Published June 16, 2004Mario Skugor, MD |
Hypocalcemia,
like hypercalcemia, may vary from
a very mild and asymptomatic biochemical abnormality to a severe life-threatening
disorder depending on the duration, severity, and rapidity of development.
The causes of hypocalcemia (Table 1) are
either from increased loss of calcium from the circulation or from insufficient
entry of calcium into the circulation.
Hypoparathyroidism is most common cause of hypocalcemia and is often caused by surgery in the central neck that requires radical resections because of head and neck cancers. It develops in 1% to 2% of patients after total thyroidectomy for thyroid cancer or benign thyroid disease.1 The hypothyroidism may be transient, permanent, or even intermittent (eg, when needs exceed parathyroid reserve, such as in vitamin D deficiency during the winter months). Autoimmune hypoparathyroidism can be 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 mutations of this receptor, which constitutively activate the receptor and thus reset the calcium-PTH relationship to a lower serum calcium level. Mutations affecting intracellular processing of the pre-pro-PTH molecule are also described and lead to hypoparathyroidism. Finally, some cases of congenital hypoparathyroidism are associated with hypoplasia or aplasia of parathyroid glands; the best known is DiGeorge syndrome.2 Pseudohypoparathyroidism is a group of disorders whose exact mechanism is not known but is thought to involve postreceptor resistance to the effects of PTH. One classic variant is Albright's hereditary osteodystrophy, which is associated with low stature, round facies, short digits, and mental retardation. Hypomagnesemia induces resistance to PTH and also affects PTH production. Severe hypermagnesemia (higher than 6 mg/dL) can lead to hypocalcemia by inhibiting PTH secretion. A deficiency of vitamin D can lead to hypocalcemia when it is associated with decreased dietary calcium intake. The low calcium stimulates PTH secretion (secondary HPT) that leads to hypophosphatemia in these patients. Increased loss of the calcium from the circulation occurs with rhabdomyolysis or tumor lysis syndrome. In patients with these conditions, large amounts of phosphate are released from the intracellular pool and precipitate calcium in bone and extraskeletal tissues. A similar mechanism is responsible for hypocalcemia due to phosphate administration. In acute pancreatitis, calcium is precipitated as calcium soaps in the abdominal cavity. "Hungry bone syndrome" refers to hypocalcemia after surgical correction of HPT in patients with severe, prolonged disease, usually secondary or tertiary HPT related to renal failure. Serum calcium is rapidly taken from the circulation and deposited into the bone. Much less often, hungry bone syndrome is seen in patients after correction of long-standing metabolic acidosis or after thyroidectomy for hyperthyroidism. Several medications chelate calcium in the circulation and thus produce hypocalcemia. In these situations, ionized calcium is decreased while total calcium may be normal. These medications include EDTA, citrate (present in transfused blood), lactate, and foscarnet. Extensive osteoblastic skeletal metastases, especially from prostate and breast cancer, may also lead to hypocalcemia. Patients receiving chemotherapy, including cisplatin, 5-fluorouracil, and leucovorin develop hypocalcemia mediated through hypomagnesemia. Low serum calcium levels seen in patients after surgeries can be mediated by the citrate content of transfused blood or by large fluid administration and hypoalbuminemia. Patients with sepsis demonstrate hypocalcemia that is usually associated with hypoalbuminemia. |
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Diagnostic
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Chronic moderate hypocalcemia may be completely asymptomatic. Acute hypocalcemia directly causes increased neuromuscular irritability, and this pathophysiology underlies the most prominent symptoms. The clinical manifestation is tetany, characterized by repetitive neuromuscular discharge after a single stimulus. Tetany is seen in more severe hypocalcemia (ionized Ca <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 by tapping over cranial nerve VII at the ear is known as Chvostek's sign. It consists of contractions of perioral muscles at the angle of the mouth, ipsilateral nasal musculature, and ipsilateral eye musculature. Contraction at the oral angle alone can be 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 for a few minutes). 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 Table 2. Alkalosis (eg, induced by hyperventilation), hypokalemia, epinephrine (eg, due to emotional stress), and hypomagnesemia aggravate symptoms of hypocalcemia whereas acidosis diminishes symptoms, as seen in patients with chronic renal failure who often tolerate marked hypocalcemia without symptoms. |
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The presence of hypocalcemia needs to be confirmed, if there is any doubt, by the measurement of serum ionized calcium. When diagnosis is confirmed by the finding of serum calcium <8.2 mg/dL (2.05 mmol/L) or ionized calcium <4.4 mg/dL (1.1 mmol/L), attention should turn toward seeking the cause of hypocalcemia. Relevant medical history can establish cause in patients with postsurgical hypoparathyroidism, chronic renal insufficiency, or phosphate administration. Further laboratory evaluation of patients with confirmed hypocalcemia 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. Serum magnesium concentration below 1.0 mg/dL should be considered significant and therefore corrected. In the absence of the above conditions, disorders affecting production or action of PTH or vitamin D should be considered. Measurement of iPTH, 25-(OH) vitamin D, and 1,25-(OH) vitamin D need to be obtained, but the results are often delayed (2 to 7 days). The serum phosphate level can be helpful in interpreting causes of hypocalcemia. Low phosphate levels signify either excess PTH activity (secondary HPT) or low dietary phosphate intake. High levels of phosphate in the absence of tissue breakdown or renal failure signify hypoparathyroidism or pseudohypoparathyroidism. Interpretation of the iPTH level (Table 3) requires simultaneous determination of serum calcium. A low or even normal iPTH level associated with hypocalcemia is a powerful sign of hypoparathyroidism.
Measurements of 25-(OH) vitamin D (calcidiol) are more informative in most patients with hypocalcemia than measurements of 1,25-(OH) vitamin D (calcitriol). This is because vitamin D deficiency causes hypocalcemia and stimulates PTH secretion, which in turn stimulates renal conversion of calcidiol to calcitriol. Low dietary intake, poor absorption of vitamin D, and lack of production of calcidiol in the skin will result in a low serum cacidiol level. Calcidiol will be low also in patients taking phenytoin, those suffering from nephrotic syndrome (loss of vitamin D-binding protein), and patients with hepatobiliary disease. Calcitriol levels will be low despite normal or high calcidiol levels in patients with renal insufficiency, in patients with deficiency of the renal 1-alpha-hydroxylase (vitamin D-dependent rickets, type 1), and in patients with hypoparathyroidism. High levels of calcitriol are seen in hereditary vitamin D-resistant rickets (formerly called vitamin D-resistant rickets, type 2). |
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| Patients
with acute symptomatic hypocalcemia (serum calcium usually below 7.0 mg/dL,
and ionized calcium usually below 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 slow calcium infusion at 0.5 to
1.5 mg/kg/h. Calcium infusion should be continued 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 solution should not contain bicarbonate or phosphate because these
can form insoluble calcium salts. If bicarbonate or phosphate administration
is necessary, a separate IV line should be used.
Coexisting hypomagnesemia should be considered in every patient, and if present or if the magnesium status is unknown, magnesium should be supplemented. Great care should be taken in patients with impaired renal function because they cannot excrete excess magnesium. Magnesium is given in infusion and initiated with 2 g magnesium sulfate over 10 to 15 minutes followed by 1 g/hr.3 In patients with severe hyperphosphatemia (as in 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, and excretion
of phosphate may be aided by saline infusion (used cautiously, as this
can lead to worsening of hypocalcemia) and administration of acetazolamide,
a carbonic anhydrase inhibitor, 10 to 15 mg/kg every 3 to 4 hours. Hemodialysis
is often necessary in patients who have symptomatic hypocalcemia and hyperphosphatemia,
especially if renal function is impaired. Chronic hypocalcemia (hypoparathyroidism and so forth) is treated by administration of oral calcium 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 may lead to development of nephrocalcinosis, nephrolithiasis, and renal impairment, and must be avoided. Several oral calcium preparations are available (Table 4). Calcium carbonate is the cheapest form but may be poorly absorbed, especially in elderly patients and those with achlorhydria. Likewise, various forms of vitamin D are available (Table 5) for treatment of patients with hypoparathyroidism as well as those with vitamin D deficiency and chronic renal failure.
If oral calcium preparations alone cannot achieve adequate calcium repletion, vitamin D should be added. The usual initial daily dose is 50,000 IU of 25-(OH) Vitamin D (or 0.25 to 0.5 mcg of 1,25-(OH) vitamin D). Appropriate doses of calcium and vitamin D are established by gradual titration. When adequate calcemia is achieved, urinary calcium excretion needs to be measured. 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 calcium levels ought to be monitored carefully, as the main problem associated with thiazide use is development of hypercalcemia. Phosphorus levels should also be controlled. If phosphorus is >6.0 mg/dL at a time when calcium is satisfactory, an unabsorbable phosphate binder should be added to the regimen. Once therapeutic goals are achieved, the patient should be monitored every 3 to 6 months for serum calcium and phosphorus levels as well as for urinary calcium excretion. Special consideration is necessary in 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 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 one half of the prepregnancy dose.4 The rationale behind this management is that endogenous calcitriol production is stimulated by prolactin as well as increased production of PTH-related peptide (which is also stimulated by prolactin). With the recent availability of a synthetic PTH preparation (1-34 PTH, teriparatide), several reports have described successful control of hypocalcemia with lower risk of hypercalciuria using twice-daily subcutaneous administration.5 |
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