Hypoparathyroidism may be a primary disorder due to surgery, autoimmunity, or genetic abnormalities or it may be a functional and reversible phenomenon resulting from medications or hypomagnesemia. Postsurgical hypoparathyroidism is a rare (1–2%) but devastating complication of total thyroidectomy. It may also result from exploration of the parathyroid glands or following radical neck dissection for cancers of the head and neck. Hypocalcemia in this setting may be intermittent or permanent.
Hypoparathyroidism induced by autoimmune mechanisms may be associated with other endocrine deficiencies termed polyglandular autoimmune syndrome type I. This condition is associated with adrenal insufficiency and mucocutaneous candidiasis, which reflect defects in thymic development. Patients may also develop anemia due to vitamin B12 deficiency as a result of autoantibodies to gastric parietal cells and subsequent achlorhydria. In some patients, there may be autoantibodies to the calcium-sensing receptor on the surface of parathyroid cells. These antibodies may activate the receptor and mimic the effects of calcium, thereby reducing PTH secretion.
Hypoparathyroidism on a genetic basis is a rare condition that is the result of mutations of the gene for the calcium-sensing receptor that activate the receptor at low levels of calcium, which thereby leads to reduced PTH secretion despite hypocalcemia. The condition is associated with normal but inappropriately low PTH secretion, hypercalciuria, and nephrolithiasis and nephrocalcinosis. DiGeorge's syndrome, a genetic disorder leading to maldevelopment of the third and fourth branchial pouches, is associated with absence of parathyroid glands and an associated aplasia of the thymus as well as cardiac malformations.
Hypomagnesemia results in a syndrome characterized by hypocalcemia, hypomagnesemia, and hypokalemia. It typically requires a rather severe degree of hypomagnesemia (serum magnesium <0.8 mEq/L or 1 mg/dL) for all of the manifestations to be observed. As noted, magnesium deficiency has multiple effects including reduction of PTH release, inhibition of PTH action on bone, and possibly an action to block bone resorption that may be direct and unrelated to changes in PTH. All abnormalities rapidly resolve if magnesium is infused, but calcium administration does not correct the hypocalcemia until serum magnesium levels are restored to normal.
Pseudohypoparathyroidism is a rare set of disorders characterized by normal PTH responsiveness to hypocalcemia but failure of PTH action on target-organs of bone and kidney or some combination of the two. Patients manifest the clinical features of hypoparathyroidism, but PTH levels are elevated yet hypocalcemia persists. In Type 1, binding of the PTH receptor fails to elicit the generation of cyclic AMP as there is inactivation mutation of the gene for the G protein mutation. In Type 2 pseudohypoparathyroidism, the receptor is normal but the cellular response to cyclic AMP is deficient.
Reduced vitamin D intake or production in skin can occur in areas in which there is minimal sun exposure or in individuals in whom exposure of the skin is minimal and whose dietary intake of vitamin D-containing foods is low, particularly if foods are not fortified with vitamin D.
Malabsorption syndromes induced by postsurgical gastrectomy state, celiac sprue, inflammatory bowel disease, cystic fibrosis, or chronic pancreatitis may be associated with either reduced absorption of dietary sources of vitamin D or defects in the enterohepatic circulation leading to decreased reabsorption of secreted calcidiol.
In addition to reduced endogenous production of vitamin D in elderly individuals, vitamin D intake is often low as it is for most Americans. This may contribute to the risk for osteoporosis. Dietary vitamin D deficiency can occur in children and results in hypocalcemia as well as abnormal bone formation and development (rickets).
Patients with chronic kidney disease are usually considered to have 1,25-dihydroxyvitamin D (calcitriol) deficiency due to reduced renal synthesis of the active hormone. Diminished availability of calcidiol in patients with severe liver disease and those taking drugs that increase the activity of P-450 enzymes that metabolize vitamin D to inactive forms, such as anticonvulsants (phenobarbital, phenytoin, carbamazepine), alcohol, isoniazid, theophylline, and rifampin, may lead to vitamin D deficiency associated with calcidiol deficiency.
Genetic Abnormalities of Vitamin D Metabolism
Vitamin D-dependent rickets refers to two autosomal recessive syndromes characterized by hypocalcemia, hypophosphatemia, and rickets. Type 1 vitamin D-dependent rickets, also called pseudovitamin D deficiency rickets, is characterized by an inability to produce calcitriol due to an inactivating mutation in the 1-hydroxylase gene. Type 2 vitamin D-dependent rickets is an autosomal recessive disorder due to hereditary resistance to vitamin D. It is usually caused by mutations in the gene encoding the vitamin D receptor.
In nephrotic syndrome, there may be excessive urinary loss of vitamin D-binding protein and bound vitamin D leading to vitamin D deficiency but rarely to clinically significant hypocalcemia.
Intravascular and Tissue Complexation of Calcium Hyperphosphatemia
Intravascular and tissue complexation of calcium hyperphosphatemia induces hypocalcemia through several mechanisms including formation of deposits of calcium phosphate in bone and soft tissue when the product of the serum calcium (mg/dL) and phosphate (mg/dL) is higher than 55 mg2/dL2. This may occur as phosphate infusions or oral or rectal administration for bowel cleansing or as laxatives. Also, phosphate release from cells during chemotherapy of a variety of tumors or leukemia or during rhabdomyolysis may produce the same disturbance. Intravascular precipitation may occur if the hyperphosphatemia is acute. Intravascular complexation may also occur if patients receive large amount of citrate in blood products such as may occur with plasma exchange or massive blood transfusion. In this setting, ionized calcium must be measured, as total serum calcium will include the portion bound to citrate and total calcium will be in the normal range while ionized calcium will be reduced.
“Hungry bone” syndrome refers to the rapid uptake of calcium and phosphate into bone after parathyroidectomy, particularly in patients who have had long-standing primary or secondary hyperparathyroidism and who have severe degrees of bone resorption. The syndrome typically occurs in the first few hours after parathyroidectomy and may persist for several days. A similar phenomenon may be seen in patients with certain tumors such as prostate cancer who develop osteoblastic metastasis.
Soft tissue complexation also occurs in acute pancreatitis as calcium may combine with circulating and with tissue fats and form “soap” at the sites of precipitation. Calcium may also be deposited in the damaged muscle of patients suffering from rhabdomyolysis.
Other Causes of Hypocalcemia
Other causes of hypocalcemia include sepsis where multiple abnormalities including hypoalbuminemia, lactic acidosis, hypomagnesemia, and a primary impairment of PTH secretion may occur. During infusions of magnesium in women treated for preeclampsia, the calcium-sensing receptor may be bound by and activated by magnesium resulting in a transient reduction in PTH secretion and hypocalcemia. Typically patients are not symptomatic from hypocalcemia because of the concurrent hypermagnesemia. Finally, cinacalcet, a drug in the new class of calcimimetic agents, will induce hypocalcemia as it acts to increase the sensitivity of the calcium-sensing receptor to calcium and thereby leads to inhibition of PTH secretion in the face of hypocalcemia.
Pseudohypocalcemia has recently been described as certain gadolinium-based contrast agents used in magnetic resonance imaging, gadodiamide and gadoversetamide, may bind to the indicator reagents used in colorimetric assays for calcium and produce a false low value. This may be a particular problem in patients with renal insufficiency receiving these agents as they are renally excreted.
The clinical manifestations of hypocalcemia are rather specific and relate to the neuromuscular actions of hypocalcemia. Tetany is the hallmark of hypocalcemia and results from increased neuromuscular irritability after stimulation. It consists of a set of symptoms including circumoral and acral paresthesias. The signs of hypocalcemia include muscle spasms and specifically carpopedal spasm (adduction of thumb, flexion of wrists and metacarpals, and extension of fingers). The manifestations of hypocalcemia can be elicited during the physical examination and include Trousseau's sign (elicited by inflating a sphygmomanometer cuff above systolic pressure for 3 minutes and finding carpopedal spasm of the affected limb) or Chvostek's sign (twitching of facial muscles after tapping on the facial nerve anterior to the ear). While these findings are relatively specific for hypocalcemia, they are also found in hypomagnesemic patients. However, hypomagnesemia induces hypocalcemia, so that if tetany is found, it is usually in the setting of hypocalcemia as well. These signs of neuromuscular irritability may herald grand mal seizures and therefore represent a medical emergency when seen. Cardiac abnormalities including arrhythmias, particularly in patients on digitalis, and hypotension may be seen as well, particularly in the critical care setting. These abnormalities are typically seen when patients have a serum calcium level that is 30% or greater lower than normal.
It should be noted that occasionally patients with acute, severe respiratory alkalosis will manifest tetany as the acute alkalemia itself induces neuromuscular irritability and alkalemia decreases ionized calcium by increasing the negative charges on albumin and thereby increasing albumin binding of ionized calcium.
Some patients with chronic hypocalcemia may have neuropsychiatric manifestations including dementia or mental retardation in children and other psychiatric syndromes including depression and anxiety. In addition, idiopathic hypoparathyroidism, an important cause of chronic hypocalcemia, may be associated paradoxically with intracerebral calcifications, particularly in the basal ganglia, and a Parkinsonian syndrome may result from basal ganglia damage.
The diagnosis of hypocalcemia rests with a measurement of serum calcium as either a screening test or in response to the symptomatology described above. As the physiologically active fraction of calcium is ionized and closely regulated yet the standard measure of serum calcium includes a major fraction bound to albumin and other anions, it is important to consider the relation of total serum calcium to the bound fraction. Total serum calcium falls approximately 0.8 mg/dL for every 1 g/dL decrement in the concentration of serum albumin. Serum ionized calcium can also be measured directly by an ion electrode.
Since hypocalcemia is found only in the setting of disorders of PTH and vitamin D or as a result of tissue deposition or complexation, a variety of other assays should be made in order to diagnose the underlying disturbance. First, serum phosphate should be measured, as an elevated value might suggest kidney disease, hypoparathyroidism, or release of cellular stores of phosphate such as occurs in rhabdomyolysis or when a large tumor burden is suddenly reduced by lytic therapies such as chemotherapy for leukemia.
Serum magnesium should be measured as severe hypomagnesemia (<1 mg/dL) is associated with a failure of PTH secretion and/or a failure of bone to respond normally to circulating PTH. As chronic kidney disease reduces calcitriol levels and induces hyperphosphatemia, serum creatinine should be measured in all hypocalcemic patients.
If the diagnosis is not apparent from the patient's history, physical examination, and the above noted assays, the next step is to measure immunoreactive intact PTH levels. In diseases associated with secondary hyperparathyroidism and in defective tissue response to PTH (pseudohypoparathyroidism), the PTH level will be high in hypocalcemia. In idiopathic or postsurgical hypoparathyroidism, PTH levels will be low in hypocalcemia, although normal PTH levels may be inappropriately low if hypocalcemia is found.
If secondary hyperparathyroidism is found, then vitamin D metabolites should be measured. Low levels of 25-hydroxyvitamin D (calcidiol) suggest chronic vitamin D deficiency, usually due to decreased intake or abnormal GI absorption of vitamin D as calcidiol levels are reflective of intake and not subject to physiologic regulation. However, low or low-normal levels of calcitriol with normal calcidiol levels in hypocalcemia is a pattern seen in renal failure.
Since there are multiple systems designed to maintain the serum calcium level and there is a large store of calcium in bone, hypocalcemia will not be successfully treated in a sustained manner by calcium infusions alone. Typically, calcium infusions may correct the symptoms of acute or chronic hypocalcemia, but sustained therapy usually requires either correction of the underlying cause of hypocalcemia or use of vitamin D supplementation.
The most appropriate treatment for patients with symptomatic hypocalcemia, either acute or chronic, is intravenous calcium, in the form of 100–200 mg (2.5–5 mmol) of elemental calcium (1–2 g of calcium gluconate) in 10–20 minutes. This should be followed by a slow infusion of calcium as the serum calcium will rapidly return to low levels under most circumstances. The dose of the slow infusion should be 1.0 mg/kg/hour as 10% calcium gluconate (90 mg of elemental calcium per 10-mL ampoule). Some postparathyroidectomy patients may require prolonged, massive calcium therapy due to hungry bone disease.
If hypomagnesemia is the cause of hypocalcemia, 2 g (16 mEq) of magnesium sulfate should be infused as a 10% solution over 10 minutes, followed by 1 g (8 mEq) in 100 mL of fluid per hour until serum magnesium remains normal. Patients with hypocalcemia and severe acute hyperphosphatemia due to tumor lysis syndrome require hemodialysis to correct hyperphosphatemia. This will typically ameliorate hypocalcemia.
Chronic Hypocalcemia Induced by Hypoparathyroidism
Both oral calcium and vitamin D supplementation are usually required to correct the hypocalcemia of chronic hypoparathyroidism. The target serum calcium level should be approximately 8.0 mg/dL and at that level, most patients will be asymptomatic. If serum calcium is maintained at a higher level, patients will develop hypercalciuria because of the lack of PTH to enhance calcium reabsorption across the distal nephron. Chronic hypercalciuria may lead to development of nephrocalcinosis, nephrolithiasis, and renal insufficiency.
Occasionally in mild hypoparathyroidism 2 g of oral calcium supplements will achieve normal calcium levels. If this fails, vitamin D should be added. The usual initial daily dose is 50,000 international units of ergocalciferol (vitamin D2) or 0.25–0.5 μg of calcitriol. Appropriate doses of calcium and vitamin D are established by gradual titration. If hypercalciuria is detected, a thiazide diuretic may be added to the regimen. This will result in diminished calciuria and a further increase in the serum calcium level. Serum and urine calcium levels must be monitored carefully, as the main complications of the treatment of hypoparathyroidism are inadvertent hypercalcemia and/or hypercalciuria.
With the recent availability of a synthetic PTH preparation (1-34 PTH, teriparatide) using twice-daily subcutaneous administration has led to correction of hypocalcemia with lower risk of hypercalciuria.
While hypocalcemia is highly prevalent in patients with chronic renal failure, symptomatic hypocalcemia is rare. The approach to hypocalcemia in renal failure is primarily to lower serum phosphorus and supplement patients with active forms of vitamin D.
Holick MF: Vitamin D for health and in chronic kidney disease. Semin Dial 2005;18:266.
Locatelli F, Rossi F: Incidence and pathogenesis of tumor lysis syndrome. Contrib Nephrol 2005;147:61.
Pecherstorfer M et al: Current management strategies for hypercalcemia. Treat Endocrinol 2003;2(4):273.
Stewart AF: Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005;352:373.
Tfelt-Hansen J, Brown EM: The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005;42:35.