Pituitary Gigantism



Pituitary gigantism in a child is an extraordinarily rare condition that results from excessive production of growth hormone. It can present as early as infancy or not until adolescence. It may be congenital or acquired, occurring as a sporadic condition or in the context of a known syndrome in which hypersecretion of GH is a feature. Conditions in which GH excess occurs include Neurofibromatosis Type 1, McCune-Albright syndrome, Multiple Endocrine Neoplasia Type 1, Carney Complex, Isolated Familial Somatotropinomas, and X-Linked Acrogigantism. Therapeutic modalities for the treatment of pituitary gigantism are the same as those for acromegaly (adult-onset GH excess) and include surgery, medication, and radiation. Great strides have been made in identification of the molecular genetic basis for pituitary gigantism, affording novel insights into the mechanisms underlying normal and abnormal growth. Etiologies, phenotypic features, and diagnostic and treatment considerations are reviewed in this chapter.




A 13 year 6-month-old boy presents for evaluation of rapid growth. Parents report that he was always tall as a child, but they have noticed that he is now taller than most classmates. He developed signs of puberty (body odor, pubic hair) a year ago coincident with the onset of rapid growth. His parents are concerned and want to make sure “everything is normal”. He is asymptomatic other than periodic headaches that developed during the last year.


He was born appropriate for gestational age (AGA) at term following an uncomplicated pregnancy. By 1 year of age he was noted to be tall for his age, but this was attributed to the tall stature of his parents. Father stands 6’2” and Mother is 5’8”. They are both healthy. He is an only child.


Upon review of his medical record he has a growth velocity of 19 cm/year (7.5 in/year) over the last calendar year; last year at the PCP the height was 160 cm, which is at 82.7% (0.9SDS)


He is currently at the 99.0 % for height at 179 cm/70.5 inches (+2.36 SDS) thus confirming the rapid gain in height. (See attached growth curves. Figure 1) On physical examination he is tall, but proportionate. Visual field testing shows normal vision in all fields. Thyroid examination is normal. There are no areas of skin hyperpigmentation and no obvious skeletal abnormalities other than acral enlargement. Pubic hair is Tanner stage 3 and testicular volumes are 10 and 12 cc.

Figure 1. Growth curves

Bone Age is 14 years yielding a predicted adult height of 193.1 cm (76 inches) which, at +2.35 SDS, is above his family genetic height potential. A random serum GH concentration in the morning is 15 ng/ml with a corresponding IGF1 level of 720 ng/ml. (normal range for age and pubertal status in a male: 123-701 ng/ml). Because of the excessive growth and elevated IGF1, a GH suppression test was conducted. GH concentration 120 min after 75g of glucose administered orally was 4 ng/ml. An MRI of the brain was ordered.




Statural growth is a dynamic process that varies in children during development. Unlike adults who reach a final height greater than 2 SDS for their genetic, sex, and ethnic population of origin, the definition of gigantism in children must include a growth pattern that diverges from normal. This would include the child who exceeds expected growth curve (moving up from established percentiles) or has a growth velocity exceeding the normal range for sex, pubertal stage, and age. Once the growth rate is determined to be significantly greater than normal, establishing biochemical evidence of growth hormone hypersecretion is critical to the evaluation. Measuring IGF1 levels and assessing the suppressibility of GH following a glucose load are the most useful biochemical tests. Prompt MRI imaging evaluating size, invasiveness, and extrasellar extension of a pituitary adenoma is key. Since close to 50% of patients with pituitary gigantism have a discernable genetic cause, genetic counseling and testing are helpful in management. The case is continued at the end of the chapter.




The association between gigantism and acromegaly was recognized as early as the late 1880’s (1), when it was noted that pituitary giants invariably developed acromegalic features such as progressive enlargement of the head, face, hands, and feet (2). (See Appendix) The major difference between these two conditions is that pituitary gigantism results from excessive GH production during the period of active skeletal growth whereas acromegaly results from GH excess ensuing after epiphyseal fusion. A further distinction relates to the overall incidence of these disorders. While acromegaly is uncommon, occurring at an estimated worldwide annual rate of 2.8-4 cases per million (3), pituitary gigantism is extremely rare, with an estimated incidence of 8 per million person-years and the total number of reported cases thus far numbering only in the hundreds. Despite these disparities, a degree of clinical overlap is evident by the observation that 10% of patients with acromegaly have tall stature (4), indicating that the onset of GH excess pre-dated epiphyseal fusion in many.


GH hypersecretion may occur sporadically or within a constellation of abnormalities in the setting of several well- recognized syndromes. Conversely, a genetic predilection to the development of GH-secreting pituitary adenomas only may be present, as is the case in kindreds with isolated familial somatotropinomas. In recent years there has been increased recognition of the underlying molecular genetic abnormalities that lead to pituitary gigantism, one of which can be identified in approximately 50% of cases (5). Regardless of the underlying etiology, the clinical manifestations of chronic GH hypersecretion in childhood are indistinguishable, and the initial diagnostic evaluation standardized. The various categories and sources of GH excess along with their associated genetic abnormalities are discussed individually.




Unlike in acromegalic adults, in whom discreet pituitary adenomas are present in the overwhelming majority (6), several different pathologic mechanisms underly childhood GH hypersecretion. These relate to the concept that pituitary gigantism represents a distinct entity, with different characteristics in terms of pituitary morphology and function. Supporting this view are reports of diffuse pituitary hyperplasia in the setting of early-onset gigantism in which congenital growth hormone releasing-hormone (GHRH) excess has been proposed as the inciting cause (7;8). Additionally, the nearly ubiquitous finding of combined GH and prolactin over-secretion in nearly all cases of early childhood gigantism, a feature not universally present in acromegaly, suggests separate pathologic processes. This dual hormonal secretion has been attributed to the presence of mammo-somatotrophs (9;10), which are rare in adults but predominate in fetal life. Even in cases of apparent pituitary microadenomas or macroadenomas arising during early childhood, this unique biochemical feature has been present (11;12). In contrast, prolactin levels are usually normal in cases of pituitary GH-secreting adenomas originating during adolescence, which may be thought of as existing within the spectrum of adult GH hypersecretion. Interestingly, a reversible transformation of pituitary somatotrophs into bi-hormonal mammo-somatotrophs when exposed to ectopic overproduction of GHRH has been observed, lending additional support to the concept that hypothalamic GHRH excess may play a pivotal role in the genesis of early-onset gigantism (13).


GH-secreting tumors are all derived from PIT1-lineage cells. Those composed of somatotrophs may be densely granulated, resembling normal somatotrophs, or sparsely granulated with unusual fibrous bodies. As mentioned above, those composed of mammo-somatotrophs also produce prolactin whereas rare pluri-hormonal tumors composed of cells that resemble mammo-somatotrophs also produce TSH. Some pituitary neuroectodermal tumors (PitNETs) composed of immature PIT1-lineage cells that do not resemble differentiated somatotrophs, mammo-somatotrophs, lactotroph, or thyrotrophs may also cause GH excess. An unusual oncocytic PIT1-lineage tumor known as the acidophil stem cell tumor is predominantly a lactotroph tumor but may express GH. Immature PIT1-lineage cells that express variable amounts of hormones alone or in combination can also sometimes cause GH excess (14)


An additional cause of sporadic pituitary gigantism linked to CNS pathology is that which occurs in the setting of a hypothalamic gangliocytoma or neurocytoma. These rare tumors, comprised of large hypothalamic-like ganglion cells, produce GHRH (15;16) and are found in close proximity to pituitary growth hormone-secreting adenomas (17). Normalization of serum growth hormone levels following resection of the hypothalamic tumor in some patients further supports a central role for abnormal GHRH secretion in the development of gigantism or acromegaly in these cases (18).




A second major category of childhood GH hypersecretion is that which occurs in the setting of a recognized syndrome. In these cases, gigantism may be the sole presenting feature or it may be detected during clinical follow-up for endocrine or nonendocrine problems. Alternatively, biochemical evidence of sub-clinical GH excess may be revealed through routine surveillance in a child known to be at risk for the development of gigantism. As is the case in sporadic GH hypersecretion, a variety of different morphologic abnormalities involving the pituitary gland may be found. Paracrine pituitary GHRH secretion has also been implicated by the discovery of GHRH expression from clusters of cells in the hyperplastic pituitaries of two boys from a family with hereditary early-onset gigantism (19). Syndromes that are associated with the development of childhood GH excess are reviewed below. Table 1 outlines the characteristics of the GH excess and other clinical features in these disorders.


Table 1. Clinical Characteristics in Syndromic and Familial Pituitary Gigantism


Mode ofInheritance

Clinical Features

Frequency ofGigantism

Typical Age of Presentation




Neurofibromatosis -1

Autosomal Dominant or Sporadic

·       Optic gliomas

·       Café au lait skin pigmentation

Extremely rare

6 months on

Optic pathway tumor with normal to small pituitary

Not routine

McCune- AlbrightSyndrome


·       Precocious Puberty

·       Café au lait skin pigmentation

·       Fibrous bone dysplasia

·       Multiple endocrinopathies


Early childhood on

Pituitary adenomas or diffuse pituitary hyperplasia or no visible abnormality


Multiple Endocrine Neoplasia Type 1

Autosomal Dominant or Sporadic

Pituitary, pancreatic and parathyroid adenomas


10% by

age 40 but has occurred as early as age 5

Pituitary adenoma

Annually beginning at age 5

Multiple Endocrine Neoplasia Type 4

Autosomal Dominant or Sporadic

Pituitary, pancreatic and parathyroid adenomas



Pituitary adenoma

Not established

Carney Complex

Autosomal Dominant or Sporadic

Multiple endocrine tumors

Skin lentigines

Cardiac myxomas

Neural sheath tumors


Usually 3rd & 4th decade

Pituitary adenoma or pituitary hyperplasia

Annually beginning post-pubertally

3PA Association

Autosomal Dominant or Sporadic

Pheochromocytoma, paraganglioma, pituitary adenoma


Usually 3rd & 4th decade

Pituitary adenoma with intracytoplasmic vacuoles

As clinically indicated in unaffected family members

Isolated Familial Somatotropinomas

Autosomal Dominant or Sporadic

Isolated GH- secreting pituitary adenomas


Before 3rd decade and as early as age 5

Pituitary adenoma

As clinically indicated in unaffected family members

X-linked Acrogigantism

Sporadic or X- linked

Isolated GH excess


Early childhood with onset in late infancy or onset during adolescence

Pituitary adenoma or pituitary hyperplasia or both

As clinically indicated in unaffected family members


Neurofibromatosis-1 (NF-1)


  Beginning in the 1970’s, reports of gigantism occurring in young children with NF-1 have appeared in the medical literature (20). In these cases, excessive growth has been noted as early as 6 months of life (21).  Neuroimaging in these patients typically reveals an optic glioma (22), usually with infiltration into the medial temporal lobe. However, growth hormone excess has frequently been reported to be a transient phenomenon in children with NF-1, raising questions as to the necessity of treatment (23,24). Several investigations aimed at identifying the precise etiology of the gigantism in these children have been conducted, but in all cases in which tumor tissue has been available, immunostaining for GH, GHRH, and somatostatin has been uniformly negative (25;26). This, in conjunction with the known temporal lobe location of somatostatin-producing neurons, led to the hypothesis that GH excess in these patients was the result of a hypothalamic regulatory defect. Specifically, tumor infiltration of somatostatinergic pathways would presumably result in reduced somatostatin tone leading to overproduction of GHRH-mediated pituitary GH. Despite this plausible explanation, arginine-induced GH stimulation in a patient with gigantism in the setting of NF-1 showed an increase in GH secretion, contrary to the expected lack of response to arginine, which acts through somatostatin inhibition (27). Thus, the precise pathogenesis of gigantism in NF-1 remains unclear. Little information is available regarding the overall incidence of GH hypersecretion in patients with NF-1 and optic gliomas, although studies have suggested that it may occur in over 10% of affected patients, some of whom have concurrent central precocious puberty (28). Interestingly, all affected patients had a tumor involving the optic chiasm, without pituitary involvement. Optic pathway tumors are usually identified on magnetic resonance image scans as a contrast enhancing mass. (28). Interestingly, growth hormone excess has also been reported in children with sporadic optic pathway tumors without associated NF-1 (29). Figure 2 demonstrates the linear growth acceleration and figure 3 the café-au-lait pigmentation observed in a young boy with NF-1 and gigantism.

Figure 2. Growth acceleration seen in neurofibromatosis and gigantism.

Figure 3. Characteristic “coast of California” café au lait macules in a child with neurofibromatosis and gigantism.

McCune-Albright Syndrome (MAS)


MAS is a complex and heterogenous disorder in which GH excess typically arises in conjunction with additional endocrinopathies and other abnormalities. In the classic form, MAS displays the triad of precocious puberty, café-au-lait skin pigmentation, and fibrous dysplasia of bone. It has long been recognized, however, that individuals with MAS have a propensity to develop several additional endocrine disorders including gigantism or acromegaly (30).


  Elucidation of the molecular genetic defect in MAS in the early 1990’s (31) illuminated the mechanism underlying the abnormal hormone secretion. Activating mutations of Gsα, the stimulatory subunit of the heterotrimeric G-protein complex involved in intracellular signaling, are the basis for nearly all of the clinical manifestations of MAS (32). These mutations, which typically involve substitution of arginine at the 201 position with cysteine or histidine, result in unregulated signal transduction leading to increased intracellular cAMP accumulation and downstream gene transcription. All affected individuals are mosaic for the mutation, which may make confirmation with a molecular diagnosis challenging. The precise timing of the mutation during embryologic life, which occurs in a post-zygotic cell line, will ultimately determine the extent of abnormal cells and severity of the resultant clinical phenotype. The incidence of GH excess in classic MAS has been reported to be 15-21% (33.34) and may be more common in males (34). However, enhanced recognition of the frequency of atypical or forme fruste variants of MAS have the potential to increase the estimated frequency. Indeed, several historical reports of extreme gigantism where fibrous bone dysplasia was also present strongly suggest a diagnosis of MAS in these individuals, a hypothesis confirmed by molecular genetic analysis in at least one case (35.36). Subclinical growth hormone excess has also been reported in MAS, in which the only clinical manifestation may be the presence of normal stature as an adult (rather than short stature) in the context of a history of untreated precocious puberty. Additional phenotypic features in this subgroup of patients with MAS include a higher incidence of vision and hearing deficits, a rise in serum GH following a TRH test, and hyperprolactinemia (37). Growth hormone excess in MAS is typically accompanied by skull base fibrous dysplasia and is notorious for increasing craniofacial morbidity and macrocephaly (38). Early diagnosis and treatment have been found to decrease the risk of optic neuropathy in these patients (39).


A variety of pituitary morphologic abnormalities are found on histology and imaging in MAS patients with GH hypersecretion (40), ranging from discrete pituitary adenomas (41,42) to diffuse pituitary hyperplasia (7), to no discernible radiographic abnormality (43). Of note is the fact that the Gsα mutation found in MAS is identical to that implicated in the pathogenesis of sporadic GH-secreting pituitary adenomas, where it results in the formation of the GSP oncogene. Up to 40% of somatotroph adenomas in adults contain either an Arg201 activating mutation, or a related point substitution of glutamine at position 227 (44). Interestingly, these sporadic tumors, as well as those from patients with MAS and acromegaly, display the Gsα mutation exclusively from the maternal allele, providing evidence that the GNAS1 gene is subject to imprinting (45). Figure 4 demonstrates an area of classic café au lait skin pigmentation that crosses midline and has serrated edges in a patient with MAS.

Figure 4. Café au lait pigmentation in the typical “coast of Maine” configuration in an individual with McCune-Albright syndrome.

Multiple Endocrine Neoplasia-Type I (MEN1)


  MEN1 is a familial cancer syndrome characterized by autosomal dominant inheritance and multi-endocrine gland involvement. Although significant clinical heterogeneity exists in terms of specific tumor combinations, the most frequent manifestations of MEN1 are parathyroid, pancreatic, and pituitary adenomas (46). The gene for MEN1, which had previously been mapped to chromosomal locus 11q13, encodes the 610 amino acid nuclear protein, menin (47). Many different molecular genetic abnormalities within the menin gene have been identified in kindreds with MEN1, including nonsense, missense, deletion, insertion, and donor-splice mutations (48); genotype/phenotype correlations have not been observed. In all cases of MEN1, the development of neoplasia is thought to arise from a defect in normal tumor suppression via a 2-hit hypothesis. The first hit represents inheritance of a germline MEN1 mutation, leading to a heterozygous loss of the MEN1 gene in every cell (49). As menin is believed to function as a tumor suppressor protein, the second hit involves a somatic MEN1 mutation in one cell, with subsequent abnormal cellular transformation and clonal expansion. Indeed, somatic biallelic MEN1 mutations have been demonstrated to be present in at least 15% of sporadic pituitary adenomas, including somatotroph tumors (50). Anterior pituitary adenomas in individuals with known MEN1 have a reported prevalence of 10-60% and are thought to represent the first clinical manifestation of the disease in up to 25% of sporadic cases (51). Of these, the majority are prolactinomas, with GH-secreting adenomas developing in approximately 10% of individuals with MEN1 by age 40. The youngest reported case of gigantism in MEN1 occurred in a 5-year-old boy, who presented with growth acceleration and a GH-secreting mammo-somatotroph adenoma in the context of a family history of MEN1 (52). Molecular genetic analysis confirmed the germline and tumor tissue MEN1 mutations but failed to reveal an etiology for the accelerated presentation in this case. Nonetheless, current recommendations include screening for anterior pituitary hormone excess beginning at age 5 in all individuals with MEN1, as well as ascertaining MEN1 carrier status by germline mutation testing in several clinical situations (53). Interestingly, GH excess due to ectopic elaboration of GHRH from a pancreatic neuroendocrine tumor has also been reported in several individuals with MEN1 (54).


Multiple Endocrine Neoplasia-Type 4 (MEN4)


MEN4 is caused by germline mutations in the CDKN1B gene which encodes the putative tumor suppressor p27Kip1 (55). Affected patients are typically heterozygous for mutations in CDKN1B and exhibit a phenotype similar to that seen in MEN1. Because of the low number of individuals diagnosed with MEN4, screening protocols for patients and their family members have not yet been established (56).


Carney Complex (CNC)


Initially described in 1985 (57), CNC is a rare autosomal dominant disorder in which the cardinal features include multiple endocrine tumors, skin lentigines (spotty pigmentation), cardiac myxomas and neural sheath tumors. The condition shares characteristics with several other syndromes, including MEN1 (multiple endocrine tumors), MAS (endocrine hyperfunction and skin pigmentation) and Peutz-Jeghers syndrome (mucosal lentiginoses and gonadal tumors), but has a unique clinical and molecular genetic identity. Two distinct genetic abnormalities have been implicated in the pathogenesis of CNC. The first is found on 2p16 (58), although a specific candidate gene within this region has not been identified. The second involves mutations in the gene encoding the protein kinase A regulatory subunit (1α) (PRKAR1A) and explains 35-44% of both familial and sporadic cases of CNC (59). This protein, which is intricately involved in endocrine cell signaling pathways, is thought to function as a tumor suppressor. Supporting this theory has been the observation that tumors from patients with CNC (in which diminished levels of PRKAR1A are present) exhibit a 2-fold increase in cAMP responsiveness compared with control tumors (60).The identical mutation has also been found in some sporadic endocrine tumors. As with MEN1, a germline mutation is thought to be the inciting event for eventual development of the disease. The clinical presentation of CNC is extremely heterogeneous,as is the age at diagnosis. The development of GH excess is rare, occurring usually during the 3rd   and 4th decades of life, and typically found in only 10% of patients at the time of presentation (61). Thus, annual screening for GH hypersecretion is recommended only in post pubertal patients. As in cases of gigantism/acromegaly in the setting of MAS, diffuse pituitary hyperplasia (62) and concomitant hyperprolactinemia (63) are frequently seen in individuals with CNC and GH excess.


3PA Association


The constellation of paraganglioma, pheochromocytoma, and pituitary adenoma is termed 3PA Association and has been shown to be due to germline mutations in subunits of succinate dehydrogenase (56;64). Growth hormone excess typically occurs in the 3rd and 4th decades of life (65). To date, no pediatric patients with pituitary gigantism in the setting of the 3PA phenotype have been reported.


Familial Somatotropinomas


  It has long been recognized that isolated pituitary gigantism or acromegaly may occur in a familial pattern. This condition, “Familial Isolated Pituitary Adenomas” (FIPA), is defined as “the development of pituitary adenomas of any type in two or more members of a family in the absence of clinical and genetic evidence of other known syndromic diseases”.  At least 46 different affected kindreds have been reported (66). Unlike in MEN1 and CNC, GH excess tends to arise early in life, with 70% of those with the disorder diagnosed before the 3rd decade. Early childhood gigantism in this setting has also occurred, involving sisters with abnormal linear growth since age 5 (67) and a more virulent course than is seen in sporadic somatotropinomas has been suggested by a case series (68). Once assumed to represent a variant of MEN1, mutations within the menin gene as the etiology for FIPA were conclusively excluded (69;70). However, the precise molecular genetic basis for the development of pituitary GH-secreting adenomas in the majority of affected families has eluded detection. Initial investigation revealed loss of heterozygosity and linkage to a 9.7 Mb region of 11q13, suggesting the presence of an additional putative tumor suppressor gene in this region,distinct from that involved in MEN1. Subsequent studies identified inactivating mutations in the gene encoding aryl hydrocarbon receptor interacting protein (AIP) at 11q13.3 in 15%-25% of families with FIPA (71-73) making it the most common genetic defect found in these kindreds. Although the mechanism by which these mutations cause pituitary adenomas is unknown, the resulting phenotype is characterized by early-onset and aggressive disease. In an amazing case of medical sleuthing, a germline AIP mutation identified in DNA from the preserved teeth of an 18th century Irish giant was found to be an exact match for the mutation harbored by four contemporary Irish families with FIPA, indicating a common ancestor dating back more than 50 generations! Interestingly, a second potential locus for FIPA has been mapped to 2p12-16, very close to the region implicated in several kindreds with CNC (66). Additional molecular genetic analysis performed in these patients has included a search for germline mutations within the GHRH receptor gene, Gsα and Gi2α genes, all of which were normal. Similar to observations in MEN1, patients with FIPA have discreet pituitary adenomas, the majority of which are comprised solely of somatotrophs (75). However, prolactinomas, gonadotropinomas, and silent pituitary adenomas may occur in different members of the same kindred (76;77) . Macroadenomas with invasion into the cavernous sinus are common in the setting of FIPA, and treatment is notoriously difficult (77).


X-Linked Acrogigantism


An additional cause of familial gigantism and acromegaly is due to microduplication of Xq26.3 and termed X-linked acrogigantism (X-LAG). This genomic duplication was initially identified in 14 patients with gigantism and is associated with both sporadic and familial cases (78; 79). Of the four genes contained in the duplicated region, the growth hormone excess appears to result from an abnormality of GPR101, a gene that encodes for an orphan G-protein coupled receptor. This gene is markedly over-expressed in pituitary tissue from affected patients. The condition can result from either germline or somatic duplications in GPR101 and has a female predominance (80, 81). That more girls than boys have X-LAG might be related to their greater number of X chromosomes. However, a potentially lethal effect of an Xq26.3 microduplication on hemizygous male embryos is also a proposed explanation (82). Mosaicism for GPR101 duplication resulting in X-LAG has also been reported in sporadic cases involving boys (83). Patients harboring the Xq26.3 microduplication exhibit a distinct phenotype characterized by strikingly early gigantism with a median age of onset of 12 months. In addition to hypersecretion of GH, elevated circulating GHRH and prolactin have also been noted (84). Both pituitary adenomas and pituitary hyperplasia have been seen among cases testing positive for X-LAG. This discovery highlights new biological processes that will undoubtedly lead to novel insights regarding the central regulation of human growth.


A summary of the genetic abnormalities causing gigantism and their putative abnormalities is shown in figure 5.

Figure 5. Schematic of disorders leading to pituitary gigantism, genetic loci, and their putative targets. NF1: Neurofibromatosis type 1; XLAG: X-linked acrogigantism; MAS: McCune-Albright syndrome; CNC1: Carney complex type 1; FIPA: Familial isolated pituitary adenomatosis; MEN1: Multiple endocrine neoplasia syndrome type 1; MEN4: Multiple endocrine neoplasia syndrome type 4. The MEN syndromes display unrestrained cell replication due to lack of a tumor suppressor whereas the others affect the GH secretory pathway at the points shown. See text above for details.



As would be predicted, linear growth acceleration is the cardinal feature of excessive GH production in a child or adolescent. However, the excessive linear growth observed in young children with gigantism may be accompanied or even preceded by macrocephaly and or increased weight for height. (9;11). In a large international study of patients with pituitary gigantism, the median onset of rapid growth was 13 years and occurred earlier in girls than in boys (85). Additional clinical features frequently encountered include frontal bossing, broad nasal bridge, prognathism, excessive sweating, voracious appetite, coarse facial features, and enlargement of the hands and feet. Bone age radiographs in these patients have been reported to be normal or advanced, even in the complete absence of sex steroid production. Figure 6 demonstrates the prognathism, coarse facial features and typical tall stature seen in a 12-year-old boy with gigantism, and Figure 7 illustrates enlargement of the hands in this same patient.

Figure 6. Twelve-year-old boy with pituitary gigantism measuring 6’5” with his mother. Note the coarse facial features and prominent jaw.

Figure 7. Enlarged hand of the same patient in comparison with the hand of an adult male with a height of 6’1”. The patient’s middle digit has a circumference of 9 centimeters.

The most consistent biochemical abnormality observed in patients with gigantism is an elevated IGF-1, which is known to exhibit an excellent correlation with 24-hour GH secretion (86). As previously mentioned, hyperprolactinemia is extremely common in early-onset GH hypersecretion. Depending on the individual situation, the additional pituitary screening evaluation may be normal, indicative of hypopituitarism, or central precocious puberty. Concurrent endocrinopathies may also be present, particularly in patients with syndromes such as MAS or MEN1. Rarely, alterations in glucose tolerance brought about by GH excess may result in the development of overt diabetes, leading to transient diabetic ketoacidosis (87-89) which may even be the presenting feature in rare instances (90). An additional physiologic effect of GH excess that may have clinical significance is that of increased erythropoiesis, as demonstrated by a case of acromegaly-induced polycythemia vera that resolved following surgical resection of the GH-secreting adenoma (91). The importance of GH in the regulation of red blood cell production has further been supported by the observation that pre- treatment hemoglobin concentrations in children with idiopathic growth hormone deficiency are lower than controls (92)




The gold standard for making the diagnosis of GH excess relies on the inability to suppress serum GH concentration following an oral glucose load. While the OGTT has been the diagnostic test of choice for many years, numeric guidelines for the expected degree of suppression in a normal individual have steadily decreased. This trend is the direct result of newer assays with an improved threshold of sensitivity for detection (93).  A normal response to a standardized glucose bolus (1.75 gm/kg up to 75 grams) utilizing the newer IRMA/ICMA assays is a GH level below 1 ng/ml (94). However, given the observation that recurrence of GH excess may be detected in patients with a GH nadir less than 1 ng/ml, and that healthy subjects nearly always suppress to below 0.14 ng/ml, some investigators have suggested that the 1 ng/ml cut-off is too liberal (95). The nadir in serum GH is typically occurs within the first 2 hours of the test. Occasionally, 24-hour integrated GH assessment may be helpful in cases in which an equivocal response to OGTT is seen (96). Despite the development of highly sensitive GH assays, generalizability of results across institutions or regions is hampered by significant heterogeneity in the availability of reference preparations and methods used by specific laboratories (97). Depending on the individual circumstance, measurement of peripheral GHRH may also be indicated to investigate the possibility of ectopic GHRH secretion. Once biochemical evidence of GH excess has been demonstrated, MRI scanning of the H-P region is obviously the next step. Figure 8 illustrates the typical appearance of a GH-secreting pituitary macroadenoma in an adolescent with gigantism.

Figure 8. Pituitary somatotroph macroadenoma in an adolescent with gigantism.

A potential pitfall in the evaluation of gigantism in adolescents is the fact that significant elevations of IGF-1 may be present during normal puberty (98). Moreover, growth hormone response to an oral glucose load in normal children has been found to be gender and pubertal-stage specific, with the highest nadir GH occurring in Tanner stage 2-3 girls (99). The effect of sex steroids on IGF-1 and GH suppression must also be considered when a diagnosis of gigantism is being considered in a child with concurrent precocious puberty, as may be the case in NF-1 or MAS. Adding to the possible diagnostic ambiguity is the fact that a significant percentage of normal tall adolescents fail to suppress serum GH in response to oral glucose testing (100). Therefore, both screening and definitive testing for GH excess should be performed in the context of high clinical suspicion, and IGF-1 levels interpreted according to age and pubertal stage-adjusted normal ranges (see figure 9).

Figure 9. Schematic evaluation of patients with suspected pituitary gigantism



No large-scale studies evaluating various therapeutic approaches to the treatment of GH excess in pediatric patients are available. Therefore, the optimal treatment of gigantism has traditionally been extrapolated from the adult literature as well as case reports or small series involving children. As is the case in adults, the three separate modalities available for the treatment of children and adolescents are surgery, radiation, and medical therapy. Of these, the greatest recent advances by far have occurred in the realm of pharmacologic agents, resulting in an exciting armamentarium of drugs promising truly enhanced efficacy and excellent safety. Regardless of the individual treatment strategy, the goals of therapy remain the same, namely the restoration of GH and IGF-1 levels to normal (101). Of all parameters investigated, GH levels themselves appear to correlate best with overall morbidity and mortality in acromegaly (102). Table 2 summarizes the current therapeutic options as they pertain to pediatric patients, each of which is discussed below.


Table 2. Therapeutic Modalities in GH Excess in Pediatric Patients



Specific Options

Current Indications

Pediatric Experience


Transphenoidal resection

Pituitary microadenoma or macroadenoma

Performed safely in children as young as 2 years old




Conventional radiation

Adjuvant to surgical or medical therapy

Typically avoided if at all possible, but has been used as adjuvant therapy

Stereotactic radiosurgery,ex: gamma knife

Adjuvant therapy in patients with residual GH hypersecretion

No experience with use in children

Medical Therapy

Somatostatin analogues

·       Octreotide (Sandostatin)

·       Lanreotide

·       Primary therapy in cases of diffuse pituitary hyperplasia or severe bone disease

·       Adjuvant to surgery or radiation

·       Ectopic GH excess

Used safely in children with both sporadic and syndromic gigantism for extended periods of time alone and in combination with dopamine analogues

Depot somatostatin analogues

Sandostatin LAR


·       Same as above

Safety and efficacy appear equivalent to non-depotpreparations

Dopamine agonists

·       Bromocriptine


·       Adjuvant to somatostatin analogues and other therapies

·       Particularly useful when concurrenthyperprolactinemia is present

Used safely in children in combination with somatostatin analogues

GH receptor antagonists


·       Particularly useful for treatment of refractory disease

Has been used alone and in combination with somatostatin analogues Preliminary experience in children appears promising




Transphenoidal resection is the treatment of choice for discreet pituitary microadenomas or macroadenomas (103), with the objective being preservation of pituitary function in association with the elimination of the GH excess, as evidenced by a rapid normalization of serum GH levels (often within one hour) and response to OGTT.  Not surprisingly, the expertise of the individual surgeon impacts the likelihood of success (104). However, while surgery cures the majority of patients with microadenomas, less than 50% of patients with macroadenomas are cured of their disease (105, 106). Moreover, extended post-operative follow-up has revealed a gradual return of GH excess over time in a substantial number of patients in whom the disease was previously deemed to be well controlled (107;108). In one large retrospective study of 208 patients with pituitary gigantism, long-term control of GH/IGF1 was achieved in only 39% (108). Experience with surgical treatment of gigantism in children and adolescents has been comparable to that observed in adults (109;110), and it has been employed safely in patients as young as 24 months (12). Although further investigation is needed, a potential role for pre-operative medical therapy has been suggested by studies indicating higher surgical remission rates and lower anesthesia risk following a several month course of a somatostatin analogue (111).




Although traditionally included as a therapeutic option, significant problems exist with the use of conventional radiotherapy in gigantism or acromegaly. These include a low level of efficacy, delayed normalization of GH levels, and a high incidence of hypopituitarism. In the setting of MAS, radiation therapy for GH hypersecretion may contribute to malignant transformation of dysplastic bone tissue (112). Additional concerns particularly relevant to children include potential adverse neurocognitive effects and the possible development of hypothalamic obesity, both of which have been linked to cranial irradiation in pediatric patients (112;113). Therefore, radiation therapy would be considered a last resort. Improved precision and safety are observed with use of stereotactic radiosurgery in the form of the gamma knife technique, which has been successfully employed as adjuvant therapy in adults with acromegaly (112;114-116).


Medical Therapy


Although most commonly considered adjunctive to surgery or radiation, a primary role for medical therapy has always existed for those patients with diffuse pituitary hyperplasia or severe bony deformities precluding a surgical approach. As tremendous improvements in the pharmacologic agents available for use in GH excess continues to evolve (117), the number of patients offered medical therapy as first-line treatment will surely expand. The three currently existing classes of drugs for suppression of GH and IGF-1 levels are reviewed below.




Ever since their development in the mid-1980’s, long-acting analogues of somatostatin have held a pivotal place in the medical treatment of GH excess. These agents act by binding to somatostatin receptors within somatotroph adenomas (118). By far the greatest experience in the United States has been with octreotide, which is typically administered subcutaneously in three divided doses daily. Short-term administration of octreotide decreases GH levels within one hour in > 90% of patients with acromegaly (119), while sustained use normalizes GH and IGF-1 levels in up to 65% of patients (120). Experience with the use of octreotide in children has been similarly favorable, where it has been beneficial in the treatment of sporadic as well as syndromic gigantism (121;122). Continuous subcutaneous infusion of octreotide has also resulted in superior efficacy in controlling GH hypersecretion in a pubertal patient (123). Long-acting depot preparations of octreotide in the form of Sandostatin LAR and SR-lanreotide are also available, in which a slow release of drug is achieved through degradation of a polymer in which microspheres are encapsulated (124). This allows for monthly IM administration, resulting in a safety and efficacy profile that is comparable to or improved in contrast to traditional dosing (125). Both slow-release preparations have also been used in the treatment forms of GH excess due to ectopic GHRH secretion (126) and in MAS associated gigantism (127-129), and have been noted to have equivalent safety and efficacy (130). The development of novel somatostatin analogues has the potential to improve efficacy over existing agents (131). The major side effect of all the somatostatin analogues is an increased risk of biliary sludge and gallstones after sustained use, necessitating periodic ultrasound examinations in patients treated long-term (132).




Although rarely effective alone, dopamine agonists have a valuable role as adjunctive agents in the treatment of GH excess. Due to their suppressive effects on prolactin, these drugs are particularly advantageous when hyperprolactinemia is also present, as is often the case in childhood-onset gigantism. Both bromocriptine and the more potent dopamine agonists such as cabergoline have been administered to children in combination with octreotide long-term with no apparent adverse effects (128).




The latest development in the realm of medical therapy has been the emergence of pegvisomant, a genetically engineered human GH analogue that acts as a highly selective GH antagonist (133). This is achieved through alterations in GH structure altering receptor binding compared to the native GH molecule (121), resulting in prevention of the normal extracellular dimerization of the growth hormone receptor. Administration of pegvisomant long-term to adults with acromegaly has been shown to result in normalization of serum IGF-1 levels in 97% of patients (134). Despite these extremely promising results, the implications of the nearly ubiquitous elevations in serum GH levels observed in conjunction with pegvisomant treatment initially created some concerns. Although early reports recounted an increase in tumor volume and abnormal liver enzymes in association with pegvisomant use (135;136), long-term follow has demonstrated that these complications are rare and that efficacy is very good (137;138). Combination therapy using pegvisomant along with a dopamine agonist or somatostatin analogue also appears promising (137). Thus far, preliminary experience with the use of pegvisomant alone or in combination with a somatostatin analogue for the treatment of gigantism in children also appears favorable (139). This approach resulted in successful normalization of IGFI levels in a 4 year old with NF-1 (140), a 12 year old with MAS (141), and a couple of children with persistent GH hypersecretion following surgical removal of a pituitary adenoma who had failed a somatostatin analogue (142;143). Even more reassuring is a report of long-term (up to 3.5 years) treatment using pegvisomant in 3 children with gigantism, all of whom experienced a decline in growth velocity and resolution of acromegalic features(144).


Treatment of Tall Stature


Medical treatment of children and adolescents with tall stature was more common in the past (145), particularly for girls, but is now strongly discouraged except in exceptional cases. This is because of increased cultural acceptance of tall stature and recognition of side effects of treatment, which include reduced fertility (146) and increased prevalence of depression (147) not related to adult height. Depending on the absolute height and the degree of growth potential remaining, one of the goals in the treatment of gigantism may be prevention of further linear growth in these exceptional cases. When this is the case, acceleration of epiphyseal fusion can be achieved with exogenous sex steroids (145). Short-term administration of both high dose testosterone and estrogen have been utilized for this purpose in children with gigantism, resulting in significant improvements in terms of adult height (148;149). However, such an approach would require great caution given reports of subfertility in women who were treated with high dose estrogen during adolescence with the goal of attenuating growth in the setting of constitutional tall stature (150;151).




The differential diagnosis of pituitary gigantism includes a significant number of heterogeneous disorders exhibiting a vast array of clinical and genetic features (66). In most cases, the history, physical examination and adjunctive biochemical, imaging, and/or molecular genetic testing will ultimately reveal the diagnosis. Albeit rare, pituitary gigantism affords the unique opportunity for a glimpse into the complex mechanisms of growth regulation. Thus, continued clinical and scientific investigation will enhance not only individual patient care, but also collective insight into the intricacies of the fundamental processes of human growth.




The MRI revealed a pituitary macroadenoma after which he underwent transsphenoidal surgery. Histopathological diagnosis was mammosomatotropic adenoma. Three months after surgery, IGF-1 normalized, nadir GH during OGTT suppressed to less than 1 ng/mL and no residual tumor was found on the MRI. Genetic testing identified a mutation in the AIP gene. This case points out the importance of early diagnosis of gigantism, as treatment delay increases long-term morbidity.




  • Pituitary gigantism is rare but important condition resulting from excessive secretion of GH (and therefore IGF1) before fusion of epiphyseal growth plates leading to tall stature, acral enlargement, facial changes, headaches, and excessive sweating.
  • Excessive linear growth is the cardinal feature of excessive GH production in children and adolescents who have open epiphyseal growth plates.
  • There is a male preponderance (78%) in pituitary gigantism in contrast to the slight female predominance (54.5%) observed in acromegaly.
  • Once growth hormone (GH) hypersecretion has been established, prompt studies to examine pituitary anatomy and define the etiology via family history and genetic testing should be performed.
  • Normalization of GH and IGF-1 levels is the goal of therapy
  • Because nearly 50% of patients with pituitary gigantism have a known underlying genetic cause, these patients should receive genetic counseling and testing for mutations.
  • Somatotropinomas in pituitary gigantism are usually large (macroadenomas) and difficult to cure with surgery or medical therapy alone.
  • Patients with large tumors and multiple surgeries and radiotherapy are often left with multiple pituitary hormone deficiencies.



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  72. Higham CE, Atkinson AB, Aylwin S et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab 2012; 97(4):1187-1193.
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Research into the function of the pituitary, and GH in particular, started with clinical observations and ana­tomical descriptions of people with gigantism and adults with acromegalic features (1). In 1884, the Swiss general physician Fritsche reported in great detail the history of a 44‑year-old man developing the characteristic features of acromegaly — a term later coined by Pierre Marie in 1886 (2) — and an enlarged pituitary, which was observed post-mortem (3). Minkowski proposed the connection between the pituitary and acromegaly before eosinophilic tumors of the anterior pituitary emerged as the anatomical basis of gigantism and acromegaly (4).


  1. de Herder, W. W. Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886). Pituitary 12, 236–244 (2009).
  2. Marie, P. Sur deux cas d’acromégalie. Revue Med. Paris 6, 297–333 (1886).
  3. Fritsche, C. F. & Klebs, E. Ein Beitrag zur Pathologie des Riesenwuchses. Klinische und Pathologisch Anatomische Untersuchungen (Vogel, FCW, 1884).
  4. Minkowski, O. Übereinen fall von akromegalie. Berlin Klin. Wochenschr. 24, 371–374 (1887).





Hypocalcemia can occur acutely over minutes to hours or chronically over weeks to months. Correspondingly, the signs and symptoms of hypocalcemia can develop acutely or chronically and can be life-threatening. The clinical manifestations of hypocalcemia are due to the increased neuromuscular tingling in the extremities and around the mouth. Chvostek’s and Trousseau’s signs can be elicited. When severe, tetany, convulsions, laryngospasm and bronchospasm can occur. Hypocalcemic symptoms are a result of both the absolute level of serum calcium and the rate of change in serum calcium concentration. Major signs and symptoms of hypocalcemia are summarized in Table 1.


Table 1. Signs/Symptoms of Hypocalcemia

I. Neuromuscular

.    Paresthesias - perioral and extremities

.    Muscle spasms

.    Laryngeal stridor, bronchospasm

.    Seizures

.    Cardiac arrhythmias

.   Coma

.   Chvostek’s sign

.   Trousseau’s sign (main d’accoucheur)

.   Tetany - Clinical or latent

.   Pseudotumor cerebri

.   Papilledema

II. Cardiovascular

.   Arrhythmias

.   Hypotension

.   Congestive heart failure

III. Other

.   Cataracts - subcapular, punctate

.   Extra-skeletal calcifications - Basal ganglia, Ligamentous and soft tissue

.   Dental enamel hypoplasia

.   Alopecia

.   Xeroderma




The major causes of hypocalcemia are summarized in Table 2.


Table 2. Major Causes of Hypocalcemia

Renal failure

Hypoparathyroidism (see Table 3)

Magnesium deficiency


Osteoblastic metastases


Pseudohypocalcemia (e.g., hypoalbuminemia, gadolinium-contrast agents)

Massive transfusion of citrated blood products



Vitamin D deficiency

Vitamin D receptor defect(s)

Calcium-sensing receptor (CaSR) constitutive activating mutations

Drugs (e.g., imatinib, bisphosphonates, denosumab, calcitonin)


Renal Failure


Hypocalcemia in chronic renal failure is due to two primary causes - increased serum phosphorus and decreased renal production of 1,25 (OH)2 vitamin D. The former causes hypocalcemia by complexing with serum calcium and depositing it into bone and other tissues.  The latter causes hypocalcemia by decreasing the GI absorption of calcium. 



There are several causes of hypoparathyroidism, as summarized in Table 3. Neck surgery that removes or destroys the parathyroid glands is the most common cause of hypoparathyroidism.  These operations include: (1) thyroidectomy due to thyroid cancer or benign goiter, with inadvertent removal or destruction of parathyroid tissue; (2) parathyroidectomy, especially for multigland hyperplasia; and (3) laryngectomy. Post-surgical hypoparathyroidism can occur within hours after surgery or gradually over time when glands injured at surgery ultimately become non-functioning. 


Idiopathic hypoparathyroidism can occur in isolation or in association with other endocrine or autoimmune disorders (Table 4), typically with adrenal insufficiency. The parathyroid glands can be absent, remnant, or compromised by an immune destruction.  Anti-cytokine antibodies (e.g., against alpha interferons) or antibodies directed against parathyroid cell antigens (e.g., NALP5) may be present.   


Pseudohypoparathyroidism (PHP) is a genetic disorder characterized by target-organ unresponsiveness to PTH.  PHP mimics the hormone-deficient forms of hypoparathyroidism, with hypocalcemia and hyperphosphatemia, but PTH levels are elevated rather than low or absent.


Hypoparathyroidism can occur in an autoimmune setting (Table 4) associated with autoantibodies. The most commonly associated disorders are Addison disease and mucocutaneous candidiasis. Two of the 3 disorders in the triad are necessary for the diagnosis of APS1. These patients can be affected by other endocrinopathies or immune-mediated disorders (e.g., thyroid disease, diabetes mellitus, pernicious anemia, and ovarian failure).


TABLE 3.  Causes of Hypoparathyroidism

Postoperative - acute and chronic



      Cancer surgery – laryngeal, thyroid



            Associated with autoimmune polyendocrine 



            Magnesium deficiency (or excess)

            Newborn of mother with hyperparathyroidism

Pseudohypoparathyroidism (Types 1a, 1b, 2)

Genetic disease

            DiGeorge Syndrome - aplasia/dysgenesis of the parathyroids and thymus along with other features

            Activating mutation of the calcium-sensing receptor (CaSR) or of the G protein subunit G alpha 11

            PTH gene mutation

            GATA3 deficiency

            GCMB deficiency

            Mitochondrial DNA mutations

Infiltration of the glands

Iron deposits (Hemochromatosis, transfusions)

Copper deposits (Wilson’s Disease)

Radiation to neck

Metastases to the parathyroid glands from non-parathyroid tumors

Magnesium deficiency

Drugs (e.g., calcimimetics cinacalcet and etelcalcitide)


TABLE 4. Autoimmune Polyendocrine Syndrome Type 1 (APS1) Associated with Hypoparathyroidism

Mucocutaneous candidiasis

Addison disease


Grave’s disease




Malabsorption (steatorrhea)

Chronic active hepatitis

Pernicious anemia

Diabetes mellitus



Other Causes of Hypocalcemia


Magnesium deficiency causes hypocalcemia by interfering with the end-organ actions of PTH and/or by inhibiting its secretion. Pancreatitis causes hypocalcemia through sequestration of calcium by saponification with fatty acids. Osteoblastic metastases similarly take up blood calcium. Excessive transfusion of citrated blood products may transiently lower ionized calcium and cause symptoms until citrate is cleared by the liver. In hyperphosphatemia, high levels of blood phosphorus complexes with calcium, and the product can precipitate into organs and soft tissues. Causes include renal failure, administration of phosphate, rhabdomyolysis, tumor lysis, and some cases of tumoral calcinosis. Vitamin D deficiency (or resistance syndromes) contributes to the hypocalcemia of osteomalacia and malabsorption. Iatrogenic causes include cancer chemotherapy, notably certain tyrosine kinase inhibitors. Other drugs reported to cause hypocalcemia include inhibitors of bone resorption, loop diuretics, and agents that accelerate vitamin D metabolism, like anticonvulsants.  All inhibitors of bone resorption used to treat hypercalcemia (e.g., calcitonin, intravenous bisphosphonates, the receptor activator of nuclear factor kappa B ligand or RANK-L inhibitor denosumab) and the calcimimetics cinacalcet or etelcalcitide used to treat hyperparathyroidism can cause hypocalcemia.   




The first step in assessing hypocalcemia is to confirm the results and rule out artifactually low calcium due to hypoalbuminemia. In hypoalbuminemic patients, ionized calcium can be measured, or total serum calcium can be corrected using the following formula: corrected Ca=measured Ca + (0.8) X (4- measured albumin). In critically ill patients with acid-base disturbances, measurement of ionized calcium is preferable due to altered calcium-albumin binding that can occur. Measuring serum phosphorus, PTH, creatinine, and 25 hydroxyvitamin D can usually identify the cause of the hypocalcemia. Interpreting PTH levels must be done in the context of serum calcium concentration. PTH can be low in hypoparathyroidism and hypomagnesemia and high when there is secondary (compensatory) hyperparathyroidism or pseudohypoparathyroidism. The PTH assay used should be an intact assay with reliable performance at the low end of the normal range. Patients with hypoparathyroidism may have a frankly low intact PTH or a low normal PTH that is inappropriate in the presence of hypocalcemia. Additional testing is done according to the clinical presentation and can include magnesium (hypomagnesemia), pancreatic enzymes (lipase), biochemical markers of bone turnover (osteoblastic metastases), ACTH/cortisol, and TSH (polyendocrine failure), and 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D (deficiency states).  Imaging can be useful for bone disease (osteomalacia, osteoblastic metastases).




Acute Hypocalcemia


Hypocalcemia can be an endocrine emergency requiring rapid intervention. Patients with either severe hypocalcemia, usually <7.5 mg/dl, or with neurological manifestations or stridor (laryngo/bronchospasm) should receive intravenous calcium. Calcium gluconate (90 mg calcium per 10 mL) should be given as intravenous slow pushes, generally one vial over 10 minutes, repeated once with electrocardiographic monitoring. A chronic intravenous drip is then started if the patient is still symptomatic and oral treatment cannot act rapidly enough. The infusion rate should be guided by signs, symptoms, and calcium measurements checked every 1-2 hours, preferably ionized calcium levels. Magnesium deficiency should also be treated when present, since it can attenuate the effect of the treatment by calcium and vitamin D (see below). Oral calcium (e.g., 1-2 grams of elemental calcium) and a rapidly acting preparation of vitamin D (e.g., 0.5-1.0 micrograms of calcitriol in divided doses) should be started as soon as practical.  This is often limited by neck surgery. If necessary, intravenous calcium can be given for as long as necessary until oral therapy has taken effect. Patients taking cardiac drugs, especially digoxin, are predisposed to cardiotoxicity by the infusion of calcium, so an EKG should be used for cardiac monitoring. Treatment must be assessed with frequent serum ionized calcium levels. Several preparations of calcium for oral use are available. The most commonly used are calcium carbonate and calcium citrate (Table 5). Recombinant human PTH(1-84) has been recently approved for the treatment of chronic hypoparathyroidism in adults and can reduce the amount of calcium and activated vitamin D supplements that a patient is required to take to control serum calcium levels in this disorder. However, in the United States this drug was removed from formularies because of rubber particulates discovered in the solution. Hopefully, this problem will be resolved soon. In the meantime, some clinicians are using other PTH preparations.



Grams to provide 1 gm of elemental calcium

Carbonate                         2.5
Chloride                            3.7

Acetate                              4.0

Citrate                               5.0

Glycerolphosphate           5.7

Levulinate                         7.7
Lactate                              7.7

Orthophosphate                9.0

Gluconate                         11.1
Glubionate                        15.2


Hypomagnesemia should always be considered as a potential contributory cause of hypocalcemia, especially in post-operative and hospitalized patients. Low serum magnesium may reveal this, but the serum magnesium may be normal or low normal, since serum magnesium does not accurately reflect the stores of this primarily intracellular ion. Therefore, a therapeutic trial of magnesium, usually parenteral, may be needed to assess for magnesium deficiency.Oral magnesium is used for mild, chronic magnesium deficiency (e.g., daily dose of 200-300 mg). Many preparations are available including magnesium oxide, magnesium carbonate or magnesium sulfate. Parenteral magnesium (10% or 50% solutions of magnesium sulfate) is used for severe hypomagnesemia.  A common regimen is 2-4 mls IV of a 50% solution given over 10-15 minutes followed by similar amounts given daily. Several days of treatment are usually required to replete magnesium stores.


Chronic Hypocalcemia


The objective of chronic therapy for hypocalcemia is to keep the patient free of symptoms and to maintain serum calcium at approximately 8.0-9.0 mg/dL. With lower serum calcium levels, the patient may continue to experience symptoms over time. With serum calcium concentrations in the upper normal range, there may be significant hypercalciuria, especially when the hypocalciuric effect of PTH has been lost. This can predispose to nephrolithiasis, nephrocalcinosis, and renal damage.  When the calcium x phosphorus product rises to near 55 mg2/dL2 or greater, as it can in patients with hypoparathyroidism who also have a chronically elevated serum phosphorus level (due to the loss of PTH actions in the kidney), ectopic calcifications in other soft tissues like the brain (especially the basal ganglia), blood vessels, and eyes can occur.     


Calcium and vitamin D are used to treat most causes of chronic hypocalcemia, such as renal failure and hypoparathyroidism. Vitamin D is used to establish a baseline calcium level and calcium is added (or subtracted) for acute changes in calcium. Calcitriol is the preferred preparation of vitamin D because it is rapidly active and has a short half-life (i.e., rapidly reversible) in contrast to the other forms of vitamin D (Table 6). In patients with renal failure, treatment is directed at maintaining normal levels of calcium, phosphorus, and the calcium x phosphorus product and the intact PTH within an acceptable range for the chronic kidney disease. 1,25 dihydroxy-vitamin D or calcitriol or one of its analogs can be given orally or parenterally. Vitamin D2 or D3 may be used for nutritional deficiency. Recombinant human PTH(1-84) has been approved for the treatment of chronic hypoparathyroidism in adults and can reduce the amount of calcium and activated vitamin D supplements that a patient is required to take to control serum calcium levels in this disorder. However, in the United States this drug was removed from formularies because of rubber particulates discovered in the solution. Hopefully, this problem will be resolved soon. In the meantime, some clinicians are using other PTH preparations.


Table 6. Vitamin D Preparations for Hypocalcemia Treatment


Daily dose

Time until normocalcemia

Duration of action

Vitamin D2 (Ergocalciferol)

400 units

4-8 weeks

2-6 months

Vitamin D3(Cholecalciferol)

Same as D2

Same as D2

Same as D2

1,25(OH2)D3 (Calcitriol)


2-5 days

1-2 days




The hypocalcemic patient should be periodically followed clinically (for signs and symptoms of recurrence) and biochemically (with serum calcium measurements, and less frequently with urinary calcium measurements). Other tests, such as magnesium and PTH, can be conducted as clinically indicated. Optimal therapy is best maintained by manipulating few variables, so patients on both vitamin D and calcium should hold vitamin D doses constant and change the oral intake of calcium when signs, symptoms, or measurements of calcium so dictate. Most patients can be treated with a reasonable degree of success, but some patients have frequent swings in symptoms, even though serum calcium levels are not abnormal.




Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, Van Biesen W, Dekkers OM.  European Society of Endocrinology Clinical Guideline:  treatment of chronic hypoparathyroidism in adults.  Eur J Endocrinol 173:  G1-G20, 2015. PMID: 26160136


Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke B, Thakker R, Khan A, Potts Jr JT.  Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 101: 2273-83, 2016. PMID: 26943719


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Schafer AL, Shoback DM. Hypocalcemia: Diagnosis and Treatment. 2016 Jan 3. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000–. PMID: 25905251


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Hypercalcemia can be defined as a serum calcium greater than 2 standard deviations above the normal mean in a reference laboratory. Calcium in the blood is normally transported:

partly bound to plasma proteins (about 45%), notably to albumin; partly bound to small anions such as phosphate and citrate (about 10%); partly in the free or ionized state (about 45%).


Only the ionized calcium is metabolically active i.e., subject to transport into cells, but most laboratories report total serum calcium concentrations. Hypercalcemia is therefore often defined as a total serum calcium (bound plus ionized) greater than 10.6 mg/dl (2.65 mM) or an ionized serum calcium greater than 5.3 mg/dl (1.3 mM) but values may vary between laboratories.


Dehydration, or hemoconcentration during venipuncture, may elevate total serum albumin whereas ionized calcium may remain normal. Consequently, a falsely elevated total serum calcium may be reported. Conversely when serum albumin levels are low, total serum calcium may be falsely low. To correct for an abnormally high or low serum albumin the following formula can be used:


Corrected calcium (mg/dL) = measured total serum calcium (mg/dL) + [4.0-serum albumin (g/dL) X 0.8] or Corrected calcium (mM) = measured total serum Ca (mM) + [40 - serum albumin (g/L) X 0.02]


Changes in blood pH can also alter the equilibrium constant of the albumin-calcium complex: Acidosis reduces binding and alkalosis enhances binding. Consequently, when major shifts in serum protein or pH are present it is prudent to directly measure the ionized calcium level in order to determine the presence of hypercalcemia.


Clinical Manifestations may be due to hypercalcemia or may be due to the causal disorder or may be due to both. Hypercalcemic manifestations will vary depending on whether the hypercalcemia is of acute onset and severe (greater than 12 mg/dL or 3 mM) or whether it is chronic and relatively mild. Patients may also tolerate higher serum calcium levels more readily if the onset is relatively gradual, but at concentrations above 14 mg/dL (3.5 mM) most patients are symptomatic. In both acute and chronic cases, the major manifestations affect gastrointestinal, renal and neuromuscular function (Table 1).


Table 1. Manifestations of Hypercalcemia





Anorexia, nausea, vomiting

Dyspepsia, constipation, pancreatitis


Polyuria, polydipsia

Nephrolithiasis, nephrocalcinosis


Depression, confusion,
stupor, coma



Short Q-T interval
bradycardia, first degree
atrioventricular block,
digitalis sensitivity





Fluxes of calcium across the skeleton, the gut, and the kidney play a major role in maintaining calcium homeostasis. When the extracellular fluid (ECF) calcium is raised above the normal range, the calcium ion per se, by stimulating the G-protein coupled calcium sensing receptor (CaSR), can inhibit parathyroid hormone (PTH) release. Decreased PTH and CaSR stimulation will both facilitate reduced renal calcium reabsorption, and decreased PTH will result in reduced bone resorption and diminished release of calcium from bone. Decreased PTH and hypercalcemia will also reduce renal production of the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], and decrease gut absorption of calcium. The net effect of the diminished renal calcium reabsorption, intestinal calcium absorption, and skeletal calcium resorption will be to reduce the elevated ECF calcium to normal. Consequently, decreased levels of PTH and decreased levels of 1,25(OH)2D should accompany hypercalcemia unless the PTH or 1,25(OH)2D is the cause of the hypercalcemia. The converse sequence of events occurs when the ECF calcium is reduced below the normal range.


A genetic relative of PTH, PTH-related peptide (PTHrP), can also resorb bone, when released from certain tumors. Both PTH and PTHrP act on osteoblastic cells to increase production of cytokines, notably receptor activator of nuclear factor kappa B ligand (RANKL) which increases production and activation of multinucleated osteoclasts which then resorb mineralized bone.



Figure 1. Algorithm for Diagnosing the Cause of Hypercalcemia


Hypercalcemic disorders can be broadly grouped into Endocrine Disorders, Malignant Disorders, Inflammatory Disorders, Medication-Induced Hypercalcemia, and Immobilization as shown in Tables 2-8. Primary hyperparathyroidism (HPTH) and malignancy-associated hypercalcemia (MAH) account for the vast majority of hypercalcemic disorders. (For a more complete discussion of hypercalcemic disorders and the underlying pathophysiology, see reference 1)


Table 2. Endocrine Disorders Associated with Hypercalcemia

1. Endocrine Disorders with Excess PTH Production

Primary Sporadic Hyperparathyroidism (HPTH)

Adenoma (85-95%)

Hyperplasia (10-15%)

Carcinoma (<1%)

(80% of primary hyperparathyroidism is “asymptomatic”)

Primary Familial HPTH (Syndromic HPTH)

Multiple Endocrine Neoplasia, Type I (MEN1)- Autosomal dominant, MEN1 mutation (encodes menin)

Multiple Endocrine Neoplasia, Type II (also called MENIIA)- Autosomal dominant, RET mutation (encodes c-Ret)

Multiple Endocrine Neoplasia, Type IV (MENIV)- Autosomal dominant, CDKN1B mutation (encodes P27(Kip1))

Hyperparathyroidism – Jaw Tumor Syndrome-

   Autosomal dominant, CDC73/HRPT2 mutation (encodes parafibromin)

Non-Syndromic HPTH

Familial Hypocalciuric Hypercalcemia (FHH)
Heterozygotes and Neonatal Severe Primary Hyperparathyroidism (NSHPT) (homozygotes)
   FHH1:  CaSR mutation (encodes calcium sensing receptor)

   FHH2: GNA11 mutation (encodes G protein subunit α11)

   FHH3: AP2S1 mutation (encodes adaptor protein-2 sigma subunit)

Familial Isolated HPTH(Non-Syndromic)

  Mutations inf MEN1, CDC73/HRPT2 or CASR may account for a minority of kindreds with the FIHP phenotype upon initial ascertainment. Activating variants in GCM2 (encodes the transcription factor GCM2) have also been described.  

Tertiary HPTH

Chronic Kidney Disease

Phosphate Treatment of Hypophosphatemic Rickets/Osteomalacia

2. Endocrine Disorders without Excess PTH Production





Jansen’s Metaphyseal Chondrodysplasia- Due to activating mutation of PTHR1, the gene encoding the type1 PTH/PTHrP receptor


Table 3. Malignancy-Associated Hypercalcemia (MAH)

Accounts for about 90% of hypercalcemia in hospitalized patients.
Hypercalcemia is often acute and severe and usually a late manifestation of malignancy

1. MAH with Elevated PTHrP

Solid tumors (e.g. breast, lung, kidney, GI)

Hematologic malignancies (e.g. Non-Hodgkin’s lymphoma, adult T cell leukemia/lymphoma, chronic myelogenous, leukemia, chronic lymphocytic leukemia)

2. MAH with Elevation of Other Systemic Factors

1,25(OH)2D (e.g. Hodgkin’s Disease), cytokines (Multiple Myeloma and malignancies metastatic to bone), and rarely ectopic PTH production (e.g. ovarian, lung, thyroid and thymus)


Table 4. Granulomatous Disorders Causing Hypercalcemia

Due to extra-renal mononuclear cell 1,25(OH)2D production

1 Non-infectious (e.g. Sarcoidosis, Wegener’s granulomatosis, berylliosis)

2 Infectious (e.g. TB, histoplasmosis)


Table 5. Pediatric Syndromes

1. Williams Syndrome

2. Idiopathic Infantile Hypercalcemia
Due to loss-of-function of CYP24A1, encoding CYP24A1, the enzyme metabolizing 1,25(OH)2D, or due to loss-of-function of SLC34A1, encoding the renal proximal tubular sodium-phosphate cotransporter, Na/Pi-IIa.


Table 6. Viral Syndromes

Human Immunodeficiency Virus (HIV) infections

Cytomegalovirus (CMV) infections


Table 7. Medication-Induced

1. Thiazides

2. Lithium

3. Vitamin D

4. Vitamin A

5. Tamoxifen (during treatment of skeletal breast cancer metastases)

6. Aminophylline/theophylline

7. Aluminum Intoxication

8. Milk-Alkali Syndrome


Table 8. Immobilization

Immobilized patients continue to resorb bone whereas bone formation is inhibited. Consequently, immobilization may precipitate hypercalcemia and hypercalciuria in individuals with high bone turnover such as growing children, patients with Paget’s Disease or patients with primary HPTH or MAH.




Laboratory testing should be guided by the results of a careful history and a detailed physical examination and should be geared toward assessing the extent of the alteration in calcium homeostasis and toward establishing the underlying diagnosis and determining its severity. Most patients with primary HPTH, the most common cause of hypercalcemia in the clinic, present with mild hypercalcemia discovered on a routine biochemical assessment. There may be a history of a recent or remote renal stone. Bone pain and fractures are rare although the patient may carry a diagnosis of osteoporosis based on a previous bone mineral density (BMD) measurement. A history of a documented peptic ulcer is rare in primary sporadic HPTH and should raise concern about MEN1. Although cardiovascular and neuropsychiatric manifestations have been described they appear to require more validation. Documentation of at least two elevated corrected (or ionized) serum calcium levels with concomitant elevated (or at least normal) serum PTH levels is required to establish the diagnosis (Figure 1). Lithium treatment has been associated with hypercalcemia, elevated or normal serum PTH, and increased renal calcium reabsorption. The presence of a family history of hypercalcemia or of kidney stones should raise suspicion of MEN1 or MEN2a (reference 3 and 4). If, in addition to primary HPTH in the proband, one or more first-degree relatives are found to have at least one of the three tumors characterizing MEN1 (parathyroid, pituitary, pancreas) or MEN2a (parathyroid, medullary thyroid carcinoma, pheochromocytoma) then it is highly likely that the disease is familial. The presence of ossifying fibromas of the mandible and maxilla, and renal lesions such as cysts and hamartomas in addition to HPTH would suggest HPTH-jaw tumor syndrome. In all patients with documented primary HPTH, a 24-hour urine calcium and creatinine level should be obtained to exclude familial hypocalciuric hypercalcemia (FHH). If the urine calcium to creatinine ratio is less than 0.01 and if testing serum and urine calcium in three relatives discloses hypercalcemia and relative hypocalciuria in other family members, then this diagnosis is likely and parathyroid surgery is to be avoided. If the urine calcium to creatinine ratio is greater than 0.01 then estimated glomerular filtration rate (eGFR) and a BMD test should be performed and guidelines for treatment of primary HPTH should be considered (see below).


Tertiary hyperparathyroidism with hypercalcemia and elevated PTH has been described in chronic kidney disease patients on hemodialysis, or in patients with hypophosphatemic syndromes (e.g., x-linked hypophosphatemic rickets) receiving long-term oral phosphate therapy without concomitant calcitriol.


If hypercalcemia is associated with very low or suppressed serum PTH levels, then malignancy would be an important consideration, either in association with elevated serum PTHrP or in its absence, in which case it is generally as a result of the production of other cytokines, often with osteolytic metastases. When malignancy-associated hypercalcemia is suspected then an appropriate malignancy screen should be done including skeletal imaging to identify skeletal metastases. As well appropriate general biochemical assessment such as a complete blood count and serum creatinine and specific biochemical assessment such as serum and urine protein electrophoresis to exclude multiple myeloma would be appropriate.


Detection of elevated serum 1,25(OH)2D levels in the absence of elevated serum PTH levels, suggests the need for a search for lymphoma or for non-infectious (e.g., sarcoidosis) or infectious granulomatous disease.


Hypercalcemia may also occur with thyrotoxicosis, pheochromocytoma, VIPoma, and hypoadrenalism. Increased PTHrP may be associated with neuroendocrine tumors. Serum PTH levels are suppressed in these disorders and 1,25(OH)2D levels are not elevated. Although these conditions may be suspected from clinical examination, detailed biochemical evaluation of these non-PTH associated endocrine disorders is required for confirmation.


Detection of elevated serum 25-hydroxyvitamin D [25(OH)D], should lead to a search for vitamin D intoxication. Vitamin A intoxication may also lead to hypercalcemia, but in the absence of elevated serum 25(OH)D, 1,25(OH)2D, or PTH. Hypercalcemia has been reported in association with human immunodeficiency virus (HIV), HTLV-III or cytomegalovirus (CMV) infections of the skeleton, presumably due to direct skeletal resorption. Use of foscarnet as an antiviral agent has also been associated with hypercalcemia. Transient hypercalcemia may accompany thiazide diuretic ingestion, possibly associated with dehydration, but prolonged hypercalcemia with thiazides requires a search for other causes. Hypercalcemia may be seen in patients with advanced breast cancer with skeletal metastases, at the initiation of treatment with tamoxifen. Aminophylline and theophylline used as bronchodilators have (rarely) been reported to be associated with hypercalcemia. The use of aluminum-containing phosphate binders in patients on chronic hemodialysis was associated with hypercalcemia in the past but, with the advent of other modes of therapy, this is rarely seen today. Similarly, the use of absorbable alkali (NaHCO3) along with large quantities of milk for ulcer treatment was a cause of hypercalcemia in the past but this therapy has been superseded today.


In the pediatric age group, hypercalcemia may include Jansens’s Metaphyseal Chondrodysplasia due to an activating mutation of the type 1 PTH/PTHrP receptor; neonatal severe hyperparathyroidism (NSHPTH) which may present with life-threatening hypercalcemia in neonates that are homozygous for inactivating mutations in CaSR; William’s Syndrome, an autosomal dominant disorder with hemizygous submicroscopic deletions of chromosome 7q11.23, characterized phenotypically by multiple congenital abnormalities, and in which hypercalcemia may occur possibly due to aberrant vitamin D metabolism; and idiopathic infantile hypercalcemia (IIH) in which hypercalcemia may be associated with increased 1,25(OH)2D.due to loss-of-function mutations in CYP24A1, the gene encoding the enzyme responsible for the first step in inactivation of 1,25(OH)2D. IIH may also be caused by loss-of-function mutations in SLC34A1, encoding the renal proximal tubular sodium-phosphate cotransporter, Na/Pi-IIa, leading to phosphaturia, phosphate depletion, suppression of the hormone fibroblast growth factor-23 (FGF-23), decreased CYP24A1,and increased 1,25(OH)2D production.




If the patient's serum calcium concentration is less than 12 mg/dL (3 mM) without symptoms of hypercalcemia then treatment of the hypercalcemia can be aimed solely at treatment of the underlying disorder. If the patient has symptoms and signs of acute hypercalcemia as described above and serum calcium is greater than 12 mg/dL (3 mM), then a series of urgent measures should be instituted (Table 9). These measures are almost always required with a serum calcium above 14 mg/dL (3.5 mM).


Table 9. Management of Acute Hypercalcemia

1. Hydration to Restore Euvolemia

0.9% saline (e.g. an initial rate of 200-300 mL/h subsequently adjusted to maintain a urine output at 100-150 mL/h). Use caution in patients with compromised cardiovascular or renal function.

2. Inhibition of Bone Resorption

Zoledronate 4 mg intravenously in 5 ml over 15 min or Pamidronate, 90 mg, intravenously in 500 ml of 0.9% saline or 5% dextrose in water over 4 hours.
Peak decrease in serum calcium after 4 days but may last for 8 weeks.
Flu-like syndrome or myalgias may occur

If bisphosphonates are contraindicated due to severe renal impairment, denosumab can be given instead (e.g. 0.3 mg/kg sc), with a second dose administered if the calcium is not lowered within approximately one week. Low serum 25(OH)D, if present, should be corrected before administering denosumab

Calcitonin, 4 to 8 IU/Kg im or sc, every 6-12 hours may be used with a bisphosphonate or denosumab because of its more rapid onset of action.
Peak decrease in serum calcium within 2-6 hours
Tachyphylaxis may occur after 24-48 hours
May use with a parenteral bisphosphonate for severe hypercalcemia because onset of calcium reduction is earlier

3. Calciuresis (when decreased renal excretion is suspected e.g. with excess PTH or PTHrP)

Loop diuretic e.g. furosemide, 10 to 20 mg IV
Administer only after rehydration

4. Glucocorticoids (when indicated)

e.g. hydrocortisone 200 to 300 mg intravenously over 24 hours for 3 to 5 days
For patients with responsive hematologic malignancies such as lymphoma or myeloma
For patients with vitamin D intoxication or granulomatous disease with increased 1,25(OH)2D

5. Dialysis

Patients refractory to other therapies
Patients with renal insufficiency
Either peritoneal dialysis or hemodialysis can be effective

6. Calcimimetics

The calcimimetic, cinacalcet, may be used in doses starting from 30 mg twice daily orally to as high as 90 mg 4 times daily for the treatment of hypercalcemia due to severe primary HPTH (especially if caused by a parathyroid carcinoma)

7. Mobilization

Mobilize as rapidly as possible after the acute episode




In the patient with primary sporadic HPTH who presents with kidney stones, fractures, or a low BMD (T-score less than -2.5) surgery would be indicated. In the patient with documented asymptomatic primary HPTH, follow-up should be done annually with measurement of serum calcium and serum creatinine (to determine estimated GFR). BMD should be repeated every one to two years. Guidelines below should be considered for recommending surgery in asymptomatic patients (table 10) (reference 2). The diagnosis of familial disease raises issues of management of HPTH in the proband and affected family members in view of the fact that familial HPTH generally is generally associated with multigland disease, whereas the sporadic disease is usually due to an adenoma. In HPTH jaw tumor syndrome there should be recognition of the high frequency of parathyroid carcinoma.


Table 10. Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidism

Serum calcium

1.0 mg/dL elevation


24-h urine for FHH/stone risk
U Ca >400 mg/day
Creatinine clearance: <60 mL/min
Calcification on renal imaging


T-score < −2.5
Vertebral fracture on imaging




Management of other etiologies of hypercalcemia are generally directed toward the specific entity involved.




  1. Goltzman D. Approach to Hypercalcemia. 2019 Oct 29. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000–. PMID: 25905352
  2. Walker MD, Bilezikian JP. Primary Hyperparathyroidism. 2021 Apr 19. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000–. PMID: 25905161
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Primary Disorders of Phosphate Metabolism



Phosphorus is critical to many functions in human biology. Deprivation of phosphorus may manifest as disorders of the musculoskeletal system, reflecting its important role in energy metabolism and skeletal mineralization. Phosphorus excess can promote heterotopic mineralization and is associated with mortality, particularly in the setting of chronic kidney disease. Inorganic phosphorus, primarily occurring as phosphate (PO4), is highly regulated by transport systems in intestine and kidney, and is essential for the formation of a mineralized skeleton. Parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23) are major hormonal regulators of phosphate homeostasis and membrane abundance of PO4 transporters. Tissue distribution of alpha-klotho permits a primary renal specificity for FGF23 actions. Disorders of phosphate metabolism that are encountered in clinical practice are described in this Endotext chapter, with an emphasis on pathophysiologic processes, diagnostic measures, and treatment. The identification of FGF23 as an important mediator of phosphate homeostasis has brought to light the underlying disease processes in many of these conditions, along with the possibility of novel, physiologic-based therapies.




Phosphorus plays an important role in growth, development, bone formation, acid-base regulation, and cellular metabolism. Inorganic phosphorus exists primarily as the critical structural ion, phosphate (PO4), which serves as a constituent of hydroxyapatite, the mineral basis of the vertebrate skeleton, and at the molecular level, providing the molecular backbone of DNA. Its chemical properties allow its use as a biological energy store as adenosine triphosphate. Additionally, phosphorus influences a variety of enzymatic reactions (e.g., glycolysis) and protein functions (e.g., the oxygen-carrying capacity of hemoglobin by regulation of 2,3-diphosphoglycerate synthesis). Finally, phosphorus is an important signaling moiety, as phosphorylation and dephosphorylation of protein structures serves as an activation signal. Indeed, phosphorus is one of the most abundant components of all tissues, and disturbances in its homeostasis can affect almost any organ system. Most phosphorus within the body is in bone (600-700 g), while the remainder is largely distributed in soft tissue (100-200 g). The plasma contains 11-12 mg/dL of total phosphorus (in both organic and inorganic states) in adults. Inorganic phosphorus (Pi) primarily exists as phosphate (PO4), and is the commonly measured fraction, found in plasma at concentrations averaging 3-4 mg/dl in older children and adults. Plasma Pi concentrations values in children are higher, not infrequently as high as 8 mg/dl in small infants, and gradually declining steeply throughout the first year of life, and further in later childhood to adult values. The organic phosphorus component is primarily found in phospholipids. Although this fraction is not routinely assessed clinically, it comprises approximately two-thirds of the total plasma phosphorus (1). Thus, the term “plasma phosphorus” generally is used when referring to plasma inorganic Pi concentrations, and because plasma inorganic Pi is nearly all in the form of the PO4 ion, the terms phosphorus and phosphate are often interchangeably used in the clinical chemistry laboratory. It should be noted that this terminology can be confusing when using mass units (i.e., mg/dl) as the weight of the phosphorus content of the phosphate is reported, yet “serum phosphate” is often used in the clinic setting.  When using molar units the concentration of the phosphate and of the phosphorus are equivalent, and less confusion may arise.


Elaborate mechanisms have evolved to maintain phosphate balance, reflecting the critical role that phosphorus plays in cell and organism physiology. Adaptive changes are manifest by a variety of measurable responses, as modified by metabolic Pi need and exogenous Pi supply. Such regulation maintains the plasma and extracellular fluid phosphorus within a relatively narrow range and depends primarily upon gastrointestinal absorption and renal excretion as adjustable mechanisms to effect homeostasis. Although investigators have recognized a variety of hormones and transporter proteins which influence these various processes, in concert with associated changes in other metabolic pathways, the sensory system, the messenger and the mechanisms underlying discriminant regulation of Pi balance remain incompletely understood.


While long-term changes in Pi balance depend on these variables, short-term changes in Pi concentrations can occur due to redistribution between the extracellular fluid and either bone or cell constituents. Such redistribution results secondary to various mechanisms including: elevated levels of insulin and/or glucose; increased concentrations of circulating catecholamines; respiratory alkalosis; enhanced cell production or anabolism; and rapid bone remineralization.




The majority of ingested phosphorus is absorbed in the small intestine. Active transport is mediated by sodium dependent transporter protein(s), and sodium-independent P-transport also occurs. Hormonal mechanisms regulating Pi homeostasis in the kidney are established in more detail. Indeed, the kidney has long been considered the dominant site of regulation of Pi balance, as renal tubular reclamation of filtered Pi occurs in response to complex regulatory mechanisms. Although the fate of Pi has generally been considered a matter of renal elimination, incorporation into organic forms in proliferating cells, or deposition into the mineral phase of bone as hydroxyapatite, the role of intestinal phosphate transport warrants further study. Indeed, it appears that presentation of Pi to the intestine can affect systemic phosphate handling before changes in serum Pi concentration are evident. Moreover, in the setting of severe phosphorus deprivation, the phosphate contained in bone mineral provides a source of phosphorus for the metabolic needs of the organism. The specific roles that the intestine and kidney play in this complex process are discussed below.


Gastrointestinal Absorption Of Phosphorus


Studies of Pi absorption in the intestine have yielded variable results, in part due to confounding influences of nutritional status, the effects of anesthesia on gut transit, species differences, and potential effects of studying whole organisms as opposed to isolated bowel segments. The small intestine is the dominant site of Pi absorption; in mice Pi is absorbed along the entire length of small bowel, but at the highest rate in the ileum. In rats, duodenum and jejunum provide the primary sites of Pi absorption, whereas very little occurs in ileum. This is felt to be more consistent with the pattern of Pi absorption in humans, however studies are subject to the confounding issues noted above. In normal adults net Pi absorption is a linear function of dietary Pi intake. For a dietary Pi range of 4 to 30 mg/kg/day, the net Pi absorption averages 60 to 65% of the intake (2). Intestinal Pi absorption occurs via two routes (Figure 1), a cellularly mediated sodium-dependent active transport mechanism, and sodium independent transport, which is not well characterized.  Mechanisms for the latter have been attributed in part to paracellular pathways (3), however recent findings suggest that for glucose, this pathway only accounts for 1-2% of passive glucose uptake in the intestine, far less that once speculated. Finally, the relative roles of these processes appear to be age dependent (4). Animal models suggest that weanling mice have both greater intestinal P transport (and greater expression of NaPi-IIb) than at other ages, presumably to support skeletal growth.


Controversy exists as to what proportion of intestinal Pi absorption is absorbed via sodium-dependent mechanisms and what proportion is sodium-independent. In this regard, the major Na+-dependent phosphate cotransporter identified in intestinal brush border membranes is NPT2b, a member of the SLC34 solute carrier family, also referred to as type II sodium-phosphate cotransporters (5). Earlier studies suggested that approximately 50% of intestinal P transport occurs by sodium-dependent mechanisms, and that most of this activity can be accounted for by the sodium-dependent transporter NPT2b. A lesser contribution to sodium-independent transport has been attributed to either type III transporters (PiT1 and PiT2, see below), and other unknown mechanisms. NPT2b is also expressed in lung, colon, testis/epididymis, liver, and in mammary and salivary glands, with most abundant expression in mammary glands (4). NPT2b is electrogenic, maintains a 3:1 stoichiometry of Na: Pi, prefers the divalent P species, and has a high affinity for Pi binding (6-10). Depending upon species and bowel segment, NPT2b transporters can be regulated by 1,25 dihydroxyvitamin D (­), FGF23 (¯), low Pi diet (­), and acute phosphate loading (­). Energy for the electrochemical uphill process is provided by the sodium gradient, which is maintained by sodium-potassium ATPase. The phosphate incorporated into intestinal cells by this mechanism is ferried from the apical pole to the basolateral pole likely through restricted channels such as the microtubules. Exit of Pi from the enterocyte across the basolateral membrane and into the circulation is a poorly understood process. More recently widely-expressed members of the SLC20 solute carrier family, the type III sodium-phosphate cotransporters PiT1 and PiT2, have been found to be variably expressed in the intestine (11), and PiT2 primarily in ileum.  Pit1 and Pit2 prefer to transport the monovalent Pi species (HPO4 -), and maintain a 2 Na: 1 P stoichiometry. These transporters may play a greater role in adaptive responses to intestinal Pi transport than previously recognized. PiT1 upregulates in response to phosphate deprivation, but in a relatively slow time frame, whereas expression of PiT2 and NPT2b upregulate within 24 hrs (12). In NPT2b-/- mice there is approximately 10% sodium-dependent Pi transport activity, suggesting that the type III transporters are of limited significance in the intestine in murine models. The process is further complicated by significant effects of alkaline pH as inhibitory to intestinal Pi transport, Moreover, the adaptation to P deprivation occurs with greater rates of transport occurring at more acidic pH (12) Given the variable nature and segment-specific regulation of NPT2b, the ultimate impact on overall phosphate homeostasis appears to be less well understood at the intestine than at the kidney. The presence of different classes of transporters in the intestine provide for Pi transport under a variety of different conditions such as variable pH, species of PO4 substrate, and Pi supply.  Indeed, recent work leads to speculation that much of the adaptive response to intestinal phosphate transport likely occurs by yet unrecognized transporters or transport processes (12).

Figure 1. Model of inorganic phosphate (HPO4=) transport in the intestine. At the luminal surface of the enterocyte the brush border membrane harbors sodium-dependent phosphate transporters of the NPT2b type. NPT2b transporters are electrogenic, have high affinity for Pi, and a stoichiometry of 3 Na ions: 1 phosphate. Energy for this transport process is provided by an inward downhill sodium gradient, maintained by transport of Na+ from the cell via a Na+/K+ ATPase cotransporter at the basolateral membrane. The HPO4= incorporated into the enterocytes by this mechanism is transferred to the circulation by poorly understood mechanisms. Type III sodium-dependent transporters are also expressed on the intestinal luminal surface (PiT1 and PiT2) and contribute to this process. Considerable HPO4= absorption occurs via a sodium-independent process(es) such diffusional absorption across the intercellular spaces in the intestine. Other processes have also been hypothesized.

As most diets contain an abundance of Pi, the quantity absorbed nearly always exceeds the need. Factors which may adversely influence the non-regulable, sodium-independent process are the formation of nonabsorbable calcium, aluminum or magnesium phosphate salts in the intestine and age, which reduces Pi absorption by as much as 50%.


Renal Excretion Of Phosphorus


The kidney responds rapidly to changes in serum Pi levels or to dietary Pi intake. The balance between the rates of glomerular filtration and tubular reabsorption (13) determines net renal handling of Pi. Pi concentration in the glomerular ultrafiltrate is approximately 90% of that in plasma, as not all of the plasma Pi is ultrafilterable (14). Since the product of the serum Pi concentration and the glomerular filtration rate (GFR) approximates the filtered load of Pi, a change in the GFR may influence Pi homeostasis if uncompensated by commensurate changes in tubular reabsorption.


The major site of phosphate reabsorption is the proximal convoluted tubule, at which 60% to 70% of reabsorption occurs (Figure 2). Along the proximal convoluted tubule, the transport is heterogeneous, with greatest activity in the S1 segment. Further, increasing, but not conclusive, data supports the existence of a Pi reabsorptive mechanism in the distal tubule. Currently, however, conclusive proof for tubular secretion of Pi in humans is lacking (15).

Figure 2. Distribution of Pi reabsorption and hormone-dependent adenylate cyclase activity throughout the renal tubule. The renal tubules consist of a proximal convoluted tubule (PCT), composed of an S1, S2 and S3 segment, a proximal straight tubule (PST), also known as the S3 segment, the loop of Henle, the medullary ascending limb (MAL), the cortical ascending limb (CAL), the distal convoluted tubule (DCT) and three segments of the collecting tubule: the cortical collecting tubule (CCT); the outer medullary collecting tubule (OMCT); and the inner medullary collecting tubule (IMCT). Pi reabsorption occurs primarily in the PCT but is present is the PST and DCT, sites at which parathyroid hormone (PTH) dependent adenylate cyclase is localized. In contrast, calcitonin alters Pi transport at sites devoid of calcitonin dependent adenylate cyclase, suggesting that Pi reabsorption in response to this stimulus occurs by a distinctly different mechanism.

At all three sites of Pi reabsorption, the proximal convoluted tubule, proximal straight tubule and distal tubule, PTH has been shown to decrease Pi reabsorption either by a cAMP-dependent process, or in some cases a cAMP-independent signaling mechanism. In contrast, calcitonin-sensitive adenylate cyclase maps to the medullary and cortical thick ascending limbs and the distal tubule (Figure 2) (16). Although calcitonin has been shown to inhibit Pi reabsorption in proximal convoluted and straight tubules by a cAMP-independent mechanism, the physiologic importance of this action is likely limited. It appears that the major regulators of renal tubular phosphate retention are PTH and the endocrine fibroblast growth factor, FGF23 (see below).




Investigations of the cellular events involved in Pi movement from the renal tubule luminal fluid to the peritubular capillary blood indicate that Pi reabsorption occurs principally by a unidirectional process that proceeds transcellularly. Entry of Pi into the tubular cell across the luminal membrane proceeds by way of a saturable active transport system that is sodium-dependent (analogous to the sodium-dependent co-transport in the intestine) (Figure 3). The rate of Pi transport is dependent on the abundance of transporters functioning in the membrane, and the magnitude of the Na+gradient maintained across the luminal membrane. This gradient depends on the Na+/ATPase or sodium pump on the basolateral membrane. The rate limiting step in transcellular transport is likely the Na+-dependent entry of Pi across the luminal membrane, a process with a low Km for luminal phosphate (~0.43M) which permits highly efficient transport.

Figure 3. Model of inorganic phosphate transcellular transport in the proximal tubule. At the brush border a Na+/H+ exchanger and NPT2 co-transporters operate. Nearly all proximal tubular reabsorption can be accounted for by the SLC34 (type II) family of sodium-dependent Pi transporters. In mice, NPT2a appears to be the more abundant transporter; it is electrogenic with a 3:1 (Na: PO4) stoichiometry, preferentially transporting the divalent phosphate anion. The lesser abundant NPT2c transporter is electroneutral with a 2:1 (Na: PO4) stoichiometry, but also prefers the divalent phosphate species. In humans NP2c appears to have a more significant role than in mice. The HPO4- that enters the cell across the luminal surface mixes with the intracellular pool of Pi and is transported across the basolateral membrane. This process is poorly understood, but anion exchange mechanisms have been suggested. A Na+/K+ ATPase located on the basolateral membrane pumps Na+ out of the cell maintaining the inward downhill Na gradient, which serves as the driving force for luminal entry of Na+.

The phosphate that enters the tubule cell plays a major role in governing various aspects of cell metabolism and function and is in rapid exchange with intracellular phosphate. Under these conditions the relatively stable free Pi concentration in the cytosol implies that Pi entry into the cell across the brush border membrane must be tightly coupled with either subcellular compartmentalization, organification, or exit across the basolateral membrane (Figure 3). The transport of phosphate across the basolateral membrane is poorly understood, however, several P transport pathways have been postulated, including Na+-Pi cotransport via type III Na-Pi cotransporters, passive diffusion, and anion exchange. The XPR1 transporter has been implicated in transport of phosphate out of cells but the significance of its role in total body P homeostasis is uncertain in humans (17). One animal study provides reasonable evidence for a critical role for this transporter in generalized tubular function (18). In any case, the basolateral Pi transport serves at least two functions: 1) complete transcellular Pi reabsorption when luminal Pi entry exceeds the cellular Pi requirements; and 2) basolateral Pi influx if apical Pi entry is insufficient to satisfy cellular requirements (19).

Pi entry into renal epithelium is primarily performed by the type II class of Na-Pi cotransporters (SLC34 family members), although recently the finding of type III transporters (SLC20 family members, PiT1 and PiT2) in kidney have raised the possibility of a potential role for this class as well (20).These two families of Na-Pi cotransporters share no significant homology in their primary amino acid sequence and as noted above, exhibit substantial variability in substrate affinity, pH dependence and tissue expression. The NPT2 class of transporters account for the bulk of regulated phosphate transport in kidney, and disruption of this regulation may result in significant disease, documenting their physiological importance (21, 22). As with intestinal Pi transport, physiologic differences between these families of Pi transporters provides for functional diversity allowing the body to transfer Pi between compartments in a variety of situations. Of the class II transporters NPT2a and NPT2c transporters are the predominant actors in the proximal renal tubule. NPT2a, the more abundant species in mice, is electrogenic with a 3:1 (Na: PO4) stoichiometry, preferentially transporting the divalent phosphate anion, and has a high affinity for Pi (all features of the NPT2b member of this family, the predominant intestinal sodium-dependent Pi transporter, see above). NPT2c differs from its type 2a/b family members in that is electroneutral with a 2:1 (Na: PO4) stoichiometry, but also prefers the divalent phosphate species. It has a much lower affinity for Pi, but is an efficient transporter due to its electroneutrality. An aspartic acid residue (Asp 224 in human NaPi-IIa) in a sodium binding site within a conserved amino acid cluster in the electrogenic transporters NPT2a and NPT2b, appears to be critical for electrogenicity. It is replaced with a glycine residue (Gly 196 in human NPT2c) in the electroneutral type IIc transporter (23).

Initial attention focused on NPT2a, as it was determined to be the most abundant Na-Pi cotransporter in kidney. Molecular and/or genetic suppression of NPT2a supports its role in mediating brush-border membrane Na-Pi cotransport. Intravenous injection of specific antisense oligonucleotides reduces brush-border membrane Na-Pi cotransport activity in accord with a decrease in NPT2a protein (24). In addition, disruption of the gene encoding NPT2a in mice (Slc34a1) leads to a 70% reduction in brush-border Na-Pi cotransport rate and complete loss of the protein (25, 26). However, the NPT2c transporter may have a relatively more important role for Pi transport in humans as compared to rodents, and appears to have a more widespread tissue distribution. The identification of a unique form of hypophosphatemia, Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) as a loss-of-function mutation in NPT2c has demonstrated an important physiologic role in humans for this transporter (27).

The roles of type III transporters in this process are not established at this time, and the previously described class of type I sodium-dependent phosphate transporters (of the SLC17 family) are not specific Pi transporters and do not appear to be central to the regulation of phosphate homeostasis.


Several hormones and metabolic perturbations are able to modulate phosphate reabsorption by the kidney. Among these FGF23, PTH, PTHrP, calcitonin, atrial natriuretic peptide, acidosis, TGFb, glucocorticoids, hypercalcemia, and phosphate loading inhibit renal phosphate reclamation (for review, see reference 28). In contrast, IGF-1, growth hormone, insulin, thyroid hormone, EGF, alkalosis, hypocalcemia, and phosphate deprivation (depletion) stimulate renal phosphate reabsorption. The central role of FGF23 in this regard, revealed by the study of clinical disorders of renal phosphate wasting. Indeed, PTH and FGF23 are likely the two most important regulators of renal tubular phosphate handling, and are discussed in greater detail below. The common target for regulation by these factors is the renal proximal tubular cell. Effects of 1,25(OH)2D are less clearly delineated, and such effects in vivo may be mediated by PTH or FGF23.


Investigations of classical PTH effects on proximal tubule phosphate transport indicate that both the cAMP-protein kinase A (PKA) and the phospholipase C-protein kinase C (PKC) signal transduction pathways are able to modulate this process. The PTH mediated inhibition of phosphate reabsorption operates through the PKC system at low hormone concentrations (10-8 to 10-10 M) and via PKA at higher concentrations. The PKA pathway is the more important mediator of PTH’s role on P handling at the kidney. PTH, after interaction with its receptor, PTHR1, effects a rapid and irreversible endocytosis of NaPi-IIa transporters to the lysosomal compartment, where subsequent proteolytic degradation occurs (29). Stabilization of NPT2a is mediated by NHERF1 which is phosphorylated by PTH’s activation of the PKA and PKC pathways. NHERF3 also binds to NPT2a, but it does not appear to be necessary for apical retention of the transporter.

In contrast to NPT2a, NPT2c transporters are not targeted to lysosomes and their removal from the apical membrane may not be entirely irreversible (30, 31). Although recovery of NPT2a cotransport activity following PTH inhibition requires protein synthesis, this may not be the case for NPT2c. In addition, the abundance of NPT2a-specific mRNA is not changed by parathyroidectomy but is minimally decreased in response to PTH administration. These data implicate PTH as a regulator of renal Na-Pi cotransport in an acute time frame, and that the regulation is determined by changes in the abundance of NaPi-II proteins in the renal brush border membrane (32). Certain aspects of Pi homeostasis at the renal level, however, are not explained by actions of PTH. For instance, even in the setting where parathyroid glands have been removed, regulation of renal P transport by dietary P content still exists, implying that other mediators of this process are at work.


FGF23 is the most recently identified important physiologic regulator of renal Pi excretion (33). This novel member of the fibroblast growth factor (FGF) family is produced by osteocytes and osteoblasts, thereby serving as a mechanism by which skeletal mineral demands can be communicated to the kidney, and influencing phosphate economy of the entire organism. In rodents and humans, after days of dietary phosphate loading, circulating FGF23 levels increase, and similarly, with dietary Pi deprivation, FGF23 levels decrease (34). FGF23 activates FGF receptors on the basolateral membrane of renal tubules resulting in removal of type II sodium-dependent Pi transporters from the apical surface of the tubular cell by a NHERF1 dependent process, similar to the mechanism described for PTH above. However, in contrast to PTH, FGF23 actions are mediated activation of ERK1/2 rather than the PTH driven PKA dependent pathway. Evidence also exists for decreased expression of type II sodium-dependent Pi via genomic mechanisms. FGF23 interacts with its receptor via a mechanism now identified as characteristic of the endocrine FGFs. FGF23 recognizes its cognate FGFR only in the presence of the co-receptor, alpha-klotho (35). Activation of this complex results in downstream ERK phosphorylation, and subsequently reduced expression of NaPi-IIa and NaPi-IIc, and CYP27B1 (1-hydroxylase), with an increase in expression of CYP24A1 (24-hydroxylase). This mechanism of signaling is apparent for the endocrine FGFs, FGF19 and FGF21, which require a separate member of the klotho family (beta-klotho) for specific tissue specific activation of FGFRs (for detailed review, see reference 36).

FGF23 contains a unique C-terminal domain, thought to be the site of the interaction with klotho. The FGF-like domain, N-terminal to a furin protease recognition site, is the basis for the interaction of FGF23 with FGFR. Alpha-klotho appears to be able to associate with “c” isoforms of FGFR1 and FGFR3, and also FGFR4 (35). Renal signaling is thought to occur via FGFR1c, thereby rendering the reduced expression of the apical membrane NaPi-II transporters. FGF23 also may play a role movement of transporters from the apical membrane; PTH may play a modulatory or necessary role for this effect (37). The physiologic importance of this system has been demonstrated in several ways. First, mice overexpressing FGF23 demonstrate increased renal Pi clearance and concomitant hypophosphatemia (38). Secondly, FGF23 null mice retain P at the kidney and are hyperphosphatemic (39). Thirdly, administration to mice of an FGF23 neutralizing antibody increases serum Pi (40).

Nevertheless, gaps in our understanding of this pathway remain. Alpha-klotho appears to be more abundantly expressed in distal renal tubules as compared to proximal tubular sites. Thus, the mechanism by which this pathway effects the transporters in the proximal tubule is unclear. Most recently klotho alone has been shown to increase expression of FGF23, and appears to be able to reduce renal tubular phosphate reabsorption, independent of FGF23 (41). These findings are consistent with a unique case of hypophosphatemia associated with a mutation in the klotho region resulting in overexpression of the protein and an abundance of circulating klotho (42). Finally, recent evidence indicating that it certain tissues (heart) FGF signaling may occur in the absence of alpha-klotho, although the physiologic significance of this finding is not certain (43).

The actions of FGF23 and other related proteins as mediators of disease are discussed in detail in the section on Pathophysiology of XLH (see below). Other potential regulators of renal Pi handling have been suggested. These include fragments of matrix extracellular glycoprotein (MEPE), secreted frizzled related protein-4 (sFRP4), stanniocalcin, and other FGFs, including FGF2, and FGF7 (44-47).

The Osteocyte As A Coordinating Center For Phosphate Homeostasis

Osteocytes are distributed throughout lamellar bone in an organized array with interconnections occurring through small tunneling caniculi (for review, see reference 48). Cellular processes extending from the cell body of the osteocyte pass through these caniculi and serve as a means of communication with other cells and to bony surfaces. Interestingly, many of the proteins involved in phosphate regulation are secreted by the osteocyte, including: 1) PHEX, which regulates FGF23 secretion, with loss-of-function resulting in elevated circulating FGF23; 2) DMP1, a SIBLING protein, in which loss-of-function also results in elevated circulating FGF23; 3) FGF23 itself, and 4) FGFR1 which appears to be activated in osteocytes resulting in elevated FGF23 expression. These observations have led to the consideration that the osteocyte may directly respond to phosphate nutritional status, and the osteocytic network throughout the skeleton may relay the mineral demands for bone maintenance to the kidney, where phosphate conservation is regulated. The osteocyte’s response to phosphate status does not appear to be an acute process, as that observed with the extracellular calcium sensing receptor system that regulates PTH secretion in PT glands. The coordination of certain specific matrix proteins may play a role in the local regulation of phosphate supply and mineralization. For instance, skeletal pyrophosphate (PPi) has been identified in increased abundance in the perilacunar bone of Hyp mice, suggesting a potential role of this potent inhibitor of mineralization in the skeletal pathophysiology of the disease (49). Others have demonstrated aberrations in osteopontin in skeletal matrix (50). It follows that genetic disruption of this pathway may result in the profound systemic disturbances observed in the diseases discussed herein.

In sum, repeated observations have confirmed that the balance between urinary excretion and dietary input of Pi is maintained in normal humans, in patients with hyper- and hypoparathyroidism, and under man conditions. This is predominantly due to the ability of the renal tubule to adjust Pi reabsorption rate according to the body’s Pi supply and demand. Thus, Pi reabsorption is increased under conditions of greater need, such as rapid growth, pregnancy, lactation and dietary restriction. Conversely, in times of surfeit, such as slow growth, chronic renal failure or dietary excess, renal Pi reabsorption is curtailed. Such changes in response to chronic changes in Pi availability are characterized by parallel changes in Na-phosphate cotransporter activity, the NPT2 mRNA level and NPT2 protein abundance. These changes are likely mediated by FGF23, as well as other possible factors. Removal of NPT2 cotransporters from the apical membrane of renal tubular cells is an acute process, mediated by PTH. The interaction of these two agents on the overall process may also be important. Indeed, ablation of PTH in a murine model of excess FGF23 abrogates hypophosphatemia. Likewise, suppression of PTH may reduce phosphate losses even with persistence of high FGF23 (51, 52), suggesting an interaction between the two pathways at the renal tubule (53).


Primary disorders of phosphate homeostasis are listed in Table 1. Phosphate abnormalities may also occur in the setting of chronic kidney disease, as effects of therapeutic agents, and nutritional or intestinal absorption problems. Not surprisingly, since the kidney is the primary regulatory site for phosphate homeostasis, aberrant phosphate metabolism results most commonly from altered renal Pi handling. Moreover, the majority of the primary diseases are phosphate-losing disorders in which renal Pi wasting and hypophosphatemia predominate and osteomalacia and rickets are characteristic. Osteomalacia and rickets are disorders of calcification characterized by defects of bone mineralization in adults and bone and cartilage mineralization during growth. In osteomalacia, there is a failure to normally mineralize the newly formed organic matrix (osteoid) of bone. In rickets, a disease of children, there is not only abnormal mineralization of bone but defective cartilage growth plate calcification at the epiphyses as well. Apoptosis of chondrocytes in the hypertrophic zone is reduced, typically resulting in an expanded hypertrophic zone, delayed mineralization and vascularization of the calcification front, with an overall appearance of a widened and disorganized growth plate (54).

The remainder of this chapter reviews the pathophysiology of hypophosphatemic rachitic and osteomalacic disorders, and provides a systematic approach to the diagnosis and management of these diseases. The discussion will focus on disorders in which primary disturbances in phosphate homeostasis occur, emphasizing X-linked hypophosphatemic rickets/osteomalacia (XLH). Other FGF23-mediated disorders including autosomal dominant and autosomal recessive hypophosphatemic rickets (ADHR, ADHR, ARHR1, ARHR2, ARHR3), and tumor-induced osteomalacia (TIO) will be discussed. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Dent's disease will be described as examples of FGF23-independent hypophosphatemia.

Table 1. Primary Disorders of Phosphate Homeostasis




FGF23-mediated                                                                                 Hypophosphatemia (XLH)                             

Autosomal dominant hypophosphatemic rickets (ADHR)       

Autosomal recessive hypophosphatemic rickets 1 (ARHR1)    

Autosomal recessive hypophosphatemic rickets 2 (ARHR2)    

Autosomal recessive hypophosphatemic rickets 2/Raine

       syndrome related hypophosphatemia (ARHR3)                    

McCune-Albright syndrome/fibrous dysplasia                           

Osteoglophonic dysplasia                                                         

Jansen metaphyseal chondrodysplasia                                    

Klotho overexpression                                                                         

Epidermal nevus syndrome (ENS)/Cutaneous Skeletal

        Hypophosphatemia Syndrome (CSHS)                     


Tumor-induced osteomalacia (TIO)











9;13 translocation











GOF (somatic)




GOF (somatic)




Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) (NaPi-IIc deficiency)                                                   

Dent’s disease (X-linked recessive hypophosphatemic)                                                                          

NPT2a deficient Fanconi syndrome                                      

Fanconi-Bickel syndrome.                                                     

Hypophosphatemia with osteoporosis and nephrolithiasis   
















Hyperphosphatemic tumoral calcinosis          






Mineralization Of Bone And Cartilage

Mineralization of bone is a complex process in which a calcium-phosphate mineral phase is deposited in a highly ordered fashion within the organic matrix (55). Apart from the availability of calcium and phosphorus, requirements for normal mineralization include: 1) adequate metabolic and transport function of chondrocytes and osteoblasts to regulate the concentration of calcium, phosphorus and other ions at the calcification sites; 2) the presence of collagen with unique type, number and distribution of cross-links, distinct patterns of hydroxylation and glycosylation and abundant phosphate content, which collectively facilitate deposition of mineral at gaps (or "hole zones") between the distal ends of collagen molecules; 3) a low concentration of mineralization inhibitors (such as pyrophosphates and proteoglycans) in bone matrix; and 4) maintenance of an appropriate pH of approximately 7.6 for deposition of calcium-phosphate complexes.

The abnormal mineralization in the hypophosphatemic disorders, is due most likely to the limited availability of phosphorus at calcification sites and, in some cases, paracrine inhibitory factors, which result in accumulation of unmineralized osteoid, a sine qua non for the diagnosis of osteomalacia. Since the resultant abundant osteoid is not unique to osteomalacia, establishing the diagnosis of osteomalacia requires dynamic histopathologic demonstration that abnormal mineralization, and not increased production, underlies the observed excess accumulation of osteoid (56, 57). Static histomorphometrical parameters seen in osteomalacia include an increase in osteoid volume and thickness, an increase in bone forming surface covered by incompletely mineralized osteoid, and a decrease in the mineralization front (the percentage of osteoid-covered bone-forming surface undergoing calcification). The critical dynamic parameter used to confirm that osteoid accumulation is due to osteomalacia is the mineral apposition rate.

Inadequate growth plate cartilage mineralization in rickets is primarily observed in the hypertrophic zone of chondrocytes. Irregular alignment and more extensive disorganization of the growth plate may be evident with increasing severity of disease. Calcification in the interstitial regions of this hypertrophic zone is defective. Grossly, these changes result in increased thickness of the epiphyseal plate, and an increase in transverse diameter that often extends beyond the ends of the bone and causes characteristic cupping or flaring.

Clinical Disorders: FGF23-mediated Hypophosphatemia


X-linked hypophosphatemic rickets/osteomalacia (XLH) was initially recognized in the 1930s as a form of “vitamin D resistant" and only later, as disorder of renal phosphate wasting. The disorder is inherited in X-linked dominant fashion and is manifest biochemically by a low renal threshold maximum for renal tubular phosphate reabsorption, consequent hypophosphatemia, and low, or inappropriate circulating levels of 1,25(OH)2D. Known biochemical characteristics of XLH and other hypophosphatemic disorders are shown in Table 2. Characteristic features of the disease include growth retardation, osteomalacia and rickets in growing children. The clinical expression of the disease is widely variable, ranging from mild skeletal abnormalities to severe bone disease. Most would agree that a wide spectrum of phenotypic severity occurs in both males (with a mutated gene on their only X chromosome) and females (who are heterozygous for the defective X-linked gene), although clinical experience suggests that females, particularly with certain mutations may express less severe disease (58). Bowing of the lower extremities is usually the first physical sign of the disorder, but is not often evident until 1-2 yrs of age, after the child is standing or walking (59). Biochemical evidence of disease can be detected shortly after birth, however may not become apparent until several weeks to months of age. Short stature generally becomes evident after the first year of life, as well (60), coincident with the timing of bow deformities. Growth abnormalities and limb deformities are both more evident in the lower extremities, since they represent the fastest growing body segment before puberty.

XLH, X-linked hypophosphatemia; ADHR, Autosomal dominant hypophosphatemic rickets; ARHR, Autosomal recessive hypophosphatemic rickets; TIO, Tumor-induced osteomalacia; XLHR, X-linked recessive hypophosphatemia (Dent's Disease); HHRH, Hereditary hypophosphatemic rickets with hypercalciuria. N, normal; , decreased; , increased, ( ), decreased relative to the serum phosphorus concentration; ?, unknown.

The majority of affected children exhibit clinical evidence of rickets (Figure 4), varying from enlargement of the wrists and/or knees to severe malalignment defects such as bowing or knock-knee deformities. (Figure 4). Such defects may result in waddling gait and leg length abnormalities (61). X-ray examination reveals expanded areas of non-mineralized cartilage in epiphyseal regions and lateral curvature of the femora and/or tibia. Strikingly absent are features observed in vitamin D deficiency rickets attributable to hypocalcemia, such as, tetany and convulsions. Muscle weakness and pain are not usually presentations of XLH in early childhood, but emerge later in life.

Figure 4. Radiograph of the lower extremities in a patient with X-linked hypophosphatemia. Bowing of the femurs is evident bilaterally. The distal femoral metaphysis is cupped, frayed and widened, radiographic features of an expanded and disorganized growth plate.

Additional signs of the disease may include delayed dentition and dental abscesses (62, 63), which are usually manifest clinically by pain and a gingival papule at the site of involvement. Radiographically there is an enlarged air compartment seen around the root of the affected tooth and an enlarged pulp chamber. Other dental findings that may play a role in the process include impaired mineralization of the dentine compartment of the tooth, and diminished cementum. Craniofacial structural anomalies may also result in crowding of teeth, requiring orthodontic management. Indeed, suture fusion of the cranial bones is aberrant, and craniosynostosis to some degree occurs frequently, and in severe cases require neurosurgical intervention.


Adults with XLH manifest a broad spectrum of disease. They may be asymptomatic or present with severe bone pain. On clinical examination they often display evidence of post-rachitic deformities, such as bowed legs or short stature. However, overt biochemical changes such as elevated serum alkaline phosphatase activity or other biomarkers of bone turnover may not be evident. Adult patients frequently demonstrate features of "active" osteomalacia, characterized radiographically by pseudofractures, coarsened trabeculation, rarified areas and/or non-union fractures, and although variably present, may have elevated serum alkaline phosphatase activity. Symptoms at presentation may reflect the end-result of chronic changes, and may not correlate with apparent current activity of the disease. In spite of marked variability in the clinical presentation of the disease, bone biopsy in affected children and adults nearly always reveals osteomalacia without osteopenia (Figure 5). Histomorphometry of biopsy samples usually demonstrates a reduced rate of formation, diffuse patchy hypomineralization, a decrease in mineralizing surfaces and characteristic areas of hypomineralization of the periosteocytic lacunae (64). Of note, as noted above, increased skeletal PPi identified in the perilacunar bone of Hyp mice, the syngeneic animal model of XLH, may serve to inhibit mineralization locally as well (49).

Figure 5. Section from an undecalcified bone biopsy in an untreated patient with X-linked hypophosphatemia. The Goldner stain reveals mineralized bone (blue/green) and an abundance of unmineralized osteoid (red) covering a substantial portion of the surfaces. The width of the osteoid seams is substantially increased.

Osteophytes and other findings of a mineralizing enthesopathy (65) occur frequently and may result in the most severe clinical symptomatology in adulthood. A great deal of the morbidity of XLH in adults arises from the high incidence of arthritis, calcified entheses, and osteophytes. Enthesopathy generally is first detectable radiographically by late in the second decade, or early in the third decade. Older subjects have more sites of involvement, and generally increasing involvement with age; the frequency of involvement appears to be greater in males. With progressive enthesopathy and bony overgrowth, excruciating pain may occur, particularly with fusion of the sacroiliac joint(s) and spinal stenosis (66). These manifestations do not appear to be affected for the better or worse with respect to exposure to currently available therapies (67).  It is peculiar that XLH represents a deficiency of mineralization at many skeletal sites, and pathologic ectopic mineralization elsewhere. This paradoxical situation raises the possibility that aberrant humoral factors, in addition to the ambient hypophosphatemia, may play a role in the discordant mineralization abnormalities observed.


Clinical Biochemistry


As previously noted, the primary biochemical abnormality of XLH is hypophosphatemia due to increased urinary phosphate excretion. Moreover, mild gastrointestinal phosphate malabsorption is present in the majority of patients, which may contribute to the evolution of the hypophosphatemia (Table 2) (68, 69).


In contrast, the serum calcium concentration in affected subjects is normal despite gastrointestinal malabsorption of calcium. However, as a consequence of this defect, urinary calcium is often decreased. The severe secondary hyperparathyroidism that occurs in vitamin D deficiency is not present as the degree of calcium malabsorption is not a severe in that condition. However, mildly elevated circulating levels of PTH occur in many patients naive to therapy, and thought to represent the inadequate production of 1,25(OH)2D. Other non-specific but typical findings include elevated serum alkaline phosphatase activity. Serum alkaline phosphatase activity, although usually elevated to 2-3 times the upper limit of normal in childhood, is generally less than the levels observed in nutritional rickets.  As noted above, circulating PTH levels may be normal to modestly elevated in naïve patients, but treatment with phosphate salts often aggravate this tendency such that persistent secondary hyperparathyroidism may occur. Because of variability in adulthood, this measure is not a reliable marker of disease involvement in the older age group. Prior to the initiation of therapy, serum 25-OHD levels are normal, and serum 1,25(OH)2D levels are in the low normal range (70, 71). The paradoxical occurrence of hypophosphatemia and normal serum calcitriol levels in affected subjects is consistent with aberrant regulation of both synthesis and clearance of this metabolite (due to increased 25-OHD-24-hydroxylase activity) (72, 73). Circulating levels of FGF23 are generally elevated in individuals with XLH, although overlap may occur. Thus, caution should be applied when using this measure as a strict diagnostic criterion for the diagnosis of XLH, as some subjects have been shown to have circulating FGF23 levels within the normal range, and commercially available assays (which recognize “intact” species or both intact and C-terminal species) do not always provide concordant results.




With the recognition that hypophosphatemia is the definitive marker for XLH, Winters et al (74) and Burnett et al (75) discovered that this disease is transmitted as an X-linked dominant disorder. Analysis of data from 13 multigenerational pedigrees identified PHEX (for phosphate regulating gene with homologies to endopeptidases located on the X chromosome) as the gene disrupted in XLH (76). PHEX is located on chromosome Xp22.1, and encodes a 749-amino acid protein with three putative domains: 1) a small amino-terminal intracellular tail; 2) a single, short transmembrane domain; and 3) a large carboxyterminal extracellular domain, containing ten conserved cysteine residues and a HEXXH pentapeptide motif, which characterizes many zinc metalloproteases. Further studies have revealed that PHEX is homologous to the M13 family of membrane-bound metalloproteases, or neutral endopeptidases. M13 family members, including neutral endopeptidase 24.11 (NEP), endothelin-converting enzymes 1 and 2 (ECE-1 and ECE-2), the Kell blood group antigen (KELL), neprilysin-like peptide (NL1), and endothelin converting enzyme-like 1 (ECEL1), degrade or activate a variety of peptide hormones. In addition, like other neutral endopeptidases, immunofluorescent studies have revealed a cell-surface location for PHEX in an orientation consistent with a type II integral membrane glycoprotein (77). It has been demonstrated that certain missense variants in PHEX that substitute a highly conserved cysteine residue will interfere with normal trafficking of the molecule to the plasma membrane (78). Thus, it appears that one mechanism associated with the pathophysiology of XLH is to prevent PHEX from locating to the cell membrane. Other missense variants have been shown in in vitro studies to disrupt enzymatic function of the protein, alter its conformation, or disrupt cellular processing in other ways (79, 80).


Studies in rodents have demonstrated that Phex is predominantly expressed in bones (in osteoblasts/osteocytes) and teeth (in odontoblasts/ameloblasts) (81-84); mRNA, protein or both have also been found in lung, brain, muscle, gonads, skin and parathyroid glands. Subcellular locations appear to be the plasma membrane, endoplasmic reticulum and Golgi organelle. Immunohistochemistry studies suggest that Phex is most abundant on the cell surface of the osteocyte. In sum, the ontogeny of Phex expression suggests a possible role in mineralization in vivo.


Recently combined efforts of many investigators and genetic sequencing laboratories have documented over 850 pathogenic PHEX variants (85). Most of these (>70%) are predicted to generate a truncated PHEX protein. Overall, frameshift, splicing, copy-number, nonsense, and missense variants have been described, and are predicted to cause loss of function of the PHEX protein.  A recently updated on-line database of PHEX variants can be accessed at:


The location of Phex expression in bone cells have led to the hypothesis that diminished PHEX/Phex expression in bone initiates the cascade of events responsible for the pathogenesis of XLH. In order to confirm this possibility, several investigators have used targeted over-expression of Phex in attempts to normalize osteoblast mineralization, in vitro, and rescue the Hyp phenotype in vivo (86-88). Results from these studies have not resulted in a complete skeletal rescue, raising questions as to the role of early developmental expression of PHEX, or at least the success of expression when targeted with osteocalcin or type I collagen promoters. Nevertheless, partial rescue of the mineralization defect in Hyp mice occurs, suggesting that local effects of the PHEX mutation may play some role in the mineralization process, but cannot completely restore the skeleton to normality. Of note, this partial rescue occurs in concert with a reduction in FGF23 levels, although not lowered to a truly normal range (88).


In sum, although a physiologic substrate for PHEX has not been identified, the consequence of loss-of-function of PHEX is an elevation in the circulating FGF23 level. Failure of targeted osteoblastic PHEX overexpression to completely rescue Hyp mice may reflect that critical sites (or developmental timing) for PHEX expression are not effectively generated with these models to effectively rescue the skeletal phenotype; this effect may be dependent upon the resultant capacity in these transgenic models of normal PHEX to reduce FGF23 production in mutant cells. ASARM peptides, fragments of SIBLING (small integrin binding ligand N-glycated) proteins, have been shown to inhibit mineralization and potentially play a role in modulation of renal P transport; these peptides have also been shown to be degraded by PHEX (89).  Other evidence has suggested that expression of osteopontin expression may be altered in the context of PHEX loss of function as well, (50).




Hypophosphatemia in XLH results from the impaired renal proximal tubule function of Pi reabsorption. For some time, XLH was thought to be a primary disorder of the renal tubule, however the consideration that humoral mediation of phosphate wasting in XLH was suggested by two novel clinical findings. First, the persistence of renal phosphate wasting after renal transplantation in a man with XLH indicated a new donor kidney continued to manifest the defect (90). Second, the clinical course of a similar phosphate-wasting syndrome, Tumor Induced Osteomalacia (also referred to as Oncogenic Osteomalacia), resolved upon removal of a tumor, suggesting that the tumor was the source of a mediating factor. Further evidence for humoral mediation was provided by classical parabiosis experiments, suggested that a cross-circulating factor could mediate renal phosphate wasting (91), and by renal cross-transplantation between Hyp and normal mice. These experiments demonstrated continued normal renal phosphate handling after transplantation of Hyp kidney to a normal host, as well as the failure to correct the mutant phenotype upon introduction of a normal kidney to a Hyp host (92). These findings, most consistent with humoral mediation of the Pi wasting in the disease, led to the search for candidate mediators of renal phosphate handling, and eventually to the discovery that FGF23 is an important regulator of renal phosphate homeostasis.  Subsequently mean circulating FGF23 concentrations were found to be greater in XLH patients than in unaffected control subjects, providing evidence for the role of this endocrine FGF in XLH.


Renal tubular wasting occurs on the basis of a decreased abundance of NPT2 transporters in the proximal convoluted tubule cells (93-95), and in turn, this reduction in NPT2 abundance is mediated by increased circulating levels of FGF23 (see above, Regulation of Renal Tubular Phosphate Handling). Increased FGF23 occurs in the context of disruption of PHEX, which, like FGF23, is primarily expressed in osteocytes, and FGF23 appears to be produced in a phosphate-sensitive manner.


It remains unclear as to how the loss-of-function of PHEX results in elevated FGF23 levels. The hypothesis that PHEX (a member of the M13 family of zinc-dependent type II cell surface membrane metalloproteinases) could serve as a processor of a phosphaturic hormone such as FGF23 has not been borne out, and the role PHEX plays in this pathway is not clear. Several other phosphate wasting disorders have been described (see below) in which elevated FGF23 occurs in the setting of (presumably) normal PHEX.  Such conditions include TIO, where overproduction of FGF23 results in a comparable Pi wasting phenotype. In Autosomal Dominant Hypophosphatemic Rickets (ADHR) specific mutations in FGF23 result in gain of function of the protein (96, 97). The specific mutations disrupt an RXXR protease recognition site, and thereby protect FGF23 from proteolysis, resulting in reduced clearance and elevating circulating levels of this protein, with coincident renal Pi wasting. In yet another genetic disorder, Autosomal Recessive Hypophosphatemic Rickets type I (98), due to homozygous loss of function mutations in dentin matrix protein-1 (DMP1), renal tubular Pi wasting occurs in the setting of increased FGF23 levels. DMP1 is a matrix protein of the SIBLING (small integrin binding ligand N-glycated) family, and, like PHEX and FGF23, has been primarily identified in osteocytes.


In Autosomal Recessive Hypophosphatemic Rickets type II, due to mutations in ENPP1, elevated FGF23 concentrations occur (99, 100). ENPP1 encodes a phosphatase with a critical local role in mineralization, serving to generate the mineralization inhibitor, pyrophosphate (PPi); loss of function of ENPP1 may result in Generalized Arterial Calcification of Infancy (GACI), a fatal disease of infants in which rampant vascular mineralization occurs (101). These findings have suggested the hypothesis that loss of the mineralization inhibitor PPi prompts a signal to compensate for the severe excess vascular mineralization, and increasing FGF23 levels results in an attempt to induce renal phosphate excretion and to limit further excessive mineralization. Nearly all patients who have survived GACI develop renal phosphate wasting and often consequent rickets (102).


Furthermore, FGF23 levels are elevated in mice with biallelic disruptions of DMP1 and with biallelic loss of ENPP1. Transgenic mice which overexpress FGF23, exhibit retarded growth, hypophosphatemia, decreased (or inappropriately normal) serum 1,25(OH)2D levels and rickets/osteomalacia, all features of XLH.   Indeed, murine models of all of these disorders (XLH, ADHR, TIO, and ARHR) similarly demonstrate elevated circulating FGF23 levels with concomitant renal phosphate wasting


In sum, enhanced FGF23 activity is common to several phosphate-wasting disorders. In particular, those disorders that share the combined defects of inappropriately low circulating levels of 1,25(OH)2D and renal tubular Pi wasting are associated with increased FGF23 levels. This coincidence of findings holds for XLH, ADHR, ARHR (types I, II, and III), and TIO, and are consistent with the notion that FGF23 is a both a direct regulator of Pi homeostasis at the renal level, a down-regulator of 1a-hydroxylase activity, responsible for the catalysis of 25-OH vitamin D to its active form, and stimulus for its clearance via the 24-hydroxylation pathway. The teleological appeal to this argument stems from the provision of 2 major Pi regulating hormones in the body: firstly, PTH (primarily responsive to serum Ca levels), which also serves to increase Ca levels via an increase in circulating 1,25(OH)2D, and secondly, FGF23 (primarily responsive to Pi), which counters PTH’s calcemic effect by reducing 1,25(OH)2D levels (Figure 6).

Figure 6. Scheme for the speculated pathophysiology of XLH, ARHR, TIO, and ADHR. Upper panel, osteocytes, comprising a network of connected cells embedded in mineralized bone are the cellular source of PHEX (which is mutated in XLH), DMP1 (which is mutated in ARHR), and FGF23 (which is found in high concentrations in all four of these hypophosphatemic disorders). It follows that loss of PHEX or DMP1 results in increased FGF23 production/secretion by mechanisms that are not currently understood. Circulating FGF23 concentrations may also occur secondary to the increased production associated with various tumors. Lower panel, circulating FGF23 interacts with an FGF receptor (presumably FGFR1) on the basolateral surface of the proximal renal tubular cell. Klotho, produced by the distal renal tubule in both membrane bound and secretory forms, is necessary for the FGF23/FGFR interaction. Signaling through this pathway results in a decrease in NPT2 mRNAs, thereby reducing the abundance of Pi cotransporters on the apical membrane as well as a more rapid action of translocating the transporter off of the apical membrane. Thus, impairment of renal tubular Pi reabsorption results. Likewise, synthesis of 1,25(OH)2D is impaired, while its clearance is augmented. In XLH and ARHR, increased production of FGF23 occurs in the skeleton; in TIO, increased production of FGF23 occurs in tumors; in ADHR, enhanced activity of FGF23 occurs as a result of the specific mutations that retard its metabolic clearance.

Other recent findings have provided support for the role of klotho in the FGF23-mediated hypophosphatemia pathway. An unusual patient with renal tubular Pi wasting and abnormally increased serum klotho has been described (42). Investigation revealed a translocation breakpoint disrupting the region upstream of that encoding klotho. Indeed, mice with disruption of the klotho gene manifest hyperphosphatemia and elevated circulating 1,25(OH)2D levels (103). The proof that klotho is distal to PHEX in this regulatory pathway was shown by crossing the klotho disrupted mice with Hyp (PHEX-deletion) mice. The double mutant (Hyp/Kl-/-) mice were hyperphosphatemic, with elevated 1,25(OH)2D levels, despite having extremely elevated circulating FGF23 levels due to PHEX loss-of-function (104).  The unexpected finding that overexpression of klotho can upregulate FGF23 production has also been reported (105).


Indeed, further evidence for the central role of FGF23 in the Pi-regulating process comes from the investigation of another group of rare disorders of Pi homeostasis in which renal Pi conservation is excessive in the setting of increased circulating Pi levels. This group of disorders, known as hyperphosphatemic tumoral calcinosis (HTC), is manifest clinically by precipitation of amorphous calcium-phosphate crystals in soft tissues. This phenomenon is thought to result from an increase in the ambient Ca x Pi solubility product, and occurs as a direct result of enhanced renal tubular reabsorption of Pi (106). In addition, circulating 1,25(OH)2D levels are inappropriately in the high-normal to high range. Thus, the precise converse of primary metabolic derangements occurs, as compared to the XLH-related group of diseases. Initially, HTC was been shown to directly result from loss of function mutations in GALNT3, a glycosylating enzyme important for appropriate O-glycosylation of proteins. This modification appears to be necessary for efficient Golgi secretion of full length FGF23 (107). Interestingly patients with HTC due to GALNT3 mutations have increased circulating levels of the inactive C-terminal fragment of FGF23, but low circulating levels of intact active form of FGF23 (108). Recent evidence implicates that variant post-translational modification of FGF23 can also be modulated by FAM20C: mutations in this gene can result in elevated FGF23 levels, renal phosphate wasting and hypophosphatemia, and referred to as Autosomal Recessive Hypophosphatemic Rickets, type III (ARHR3) and may have clinical features described as Raine syndrome (see table 1) (109, 110).


HTC may also occur in the setting of loss-of-function mutations of FGF23 (111). As with GALNT3-related HTC, these patients have low intact FGF23 level. Loss of function of klotho has also been described in a case of HTC, despite the finding of elevated FGF23 levels, thus rendering the FGF23 inactive at the renal proximal tubule (112). As with hypophosphatemia syndromes, animal models have confirmed the physiologic implications of these clinical scenarios:  FGF23 null mice develop a hyperphosphatemic, calcifying phenotype with elevated 1,25(OH)2D levels (39), similar to mice with disruption of the klotho gene (103, 113). As noted above, the klotho protein is now known to be an essential co-factor in FGFR1c activation when FGF23 serves as the activating ligand (35).


The overall physiologic importance of this regulating system requires further study. It is not clear how PHEX or DMP1 result in elevated FGF23 levels. The intriguing aspect of the osteocyte as a potential central cell in this pathway also bears further study.




Decades ago, physicians employed pharmacological doses of vitamin D as the cornerstone for treatment of XLH. However, long-term observations indicate that this therapy fails to cure the disease and poses the serious problem of recurrent vitamin D intoxication and renal damage. Indeed, such treatment results only in incomplete healing of the rachitic abnormality, while hypophosphatemia and impaired growth remain. Similar unresponsiveness is typical with use of 25(OH)D.


With the recognition that phosphate depletion is an important contributor to impaired skeletal mineralization, physicians began to devise treatment strategies that employed oral phosphate supplementation to compensate for the renal phosphate wasting and thereby increasing the available Pi to the mineralizing skeleton. This strategy was somewhat successful in terms of improving skeletal lesions, although it was soon realized that pharmacologic amounts of vitamin D were necessary in combination with phosphate supplements to counter the exacerbation of hyperparathyroidism observed in this setting. Such combination therapy was found to be more effective than either administering vitamin D or phosphate alone. With the recognition that circulating 1,25(OH)2D levels are not appropriately regulated in XLH, the use of this metabolite in combination with phosphate was subsequently used to treat the disease (67, 114-116). The current treatment strategy directly addresses the combined calcitriol and phosphorus deficiency characteristic of the disorder. Although this combination therapy has become the conventional therapy for XLH, complete healing of the skeletal lesions is usually not the case, and late complications of the disease are persistent and often debilitating.


In children the goal of therapy is to improve growth velocity, normalize any lower extremity defects, and heal the attendant bone disease. Generally, the treatment regimen includes a period of titration to achieve a maximum dose of 1,25(OH)2D3 (Rocaltrol® or calcitriol), 20-50 ng/kg/day in two divided doses, and phosphorus, (20-50 mg/kg/day, to a maximum of 1-2 gms/day) in 3-5 divided doses.


Use of 1,25(OH)2D3/phosphorus combination therapy involves a significant risk of toxicity. Hypercalcemia, hypercalciuria, renal calcinosis, and hyperparathyroidism can be sequelae of unmonitored therapy. Detrimental effects on renal function were particularly common prior to the frequent monitoring now generally employed with this therapy. Indeed, hypercalcemia, severe nephrocalcinosis and/or diminished creatinine clearance necessitates appropriate dose adjustment, and in some cases discontinuation of therapy. Throughout the treatment course careful attention to renal function, as well as serum and urine calcium is extremely important. Nevertheless, the improved outcome of this therapeutic intervention compared to that achieved by previous regimens, justifies its use, albeit requires an aggressive clinical monitoring schedule.


While such combined therapy often improves growth velocity, refractoriness to the growth-promoting effects of treatment can be encountered in children who present with markedly short stature prior to 4 years of age. For that reason the use of recombinant growth hormone as additional treatment has been suggested (117), however this approach has not been universally recommended in view of the lack of definitive benefits in controlled studies, and a risk of resultant worsening of the disproportional stature (118), although others have not identified significant concerns in this regard (119).  A recent meta-analysis concluded there as insufficient evidence to support recommendation of its use (120)


Indications for therapy in adults with XLH are less clear. The occurrence of intractable bone pain and refractory non-union fractures often respond to treatment with calcitriol and phosphorus (121). However, data remain unclear regarding the effects of treatment on fracture incidence (which may not be increased in untreated patients). There does not appear to be any effect of this therapy on enthesopathy, however superior dentition appears to occur in the setting of higher medication exposure through adulthood as well as the entire life span (64). Muscle weakness and general well-being may occur with therapy in some adults. In sum, the decision to treat affected adults must be individualized. In general, it is beneficial to offer adults with significant symptomatology a trial of this therapy, but only if routine biochemical monitoring can be performed. Several detailed strategies for the management of children and adults with XLH are available (122-124).


A more recent development has been a more directed approach to the etiology of the renal phosphate loss. After demonstration of the efficacy of this strategy in the Hyp mouse model of XLH (40), trials of an antibody to the human FGF23 protein, burosumab (KRN23) have been conducted in children and adults (125-131) leading to its approval for use in both North America, several S. American countries, Europe, and other regions. The initial study using burosumab to treat in children with XLH resulted in improvement of radiographic features of rickets in concert with correction of abnormal biochemical indices after previous treated with conventional phosphate and active vitamin D therapy (127). Steady and stable correction of hypophosphatemia was attained with administration of the antibody every 2 weeks and a favorable safety profile was evident. The improved musculoskeletal status has been demonstrated to persist as seen in follow up extension studies for a total of 3 years (132). Moreover, one study has provided evidence that burosumab was superior to conventional therapy with calcitriol and phosphate in terms of skeletal improvement and growth (133).




Several studies have documented autosomal dominant inheritance of a hypophosphatemic disorder similar to XLH (134, 135). The phenotypic manifestations of this disorder include the expected hypophosphatemia due to renal phosphate wasting, lower extremity deformities, and rickets/osteomalacia. Affected patients also demonstrate normal serum 25(OH)D levels, while maintaining inappropriately normal serum concentrations of 1,25(OH)2D, in the presence of hypophosphatemia, all hallmarks of XLH (Table 2). PTH levels are normal. Long-term studies indicate that a few of the affected female patients demonstrate delayed penetrance of clinically apparent disease and an increased tendency for bone fracture, uncommon occurrences in XLH. In addition, among patients with the expected biochemical features documented in childhood, rare individuals lose the renal phosphate-wasting defect after puberty. As noted above, specific mutations in FGF23 in the 176-179 amino acid residue sequence are present in patients with ADHR (97). These mutations disrupt an RXXR furin protease recognition site, and the resultant mutant molecule is thereby protected from proteolysis, and resultant elevated circulating levels of FGF23 are the likely cause of the renal Pi wasting. Interestingly, circulating FGF23 levels can vary and reflect the activity of disease status (136).


Exploration of the waxing/waning severity of disease in ADHR has identified that iron may play a significant role in the regulation of circulating FGF23 (137).  Iron deficiency appears to upregulate FGF23 expression, and in normal individuals, processing of the intact protein to its inactive N- and C-terminal fragments is efficient, thereby compensating for the increased intact FGF23 production seen with iron deficiency. Thus. in normal individuals who become iron deficient normal circulating levels of intact FGF23 are maintained despite the increase in production. However, in ADHR, inefficient processing of FGF23, due to the lack of protease recognition at the usual amino acid 179/180 cleavage site, may not be able to compensate for increased FGF23 synthesis during periods of iron deficiency. Thus, the waxing and waning clinical severity observed in some cases of ADHR may be amenable to iron supplementation, and provide a straightforward approach to therapy. A recently reported case demonstrates that correction of serum iron levels to high normal levels allowed for discontinuation of conventional rickets medications (138)


An apparent forme fruste of ADHR (autosomal dominant) hypophosphatemic bone disease has many of the characteristics of XLH and ADHR, but recent reports indicate that affected children display no evidence of rachitic disease. Because this syndrome is described in only a few small kindreds, and radiographically evident rickets is not universal in children with familial hypophosphatemia, these families may have ADHR. Further observations are necessary to discriminate this possibility.




Families with phosphate wasting rickets inherited in an autosomal recessive manner have been described and demonstrate the same constellation of progressive rachitic deformities seen in both XLH and ADHR (98, 139).  Moreover, the biochemical phenotype is manifest by the same measures of hypophosphatemia, excess urinary Pi losses, and aberrant vitamin D metabolism (normal circulating 25-OHD and 1,25(OH)2D levels, despite ambient hypophosphatemia) as observed in both XLH and ADHR. In addition to the expected phenotypic features, and in contrast to XLH, spinal radiographs of patients with ARHR reveal noticeably sclerotic vertebral bodies. In addition to the enlarged pulp chamber characteristic of teeth in individuals with XLH, enamel hypoplasia can be evident in heterozygotes. Of particular interest is the identification of elevated levels of FGF23 in the affected individuals. Experience with long-term follow-up is not widespread in ARHR and therapeutic response or guidelines have not been definitively established.


The identification of a progressive mineralization defect associated with hypophosphatemia in DMP1 knockout mice led to the consideration of homozygous loss of function in this candidate gene as a cause of ARHR. Indeed, this was proven to be the case for the first families identified with the disorder. Thus, the role of the osteocyte product, DMP1, appears as either part of the PHEX-FGF23 pathway, or at least can affect circulating FGF23 levels, perhaps independently of PHEX. These observations reinforce the central role that the osteocyte plays in mineral homeostasis.


Moreover, hypophosphatemic rickets in association with renal Pi wasting has been recently described in the setting of the extremely rare disorder, generalized arterial calcification of infancy (GACI) (99-101). This disorder occurs with homozygous loss-of-function mutations of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). Loss-of-function of ENPP1 results in the inability to generate the mineralization inhibitor, pyrophosphate, thereby disrupting the restriction of heterotopic (e.g., vascular) mineralization. GACI is often fatal, but hypophosphatemia, identified in the setting of elevated FGF23 levels in an adult with a homozygous ENPP1 mutation raised this consideration of rickets in survivors of GACI (140). Moreover, the patient’s son was affected with both GACI and hypophosphatemia. The mechanism by which this enzyme influences renal tubular phosphate wasting is not evident, and further study is necessary to understand this intriguing problem. One speculated mechanism may reflect a bone cell response to a relatively hypermineralized (or high-phosphate/low pyrophosphate) milieu which results in a compensatory, prolonged secretion of FGF23. Such a mechanism may effectively signal the kidney to reduce the body’s mineral load, but apparently cannot be down-regulated to protect against excessive Pi losses. Although there has been concern that the treatment of rickets in patients affected with GACI patients may promote worsening of vascular calcification, no evidence to sustain this concern has emerged and one long term observational report suggests that treatment does not worsen this finding (141). A recent phenotyping study with long-term observations in this regard corroborates this initial impression (102).




Rickets and/or osteomalacia have been associated with various types of tumors (96). In many cases, the metabolic disturbances improved or completely disappeared upon removal of the tumor, indicating a causal role of the tumor. Affected patients generally present with bone and muscle pain, muscle weakness, rickets/osteomalacia, and occasionally recurrent fractures of long bones. Biochemistries include hypophosphatemia secondary to renal phosphate wasting and normal serum levels of calcium and 25(OH)D. Serum 1,25(OH)2D is often overtly low or is otherwise inappropriately normal in the setting of hypophosphatemia (Table 2). Aminoaciduria and/or glucosuria may be present. Radiographic abnormalities include generalized osteopenia, pseudofractures and coarsened trabeculae, as well as widened epiphyseal plates in children. The histologic appearance of trabecular bone in affected subjects most often reflects the presence of a low turnover osteomalacia.


The large majority of patients with this syndrome harbor tumors of mesenchymal origin, including primitive-appearing, mixed connective tissue lesions. These tumors are often classified as osteoblastomas, osteochondromas, non-ossifying fibromas and ossifying fibromas. In addition, tumors of epidermal and endodermal derivation have been implicated as causal of the disease. Indeed, the observation of tumor-induced osteomalacia concurrent with breast carcinoma, prostate carcinoma oat cell carcinoma, small cell carcinoma, multiple myeloma and chronic lymphocytic leukemia have been reported.


Although this syndrome is relatively rare compared to XLH, investigation of causative tumors eventually led to the identification and isolation of FGF23 (38, 142), the mediator of many heritable hypophosphatemic disorders, and the recognition that this protein is the central factor in a major regulatory system affecting Pi homeostasis. Moreover, the discovery represented the first disorder related to the endocrine subfamily of FGFs, acting at distant sites with specificity of site activity conferred by the family of klotho co-receptors. 


Regardless of the tumor cell type, the lesions at fault for the syndrome are often small, difficult to locate and present in obscure areas which include the nasopharynx, jaw, sinuses, the popliteal region and the suprapatellar area. In any case, a careful and thorough examination is necessary to document/exclude the presence of such a tumor. Indeed, CT and/or MRI scan of a clinically suspicious area should be undertaken. Recently newer imaging techniques such as octreotide scintigraphy or PET scans have been used to successfully identify tumors that remained unidentified by other means of localization. Newer agents with greater specificity for somatostatin receptors type 2 and type 5 appear to increase the sensitivity of PET scanning (143, 144), and co-registry with high resolution anatomic imaging has considerably advanced detection of small tumors.


Selective venous sampling has been suggested as a complementary approach to diagnosis. This technique may provide confirmation of local FGF23 secretion in suspicious areas identified by imaging (as to avoid unnecessary operations from false-positive imaging studies). The technique may serve to direct local imaging to anatomic regions defined by step-ups in FGF23 concentrations, but is limited by the relatively long half-life of FGF23, which may be misleading if the sampling is not in very close proximity to the offending tumor. Although useful in the settings mentioned above, the technique is not thought to be an optimal first-line approach in identification of TIO causing tumors (145).




TIO is a result of Pi wasting secondary to circulating factor(s) secreted by causal tumors. FGF23 has proven to be the primary factor identified in most patients where examination of serum levels or tumor material has occurred. Nevertheless, a variety of other factors have been considered as a potential part of the cascade that can lead to renal Pi wasting including: 1) FRP4 (frizzled related protein 4) (45), a secreted protein with phosphaturic properties, 2) FGF7, a paracrine FGF identified in TIO tumors that has been shown to directly inhibit renal Pi transport (47), 3) the SIBLING protein, MEPE (matrix extracellular phosphglycoprotein), which has been reported to generate fragments (ASARM peptide) with potential Pi wasting activity (44), 4) the SIBLING protein, DMP1, which has now been implicated in ARHR, and has been shown to be in particularly high abundance in TIO tumors (38, 98, 140, 146), and 5) the high molecular weight isoform of FGF2 (another paracrine FGF), which when expressed transgenically in mice, results in hypophosphatemic rickets (147). It is also possible that these or other tumor products may have direct effects on the mineralization function of the skeleton.


A novel genetic mechanism by which TIO tumors may develop autonomous FGF23 production involves a somatic chromosomal rearrangement which has been identified in a high proportion of TIO tumors (142). The rearrangement sequence predicts a fusion protein consisting of the N-terminal portion of fibronectin and the FGFR1 receptor. The extracellular fibronectin domain is proposed to promote dimerization and activation of the complex leading to downstream signaling resulting in FGF23 secretion. FGF23 itself is further proposed as an additive stimulus, amplifying FGF23 production as part of a feed-forward loop resulting in the substantial FGF23 production characteristic of TIO (148). More recently another rearrangement generating a fibronectin/FGF1 fusion protein has been described (149).


In contrast to these observations, other rare patients with TIO secondary to hematogenous malignancy manifest abnormalities that would suggest a different pathophysiologic mechanism. In these subjects a nephropathy induced with light chain proteinuria or other immunoglobulin derivatives appears to result in decreased renal tubular reabsorption of phosphate. Thus, light-chain nephropathy has been considered a possible mechanism for the TIO syndrome.




The first and foremost treatment of TIO is complete resection of the tumor. However, recurrence of mesenchymal tumors, such as giant cell tumors of bone, or inability to resect completely certain malignancies, such as prostatic carcinoma, has resulted in development of alternative therapeutic intervention for the syndrome. In this regard, administration of 1,25(OH)2D alone or in combination with phosphorus supplementation has served as effective therapy for TIO. Doses of calcitriol required range from 1.5-3.0 µg/d, while those of phosphorus are 2-4 g/d. Although little information is available regarding the long-term consequences of such treatment, the high doses of medicine required raise the possibility that nephrolithiasis, nephrocalcinosis, and hypercalcemia may frequently complicate the therapeutic course. Indeed, hypercalcemia secondary to parathyroid hyperfunction has been documented in several subjects. Generally, these patients receive phosphorus as part of a combination regimen, exacerbating the path to parathyroid autonomy. Thus, as with treatment of XLH, careful assessment of parathyroid function, serum and urinary calcium, and renal function are essential to ensure safe and efficacious therapy.  Recent studies using burosumab, the antiFGF23 antibody, have demonstrated improvement in both biochemical indices and biopsy parameters of osteomalacia in inoperable TIO (150). 




In widespread fibrous dysplasia of bone (due to mosaic activating mutations in GNAS), neurofibromatosis and cutaneous skeletal hypophosphatemic syndrome (associated with somatic mutations in HRAS and NRAS) (151), hypophosphatemic osteomalacia/rickets can result as a result of elevated circulating FGF23 levels (152). Indeed, variable degrees of decreased renal tubular phosphate reabsorption, as assessed by TMP/GFR assessments, occur in patients with fibrous dysplasia of bone. Other primary skeletal disorders in which elevated FGF23 levels have been reported include osteoglophonic dysplasia (due to mutations in the FGFR1 receptor) (153), Jansen metaphyseal chondrodysplasia, (due to activating mutations of the PTH1 receptor) (154), opsismodysplasia (155), and in FAM20C mutations (110). The mechanism(s) by which elevations in FGF23 occur in these settings is not certain at this time.


Clinical Disorders: FGF23-independent Hypophosphatemia




This rare autosomal recessive disease is marked by hypophosphatemic rickets with hypercalciuria (156). Initial symptoms of the disorder generally manifest between 6 months to 7 years of age and usually consist of bone pain and/or deformities of the lower extremities. Such deformities may include genu varum or genu valgum or anterior bowing of the femur and coxa vara. Additional disease features include short stature, and radiographic signs of rickets or osteopenia. In contrast to XLH, muscle weakness may be elicited as a presenting symptom.


Many of the distinguishing characteristics of HHRH stem from the fact that HHRH is not a disorder of FGF23-mediated hypophosphatemia. In fact, levels are often decreased compared to the normal population. Consequently, in contrast to the previously described disorders in which renal phosphate transport is limited, patients with HHRH exhibit increased 1,25(OH)2D production. The resultant elevated serum calcitriol levels enhance gastrointestinal calcium absorption, which in turn increases the filtered renal calcium load and inhibits PTH secretion. Collectively these events produce the hypercalciuria observed in affected patients (Table 2). Although initially not thought to be part of the syndrome, the propensity for kidney stones to occur has been reported in several patients.


In general, the severity of the bone mineralization defect correlates inversely with the prevailing serum Pi concentration. Relatives of patients with evident HHRH may exhibit an additional mode of disease expression (157). These subjects manifest hypercalciuria and hypophosphatemia, but the abnormalities are less marked and occur in the absence of discernible bone disease, which would suggest a mild phenotype in the heterozygous state with certain mutations.


After mutations in the candidate NaPi-IIa gene were excluded as causal to HHRH, the genetic defect was identified in NaPi-IIc (27, 158), previously thought to be of less importance than the type IIa transporter. As would be predicted by the isolated loss of function of a Pi transporter, reduced serum Pi and increased renal Pi losses occur, independent of FGF23 status. However, unlike the findings in XLH, Pi wasting does not coexist with limitations in 1,25(OH)2D production, and the system retains its capacity to increase 1,25(OH)2D levels in response to the ambient hypophosphatemia. Recently it has been suggested that specific mutations in NaPi-IIc may be associated with sodium wasting and potentially the tendency to form urinary tract stones (159).


Patients with HHRH have been treated successfully with high-dose phosphorus (1 to 2.5 g/day in five divided doses) alone. In response to therapy, bone pain disappears and muscular strength improves substantially. Moreover, the majority of treated subjects exhibit accelerated linear growth, and radiologic signs of rickets are completely absent within several months. Despite this favorable response, limited studies indicate that such treatment does not completely heal the associated osteomalacia. Indeed, there is no collective experience with long-term follow-up of this rare disorder, and the necessity and/or complications of long-term therapy are not well-established. Curiously an accompanying osteoporosis appears to occur in concert, a finding that is also quite different from the usual picture in XLH.




Although SLC34A3 (Na-Pi2c) mutations were identified as the mutated gene in the specific disorder of HHRH, homozygous loss-of-function mutations in SLC34A1 (Na-Pi2a) occur in yet another syndrome of autosomal recessive hypophosphatemic rickets accompanied by a generalized renal tubular disorder consistent with Fanconi syndrome (160). This disorder appears to occur with less frequency than HHRH, however in a recent search for genetic causes of idiopathic infantile hypercalcemia (IIH), loss-of-function mutations in SLC34A1 have been identified (161). Rickets is not a prominent feature of this disorder, but rather hypercalcemia, hypercalciuria, nephrocalcinosis and renal phosphate wasting. Resultant elevations in circulating 1,25(OH)2D levels lead to the hypercalcemia. It is important to distinguish this cause of IIH from those attributable to defects in CYP24A1 (vitamin D 24-hydroxylase) as therapy in cases attributable to NaPi2a deficiency should respond to phosphate supplementation whereas restriction of dietary calcium and vitamin D are recommended in cases due to CYP24A1 mutations.




The initial description of X-linked recessive hypophosphatemic rickets involved a family in which males presented with rickets or osteomalacia, hypophosphatemia, and a reduced renal threshold for phosphate reabsorption. In contrast to patients with XLH, affected subjects exhibited hypercalciuria, elevated serum 1,25(OH)2D levels (Table 1), and proteinuria of up to 3 g/day. Patients also developed nephrolithiasis and nephrocalcinosis with progressive renal failure in early adulthood. Female carriers in the family were not hypophosphatemic and lacked any biochemical abnormalities other than hypercalciuria. Three related syndromes have been reported independently: X-linked recessive nephrolithiasis with renal failure, Dent's disease, and low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis. These syndromes differ in degree from each other, but common themes include proximal tubular reabsorptive failure, nephrolithiasis, nephrocalcinosis, progressive renal insufficiency, and, in some cases, rickets or osteomalacia. Identification of mutations in the voltage-gated chloride-channel gene CLCN5 in all four syndromes has established that they are phenotypic variants of a single disease and are not separate entities (162,163). However, the varied manifestations that may be associated with mutations in this gene, particularly the presence of hypophosphatemia and rickets/osteomalacia, underscore that environmental differences, diet, and/or modifying genetic backgrounds may influence phenotypic expression of the disease.




Although primary disorders of intestinal phosphate absorption have not been considered of clinical significance, we have encountered a curious phenomenon of phosphate malabsorption in children with complex disorders associated with intestinal compromise, when fed amino-acid based elemental formula (164,165). Associated tube-feeding and use of antacid medications appear to be risk factors, and the phenomenon does not appear to occur when used for the labeled indication of milk protein allergy in children who are otherwise healthy (166). We have recommended that serum phosphorus levels be monitored periodically with the use of such formulas.




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Severe Hypothyroidism in the Elderly



Elderly patients with severe hypothyroidism often present with variable symptoms that may be masked or potentiated by co-morbid conditions. Characteristic symptoms may include fatigue, weight gain, cold intolerance, hoarseness, constipation, and myalgias. Neurologic symptoms may include ataxia, depression, and mental status changes ranging from mild confusion to overt dementia. Clinical findings that may raise suspicion of thyroid hormone deficiency include hypothermia, bradycardia, goitrous enlargement of the thyroid, cool dry skin, myxedema, delayed relaxation of deep tendon reflexes, a pericardial or abdominal effusion, hyponatremia, and hypercholesterolemia.




Autoimmune (Hashimoto’s) thyroiditis with destruction of functioning tissue is the most common endogenous cause of hypothyroidism in elderly patients. Checkpoint inhibitors that are used to treat a variety of malignancies can induce a rapidly progressing form of autoimmune thyroiditis. Unrecognized or untreated cases can progress to a state of pronounced thyroid hormone deficiency over weeks to months. Administration of radioactive iodine to treat hyperthyroidism ascribed to Graves’ disease usually causes permanent hypothyroidism. Surgery performed to remove thyroid cancer or an enlarged multinodular goiter inevitably leads to overt hypothyroidism. External beam radiation used to treat lymphoid malignancies and head and neck cancer can lead to rapid or delayed development of hypothyroidism. Pituitary dysfunction that inhibits secretion of TSH may be caused by growth of a mass in the sella turcica or may develop as a complication of surgery performed to remove a tumor. 


Table 1: Causes of Hypothyroidism in the Elderly

Primary hypothyroidism

Autoimmune (Hashimoto’s) thyroiditis

Amiodarone induced hypothyroidism

Lithium induced hypothyroidism

Post-ablative hypothyroidism

Post-surgical hypothyroidism

Radiation-induced hypothyroidism
Thyroiditis induced by checkpoint inhibitors, tyrosine kinase inhibitors, interferon alpha, or CAMPATH

Central hypothyroidism

Pituitary or hypothalamic dysfunction

Decreased absorption of levothyroxine

Celiac disease

Drugs: iron sulfate, bile acid resins, sucralfate, calcium

Accelerated metabolism of thyroid hormone

Increased deiodinase activity (consumptive hypothyroidism)

Drugs: phenytoin, phenobarbital, carbamazepine, rifampin




Laboratory tests that demonstrate an elevated TSH level in tandem with a low free or total T4 level confirm a diagnosis of primary hypothyroidism. Commonly used drugs including ASA and phenytoin lower total T4 levels and may cause interference with FT4 assays. Anti-thyroid peroxidase and anti-thyroglobulin antibody levels may be checked to confirm the presence of autoimmune thyroiditis, but this usually isn’t necessary as it is the presumptive diagnosis in patients who haven’t been treated with other predisposing therapies. A low free or total T4 level detected in tandem with a low or inappropriately normal TSH level may raise suspicion of central hypothyroidism. This may prompt further biochemical evaluation of other pituitary hormones and anatomic imaging of the pituitary and hypothalamus. Serious illness in the elderly is often accompanied by the non-thyroidal illness (euthyroid sick) syndrome that presents with a normal or low total T4 level, a low total T3 level, and an inappropriately low or normal TSH level. Recognition of this syndrome requires exclusion of other causes of hypothyroidism or pituitary dysfunction. Appropriate treatment of this condition is controversial. Subclinical hypothyroidism, with a normal range freeT4 level and elevated TSH level is not infrequent in elderly patients, and if due to autoimmune thyroiditis, often progresses to overt hypothyroidism.




Levothyroxine (T4) is the principal thyroid hormone preparation used to treat hypothyroidism. Regimens that include liothyronine (T3) have not been shown to be any more efficacious and run the risk of triggering atrial arrhythmias in susceptible individuals. Most adults require a full replacement dose of 1.6 mcg per kilogram of body weight. The major concern in elderly patients with known or suspected cardiovascular disease is to avoid exacerbating underlying conditions. In these circumstances levothyroxine should be started at a low dose of 12.5-25 mcg daily. If this dose does not provoke ischemic symptoms or an atrial arrhythmia, it can be increased in 25 mcg increment at 4-week intervals. Patients who develop hypothyroidism after treatment of hyperthyroidism can be treated with full replacement doses from the outset. Agents that may block absorption of levothyroxine include iron sulfate, bile acid resins, sucralfate, and supplemental forms of calcium. Doses should be separated from ingestion of these agents by at least 4 hours. Higher than anticipated doses may be required in patients treated with other agents that increase metabolism of levothyroxine including phenytoin, phenobarbital, carbamazepine, and rifampin.

Appropriate treatment of subclinical hypothyroidism is open to debate. Some clinicians feel that treatment is indicated with any confirmed and unexplained elevation of TSH above normal but most clinicians do not initiate replacement therapy in elderly patients until the TSH level is > 10uU/ml on several occasions.




When treating primary hypothyroidism, a TSH level should be checked 6 weeks after starting a dose or 4 weeks after changing a dose of levothyroxine. Doses should be adjusted to maintain a TSH level within the reference range. Maintenance of a slightly elevated TSH level may be acceptable in cases where treatment to a full replacement dose triggers ischemic symptoms or atrial arrhythmias. When treating central hypothyroidism, doses should be adjusted to maintain a free T4 level in the upper half of the reference range. The TSH level is unreliable in this setting and should not be used to guide treatment.




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Jeffrey R. Garber, Rhoda H. Cobin, Hossein Gharib, James V. Hennessey, Irwin Klein, Jeffrey I. Mechanick, Rachel Pessah-Pollack, Peter A. Singer, and Kenneth A. Woeber. Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18(6):988-1028.




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Myxedema and Coma (Severe Hypothyroidism)



Myxedema coma is a rare life-threatening clinical condition in patients with longstanding severe untreated hypothyroidism, in whom adaptive mechanisms fail to maintain homeostasis. Most patients, however, are not comatose, and the entity rather represents a form of very severe, decompensated hypothyroidism. 




Usually a precipitating event disrupts homeostasis which is maintained in hypothyroid patients by a number of neurovascular adaptations. These adaptations include chronic peripheral vasoconstriction, diastolic hypertension, and diminished blood volume, in an attempt to preserve a normal body core temperature. Homeostasis might no longer be maintained in severely hypothyroid patients if blood volume is reduced any further (e.g., by gastrointestinal bleeding or the use of diuretics), if respiration already compromised by a reduced ventilatory drive is further hampered by intercurrent pulmonary infection, of if CNS regulatory mechanisms are impaired by stroke, the use of sedatives, or hyponatremia.




The three key features of myxedema coma are: 

  1. Altered mental status. Usually somnolence and lethargy have been present for months. Lethargy may develop via stupor into a comatose state. There may have been transient episodes of reduced consciousness before a more complete comatose state develops.
  2. Defective thermoregulation: hypothermia. The lower the temperature, the worse the prognosis. Please check the ability of the thermometer to accurately measure decreased temperatures (automatic thermometers may not register frank hypothermia). Fever may be absent despite infections. With cold weather the body temperature may drop sharply. Myxedema coma commonly develops during winter months.
  3. Precipitating event. Look for cold exposure, infection, drugs (diuretics, tranquillizers, sedatives, analgesics), trauma, stroke, heart failure, gastrointestinal bleeding. The typical patient often has a history of hypothyroidism, neck surgery or radioactive iodine treatment.

Physical examination may reveal hypothermia, hypoventilation, hypotension, bradycardia, dry coarse skin, macroglossia, and delayed deep-tendon reflexes. Absence of mild diastolic hypertension in severely hypothyroid patients is a warning sign of impending myxedema coma. 

Laboratory examination may reveal anemia, hyponatremia, hypoglycemia, hypercholesterolemia, and high serum creatine kinase concentrations. Most patients have low serum FT4 and high serum TSH. Serum TSH can be low or normal, however, due to the presence of central hypothyroidism or the nonthyroidal illness syndrome. 




Myxedema coma is a medical emergency. Early diagnosis, rapid administration of thyroid hormones and adequate supportive measures (Table) are essential for a successful outcome. The prognosis, however, remains poor with a reported mortality between 20% and 50%. In-hospital mortality was 29.5% among 149 patients with myxedema coma identified between 2010-2013 through a national inpatient database in Japan (Ono et al. 2017).




large initial iv dose of 300-500 μg T4, if no response add T3;


Alternative- initial iv dose of 200-300 μg T4 plus 10-25 μg T3


iv hydrocortisone 200-400 mg daily

3. Hypoventilation       

don’t delay intubation and mechanical ventilation too long

4. Hypothermia

blankets, no active rewarming

5. Hyponatremia          

mild fluid restriction

6. Hypotension

cautious volume expansion with crystalloid or whole blood

7. Hypoglycemia

glucose administration

8. Precipitating event  

identification and elimination by specific treatment, liberal use of antibiotics


Note 1. Administration of thyroid hormone is essential, but opinions differ about the dose and the preparation (T4 or T3). A high dose carries the risk of precipitating fatal tachycardia or myocardial infarction, but a low dose may be unable to reverse a downhill course. Treatment with T4 may be less effective due to impaired conversion of T4 into T3 (associated with severe illness and inadequate caloric intake), but treatment with T3 may expose tissues to relatively high levels of thyroid hormone. In the absence of RCT’s, the available case series suggest higher mortality with initial T4 doses larger than 500 μg and with T3 doses larger than 75 μg daily. Treatment should be started intravenously because gastrointestinal absorption may be impaired. Typically, a large initial intravenous loading dose of 300-500 μg T4 may be given, followed by daily doses of 1.6 μg/kg (initially intravenously, and orally when feasible). If there is no improvement in clinical abnormalities within 24 hours, addition of T3 is recommended. An alternative scheme is an initial intravenous dose of 200-300 μg T4 plus 10-25 μg T3, followed by 2.5-10 μg T3 every 8 hours depending on the patient’s age and presence of cardiovascular risk factors. Upon clinical improvement, T3 is discontinued and a daily oral T4 replacement dose is maintained.


Note 2. Pituitary-adrenal function is impaired in severe hypothyroidism. Restoration of a normal metabolic rate with exogenous thyroid hormones may precipitate adrenal insufficiency. It is therefore prudent to administer glucocorticoids in stress doses (e.g., hydrocortisone 100 mg intravenously every 8 hours).


Note 3. Mechanical ventilation may be needed, particularly when obesity and myxedema coexist.


Note 4. The cutaneous blood flow is markedly reduced in severe hypothyroidism in order to conserve body heat. Warming blankets will defeat this mechanism. Thus, central warming may be attempted, but peripheral warming should not, since it may lead to vasodilatation and shock.                                                                                                                                                                                                                                              


Note 5. Fluid restriction and the use of isotonic sodium chloride will usually restore normal serum sodium. Normal saline should not be administered in patients with suspicious hyponatremic encephalopathy. In cases with severe symptomatic hyponatremia, 100 ml of 3% NaCl should be administered (Liamis et al. 2017). The new vasopressin antagonist conivaptan might be potentially useful in hyponatremia as high vasopressin levels have been observed in myxedema coma; however, no cases of myxedema coma have been reported in which this drug was administered.                                                                                                                                      


Note 6. Volume expansion is usually required in case of hypotension since patients are maximally vasoconstricted. Dopamine should be added if fluid therapy does not restore efficient circulation.                                                                                                                                                                                                         


Note 7. Serum glucose should be monitored. Supplemental glucose may be necessary, especially if adrenal insufficiency is present.                                                                                                                                                                              


Note 8. A vigorous search for precipitating events is mandatory. Signs of infection (like fever, tachycardia, leukocytosis) may be absent. Prophylactic antibiotics are indicated until infection can be ruled out.




In case treatment was initiated with intravenous T4 but after 24 hours the patient is still comatose or vital functions have not improved, iv administration of T3 should be considered. T3 should be discontinued and replaced by T4 once circulation and respiration have been stabilized. Intravenous administration of thyroid hormones is replaced by oral administration when the patient is fully awake.




Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. Guidelines for the treatment of hypothyroidism. Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid 2014; 24: 1670-1751.


Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18(6):988-1028.




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Severe Thyrotoxicosis in the Elderly



Thyrotoxicosis in the elderly may elude detection by manifesting only fatigue, weakness, and relative apathy. More commonly it presents with any of a range of symptoms including fatigue, weight loss, heat intolerance, palpitations, weakness, insomnia, irritability, confusion, and agitation. Clinical findings that may raise suspicion include tachycardia, proptosis, goitrous enlargement of the thyroid, palpable thyroid nodules, warm moist skin, brisk deep tendon reflexes, and a resting tremor. A newly detected atrial arrhythmia may be the first manifestation identified.




Endogenous thyrotoxicosis may be caused by disorders that increase thyroid hormone production in functional thyroid tissue, or by disorders associated with inflammation of the thyroid that cause leakage of preformed thyroid hormone. The distinction between these classifications helps to dictate treatment. Increased thyroid hormone production may be caused by autoimmune stimulation of the thyroid, or by the growth of autonomously functioning nodules or neoplasms. Checkpoint inhibitors that are used to treat a range of malignancies can induce a rapidly progressing form of autoimmune thyroiditis associated with transient thyrotoxicosis. In patients treated with thyroid hormone preparations, ingestion of excessive doses may lead to severe thyrotoxicosis. Rarely thyrotoxicosis is induced during therapeutic administration of interferon alpha or CAMPATH. Finally, tyrosine kinase inhibitors can also induce hyperthyroidism.


Table 1. Causes of Thyrotoxicosis in Elderly

Increased thyroid hormone production

Graves’ disease

Toxic multinodular goiter

Toxic adenoma

Type 1 amiodarone-induced thyrotoxicosis

Metastatic thyroid cancer

Inflammation with leakage of thyroid hormone

Subacute thyroiditis

Autoimmune (Hashimoto’s) thyroiditis

Type 2 amiodarone-induced thyrotoxicosis

Ingestion of exogenous thyroid hormone

Iatrogenic thyrotoxicosis

TSH-secreting pituitary adenoma




Suspected thyrotoxicosis may be confirmed when lab tests reveal a suppressed TSH level in tandem with an elevated free or total T4 level. A total T3 level should also be checked, as it is often disproportionately elevated in cases of untreated Graves’ disease. In patients who aren’t taking amiodarone and haven’t been recently exposed to iodinated contrast, a thyroid uptake study can distinguish increased production of thyroid hormone (marked by increased uptake), from inflammation with leakage of thyroid hormone (marked by decreased uptake). Thyroid scan images that reveal the distribution of increased uptake can help to distinguish Graves’ disease from toxic nodular disorders. In cases that demonstrate decreased uptake, an elevated ESR or CRP may reflect subacute thyroiditis, while elevated anti-thyroid peroxidase or anti-thyroglobulin antibody levels may reflect autoimmune thyroiditis. The absence of either of these findings may raise suspicion of iatrogenic thyrotoxicosis.


A suppressed TSH level with “normal” T4 and T3 levels indicates subclinical hyperthyroidism. This problem is common in elderly individuals with multinodular goiter or “hot” nodules. Long standing subclinical hyperthyroidism is associated with atrial arrhythmias, and for this reason, if confirmed and persistent, is often treated in the same manner as overt hyperthyroidism.




Severe thyrotoxicosis may induce or exacerbate atrial arrhythmias, ischemia, congestive heart failure or diabetes mellitus, problems requiring urgent diagnosis and therapy. Coincident anemia should be recognized. If tolerated, and in the absence of CHF, beta blockers may help to ameliorate some symptoms in patients presenting with thyrotoxicosis. Since administration of beta-blockers to patients with severe thyrotoxicosis has rarely been associated with vascular collapse, a reduced dose may be administered initially. In cases of severe hyperthyroidism ascribed to Graves’ disease, a toxic multinodular goiter, or a toxic adenoma, antithyroid drugs are usually administered as first line treatment. Methimazole is the usual agent of choice. Relatively high doses (20-40 mg daily) may be needed at the outset. Once adequate control of hyperthyroidism has been achieved, definitive therapy with radioactive iodine ablation or thyroid surgery may be considered. Patients who demonstrate an allergy or adverse side effects when taking antithyroid drugs may need to proceed directly to treatment with radioactive iodine ablation. Consideration should be given to the possibility of triggering increased thyrotoxicosis as a result of radioactive iodine treatment with adverse effects on cardiovascular disease. Pre-treatment with antithyroid drugs, repeated partial dose radioactive iodine therapy, or post-treatment with beta blockers or saturated solution of potassium iodide (at least 10 mg daily) may be considered. Thyroid surgery may be indicated in cases where substernal enlargement of a toxic multinodular goiter has caused significant compressive symptoms, and in cases with any suggestion of a thyroid malignancy. Temporizing treatment with high doses of NSAIDs or prednisone may help to relieve discomfort associated with the onset of subacute thyroiditis.


Table 2. Treatment

Beta blockers

Propranolol: 10-30 mg tid-qid, or 60-120 mg ER daily

Atenolol: 25-100 mg daily

Metoprolol: 25-50 mg bid, or 50-100 mg ER daily

Antithyroid drugs

Methimazole: 10-60 mg daily

Propylthiouracil: 50-150 mg bid-tid

Radioactive iodine

Thyroid surgery


Saturated solution of potassium iodide: 1 drop bid

Antinflammatory agents

Ibuprofen 400-800 mg tid

Prednisone 10-40 mg daily




Serial profiles of thyroid function tests including TSH, free or total T4, and total T3 levels should be followed at regular 2-4 week intervals when treating and monitoring thyrotoxic disorders. In cases of treated hyperthyroidism, suppression of the TSH level may persist for several weeks after thyroid hormone levels have been brought under control. Treatment of post-ablative or post-surgical hypothyroidism with levothyroxine should be considered once T4 and T3 levels drop to low normal or subnormal ranges.




2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA.

Thyroid. 2016 Oct;26(10):1343-1421.




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Kopp P. Thyrotoxicosis of other Etiologies. 2010 Dec 1. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000–.


Macchia PE, Feingold KR. Amiodarone Induced Thyrotoxicosis. 2018 Dec 24. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000–.

Amiodarone Induced Thyrotoxicosis



Patients treated with amiodarone for a cardiac arrhythmia may develop amiodarone Induced thyrotoxicosis (AIT). The risk of AIT is increased in iodine-deficient regions. The incidence of AIT varies greatly (between 0.003% and 10%). AIT occurs in 3% of patients treated with amiodarone in North America, but is much more frequent (up to 10%) in countries with a low iodine dietary intake. In contrast to the other forms of hyperthyroidism, AIT is more frequent in males than in females (M/F = 3/1).


AIT manifests with clinical signs indistinguishable from spontaneous hyperthyroidism, however symptoms and signs of thyrotoxicosis are not apparent in all patients, and may be obscured by an underlying cardiac condition. The reappearance or exacerbation of an underlying cardiac disorder after amiodarone is started, in a patient previously stable, should prompt an investigation into thyroid function for suspected development of AIT. Sometimes worsening of a cardiac arrhythmia with recurrence of atrial fibrillation and palpitations is the only clinical evidence of AIT. The development of angina may also occur. Similarly, unexplained changes in warfarin sensitivity, requiring a reduction in the dosage of this drug, can be the consequence of increased thyroid hormone levels, since hyperthyroidism increases warfarin effects.


AIT may develop early during amiodarone treatment, after many months of treatment, and has even been reported to occur several months after amiodarone withdrawal, since amiodarone and its metabolites have a long half-life due to accumulation in several tissues, especially fat.



There are two different forms of AIT, and differential diagnosis between the two forms is important, since treatments are different. However, it is often not possible to clearly distinguish AIT1 and AIT2.


Type 1 AIT usually occurs in an abnormal thyroid gland (latent Graves’ disease, multinodular gland) and is the consequence of increased thyroid hormone biosynthesis due to iodine excess in patients with a preexisting thyroid disorder (Amiodarone contains 37% iodine by weight). Type 1 AIT is more common in iodine deficient regions. Type 2 AIT is a destructive process of the thyroid gland leading to the release of pre-formed hormone. This thyroiditis is an intrinsic toxic effect of amiodarone. Type 2 AIT usually persists for one to three months until thyroid hormone stores are depleted. In most countries Type 2 AIT is more common than Type 1 AIT. Differences between Type 1 and Type 2 AIT are described in table 1. Differentiating between AIT Type 1 and 2 is often very difficult.


Table 1 Differences between Type 1 and 2 Amiodarone Induced Thyrotoxicosis


Type 1

Type 2

Underlying thyroid disease

Yes (Multinodular goiter, Grave’s)


Time after starting amiodarone

Short (median 3 months)

Long (median 30 months)

24-hour iodine uptake

Low-Normal (may rarely be high in iodine deficient regions)

Low to Suppressed

Thyroid Ultrasound

Diffuse or Nodular Goiter may be present

Normal or small gland

Vascularity on Echo-color Doppler ultrasound



T4/T3 ratio

Usually <4

Usually >4


May be present

Usually absent

Circulating interleukin-6

Normal to high

Sometimes markedly elevated but usually doesn’t differentiate from AIT1




To confirm the diagnosis of AIT it is necessary to demonstrate a suppressed serum TSH associated with an increase in serum FT3 and FT4 levels in a patient currently or previously treated with amiodarone. T3 levels may not be as elevated as expected as amiodarone inhibits the conversion of T4 to T3 and severe non-thyroidal illness may be present blocking the increase in T3. The presence of a preexisting thyroid disorder is suggestive for Type 1 AIT. Frequently in patients with Type 2 AIT an increased T4/T3 ratio is present as a feature of destructive thyroiditis. Thyroid antibodies may be present in Type 1 AIT depending upon the underlying thyroid disorder. High levels of thyroglobulin antibodies and TPO antibodies have also been reported in 8% of Type 2 AIT patients. Type 2 AIT develops as an inflammatory process in a normal thyroid and therefore the levels of IL-6 may be markedly elevated but typically the IL-6 levels do not distinguish AIT2 from AIT1.


Color flow Doppler ultrasonography is useful to differentiate between Type 1 and Type 2 AIT. Intra-thyroidal vascular flow is increased in Type 1 AIT (pattern II-III) and reduced or absent in Type 2 (pattern 0).

In many patients with Type 1 AIT the 24-hr iodine uptake is low.  In rare patients with Type 1 AIT, despite the very high iodine load, a normal or inappropriately elevated 24-hr iodine uptake may be observed, especially if the patients live in an iodine deficient area. Patients with Type 2 AIT typically have a radioactive iodine uptake < 1%.


While the distinction between Type 1 and Type 2 may sometimes be clear, in many patients neither the clinical findings nor the response to treatment clearly indicate whether the patient has Type 1 or Type 2 AIT. Some patients may have a mixed form of AIT.




AIT may lead to increased morbidity and mortality, especially in older patients with impaired left ventricular function. Thus, in most patients, prompt restoration and stable maintenance of euthyroidism should be achieved as rapidly as possible.


Mild AIT may spontaneously resolve in about 20% of the cases. Type 1 AIT should be treated with high doses of methimazole (20-60 mg/day) or propylthiouracil (400-600 mg/day) to block the synthesis of thyroid hormones (Figure 1). The response to methimazole or propylthiouracil is often modest due to the high iodine levels in patients taking amiodarone. In selected patients, potassium perchlorate when available can also be used to increase sensitivity of the gland to methimazole or propylthiouracil by blocking iodine uptake in the thyroid. KClO4 should be used for no more than 30 days at a daily dose < 1 g/day, since this drug, especially in higher doses, is associated with aplastic anemia or agranulocytosis. Once thyroid hormone levels are back to normal, definitive treatment of the hyperthyroidism should be considered. If thyroid uptake is sufficient (>10%) radioactive iodine can be used. Thyroid surgery is a good alternative. If thyrotoxicosis worsens after initial control, a mixed form Type1-Type 2 should be considered, and treatment for Type 2 AIT should be started.


Type 2 AIT can be treated with prednisone, starting with an initial dose of 0.5-0.7 mg/kg body weight per day and the treatment is generally continued for three months. If a worsening of the toxicosis occurs during the taper, the prednisone dose should be increased. Methimazole and propylthiouracil are generally not useful in Type 2 AIT.


Because the distinction between AIT Type 1 and 2 is difficult and not always clear, and because some patients have mixed forms of AIT, these therapies for AIT Type 1 and 2 are often combined.


For patients with persistent hyperthyroidism surgery is the optimal choice.  Propylthiouracil can be used to inhibit T4 to T3 conversion. Beta blockers will be helpful in preparation for surgery.


Figure 1. Management of Patients with Amiodarone Induced Thyrotoxicosis


It is still debatable whether amiodarone should be discontinued once the diagnosis of AIT is made. Because of the long half-life, there is no immediate benefit in stopping the drug. However, some forms of Type 2 AIT may remit with amiodarone withdrawal. If feasible from the cardiological point of view, it is probably safer to withdraw amiodarone and use a different anti-arrhythmic drug, but no controlled trials have been published on this question. A good alternative to amiodarone in patients with atrial fibrillation and atrial flutter can be dronedarone, but this drug is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II–III heart failure with a recent decompensation. Some patients with Type 2 AIT may develop hypothyroidism due to thyroid gland destruction.


Bartalena L, Bogazzi F, Chiovato L, Hubalewska-Dydejczyk A, Links TP, Vanderpump M. 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction. Eur Thyroid J. 2018 Mar;7(2):55-66


Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421.



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Bogazzi F, Tomisti L, Bartalena L., Aghini-Lombardi F, Martino E. Amiodarone and the thyroid: a 2012 update. J Endocrinol. Invest. 2012; 35:340-48.


Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2010; 95:2529-35.


Cohen-Lehman J, Dahl P, Danzi S, Klein I. Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol 2010; 6:34-41.


Trohman RG, Sharma PS, McAninch EA, Bianco AC. Amiodarone and the thyroid physiology, pathophysiology, diagnosis and management. Trends Cardiovasc Med. 2018 Sep 20. pii: S1050-1738(18)30195-6.


Ylli D, Wartofsky L, Burman KD. Evaluation and Treatment of Amiodarone-Induced Thyroid Disorders. J Clin Endocrinol Metab. 2021 Jan 1;106(1):226-236.


Subacute Thyroiditis



Subacute thyroiditis (SAT) is an inflammatory condition of the thyroid with characteristic presentations and clinical course. Patients with the classic, painful (DeQuervain’s; Granulomatous) thyroiditis, (PFSAT) typically present with painful swelling of the thyroid. Transient vocal cord paresis may occur. At times, the pain begins and may be confined to the one lobe, but usually spreads rapidly to involve the rest of the gland ("creeping thyroiditis"). Pain may radiate to the jaw or the ears. Malaise, fatigue, myalgia and arthralgia are common. A mild to moderate fever is expected, and at times a high fever of 104°F (40.0°C) may occur. The disease process may reach its peak within 3 to 4 days and subside and disappear within a week, but more typically, onset extends over 1 to 2 weeks and continues with fluctuating intensity for 3 to 6 weeks. The thyroid gland is typically enlarged, smooth, firm and tender to palpation, sometimes exquisitely so. Approximately one-half of the patients present during the first weeks of the illness, with symptoms of thyrotoxicosis. Subsequently patients often experience hypothyroidism before returning to normal (see figure 1). This painful condition lasts for a week to a few months, usually demonstrates a very high erythrocyte sedimentation rate (ESR), elevated C- reactive protein (CRP) levels, and has a tendency to recur.


Painless (silent, autoimmune) subacute thyroiditis (PLSAT) occurs spontaneously or following pregnancy when it is referred to as postpartum thyroiditis [PPT]). Autoimmune thyroiditis is histologically similar to Hashimoto's thyroiditis and occurs following 3.9-10% of pregnancies. The combination of thyroid enlargement usually without discomfort and positive anti-thyroid antibodies, associated with typical thyroid function test abnormalities (see figure 1), over a 9-12 month course should alert the clinician to the presence of PLSAT.




A tendency for the painful form of the disease to follow upper respiratory tract infections or sore throats has suggested a viral infection. An autoimmune reaction is possible as patients with PFSAT often manifest HLA-Bw35 and those with PLSAT are frequently TPO or TG-ab positive. In both forms, clinical thyroid symptoms result from either the initial release of thyroid hormone from the inflamed tissue during the thyrotoxic phase or the lack of circulating thyroid hormones in the hypothyroid phase (See figure 1). Medications associated with SAT are summarized in table 4.

Figure 1. Time Course of Subacute Thyroiditis



Subacute thyroiditis is a diagnosis made clinically. Anterior neck pain, preceded by an upper respiratory inflammation, alerts the clinician to the classic PFSAT. Differential diagnostic considerations include acute (suppurative, thyroid abscess) thyroiditis (see table 1), which is usually a painful nodular enlargement of the thyroid or unusual presentations of Graves’ or nodular thyroid disease (see table 2 below) with pain generated by capsular stretching.


Thyroid function tests (see table 3) during the painful (initial) phase of SAT often reveal a suppressed TSH and elevation of total T4 and T3 levels consistent with the thyrotoxic state. T3 (ng/dl) to T4 (ug/dl) ratio is less than 20 in all forms of SAT. ESR is almost always greater than 50 and WBC counts and CRP levels are usually elevated in PFSAT. PLSAT (including PPT) is typically associated with the presence of anti-thyroid peroxidase (TPO-ab) and thyroglobulin (Tg-ab) antibodies, both of which are usually absent or present only in low titers in PFSAT. Thyrotropin receptor antibodies (TRAb) are usually positive in Graves' disease and absent or low level in patients with PFSAT as well as PPT.


Radioactive iodine uptake and scan typically reveals a low RAIU and poor visualization of the thyroid in PFSAT and PLSAT whereas significant uptake is expected in Graves’ disease (GD) or toxic nodular goiters (TNG). PLSAT must be differentiated from other forms of low uptake thyrotoxicosis (see Table 2). Iatrogenic thyrotoxicosis (factitious [l-thyroxine (LT4), l-triiodothyronine (LT3) or T4/T3 combination] results in a suppressed thyroglobulin (TG) level. Ectopic thyroid hormone production in a Struma Ovarii or functional metastatic thyroid cancer can be detected with total body scanning. Iodine contamination after a contrast enhanced CT, obliterates the RAIU and obscures the presence of the more frequently encountered Graves’ disease or a toxic multinodular goiter. A recent CT scan will frequently alert the clinician to this artifact. Urine iodine measurement can quantify the degree of iodine contamination present.


Thyroid ultrasound typically shows a heterogeneously hypoechoic pattern and has a suppressed vascular pattern in SAT while patients with Graves’ disease demonstrate hyper-vascularity. The presence of thyroid nodules supports the presence of a toxic nodular goiter. Localized PFSAT, can be suggestive of thyroid cancer. Usually the pain, elevated erythrocyte sedimentation rate and leukocytosis, and clinical remission or spread to other parts of the gland make clinical differentiation possible but may require a fine needle aspiration for definitive diagnosis.


Table 1. Features Useful in Differentiating Acute Suppurative Thyroiditis (AST) and Subacute Thyroiditis (SAT)




Prior URI






Symptoms of Hyperthyroidism



Sore throat



Painful thyroid swelling



Left side affected


not specific

Migrating tenderness



Erythema of skin


not usually

Elevated WBC count



Elevated ESR



Abnormal TFTs



Enzymes- Alk-phos., AST/ALT 



FNA Purulent, bacteria or fungi present



Lymphocytes, macrophages, PNMs, giant cells



123I uptake low



Abnormal thyroid scan


Scan / US helpful in D/D



Gallium scan positive



Barium swallow = fistula



CT scan useful


not useful

Clinical response to glucocorticoid treatment



Incision/drainage required



Recurrence following operative drainage



Pyriform sinus fistula discovered



URI= Upper Respiratory Infection, WBC= white blood cell count, ESR= Erythrocyte Sedimentation Rate, TFT’s= Thyroid function tests, Alk-Phos= Alkaline Phosphatase, AST= Aspartate Aminotransferase, ALT= Alanine Aminotransferase, FNA= Fine needle aspiration, US= Ultrasound examination, ↑= elevated


Table 2. Differential Diagnosis of Thyrotoxic Patients Based on Radioactive Iodine Uptake (RAIU)

Normal to ↑ 123-I RAIU

Near absent 123-I RAIU

Graves’ disease

Painless (silent) thyroiditis

Toxic multinodular goiter

Amiodarone-induced thyroiditis

Toxic solitary nodule

Subacute (painful) thyroiditis

Trophoblastic (hCG mediated) disease

Iatrogenic or factitious thyrotoxicosis

TSH-producing pituitary tumor

Ectopic tissue (Struma Ovarii, functional cancer)

Thyroid hormone resistance

Acute thyroiditis


Table 3. Differential Diagnostic Considerations in the Thyrotoxic Patient (Typical findings in each disease)






Neck Pain





Recent URI





Systemic symptoms





Recent Pregnancy





Thyroid symptoms
















↑/ ↓/ Nl

↑/ ↓/ Nl

↑/ ↓/ Nl



↑/ ↓/ Nl

↑/ ↓/ Nl

↑/ ↓/ Nl



↑/ ↓/ Nl

↑/ ↓/ Nl

↑/ ↓/ Nl

Nl/ ↑


< 20

< 20

< 20

> 20








+/−, Pos

+/−, Pos

+/−, Pos



+/−, Pos

+/−, Pos

+/−, Pos







Low/ Not visible

Low/ Not visible

Low/ Not visible

High/ diffuse

US Echogenicity










PFSAT= painful subacute thyroiditis; PLSAT= painless subacute thyroiditis; PPT= postpartum thyroiditis


Table 4. Causes of Drug Associated Thyrotoxicosis






Iodine (AIT 1)

months to years

Supportive, ATDs, Perchlorate, Surgery


Thyroiditis (AIT 2)

Often > 1 year

Supportive care, Surgery, Prednisone



Often > 1 year

ATDs, Supportive


Thyroiditis or Graves’


Supportive, ATDs, and /or 131-I (Graves’ only)


Thyroiditis or Graves’


Supportive, ATDs, and /or 131-I (Graves’ only)

Contrast (I)

Thyroid autonomy

Weeks to months


131-I Ablation

Destructive thyroiditis

1-4 weeks

Supportive, prednisone

131-I Rx of TMNG

Graves’ disease

3-6 months

131-I, surgery, ATDs

Check Point Inhibitors

Thyroiditis or autoimmune

Weeks to months

Supportive, 131-I, surgery, ATDs

Tyrosine Kinase Inhibitors


Weeks to months


ATD= Anti thyroid drugs, TMNG= Toxic Multinodular Goiter




In some patients, no treatment is required. For many, analgesic therapy for relief of pain can be achieved with non-steroidal anti-inflammatory agents. If this fails, prednisone administration should be employed with daily doses of 20-40 mg prednisone. After one to 2 weeks of this treatment, the dosage is tapered over a period of 6 weeks. Most patients have no recrudescence of symptoms, but occasionally this does occur and the dose must be increased again. The recurrence rate of painful subacute thyroiditis after cessation of prednisone therapy is about 20%. Beta blocking agents are usually administered for relief of thyrotoxic symptoms in the initial stage of SAT. Antithyroid drugs have no role in the management of established SAT as the excess thyroid hormone levels result from release of preformed thyroxine and triiodothyronine from inflamed tissue. Levothyroxine administration may be useful, at least transiently, if the patient enters a phase of hypothyroidism. Surgical intervention is not the primary treatment for subacute thyroiditis but is safe and with low morbidity, if necessary, because of the possibility of associated papillary cancer based on cytological examination.




In 90% or more of patients with classic painful subacute thyroiditis, there is a complete and spontaneous recovery and a return to normal thyroid function. However, the thyroid glands of patients with subacute thyroiditis may exhibit irregular scarring between islands of residual

functioning parenchyma. Up to 10% of the patients may become hypothyroid and require permanent replacement with levothyroxine. Rates of permanent hypothyroidism after antibody positive PLSAT and especially PPT are significantly higher.




Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Waiter MA. American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016;26(10):1343–1421. 




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Thyroid Storm


Thyroid (or thyrotoxic) storm is an acute, life-threatening syndrome due to an exacerbation of thyrotoxicosis. It is now an infrequent condition because of earlier diagnosis and treatment of thyrotoxicosis and better pre- and postoperative medical management. In the United States the incidence of thyroid storm ranged between 0.57 and 0.76 cases/100,000 persons per year. Thyroid storm may be precipitated by a number of factors including intercurrent illness, especially infections (Table 1). Pneumonia, upper respiratory tract infection, enteric infections, or any other infection can precipitate thyroid storm. Thyroid storm in the past most frequently occurred after surgery, but this is now unusual. Occasionally it occurs as a manifestation of untreated or partially treated thyrotoxicosis without another apparent precipitating factor. In the Japanese experience approximately 20% of patients developed thyroid storm before they received anti-thyroid drug treatment. Finally, if patients are not compliant with anti-thyroid medications thyroid storm may occur and this is a relatively common cause. Thyroid storm is typically associated with Graves' disease, but it may occur in patients with toxic nodular goiter or any other cause of thyrotoxicosis.


Table 1. Factors That May Precipitate Thyroid Storm


Acute Illness such as acute myocardial infarction, stroke, congestive heart failure, trauma, etc.

Non-thyroid surgery in a hyperthyroid patient

Thyroid surgery in a patient poorly prepared for surgery

Discontinuation of anti-thyroid medications

Radioiodine therapy

Recent use of iodinated contrast

Pregnancy particularly during labor and delivery


Classic features of thyroid storm include fever, marked tachycardia, heart failure, tremor, nausea and vomiting, diarrhea, dehydration, restlessness, extreme agitation, delirium or coma (Table 2). Fever is typical and may be higher than 105.8 F (41 C). Patients may present with a true psychosis or a marked deterioration of previously abnormal behavior. Rarely thyroid storm takes a strikingly different form, called apathetic storm, with extreme weakness, emotional apathy, confusion, and absent or low fever.


Signs and symptoms of decompensation in organ systems may be present. Delirium is one example. Congestive heart failure may also occur, with peripheral edema, congestive hepatomegaly, and respiratory distress. Marked sinus tachycardia or tachyarrhythmia, such as atrial fibrillation, are common. Liver damage and jaundice may result from congestive heart failure or the direct action of thyroid hormone on the liver. Fever and vomiting may produce dehydration and prerenal azotemia. Abdominal pain may be a prominent feature. The clinical picture may be masked by a secondary infection such as pneumonia, a viral infection, or infection of the upper respiratory tract.


Table 2. Clinical Manifestations of Thyroid Storm

History of thyroid disease

Goiter/thyroid eye disease

High fever

Marked tachycardia, occasionally atrial fibrillation

Heart Failure



Nausea and vomiting




Abdominal pain


Death from thyroid storm is not as common as in the past if it is promptly recognized and aggressively treated in an intensive care unit, but is still approximately 10-25%. In recent nationwide studies from Japan the mortality rate was >10%. Death may be from cardiac failure, shock, hyperthermia, multiple organ failure, or other complications. Additionally, even when patients survive, some have irreversible damage including brain damage, disuse atrophy, cerebrovascular disease, renal insufficiency, and psychosis. 



Thyroid storm classically began a few hours after thyroidectomy performed on a patient prepared for surgery by potassium iodide alone. Many such patients were not euthyroid and would not be considered appropriately prepared for surgery by current standards. Exacerbation of thyrotoxicosis is still seen in patients sent to surgery before adequate preparation, but it is unusual in the anti-thyroid drug-controlled patient. Thyroid storm occasionally occurs in patients operated on for some other illness while severely thyrotoxic. Severe exacerbation of thyrotoxicosis is rarely seen following 131-I therapy for hyperthyroidism; but some of these exacerbations may be defined as thyroid storm.

Thyroid storm appears most commonly following infection, which seems to induce an escape from control of thyrotoxicosis. Pneumonia, upper respiratory tract infections, enteric infections, or any other infection can cause this condition. Interestingly, serum free T4 concentrations were higher in patients with thyroid storm than in those with uncomplicated thyrotoxicosis, while serum total T4 levels did not differ in the two groups, suggesting that events like infections may decrease serum binding of T4 and cause a greater increase in free T4 responsible for storm occurrence. Another common cause of thyroid storm is a hyperthyroid patient suddenly stopping their anti-thyroid drugs.



Diagnosis of thyroid storm is made on clinical grounds and involves the usual diagnostic measures for thyrotoxicosis. A history of hyperthyroidism or physical findings of an enlarged thyroid or hyperthyroid eye findings is helpful in suggesting the diagnosis. The central features are thyrotoxicosis, abnormal CNS function, fever, tachycardia (usually above 130bpm), GI tract symptoms, and evidence of impending or present CHF. There are no distinctive laboratory abnormalities. Free T4 and, if possible, free T3 should be measured. Note that T3 levels may be markedly reduced in relation to the severity of the illness, as part of the associated “non-thyroidal illness syndrome”. As expected, TSH levels are suppressed. Electrolytes, blood urea nitrogen (BUN), blood sugar, liver function tests, and plasma cortisol should be monitored. While the diagnosis of thyroid storm remains largely a matter of clinical judgment, there are two scales for assessing the severity of hyperthyroidism and determining the likelihood of thyroid storm (Figures 1 and 2). Recognize that these scoring systems are just guidelines and clinical judgement is still crucial. Data comparing these two diagnostic systems suggest an overall agreement, but a tendency toward underdiagnosis using the Japanese criteria. Unfortunately, there are no unique laboratory abnormalities that facilitate the diagnosis of thyroid storm.

Figure 1. Burch-Wartofsky Point Scale for the Diagnosis of Thyroid Storm

Figure 2. Japanese Thyroid Association Criteria for Thyroid Storm


Thyroid storm is a medical emergency that has to be recognized and treated immediately (Table 3). Admission to an intensive care unit is usually required. Besides treatment for thyroid storm, it is essential to treat precipitating factors such as infections. As would be expected given the rare occurrence of thyroid storm there are very few randomized controlled treatment trials and therefore much of what is recommended is based on expert opinion.


Table 3. Treatment of Thyroid Storm

Supportive Measures
1. Rest
2. Mild sedation
3. Fluid and electrolyte replacement
4. Nutritional support and vitamins as needed
5. Oxygen therapy
6. Nonspecific therapy as indicated
7. Antibiotics
8. Cardio-support as indicated
9. Cooling, aided by cooling blankets and acetaminophen
Specific therapy
1. Beta-blocking agents. Propranolol (60 to 80 mg orally every 4 hours, or 1 to 3 mg intravenously every 4 to 6 hours), Start with low doses. Esmolol in ICU setting (loading dose of 250 mcg/kg to 500 mcg/kg followed by 50 mcg/kg to 100 mcg/kg/minute).
2. Antithyroid drugs (PTU 500–1000mg load, then 250mg every 4 hours or Methimazole 60-80mg/day), then taper as condition improves
3. Potassium iodide (one hour after first dose of antithyroid drugs):
 250mg orally every 6 hours
4. Hydrocortisone 300mg intravenous load, then 100mg every 8 hours.
Second Line Therapy
1. Plasmapheresis
2. Oral T4 and T3 binding resins- colestipol or cholestyramine
3. Dialysis

4. Lithium in patients who cannot take iodine

5. Thyroid surgery


It should be noted that if any possibility is present that orally given drugs will not be appropriately absorbed (e.g., due to stomach distention, vomiting, diarrhea or severe heart failure), the intravenous route should be used. If the thyrotoxic patient is untreated, an antithyroid drug should be given. PTU, 500–1000mg load, then 250mg every 4 hours, should be used if possible, rather than methimazole, since PTU also prevents peripheral conversion of T4 to T3, thus it may more rapidly reduce circulating T3 levels. Methimazole (60–80mg/day) can be given orally, or if necessary, the pure compound can be made up in a 10 mg/ml solution for parenteral administration. Methimazole is also absorbed when given rectally in a suppository. After initial stabilization, one should taper the dose and treat with Methimazole if PTU was started at the beginning as the safety profile of Methimazole is superior. If the thyroid storm is due to thyroiditis neither PTU not Methimazole will be effective and should not be used.


An hour after PTU or Methimazole has been given, iodide should be administered. A dosage of 250 mg every 6 hours is more than sufficient. The iodine is given after PTU or Methimazole because the iodine could stimulate thyroid hormone synthesis. Unless congestive heart failure contraindicates it, propranolol or other beta-blocking agents should be given at once, orally or parenterally, depending on the patient's clinical status. Beta-blocking agents control tachycardia, restlessness, and other symptoms. Additionally, propranolol inhibits type 1 deiodinase decreasing the conversion of T4 to T3. Probably lower doses should be administered initially, since administration of beta-blockers to patients with severe thyrotoxicosis has been associated with vascular collapse. Esmolol, a short-acting beta blocker, at a loading dose of 250 mcg/kg to 500 mcg/kg followed by 50 mcg/kg to 100 mcg/kg/minute can be used in an ICU setting.  For patients with reactive airway disease, a cardioselective beta blocker like atenolol or metoprolol can be employed.


Permanent correction of the thyrotoxicosis by either 131-I or thyroidectomy should be deferred until euthyroidism is restored. Other supporting measures should fully be exploited, including sedation, oxygen, treatment for tachycardia or congestive heart failure, rehydration, multivitamins, occasionally supportive transfusions, and cooling the patient to lower body temperature down. Antibiotics may be given on the presumption of infection while results of cultures are awaited.


The adrenal gland may be limited in its ability to increase steroid production during thyrotoxicosis. Therefore, hydrocortisone (100-300 mg/day) or dexamethasone (2mg every 6 hours) or its equivalent should be given. The dose can rapidly be reduced when the acute process subsides. Pharmacological doses of glucocorticoids (2 mg dexamethasone every 6 h) acutely depress serum T3 levels by reducing T4 to T3 conversion. This effect of glucocorticoids is beneficial in thyroid storm and supports their routine use in this clinical setting.


Usually rehydration, repletion of electrolytes, treatment of concomitant disease, such as infection, and specific agents (antithyroid drugs, iodine, propranolol, and corticosteroids) produce a marked improvement within 24 hours. A variety of additional approaches have been reported and may be used if the response to standard treatments is not sufficient. For example, plasmapheresis can remove circulating thyroid hormone and rapidly decrease thyroid hormone levels. Orally administered bile acid sequestrants (20-30g/day Colestipol-HCl or Cholestyramine) can trap thyroid hormone in the intestine and prevent recirculation. In most cases these therapies are not required but in the occasion patient that does not respond rapidly to initial therapy these modalities can be effective. Finally, in rare situations where medical therapy is ineffective or the patient develops side effects and contraindications to the available therapies’ thyroid surgery may be necessary.



Antithyroid treatment should be continued until euthyroidism is achieved, when a decision regarding definitive treatment of the hyperthyroidism with antithyroid drugs, surgery, or 131-I therapy can be made. Rarely urgent thyroidectomy is performed with antithyroid drugs, iodide, and beta blocker preparation.


Prevention of thyroid storm is key and involves recognizing and actively avoiding common precipitants, educating patients about avoiding abrupt discontinuation of anti-thyroid drugs, and ensuring that patients are euthyroid prior to elective surgery and labor and delivery.



Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421.


Satoh T, Isozaki O, Suzuki A, Wakino S, Iburi T, Tsuboi K, Kanamoto N, Otani H, Furukawa Y, Teramukai S, Akamizu T. 2016 Guidelines for the management of thyroid storm from The Japan Thyroid Association and Japan Endocrine Society (First edition). Endocr J. 2016 Dec 30;63(12):1025-1064



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