176 HYPERCALCEMIC AND HYPOCALCEMIC DISORDERS
Harrison’s Manual of Medicine
HYPERCALCEMIC AND HYPOCALCEMIC DISORDERS
Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, constipation, renal tubular defects, polyuria, a short QT interval, and arrhythmias. CNS and GI symptoms can occur at levels of serum calcium >2.9 mmol/L (>11.5 mg/dL), and nephrocalcinosis and impairment of renal function occur when serum calcium is 3.2 mmol/L (>13 mg/ dL). Severe hypercalcemia, usually defined as 3.7 mmol/L (>15 mg/dL), can be a medical emergency, leading to coma and cardiac arrest.
Etiology The causes of hypercalcemia are listed in Table 176-1. Hyperparathyroidism and malignancy account for 90% of cases.
Table 176-1 Classification of Causes of Hypercalcemia
Primary hyperparathyroidism is a generalized disorder of bone metabolism due to increased secretion of parathyroid hormone (PTH) by an adenoma (81%) or carcinoma (4%) in a single gland, or by parathyroid hyperplasia (15%). Familial hyperparathyroidism may be part of multiple endocrine neoplasia type 1 (MEN 1), which also includes pituitary and pancreatic islet tumors, or of MEN 2a, in which hyperparathyroidism occurs with pheochromocytoma and medullary carcinoma of the thyroid.
Hypercalcemia associated with malignancy is often severe and difficult to manage. Mechanisms for this include release of PTH-related protein (PTHrP) in lung, kidney, and squamous cell carcinoma; local bone destruction in myeloma and breast carcinoma; activation of lymphocytes leading to release of interleukin 1 (IL-1) and tumor necrosis factor (TNF) in myeloma and lymphoma; or an increased synthesis of 1,25(OH)2D in lymphoma.
Several other conditions have been associated with hypercalcemia. These include: sarcoidosis and other granulomatous diseases, which lead to increased synthesis of 1,25(OH)2D; vitamin D intoxication from chronic ingestion of large vitamin doses (50–100× physiologic requirements); lithium therapy, which results in hyperfunctioning of the parathyroid glands; and familial hypocalciuric hypercalcemia (FHH) due to autosomal dominant inheritance of a mutation in the calcium-sensing receptor, which results in inappropriate secretion of PTH and enhanced renal calcium resorption. Severe secondary hyperparathyroidism may also complicate end-stage renal disease. Progression to tertiary hyperthyroidism occurs when PTH hypersecretion becomes autonomous and is no longer responsive to medical therapy.
Clinical Features Most pts with hyperparathyroidism are asymptomatic, even when the disease involves the kidneys and the skeletal system. Pts frequently have hypercalciuria and polyuria, and calcium can be deposited in the renal parenchyma or form calcium oxalate stones. The characteristic skeletal lesion is osteopenia or, rarely, the more severe disorder osteitis fibrosa cystica. Resorption of the phalangeal tufts, subperiosteal resorption of bone in the digits, and tiny “punched out” lesions in the skull may also be present. Increased bone resorption primarily involves cortical rather than trabecular bone. Hypercalcemia may be intermittent or sustained, and serum phosphate is usually low but may be normal.
Diagnosis Primary hyperparathyroidism is confirmed by demonstration of an inappropriately high PTH level for the degree of hypercalcemia. Hypercalciuria helps to distinguish this disorder from FHH, in which PTH levels are usually in the normal range and the urine calcium level is low. Levels of PTH are low in hypercalcemia of malignancy (Table 176-2).
Table 176-2 Differential Diagnosis of Hypercalcemia: Laboratory Criteria
The type of treatment is based on the severity of the hypercalcemia and the nature of the associated symptoms. Table 176-3 shows general recommendations that apply to therapy of acute hypercalcemia from any cause.
Table 176-3 Therapies for Severe Hypercalcemia
In pts with severe primary hyperparathyroidism, surgical parathyroidectomy should be performed promptly. Asymptomatic disease may not require surgery; usual surgical indications include age <50, nephrolithiasis, urine Ca >400 mg/d, reduced creatinine clearance, reduction in bone mass <2 SD below normal, or serum calcium >0.25 mmol/L (>1 mg/dL above the normal range). If neck exploration does not reveal an abnormal gland, sestamibi scans, ultrasound, CT, or intraarterial digital angiography may help localize the abnormal tissue. Postoperative management requires close monitoring of calcium and phosphorus. Calcium supplementation is given for symptomatic hypocalcemia.
No therapy is recommended for FHH. Secondary hyperparathyroidism should be treated with phosphate restriction, the use of nonabsorbable antacids, and calcitriol. Tertiary hyperparathyroidism requires parathyroidectomy.
Chronic hypocalcemia is less common than hypercalemia but is usually symptomatic and requires treatment. Symptoms include peripheral and perioral paresthesia, muscle spasms, carpopedal spasm, laryngeal spasm, seizure, and respiratory arrest. Increased intracranial pressure and papilledema may occur with longstanding hypocalcemia, and other manifestations may include irritability, depression, psychosis, intestinal cramps, and chronic malabsorption. Chvostek’s and Trousseau’s signs are frequently positive, and the QT interval is prolonged. Both hypomagnesemia and alkalosis lower the threshold for tetany.
Etiology Transient hypocalcemia often occurs in critically ill pts with burns, sepsis, and acute renal failure; following transfusion with citrated blood; or with medications such as protamine and heparin. Hypoalbuminemia can reduce serum calcium below normal, although ionized calcium levels remain normal. A simplified correction is sometimes used to assess whether the serum calcium concentration is abnormal when serum proteins are low. The correction is to add 0.25 mmol/L (1 mg/dL) to the serum calcium level for every 10 g/L (1 g/dL) by which the serum albumin level is below 40 g/L (4.0 g/dL). Alkalosis increases calcium binding to proteins, and in this setting direct measurements of ionized calcium should be used.
The causes of hypocalcemia can be divided into those in which PTH is absent (hereditary or acquired hypoparathyroidism, hypomagnesemia), PTH is ineffective (chronic renal failure, vitamin D deficiency, intestinal malabsorption, pseudohypoparathyroidism), or PTH is overwhelmed (severe, acute hyperphosphatemia in tumor lysis, acute renal failure, or rhabdomyolysis; hungry bone syndrome postparathyroidectomy). The cause of hypocalcemia associated with acute pancreatitis is unclear.
Symptomatic hypocalcemia may be treated with intravenous calcium gluconate (1 mg/mL in D5W infused 30–100 mL/h). Management of chronic hypocalcemia requires an oral calcium preparation, usually along with a vitamin D preparation (Chap. 177). Hypoparathyroidism requires administration of calcium (1–3 g/d) and vitamin D or calcitriol (0.25–1 µg/d), adjusted according to serum calcium levels and urinary excretion. Restoration of magnesium stores may be required to reverse hypocalcemia in the setting of severe hypomagnesemia (<1.0 mg/dL).
Mild hypophosphatemia is not usually associated with clinical symptoms. In severe hypophosphatemia (£1.0 mg/dL), pts may have muscle weakness, numbness, and paresthesia. Rhabdomyolysis is common in chronic alcoholism or can be precipitated during treatment of diabetic ketoacidosis or by hyperalimentation or refeeding in a malnourished pt. Respiratory insufficiency can result from diaphragm muscle weakness.
Etiology The causes of hypophosphatemia include: decreased intestinal absorption (vitamin D deficiency, phosphorus-binding antacids, malabsorption, vitamin D–dependent rickets); urinary losses (hyperparathyroidism, vitamin D deficiency, vitamin D–dependent rickets, hyperglycemic states, oncogenic osteomalacia, alcoholism); and shifts of phosphorus from extracellular to intracellular compartments (administration of insulin or consumption of nutrients that stimulate insulin release).
Mild hypophosphatemia can be replaced orally with milk, carbonated beverages, or Neutraphos or K-phos (up to 3 g/d in 4–6 divided doses/d). For severe hypophosphatemia, >3 g/d of phosphorus may be required over several days. Intravenous phosphorus (1g in 1L fluid over 8–12 h) can be administered with caution: a serum calcium × phosphorus product of >70 markedly increases the risk of soft tissue calcification and nephrocalcinosis.
In adults, hyperphosphatemia is defined as a level ³1.6 mmol/L (>5 mg/dL). The most common causes are acute and chronic renal failure, but it may also be seen in hypoparathyroidism, vitamin D intoxication, acidosis, rhabdomyolysis, and hemolysis. In addition to treating the underlying disorder, dietary phosphorus intake should be limited. For control of chronic hyperphosphatemia, oral calcium or aluminum phosphate binders may be used.
Muscle weakness, prolonged PR and QT intervals, and cardiac arrhythmias are the most common manifestations of hypomagnesemia. Magnesium is important for effective PTH secretion as well as the renal and skeletal responsiveness to PTH. Therefore, hypomagnesemia is often associated with hypocalcemia.
Etiology Hypomagnesemia generally results from a derangement in renal or intestinal handling of magnesium and is classified as primary (hereditary) or secondary (acquired). Secondary causes are much more common, with renal losses being due to volume expansion, hypercalcemia, osmotic diuresis, loop diuretics, alcohol, aminoglycosides, cisplatin, cyclosporine, and amphotericin B, and gastrointestinal losses most commonly resulting from vomiting and diarrhea.
For mild deficiency, oral replacement is effective, though diarrhea may result. Parenteral magnesium administration (2 g of magnesium sulfate IV, with a cumulative dose of 6 g over 24 h) is usually needed for serum levels <1.2 mg/dL (1.0 meq/L). Patients with associated seizures or acute arrhythmias can be given 1–2 g of magnesium sulfate IV over 5–10 min.
Hypermagnesemia is rare but can be seen in renal failure when pts are taking magnesium-containing antacids, laxatives, enemas, or infusions, or in acute rhabdomyolysis. The most readily detectable clinical sign of hypermagnesemia is the disappearance of deep tendon reflexes, but paralysis of respiratory muscles, complete heart block, and cardiac arrest can occur. Treatment includes stopping the preparation, dialysis against a low magnesium bath, or, if associated with life-threatening complications, 100–200 mg of elemental calcium IV over 5–10 minutes.
For a more detailed discussion, see Holick MF, Krane SM: Introduction to Bone and Mineral Metabolism, Chap. 340, p. 2192; and Potts JT Jr: Diseases of the Parathyroid Gland and Other Hyper- and Hypocalcemic Disorders, Chap. 341, p. 2205, in HPIM-15.