Published: May 2014
Hypocalcemia varies from an asymptomatic biochemical abnormality to a life-threatening disorder, depending on the duration, severity, and rapidity of development. Hypocalcemia is caused by loss of calcium from or insufficient entry of calcium into the circulation (Table 1).
Hypoparathyroidism is the most common cause of hypocalcemia and often develops because of surgery in the central neck requiring radical resection of head and neck cancers. It develops in 1% to 2% of patients after total thyroidectomy.1 The hypocalcemia may be transient, permanent, or intermittent, as with vitamin D deficiency during the winter. Autoimmune hypoparathyroidism is seen as an isolated defect or as part of polyglandular autoimmune syndrome type I in association with adrenal insufficiency and mucocutaneous candidiasis. Most of these patients have autoantibodies directed against the calcium-sensing receptor. Congenital causes of hypocalcemia include activating mutations of calcium-sensing receptor, which has reset the calcium–parathyroid hormone (PTH) relation to a lower serum calcium level. Mutations affecting intracellular processing of the pre-pro-PTH molecule are also described and lead to hypoparathyroidism, hypocalcemia, or both. Finally, some cases are associated with hypoplasia or aplasia of the parathyroid glands; the best known is DiGeorge syndrome.2
Pseudohypoparathyroidism is a group of disorders with postreceptor resistance to PTH. One classic variant is Albright's hereditary osteodystrophy, associated with low stature, round facies, short digits, and mental retardation. Hypomagnesemia induces PTH resistance and also affects PTH production. Severe hypermagnesemia (>6 mg/dL) can lead to hypocalcemia by inhibiting PTH secretion. Vitamin D deficiency leads to hypocalcemia when associated with decreased dietary calcium intake. The low calcium level stimulates PTH secretion (secondary hyperparathyroidism), leading to hypophosphatemia.
Rhabdomyolysis and tumor lysis syndrome cause loss of calcium from the circulation when large amounts of intracellular phos-phate are released and precipitate calcium in bone and extraskeletal tissues. A similar mechanism causes hypocalcemia with phosphate administration.
Acute pancreatitis precipitates calcium as a soap in the abdomen, causing hypocalcemia. Hungry bone syndrome is hypocalcemia after surgery for hyperparathyroidism (HPT) in patients with severe prolonged disease (secondary or tertiary HPT in renal failure). Serum calcium is rapidly deposited into the bone. Hungry bone syndrome is rarely seen after correction of longstanding metabolic acidosis or after thyroidectomy for hyperthyroidism.
Several medications (e.g., ethylenediaminetetraacetic acid [EDTA], citrate present in transfused blood, lactate, foscarnet) chelate calcium in the circulation, sometimes producing hypocalcemia in which ionized calcium is decreased, cohereas total calcium may be normal. Extensive osteoblastic skeletal metastases (prostate and breast cancers) may also cause hypocalcemia. Chemotherapy, including cisplatin, 5-fluorouracil, and leucovorin, causes hypocalcemia mediated through hypomagnesemia. Hypocalcemia after surgery can be mediated by the citrate content of transfused blood or by a large volume of fluid administration and hypoalbuminemia. Patients with sepsis demonstrate hypocalcemia usually associated with hypoalbuminemia.
|Decreased Entry of Calcium Into the Circulation||Increased Loss of Calcium From the Circulation||Other Causes|
CaSR, calcium-sensing receptor; EDTA, ethylenediaminetetraacetic acid; PTH, parathyroid hormone.
© 2004 The Cleveland Clinic Foundation.
Chronic moderate hypocalcemia may be completely asymptomatic. Acute hypocalcemia causes increased neuromuscular irritability, underlying the most prominent symptoms. The clinical manifestation is tetany, repetitive neuromuscular discharge after a single stimulus. Tetany is seen in severe hypocalcemia (ionized Ca level lower than 1.1 mmol/L). Milder forms of neuromuscular irritability are paresthesias and numbness of the fingertips and perioral area. Twitching of the ipsilateral facial musculature (perioral, nasal, and eye muscles) by tapping over cranial nerve VII at the ear is known as Chvostek's sign. Contraction at the oral angle alone is seen in 10% to 25% of the normal population. Trousseau's sign consists of carpal spasm provoked by ischemia, induced by inflation of the blood pressure measuring cuff around the arm, or alkalosis, provoked by hyperventilation. Spontaneous muscle cramps are commonly seen in hypocalcemia. Prolonged contraction of the respiratory and laryngeal muscles causes stridorous breathing and can cause cyanosis. Other symptoms and signs are listed in Box 1.
|Box 1: Clinical Manifestations of Hypocalcemia|
|Seizures (all types)|
|Dementia (in adults), mental retardation (in children)|
|Emotional problems (anxiety, depression)|
|Extrapyramidal symptoms (parkinsonism is most common)|
|Calcifications of basal ganglia (in longstanding disease)|
|Increased Neuromuscular Irritability|
|Paresthesias in circumoral and acral areas (fingers, toes)|
|Muscle stiffness, myalgias, and spasms|
|Prolongation of QT interval|
|Congestive heart failure|
|Dry coarse skin, dermatitis, hyperpigmentation, and eczema|
© 2004 The Cleveland Clinic Foundation.
Alkalosis (hyperventilation), hypokalemia, epinephrine (emotional stress), and hypomagnesemia aggravate symptoms of hypocalcemia, whereas acidosis diminishes symptoms; patients with chronic renal failure often tolerate marked hypocalcemia without symptoms.
Hypocalcemia needs confirmation, if there is any doubt, by measurement of the serum ionized calcium level. When the diagnosis is confirmed by the finding of a serum calcium level lower than 8.2 mg/dL (2.05 mmol/L) or an ionized calcium level lower than 4.4 mg/dL (1.1 mmol/L), attention should turn toward seeking the cause.
Medical history can establish cause in patients with postsurgical hypoparathyroidism or chronic renal insufficiency, or who have been given phosphate. Laboratory evaluation should be guided by history and physical examination. Renal failure, cell lysis syndromes, hypomagnesemia or hypermagnesemia, and acute pancreatitis can be diagnosed or excluded using measurements of serum creatinine, creatine kinase, magnesium, and amylase levels. A serum magnesium concentration lower than 1.0 mg/dL should be considered significant and corrected. In the absence of these conditions, disorders affecting the production or action of PTH or vitamin D should be con-sidered. The immunoreactive PTH (iPTH), 25-hydroxyvitamin D, and 1,25-hydroxyvitaminvitamin D levels need to be determined; results are often delayed 2 to 7 days.
The serum phosphate level can help delineate causes of hypocalcemia. Low phosphate levels signify excess PTH activity (secondary HPT) or low dietary phosphate intake. High phosphate levels in the absence of tissue breakdown or renal failure signify hypoparathyroidism or pseudohypoparathyroidism.
Interpretation of the iPTH level (Table 2) requires simultaneous serum calcium determination. A low or even normal iPTH level associated with hypocalcemia is a powerful sign of hypoparathyroidism.
|Hypoparathyroidism||Mostly reduced, occasionally normal|
|Vitamin D abnormalities||Elevated|
|Hypomagnesemia||Low, normal, or high|
|Autosomal dominant hypocalcemia||Normal|
iPTH, immunoreactive parathyroid hormone.
Measurements of 25-hydroxyvitamin D are more informative in most patients with hypocalcemia than measurements of 1,25-hydroxyvitamin D. This is because vitamin D deficiency causes hypocalcemia and stimulates PTH secretion, which in turn stimulates renal conversion of 25-hydroxyvitamin D to 1,25-hydroxyvitamin D. Low dietary intake, poor absorption of vitamin D, and lack of production in the skin results in a low serum 25-hydroxyvitamin D level. The 25-hydroxyvitamin D level is also low in patients taking phenytoin, those suffering from nephrotic syndrome (loss of vitamin D–binding protein), and patients with hepatobiliary disease. The 1,25-hydroxyvitamin D level will be low despite a normal or high 25-hydroxyvitamin D level in patients with renal insufficiency, patients with deficiency of renal 1a-hydroxylase (vitamin D–dependent rickets, type 1), and patients with hypoparathyroidism. High levels of 1,25-hydroxyvitamin D are seen in hereditary vitamin D–resistant rickets (formerly called vitamin D–resistant rickets, type 2).
Patients with acute symptomatic hypocalcemia (calcium level lower than 7.0 mg/dL, ionized calcium level lower than 0.8 mmol/L) should be treated promptly with IV calcium. Calcium gluconate is preferred over calcium chloride because it causes less tissue necrosis if extravasated. The first 100 to 200 mg of elemental calcium (1 to 2 g calcium gluconate) should be given over 10 to 20 minutes. Faster administration may result in cardiac dysfunction, even arrest. This should be followed by a slow calcium infusion, at 0.5 to 1.5 mg/kg/hr. Calcium infusion should continue until the patient is receiving effective doses of oral calcium and vitamin D. Calcium for infusion should be diluted in saline or dextrose solution to avoid vein irritation. The infusion should not contain bicarbonate or phosphate because this can form an insoluble calcium salt. If bicarbonate or phosphate administration is necessary, a separate IV line should be used.
Coexisting hypomagnesemia should be corrected in every patient. Care should be taken in patients with renal insufficiency because they cannot excrete excess magnesium. Magnesium is given via infusion and initiated with 2 g magnesium sulfate over 10 to 15 minutes, followed by 1 g/hr.3 In patients with severe hyperphosphatemia (tumor lysis syndrome, rhabdomyolysis, or chronic renal failure), treatment is focused on correcting the hyperphosphatemia.
Acute hyperphosphatemia usually resolves in patients with intact renal function. Phosphate excretion may be aided by saline infusion (caution—this can lead to worsening of hypocalcemia), and acetazolamide, a carbonic anhydrase inhibitor, 10 to 15 mg/kg every 3 to 4 hours. Hemodialysis may be necessary for patients with symptomatic hypocalcemia and hyperphosphatemia, especially if renal function is impaired. Chronic hyperphosphatemia is managed by a low-phosphate diet and use of phosphate binders with meals.
Chronic hypocalcemia (hypoparathyroidism) is treated by oral calcium administration and, if this is insufficient, vitamin D supplementation. The serum calcium level should be targeted to about 8.0 mg/dL. Most patients will be entirely asymptomatic at this level, and further elevation will lead to hypercalciuria because of the lack of PTH effect on the renal tubules. Chronic hypercalciuria carries the risks of nephrocalcinosis, nephrolithiasis, and renal impairment.
Several oral calcium preparations are available (Box 2). Calcium carbonate is the cheapest form but may be poorly absorbed, especially in older patients and those with achlorhydria. Similarly, various forms of vitamin D are available (Table 3).
|Box 2: Oral Calcium Preparations|
|Calcium carbonate: 250, 650 mg|
|Calcium gluconate: 90, 1000 mg|
|Calcium citrate: 200, 950 mg|
|Calcium lactate: 60, 300 mg|
|Vitamin D Preparation||Half-Life||Form of Therapy|
Calcitriol (Rocaltrol; Calcijex)
|2-6 hr||Capsule: 0.25, 0.5 μg
Injection: 1, 2 μg/mL
Calcifediol (Calderol; requires activation in the kidneys)
Ergocalciferol (vitamin D2, Drisdol)
|Capsule: 20, 50 μg
Capsule: 1.25 mg to 50,000 IU
Solution: 12.5 mg/mL
Drops: 200 μg/mL to 8,000 IU
|Cholecalciferol (vitamin D3; Delta-D)||Long (months)||Tablet: 400, 1000 IU|
If oral calcium preparations cannot achieve adequate calcium repletion, vitamin D should be added. The usual initial daily dose is 50,000 IU of 25-hydroxyvitamin D (or 0.25 to 0.5 mg of 1,25-hydroxyvitamin D). Calcium and vitamin D doses are established by gradual titration. When adequate calcemia is achieved, urinary calcium excretion is measured. If hypercalciuria is detected, a thiazide diuretic may be added to diminish calciuria and further increase the serum calcium level. The serum calcium level should be monitored. If the phosphorus level is higher than 6.0 mg/dL when the calcium level is satisfactory, an unabsorbable phosphate binder should be added. Once controlled, the patient should be monitored every 3 to 6 months for calcium and phosphorus levels and for urinary calcium excretion.
Special consideration is necessary for the treatment of women with hypoparathyroidism during pregnancy and nursing. Vitamin D requirements increase gradually during pregnancy and may reach three times prepregnancy needs. Supplementation doses of vitamin D should be titrated using frequent serum calcium level measurements. After delivery, if there is no plan to nurse, the dose could be decreased to the prepregnancy level. If the baby is to be nursed, the dose of calcitriol should be decreased to 50% of the prepregnancy dose,4 because endogenous calcitriol production is stimulated by prolactin and increased production of PTH-related peptide, which is also stimulated by prolactin).
Several reports have described successful control of hypocalcemia using synthetic PTH (1,34-PTH, teriparatide) by twice-daily subcutaneous administration, with a lower risk of hypercalciuria.5