Contents
Contributors
Search

Hypocalcemia can present as an asymptomatic laboratory finding or as a severe, life-threatening condition (Table 1). In the setting of acute hypocalcemia, rapid treatment may be necessary. In contrast, chronic hypocalcemia may be well tolerated, but treatment is necessary to prevent long-term complications.

The hallmark of acute hypocalcemia is neuromuscular irritability. Patients often complain of numbness and tingling in their fingertips, toes, and the perioral region. Paresthesias of the extremities may occur, along with fatigue and anxiety. Muscle cramps can be very painful and progress to carpal spasm or tetany. In extreme cases of hypocalcemia, bronchial or laryngeal spasm may occur. Muscle symptoms can be so severe as to present as polymyositis with associated elevated muscle-associated isoenzymes. These symptoms are corrected by calcium replacement. Clinically, neuromuscular irritability can be demonstrated by eliciting Chvostek's or Trousseau's signs (Figures 1 and 2). Chvostek's sign is present in 10% of normal individuals. Tapping the skin over the facial nerve anterior to the external auditory meatus produces this sign. Ipsilateral contraction of the facial muscles occurs in individuals with hypocalcemia. Trousseau's sign is induced by inflation of a blood pressure cuff to 20 mm Hg above the patient's systolic blood pressure for 3-5 minutes. Carpal spasm presents as flexion of the wrist in metacarpal phalangeal joints, extension of the interphalangeal joints, and abduction of the thumb.

Cardiovascular manifestations may be present as a sign or symptom of hypocalcemia 1. Prolongation of T-interval due to lengthening of the ST-segment on electrocardiogram has been noted and T-waves are abnormal in approximately 50% of patients. A pattern of acute anteroseptal injury on EKG without infarction has been associated with hypocalcemia and after electrolyte abnormalities 2. Hypomagnesemia in concert with hypocalcemia may magnify the EKG abnormalities. Rarely congestive heart failure may occur 1,3,4. Reversible cardiomyopathy due to hypocalcemia has been reported 5. In patients with mild, asymptomatic hypocalcemia, improved cardiac output, peak velocity of blood flow, exercise tolerance, and ascending aortic resistance are improved with calcium replacement 6.

Chronic hypocalcemia may have a different presentation. Patients with idiopathic hypoparathyroidism or pseudohypoparathyroidism may develop calcification of the basal ganglia and extrapyramidal neurologic symptoms. Grand mal, petit mal, or focal seizures have been described. Increased intracranial pressure and papilledema may be present. If the patient has pre-existing subclinical epilepsy, hypocalcemia may lower the excitation threshold for seizures 7. Electroencephalographic changes may be acute and nonspecific or present with distinct changes in the electroencephalogram (EEG). EEG changes may be present with or without symptoms of hypocalcemia. Some patients on anticonvulsive therapy have not needed medication after appropriate treatment of their hypocalcemia 8. The relationship between calcification of basal ganglion 9, cerebral cortex, or cerebellum with pre-existing epileptic or convulsive disorders is not well understood. A recent report describes a male subject with paroxysmal kinesigenic dyskinesia, characterized by abnormal brief facio-brachial movement and apraxia of eyelid opening secondary to idiopathic hypoparathyroidism 10.

Epidermal changes are frequently found in patients with chronic hypocalcemia. These include dry skin, coarse hair, and brittle nails. If hypocalcemia has occurred prior to the age of 5, dental abnormalities may be present. Dental abnormalities include enamel hypoplasia, defects in dentin, shortened premolar roots, thickened lamina dura, delayed tooth eruption, and an increase in the number of dental caries. Alopecia has been noted following surgically-induced hypoparathyroidism and associated with autoimmune hypoparathyroidism. Other skin lesions, reported in patients with hypoparathyroidism, include atopic exema, exfoliative dermatitis, impetigo herpetiformis, and psoriasis. Restoration of normocalcemia has improved these skin disorders.

Involvement of smooth muscle with lowered levels of calcium may be due to irritability of autonomic ganglia and can result in dysphasia, abdominal pain, biliary colic, wheezing, and dyspnea. Subscapular cataracts occur in hypocalcemia 11. Paravertebral ligamentous ossification has been noted in 50% of cases with hypoparathyroidism and antalgic gait may be noted. In some cases of chronic hypoparathyroidism, psychoses, psychoneuroses, organic brain syndrome, and subnormal intelligence has been noted. In some cases, treatment of the hypocalcemia may improve intelligence and personality, but amelioration of psychiatric symptoms is inconsistent. In the elderly population, disorientation or confusion may be manifestations of hypocalcemia.

Factitious Hypocalcemia

Hypocalcemia due to hypoalbuminemia

In patients with chronic illness, psoriasis, malnutrition, or volume over-expansion, serum albumin may be low with a reduction in the total, but not the ionized, fraction of serum calcium. This is referred to as "factitious" hypocalcemia. Patients do not have any of these signs or symptoms listed above of hypocalcemia. There is a correlation between the extent of hypoalbuminemia and hypocalcemia such that one can calculate the total serum calcium. If the serum albumin levels fall to <4.0 g/dL, the usual correction is to add 0.8 mg/dL to the measured total serum calcium for every 1.0 g/dL by which the serum albumin is lowered. This is not a completely precise method, and ionized calcium measurements in the serum can confirm whether true hypocalcemia is present.

Magnesium Depletion and Hypocalcemia

Magnesium depletion is relatively common in the hospitalized patient and occurs in 10% of this population. Hypocalcemia is commonly associated with magnesium depletion. The usual cause of hypomagnesemia is due to loss through the kidney or gastrointestinal tract and gene mutations may cause intestinal magnesium loss. Chronic diarrhea is a frequent cause due to non-tropical sprue, radiation therapy, and intestinal lymphangiotasia. Hypomagnesemia has been associated with severe pancreatitis. Bypass or resection of the small bowel may also result in intestinal magnesium loss.

Loss of magnesium through renal mechanisms may be due to osmotic diuresis, secondary glycosuria, or occur in hypoparathyroid patients. Many drugs cause magnesium renal wasting such as the diuretics. Other drugs that are involved include the aminoglycosides, amphotericin B, cisplatinum, cyclosporins, and pentamidine. Extensive burns can result in magnesium depletion, hypocalciuria, and hypoparathyroidism. These patients have renal resistance to the administration of exogenous parathyroid hormone 12.

A rare finding is primary familial hypomagnesemia, which usually is diagnosed at a very young age. Hypomagnesemia with secondary hypocalcemia due to a mutation in TRPM6 was described simultaneously by 2 research groups 13,14. TRPM6 is a protein of the long transient receptor potential channel (TRPM) family and highly similar to TRPM7. TRPM7 is a bifunctional protein combining calcium- and magnesium-permeable cation channel activities with protein kinase activity. TRPM6 is present in both kidney tubules and intestinal epithelia and maps to chromosome 9q. This autosomal recessive disorder is treatable with life-long magnesium supplementation. Recognition and treatment can prevent long-term neurological defects. Patients can sometimes present in a triad of hypomagnesemia, hypokalemia, and hypocalcemia 15.

Patients with hypocalcemia due to magnesium depletion should be treated with intravenous magnesium at a dose of 48 mEq over 24 hours. Although magnesium can be administered intramuscularly, these injections are usually painful. Even though intravenous magnesium administration may result in normalization of magnesium levels, hypocalcemia may not be corrected for 3-7 days.

Hypocalcemia and hyperphosphatemia

Hyperphosphatemia has an extensive list of causes and may be due to an increased intake of phosphorus, decreased excretion, or translocation from tissue breakdown into the extracellular fluid. Renal insufficiency is probably the most common cause of hyperphosphatemia. The use of phosphate-containing enemas or zealous use of oral phosphate may also lead to hyperphosphatemia. Vitamin D administration may be responsible for the development of hyperphosphatemia. The transcellular shift of phosphorus from cells into the extracellular fluid compartment is seen in tissue destruction or increased metabolism. Examples of this include acute leukemias or lymphomas that received effective chemotherapy for large bulky tumors. Rapid release of cellular phosphorus may occur causing a "tumor-lysis-syndrome." In rhabdomyolysis due to crush injury, hypocalcemia and hyperphosphatemia may occur. Severe intravascular hemolysis may lead to a similar syndrome. In diabetic ketoacidosis, ketone-induced urinary losses of phosphorus deplete total body stores, but patients may present with hyperphosphatemia. When the volume shifts during the correction of hyperglycemia and acidosis, the shift of phosphorus back into cells can result in mild transient hypophosphatemia.

Hypocalcemia and tetany may occur if serum phosphorus rises rapidly. Hyperphosphatemia alters calcium and phosphate ion solubility products, and calcium deposition in soft tissue may occur. Hyperphosphatemia inhibits la-hydroxylase activity in the kidney. The lower circulating concentrations of 1,25(OH)₂D may further aggravate the hypocalcemia by impairing intestinal absorption of calcium.

Hyperphosphatemic-induced hypocalcemia inhibits vitamin D synthesis and results in an increase in PTH secretion. Secondary hyperparathyroidism from long-term hyperphosphatemia has been well described and is usually associated with renal insufficiency. Ectopic calcification in tissues may occur, including blood vessels, skin, periarticular tissues, and cornea (band keratopathy). Treatment should be directed towards the hyperphosphatemia in order to correct the hypocalcemia.

Ingestion of phosphoric acid-containing soft drinks has been suggested to be a cause of hypocalcemia. It is debatable as to whether this actually occurs. It is likely that the hypocalcemia is the result of reduced calcium intake, as individuals are replacing milk, a common source of calcium, with soft drinks. A low calcium diet in itself does not cause hypocalcemia if all the normal homeostatic mechanisms are functional.

Medications and Toxins Causing Hypocalcemia

There are many drugs associated with hypocalcemia, and one class may inhibit excessive bone resorption. These drugs include mithramycin (plicamycin), bisphosphonates, calcitonin, and oral or parental phosphate preparations 16. Hypocalcemia after administration of a bisphosphonate can be prolonged 17. Hypocalcemia and osteomalacia have been described with prolonged therapy with anticonvulsants such as diphenolhydantoin (phenytoin) or phenobarbital. Hypocalcemia has also been found in patients undergoing pheresis and plasmapheresis with citrated blood. Radiographic contrast dyes may contain the calcium chelator, ethylenediaminetetra-acetic acid (EDTA), resulting in low serum calciums. Gadolinium administration for MRI imaging causes a transient hypocalcemia. Fluid overdoses during dialysis, over-fluorinated public water supplies, and ingestion of fluoride-containing cleaning agents have all been associated with low serum calcium levels. In this case, the hypocalcemia is thought to be due to excessive rates of skeletal mineralization secondary to formation of calcium difluoride complex. Chemotherapeutic agents such as the combined use of 5-fluorouracil and leucovorin, may result in mild hypocalcemia. The hypomagnesemia caused by cisplatinum can induce hypocalcemia. AIDS patients that are treated with the drug phosphocarnate (trisodium phosphonoformate) have been reported to have hypocalcemia. It is unclear whether this is due to chelation or complexing of calcium in the extracellular fluid.

During surgical procedures, hypocalcemia has been recognized to occur in the absence of citrated blood infusions 18 and was associated with physiologic increases in serum PTH levels. It is thought that surgery-associated hypocalcemia was due to acute hemodilution by physiological saline. Symptoms are variable in this setting. Hypoparathyroidism is also associated with transfusion-dependent patients with beta-thalassemia 19. In a study of 28 patients with beta-thalassemia, 10.7% had hypoparathyroidism and all were hypogonadal. Two of three of these transfusion-dependent patients had insulin-dependent diabetes mellitus. The authors suggest that the endocrinopathies may be due to severe iron overload.

"Hungry Bone Syndrome""Hungry Bone Syndrome"

Recalcification that occurs in bone postoperatively, after thyrotoxicosis or hyperparathyroidism is referred to as "hungry bone syndrome", due to a rapid increase in bone remodeling. If the stimulus is removed (thyroid hormone or parathyroid hormone), there is a dramatic increase in bone formation. Hypocalcemia can occur if the rate of skeletal mineralization exceeds the rate of osteoclast-mediated bone resorption. This syndrome can be associated with severe and diffuse bone pain.

Another cause of hypocalcemia is osteoblast metastases in a patient with prostate or breast cancer. The setting of acute leukemia or osteosarcomatosis can also result in hypocalcemia. In patients with vitamin D deficiency and symptoms of osteomalacia, institution of vitamin D therapy can result in hypocalcemia. All of these disease states result in hypocalcemia due to mineralization of large amounts of unmineralized osteoid.

HYPOCALCEMIA AND PANCREATITIS

True pancreatitis can be associated with tetany, lipid abnormalities and hypocalcemia. With the development of a few animal models, the mechanism of hypocalcemia has been elucidated 20. When the pancreas is damaged, free fatty acids are generated by the action of pancreatic lipase. There are insoluble calcium salts present in the pancreas and the free fatty acids avidly chelate the salts resulting in calcium deposition in the retroperitoneum. In addition, hypoalbuminemia may be part of the clinical picture so that there is a reduction in total serum calcium. If there is concomitant alcohol abuse, emesis or poor nutritional status, hypomagnesemia may augment the problem. Parathyroid hormone levels can be normal, suppressed or elevated. If PTH levels are normal or suppressed, hypomagnesemia may be present. If PTH levels are elevated, this is a reflection of the hypocalcemia. In the treatment of these patients, parenteral calcium and magnesium replacements are indicated. Vitamin D status should be assessed to rule out malabsorption or nutritional deficiencies.

Hypocalcemia Associated With Critical Illness

There are multiple reasons why a patient with acute illness may experience hypocalcemia. Acute or chronic renal failure, hypomagnesemia, hypoalbuminemia ("factitious hypocalcemia"), medications, or transfusions with citrated blood may all alter levels of serum calcium. Pancreatitis, as stated above, may also result in hypocalcemia. Another setting in which hypocalcemia can occur is sepsis and usually confirms a grave prognosis 21. In gram negative sepsis ("toxic shock syndrome"), there is a reduction in both total and ionized serum calcium. The mechanism of action remains unknown, but elevated levels of the IL-6 cytokines or TNF-a may be mediators of the hypocalcemia.

In a recent study of patients with acute illnesses, the three most common factors identified with low calcium levels were hypomagnesemia, presence of acute renal failure, and transfusions. The level of hypocalcemia correlated with patients' mortality 22.

To assess the incidence of hypocalcemia in critically ill patients, Zivin and colleagues 22 compared the frequency and degree of hypocalcemia in nonseptic critically ill patients. Three groups of hospitalized patients were studied: critically ill patients admitted to medical, surgical, trauma, neurosurgical, burn, respiratory and coronary intensive care units (ICUs) (n=99); non-critically ill ICU patients discharged from an ICU within 48 hours (n=50) and non-ICU patients (n=50). Incidences of levels of ionized calcium were 88%, 66% and 26% for the three groups, respectively. The occurrence of hypocalcemia correlated with mortality/hazard ratio for death, 1.65 for calcium decrements of 0.1 mmol/L, (p<0.002). No specific illness (renal failure, blood transfusions) was associated with hypocalcemia.

Hypocalcemia Associated with Chronic Illness

It is well recognized that the lower albumin levels associated with chronic illness can be associated with hypocalcemia. In some chronic illnesses, however, normal albumin levels may exist but chronic hypocalcemia has been noted. Examples of these include patients with HIV infection and AIDS 23. Etiology may be related to circulating cytokines but vitamin D or magnesium deficiency must be ruled out in these patients.

Thyroid or Parathyroid Surgery as A Cause of Hypocalcemia

One of the common causes of hypocalcemia is inadvertent removal of all parathyroid glands after surgery for parathyroid or thyroid disease. Other causes of postoperative hypocalciuria include the hungry bone syndrome resulting in low serum calcium levels as remineralization occurs. There may be edema in the surgical field resulting in hypocalcemia due to the surgery itself, which may remit as the swelling subsides. The vascular supply to the remaining parathyroid glands may be compromised resulting in hypocalcemia. In chronic hyperparathyroidism, the dominant parathyroid gland may have suppressed the remaining normal parathyroid glands. After removal of the adenoma, the remaining suppressed parathyroid glands will eventually self-correct although this may take time.

After surgery for primary hyperparathyroidism, hypocalcemia can be a significant source of delayed discharge from the hospital. Risk factors for patients who develop hypocalcemia postparathyroidectomy have been evaluated. Higher levels of serum osteocalcin or phosphate prior to surgery correlated with patients who were symptomatic from hypocalcemia. Cardiac disease is another association with increased morbidity after surgery. Unilateral versus bilateral neck exploration is also an independent risk factor for the development of symptomatic hypocalcemia. Increased risks for hypocalcemia are associated with high bone turnover and local neck edema postoperatively 24. The more extensive the surgery, the more common hypocalcemia may occur. For example, surgery for parathyroid hyperplasia is associated more frequently with hypocalcemia than surgery for parathyroid adenoma 25.

Surgery for primary hyperparathyroidism may result in permanent hypocalcemia 26. In a series of 500 patients, 2% were noted to have permanent hypocalcemia. More recently, minimally invasive parathyroidectomy has been utilized and it is predicted that this change in surgical technique may result in less permanent hypocalcemia although no data is available. Repeated neck surgery for recurrent or persistent hyperparathyroidism may result in permanent hypoparathyroidism.

Other surgical neck explorations can also be associated with hypocalcemia. Thyroid surgery, for example, is associated with hypocalcemia and the type of surgery performed is associated with the risk of developing hypocalcemia. Hypocalcemia is more common after surgery for thyrotoxic goiter than after surgery for euthyroid goiter 27. Total thyroidectomy is also associated with an increased risk for hypocalcemia 28. Not surprising, surgical inexperience or neck reoperation are also both associated with an increase in the incidence of hypocalcemia post-thyroid surgery. Two-thirds of patients undergoing partial thyroidectomy for Grave's disease exhibits symptoms of hypocalcemia postoperatively; permanent hypoparathyroidism occurs in <10% of cases.

Several hypotheses have been proposed as to why patients undergoing thyroid surgery experience hypocalcemia. Vascular compromise or surgical extirpation of the parathyroid glands may occur. The incidence of transient and permanent hypoparathyroidism after thyroid surgery has been evaluated. In 1071 consecutive patients followed between 1990 and 1991, 0.5% had persistent hypoparathyroidism at one year. In France, temporary and permanent hypoparathyroidism rates were 20% and 4% respectively, after thyroidectomy 29. After complete or total thyroidectomy with node dissection, permanent hypoparathyroidism occurs more frequently 30. In a second study comparing subtotal (n=108) and total thyroidectomy (n=451), transient hypoparathyroidism occurred in 25% and 29%, respectively, of subjects. These subjects were asymptomatic. Symptomatic hypoparathyroidism occurred only in 1.8 and 2.9%, transiently. Higher rates of transient symptomatic hypocalcemia occur after reoperation (14%). The incidence of postoperative hypoparathyroidism is also associated with a number of ligatures placed in close approximation to the parathyroid gland 31. Hypomagnesemia can cause hypocalcemia postoperative and is probably related to the volume of fluid administered 32.

With the limitation on hospital stays, one of the clinical problems is knowing how long to monitor a postoperative thyroid or parathyroid surgical patient for hypocalcemia. The progress of 120 patients undergoing total/near total thyroidectomy and/or parathyroidectomy was analyzed by Bentrem et al. In this study, 18 patients (15%) met criteria for hypocalcemia defined as total calcium <7.2 mg/dL or ionized calcium <1.0 mmol/L or symptoms. The best predictor was an ionized calcium level obtained 16 hours postoperatively. Patients who had lower ionized calcium (94.5%) required supplementation 33.

Another study attempted to use both perioperative parathyroid levels and serum calcium levels to predict hypocalcemia after total or near-total thyroidectomy 34. PTH levels after surgical resection of the second thyroid lobe, age, and number of parathyroid glands identified intraoperatively, were independently associated with decreased serum calcium levels measured at the nadir on postoperative day 1 or 2. Low levels of intraoperative PTH and serum calcium less than 2.00 mmol/L predicted biochemical hypocalcemia with a similar sensitivity (90% vs 90%) and specificity (75% vs 82%).

Vitamin D Disorders Resulting in Hypocalcemia

Both inherited and inquired disorders of vitamin D and its metabolites may be associated with hypocalcemic disorder. Decreased synthesis of vitamin D3 in the skin is not uncommon and may be due to the lack of sun exposure due to excessive sun screen usage, protective clothing, winter season, increased latitude or aging. Fat malabsorption syndromes such as hepatic dysfunction, sprue, Whipple's disease and Crohn's disease may result in intestinal malabsorption of vitamin D and result in lower detectable concentration of circulating 25(OH) vitamin D.
Liver disease is not a common cause of inadequate 25(OH) vitamin D, as over 90% of the liver has to be dysfunctional before inadequate amounts are synthesized. However, intestinal fat malabsorption occurs in either parenchymal or cholestatic liver disease and this may cause vitamin D deficiency. The anticonvulsant drugs can alter the kinetics and metabolism of vitamin D to 25(OH) vitamin D, and vitamin D deficiency is easily corrected by additional vitamin D administration. Nephrotic syndrome with excretion of large amounts of protein has also been associated with lower levels of 25(OH) vitamin D and may be due to excretion of vitamin D binding protein. Chronic renal failure with a reduction in glomerular filtration rate to <30% may present decreased production of 1,25-dihydroxyvitamin D. In the setting of chronic renal failure, hyperphosphatemia and secondary hyperparathyroidism occur. Calcium tends to be in the low-normal range. Hypocalcemia is usually not observed in the presence of low levels of 25-hydroxyvitamin D due to the compensatory rise of PTH, which will mobilize the calcium stores. Hypocalcemia only occurs when skeletal stores are completely depleted.

Inherited disorders of hypocalcemia can occur resulting in a deficiency in the renal production of 1,25-dihydroxyvitamin D (vitamin D-dependent rickets type 1) or a defect in the deficiency of the VDR (vitamin D-dependent rickets type 2 or 1,25?dihydroxyvitamin D-resistance syndrome). Another rare disorder is X-linked hypophosphatemic rickets in which patients have low-normal or normal 1,25-dihydroxyvitamin D. The defect in the renal production of 1,25-dihydroxyvitamin D is the underlying pathophysiology.

Nutritional Vitamin D Deficiency

The fortification of milk, cereals, and breads with vitamin D results in rare cases of vitamin D deficiency in children. Vitamin D deficiency has been recognized in the United States in children who have restricted diets or specialized diets 35. Children in countries, which do not fortify foods, vitamin D deficiency is more common in children. Vitamin D deficiency is being recognized as a world-wide problem in older adults 36.

Patients who are at high risk for vitamin D deficiency include vegetarian mothers as there is little vitamin D in human milk and breast feed infants may be at higher risk. Patients who are unable to be exposed to solar ultraviolet D radiation may have vitamin D deficiency 37. In some cultures, traditional dress that includes long garments, hoods or veils may also result in reduced sun exposure and vitamin D deficiency 38. Postmenopausal women may be at high risk as in a study of community-dwelling women who had a hip fracture, women with a fracture had lower levels of 25(OH) vitamin D compared to a control group admitted for elective joint replacement 39. The true prevalence of vitamin D deficiency is not known.

Inherited Vitamin D Disorders

Patients with vitamin D-dependent rickets (VDDR) type 1 present with rickets, hypocalcemia, hypophosphatemia, elevated alkaline phosphatase and as a result of their hypocalcemia, secondary hyperparathyroidism. This disorder is often termed "X-linked hypophosphatemic rickets". Serum concentrations of 1,25-dihydroxyvitamin D are normal and urinary calcium is not increased. The hypophosphatemia is associated with a low threshold for renal tubular phosphate reabsorption. In spite of this, there is no stimulation of production of 1,25-dihydroxyvitamin D. From these observations, type 1 VDDR may involve a defect in the renal 1-a-hydroxylase 40. This disorder has been mapped to the short arm of the X chromosome at Xp22.1. A gene designated PHEX (phosphate-regulatory gene with homology to endopeptidase on the X chromosome) has been identified 41.

Vitamin D-resistant rickets type 2 is a rare disorder. Disruption in the production or function of the vitamin D receptor results in end-organ resistance to 1,25-dihydroxyvitamin D. The clinical presentation includes severe hypocalcemia, hypophosphatemia, and resultant secondary hyperparathyroidism with elevated alkaline phosphatase and rickets. In this disorder, however, the constant stimulation of renal 1a-hydroxylase from the chronic hypocalcemia, hypophosphatemia and increased PTH levels results in elevated serum levels of 1,25-dihydroxyvitamin D 42. This is marked contrast to VDDR type 1 where 1,25-dihydroxyvitamin D levels are decreased or undetectable.

Neonatal Hypoparathyroidism

Skeletal mineralization of a fetus is due to active calcium transport from the mother across the placenta. At term, the fetus is hypercalcemic relative to the mother and may have suppressed parathyroid hormone levels. Over the first 4 days of life, parathyroid hormone levels fall and rise to normal adult levels by 2 weeks after birth.

In the first 24-48 days of life, early neonatal hypocalcemia may occur and is more common in premature infants, infants of diabetic mothers, and infants who have suffered asphyxia. The proportional drop in ionized calcium may be less than the drop in total calcium so those symptoms may not be manifest. Hypocalcemia in premature infants is not unusual, however the reason is not understood. One proposal is that an exaggerated rise in calcitonin occurs that provokes hypercalcemia. Other hypotheses include the fact that PTH secretion may be impaired in the premature infant. Infants of diabetic mothers have an exaggerated postnatal drop in circulating calcium levels and strict maternal glycemic control during pregnancies reduces the incidence of hypocalcemia in these infants. During asphyxia, the calcitonin response is augmented and PTH levels are elevated resulting in hypocalcemia.

Between 5 and 10 days of life, the term "late" neonatal hypocalcemia may result in tetany and seizures. This disorder is more common on full-term infants than in premature infants. One risk factor is the hyperphosphatemia due to administration of cow's milk and may reflect an inability of the immature kidney to secrete phosphate. Magnesium deficiency may also masquerade as hypercalcemia in an infant. Congenital defects of intestinal magnesium absorption or renal tubular absorption can occur resulting in severe hypocalcemia.

Hyperparathyroidism during pregnancy is unusual but can result in hypocalcemia in a newborn child 43. Atrophy of the fetal parathyroid glands can occur during intrauterine life due to the increased calcium delivery to the fetus. The infant's parathyroid glands are not able to respond to the hypocalcemic stimulus after birth and maintain normal serum calcium levels 44.

A benign autosomal recessive disorder (see section on genetic disorders), familial hypocalciuric hypercalcemia (FHH) can result in life-threatening neonatal hyperparathyroidism in a child who is homozygous for the disorder. A report has been published describing an ininfant with late onset life-threatening hypocalcemia secondary to relative hypoparathyroidism. The hypoparathyroidism in this case was thought due to fetal parathyroid suppression secondary to high maternal calcium levels in a heterozygous mother affected with FHH 44.

Developmental Disorders of the Parathyroid Gland

Developmental abnormalities in the third and fourth pharyngeal pouches result in the DiGeorge syndrome. Aplasia or hyperplasia of the thymus, aplasia or hypoplasia of the parathyroid glands and associated conotruncal cardiac malformation are hallmarks of this disorder. Severe hypocalcemia resulting in seizures and tetany can occur. Immunoregulatory defects result in recurrent infections. Other common associations are tetralogy of Fallot or truncous arteriosis. Abnormal patterns of aortic arch arteries, improper alignment of the aortic pulmonary outflow vessels, and defects in septation of the ventricles can occur. Occasionally, partial forms of the DiGeorge syndrome occur and an EDTA challenge test is necessary to confirm the diagnosis and unmask the hypoparathyroidism 45.

DiGeorge syndrome is the most frequent contiguous gene deletion syndrome in humans and occurs in 1 in 4000 live births. The microdeletion has been found in chromosome 22q11.2. The phenotypic presentation is variable 46. In a small cohort of 16 patients who met clinical criteria for DiGeorge syndrome, correlation was made of the microdeletion on chromosome 22q11.2 with potential problems with the immune system. All patients had low thymulin levels, recurrent respiratory infection and absent thymus gland. Mild cell-mediated immunodeficiency syndrome was associated with infections characteristic of humeroimmunodeficiency 47. Other studies suggest that newborns with DiGeorge syndrome have preserved T-cell function but the numbers of T cells are decreased. There is variable improvement in peripheral blood T-cell counts as the patients increase in age 48. Three separate groups have identified a candidate gene for the cause of DiGeorge syndrome. This transcription factor, Tbx1, is associated with aortic arch malformations 49-51. Transgenic mice studies indicate that haploinsufficiency of Tbx1 is sufficient to generate at least one component of the DiGeorge syndrome 49. The null mutations, although lethal, in mice results in a high incidence of cardiac outflow tract abnormalities 51.

IDIOPATHIC HYPOPARATHYROIDISM (Table 2)

Isolated Hypoparathyroidism

Sporadic cases of hypoparathyroidism have been described. Some cases are associated with specific disorders such as the Kearns-Sayre syndrome, which presents with heart block, retinitis pigmentosa and ophthalmoplegia. The Kenny-Caffey syndrome has also been associated with hypoparathyroidism and includes medullary stenosis of the long bones and growth retardation 52. One particularly rare case has been described of a patient with immunoglobulin G that cross-reacted with the antiserum specific for the C-terminal region of human PTH 65-68 resulting in hypoparathyroidism. X-linked recessive idiopathic hypoparathyroidism has been observed in 2 kindreds from Missouri, USA. Epilepsy and hypocalcemia were discovered in affected males during infancy. There was an isolated congenital defect of the parathyroid gland development and linkage studies established this recessive idiopathic hypoparathyroidism was linked to a gene Xq26-q27 53.

MOLECULAR GENETICS OF HYPOPARATHYROIDISM

Familial isolated hypoparathyroidism

A few cases of familial isolated hypoparathyroidism have been described and are heterogenous with different Mendelian modes of inheritance. X-linked recessive, autosomal recessive, and autosomal dominant forms of hypoparathyroidism have been described 54-59.

In one kindred, the primary molecular defect in autosomal dominant isolated hypoparathyroidism was an abnormal prepro-PTH allele that contained a specific mutation 60. A highly charged arginine residue was found in place of cystine within the hydrophobic core of the prepro-PTH signal peptide sequence. This sequence is critical for the movement of newly formed prepro-PTH through the endoplastic reticulum. This inability to progress through the cell secretory pathway could explain the inactivity of PTH in this condition. Other mutations in the signal peptide of prepro-PTH gene have also been reported 61.

An autosomal recessive mode of inheritance has been described in isolated hypoparathyroidism in a Bangladesh-Asian kindred 62. The prepro-PTH gene mutation resulted in a substitution of G to C in the first nucleotide position of the prepro-PTH intron 2. This mutation resulted in an aberrant prepro-PTH mRNA so that the entire signal sequence would be absent preventing parathyroid hormone secretion. The patients were homozygous for the mutant allele and were the product of a consanguineous marriage.

X-linked recessive hypoparathyroidism has been described in two kindreds 58,59. Only males were affected and suffer from infancy-onset epilepsy and hypocalcemia. This X-linked gene has not yet been identified but may well be involved in embryologic development of the parathyroid glands.

Ding and coworkers described an extensive kindred with hypoparathyroidism due to a homozygous mutation in the GCMB transcription factor mapped to 6p23-24 63. The GCMB transcription factor is expressed in parathyroid cells.

Mutations Affecting the Extracellular Calcium Sensing Receptor

The calcium sensing receptor (CaR) gene is an important gene in the regulation of parathyroid gland secretion. Activating mutations of the CaR gene have been identified in patients with sporadic hypoparathyroidism and in autosomal dominant hypoparathyroidism. The calcium sensitive receptor is a member of the G-protein coupled receptor superfamily and is expressed in the kidney and parathyroid gland. If hypercalcemia occurs, CaR activates the G-protein signaling pathway, resulting in increased intracellular calcium levels and the suppression of PTH gene transcription. Heterozygous inactivating mutations of CaR result in familial "benign" hypercalcemic hypocalciuria. Homozygous inactivating mutations cause neonatal severe hyperparathyroidism. Autosomal dominant sporadic and familial hyperparathyroidism can result from gain of function mutations of CaR 64. The clinical presentation in these patients ranges from asymptomatic to life threatening. PTH levels are low to normal and hypercalciuria may be present. Activating mutations can occur in the amino-terminus extracellular domain of the receptor 40. Hypercalciuria can be exacerbated resulting in nephrocalcinosis and impairment of renal function if patients are treated with vitamin D or their analogues.

A Japanese family with hypocalcemia and hypomagnesemia and a novel gain of function mutation in CaR has been reported 65. This heterozygous mutation substituted phenylalanine for serine at codon 820 in the sixth transmembrane helix of CaR. When the mutant CaR was transiently expressed in HEK293 cells, the concentration-response curve of the mutant receptor was shifted to the left (EC50=2.5mM) compared to the wild-type CaR (EC50=3.3 mM). Correlations of calcium and magnesium levels suggest the CaR may sense magnesium and calcium.

Hypoparathyroidism-Sensory Neural Deafness, Renal Dysplasia Syndrome

The HDR (hypoparathyroidism, sensory neural deafness and renal dysplasia) syndrome is a rare autosomal dominant inherited syndrome. Inheritance of homozygous of a single recessive mutation has been found and in another kindred, the gene responsible was located on 1q42-43 66,67. Deletion mapping and mutational analysis has also identified the gene encoding GATA3, a zinc finger transcription factor involved in embryonic development 68, as a cause of this syndrome. Patients are usually asymptomatic with inappropriate normal levels of PTH given their level of hypocalcemia.

Polyglandular Autoimmune Disease Type I

The association of autoimmune parathyroid disease, adrenal disease and moniliasis is termed polyglandular autoimmune syndrome type I (PGAI) (Table 3). PGAI is not associated with a particular HLA locus and is inherited in autosomal recessive pattern. The mutation is located on chromosome 21q22.3 and is due to the single gene APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia) or AIRE (autoimmune regulator). This gene codes for a punitive transcription factor featuring 2 zinc finger motifs. PGAI begins in childhood with almost 100% penetrance. There are other autoimmune disorders associated with this syndrome which include gonadal failure, hepatitis, malabsorption, IDDM, alopecia (totalis or aerata) and vitiligo 69.

The most common age of onset of PGAI is 8 years and it occurs equally in males and females. There is a temporal sequence of development of PGAI with chronic cutaneous candidiasis frequently the herald event. Hypoparathyroidism may occur next and may present as a seizure during an acute illness. Addison's disease (adrenal insufficiency) follows. These disorders occur at the average of 5, 9 and 14 years of age respectively 70. There may be variation within an individual family in the clinical presentation.

As many as 50% of patients with PGAI experience keratoconjunctivitis 71. Keratoconjunctivitis can intermittently recur but also can be recurrent, chronic or disabling. Some propose that this is a hypersensitivity response to the candidiasis as opposed to a component of PGAI per se. Histopathological features have been evaluated in corneal buttons obtained at keratoplasties. Severe atrophy of the corneal epithelium was evident. The anterior corneal layers, epithelium, the Bowman's membrane and anterior corneal stoma only are affected. The anterior corneal stroma is replaced by scar tissue with features of chronic inflammation consisting of lymphocytes and plasma cells 72. There are reported cases of keratoconjunctivitis with the absence of a candida infection. Other ocular abnormalities include retinitis pigmentosa, exotropia, pseudo-optosis, cataracts, papilledema, strabismus, recurrent blepharitis, and loss of eyebrows and eyelashes 73.

In children with PGAI, other ectodermal disorders have been described but are also found in patients with non-autoimmune mediated hypocalcemia. These include alopecia totalis or areata, piebaldism, vitiligo, cataracts and papilledema. In PGAI, approximately 20 to 30% of individuals have some form of alopecia. Vitiligo has been reported in 10% of infected individuals 74.

Another immune problem associated with PGAI is delayed sensitivity due to T-cell abnormalities 75. Dental dysplasia including enamel hypoplasia may predate the onset of hyperparathyroidism. Fifteen percent of affected individuals have gastric atrophy and pernicious anemia. Ten percent of PGAI individuals develop chronic active hepatitis with cirrhosis which may be a significant cause of mortality. Due to intestinal malabsorption, management may be difficult due to malabsorption of calcium and vitamin D.

Blizzard et al. described cytotoxic antibodies to pathologic human parathyroid tissue determined by immunofluorescence in 38% of 74 patients with idiopathic hypoparathyroidism 76,77. The IgM antibody is not organ- or species-specific 78. The antibodies in any endocrine organ correlate poorly with symptoms in autoimmune endocrinopathies.

Treatment of patients with hypoparathyroidism due to autoimmune mechanism can be difficult. In children with autoimmune hypoparathyroidism, the symptoms of Addison's disease can be masked and lack of glucocorticoid therapy can result in a fatal outcome. In adrenal cortical insufficiency, serum calcium concentrations may be elevated and decrease rapidly to hypocalcemic levels after the introduction of cortical steroid therapy. The introduction of hormone replacement therapy for ovarian cell senescence can also lead to a diminution in serum calcium levels. Vitamin D malabsorption can occur secondary to diarrhea due to intestinal malabsorption. Patients with features of PGAI should be screened regularly for associated autoimmune abnormalities. It is recommended that healthy siblings be screened in the first decade of life.

Autoimmune Thyroid Disease and Hypoparathyroidism

In one unusual report, hypothyroidism, hypoparathyroidism and bilateral vocal cord paralysis are described 79. The patient had Riedel's thyroiditis, a rare inflammatory disorder. Fibrous tissue extended to the surrounding tissue causing the hypoparathyroidism. With aggressive prednisone and levothyroxine therapy, parathyroid and vocal cord functions were recovered.

PSEUDOHYPOPARATHYROIDISM

Pathophysiology

Pseudohypoparathyroidism was initially described by Dr. Fuller Albright and his colleagues (Table 4). These patients had clinical and biochemical features consistent with hypoparathyroidism but had neither a hypercalcemic or phosphaturic response to exogenous parathyroid hormone extract. Parathyroid hormone resistance is the biochemical hallmark of pseudohypoparathyroidism and in untreated patients, serum levels of parathyroid hormone are elevated. Biological resistance to PTH causes inadequate flow of calcium into extracellular fluids and deficient phosphate excretion by the kidney. Hypocalcemia is due to impaired mobilization of calcium from bone, reduced intestinal absorption of calcium, and increased urinary losses.

Table 4. Comparison of Features of Pseudohypoparathyroidism (PHP) and Pseudopseudohypoparathyroidism
	PHP Ia	PHP Ib	PHP II	PPHP
AHO	+	-	-	+
Serum calcium				NL
Response to PTH cAMP				NL
Response to Phosphorus			() NL	NL
Hormone Resistance	All hormones	PTH target tissues only	PTH target tissues only	None
Molecular defect	Gsa	Unknown?PTH R	Unknown	Gsa
PTH = parathyroid hormone NL = normal R = receptor Gsa = alpha subunit of the stimulatory guanine nucleotide regulation protein + = present; = decreased PHP = pseudohypoparathyroidism; PPHP = pseudopseudohypoparathyroidism Fitzpatrick, L.A.: The hypocalcemic states. Disorders of Bone and Mineral Metabolism. M. Favus (ed), Lippincott Williams & Wilkins, Philadelphia, PA, pp. 568-588, 2002.

In pseudohypoparathyroidism type I, inheritance can be an autosomal dominant, autosomal recessive, or X-linked dominant form. The hallmark test is a markedly attenuated urinary cyclic AMP response to exogenous administration of PTH. The resistance to PTH is caused by a defect in the plasma membrane bound hormone receptor-adenylate cyclase complex that produces cyclic AMP. Receptors communicate with the catalytic unit of adenylate cyclase through the interaction of a pair of guanine nucleotide binding regulatory proteins (G-proteins). There are many G-proteins, some of which are stimulatory (Gs) or inhibitory (Gi).

The original description by Fuller Albright of pseudohypoparathyroidism focused on PTH resistance. However, patients with pseudohypoparathyroidism Ia displayed partial resistance to other hormones and may present with short stature, hypothyroidism, hypogonadism, and mental retardation 80. Patients with pseudohypoparathyroidism Ia also have ovulatory, gustatory and auditory dysfunction. The defect is in Gs, an ubiquitous protein required for functional cyclic AMP production and the amounts of G-protein present can be measured in plasma membrane of accessible cells. Patients with pseudohypoparathyroidism type Ia have a 50% reduction in GSa in all tissues studied. A variety of mutations in the GSa gene have been identified 40.

Patients with pseudohypoparathyroidism also have a constellation of developmental and somatic defects that are referred to as Albright's Hereditary Osteodystrophy (AHO). Short stature, round faced, brachydactyly (Figure 3), obesity, and subcutaneous calcifications are classic features of AHO 81. Phenotypes can vary and presentations may be subtle. A variant phenotype or patients with features of AHO but lack hormone resistance and are termed pseudopseudohypoparathyroidism. These patients have normal serum calcium levels. There are a variety of mutations of GSa gene in patients with pseudohypoparathyroidism type Ia 40,82. Because of this, a simple genetic test is not available. In two AHO kindreds, for example, heterozygous frameshift mutation in the GSa gene was identified which encoded a premature termination codon 83. In other subjects, a defective adenylate cyclase has been detected.

Figure 3. X-rays demonstrate congenital shortening of the third, fourth and fifth metacarpals on the right hand. This patient was a 40-year-old female with normal serum calcium, phosphorus and alkaline phosphatase. Her findings are consistent with pseudopseudohypoparathyroidism.

Individuals classified as pseudohypoparathyroidism type Ib lack features typical of AHO. The patients have similar biochemical presentation with hypocalcemia and hyperphosphatemia with elevated levels of PTH. There is not an appropriate increase in urinary cyclic AMP in response to PTH infusion. Different genetic abnormalities such as promoter defects in the PTH-related peptide gene are thought to occur in this subset of patients 84.

Pseudohypoparathyroidism type II, is reduced phosphaturic response to administration of exogenous PTH, but a normal increase in urinary cyclic AMP excretion. Pseudohypoparathyroidism type II is a clinically heterogenous syndrome. The pathophysiology is poorly understood. In type II, there may be normal cyclic AMP but an absent phosphaturic response to PTH. Hypocalcemia, decreased bone mobilization response to PTH, and decreased serum 1,25-dihydroxyvitamin D are the prominent features of PTH resistance.

Signs and Symptoms

Patients with pseudohypoparathyroidism can present with signs and symptoms of hypocalcemia. Neuromuscular irritability, with an average age of onset at age 8, has been described. Other patients may remain asymptomatic and not be diagnosed with pseudohypoparathyroidism until adulthood. Symptoms of hypercalcemia such as carpopedal spasms, paresthesias, convulsions, muscle cramps and stridor can all be found in pseudohypoparathyroidism. In some severe cases, life-threatening laryngeal spasm have been reported in children. Posterior subscapular cataracts can occur in patients with long-standing untreated hypocalcemia. Basal ganglion calcifications have been found in 50% of patients with pseudohypoparathyroidism and may produce extrapyramidal movement disorders. In some patients with pseudohypoparathyroidism, normal serum calcium levels may be present. Hypocalcemia may develop insidiously and be preceded by increasing levels of serum PTH. Psychiatric problems such as depression, paranoia, psychosis and delusions have been described in the presence of hypocalcemia. Cognitive defects such as mental retardation and memory impairment have been encountered. Dental defects include dental and enamel hypoplasia, blunted tooth root development, and delay of tooth eruption.

In patients with radiographic evidence of osteitis fibrosis cystica, plasma alkaline phosphatase levels are usually normal but resorption markers may be increased. Bone density may be normal or increased although some studies reported decreases in BMD in selected subjects.

As mentioned above, ovulatory dysfunction and impairments in taste have been described in pseudohypoparathyroidism. Types Ia and Ib pseudohypoparathyroidism, patients have olfactory dysfunction while pseudohypoparathyroid patients with AHO and no deficient GSa protein activity have normal olfactory function 85. Reproductive abnormalities have been described. In patients with Albright's Hereditary Osteodystrophy, 76% of patients were oligomenorrheic or amenorrheic, had later sexual development, and only 2 of 17 patients had a history of pregnancy. All of these patients had typical PTH resistance and a 50% reduction in GSa activity. These patients were mildly hypoestrogenemic with normal to slightly elevated serum gonadotropin levels. It was proposed that the reproductive dysfunction was due to partial resistance to gonadotropins since administration of the synthetic GnRH analog produced normal FSH and LH responses 80.

Phenotypic variability is another problem with the diagnosis of Albright's Hereditary Osteodystrophy even among affected individuals of a different kindred. Nonspecific physical characteristics include short stature and obesity. Brachydactyly is a more specific criterion and can be diagnosed by physical or radiographic examination. In AHO, the most commonly shortened bones are the distal phalanx of the thumb and the fourth metacarpal. On a radiograph of a normal hand, a line is drawn transgential to the distal portion of the fourth and fifth metacarpals in normal individuals it should not intersect third metacarpal (Archibald's sign) 86. Heterotopic ossification can occur but little is known about the cause. Serious complications have occurred including ossification of paravertebral ligaments requiring neurosurgical decompression.

PSEUDOPSEUDOHYPOPARATHYROIDISM

Patients who express only the AHO phenotype are described as having pseudopseudohypoparathyroidism (Table 4). The subjects have normal serum calcium levels and have no other evidence of hormone resistance. Some patients may have the same deficiency in GS as other affected family members who have hormone resistance 87. It is thought that since there are 2 different nonallelic genes that could be involved in causing hormone resistance, the inheritance of 1 abnormal allele of GSa may be sufficient to cause AHO. Inheritance of both alleles would be necessary for full expression of hormone resistance and AHO that comprises of pseudohypoparathyroidism.

DIAGNOSIS AND MANAGEMENT OF PSEUDOHYPOPARATHYROIDISM

Patients who present with hypoparathyroidism and an elevated serum level of parathyroid hormone should be suspect for pseudohypoparathyroidism. The typical phenotype of AHO (short stature, obesity, brachydactyly of the hands and feet, subcutaneous and cutaneous calcifications) should suggest PHP type Ia or pseudopseudohypoparathyroidism. Hypocalcemia, hyperphosphatemia, elevated levels of PTH and normal renal function lead one to be highly suspicious of the diagnosis. A positive family history lends further support.

The biochemical hallmark is failure of bone and kidney to respond adequately to PTH. The classical test of Ellsworth and Howard and of Chase, Nelson and Auerbach involved administration of 200 to 300 USP units of bovine parathyroid extract with measurements of urinary cyclic AMP and phosphate. The inability to obtain PTH preparations led to the development of tests using synthetic human PTH (1-34) fragment. After administration of human PTH (1-34), normal subjects and patients with hypoparathyroidism display a 10- to 20-fold increase in urinary cyclic AMP. Patients with pseudohypoparathyroidism type Ia and Ib have a markedly blunted response. A research test for the diagnosis of PHP type I is the analysis of the GSa protein or the GSa gene.

Treatment of hypocalcemia in patients with pseudohypoparathyroidism is the same for other types of hypoparathyroidism. However, patients with AHO may require specific therapies related to skeletal abnormalities. Approximately 30% of patients with AHO have atopic calcification and occasionally, large extraskeletal osteomas require surgical removal to relieve symptoms 88. Ossification of ligaments may also require surgery to relieve neurological problems 89. Orthopedic intervention may be necessary for skeletal abnormalities such as coxa valga, and vara or bow tibia. Hyperkeratosis can occur between the prominent metatarsal heads and require surgical intervention. Custom-made shoes that are cushioned in the weight bearing area and medical and physical therapy are recommended to relieve symptoms of bursitis and capsulitis.

TREATMENT OF HYPOCALCEMIA

Acute Hypocalcemia

In chronic hypocalcemia, patients can often tolerate severe hypocalcemia and remain asymptomatic. The decision to treat is dependent on presenting symptoms, and the severity and rapidity with which hypocalcemia develops. The patient with acute hypocalcemia may have symptoms of tetany, seizure, or laryngeal spasm requiring aggressive treatment with intravenous calcium administration.

Calcium gluconate is the preferred intravenous calcium type as calcium chloride often causes local irritation. Calcium gluconate contains 90 mg of elemental calcium per 10 mL ampule and usually 1 to 2 ampules (180 mg of elemental calcium) diluted in 50 to 100 mL of 5% dextrose is infused over 10 minutes. This can be repeated until the patient's symptoms have cleared. With persistent hypercalcemia, administration of dilute calcium solution over longer periods of time may be necessary. The goals should be to raise serum calcium by 2 to 3 mg/dL with the administration of 15 mg/kg of elemental calcium over 4 to 6 hours. Calcium should be maintained in the low-normal range. If possible, oral calcium supplementation should be initiated concurrently with 1 to 2 grams of elemental calcium and if warranted, 1,25-dihydroxyvitamin D.

Intravenous administration of calcium is not without problems. Patients taking digitalis may have increased sensitivity to intravenous calcium. Rapid administration could result in arrhythmias so that intravenous calcium administration should be carefully monitored. Local vein irritation can occur with solutions >200 mg/100 mL of elemental calcium. If local extrapolation into soft tissues occurs, calcification with precipitation of calcium phosphate crystals can occur 90. Calcium phosphate deposition can occur in any organ and is more likely to occur if the calcium-phosphate ratio exceeds solubility product. The term "salting out" is used to describe calcium phosphate deposition in the lungs, kidney or other soft tissue and may occur in patients receiving intravenous calcium and the presence of high serum phosphate levels such as in the tumor lysis syndrome 91.

It is essential to measure serum magnesium in any patient who is hypocalcemic as correction of hypomagnesemia must occur to overcome PTH resistance before serum calcium will return to normal. If one were uncertain about the level of magnesium, it would be appropriate to treat with magnesium while awaiting laboratory confirmation of hypomagnesemia.

Chronic Hypocalcemia

Patients who are asymptomatic or with mild symptomatic hypocalcemia can be treated with oral calcium and vitamin D. Oral calcium carbonate is often the most commonly administrated although many different types exist. Oral calcium in the amounts of 1 to 3 grams of elemental calcium in 3 to 4 divided doses with meals insures optimal absorption. Calcium carbonate contains 40% elemental calcium and is relatively inexpensive. Lower amounts of elemental calcium are present in other types of calcium such as calcium lactate (13%), calcium citrate (21%) and calcium gluconate (9%) requiring a larger number of tablets. There are expensive forms of calcium supplements that have relatively few additional advantages. Liquid calcium supplements are available such as calcium glubionate that contains 230 mg of calcium per 10 mL or liquid forms of calcium carbonate. In patients with achlorhydria, a solution of 10% calcium chloride (1- to 30 ml) every 8 hours can also effectively raise calcium levels. Calcium phosphate salts should be avoided.

The overall goal of therapy is to maintain serum calcium in the low-normal range. Serum calcium should be tested very 3 to 6 months. One potential side effect is hypercalciuria with nephrocalcinosis and/or nephrolithiasis. A 24-hour urine calcium should be determined at least annually once a stable dose is established and should be <4 mg/kg/24 hr. Serum levels of calcium are poor modulators of hypercalciuria and nephrocalcinosis 92. The patient should also see an ophthalmologist to screen for cataracts.

For patients with hypoparathyroidism, vitamin D or vitamin D analogues are required. Calcitriol, the active form of vitamin D, is a rapid-acting physiologic treatment and is often used for initial therapy. Where rapid dose adjustment is necessary, such as growing children, this may be the most useful 93. Most patients require 0.25 mg twice daily up to 0.5 mg four times a day of calcitriol. Due to the need for multiple daily doses and expense, other long-acting and less expensive vitamin D preparations are frequently used. Ergocalciferol is the least expensive choice and has a long duration of action. The usual dose is 50,000 to 100,000 IU/day. Administration of therapy is needed acutely, calcitriol should be administered for the first three week but then tapered off as the dose of ergocalciferol becomes effective.

Thiazide diuretics can increase renal calcium absorption in patients with hypoparathyroidism. These may be useful to titrate urinary calcium to <4 mg/kg/day. Furosemide and other loop diuretics can depress serum calcium levels and should be avoided. Other factors that may precipitate hypocalcemia are glucocorticoids that can antagonize the action of vitamin D and its analogues.

Administration or withdrawal of exogenous estrogen can also influence calcium and vitamin D replacement therapy. Estrogen increases calcium absorption at the level of the intestine and indirectly through stimulation of renal 1a-hydroxylase activity. Dose adjustment may be required after changes in estrogen therapy due to alteration in calcium homeostasis. During the pre- and postpartum period in pregnant patients with hypoparathyroidism, doses of vitamin D often need adjustment and are thought to be due to the changing estrogen levels.

In hypoparathyroidism, autotransplantation of parathyroid tissue has been utilized at the time of parathyroidectomy to preserve parathyroid function 94. Using microencapsulated human parathyroid cells, xenotransplantation has also been reported 95. These studies have varying degrees of success 96.

The success of treatment of permanent, chronic hypoparathyroidism has recently been assessed 97. In a cross-sectional, controlled study, 25 women with postsurgical hypoparathyroidism on stable calcium and vitamin D treatment were compared to 25 control subjects with a history of thyroid surgery. Two of 25 and 4 of 25 hypoparathyroid patients had nephrolithiasis and cataracts, respectively, underscoring the need for monitoring and adjusting therapy. Compared to controls, the hypoparathyroid subjects had higher global complaint scores with predominant increases in anxiety and phobic anxiety subscores using validated questionnaires.

In hypoparathyroidism, the ideal replacement would be to replace the hormone itself. Few clinical studies have evaluated parathyroid hormone as a replacement for hypoparathyroidism. In a series of hypoparathyroid patients, once daily administration of PTH (1-34) normalized serum and urine calcium levels, but the action lasted only 12 hours. Twice daily administration preserved normal serum calcium levels in patients with a calcium sensing receptor (CaR) mutation 98.

Acute hypocalcemia can be a life-threatening situation with patients presenting with seizures, tetany, and cardiac arrhythmias. Although intravenous calcium can alleviate symptoms quickly, there are risks associated with this route of administration. For chronic hypocalcemia, calcium homeostasis can be restored with oral supplementation with calcium and vitamin D analogues. With under-replacement, cataracts and symptoms of numbness and tingling can occur. With over-replacement, nephrocalcinosis and nephrolithiasis are attendant risks.