestational diabetes	Large for gestational age (LGA) Cardiac Hypertrophy
	Perinatal stress-induced HI	Small for gestational age (SGA) Maternal hypertension, pre-eclampsia, eclampsia
	Maternal drugs	Ritodrine, sulfonylurea, high GIR during labor etc.
Acquired non-neonatal HI	Categories	Clinical features
	Neoplastic HI	Insulinoma (sporadic or MEN1)
	Surgically induced HI	Post-gastric bypass, post-fundoplication for gastro-esophageal reflux (NIPHS: non-insulinoma pancreatogenous hypoglycemia syndrome)
	Drug-induced HI	Antidiabetic medications (Insulin, sulfonylureas)
	Autoimmune HI (anti-insulin or insulin receptor-activating antibodies)	Spontaneous or associated with drugs or viral infections Hirata's disease (Insulin Autoimmune Syndrome: anti-insulin antibodies post sulfhydryl medications: methimazole, carbimazole, alpha-lipoic acid and post measles virus, mumps virus, rubella virus, varicella zoster virus, coxsackie B virus and hepatitis C virus)
Genetic HI: Isolated HI	Histology	Genes
	Diffuse form	ABCC8, KCNJ11, GLUD1, GCK, HK1, HNF4A, HNF1A, HADH, SLC16A1, UCP2
	Focal form	Paternally inherited AR variants of ABCC8 or KCNJ11
	LINE- HI (Mosaic HI, Atypical HI)	Sporadic mosaic AD variants of ABCC8, GCK, and inappropriate expression of HK1
Genetic HI: Syndromic HI, select forms	Syndrome	Gene
	Beckwith-Wiedemann syndrome	Genetic or epigenetic changes of imprinted region 11p15.5 (especially paternal UPD11p), mutations of imprinting control genes Paternal UPD11p combined with paternal recessive ABCC8 or KCNJ11 mutation
	Kabuki syndrome	KMT2D, KDM6A (usually mosaic)
	Turner syndrome	Mosaic partial or complete X chromosome monosomy
HI mimickers: Hypoinsulinemic hypoketotic hypoglycemia
Autoimmune mimicker	Insulin resistance syndrome type B (anti-insulin receptor antibodies post viral infection (HIV, HTLV1, hepatitis C) or lymphoproliferative disease, or autoimmune disease)
Paraneoplastic secretion of pro-IGF2	Non-islets cells tumor hypoglycemia (NICTH, Doege-Potter syndrome)
Genetic disorders of insulin signaling	Mutations in AKT2, AKT3, PIK3CA, PIK3R2, CCND2, INSR
Fatty acid oxidation disorders	Abnormalities in the carnitine cycle, beta-oxidation, electron transfer and ketone synthesis.

Adapted from De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu JF, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TLS, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS. International Guidelines for the Diagnosis and Management of Hyperinsulinism. Horm Res Paediatr. 2023 (32).

Clinically, hyperinsulinism should be suspected when a higher than typical glucose infusion rate (GIR >8 mg/kg/minute) is required to maintain plasma glucose >70 mg/dL. Neonates with hyperinsulinism are often (but not always) born large for gestational age because insulin promotes fetal growth in utero.

Diagnosis is established by biochemical findings of inappropriate insulin action at the time of hypoglycemia (Table 6). These include inappropriately suppressed beta-hydroxybutyrate and free fatty acids, and a glycemic response to 1 mg intramuscular or intravenous glucagon administration (rise in plasma glucose >30 mg/dL within 40 minutes following glucagon administration) (33). Importantly, the diagnosis does not rest entirely on the presence or absence of detectable insulin and c-peptide levels at the time of hypoglycemia. Elevated insulin levels may not be observed in cases of HI if the laboratory specimen is hemolyzed (33), or when the plasma insulin concentration is below the detection threshold of the insulin assay utilized. Conversely, with improvements in assay sensitivity, plasma insulin may be reported as detectable in the absence of HI. Thus, accurate diagnosis of HI requires a comprehensive interpretation of biochemical markers of insulin action and does not rely solely upon an insulin level.

Table 6. Diagnostic Features of HI at the Time of Hypoglycemia (plasma glucose <50 mg/dL [2.8 mmol/L]).

Evidence of excessive insulin action at the time of hypoglycemia

Suppressed plasma β-hydroxybutyrate (< 1.8 mmol/L)

Suppressed plasma free fatty acids (< 1.7 mmol/L)

Inappropriately large glycemic response to glucagon (≥ 30 mg/dL [≥1.7 mmol/L])

Increased glucose infusion rate required to maintain euglycemia (above normal for age):

>8 mg/kg/min for neonates

>3 mg/kg/min for adults

Evidence of excessive insulin secretion/inadequate suppression of insulin secretion at the time of hypoglycemia (these are less definitive than evidence of excessive insulin action)

Plasma Insulin >1.25 μU/mL (8.7 pmol/L)*

C-peptide >0.5 ng/mL (> 0.17 nmol/L)*

*Note that these thresholds depend upon the assay utilized. Adapted from De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu JF, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TLS, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS. International Guidelines for the Diagnosis and Management of Hyperinsulinism. Horm Res Paediatr. 2023 (32).

Regardless of the etiology, prompt identification and treatment of hyperinsulinism is critical. Since insulin inhibits gluconeogenesis and ketogenesis, ketones and lactate are not sufficiently available as alternative fuels for the brain during hyperinsulinemic hypoglycemia. Consequently, the risk of brain injury is high. Initial management is thus to rapidly correct hypoglycemia via administration of IV dextrose bolus (200 mg/kg or 2 ml/kg D10%). Following this, continuous IV dextrose infusion should be started at a GIR of 4-8 mg/kg/min and quickly titrated (by 4 mg/kg/min if hypoglycemia persists on a GIR of 8 mg/kg/min) as needed to maintain plasma glucose >70 mg/dL. Some infants with hyperinsulinism may require GIRs as high as 20-30 mg/kg/min to maintain euglycemia. Higher concentrations of dextrose (D20%-D50%) may be utilized via a central line to minimize fluid overload in these settings. Glucagon can be administered intramuscularly if IV access is lost, or unable to be obtained, as a temporizing measure to raise plasma glucose. Glucagon can also be administered as a continuous IV infusion (doses of 2-3 mcg/kg/day up to 10 mcg/kg/day, or alternatively, infusion of 1 mg/day) to permit lowering of GIR (and thus fluid load) in cases where fluid overload is a concern. In general, use of glucagon may be associated with up to 50% reduction in the GIR (34).

MONOGENIC FORMS OF HYPERINSULINISM

The incidence of congenital hyperinsulinism caused by genetic defects in the insulin secretion pathway is estimated at 1 in 40,000 live births (35). A higher incidence, of up to 1 in 2,500 births, has been described in Saudi Arabia, in a region of Finland, and in some of the Ashkenazi-Jewish population. Congenital hyperinsulinism can be classified by genetic etiology, histology, and response to treatment with diazoxide. At least 11 different monogenic causes have been identified. A high likelihood that yet undiscovered genetic etiologies exist is suggested by the low rate (approximately 50%) of mutation detection in patients with diazoxide-responsive forms of hyperinsulinism (36).

First-line treatment for congenital hyperinsulinism is diazoxide, a K_ATP channel opener that inhibits insulin secretion. Diazoxide therapeutic dose range is 5-15 mg/kg/day. Response to diazoxide should be assessed after 5 days of treatment with a carefully monitored fast (safety fast, Table 7). Responsiveness to diazoxide is both of clinical and diagnostic value (Figure 6). It is defined by maintenance of plasma glucose >70 mg/dL over the fasting period (Table 7) or a rise in beta-hydroxybutyrate >2 mmol/L prior to decline in plasma glucose below 50 mg/dL (37). Side effects of diazoxide include hypertrichosis (prevalence 30%), fluid overload — which may be complicated by pulmonary hypertension (prevalence 2-3%) — neutropenia and thrombocytopenia (prevalence 15%), and hyperuricemia (prevalence 5%) (38,39). To mitigate risks of fluid overload, empiric co-administration of a diuretic is recommended (40). Recommended surveillance on diazoxide includes echocardiogram, complete blood count with differential, electrolytes, and uric acid level at baseline and 5-7 days after diazoxide initiation. Following this, it is recommended to measure complete blood count with differential, electrolytes, and uric acid levels every 6 months (38-40).

Table 7. Safety/Cure Fasting Test Procedure

Have blood drawing IV line in place

Check glucose (POC meter) and beta-hydroxybutyrate every 2-3 hours until glucose <70 mg/dL; then every 2 hours until <60 mg/dL; then hourly until < 50mg/dL

When glucose <60mg/dL by POC meter, send specimen for laboratory confirmation of plasma glucose

Terminate fast when:

Plasma BOHB >2 mmol/L on two separate samples 1 hour apart, or

Plasma glucose <50 mg/dL, or

Duration of fasting

Safety fast: >9-12 hours in <1 month old, or >12 hours in 1 month-1 year old, or >18

hours in >1 year old

Cure fast: >18 hours in <1 year old, or >36 hours in 1-10 years old, or 72 hours in >10

years old

Notably, most children with hyperinsulinism due to mutations in genes encoding the K_ATP channel will not respond to diazoxide. Histologically, there are several forms of K_ATP channel hyperinsulinism including focal, diffuse and atypical. Many of these children will have a focal form of hyperinsulinism that can be cured by surgery (see below). In children with diazoxide-unresponsive hyperinsulinism, genetic testing that includes sequencing of K_ATP channel genes should be sent on DNA from the affected child and their parents simultaneously. This approach permits timely identification of children likely to have focal hyperinsulinism, and who can be cured by surgery. Sending the parental DNA with the child saves 1-2 weeks of time and many of the laboratories perform the testing free of charge if a mutation is found in the child in which diagnosing the parent of origin will change the management. In addition, rapid genetic testing with a turnaround time of 4-7 days is critical in the management of diazoxide-unresponsive hyperinsulinism because this quickly allows the physician to determine who should be referred to a multidisciplinary hyperinsulinism center for imaging with 18F-DOPA PET scan which can currently be used only under an investigational new drug license (IND) and is only available in several places in the country. Obtaining results of the patient and both parents within 7 days compared to 28-40 days if sent to a conventional genetic laboratory could save upwards of $100,000 to $200,000 and 21 days of hospital stay during which time the patient is at risk of severe hypoglycemia, development of feeding intolerance, line infections, and other iatrogenic complications of prolonged hospitalization.

Figure 6. HI Diagnostic and Treatment Algorithm. Once HI is diagnosed, effectiveness of diazoxide treatment needs to be assessed. Responsiveness to diazoxide is shown by demonstrating the ability to fast an age-appropriate interval (minimum 9 hours for neonate) with plasma glucose >70 mg/dL and/or generate beta-hydroxybutyrate >2 mmol/L prior to plasma glucose <50 mg/dL. For patients unresponsive to diazoxide, expedited genetic testing is obtained to differentiate diffuse and focal forms of HI. 18F-DOPA PET/CT is performed when genetic testing is suggestive of possible focal disease. For patients with diffuse, diazoxide-unresponsive disease, intensive medical therapy is initiated, with near-total pancreatectomy reserved for medically unresponsive cases. 18F-DOPA PET/CT 18-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography.

Second-line medical management options include somatostatin analogues – octreotide and the long-acting analog lanreotide - and enteral dextrose. Enteral dextrose is administered as a continuous infusion of 20% dextrose solution via nasogastric or gastrostomy tube (maximum enteral GIR 10 mg/kg/min). Octreotide is a short-acting somatostatin analogue administered multiple times per day subcutaneously (dose range: 2-20 mcg/kg/day, divided every 6-8 hours). Octreotide should not be used in children <2 months of age due to an association with fatal necrotizing enterocolitis. Lanreotide is used in children >1 year of age (administered as 60 mg injection monthly) (41). Several new therapies, including glucagon analogues, oral somatostatin analogues, insulin receptor modulators, and GLP-1 receptor antagonists, are under development (42).

In diffuse congenital hyperinsulinism cases that do not respond to medical treatment, near-total pancreatectomy is performed. Near-total pancreatectomy is palliative, not curative; significant hypoglycemia persists in up to 50% of children. Additionally, this procedure is complicated by development of exocrine pancreatic insufficiency and late-onset post-pancreatectomy diabetes.

K_ATP Hyperinsulinism (K_ATP HI)

The most common and severe form of congenital hyperinsulinism, K_ATP HI, is caused by inactivating mutations in ABCC8 or KCNJ11. Both located on chromosome 11p15.1, these genes each encode a subunit of the pancreatic beta-cell K_ATP channel. Inactivation of the K_ATP channel results in beta-cell depolarization (Figure 5), and inappropriate secretion of insulin. In addition to severe fasting hypoglycemia, K_ATP HI is characterized by protein-induced hypoglycemia mediated by GLP-1 receptor signaling (6).

K_ATP HI is histologically classified as diffuse, in which all beta-cells are affected, focal, in which a localized subset beta-cells are affected, or less commonly, atypical (also termed Localized Islet Nuclear Enlargement [LINE-HI]). Focal K_ATP HI results from a “two hit” mechanism involving paternal transmission of a recessive K_ATP HI mutation and a somatic loss of heterozygosity for the maternal 11p15 region yielding imbalanced expression of imprinted tumor suppressor genes (43). Dominant or recessive mutations in K_ATP HI genes cause diffuse K_ATP HI. Often, children with atypical histology (LINE-HI) do not have an identifiable mutation in standard sequencing of peripheral blood; however, low-level mosaic mutations are increasingly recognized as causative (44).

Infants with diffuse forms of K_ATP HI are often born large for gestational age and present with symptomatic hypoglycemia in the first few days of life. While infants with the focal form of K_ATP HI are more likely to have normal birth weight and present at an older age than those with diffuse disease, the two histologic forms are often indistinguishable in clinical practice (45). The recessive, focal, and atypical (LINE-HI) forms of K_ATP HI are usually not responsive to diazoxide. In contrast, dominant K_ATP HI may be diazoxide responsive due to retained partial function of K_ATP channels.

For infants with diazoxide-unresponsive hyperinsulinism, the goal is to identify those children with focal K_ATP HI since these children can be cured by surgery. Findings of a single recessive K_ATP mutation in the father, but not the mother, will have a 94% positive predictive value for focal hyperinsulinism (36) in the symptomatic infant. When suspected, 18-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) is used to localize the focal lesion and guide surgical excision (46,47). Surgical cure rates for focal hyperinsulinism exceed 95%, when performed by experienced surgeons at a multidisciplinary hyperinsulinism center (48).

For patients with diffuse K_ATP HI, intensive medical management is attempted, initially with continuous enteral dextrose (maximum enteral GIR 10 mg/kg/min). Octreotide can be added after 2 months of age (as above). Surgical management (near-total pancreatectomy with gastrostomy tube placement) is reserved for patients who fail to achieve adequate glycemic control with intensive medical therapy because this procedure is not curative and carries long-term risks of exocrine pancreatic insufficiency and insulin-dependent diabetes mellitus (45,49). Notably, regardless of initial treatment, the severity of hypoglycemia tends to improve with age in children with diffuse K_ATP HI. Determination of optimal management strategy thus depends on balancing short/intermediate-term risks of suboptimal hypoglycemia control and labor-intensive home management with potential further increased risk of long-term risk of adverse neurodevelopmental outcomes in the case of medical management versus inevitable post-pancreatectomy complications in the case of surgery. Management decisions are thus informed by the initial severity of hypoglycemia, responsiveness to intensive medical therapy, and the preferences and values of the child’s family. These children thus require specialized care and should be referred to a multidisciplinary hyperinsulinism center.

Glycemic status should be assessed in all children following pancreatectomy. Those children who do not require dextrose to maintain euglycemia postoperatively should undergo fasting study to demonstrate whether they are cured or need further medical management (Table 7) (32). Cure of HI can be demonstrated by the development of hyperketonemia (beta-hydroxybutyrate >1.8 mmol/L) prior to development of hypoglycemia (glucose <50 mg/dL).

Later in life, dysregulated insulin secretion in diffuse K_ATP HI may additionally manifest as gestational, and in some cases insulin-dependent, diabetes mellitus even in the absence of prior pancreatectomy. This finding has been observed both in dominant and recessive forms of diffuse K_ATP HI (50,51). Mechanisms underlying the switch from hypoglycemia in early life to hyperglycemia later on remain incompletely understood. Impaired glucose-stimulated insulin secretion has been implicated based upon findings of reduced first-phase and maximal glucose-stimulated insulin secretion during oral glucose tolerance testing in adults with dominant K_ATP (51), and reduced acute insulin response to graded IV glucose infusion in children with recessive K_ATPHI (50). Impaired insulin secretory response to glucose (beta-cell “glucose blindness”) has also been proposed to underlie progression from hyperinsulinemic hypoglycemia to hyperglycemia in maturity-onset diabetes of the young (MODY) type 1 and type 3 (discussed below) (52-54). In mouse models of K_ATPHI, increased beta-cell apoptosis has been observed prior to the development of hyperglycemia, suggesting that a progressive decline in beta-cell mass may also play a role (55).

GCK Hyperinsulinism (GCK HI)

Dominant activating mutations in the GCK gene (chromosome 7p13), encoding glucokinase, cause hyperinsulinism by increasing the affinity of glucokinase for glucose, thereby lowering the threshold for pancreatic beta-cell insulin secretion (Figure 5). Clinical phenotype is highly variable, even within the same family. Presentation ranges from severe hypoglycemia at birth with large for gestational age birth weight, to milder hypoglycemia detected in adulthood. Response to diazoxide is also variable. In severe cases, near-total pancreatectomy may be required.

HK1 Hyperinsulinism (HK1 HI)

The HK1 gene (chromosome 10q22.1) encodes hexokinase, which has a much higher affinity for glucose than glucokinase. Normally, expression of HK1 is suppressed in pancreatic beta-cells postnatally. Dominantly inherited variations in non-coding regions of the HK1 gene result in aberrant beta-cell expression of hexokinase. As a consequence, appropriate suppression of insulin secretion at low plasma glucose levels is impaired, resulting in hypoglycemia (56). The clinical phenotype is variable. Most affected individuals present in the first weeks of life, but delayed presentation is not infrequently reported. Severity ranges from severe symptoms at birth to mild symptoms detected only following identification of an affected relative. Response to diazoxide is similarly heterogeneous and some affected individuals have required pancreatectomy (56,57).

GDH Hyperinsulinism (GDH HI)

Dominant activating mutations in the GLUD1 gene (chromosome 10q23.2), encoding glutamate dehydrogenase (GDH), cause the hyperinsulinism hyperammonemia syndrome. Constitutively hyperactive GDH results in increased oxidation of glutamate to ammonia and alpha-ketoglutarate, the latter of which enters the citric acid cycle, thereby increasing the ATP-to-ADP ratio, triggering insulin secretion (58). Profound protein-induced hypoglycemia occurs because the amino acid leucine is potent allosteric activator of GDH (Figure 5).

Individuals with GDH HI typically have normal birth weight and later age of presentation (median age 4-5 months). In addition to fasting and protein-induced hypoglycemia, GDH HI is associated with an increased risk of epilepsy as well as higher rates of intellectual impairment, both of which appear to be independent of hypoglycemic neurological injury (59). Rates of learning and intellectual impairments have ranged from 37-77% in studies of children with GDH HI in which these outcomes were measured (59-61). The characteristic seizure type observed is generalized, atypical absence (62). These seizures occur in the setting of euglycemia and notably are distinct from the focal-onset seizures that may occur following hypoglycemic brain injury (62). Aberrant GDH activity in the central nervous system, and resultant altered glutamate balance, have been hypothesized to underlie these neurological differences. However, the mechanism by which these deficits occur has not yet been definitively established.

Persistent hyperammonemia (ammonia elevation 2-5 the normal range) due to GDH overactivity in the kidney is a cardinal feature but appears to be clinically asymptomatic (63). Importantly, affected individuals do not manifest symptoms of acute hyperammonemia encephalopathy (lethargy, headache, vomiting) as do children with urea cycle disorders. Plasma ammonia levels are not influenced by dietary protein load, nor are they lowered by typical therapies for hyperammonemia (sodium benzoate, N-carbamyl-glutamate) (64). The finding of hyperammonemia is thus useful in establishing a clinical diagnosis of GDH HI. However, once identified, plasma ammonia levels do not require serial monitoring or targeted intervention.

Hypoglycemia in GDH HI is usually well-managed with diazoxide and dietary modification. While dietary protein should not be restricted, it is imperative that affected individuals consume carbohydrate prior and concomitant to protein intake. Most individuals with GDH HI will respond to a 2:1 gram ratio of carbohydrates to protein to prevent protein induced hypoglycemia but some will need ratios of 3:1. Typically breast milk or formula milk will not trigger hypoglycemia, but once solid foods are introduced, especially meats, care must be taken to prevent protein induced hypoglycemia. The cardinal warning sign of this is patients in whom glucose control was adequate including fasting overnight but who suddenly develop post prandial hypoglycemia.

A formalized protein challenge test (Table 8) may be performed to evaluate adequacy of treatment in individuals with GDH HI. This test is also helpful to evaluate protein sensitivity in K_ATP HI, HADH HI (below), and congenital HI with negative genetic testing. A drop in the plasma glucose of more than 10 mg/dL or below 70 mg/dl is considered an abnormal result (evidence of protein sensitivity). Because this test must be done following a 3-4 hour fast to ensure the glucose levels are stable prior to starting the test it can only be done in patients whose fasting glucose is controlled. Patients who are very protein sensitive may drop the plasma glucose in the first 15-60 minutes.

Table 8. Oral Protein Challenge Test Procedure

Make patient NPO for food and carbohydrate containing fluids for 3-4 hours pre procedure

Insert peripheral intravenous line and have dextrose 10% available for emergency use

Measure baseline glucose and insulin

Administer 1g/kg of food protein PO over 10-15 minutes. Alternatively, protein powder may be used (administered via nasogastric or gastrostomy tube).

Measure glucose and insulin every 30 minutes for 3 hours

If the plasma glucose drops to <60 mg/dL terminate test with carbohydrate drink of 15 g or intravenous push of 200 mg/kg (2ml/kg D10%)

HADH Hyperinsulinism (HADH HI)

Inactivating mutations in HADH (chromosome 4q25) cause a rare, autosomal recessive form of diazoxide-responsive hyperinsulinism. The HADH gene encodes short chain 3-hydroxyacyl-coenzyme A dehydrogenase (HADH, also referred to as SCHAD) which inhibits GDH and also plays a role in mitochondrial fatty acid beta-oxidation. Loss of normal GDH inhibition results in a similar phenotype as GDH HI with fasting and protein-induced hyperinsulinemic hypoglycemia, but without hyperammonemia. Elevated levels of 3-hydroxybutyryl-carnitine in plasma and 3-hydroxyglutaric acid in urine may serve as clues to the diagnosis in some but are not universally observed (65). Treatment is with diazoxide and dietary modification as in GDH HI.

HNF1A and HNF4A Hyperinsulinism (HNF1A and HNF4A HI)

Dominant inactivating mutations in the genes encoding transcription factors hepatocyte nuclear factor 1 alpha and hepatocyte nuclear factor 4 alpha, cause both hyperinsulinism and maturity-onset diabetes of the young (MODY3 and MODY1, respectively). Affected infants are often born large for gestational age. Severity of hyperinsulinism varies from transient neonatal hypoglycemia to persistent hyperinsulinism requiring treatment into school age (66). The p.Arg63Trp HNF4A mutation is associated with an additional extra-pancreatic phenotype of renal Fanconi syndrome and hepatic dysfunction (66,67). Response to diazoxide is often robust. Establishing the diagnosis has important implications both for the affected child, who requires ongoing surveillance after hyperinsulinism resolution due to the risk of developing diabetes later in life, and for family members carrying the mutation who could benefit from early diagnosis of diabetes or targeted therapy (i.e., sulfonylureas).

MCT1 Hyperinsulinism (MCT1 HI)

Dominant mutations in the non-coding regions of SLC16A1 (chromosome 1p13.2), encoding monocarboxylate transporter 1 (MCT1), result in exercise-induced hyperinsulinism (68). MCT1

catalyzes transport of monocarboxylates, such as lactate, pyruvate and beta-hydroxybutyrate, across the plasma membrane. Normally, MCT1 expression is disallowed in pancreatic beta cells. Promoter-activating mutations induce inappropriate MCT1 expression in beta cells, permitting uptake of pyruvate during exercise when plasma pyruvate is elevated. Pyruvate metabolism leads to increased ATP production, and resultant pyruvate-stimulated (exercise-induced) insulin release despite hypoglycemia (69). Response to diazoxide is variable, and carbohydrate loading prior to exercise is recommended to control hypoglycemia. Nonfunctional variants in the coding regions of SLC16A1 cause ketotic hypoglycemia (see section on Pathologic Ketotic Hypoglycemia and Ketone Utilization and Transport Defects). This is a very uncommon clinical entity.

UCP2 Hyperinsulinism

Dominant inactivating mutations in the UCP2 gene (chromosome 11q13.4) encoding uncoupling protein 2 (UCP2) have been associated with a diazoxide-responsive form of hyperinsulinism (70). Following initial reports, the prevalence of UCP2 variants in the general population has been found to be high, raising the role of UCP2 variants as a monogenic cause of hyperinsulinism into question (71).

SYNDROMIC HYPERINSULINISM

Hyperinsulinism is a feature of several recognized syndromes. These include the overgrowth syndromes: Beckwith-Wiedemann, Sotos, Simpson-Golabi-Behmel, and Perlman syndromes, as well as Kabuki syndrome, Turner syndrome, Tyrosinemia type 1, Usher syndrome type 1C (in which there is contiguous gene deletion at 11p15.2 including ABCC8), Rubinstein-Taybi syndrome, and several congenital disorders of glycosylation, among others (72). Beckwith-Wiedemann, Kabuki, and Turner syndromes are most frequently observed (72), and are discussed in the sections below along with the congenital disorders of glycosylation associated with hyperinsulinism.

Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome, caused by genetic or epigenetic changes on chromosome 11p15.5, is an overgrowth disorder with classical features of macrosomia, macroglossia, hemihypertrophy, abdominal wall defects, and embryonal tumors. Due to the varying molecular etiologies, and the postzygotic nature of the epigenetic changes in most cases, affected children can present with a variety of clinical features along a spectrum of “classic” to “atypical” to isolated lateralized overgrowth (73). Hyperinsulinism occurs in approximately 50% of all cases and is the presenting symptom of Beckwith-Wiedemann syndrome in 16% of cases (73). While the hyperinsulinism is typically mild in severity and resolves within the first days to years of life, in roughly 5% of cases (particularly cases due to paternal uniparental isodisomy for chromosome 11p), it can be severe and persistent, requiring pancreatectomy (74). Hyperinsulinism persisting beyond the first week of life is considered a cardinal feature of Beckwith-Wiedemann syndrome (75). Thus, all patients presenting with hyperinsulinism should be evaluated for subtle limb asymmetry and other suggestive features (Table 9) (75). Molecular testing for investigation of Beckwith-Wiedemann syndrome should be considered in these patients. Additional suggestive features in the context of a hyperinsulinism evaluation include marked pancreatic enlargement and diffuse 18-F-DOPA uptake, or alternatively, very large areas of focal 18-F-DOPA uptake, on PET/CT imaging (76). In the latter setting, areas of increased involvement on PET imaging may be used to tailor the extent of pancreatectomy. Histologically, resected pancreatic tissue in cases of Beckwith-Wiedemann syndrome are characterized by a dramatic increase in endocrine tissue relative to the amount of exocrine tissue, often with a loss of the normal lobular architecture, and prominent trabecular arrangement of endocrine cells (76,77). Since the genetic or epigenetic changes causing Beckwith-Wiedemann syndrome usually occur during embryonal development, yielding a mosaic pattern, failure to detect these changes in blood (leukocytes) is thus not conclusive, and additional testing (e.g., from skin or pancreas) may be required.

Table 9. Clinical Features of Beckwith-Wiedemann Syndrome (BWS)

Cardinal features (2 points per feature)

Macroglossia

Exomphalos

Lateralized overgrowth

Multifocal and/or bilateral Wilms tumor or nephroblastomatosis

Hyperinsulinism (lasting >1 week and requiring escalated treatment)

Pathology findings: adrenal cortex cytomegaly, placental mesenchymal dysplasia or pancreatic adenomatosis

Suggestive features (1 point per feature)

Birthweight >2SDS above the mean

Facial nevus simplex

Polyhydramnios and/or placentomegaly

Ear creases and/or pits

Transient hypoglycemia (lasting <1 week)

Typical BWS tumors (neuroblastoma, rhabdomyosarcoma, unilateral Wilms tumor, hepatoblastoma, adrenocortical carcinoma or phaeochromocytoma)

Nephromegaly and/or hepatomegaly

Umbilical hernia and/or diastasis recti

Score interpretation

≥4: Clinical diagnosis of classical BWS. Genetic testing for investigation and diagnosis of BWS recommended. Note that clinical diagnosis does not require the molecular confirmation of an 11p15 anomaly.

≥2: Merit genetic testing for investigation and diagnosis of BWS

Patients with a score of ≥2 with negative genetic testing should be considered for an alternative diagnosis and/or referral to a BWS expert for further evaluation

Adapted from Brioude F. et al, Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229-249 (75).

Kabuki Syndrome

Kabuki syndrome is caused by dominant mutations in KMT2D (~75% of cases) or X-linked mutations in KDM6A. While the true incidence of hyperinsulinism in Kabuki syndrome is unknown, it is increasingly recognized as a feature of this disorder, often as the presenting feature (78). Clinically, affected children have distinctive facial features – long palpebral fissures with eversion of the lateral lower eyelid, arched eyebrows, and prominent ears – skeletal anomalies, intellectual disability, and post-natal growth deficiency. Congenital heart defects, genitourinary and gastrointestinal anomalies, and immune dysfunction may also be observed. Haploinsufficiency of KDM6A has been proposed as the pathophysiologic mechanism of hyperinsulinism, and human islets treated with KDM6A inhibitor demonstrate abnormal insulin secretion (79). Most cases are diazoxide-responsive. Somatostatin analogues have been used with success in cases where diazoxide was contraindicated due to cardiac comorbidity.

Turner Syndrome

The incidence of hyperinsulinism in infants with Turner syndrome is roughly 50 times that expected in the general population (79). As in Kabuki syndrome, haploinsufficiency of KDM6A (located on X chromosome) has been proposed as the underlying mechanism. Many, but not all, children with Turner syndrome and associated hyperinsulinism are diazoxide-responsive.

FOXA2 Hyperinsulinism

Inactivating mutations in FOXA2, encoding the transcription factor forkhead box A2 (Foxa2), have been associated with a clinical phenotype of congenital hyperinsulinism, hypopituitarism, and endodermal-derived organ anomalies (80,81). Treatment with both pituitary hormone replacement and diazoxide has been reported to be effective.

Congenital Disorders of Glycosylation

Monogenic defects in the synthesis of oligosaccharides are responsible for congenital disorders of glycosylation (CDG), over 100 of which have been identified to date. Endocrine dysfunction (including growth failure, hypothyroidism, hypogonadotropic hypogonadism) is common to many congenital disorders of glycosylation because both endocrine peptides and their receptor targets are glycosylated. These disorders have a wide phenotypic spectrum, and three have been associated with hyperinsulinism: phosphomannomutase 2 deficiency (PMM2-CDG, formerly CDG-1a), mannose phosphate isomerase deficiency (MPI-CDG, formerly CDG-1b), and phosphoglucomutase 1 deficiency (PGM1-CDG, formerly CDG-1t, also formerly referred to as GSD XIV). PMM2-CDG is the most common congenital disorder of glycosylation. Hyperinsulinism in PMM2-CDG has been proposed to result from impaired function of beta-cell K_ATP channels and most cases have been diazoxide-responsive (82). MPI-CDG predominantly manifests with gastrointestinal and hepatic involvement (protein losing enteropathy, liver dysfunction and fibrosis), and hyperinsulinemic hypoglycemia. MPI-CDG is treated with mannose, however hyperinsulinism-specific therapies (e.g., diazoxide) may also be required to adequately manage hypoglycemia (83). PGM1 catalyzes the interconversion of G-1-phos and G-6-phos and is thus involved in glycogenesis, glycogenolysis, and gluconeogenesis. Both fasting ketotic hypoglycemia, due to the role of PGM1 in these metabolic pathways, and post-prandial hyperinsulinemic hypoglycemia, due to a lowered threshold for glucose-stimulated insulin secretion, are observed in PGM1-CDG. Thus, this condition mimics GSD 0 and should be considered in that differential diagnosis. Diagnosis can be established by biochemical or molecular testing. Biochemical methods include analysis of serum transferrin glycoforms (also termed carbohydrate-deficient transferrin analysis) by isoelectric focusing or by mass spectroscopy to determine the number and presence of incomplete sialylated N-linked oligosaccharide residues linked to serum transferrin (84). If biochemical testing is not suggestive of a particular CDG, molecular testing approaches include multigene panels or more comprehensive genomic (whole exome, whole genome) testing.

TRANSIENT AND PERINATAL STRESS-INDUCED HYPERINSULINISM

Transient hyperinsulinism occurs secondary to maternal factors, most commonly gestational diabetes mellitus. In uncontrolled gestational diabetes, hyperglycemia induces fetal hyperinsulinism resulting in macrosomia and hypoglycemia following delivery. Transient hyperinsulinism can also result from maternal use of medications affecting glucose homeostasis, including hypoglycemic agents (e.g., oral sulfonylureas), terbutaline, or propranolol. Hyperinsulinism due to these factors resolves within the first days of life. Resolution can be confirmed by performing a 6-9 hour fast and demonstrating the baby can maintain plasma glucose >60-70 mg/dL throughout. If hyperinsulinism persists beyond 5-7 days of life alternate causes should be sought, particularly perinatal stress-induced hyperinsulinism (see below).

Perinatal factors are also associated with development of perinatal stress-induced hyperinsulinism (PSHI), which has a more prolonged course than transient hyperinsulinism. Neonates with perinatal complications such as birth asphyxia, maternal preeclampsia, prematurity, intrauterine growth retardation, or other peripartum stress may develop PSHI. As previously noted, fetal hypoxia results in decreased trafficking of K_ATP channels to the beta-cell membrane, decreasing the threshold for insulin secretion (23,85). Hyperinsulinism spontaneously resolves within weeks to months as beta-cell insulin regulation normalizes. Median age of resolution is six months. By definition, PSHI resolves by one year of age. PSHI typically responds to treatment with diazoxide, typically at doses on the lower end of the therapeutic range (5-7.5 mg/kg/day). Rates of adverse effects of diazoxide may be higher in children with PSHI, and empiric initiation of diuretic and close monitoring are paramount (39). Given these factors, it is recommended to start with a diazoxide dose of 5 mg/kg/day, initially, and to increase the dose after 3-5 days of treatment if adequate response is not achieved. Timing of initiating diazoxide in cases of suspected PSHI should be tailored to the infant’s overall clinical course. For infants with ongoing intensive care nursery needs (e.g., intubation, warming bed, parenteral feeds), plasma glucose support with IV or enteral dextrose-containing fluids offers optimal initial management, especially as some infants will demonstrate resolution of hyperinsulinism before they are otherwise prepared for hospital discharge. In these cases, repeat fasting evaluation should be performed prior to discharge to assess for resolution versus need for initiation of targeted treatment. As above, in these at-risk infants in whom hypoglycemia is considered likely to resolve within a short time, resolution can be confirmed by performing a 6-9 hour fast and demonstrating the baby can maintain plasma glucose >60-70 mg/dL throughout. Diazoxide should be initiated for infants approaching discharge in whom hyperinsulinemic hypoglycemia has not yet resolved, and safety fast (Table 7) should be performed to confirm adequate diazoxide efficacy. While the diagnosis of PSHI may be suspected by the clinical history, it is established only when hyperinsulinism resolution is confirmed by a repeat fasting test after treatment has been discontinued, cure fast (Table 7).

ACTIVATING MUTATIONS IN THE INSULIN SIGNALING PATHWAY

Activating mutations in insulin signaling pathway genes, including AKT2, AKT3, and PIK3CA, cause hypoglycemia with biochemical findings of inappropriate insulin action, but with low or absent plasma insulin levels (86). Asymmetric somatic overgrowth may serve as a clinical clue to the diagnosis. Frequent feedings or continuous enteral dextrose are effective treatments.

ACQUIRED FORMS OF HYPERINSULINISM

Insulinoma

Insulinomas are pancreatic neuroendocrine tumors. The incidence of pediatric insulinoma is unknown, however, these lesions are less common in children than in adults (1-3 cases per million per year) and are thus exceedingly rare. While most pediatric cases present in adolescence, presentation as young as 2 years of age has been described.

Insulinomas are typically benign, solitary lesions. They can occur sporadically, or in association with multiple endocrine neoplasia, type 1 (MEN1). The frequency of MEN1 mutations in children with insulinoma has been reported to range 26-42% (87,88), which is higher than that in adults (5-10% in adults) (89). Clinically, insulinomas typically manifest with recurrent episodes of fasting hypoglycemia associated with neuroglycopenic symptoms. Weight gain is commonly noted at presentation, and occurs due to increased carbohydrate intake to treat symptoms of hypoglycemia (88). Notably, however, hypoglycemia unawareness is common. This is because repeated and prolonged hypoglycemia episodes can both decrease the counter regulatory hormonal response to hypoglycemia and induce unawareness of the autonomic and neuroglycopenic symptoms of hypoglycemia (90). Consequently, delays in establishing the diagnosis and initial misdiagnosis with neurologic and psychiatric disorders are not uncommon (91).

Suppressed beta-hydroxybutyrate, free fatty acids, and IGF-BP1, with inappropriately elevated proinsulin, insulin, and c-peptide levels at the time of hypoglycemia are consistent with the diagnosis. However, these biochemical findings do not differentiate insulinoma from sulfonylurea ingestion or congenital hyperinsulinism. Consequently, surreptitious use of insulin secretagogues (discussed in the section Exogenous hypoglycemia below) must be excluded in all suspected cases of insulinoma. Once the diagnosis is made, localization of the insulinoma is critical to direct the definitive treatment, surgery. Various imaging modalities have been used, including endoscopic ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), single-photon emission CT (SPECT), positron emission tomography (PET) and intraoperative ultrasound, each with variable sensitivity. The addition of GLP-1 receptor agonists (exendin-4) has increased the sensitivity of nuclear imaging modalities for detecting insulinomas, and exendin-4 PET/CT appears to be more sensitive than exendin-4 SPECT/CT (92). Historically, arterial calcium stimulation with venous insulin sampling was used, however, these invasive procedures have become less common with improvements in the imaging modalities available. Insulinomas are typically small lesions measuring <1 cm, and multiple lesions may be present. Preoperative localization can be challenging, and use of multiple imaging modalities may be required.

Diazoxide may be effective treatment in patients awaiting surgery or for whom the lesion cannot be localized. Surgical excision is curative, and prognosis is generally excellent. Genetic testing for MEN1 should be conducted in all patients, and appropriate screening should be initiated if a mutation is found. Insulinomas may be recurrent, with higher risk of recurrence in those with MEN1. For more information on histopathology, risks of malignancy, and suggested follow up protocols see the chapter entitled “Insulinoma” in the Diffuse Hormonal Systems and Endocrine Tumor Syndromes section of Endotext (93).

Autoimmune Hypoglycemia

Autoimmune hypoglycemia may result from the development of antibodies to insulin, referred to as Hirata disease, or to the insulin receptor. Onset may be triggered by viral infection or medication in a susceptible individual, and association with specific HLA haplotypes has been reported. Biochemically, plasma beta-hydroxybutyrate and free fatty acids are inappropriately low at the time of hypoglycemia, and c-peptide is suppressed. When autoimmune hypoglycemia occurs due to antibodies to insulin, plasma insulin levels may be very high (>1000 pmol/L), due to interference of insulin antibodies with the assay. Detection of insulin antibodies can confirm the diagnosis in patients naïve to exogenous insulin, which must be excluded. Autoimmune hypoglycemia is a spontaneously remitting condition. Various immune modulating treatments, including glucocorticoids, plasmapheresis, intravenous immunoglobulin, and rituximab have been utilized. A comparison of the different therapeutic approaches has not been conducted, owing to the rarity of this condition and its self-resolving course.

Post-prandial Hypoglycemia (Late Dumping Syndrome)

Post-prandial hypoglycemia (late dumping syndrome) occurs due to disrupted gastric motility, most commonly as a consequence of gastrointestinal surgery. In children, fundoplication surgery is implicated most frequently, whereas in adults, bariatric surgery is the most common cause. Hypoglycemia usually develops 1-3 hours after a meal, and results from imbalance between glucose absorption and insulin secretion. Rapid gastric emptying and intestinal absorption of carbohydrate, result in early hyperglycemia and exaggerated GLP-1 secretion, both of which trigger an exaggerated insulin response (94). The diagnosis can be confirmed by serial monitoring of insulin and glucose following feeding or with formal mixed meal tolerance testing. Fasting studies may be required to fully distinguish fasting hypoglycemia from post-prandial hypoglycemia (which may be comorbid in some patients). When conducting fasting studies in children with risk factors for (gastrostomy tube placement, Nissen fundoplication, esophageal or ileal surgery), or suspected, post-prandial hypoglycemia, it is important to slowly taper off feeds to avoid confounding of the fasting tolerance assessment by “dumping.” Treatment is often dietary manipulation. Decreasing the volume or rate of feeding, tapering the rate of feeding prior to stopping, increasing dietary fat, and decreasing simple carbohydrates may all be helpful. In older children, acarbose, which acts to slow carbohydrate digestion, has been used successfully. The efficacy of these approaches should be confirmed by repeat serial monitoring of glucose following at least two feeds to ensure plasma glucose is maintained within target range. In some cases, continuous enteral feeds, or enteral dextrose may be required. Typical treatments for genetic forms of HI such as diazoxide or octreotide generally have been unsuccessful. However, some of the novel therapies for HI under development (42,95), are also being studied in post bariatric surgery hypoglycemia.

Exogenous

Exogenous, factitious, and drug-induced hypoglycemia all refer to hypoglycemia that results from the use (intentional or accidental) of insulin or insulin secretagogues. Clinical clues to the diagnosis may include unusual or inconsistent histories, such as severe, recurrent hypoglycemia without typical precipitating factors (e.g., fasting, illness), or access to antidiabetic agents. Biochemical findings of elevated plasma insulin with suppressed c-peptide (or an insulin to c-peptide molar ratio >1) confirm exogenous insulin administration. Various insulin assays differ in their sensitivity to detect insulin analogs, so it is important to understand the detection abilities – and limitations – of the assay used. Failure to do so may result in incorrectly excluding the diagnosis of exogenous insulin administration. Information on the cross-reactivity of commercially available insulin formulations with the ordered insulin assay is available on the test information page of most laboratories and can also be requested. For example, currently, cross-reactivity of most insulin assays with glulisine is very low (96). When clinical suspicion is high, sending specimens for testing using different immunoassays with different insulin formulation cross-reactivity profiles may be helpful. In contrast, insulin secretagogues (e.g., sulfonylureas, meglitinides, GLP-1 receptor agonists) stimulate both insulin and c-peptide secretion. Consequently, the biochemical evaluation of hypoglycemia due to insulin secretagogue use may be indistinguishable from that of insulinoma. Specialized toxicology panels, including measurement of plasma or urine sulfonylureas, may be required to confirm the diagnosis. A high index of suspicion, and knowledge of hypoglycemia agents available in the home can help guide the evaluation. As with exogenous insulin administration, the laboratory evaluation is subject to pitfalls in sensitivity and interpretation, and consultation with the laboratory is recommended (97).

Hypoglycemia Due to Growth Hormone and Cortisol Deficiencies

Deficiencies in the counter regulatory hormones, growth hormone and cortisol – either in isolation, or more commonly, in combination – cause hypoglycemia. Growth hormone acts to stimulate lipolysis and decrease peripheral glucose uptake. Cortisol stimulates gluconeogenesis and release of gluconeogenic substrates, including alanine, from muscle. Although secretion of both growth hormone and cortisol is triggered by falling plasma glucose, findings of a single low growth hormone or cortisol level at the time of hypoglycemia has poor specificity for deficiency of either hormone (18,19). Stimulation testing may be needed to confirm the diagnosis.

In the older child, hypoglycemia due to growth hormone and/or cortisol deficiency is ketotic. However, in neonates, the biochemical picture may mirror that of hyperinsulinism due to both inappropriate conservation of glycogen reserves during hypoglycemia and immature ketogenesis at this age.

HYPOPITUITARISM

Hypopituitarism may be congenital or acquired. Congenital hypopituitarism may result from malformation of the hypothalamus and pituitary (e.g., holoprosencephaly, septo-optic dysplasia) or from mutations in transcription factors vital for normal hypothalamic-pituitary development (see the chapter entitled “Genetic Etiology of Congenital Hypopituitarism” in the Pediatric Endocrinology section of Endotext (98)). As discussed above, mutations in FOXA2cause both hypopituitarism and hyperinsulinism. Acquired hypopituitarism may develop following trauma, infection, tumor, intracranial surgery, or radiation. In neonates, hypoglycemia is often a presenting feature of panhypopituitarism. Other clinical clues in neonates include unconjugated hyperbilirubinemia, nystagmus, midline developmental defects (e.g., cleft lip and palate), and in males, micropenis or smaller than average penis. An MRI of the hypothalamic-pituitary region is essential and often reveals an ectopic “bright spot” indicating disruption of the normal descent of the neurohypophysis with interruption of hypothalamic releasing factors that regulate hormone secretion. In such cases, prolactin concentration may be elevated, whereas GH, TSH and ACTH are suppressed. In older children, the diagnosis may be suspected based upon clinical history, growth failure, or neuroimaging findings. Hypoglycemia is found more commonly in neonates with multiple pituitary hormone deficiencies compared to isolated growth hormone deficiency and therefore careful consideration of multiple hormonal deficiencies must be given when growth hormone deficiency is found to be the cause of hypoglycemia in neonates (99). Hypoglycemia is treated by replacement of the deficient hormones. From a practical aspect some neonates and infants will need a higher-than-expected dose of cortisol replacement and may even need growth hormone treatment divided twice daily. A safety fast (Table 7) should be performed prior to discharge to ensure the therapy is effective.

ISOLATED GROWTH HORMONE DEFICIENCY

Growth hormone deficiency has an estimated prevalence of between 1:4,000-1:10,000. Growth failure is the most common presenting feature, but this typically does not manifest until after the first year of life. Other clinical clues include midface hypoplasia and altered body composition with truncal adiposity. Most cases of isolated growth hormone deficiency are idiopathic. Genetic, anatomic, and acquired causes are detailed in the chapters entitled “Disorders of Growth Hormone in Childhood” and “Genetic Etiology of Congenital Hypopituitarism” in the Pediatric Endocrinology section of Endotext (98,100). Growth factors (IGF-1 and IGFBP-3) are low for age and bone age is delayed. The diagnosis is confirmed via stimulation testing. Treatment is with recombinant growth hormone. Importantly, depending on the underlying etiology, there is the potential for other pituitary hormone deficiencies to develop over time. Periodic screening of pituitary function is thus recommended.

ISOLATED CORTISOL DEFICIENCY

Cortisol deficiency may result either from defects in the ACTH signaling pathway or from congenital (e.g., congenital adrenal hyperplasia or hypoplasia) or acquired (e.g., bilateral adrenal hemorrhage) defects in adrenal steroidogenesis. Isolated ACTH deficiency is extremely rare. Several genetic etiologies have been described to date, including mutations in TBX19, POMC, PCSK1, and NFKB2 (see the chapter entitled “Genetic Etiology of Congenital Hypopituitarism” the Pediatric Endocrinology section of Endotext (98)). Of these, mutations in TBX19 are most frequently detected. Affected neonates universally present with severe hypoglycemia, often with hypoglycemic seizures. The mortality rate is up to 25%. In contrast to isolated ACTH deficiency, children with adrenal insufficiency due to ACTH resistance or primary adrenal disorders will have elevated plasma ACTH levels and associated skin hyperpigmentation. Primary disorders of the adrenal gland may also manifest with hyponatremia, hyperkalemia, and/or ambiguous genitalia. Congenital adrenal hyperplasia, and other disorders of the adrenal gland are detailed in the chapter entitled “Congenital Adrenal Hyperplasia” in the Adrenal Disease and Function section of Endotext (101). Treatment is with cortisol replacement. Initially, stress dose concentrations of hydrocortisone should be used.

GLYCOGEN STORAGE DISORDERS

The glycogen storage disorders (GSD) are a group of conditions in which there is either abnormal storage or release of glycogen resulting in hypoglycemia and acidosis. The acidosis may be lactic or ketoacidosis depending on the type of GSD. For the purpose of this discussion, we will include GSD 1 caused by glucose-6-phosphatase (G-6-Pase)deficiency as a glycogen storage disorder although the enzyme also represents the terminal step in gluconeogenesis. The GSDs may affect both liver and muscle glycogen storage and for this chapter we will focus on those with primarily liver expression, which are responsible for the hypoglycemic GSDs.

Under fed circumstances, excess glucose is converted into glycogen and stored in liver and muscle. Liver glycogen (but not muscle glycogen as muscle does not have G-6-Pase) later becomes available during fasting to provide glucose for metabolism in the brain and the glucose dependent tissues (red blood cells and proximal convoluted tubule of the kidney). Glucose is phosphorylated to G-6-Phos by glucokinase and then to Glucose-1-phosphate (G-1-Phos) by phosphoglucomutase. G-1-Phos is the starting point for glycogen synthesis by glycogen synthase (GSD 0, gene GYS2, inheritance autosomal recessive [AR]) to form chains with alpha 1-4 linkages. Branch points in these chains are formed by alpha 1-6 linkages approximately every 10 glucose units. During the early stages of fasting, glycogen is broken down by glycogen phosphorylase and then by glycogen debrancher enzymes. First the alpha 1-4 links are cleaved into G-1-Phos by glycogen phosphorylase (GSD VI, gene PGYL, inheritance AR) until 4 glucose units remain and then the debrancher transferase (GSD III, gene AGL, inheritance AR) moves the last 3 alpha 1-4 linked glucose over to another chain and then cleaves the alpha 1-6 branch point releasing a single glucose molecule. At this stage, the G-1-phos molecules are then converted to G-6-phos which then either undergoes glycolysis for energy or dephosphorylation by G-6-Pase (GSD 1, gene GCPC inheritance AR) and released into the blood stream as glucose.

Glycogen Storage Disease Type 0

GSD 0 is caused by deficiency of glycogen synthetase, which is encoded by the GYS2 gene on chromosome 12p12.2 and inherited in an autosomal recessive manner. The main biochemical manifestations are both fasting ketotic hypoglycemia and postprandial hyperglycemia and hyperlactatemia (102). This is due to the inability of the liver to store excess postprandial glucose resulting in hyperglycemia and glycosuria. The G-6-phos undergoes glycolysis to pyruvate and then lactate. Later as fasting progresses, there are no liver glycogen stores available, and when the glucose drops below 85 mg/dL, insulin secretion is switched off and early ketosis occurs resulting in ketotic hypoglycemia. This typically happens after 6-12 hours of fasting. Dependence on gluconeogenesis also results in over-utilization of protein, and protein deficiency is common.

Clinical features of GSD 0 may range from asymptomatic to recurrent episodes of ketotic hypoglycemia. Typically, as infants transition off nighttime feeding, episodes of fasting hypoglycemia with hyperketonemia occur. Patients may also present during mild gastrointestinal disorders with ketotic hypoglycemia. They have no hepatomegaly and a normal critical sample with elevated counter regulatory hormones, elevated free fatty acids and ketones. They may have short stature, a history of failure to thrive and hyperlipidemia. In the most severe end of the spectrum, they may present with seizures and developmental delay in addition to hypoglycemia after a very short duration fasting. The condition should be suspected in children with a history of recurrent ketotic hypoglycemia or post prandial hyperglycemia and fasting ketonemia.

Diagnosis is made by demonstrating shortened fasting tolerance with ketotic hypoglycemia (103) (typically <12 hours in children under 7 years of age and <18 hours in adolescents). In addition, an oral glucose tolerance test (OGTT) performed after an overnight fast using 1.75 g/kg up to 75 g (one of the few appropriate uses of the OGTT for diagnosis of etiology of hypoglycemia) will demonstrate postprandial hyperglycemia with elevated lactic acid. Finally, a fed (2 hours post meal) glucagon stimulation test will fail to show elevated glucose response to glucagon in the most severe cases but may cause an increase in milder cases. Once the clinical diagnosis is suspected, genetic testing for confirmation of diagnosis is strongly recommended rather than liver biopsy.

Treatment is avoidance of fasting (>3-4 hours), utilizing low glycemic index carbohydrate, and a high protein diet (2-3g/kg/day) during the day with meals and snacks to provide adequate amino acids for gluconeogenesis and overnight dextrose via gastrostomy tube or uncooked cornstarch (UCS) after age 1 year (1.5g/kg every 6 hours overnight). Glycosadeâ a soluble extended-release form of amylopectin cornstarch is available in the US for children over the age of 5 years and may be used in place of uncooked cornstarch. Early diagnosis and treatment may prevent the long-term complications of short stature and osteopenia from the recurrent keto- and lactic acidosis.

Glycogen Storage Disease Type I

This is the most severe of the GSDs and causes profound hypoglycemia because of impaired glycogenolysis and gluconeogenesis with lactic acidosis, hyperuricemia, and hyperlipidemia. Glycogen and triglycerides are stored in the liver resulting in massive hepatomegaly. Long-term consequences of GSD I include hepatic adenoma, renal Fanconi syndrome, renal failure, short stature, and osteoporosis. It occurs in approximately 1:100,000 births (104), and is caused by mutations in the gene for G-6-Pase, G6PC (GSD Ia), or G-6-P translocase 1, G6PT1 (GSD Ib). Under normal circumstances G-6-P translocase 1 transports G-6-Phos into the endoplasmic reticulum, G-6-Pase then converts G-6-P to glucose which is then transported out of the endoplasmic reticulum by GLUT-2 (hence the similarity of Fanconi Bickel syndrome caused by GLUT2 deficiency to GSD 1).

In the postprandial phase, glycogen stored in the liver is broken down to G-6-Phos and from here can enter 3 metabolic pathways: 1) G-6-Phos enters the pentose phosphate shunt resulting in formation of uric acid. 2) G-6-Phos undergoes glycolysis to form pyruvate and then to lactic acid (which is transported to brain and used as fuel for energy production). 3) G-6-Phos undergoes glycolysis and forms acetyl CoA which in turn is converted into malonyl CoA which inhibits carnitine palmitoyl-transferase I leading to decreased oxidation of fatty acids (impaired ketone body production) and increased formation of lipids causing hyperlipidemia. Thus, the cardinal biochemical features of GSD 1 occur (hypoglycemia, hyperuricemia, hyperlactatemia, and hypertriglyceridemia).

Clinical features in the newborn may include hypoglycemia with a good response to feeding, however because many newborns breast feed every 2 hours GSD 1 is rarely identified in the new-born period. Despite the occurrence of hypoglycemia, newborns are rarely diagnosed because many physicians erroneously believe that if the glucose responds to feeding then ongoing glucose testing is not needed. However, if the PES recommendations (21) are followed and persistent glucose levels <50 mg/dL are noted in the first 48 hours of life and <60 mg/dL beyond that, then investigations should be done to determine the etiology. A six-hour fasting study will identify these patients and indeed great care must be taken if suspected because glucose levels typically fall very quickly (2.5-3.5 hours after a feed) and fall deeply to the 20-30 mg/dl range. As infants get older and feeding intervals start to stretch out to >6 hours over night, significant hypoglycemia and lactic acidosis occurs and often the children present because of the tachypnea caused by the acid base disturbance, rather than the hypoglycemia. Neuroglycopenic symptoms are unlikely to occur due to the protective effect of lactate metabolism in the brain, but in circumstances of eating high carbohydrates and a rapid decline in glucose due to insulin release, the lactate levels may be low and the neuroprotective effects of lactate may not occur. In these circumstances seizures, coma, and sudden death may occur. Clinical features of undiagnosed GSD 1a include massive hepatomegaly, short stature, and failure to thrive. Biochemically, patients have high lactate levels (typically >5mmol/L) with hypoglycemia, low ketones, abnormal transaminases, high uric acid, and hypertriglyceridemia.

GSD Ib is caused by defects in the G6PT1 (also known as SLC37A4) gene and has all the same clinical findings as above but in addition has significant neutrophil dysfunction resulting in recurrent skin infections and later in life severe inflammatory bowel disease similar to Crohn disease. This form of GSD 1 represents about 10% of cases of GSD 1 and is an AR inherited condition with the gene found on chromosome 11q23. It is estimated to occur in 1:1,000,000 births.

It is important to note that untreated GSD 1a/b patients rarely present with neuroglycopenic symptoms of hypoglycemia because lactate may be used a fuel for the brain, and they also rarely present with neurogenic symptoms as they develop hypoglycemic unawareness. Thus, the hepatomegaly, short stature, intermittent tachypnea, and the finding of lipemic serum rather than symptoms of hypoglycemia raise the clinical suspicion.

Diagnosis of GSD Ia or Ib is made by finding the clinical features above and performing genetic testing for mutations in G6PC or G6PT1 to confirm the diagnosis.

Treatment is to prevent hypoglycemia by providing glucose every 2.5-3 hours in neonates using fructose/galactose free formula. In GSD 1, fructose and galactose cannot be converted to glucose due to deficiency of G-6-Pase and so if given will worsen lactic acidosis, hyperlipidemia, and hyperuricemia. The goal of treatment is to maintain the plasma glucose >75mg/dl which is the threshold for the secretion of counter-regulatory hormones that drive glycogenolysis and glycolysis to lactic acid. This can be achieved by frequent oral feeding in newborns, with continuous gastrostomy tube feeds overnight, and in older infants (>1 year), toddlers and children giving uncooked starch (UCS) 1- 1.5 g/kg every 3-6 hours including overnight. Glycosadeâ, an extended-release waxy maize cornstarch, can be used in older children to avoid overnight dosing with a duration of action of 6-8 hours, but is not recommended under 5 years of age. Placement of a gastrostomy tube to provide intra gastric glucose overnight often improves the family’s quality of life and the patient’s metabolic control. One caveat to feeding fast acting carbohydrates is that the insulin production suppresses glycogenolysis and production of lactic acid so treated patients have a higher risk of neuroglycopenic symptoms and brain damage from profound hypoglycemia without lactic acidosis if regular therapy is interrupted or delayed. Typical dietary treatments include 65% carbohydrates, 10-15% protein and low fat of approximately 20-25%. A simple rule of thumb when providing IV glucose or continuous enteral glucose is to start at around 8 mg/kg/min and titrate until lactate is <2 mmol/L and glucose >75mg/dl. Chronic provision of excess glucose is not beneficial so care must be taken to find the ideal amount of glucose (to paraphrase Goldilocks, not too much, not too little, just right!). Because hepatic production of glucose generally is equal to brain utilization of glucose, neonates have a higher glucose requirement than children and children than adults due to the relative sizes of the brain to body. Overall, 30-40% of the daily carbohydrate should be long-acting carbohydrates.

Glycogen Storage Disease Type III

GSD III is caused by glycogen debrancher enzyme deficiency. This is encoded by the AGL gene on chromosome 1p21 and is inherited in an autosomal recessive manner (105). It occurs in about 1:100,000 similar to GSD I. GSD IIIa occurs in both liver and muscle and represents the majority of cases in the US while GSD IIIb occurs in liver alone.

Clinical features of GSD III include fasting ketotic hypoglycemia and massive and firm hepatomegaly. Unlike GSD I, GSD III is characterized by normal lactic and uric acid levels and more severe elevations in liver function enzymes. In those with GSD IIIa marked elevations of creatine kinase (CK) appear before the clinical signs of proximal muscle wasting.

Clinical diagnosis is made by the finding of short fasting induced hypoglycemia without lactic acidosis, hepatomegaly, marked elevation of transaminases often with high CK. At the time of hypoglycemia, glucagon will not cause a rise in the plasma glucose but 2 hours after a meal in the fed state it will trigger a rise in glucose unlike GSD I. Genetic testing will identify mutations in the AGL gene.

Treatment is the avoidance of prolonged fasting using UCS in doses of 1-1.5g every 4-6 hours but unlike GSD I, patients with GSD III can utilize amino acids and efficiently carry out gluconeogenesis. Thus a high protein diet in addition to UCS can be very effective in preventing hypoglycemia, minimizing hepatomegaly, improving transaminases, improving growth and even proximal muscle wasting (106). Avoidance of too much carbohydrate is also important to avoid filling the liver, heart, and muscles with glycogen, which can cause long term harm. A hypertrophic cardiomyopathy is a complication of excessive glycogen storage, but the muscle disease appears to be secondary to lack of an energy substrate during activity. A ketotic diet may help improve muscle disease in adults, but it has been associated with worsening of the hepatic transaminases and suboptimal growth in the pediatric population.

Glycogen Storage Disease VI and IX

GSD VI is caused by glycogen phosphorylase and GSD IX by glycogen phosphorylase kinase. Both conditions are remarkably similar and the most common of all the hepatic GSDs. In fact there has been a suggestion that GSD VI and IX together may account for a significant number of children with recurrent ketotic hypoglycemia (107). GSD VI is caused by mutations in PYGL and is inherited in an autosomal recessive form. On the other hand, there are 4 subunits of the phosphorylase kinase enzyme, and each is encoded by different genes including the X-linked gene PHKA2. PHKB mutations lead to an autosomal recessive form of GSD IX as do mutations in PHKG. The most severe form tends to occur in patients with genetic mutations in PHKG.

Clinical manifestations of GSD VI and IX are short stature and recurrent episodes of ketotic hypoglycemia. Unlike the hepatomegaly of GSDI and III in which the examiner will need to start palpating the liver from the anterior superior iliac spine in order not to miss a giant liver, the hepatomegaly of VI and IX may be very subtle or absent. Sometimes in younger children morning ketosis is found with euglycemia because after glycogen stores are depleted, gluconeogenesis and ketogenesis are activated and glucose levels remain normal. Thus, if suspecting GSD VI or IX, check morning beta-hydroxybutyrate and if >0.6 mmol/L after a normal overnight fast this would be suggestive of this disease. Also because of the reliance on gluconeogenesis, prealbumin and total protein levels may be low, and patients may complain of intermittent muscle aches without overt weakness.

Diagnosis is suspected by finding shortened fasting tolerance with accelerated development of ketosis in a patient with mild short stature and hepatomegaly. Mild elevations of liver transaminases and hyperlipidemia may occur. Absence of hepatomegaly does not rule out GSD VI or IX. Genetic testing is the diagnostic test of choice for those with either recurrent episodes of ketotic hypoglycemia or persistent finding of elevated beta-hydroxybutyrate after a simple overnight fast.

Treatment is avoidance of prolonged fasting and administration of UCS 1-2 g/kg at bedtime to prevent early morning ketosis. A high protein diet with complex carbohydrates is effective as gluconeogenesis is unaffected. A program of daytime carbohydrates for intercurrent illness and a plan for IV dextrose with vomiting is encouraged. By the time the child reaches adulthood fasting tolerance is of 12-18 hours overnight without ketones become possible and treatment is rarely required as an adult.

FATTY ACID OXIDATION AND KETONE BODY DISORDERS

Fatty Acid Oxidation Disorders

Fatty acid oxidation (FAO) occurs in the mitochondria and is the major source of energy production in the fasted state i.e., when glucose metabolism is insufficient to provide for energy needs. Typically, FAO starts when glycogen reserves are depleted in conjunction with an increase in gluconeogenesis. As insulin levels fall, hormone-sensitive lipase acts in the adipocytes to release 3 free fatty acids and 1 glycerol from the triacyl-glycerol (triglyceride) stored in the adipose tissue (108). The metabolism of the free fatty acids occurs in 3 major steps: 1) transport into the mitochondria via the carnitine shuttle, 2) long chain fatty acids undergo beta oxidation at the inner mitochondrial membrane, and then 3) medium and short chain fatty acid oxidation (FAO) occurs in the mitochondrial matrix. The result of FAO is the production of acetyl-CoA, which in the heart and skeletal muscle enters into the citric acid cycle and by oxidative phosphorylation generates energy for these tissues. The liver however converts acetyl-CoA into ketone bodies known as beta-hydroxybutyrate (BOHB, the main ketone body in the blood) and acetoacetate via hydroxyl methyl glutaryl-coenzyme A (HMG-CoA) synthetase and HMG-CoA lyase. The ketone bodies are exported to the brain for energy use. The liver also metabolizes the amino acids leucine and isoleucine into acetyl-CoA. Because fatty acids cannot cross the blood brain barrier, fatty acid oxidation is limited in the brain due to a lack of substrate. MCT1, a member of the monocarboxylate transporter family, transports the ketone bodies across the blood brain barrier. BOHB is then converted back to acetoacetate and then to acetyl-CoA which enters the citric acid cycle and generates energy in the form of adenosine triphosphate (ATP). Studies have shown that as the plasma glucose falls the cerebral metabolic rate of glucose falls and as the plasma acetoacetate levels rise the cerebral metabolic rate acetoacetate rises replacing the lost metabolism of glucose (13). Thus, BOHB can add to glucose as a primary source of energy production by the brain. This protects the brain from hypoglycemic brain damage in circumstances of low glucose and high ketones (with the exception of patients with ketone utilization defects). This also highlights why untreated disorders of fatty acid oxidation plus ketone synthesis and utilization are dangerous as they result in accelerated development of hypoglycemia because of the loss of the glucose sparing ketones, resulting in energy failure in the brain.

Abnormalities of FAO tend to present either in periods of prolonged fasting often precipitated by intercurrent illness when the need for energy at a cellular level, increases, or during severe strenuous exercise. Common clinical features of these defects include fasting hypoglycemia with liver failure, hepatic encephalopathy, and muscular hypotonia. Rhabdomyolysis following exercise is also common. Rare clinical effects might include cardiac arrhythmias and retinitis pigmentosa. The biochemical hallmark of FAO defects is hypoglycemia associated with elevated free fatty acids and inappropriately low ketone bodies (Table 3 and Figure 2). Coagulation defects, elevated liver function tests, and hyperammonemia may occur with massive elevation of serum CK levels.

FAO disorders are inherited as autosomal recessive conditions. The overall incidence has been reported to be approximately 1:9000 (109). Since the development of newborn screening for FAO disorders, the clinical presentation has changed with almost no patients presenting with hypoglycemia. Indeed, the incidence of hypoglycemia caused by previously unknown FAO disorder presenting in emergency room situations is dramatically reduced. In a study of approximately 220,000 children presenting at an emergency room between the ages of 0 and 18 years, 160 patients had previously undiagnosed hypoglycemia and none of them had a FAO defect (110). This compares to a study by Weinstein et al prior to universal newborn screen of FAO disorders in which FAO disorders represented 19% of previously undiagnosed hypoglycemia (111). Although most FAO defects are detected on newborn screening, rarely errors in the process may account for a missed case and it is always important to demonstrate in cases of hypoketotic hypoglycemia the absence of a FAO disorder.

This chapter will focus primarily on those disorders that primarily cause hypoglycemia and the acute treatment of the hypoglycemia.

DISORDERS OF FATTY ACID UPTAKE INTO MITOCHONDRIA AND THE CARNITINE CYCLE

Free fatty acids (FFA) are released from adipose tissue and travel to target cells where they are transported across the cell membrane by fatty acid transporter proteins. Once inside the cell they are esterified by acyl-CoA synthases and enter the carnitine cycle to enter the mitochondria. Carnitine palmitoyl transferase I (CPT I) catalyzes transfer of the acyl group from acyl-CoA to form acyl-carnitine and is the rate limiting step in FAO. The acyl-carnitine is transported across the mitochondrial membrane by carnitine acylcarnitine transferase (CACT) and once on the inside the acylcarnitine is converted back to acyl-CoA by CPT II. The acyl-CoA is now ready to undergo beta oxidation. The carnitine for these reactions is transported into the cell by the carnitine transporter.

Disorders of the carnitine transporter, CPT I and CACT all cause hypoketotic hypoglycemia. Both CPT 1 and CACT cause fasting-induced Reye syndrome with acute liver failure and can be suspected when hyperammonemia is found with hypoketotic hypoglycemia, elevated free fatty acids, and abnormal acylcarnitine profile. Carnitine transporter deficiency cause severe carnitine deficiency and dilated cardiomyopathy that is progressive and generally presents before hypoglycemic episodes. Diagnosis of carnitine transporter deficiency is suspected when total carnitine levels are very low (<10% normal) in conjunction with hypoketotic hypoglycemia and elevated CK levels in a patient with cardiomyopathy. Reye syndrome and acute liver failure also occur in CPT I and CACT and acute myoglobinuria with rhabdomyolysis occur in CPT II.

DISORDERS OF BETA OXIDATION

Beta-oxidation is the process whereby sequential molecules of acetyl-CoAs are cleaved off the long acyl-CoA inside the mitochondria, until the entire acyl-CoA has been broken down to acetyl-CoA (thus an 18-carbon acyl-CoA will generate 9 acetyl-CoAs). The first step in this reaction is carried out by four individual acyl-CoA dehydrogenase enzymes each acting on a different chain length acyl-CoA. These are the short, medium, long and very long chain acyl CoA dehydrogenase (SCAD, MCAD, LCAD and VLCAD) enzymes. The next three steps of FAO are carried out in conjunction with the tri-functional protein and involve the hydratase enzymes and both long chain and short chain 3-hydroxyacyl-CoA dehydrogenases (LCHAD and SCHAD). Finally electron transport flavoproteins transfer electrons from reducing equivalents produced by multiple pathways to the electron transport chain. Defects in the electron transport chain cause multiple acyl-CoA dehydrogenase deficiency (MADD) also known as Glutaric Aciduria II.

Clinical features of defects in beta-oxidation include hypoketotic hypoglycemia, associated with lethargy, vomiting, hypotonia seizures. Acute liver failure or Reye syndrome can occur, and cardiomyopathy is particularly severe in the longer chain disorders. It should be noted that ketones can be produced in variable amounts, but they are not sufficient to prevent hypoglycemia and the ratio of FFA to ketones is increased over normal. Individual FAO disorders have diagnostic acylcarnitine profiles and urine organic acid profiles and diagnosis may be made during an acute decompensation using these tools. However, one should never subject a patient suspected of having a FAO disorder to a fasting study for the purpose of diagnosis as it can precipitate an acute decompensation and death. If a FAO disorder is suspected, perform an acylcarnitine profile, total and free carnitine and test for urine organic acids in the well state, which may diagnose the condition without triggering a decompensation.

EMERGENCY TREATMENT OF FATTY ACID OXIDATION DISORDERS

Emergency treatment of hypoketotic hypoglycemia caused by FAO disorders involves correcting the hypoglycemia with a 200 mg/kg bolus of dextrose (best provided as 2 ml/kg Dextrose 10%) followed by administration of 5-10 mg/kg/min dextrose infusion with the goal of getting the plasma glucose above 85 mg/dl to turn on insulin secretion and suppress lipolysis. Treatment of elevated ammonia may be required if levels do not promptly fall with glucose administration. Cardiopulmonary shock if present needs to be aggressively managed and liver failure and rhabdomyolysis need to be suspected and diagnosed early to implement treatment. Cerebral edema may occur particularly associated with elevated ammonia in undiagnosed cases of MCAD deficiency. Diuresis with possible alkalization of the urine can prevent acute renal failure in cases of extreme elevation of CK. Consultation with a metabolic expert is strongly recommended for endocrinologists not familiar with the ongoing management of children with FAO disorders.

Ketogenesis and Ketone Utilization Defects

Ketone synthesis involves two primary enzymes involved in converting acetyl-CoA to acetoacetate, hydroxyl methyl glutaryl-coenzyme A (HMG-CoA) synthase and HMG-CoA lyase. The ketone utilization defects are rare conditions in which ketogenesis is effective but there is an inability to either convert acetoacetate to aceto-acetyl-CoA by succinyl-CoA:acetoacetate transferase (SCOT) or acetoacetyl-CoA to acetyl-CoA by mitochondrial acetoacetic thiolase (MAT). These genetic defects are all autosomal recessive conditions. Finally, ketone transport into the brain can be diminished in patients with loss of function variations in SLC16A1 the gene encoding the monocarboxylate transporter 1 protein (MCT1) (112,113).

KETOGENESIS

There are significant similarities between the FAO defects and the ketogenesis disorders with hypoketotic hypoglycemia with or without hyperammonemia and hepatic encephalopathy. Patients present in the newborn period or during intercurrent illness with relatively short episodes of fasting (12-18 hours). The biochemical hallmarks of HMG-CoA synthase deficiency are hypoglycemia with decreased ketones, elevated FFA, normal lactate and ammonia and normal urine organic acids and plasma amino acids whereas HMG-CoA lyase deficiency presents with hypoketotic hypoglycemia with elevated lactate and ammonia and very abnormal urine organic acid profile and elevated 3-methylglutaryl carnitine in the acylcarnitine profile.

Treatment is similar to the FAO defects and includes rapid correction of hypoglycemia with 200 mg/kg intravenous bolus of dextrose (2 ml/kg Dextrose 10%) followed by an infusion of 5-8 mg/kg/min of glucose (3-5 ml/kg/h of Dextrose 10%). Treatment of the lactic acidosis with bicarbonate is not indicated unless life threatening acidosis is occurring as provision of glucose generally corrects the acidosis. Supportive care for hyperammonemia and hepatic encephalopathy should be provided.

KETONE UTILIZATION AND TRANSPORT DEFECTS

Ketone utilization defects generally present in the newborn period however some patients will survive the neonatal period and present later with intermittent severe metabolic acidosis due to ketoacidosis associated with fasting or intercurrent illness. Outside of an acute episode they may have elevated plasma BOHB >0.4 -0.6 mmol/L even when well fed indicating an inability to suppress ketones. Hypoglycemia is not the most common finding but can occur after prolonged fasting with or without hyperammonemia, hepatomegaly and encephalopathy. During fasting studies plasma BOHB continues to rise until progressive ketoacidosis occurs which is different to the rising and then stable ketosis of physiological fasting that stabilizes out as ketone utilization and ketogenesis balance out.

Treatment is to provide glucose to increase insulin levels and suppress fatty acid oxidation. This is typically achieved by providing a GIR of 8 mg/kg/min. Treatment of acidosis with bicarbonate therapy is controversial and should be used with caution in the severest cases.

CLINICAL APPROACH TO THE DIAGNOSIS OF THE ETIOLOGY OF HYPOGLYCEMIA

In order to diagnose the etiology of hypoglycemia one must first confirm the presence of hypoglycemia. Normal glucose levels are typically between 70 and 120 mg/dL and glucose levels less than 70 mg/dL in the face neurogenic or neuroglycopenic symptoms are suggestive of hypoglycemic disorders. In children (>5 to 7 years old) and young adults who are reliably able to report the symptoms of hypoglycemia, the finding of Whipple's triad (symptoms consistent with hypoglycemia, a measured plasma glucose confirming hypoglycemia, and improvement of symptoms with administration of glucose and correction of the hypoglycemia) is sufficient to warrant further investigation. For infants and younger children who are unable to reliably communicate symptoms, the Pediatric Endocrine Society (PES) guidelines suggests evaluation and management only of those whose plasma glucose concentrations are documented by laboratory quality assays to be below the normal threshold for neurogenic responses (60 mg/dL) (21). For any patient with a low glucose value measured either by point of care meter using a finger stick blood sample or using a continuous glucose monitoring system, a plasma glucose needs to be obtained to confirm hypoglycemia prior to commencing a complete evaluation. This recommendation has been made because of the known inaccuracy of point of care glucose testing and of continuous glucose monitor testing for detecting blood glucose less than 70 mg/dL. Rather than providing children and their families with a glucometer for screening for low blood sugars at home, whenever safely possible, a standing order for a plasma glucose to be analyzed immediately, should be offered to the family. When they experience symptoms consistent with hypoglycemia, they can have a plasma glucose drawn in the lab to either confirm the presence of hypoglycemia or to demonstrate that these symptoms are not related to hypoglycemia. Thus, the presence or absence of Whipple's triad may be confirmed and only those with a high likelihood of hypoglycemia undergo further investigations. Studies have shown that the frequency of pathological hypoglycemia in patients in high-risk situations (for example the emergency room or attending a hypoglycemia clinic) who have had a documented low blood sugar associated with intercurrent illness will have a risk of a serious form of hypoglycemia of approximately 10% (110,114).

History

The first step in the evaluation is to undertake a careful history specifically questioning for symptoms of hypoglycemia (Table 4), and timing of the symptoms, or measured hypoglycemia, relative to the last meal consumed. In pediatric patients, the vast majority of causes of hypoglycemia are precipitated by fasting. Documenting post prandial hypoglycemia in the absence of fasting hypoglycemic may suggest some very specific conditions, such as late dumping syndrome (Nissen fundoplication induced hypoglycemia, post bariatric surgery induced hypoglycemia), protein induced hypoglycemia found in GDH HI, HADH HI, and K_ATP HI, hereditary fructose intolerance, or a very rare presentation of insulinoma. Careful review of the history for the presence of neurogenic or neuroglycopenic symptoms should be performed. Neuroglycopenic symptoms are strongly suggestive of a serious underlying form of hypoglycemia and need rapid evaluation. A history of poor growth might suggest growth hormone deficiency, adrenal insufficiency (either primary or secondary), or GSD. Recurrent abdominal pain with nausea and vomiting is a classical symptom of severe adrenal insufficiency. A history of salt craving or darkening skin also are clues to primary adrenal insufficiency.

The most common time of presentation of hypoglycemia in childhood is in the neonatal period when the stress of transition from intrauterine to extra uterine life is greatest and genetic or metabolic forms of hypoglycemia most commonly present. It is important to always inquire about the neonatal period because of the possibility of missed diagnosis. Presentation to emergency rooms in association with intercurrent illness is the next most common time of presentation of hypoglycemia in childhood; it is recommended that emergency rooms should have protocols to draw the critical samples (Table 2) in patients who present with hypoglycemia, but with no previous etiology determined. If an emergency room does not have such protocols in place, we recommend their implementation, as up to 10% of all patients presenting to emergency rooms with previously undiagnosed hypoglycemia have a serious underlying condition requiring long-term treatment (110,114).

Physical Exam

The second step in the evaluation of the etiology of hypoglycemia is the physical exam. There are very few clues that can be obtained; however, it is critical not to miss those that are available. Short stature, with impaired growth velocity, or inappropriate height for the family, should suggest evaluation for growth hormone deficiency. Hyperpigmentation of the skin and or gums could indicate primary adrenal insufficiency with ACTH excess. Failure to thrive and weight loss could indicate chronic adrenal insufficiency. Central malformations such as cleft lip or palate could indicate an underlying pituitary problem. Scars on the abdominal wall or a gastrostomy tube could suggest a postsurgical form of hypoglycemia. Enlargement of the liver at a time when the patient is well would point to glycogen storage disorders, or if the patient is acutely unwell at the time of presentation a fatty acid oxidation defect might be more likely. Abnormal development of the genitalia might indicate adrenal hormonal production problems; a micropenis/small normal penis might indicate a growth hormone problem with or without hypogonadotropic hypogonadism. Asymmetry of the body, either hemiatrophy or hemihypertrophy, could suggest an underlying syndrome such is Russell Silver Syndrome or Beckwith-Wiedemann Syndrome. Certain syndromes such as Down syndrome are associated with an increased incidence of ketotic hypoglycemia. Overgrowth syndromes, Turner syndrome, and Kabuki syndrome may be associated with hyperinsulinism (72,78,79).

Critical Sample at Time of Hypoglycemia

As noted above, a critical sample including blood and urine (Table 2) should be collected at the time of glucose less than 50 mg/dL. In this sample, the levels of intermediary metabolites and hormones in blood, ketones and organic acids in urine, and in certain circumstances the presence or absence of drugs such as insulin or sulfonylureas, will aid the physician to diagnose the etiology of the hypoglycemia. Interpretation of the critical sample commences with the determination of the presence or absence of ketosis and lactic acidosis as in Figure 2 and Table 3.

When a critical sample has not be obtained during a spontaneous episode of hypoglycemia, a fasting study should be performed to induce hypoglycemia (Table 10). Caution prior to admitting the patient for a fasting study, includes the need to rule out fatty acid oxidation defects by performing an acylcarnitine profile in the well state. Fasting studies should be performed in the inpatient setting in a unit of highly specialized nurses trained in the performance of fasting studies. Safety precautions such as having intravenous lines inserted for both blood drawing and infusing glucose in an emergency situation are very important. It is critical to have the ability to do accurate point of care glucose and ketone testing on venous samples or warmed capillary samples and to have a rapid turnaround on plasma glucose and plasma beta-hydroxybutyrate. Intravenous glucose should be available for rescue and glucagon should also be available both for stimulation testing and for rescue when hyperinsulinism is suspected.

Table 10.  Diagnostic Fasting Test

Perform test only on a unit with trained medical and nursing staff who are experienced in the performance of fasting studies.

1. Have IV access and D10% (2-5 ml/kg) for emergency resuscitation.

2. Measure glucose by POC meter every 2-3 hours until glucose <70 mg/dL (<3.9 mmol/L); then every 2 hours until <60 mg/dL (<3.3 mmol/L); then hourly until <50mg/dL (<2.8 mmol/L)

a. When glucose <60 mg/dL (<3.3 mmol/L) send specimen for laboratory confirmation of plasma glucose

3. Measure beta-hydroxybutyrate every 2-3 hours and when glucose <50mg/dL (<2.8 mmol/L)

a. When plasma glucose ≤50 mg/dL (<2.8mmol/L) draw blood for the CRITICAL sample:

glucose, insulin, beta-hydroxybutyrate, free fatty acids, ammonia, cortisol, growth hormone, lactate, acylcarnitine profile, urine organic acids

i. Special circumstances: C-peptide, proinsulin, sulfonylurea screen, toxicology screen, serum amino-acids,

4. Perform Glucagon Stimulation Test once CRITICAL samples are obtained

1. Measure glucose using POC meter and then give glucagon 30 mcg/kg or 0.5-1 mg by IM or IV push as long as glucose is <50 mg/dL (<2.8 mmol/L)

2. Monitor glucose using POC meter every 10 minute for 40 minutes

3. Terminate test if glucose is still below 50 mg/dL (<2.8 mmol/L) after 30 minutes

4. After 40 minutes, may feed and resume treatment to maintain plasma glucose >70 mg/dL (3.9 mmol/L)

When the results of the critical sample point to the likely area of metabolic perturbation (Figure 2), further testing may be indicated at times not necessarily at the time of hypoglycemia. For conditions such as hyperinsulinism, specific testing can further subclassify the etiology (such as protein sensitivity in GDH HI or HADH HI, or ammonia levels indicating GDH HI). In the case of low counter regulatory hormones found at the time of the critical sample, stimulation testing for growth hormone, cortisol, or ACTH deficiency can confirm if deficiencies in these hormones are the cause of hypoglycemia. One should never diagnose a hormonal deficiency as the cause of hypoglycemia on a single critical sample but rather only when dynamic testing has demonstrated deficiency (18,19). In cases suspected to be due to glycogen storage disease, liver biopsy is no longer indicated due to the morbidity of the procedure and genetic testing is now the preferred diagnostic method. This is also true for the disorders of fatty acid oxidation in which an acylcarnitine profile is not sufficient to make a diagnosis and genetic panels are preferable to skin biopsies the majority of the time. With current genetic testing technology, panels including many hypoglycemia disorder associated genes may be conducted for little more cost than a single gene test.

Approach to the Patient with Ketotic Hypoglycemia

There is a common misconception that children presenting with ketotic hypoglycemic, who do not possess an already identified underlying cause, have benign physiological idiopathic ketotic hypoglycemia. In recent years it has become clear that this is not correct (110,114). We outline an approach to patients with ketotic hypoglycemia that should allow differentiation between benign physiological ketotic hypoglycemia, pathological ketotic hypoglycemia associated with known underlying conditions and idiopathic pathological ketotic hypoglycemia (IPKH) in which there is clearly an abnormality of glucose regulation, but no genetic cause can be found (Figure 7).

Figure 7. Physiological vs. Pathological Ketotic Hypoglycemia.

BENIGN PHYSIOLOGICAL KETOTIC HYPOGLYCEMIA

Based on the normal physiology of fasting, if a person is fasted for long enough, they will develop a glucose <50 mg/dL and plasma beta-hydroxybutyrate >2 mmol/L. Studies have looked at the normal duration of fasting and found that time to glucose <50 mg/dL increases with age. Children 0-2 years can generally fast about 15-18 hours, children >2 years to 5 years can fast >24 hours, children >5 years to 10 years can fast about 36 hours, and teenagers to adults can fast 48-72 hours (115). Recently Pamar et al. investigated children admitted for day surgery and found that only a small percentage developed beta-hydroxybutyrate levels >1 mmol/L by 12 hours of fasting (116). Thus, the finding of ketones in blood of >1 mmol/L after 12 hours of fasting in previously healthy and well-nourished children is unusual. However, the finding of ketosis after 24 -30 hours of no, or very poor, oral intake would be considered normal for most children over the age of 2 years. Thus, history is very important in differentiating benign physiological ketotic hypoglycemia due to prolonged starvation or intercurrent illness. It is our recommendation that previously healthy children who present with their first episode of ketotic hypoglycemia, who have a history consistent with prolonged starvation with or without intercurrent illness, who have elevated ketones >2 mmol/L and a normal physical exam, should not require further investigations. Children with recurrent episodes of ketosis despite precautions to avoid prolonged fasting need further investigation which may include admission for a fasting study. In addition to evaluating for an underlying etiology, this permits determination of the time to development of ketosis (by monitoring serial ketone levels, not just at the time of the critical sample) and hypoglycemia, which informs intervention. This is best achieved by a formal fasting study (Table 10) following three days of good feeding.

PATHOLOGICAL KETOTIC HYPOGLYCEMIA

The term pathological ketotic hypoglycemia is used to indicate that some underlying abnormality is causing disordered fasting tolerance. The key manifestation of this is ketotic hypoglycemia that occurs after an abnormally short fasting period, morning ketosis without hypoglycemia, or symptomatic ketosis causing vomiting and a vicious cycle of worsening ketosis, vomiting and dehydration. This can be secondary to hormonal deficiencies such as isolated growth hormone deficiency or cortisol deficiency (primary, secondary or tertiary). It can be caused by enzyme deficiencies in the glycogen storage pathway, disorders of gluconeogenesis, or disorders of ketone utilization or transport. In a small number of children, no cause can be found despite extensive clinical and genetic investigations. These children have idiopathic pathological ketotic hypoglycemia (IPKH). The approach to management of these children requires knowledge of the duration of fasting required to keep the beta-hydroxybutyrate <0.6 mmol/L and knowledge of how low the glucose will fall despite rising ketone levels. Thus, the therapeutic plan needs to be individually tailored to each child. Typical components will include high protein diet of 3 g/kg/day protein to promote gluconeogenesis and prevent catabolism of muscle and slow-release carbohydrates such as uncooked corn starch (UCS) or Glycosade^®. Many infants and children can be successfully treated with nighttime UCS and frequent high protein snacks during the day, but some will require intensive diets with monitoring of glucose and ketones, similar to individuals with GSD III, VI or IX. Because so little is known of the natural history of the severe forms of IPKH, careful review of metabolic control should be undertaken every few years to prevent under treatment as the patient grows but also to prevent over treatment since the natural ability to fast increases with advancing age.

CONCLUSIONS

Hypoglycemia in pediatric patients occurs predominately in the newborn period and during times of intercurrent illness, because it is most commonly caused by inherited hormonal or metabolic diseases. Rarer acquired forms of hypoglycemia must be suspected when initial presentation occurs in older children and adolescents. Because of the overlap of the normal transitional changes of glucose regulation in the newborn period with the most common time for the presentation of inherited hypoglycemic conditions, it is critical to screen for hypoglycemia and to determine the precise etiology so that rapid and appropriate interventions can be implemented. Newborn infants cannot be simply labeled as having hypoglycemia and discharged casually on frequent feeds. At the minimum a safety fast should be performed to ensure that the transient forms of hypoglycemia have truly resolved before discharge. Up to 10% of patients presenting with unexplained hypoglycemia in a pediatric emergency room setting will have a serious underlying metabolic or hormonal condition requiring long term care. It is critical that emergency rooms caring for children have protocols in place to identify these 10% of children, because these children are at risk of hypoglycemic brain damage. At all ages rapid intervention can prevent permanent neurological injury caused by the majority of conditions we discuss.

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Chronic Fatigue Syndrome

ABSTRACT

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic medical condition that has growing prevalence across the globe, often diagnosed after exclusion of other medical or mental illnesses. As there is no clinical test to confirm the presence of this condition, the diagnosis is syndromic based on different clinical definitions. There was mixed evidence to support the use of a specific therapy that provides palliative effect. Pathophysiological hypotheses can be categorized into infection, immune, mitochondrial, neurobehavioral, or stress system (HPA axis and sympathetic nervous system) disorders. The prognosis of ME/CFS is mixed but recovery does occur in many cases, over time. All-cause mortality rate is not increased.

CLINICAL DEFINITION

Fatigue is a term used to describe unexplained subjective, chronic, pervasive tiredness or weakness physically, mentally, or a combination of both. The term “myalgic encephalomyelitis” was first described in the United Kingdom after an outbreak of serious infection at the Royal Free Hospital in 1955 (1). The US originated term Chronic Fatigue Syndrome (CFS) was introduced by Holmes et al in 1988 (2). Several definitions of CFS have been developed, primarily to standardize research (3,4). The key symptoms expected in this condition was later refined in 1994 and named after Dr Fukada (3). However, it was particularly challenging to reach a consensus on a name for this condition as its etiology and pathology are unexplained. An important milestone was achieved on October 1, 2022 with the update to International Coding Disease (ICD-10-CM) that include a specific diagnostic code for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) (5). Prior to this, chronic fatigue syndrome was categorized in the “chronic fatigue, unspecified”, which could limit epidemiologic studies.

The 1994 US Centers for Disease Control and Prevention (CDC) Fukuda criteria for chronic fatigue syndrome comprise the following (3):

Primary symptoms that are clinically evaluated, unexplained, persistent or relapsing fatigue, lasting at least 6 months. The fatigue is not the result of ongoing physical exertion, and resting, sleeping, or downgrading activity is non-restorative. The fatigue causes significant impairment in personal, social, and/or occupational domains and represents a substantial reduction in premorbid levels of activity and functional capacity.
The concurrent presence of at least 4 of the 8 following symptoms over a 6-month period:

Impaired short-term memory or concentration.
sore throat.
tender lymph nodes/glands.
multiple-joint pain without swelling or redness.
headache of new type, pattern, or severity.
unrefreshing sleep.
post-exertional fatigue/malaise lasting longer than 24 hours.

The 2003 Canadian ME/CFS Case Criteria (CCC) specifies (4):

Post-exertional malaise must occur with rapid muscle or cognitive fatigability, taking 24 hours or longer to recover.
Unrefreshing sleep, myalgia, and arthralgia must be reported.
Two or more neurological/cognitive manifestations must be present.
At least one of autonomic, neuroendocrine, immune manifestations must be present.

This is a stricter criterion, compared to the Fukada Criteria and it is mainly used as case definition in research. Adults are diagnosed after 6 months of symptoms while pediatric cases were diagnosed after 3 months.

Nearly two decades after Fukada Criteria was introduced, the US Institute of Medicine (IOM), now known as National Academy of Medicine (NAM) proposed new diagnostic criteria in 2015 for chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) (5). These clinical diagnostic criteria followed a comprehensive analysis of the literature and expert consultation as below.

Substantial reduction/impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months, is accompanied by fatigue that is often profound, is of new or definite onset, is not the result of ongoing excessive exertion, and is not substantially alleviated by rest.
Post-exertional malaise (PEM).
Unrefreshing sleep.
In addition, patients are required to have at least one of the following two symptoms:

Cognitive impairment.
Orthostatic intolerance.

Symptoms must be present at least half of the time and have moderate, substantial, or severe intensity.

As a large group of patients remain stigmatized with the term ‘chronic fatigue syndrome’ (CFS), renaming the condition to 'systemic exertion intolerance disease' (SEID) was recommended to overcome the old stereotypes as CFS is more associated to a mental disorder rather than an organic illness (5). SEID highlights the somewhat unique feature of exertion intolerance, and consequent impaired functional capacity. SEID criteria may help with the treatment by increased diagnosis and awareness, calling attention to the major disabling symptoms, and by validating the major symptoms as real and debilitating. However, the new IOM criteria could increase the prevalence rate of this condition compared to the use of previous Fukada criteria due to the lack of specifying exclusionary illnesses (5).

DIAGNOSTIC APPROACH

The clinical diagnosis of CFS/ME is based on a constellation of symptoms where post-exertional malaise and fatigue are prominent; these are described in some definitions (Table 1) with an algorithm provided in Figure 1 (6). A thorough clinical assessment is necessary to exclude alternative medical and psychiatric diagnoses requiring specific treatment. For example, it is important to differentiate fatigue from weakness, which suggests a neuromuscular disease, and anhedonia from major depression. Hypersomnolence and sleep disorder suggests a need to exclude obstructive sleep apnea, particularly in groups at risk such as the obese.

Limited laboratory screening investigations are directed towards the discovery of subtle medical disorders. Unfortunately, there was no test with adequate sensitivity and specificity to verify the diagnosis of CFS/ME. The protean manifestations of CFS/ME suggest diverse causes, hence it is unlikely a single diagnostic test for CFS/ME will be developed. Routine laboratory investigations include a complete blood examination, erythrocyte sedimentation rate (ESR), calcium, phosphate, magnesium, blood glucose, serum electrolytes, thyroid stimulating hormone and free thyroxine levels, protein electrophoresis screen, C-reactive protein (CRP), ferritin, creatinine, rheumatoid factor, antinuclear antibody, creatine kinase and liver function, and routine urinalysis. Any other investigations should be carefully chosen on an individual basis depending on the clinical assessment and risk factors for other conditions. For example, sleep study may be considered in patients who have features of obstructive sleep apnea, while a morning cortisol concentration or a more definitive ACTH stimulation test may be considered for patients who have clinical features suggestive of adrenal insufficiency.

Although patients with CFS/ME tend to have more abnormalities on magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT), the significance of these findings are unclear, hence routine neuroimaging is not recommended in the diagnostic process (7,8).

Some recent studies have suggested reduced circulatory and myocardial function in CFS, although the utility of routine cardiac assessment is not established (9,10).

Table 1. Clinical Working Case Definition of ME/CFS, published in 2000 (3,4)

A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine and immune manifestations; and adhere to item.

1. Fatigue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level.

2. Post-Exertional Malaise and/or Fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period – usually 24 hours or longer.

3. Sleep Dysfunction:* There is unrefreshed sleep or sleep quantity or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.

4. Pain:* There is a significant degree of myalgia. Pain can be experienced in the muscles and/or joints, and is often widespread and migratory in nature. Often there are significant headaches of new type, pattern or severity.

5. Neurological/Cognitive Manifestations: Two or more of the following difficulties should be present: confusion, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances – e.g., spatial instability and disorientation and inability to focus vision. Ataxia, muscle weakness and fasciculations are common. There may be overload phenomena: cognitive, sensory – e.g., photophobia and hypersensitivity to noise – and/or emotional overload, which may lead to “crash” periods and/or anxiety.

6. At least one symptom from two of the following categories: (i) Autonomic Manifestations: orthostatic intolerance – neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension; lightheadedness; extreme pallor; nausea and irritable bowel syndrome; urinary frequency and bladder dysfunction; palpitations with or without cardiac arrhythmias; exertional dyspnea. (ii) Neuroendocrine Manifestations: loss of thermostatic stability – subnormal body temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities; intolerance of extremes of heat and cold; marked weight change – anorexia or abnormal appetite; loss of adaptability and worsening of symptoms with stress. (iii) Immune Manifestations: tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food, medications and/or chemicals.

7. The illness persists for at least six months. It usually has a distinct onset, ** although it may be gradual. Preliminary diagnosis may be possible earlier. Three months is appropriate for children.

To be included, the symptoms must have begun or have been significantly altered after the onset of this illness. It is unlikely that a patient will suffer from all symptoms in criteria 5 and 6. The disturbances tend to form symptom clusters that may fluctuate and change over time. Children often have numerous prominent symptoms but their order of severity tends to vary from day to day. *There is a small number of patients who have no pain or sleep dysfunction, but no other diagnosis fits except ME/CFS. A diagnosis of ME/CFS can be entertained when this group has an infectious illness type onset. **Some patients have been unhealthy for other reasons prior to the onset of ME/CFS and lack detectable triggers at onset and/or have more gradual or insidious onset.

Exclusions: Exclude active disease processes that explain most of the major symptoms of fatigue, sleep disturbance, pain, and cognitive dysfunction. It is essential to exclude certain diseases, which would be tragic to miss: Addison’s disease, Cushing’s syndrome, hypothyroidism, hyperthyroidism, iron deficiency, other treatable forms of anemia, iron overload syndrome, diabetes mellitus, and cancer. It is also essential to exclude treatable sleep disorders such as upper airway resistance syndrome and obstructive or central sleep apnea; rheumatological disorders such as rheumatoid arthritis, lupus, polymyositis and polymyalgia rheumatica; immune disorders such as AIDS; neurological disorders such as multiple sclerosis (MS), Parkinsonism, myasthenia gravis and B12 deficiency; infectious diseases such as tuberculosis, chronic hepatitis, Lyme disease, etc.; primary psychiatric disorders and substance abuse. Exclusion of other diagnoses, which cannot be reasonably excluded by the patient’s history and physical examination, is achieved by laboratory testing and imaging. if a potentially confounding medical condition is under control, then the diagnosis of cfs can be entertained if patients meet the criteria otherwise.

Co-Morbid Entities: Fibromyalgia Syndrome (FMS), Myofascial Pain Syndrome (MPS), Temporo- mandibular Joint Syndrome (TMJ), Irritable Bowel Syndrome (IBS), Interstitial Cystitis, Irritable Bladder Syndrome, Raynaud’s Phenomenon, Prolapsed Mitral Valve, Depression, Migraine, Allergies, Multiple Chemical Sensitivities (MCS), Hashimoto’s thyroiditis, Sicca Syndrome, etc. Such comorbid entities may occur in the setting of CFS. Others such as IBS may precede the development of CFS by many years, but then become associated with it. The same holds true for migraines and depression. Their association is thus looser than between the symptoms within the syndrome. CFS and FMS often closely connect and should be considered to be “overlap syndromes.”

Overload phenomena affect sensory modalities where the patient may be hypersensitive to light, sound, vibration, speed, odors, and/or mixed sensory modalities.

Figure 1. Diagnostic algorithm adapted from IOM (6).

EPIDEMIOLOGY

The frequency of CFS has been assessed in two large-scale US community-based studies and a prevalence of 0.23-0.42% has been suggested (11,12). Another study suggested the global prevalence of CFS ranges from 0.4% and 2.5% (13).

CFS is at least twice as common in women as in men, occurs more frequently in minority groups, and in those with lower levels of education and occupational status (11, 14). Geographic location has not been shown to influence the prevalence of CFS but more recent study showed the condition is more common in certain countries such as the UK, Australia, and the USA (12, 14). Twin studies suggest that genetic factors play an important role (16). Population studies also associate elevated premorbid stress and childhood trauma, especially if complicated by psychopathology, with an increased risk of CFS (17,18).

An Australian sociodemographic cross-sectional study of patients diagnosed with CFS by their primary care physician was conducted over 2 years (2013-2015) (19). Participants were classified according to Fukuda criteria and international consensus ME/ICC criteria. CFS was most prevalent between 45-55 years, with a peak onset between 25-35 years with a high proportion of females affected (78.6%). Patients were predominantly Caucasian and highly educated. Of a total of 535 patients, only 30% met the Fukuda criteria and 32% met both Fukuda and International consensus ME/ICC criteria. 15% did not meet the criteria and 23% had exclusionary conditions. There was higher proportion of participants who were obese or overweight, (41.3% and 43.3% respectively) and were unemployed or on a disability pension. The results of this study may not be representative of all CFS/ME patients in the general population due to sample recruitment bias.

PATHOPHYSIOLOGY OF CHRONIC FATIGUE SYNDROME

Viral/Immune Hypotheses

For many years CFS was suspected to arise from a persistent response to an infection. Abrupt onset of symptoms and the presence of post-infectious fatigue after infections suggest this theory. There were also reports of a high frequency of antibody titers to specific, but varying, infectious agents (20). Epstein-Barr virus, human herpes virus 6, group B Coxsackie virus, human T-cell lymphotrophic virus II, hepatitis C, enteroviruses, and retroviruses, have all been proposed as etiological agents of CFS (21). However, to date, there has been no consistent evidence that CFS results from a specific infection (22). Moreover, there is data to indicate that global increases in humoral immune responses are seen in chronic stress states and that neurohormonal changes may account for these and other immune aberrations (20,23).

Recent study has examined the characteristics of cell function and receptors in CFS patients (24). Participants between 20 and 65 years old were recruited, by using the Fukuda criteria. Patient were classified as moderate (mobile) or severely affected (housebound). Blood was collected from all participants between 8am and 11am, and sent for lytic protein analysis, cell activity analysis, respiratory burst analysis and natural killer cell receptors analysis. The study demonstrated that there was significant decrease in natural killer cell cytotoxic activity in CFS patients and there is correlation between low natural killer cells cytotoxic activity and severity of CFS illness. CFS patients have alterations in Natural Killer receptors, adhesion markers and receptors on CD4, and CD8.

A prospective population-based cohort of 42,558 atopic patients and 170,232 controls without atopy were recruited between 2005-2007, with follow up until 2011. These 2 groups were similar in sex and age distributions, with a mean age of 47 years. The overall incidence rate for CFS in the atopy cohort (1.37 per 1000 person-year) was higher than in the non-atopy cohort (0.87 per 1000 person-year (25). This suggests that that atopy might increase the risk of CFS/SEID.

Mitochondrial Hypotheses

Since mitochondria provide cellular energy, hypotheses of impaired mitochondrial function have been suggested to underlie CFS. Early studies have shown some associations between mitochondrial proteins and CFS, but these require confirmation (26).

Neuropsychiatric Hypotheses

Chronic fatigue syndrome has been suspected to be a neuropsychiatric disorder, or a type of depression (28). Although depression is frequent in CFS, most patients do not exhibit the characteristic self-reproach or biological features of endogenous depression. The depression often seen in CFS appears to be reactive and associated with marked frustration. However, the symptoms of depression can overlap with those of CFS. Profound fatigue is more commonly reported amongst CFS patients, than those with depression (28). Cognitive-behavioral models of CFS emphasize the importance of the interactions between cognitive, behavioral and biological variables in attempting to explain the genesis and maintenance of CFS. It may be that while organic factors may precipitate CFS, cognitive-behavioral factors may perpetuate the illness (28). Specifically, when individuals resume normal activity levels following an acute illness, it is common to experience symptoms of physical deconditioning. If individuals attribute these symptoms to signs of ongoing disease rather than deconditioning, they may resort to rest and inactivity in an attempt to "cure" the symptoms. A cycle of avoidance and symptom experience develops, which can lead to loss of control, demoralization and possible depression and anxiety. These psychological states can further perpetuate the illness through generating more symptoms.

The cognitive-behavioral model has been expanded to include personality as predisposing factors (29). This model proposes that predisposed people are highly achievement orientated perfectionists and base their self-esteem and the respect from others on their ability to live up to certain high standards (29). When such people are faced with factors that affect their ability to perform, such as a combination of excessive stress and an acute illness, their initial reaction is to persist and to attempt to maintain usual coping strategies. This behavior leads to exhaustion. In making sense of the situation a physical attribution for the exhaustion is made, which protects an individual's self-esteem by avoiding the suggestion that their inability to cope is a sign of personal weakness. The bias may lead to a focus on somatic rather than emotional aspects of the illness, and favors physical rather than psychological explanation. However, this model remains to be fully evaluated and it is poorly integrated with physiological aspects of CFS. There have been few systematic studies undertaken on the relationship between personality and CFS (28). However, a personality trait characterized by "perfectionism, high standards for work performance, responsibility and personal conduct and marked achievement orientation" was reported in interviews with individuals with CFS (30). Interviewees referred to a desire for accomplishment and success, aiming to achieve perfection. These desires were associated with the belief that “failure to meet these standards would indicate failure as a person, or unacceptability to others” (30).

Neurological Hypothesis

CFS as a primary brain disorder has been studied with neuroimaging including Magnetic resonance imaging MRI, Single-photon emission computed tomography (SPECT) Electroencephalogram (EEG), quantitative electroencephalogram (qEEG), and positron emission tomography (PET) (32-36, 40-41). A variety of abnormalities associated with CFS have been reported but the diagnostic or potential pathogenic implications of these findings are unknown.

Neuroendocrine Hypotheses

In recent years, there have been reports indicating neuroendocrine hypofunction, probably of hypothalamic origin, in chronic fatigue states. A tendency to hypocortisolism, has been identified, albeit inconsistently, in CFS patients. Relative hypocortisolism may reflect the primary abnormality in many CFS patients, such as a disorder of the brain regulation, or peripheral elements, of the stress system. Moreover, hypocortisolism may contribute to CFS symptomatology.

However, neuroendocrine studies in CFS have often led to contradictory results. Smaller studies may be confounded by differences between subgroups of CFS patients, such as duration of fatigue, concomitant hypotension and/or orthostasis, depression, familial occurrence, and other factors. Although melancholic major depression is associated with mild hypercortisolism, the hypocortisolism of CFS seems to persist in at least some patients with co-morbid depression (28). Moreover, hypocortisolism is a trait shared with other chronic idiopathic disorders, including post-traumatic stress disorder, fibromyalgia, and inflammatory disorders such as rheumatoid arthritis and asthma (18). Wyller et al. studied 120 CFS patients and 68 healthy controls, aged 12-18 years. CFS patients had higher levels of plasma norepinephrine, plasma epinephrine and FT4, with lower urine cortisol/creatinine ratios, (42). This accords with previous studies of attenuation of cortisol secretion and enhancement of the sympathetic nervous system activity in CFS.

THE STRESS SYSTEM AND CFS/SEID

Stress is defined as threat to homeostasis. It is generally accepted that acute stress system responses are adaptive, designed to re-establish homeostasis. However excessive and/or prolonged activation of the stress system can disturb normal physiology. The stress system comprises the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is the major mediator, and the sympathoadrenal system which produces the catecholamines epinephrine and the sympathoneural system producing norepinephrine. Both glucocorticoids and catecholamines act widely to mediate the stress response.

Stress results in stimulation of parvicellular neurons of the paraventricular nucleus (PVN) of the hypothalamus and the release of the neuropeptides corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) into the hypophyseal portal blood system (Figure 2). The combined action of CRH and AVP on the anterior pituitary corticotropes stimulates secretion of adrenocorticotropin hormone (ACTH). Circulating ACTH acts on the zona fasciculata of the adrenal cortex to stimulate cortisol synthesis. Basal (unstressed) cortisol acts to prevent arterial hypotension by augmenting the effects of catecholamines, and maintain normoglycemia through insulin counter-regulation.

ACTH secretion is influenced by stress, a light-entrained circadian rhythm, and negative feedback at the hypothalamus. During acute stress, the amplitude and synchronization of the CRH and AVP pulsations in the hypophyseal portal system markedly increases, resulting in increases of ACTH and cortisol secretory episodes (43). Stress-induced cortisol secretion activates the central nervous system, increases blood pressure, elevates blood glucose, and suppresses the inflammatory/immune response to prevent tissue damage (44).

Cortisol action is mediated by ubiquitous cytosolic corticosteroid receptors and (45). Free cortisol, unbound to corticosteroid binding globulin (3-10%), diffuses through cell membranes and binds to the carboxy-terminal end of the cytosolic glucocorticoid receptor. On cortisol binding, the ligand-receptor complex translocates into the nucleus, where it interacts with specific glucocorticoid responsive elements (GREs) within DNA to activate gene transcription (45). The activated receptors also inhibit other transcription factors, such as c-Jun/c-Fos and NF-kB, which are positive regulators of the transcription of genes involved in the activation and growth of immune and other cells (46).

Figure 2. The neurohormonal connections of the stress system.

Several complementary sets of studies have examined basal and stimulated pituitary-adrenal gland function in CFS.

Two different types of heritable disorders of this axis have been described, where fatigue is the principal symptom. These include glucocorticoid resistance due to glucocorticoid receptor abnormalities, and mutations of the corticosteroid-binding globulin gene, the chief cortisol transport protein. These disorders are rare, but reinforce the notion that primary pituitary-adrenal abnormalities may produce chronic fatigue. Studies in the broader CFS patient group have generally detected relative hypocortisolism and altered dynamic responses, providing indirect evidence of a central nervous system under-stimulation of pituitary-adrenal function.

Familial glucocorticoid resistance is a rare syndrome characterized by diminished tissue effect of cortisol as a result of a glucocorticoid receptor defect. Glucocorticoid resistance is generally due to a loss of function mutation of the glucocorticoid receptor gene, although the genetic defect has not been identified in all cases. Decreased sensitivity to cortisol results in activation of the HPA axis, with increased ACTH and cortisol levels. In most cases, elevated cortisol levels sufficiently compensate to overcome the hormone resistance, thus these patients do not clinically manifest either cortisol excess or deficiency. Increased ACTH secretion also results in elevated mineralocorticoid and androgen levels resulting in hypertension and hirsutism (47). However, fatigue as an isolated symptom has been described in a 55-year-old woman with glucocorticoid resistance (48). Fatigue in this patient was intermittent, but blood pressure was constantly in the low-normal range, with no postural hypotension. Fatigue was sufficient to prohibit full-time work. Urinary cortisol was elevated (400-800nmol/24h; Range <300nmol/24h), as were plasma cortisol levels. A thermolabile glucocorticoid receptor was noted, specifically a temperature-induced reduction in dexamethasone binding, although a specific glucocorticoid receptor mutation was not reported. It has been proposed that fatigue in such cases is a result of insufficient overproduction of cortisol (49).

Further to this, recent studies of glucocorticoid receptor polymorphisms have found an association between certain haplotypes and CFS (50). Although speculative, polymorphisms may result in altered receptor sensitivity to cortisol, and thus, impaired tissue-effect of cortisol, resulting in relative hypocortisolism.

CORTICOSTERIOD BINDING GLOBULIN ABNORMALITIES AND CHRONIC FATIGUE

Corticosteroid-binding globulin (CBG), also known as transcortin, is the high-affinity plasma transport glycoprotein for cortisol (51). It is secreted by hepatocytes as a 383-amino acid polypeptide, after cleavage of a 22-amino acid signal peptide. Each CBG molecule contains a single high-affinity steroid binding site (51). Under circadian conditions, 80% of circulating cortisol is bound to CBG, 10-15% is bound to low-affinity albumin and 5-8% of circulating cortisol is unbound or free (51). Currently, only the free fraction is thought to be biologically active. CBG levels are generally stable. CBG is traditionally thought to function primarily as a carrier molecule for cortisol, but it may also serve as a buffer and as a reservoir, during secretory surges, or during times of reduced cortisol secretion, respectively. CBG may also have a specific-tissue cortisol delivery role, in particular enabling cortisol to act in an immunomodulatory capacity (52). High-affinity cortisol binding is saturated beyond cortisol levels of 500nmol/L, hence free cortisol levels rise exponentially at high cortisol concentrations (53). Under conditions of stress, elevated cortisol levels saturate available CBG and increase the free cortisol to above 20% (53).

CBG is involved in the stress response. Immune activation releases interleukin-6 (IL-6) which increases circulating free cortisol levels by two mechanisms. IL-6 stimulates cortisol secretion through activation of hypothalamic CRH neurons and it also inhibits CBG gene transcription thereby increasing the free cortisol fraction and thus, circulating glucocorticoid activity (54,55). In vivo, exogenous IL-6 results in a 50% reduction in CBG levels in humans. Severe illness, such as sepsis and burns, are associated with similar reductions in CBG levels, in conjunction with a similar rise in endogenous IL-6 (56,57). Similar falls in circulating CBG concentrations are seen in septic shock and low CBG concentrations have been shown to be an independent predictor of mortality in ICU patients (58). Stress-induced falls in circulating CBG concentrations may also relate to cortisol elevations, as low CBG levels are seen in Cushing’s syndrome or after anti-inflammatory glucocorticoid doses (57). This effect is probably mediated through the glucocorticoid receptor as glucocorticoid receptor knockout mice exhibit increased hepatic CBG expression and 50% increased plasma CBG levels (59).

CBG Lyon refers to a CBG gene mutation that was first described in a 43-year-old Moroccan woman presenting with chronic fatigue, depressed mood and low blood pressure, suggesting adrenal insufficiency (60). She had very low plasma cortisol levels, but normal ACTH levels. She was found to be homozygous for a point mutation in exon 5, leading to an Asp-Asn substitution, and a 4-fold reduction in CBG-cortisol binding affinity. Immunoreactive-CBG levels were 50% of the lower limit of normal, suggesting that the mutation affects CBG secretion or degradation. The proband’s four children were heterozygous for the mutation. A 10-member Brazilian kindred with the same genetic mutation and reduced CBG-binding affinity has also been described, having been discovered after low cortisol levels were detected in the proband, a homozygote, who presented with fatigue (61). One other kindred member was a homozygote, the rest were heterozygotes, all were normotensive and none experienced fatigue.

In 2001, a 39-member Italian-Australian family was reported, including 21 heterozygotes and 3 homozygotes with a novel complete loss-of-function (null) CBG gene mutation involving exon 2 (62). The null mutation is a point mutation leading to a premature stop codon corresponding to residue -12 (tryptophan) of the pro-CBG molecule. It resulted in a 50% reduction of or undetectable CBG levels in heterozygotes or homozygotes, respectively. The proband was investigated because of unexplained fatigue and low blood pressure, suggesting glucocorticoid deficiency, and the finding of low plasma but normal urine cortisol levels, suggesting CBG deficiency. Amongst kindred members who were homozygous or heterozygous for the mutation, there was a high prevalence of chronic fatigue and low blood pressure. Surprisingly, five members had the previously reported CBG Lyon mutation.

Hence, CBG gene mutations are associated, albeit, inconsistently, with fatigue. Amongst CFS patients, the Lyon and Null mutations have not been detected (63- 65). To date several CBG mutations were identified following investigations of patients presenting with low plasma cortisol in variety of medical conditions such as chronic fatigue (66).

PITUITARY-ADRENAL HORMONE ABNORMALITIES IN CHRONIC FATIGUE SYNDROME

Recent interest in the role of the HPA axis in CFS has arisen from the observation that conditions in which there is low circulating cortisol are characterized by debilitating fatigue. Addison’s disease, glucocorticoid withdrawal, and bilateral adrenalectomy are all associated with fatigue and with other symptoms also seen in CFS, including arthralgia, myalgia, disturbed sleep, and mood (67). Many studies provide inconsistent data on HPA axis function in patients with CFS, in part because of methodological differences, but also reflecting, perhaps, individual variation in HPA axis activity.

Urinary free cortisol levels in CFS patients have been found to be significantly lower, or no different to, controls (68-71). Plasma morning and late evening cortisol has been shown to be reduced in CFS/ME, but this finding has not been consistently reproduced, particularly when frequent plasma cortisol sampling has been performed (69,71). Salivary cortisol has emerged as a useful test to detect hypercortisolism because of its non-invasiveness and correlation with free blood cortisol levels. In CFS, salivary cortisol day-curves are blunted compared with controls, evening salivary cortisol levels are lower, and there is a blunted salivary cortisol rise in response to waking (72-75). DHEA and its long half-life sulphated metabolite DHEA-S represent major adrenal gland products in terms of mass. They represent important contributors to circulating androgen activity, particularly in women. DHEA and DHEA-S levels were shown to be lower in 15 CFS patients relative to 11 controls; furthermore, CFS patients did not display the usual decrease in DHEA:cortisol ratio with ACTH stimulation (76). A preliminary study in eight selected CFS patients with a subnormal 1μg ACTH stimulation test showed a 50% reduction in adrenal gland volume on CT scan (77). This finding might indicate that the hypocortisolism of CFS is due to a lack of ACTH stimulation or a primary adrenal abnormality. In a recent study, however, DHEA levels were higher in CFS patients and were correlated with higher disability scores (78).

To further examine the endocrine axes, stimulation testing is a classic endocrine paradigm, where subtle hypofunction may become more evident through the administration of stimulatory hormones or neuroactive agents. Nevertheless, as central control of endocrine axes cannot be directly assessed due to the lack of accessibility of the hypothalamic-pituitary circulation, the interpretation of the findings tends to be indirect. Often it is necessary to implicate underlying receptor up or down-regulation or secondary adrenal atrophy. Moreover, neuroactive agents often have incomplete specificity and the central neurotransmitter systems under study may in fact not be exclusively tested.

Dynamic endocrine testing with human CRH (pituitary stimulus) in CFS patients revealed a trend towards lower cortisol responses – which became statistically significant if ACTH responses were analyzed as a covariate (79). ACTH responses to CRH may also be blunted in CFS (80). Other studies have found a normal ACTH and cortisol rise to CRH in CFS patients, which contradict the hypothesis, and previous data, suggesting that CFS is associated with a blunting of the HPA axis (81).

Insulin hypoglycemia is a profound stimulus of ACTH and cortisol release, as it is likely to induce release of many hypothalamic ACTH secretagogues. Studies in CFS have revealed increased ACTH but normal cortisol responses after insulin hypoglycemia (82). This could be interpreted as indicating low CRH tone, with chronic CRH hyposecretion despite an intact CRH neuron, and secondary adrenal atrophy.

Naloxone is thought to stimulate ACTH and cortisol secretion by blocking tonic opioidergic inhibition of the CRH neuron. Naloxone mediated activation may be blunted in CFS suggesting it is the CRH neuron or pathways inhibitory to this neuron that lead to HPA axis hypofunction in CFS, rather than increased opioidergic tone (83). Other studies of CFS patients have a normal ACTH and cortisol response to naloxone (81).

The waking cortisol response, where cortisol levels rise 30-50% by 30 mins after waking compared to levels immediately on waking, is attenuated in chronic fatigue syndrome as a result of both higher waking and lower 30 min salivary cortisol levels, as documented in 75 CFS patients versus controls (82).

Another explanation for the hypocortisolism of CFS is increased glucocorticoid sensitivity, particularly in relation to the cerebral structures involved in glucocorticoid feedback such as the hypothalamic-paraventricular nucleus, the site of CRH neurons, and the anterior pituitary and hippocampus. Increased glucocorticoid sensitivity has been described in other stress-related hypocortisolemic disorders, such as post-traumatic stress disorder, and has recently been reported in a small study of CFS patients (85).

Finally, it is not known if the hypocortisolism of CFS is a response to chronic deconditioning since exercise is a potent stimulator of HPA axis function. Experimental acute exercise deprivation led to some symptoms relating to pain, fatigue and mood as well as lower cortisol in a subset of healthy individuals (86).

CFS is associated with prominent features of autonomic dysregulation such as postural hypotension, disturbances in temperature regulation, and altered skin microcirculation. The other arm of the stress system, the sympathetic nervous system with its outflow components, the sympathoneural and sympathoadrenal limbs have been less studied than cortisol in CFS. However, studies of both norepinephrine levels and a variety of tests of autonomic function suggest hyperactivity of the SNS, perhaps as a response to inadequate HPA axis responsivity (87,88).

The data suggesting relative hypocortisolism in CFS, along with the co-existence of fatigue, low blood pressure, and mood alterations in both Addison’s disease and CFS, have led to trials of hydrocortisone therapy in CFS. A randomized crossover trial in 32 CFS patients, of low-dose hydrocortisone (5mg or 10mg) treatment compared with placebo showed a reduction in self-reported fatigue scores after 1 month of treatment (89). In 28% of patients taking hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score. Only 9% of patients taking placebo achieved this reduction in fatigue score. However, another trial of hydrocortisone treatment in CFS, have subsequently shown no real benefit of treatment. The trial which included 70 patients, treated with hydrocortisone (16mg/m2 daily in 2 divided doses) for 3 months reported some improvement in symptom scales (90). It is of interest that those with the lowest cortisol levels and adrenal reserve were not the most symptomatic, nor were they more likely to respond to hydrocortisone treatment. Adverse effects including weight gain, increased appetite, and disturbed sleep, occurred in those taking hydrocortisone. Hydrocortisone treatment was also associated with significant adrenal suppression, on the basis of basal and ACTH-stimulated cortisol levels in 12 patients. The authors concluded that the risks of adrenal crisis outweighed any perceived benefit of treatment and therefore that systemic corticosteroids should not be used in the treatment of CFS (90).

Blockmans et al., reported six month randomized, placebo-controlled, double-blind, crossover study of hydrocortisone (5mg/day) and fludrocortisone in 100 patients fulfilling the CDC criteria for CFS (91). There was no benefit of treatment on self-reported fatigue or well-being.

Fludrocortisone (0.1-0.2mg) was tested in a placebo-controlled, double-blind crossover trial. No improvement in symptoms, treadmill exercise performance, or reaction time was observed in the 20 CFS patients who completed the trial (92).

The available scientific data indicates that the symptomatic benefit achieved with hydrocortisone or fludrocortisone replacement is, at best, marginal, and importantly, may be associated with clinically significant adverse effects, including adrenal suppression or features of glucocorticoid excess. These adverse effects outweigh any perceived benefit of treatment. Overall, hydrocortisone and fludrocortisone treatment in CFS patients is not justified. In addition, ACTH stimulation testing has no practical relevance in the routine assessment of CFS patients, and should not be used to formulate management decisions, but may be used to rule out adrenal insufficiency.

Although low cortisol may not be the chief source of disability in CFS, it may be a marker of therapeutic significance. For example, the response to cognitive behavioral therapy is reduced in those with lower urine free cortisol or an attenuated diurnal rhythm (93).

The COVID-19 pandemic has led to a variety of symptoms after acute illness recovery. The recovery process from COVID-19 varies between individuals, depending on factors such as the illness severity, age, and underlying comorbidities. Despite not having a widely accepted definition, Centers for Disease and Prevention and the World Health Organization (WHO) has agreed the acute symptoms of COVID can last up to four weeks following the onset of the illness (94,95). Various terminologies such as “long COVID’, “post-acute sequalae of SARS-CoV-2 infection”, “post-acute COVID-19” have been used to describe the prolonged symptoms following COVID-19. In this article, we will use Long COVID to describe the condition.

While Long COVID and chronic fatigue syndrome/myalgia encephalitis (CFS/ME) are distinct conditions, they do share some similarities in terms of symptoms and impact on individual’s lives. Both conditions are characterized by persistent and debilitating fatigue. It is worth noting that CFS/ME is diagnosed after fatigue present for at least six months, which is not relieved by rest while fatigue experienced in Long COVID can last for weeks, months or longer. The accompanying symptoms of Long COVID syndrome are broad and can affect multiple organ systems including respiratory and cardiac symptoms, which does not typically present in CFS/ME (94- 97). While the triggering event of long COVID is attributed to COVID itself, the triggering event of CFS/ME is not fully understood. Patients with long COVID syndrome may have symptoms consistent with and meet diagnostic criteria of CFS/ME where similar assessment and management strategy can be employed.

MANAGEMENT

Generally, all treatment for CFS/ME must be individualized aiming to address the most debilitating symptom first. No specific treatment is known to be successful for CFS as the current evidence for pharmacological or non-pharmacological interventions was heterogenous and inconclusive (98). However, diagnosis may help patients by providing a basis for prognostic advice and validating their need for assistance in their personal lives and workplace.

Symptomatic treatments, such as non-steroidal anti-inflammatory drugs or non-opiate analgesics for pain and counselling or antidepressants for major depression, are commonly used in ME/CFS although their efficacy has not been the subject of a long-term trial. Developing good sleep hygiene to provide sufficient rest is often part of the management strategy. The latest NICE guideline also suggested dietary strategies including adequate hydration, referral to dietician for patients at risk of weight gain or malnutrition, as well as vitamin D repletion for vitamin D deficiency. It is important to explain to patients with ME/CFS that there is insufficient evidence to support routine vitamin supplementations as treatment for the condition (NICE) (98). Patients with significant cognitive decline should be referred for further neurocognitive evaluation.

Cognitive behavioral therapy involves the provision of information and counselling to reduce the psychological impediments to recovery, as well as encouraging the patient to participate at an appropriate level of social and occupational activity. It is important for clinicians to establish a rapport as patients may be mistrustful due to prior negative health care experiences (99). In randomized-controlled trials comparing CBT to control conditions, the intervention has been shown to have a positive overall effect (21). Graded-exercise therapy may also be of benefit (22).

No pharmacological agent has been reproducibly shown to be effective in the treatment of chronic fatigue syndrome.

Rintatolimod is an antiviral, restricted Toll-like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity. It also activates interferon-induced protein. A systemic review suggested some evidence that Rinatotolimod may improve symptoms of ME/CFS (100). Another double blind, randomized, placebo-controlled clinical trial showed statistically significant improvements in primary endpoints in phase II and phase III trials. About 30-40% of ME/CFS patients can be expected to respond beneficially to Rintatolimod (101). Previous double-blind, randomized clinical trial of Rintatolimod showed an improvement in exercise tolerance and improvement of medication usage for CFS/ME-related symptoms (102). However, the application to the US Food and Drug Administration (FDA) was rejected in 2009 as the previous RCTs that failed to provide credible evidence of efficacy (103). At present, Rintatolimod is only approved for use in Argentina. Therefore, some authorities suggest Rintatolimod should be considered an experimental drug until confirmatory studies are available (32).

Rituximab is an anti-CD20 monoclonal antibody. There may be some benefits shown in a small double-blind, placebo-controlled trials involving 30 patients, particularly in patients with self-reported fatigue, but a subsequent, larger study showed no difference in the treated group and the control group after 24 months of treatment (104,105).

A small trial revealed significant improvement in ME/CFS patients who received CoQ10 plus NADH supplementation, but a larger study is warranted to verify its beneficial effect in ME/CFS patients (106).

There is a list of therapies that have been trailed in the past, with no proven benefit over placebo. These therapies include acyclovir, antibiotics, cytokine inhibitors, galantamine, glucocorticoids, mofadanil, and methylphenidate (107-113).

PROGNOSIS

Overall, full recovery from untreated ME/CFS is rare but improvement of symptoms in long term is slightly more optimistic (114-116). However, the prognosis of ME/CFS also varies widely among individuals. The reported improvement rates range from 0 to 8% (117-122). Broad range improvement rate is reported at 17-64% (117,120,122,123). A study suggested although most patients with this condition improve, a significant proportion remain functionally impaired over time (118). Another study that was conducted using a questionnaire, reported 73% of patients remain functionally impaired at six weeks to six months but this improved to 33% at two to four years (115).

A systematic review showed the median full recovery only happened in 5% of patients (122). Another retrospective study that includes patients with unexplained debilitating fatigue lasting for more than six months but does not fulfil the criteria of ME/CFS showed complete resolution of symptoms only occurred in 2% of these patients (119).

As there was lack of operationalized criteria for recovery and improvement, the studies yielded contradictory results in terms of factors that predict the likelihood of recovery. Some studies suggested that old age is associated with poorer outcome while others did not support this hypothesis (118,119,124,125). There has been mixed evidence that shorter duration of illness to be a predictor of better improvement (118,121). Mixed evidence was demonstrated across studies with regards to a worse prognosis in patients with comorbid fibromyalgia (125-127). There may be an increased risk of suicide (128).

ME/CFS has not been associated with increased mortality rate. Treatment is supportive and a defined pathogenesis has not been identified, despite a syndromic definition that is quite frequent and stable across individuals and populations.

CONCLUSION

Many diagnostic criteria exist for MF/ CFS but the emphasis on exercise intolerance is thought to have significant specificity, although secondary features are also typical. The stress system has been shown to exhibit a reasonably consistent phenotypic pattern comprising relatively low cortisol and elevated sympathetic, particularly sympathoneural function. The etiology of ME/CFS is unknown and the mechanism of altered stress system function is uncertain. Several other pathogenetic mechanisms are proposed. Currently, some treatment trials have been promising and confirmation of their effect is awaited.

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