Hypocalcemia

Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and often causes chronic tetany. Hypoparathyroidism results from deficient parathyroid hormone (PTH), which can occur in autoimmune disorders or after the accidental removal of or damage to several parathyroid glands during thyroidectomy. Transient hypoparathyroidism is common after subtotal thyroidectomy, but permanent hypoparathyroidism occurs after < 3% of such thyroidectomies done by experienced surgeons. Manifestations of hypocalcemia usually begin about 24 to 48 hours postoperatively but may occur after months or years. PTH deficiency is more common after radical thyroidectomy for cancer or as the result of surgery on the parathyroid glands (subtotal or total parathyroidectomy).

Risk factors for severe hypocalcemia after subtotal parathyroidectomy include

• Severe preoperative hypercalcemia

• Removal of a large adenoma

• Elevated alkaline phosphatase

• Evidence of osteitis fibrosa cystica on bone x-rays

• Chronic kidney disease

Idiopathic hypoparathyroidism is an uncommon sporadic or inherited condition in which the parathyroid glands are absent or atrophied. It manifests in childhood. The parathyroid glands are occasionally absent and thymic aplasia and abnormalities of the arteries arising from the brachial arches (DiGeorge syndrome) are present. Other inherited forms include polyglandular autoimmune failure syndrome, autoimmune hypoparathyroidism associated with mucocutaneous candidiasis, and X-linked recessive idiopathic hypoparathyroidism.

Pseudohypoparathyroidism is an uncommon group of disorders characterized not by hormone deficiency but by target organ resistance to PTH. Complex genetic transmission of these disorders occurs.

Type Ia pseudohypoparathyroidism (Albright hereditary osteodystrophy) is caused by a mutation in the stimulatory Gs-alpha1 protein of the adenylyl cyclase complex (GNAS1). The result is failure of normal renal phosphaturic response or increase in urinary cAMP (cyclic adenosine monophosphate) to PTH. Patients are usually hypocalcemic and hyperphosphatemic. Secondary hyperparathyroidism and hyperparathyroid bone disease can occur. Associated abnormalities include short stature, round facies, intellectual disability with calcification of the basal ganglia, shortened metacarpal and metatarsal bones, mild hypothyroidism, and other subtle endocrine abnormalities. Because only the maternal allele for GNAS1 is expressed in the kidneys, patients whose abnormal gene is paternal, although they have many of the somatic features of the disease, do not have hypocalcemia, hyperphosphatemia, or secondary hyperparathyroidism; this condition is sometimes described as pseudopseudohypoparathyroidism.

Type Ib pseudohypoparathyroidism is less well known. Affected patients have hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism but do not have the other associated abnormalities.

Type II pseudohypoparathyroidism is even less common than type I. In affected patients, exogenous PTH raises the urinary cAMP normally but does not raise serum calcium or urinary phosphate. An intracellular resistance to cAMP has been proposed.

Vitamin D deficiency and dependency are discussed in full elsewhere.

Vitamin D is ingested in foods naturally high in vitamin D or fortified with it. It is also formed in the skin in response to sunlight (ultraviolet light). Vitamin D deficiency may result from inadequate dietary intake or decreased absorption due to hepatobiliary disease or intestinal malabsorption. It can also result from alterations in vitamin D metabolism as occur with certain drugs (eg, phenytoin, phenobarbital, rifampin) or from decreased formation in the skin due to lack of exposure to sunlight. Aging also decreases skin synthetic capacity.

Decreased skin synthesis is an important cause of acquired vitamin D deficiency among people who spend a great deal of time indoors, who live in high northern or southern latitudes, and who wear clothing that covers them completely or frequently use sun-blocking agents. Accordingly, subclinical vitamin D deficiency is fairly common, especially during winter months in temperate climates among older adults. Older adults in residential elder care settings are at particular risk because of decreased skin synthetic capacity, undernutrition, and lack of sun exposure. In fact, most people with deficiency have both decreased skin synthesis and dietary deficiency. However, most clinicians feel that the significant dangers of skin cancer outweigh the as yet unproven risk of moderately low vitamin D levels so increasing sun exposure or doing without sunblocks is not recommended; vitamin D supplements are readily available for patients with concerns.

Vitamin D dependency results from the inability to convert vitamin D to its active form or decreased responsiveness of end-organs to adequate levels of active vitamin.

• Type I vitamin D–dependent rickets (pseudovitamin D–deficiency rickets) is an autosomal recessive disorder involving a mutation in the gene encoding the 1-alpha-hydroxylase enzyme. Normally expressed in the kidney, 1-alpha-hydroxylase is needed to convert inactive vitamin D to the active form calcitriol.

• In type II vitamin D–dependent rickets, target organs cannot respond to calcitriol. Vitamin D deficiency, hypocalcemia, and severe hypophosphatemia occur. Muscle weakness, pain, and typical bone deformities can occur.

Renal tubular disease, including proximal and distal renal tubular acidosis, can cause severe hypocalcemia due to abnormal renal loss of calcium and decreased renal conversion of vitamin D to active 1,25(OH)2D.

Renal failure can result in diminished formation of 1,25(OH)2D due to

• Direct renal cell damage

• Suppression of 1-alpha-hydroxylase (needed for the vitamin D conversion) by hyperphosphatemia

Other causes of hypocalcemia include

• Acute pancreatitis (when lipolytic products released from the inflamed pancreas chelate calcium)

• Medications, including antiseizure drugs (eg, phenytoin, phenobarbital) and rifampin, which alter vitamin D metabolism, and medications generally used to treat hypercalcemia

• Hungry bone syndrome (persistent hypocalcemia and hypophosphatemia occurring after surgical or medical correction of moderate to severe hyperparathyroidism in patients in whom serum calcium concentrations had been supported by high bone turnover induced by greatly elevated PTH—hungry bone syndrome has been described after parathyroidectomy, after renal transplantation, and rarely in patients with end-stage renal disease treated with calcimimetics)

• Hyperphosphatemia (causes hypocalcemia by poorly understood mechanisms; patients with renal failure and subsequent phosphate retention are particularly prone)

• Hypoproteinemia (reduces the protein-bound fraction of serum calcium; hypocalcemia due to diminished protein binding is asymptomatic—because ionized calcium is unchanged, this entity has been termed factitious hypocalcemia)

• Infusion of gadolinium (may spuriously lower calcium concentration)

• Magnesium depletion (can cause relative parathyroid hormone deficiency and end-organ resistance to PTH action, usually when serum magnesium concentrations are < 1.0 mg/dL [< 0.5 mmol/L]; magnesium repletion increases PTH concentrations and improves renal calcium conservation)

• Septic shock due to suppression of PTH release and decreased conversion of 25(OH)D to 1,25(OH)2D

• Transfusion of > 10 units of citrate-anticoagulated blood

• Use of radiocontrast agents containing the divalent ion-chelating agent ethylenediaminetetraacetate (EDTA—can decrease the concentration of bioavailable ionized calcium while total serum calcium concentrations remain unchanged)

Although excessive secretion of calcitonin might be expected to cause hypocalcemia, calcitonin actually has only a minor effect on serum calcium. For example, low serum calcium concentrations rarely occur in patients with large amounts of circulating calcitonin due to medullary carcinoma of the thyroid.

Muscle cramps involving the back and legs are common.

Insidious hypocalcemia may cause mild, diffuse encephalopathy and should be suspected in patients with unexplained dementia, depression, or psychosis.

Papilledema occasionally occurs.

Severe hypocalcemia with serum calcium < 7 mg/dL (< 1.75 mmol/L) may cause hyperreflexia, tetany, laryngospasm, or generalized seizures.

Tetany characteristically results from severe hypocalcemia but can result from reduction in the ionized fraction of serum calcium without marked hypocalcemia, as occurs in severe alkalosis. Tetany is characterized by the following:

• Sensory symptoms consisting of paresthesias of the lips, tongue, fingers, and feet

• Carpopedal spasm, which may be prolonged and painful

• Generalized muscle aching

• Spasm of facial musculature

Tetany may be overt with spontaneous symptoms or latent and requiring provocative tests to elicit. Latent tetany generally occurs at less severely decreased serum calcium concentrations: 7 to 8 mg/dL (1.75 to 2.20 mmol/L).

Chvostek and Trousseau signs are easily elicited at the bedside to identify latent tetany.

Chvostek sign is an involuntary twitching of the facial muscles elicited by a light tapping of the facial nerve just anterior to the exterior auditory meatus. It is present in ≤ 10% of healthy people and in most people with acute hypocalcemia but is often absent in chronic hypocalcemia.

Trousseau sign is the precipitation of carpal spasm by reduction of the blood supply to the hand with a tourniquet or blood pressure cuff inflated to 20 mm Hg above systolic blood pressure applied to the forearm for 3 minutes. Trousseau sign also occurs in alkalosis, hypomagnesemia, hypokalemia, and hyperkalemia and in about 6% of people with no identifiable electrolyte disturbance.

Many other abnormalities may occur in patients with chronic hypocalcemia, such as dry and scaly skin, brittle nails, and coarse hair. Candida infections occasionally occur in hypocalcemia but most commonly occur in patients with idiopathic hypoparathyroidism. Cataracts occasionally occur with long-standing hypocalcemia and are not reversible by correction of serum calcium.

Ionized calcium concentration can be estimated from routine laboratory tests, usually with reasonable accuracy.

In hypoalbuminemia, measured serum calcium is often low, mainly reflecting a low concentration of protein-bound calcium, while ionized calcium can be normal. Measured total serum calcium decreases or increases by about 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL decrease or increase in albumin. Thus, an albumin concentration of 2.0 g/dL (20 g/L) (normal, 4.0 g/dL [40 g/L]) should itself reduce measured serum calcium by 1.6 mg/dL (0.4 mmol/L).

Similarly, increases in serum proteins, as occur in multiple myeloma, can raise total serum calcium. Acidosis increases ionized calcium by decreasing protein binding, whereas alkalosis decreases ionized calcium.

For tetany, calcium gluconate 10 mL of 10% solution IV over 10 minutes is given. Response can be dramatic but may last for only a few hours. Repeated boluses or a continuous infusion with 20 to 30 mL of 10% calcium gluconate in 1 L of 5% dextrose in water over the next 12 to 24 hours may be needed. Infusions of calcium are hazardous in patients receiving digoxin and should be given slowly and with continuous ECG monitoring after checking for (and correcting) hypokalemia.

When tetany is associated with hypomagnesemia, it may respond transiently to calcium or potassium administration but is permanently relieved only by repletion of magnesium, typically given as a 10% magnesium sulfate solution (1 g/10 mL) IV, followed by oral magnesium salts (eg, magnesium gluconate 500 to 1000 mg orally 3 times a day).

In transient hypoparathyroidism after thyroidectomy or partial parathyroidectomy, supplemental oral calcium may be sufficient: 1 to 2 g of elemental calcium/day may be given as calcium gluconate (90 mg elemental calcium/1 g) or calcium carbonate (400 mg elemental calcium/1 g).

Subtotal parathyroidectomy may cause hypocalcemia that is particularly severe and prolonged, particularly in patients with chronic kidney disease or in patients from whom a large tumor was removed. Prolonged parenteral administration of calcium may be necessary postoperatively; supplementation with as much as 1 g/day of elemental calcium (eg, 111 mL/day of calcium gluconate, which contains 90 mg elemental calcium/10 mL) may be required for 5 to 10 days before oral calcium and vitamin D are sufficient. Elevated serum alkaline phosphatase in such patients may be a sign of rapid uptake of calcium into bone. The need for large amounts of parenteral calcium usually does not fall until the alkaline phosphatase concentration begins to decrease.

In chronic hypocalcemia, oral calcium and occasionally vitamin D supplements are usually sufficient: 1 to 2 g of elemental calcium/day may be given as calcium gluconate or calcium carbonate. In patients without renal failure or hypoparathyroidism, vitamin D is given as a standard oral supplement (eg, vitamin D3, cholecalciferol 20 mcg [800 IU] once/day). Vitamin D therapy is not effective unless adequate dietary or supplemental calcium and phosphate are also supplied.

For patients with renal failure, calcitriol or another vitamin D analog that does not require renal metabolic alteration (eg, alfacalcidiol, dihydrotachysterol) should be used. Patients with hypoparathyroidism also have difficulty converting cholecalciferol to its active form and also usually require calcitriol, usually 0.5 to 2 mcg orally once a day. Pseudohypoparathyroidism can occasionally be managed with oral calcium supplementation alone, but calcitriol at the above dose may be needed. Dihydrotachysterol is usually given orally at 0.8 to 2.4 mg once a day for a few days, followed by 0.2 to 1.0 mg once a day. Alfacalcidiol is not available in the United States.

Use of vitamin D analogs can be complicated by vitamin D toxicity, with severe symptomatic hypercalcemia. Serum calcium concentration should be monitored weekly at first and then at 1- to 3-month intervals after calcium concentrations have stabilized. The maintenance dose of calcitriol or its analog, dihydrotachysterol, usually decreases with time.

Hypoparathyroidism that does not respond adequately to calcium and vitamin D supplementation responds to treatment with recombinant parathyroid hormone (rhPTH 1-84), decreasing hypercalciuria and improving bone strength. Because recombinant PTH has been shown to increase the risk of osteosarcoma in animal testing, it has been available to patients in the United States only through a special risk evaluation and mitigation strategy program (www.natpararems.com).