Table 383 Major Causes Of Hypocalcemia

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Normal or increased parathyroid function (renal failure, vitamin D deficiency) Protein-binding and anion-chelation of ionized ealeium Medications (anticalcemic and antineoplastic agents) Multifactorial (gram negative sepsis)

Modified from Spiegel AM: The parathyroid glands, hypercalcemia, and hvpocalcemia. In Bennett JC, Plum F (eds): Cecil Textbook ,of Medicine, 20th ed. Philadelphia, WB. Saunders, 1995, pp 1364-1373

. may be caused by PTH or 1,25-DHCC deficiency, as well as by end-organ resistance to their actions and other conditions (.,T§bJ.e,38i3 ). Ionized Ca is important for presynaptic neurotransmitter release and stabilization of nerve and muscle membranes (divalent cations stabilize the cell membranes of nerve and muscle). y Thus, it is not surprising that disturbances of ionized Ca result in neuromuscular manifestations.

Neurologically, both the PNS and CNS may be involved. Tetany, a PNS manifestation, is thought to be caused by repetitively generated nerve fiber action potentials, possibly related to the spontaneous depolarization of the nerve cell membrane in the setting of hypocalcemia. When the rate of sequential muscle fiber depolarization does not permit Ca reuptake by the sarcoplasmic reticulum, tetany occurs. The instability of the neuromuscular membranes may explain why the clinical features of hypocalcemia are positive in nature (e.g., perioral and acral paresthesias, and muscle spasms).

Epidemiology and Risk Factors. Except in neonates and patients with RF, hypocalcemia is relatively rare. The most likely cause of hypocalcemia among patients presenting to an emergency room is hypomagnesemia.y Risk factors include past thyroidectomy, neck trauma, a family history of hypocalcemia, malabsorption syndromes, antiepileptic drug usage, severe liver or kidney disease (decreased 1-alpha-hydroxylation of vitamin D), and pancreatitis. The incidence of postsurgical hypoparathyroidism (usually thyroidectomy) varies with the expertise of the surgeon. y The decrease in total serum Ca during pregnancy reflects dilutional hypoalbuminemia and, for that reason, the ionized Ca concentration is unchanged. y

Clinical Features and Associated Disorders. The clinical features of hypocalcemia are primarily neuromuscular, regardless of the underlying disorder, and are dependent on its rapidity of onset and magnitude. The earliest PNS symptoms include perioral and acral paresthesias, as well as tetany (tonic muscle spasms), the most characteristic and frequently recognized sign of hypocalcemia. y Tetany can be overt or latent, and provocative tests may be necessary to elicit latent tetany. Provocative tests include Chvostek's sign, the contraction of ipsilateral facial muscles in response to light percussion over the facial nerve (just anterior to the ear); and Trousseau's sign, carpal spasm in response to ischemia (e.g., 3-minute application of blood pressure cuff maintained just above systolic pressure). The carpal spasm produced is first preceded by acral paresthesias, followed by sensations of spasm, and then carpal spasm, paralleling the sequence of development of tetany.y Latent tetany may also become overt in the setting of alkalosis (e.g., hyperventilation or Na bicarbonate administration), a reflection of increased binding between ionized Ca and albumin. When tetany is severe, lower extremity and pedal spasms, as well as laryngeal stridor, may be observed. Opisthotonos may occur if spasms involve the trunk. A history of preceding muscle cramps, or generalized muscle aching, is frequently obtained.

CNS manifestations include irritability, delirium, delusions, hallucinations, depression, and dementia. When the onset of hypocalcemia is slow and insidious, dementia may be the initial manifestation. Seizures may occur and can be the presenting sign when hypocalcemia is severe. They are usually generalized but may be focal. y Intracerebral calcifications, seen most frequently with idiopathic hypoparathyroidism and pseudohypoparathyroidism, are usually asymptomatic. Although the basal ganglia are frequently affected, parkinsonism, athetosis, and chorea have been reported only rarely. y When the condition is persistent, cataract formation may occur. CHF and papilledema with increased ICP (idiopathic intracranial hypertension) are rarely observed. y

Differential Diagnosis. The etiologies of hypocalcemia are listed in T§.b.!e 3.8:3. . The most common cause of hypoparathyroidism is surgical (e.g., thyroidectomy) and is usually transient, becoming permanent in less than 3 percent of patients. Severe hypomagnesemia may cause hypocalcemia by inducing deficient PTH secretion and causing end-organ resistance to PTH. This explains why hypomagnesemia causes many of the same clinical manifestations as hypocalcemia.

Evaluation. Serum electrolyte, BUN, Cr, Ca (total and ionized), Mg, phosphorus, alkaline phosphatase, and albumin levels should be determined. An ABG identifies whether a hyperventilation syndrome is present. An EKG and continuous cardiac monitoring may be required. More specific tests for intestinal malabsorption may also be necessary. In osteomalacia or rickets, the serum alkaline phosphatase is elevated. CT imaging of the head may reveal intracranial calcifications, especially in the basal ganglia region. When hypocalcemia and hyperphosphatemia co-exist in the presence of normal renal function, the diagnosis of hypoparathyroidism is strongly suggested and the appropriate laboratory evaluation is required. Hypocalcemia coupled


Common causes

Malignancy, hyperparathyroidism, thiazide diureties

Less common causes

Familial hypocalciuric hypercalcemia

Vitamin D mediated

Calcium carbonate ingestion

Thyrotoxicosis and hypoadrenalism


Drugs (hypercalcemic agents, lithium, tamoxifen) Artifactual (elevated serum proteins)

Data from Olinger ML: Disorders of calcium and magnesium metabolism. Emerg Med Clin North Am 1989,7:795-822 Spiegel AM: The parathyroid glands, hypercalcemia, and hypocalcemia. In Bennett JC, Plum F (eds): Cecil Textbook of Medicine, 20th ed Philadelphia, WB. Saunders, 1995, pp 1364 1373; and Lipsky MS: Hyperealcemia. In Rakel F1E (ed): Saunders Manual of Medical Praetice, Philadelphia, XV,B, Saunders, l996, pp 663-664.

with a normal or low serum P level suggests vitamin D deficiency, malabsorption, or another cause of secondary hypoparathyroidism. Steatorrhea is frequently associated with hypomagnesemia and may serve as a clue to its presence.

Management. Acute, symptomatic hypocalcemia requires emergency treatment with IV Ca until symptoms resolve. Hypertension, bradycardia, cardiac conduction block, and digitalis toxicity may be precipitated if the infusion is provided too rapidly, and so monitoring is required. y Because this form of treatment lasts only a few hours, it must be repeated, or the patient be provided with a continuous infusion. In less urgent settings (e.g., postsurgical hypocalcemia), elemental Ca may be given as a continuous infusion over 4 to 10 hours and Ca monitored. In the setting of mild hypocalcemia, treatment with oral Ca replacement alone may suffice. Ca carbonate, up to 1200 mg orally three times daily, may safely be given. y Definitive resolution of hypocalcemia, however, requires identification and treatment of the underlying disease. For patients requiring long-term Ca supplementation, monitoring for evidence of toxicity is required (e.g., hypercalcemia, hypercalciuria).


Pathogenesis and Pathophysiology. Hypercalcemia occurs when serum Ca entry (from bone resorption and GI absorption) exceeds calciuresis. In the presence of normal serum proteins, hypercalcemia exists when the serum Ca concentration is above the normal range. However, physiological hypercalcemia is present only when the ionized Ca is above its normal range. The ionized Ca value can be calculated, based on the serum albumin level, or directly measured in most laboratories. In the setting of hypoalbuminemia, although the total serum Ca value may be normal, ionized Ca may be significantly elevated and require emergent treatment. In addition to serum protein binding, consideration of chelation (anions) and acid-base status is also important.

Epidemiology and Risk Factors. Approximately 40 percent of hypercalcemic patients develop neurological manifestations. y , '35' Nearly all patients with hypercalcemia have a malignancy or hyperparathyroidism, or are using thiazide diuretics (i.Ta.ble..,..3.8-4 ). Malignancies are most common among hospitalized patients, and hyperparathyroidism is common among ambulatory patients.y Malignancy-induced hypercalcemia occurs predominately in patients with bone metastases, such as lung (especially squamous cell), breast, ovarian, renal, hematological, head and neck, and GI cancers. '31! , y Through increased calciuresis, the majority of these patients do not develop hypercalcemia. However, in the setting of renal dysfunction, hypercalcemia is readily provoked. Disorders that result in prolonged immobilization (paralysis, coma, or trauma) can cause hypercalcemia, especially in patients undergoing bone remodeling (normal growth in a young patient, osteoporosis in the elderly, Paget's disease). Infrequently, humoral hypercalcemia of malignancy (i.e., PTH-related peptide excretion by the tumor) is observed.

Clinical Features and Associated Disorders. The presentations of hypercalcemia vary with the patient's age, underlying disorder, magnitude of hypercalcemia, albumin level, and rapidity of onset. Individuals with mild hypercalcemia are frequently asymptomatic (identified by routine blood testing), whereas those with severe hypercalcemia may present in coma and rapidly progress to death. General features may reflect the underlying disorder, such as weight loss and cachexia with malignancy, or abdominal pain with acute pancreatitis. Less specific features include dehydration, polyuria, polydipsia, nocturia, hypercalciuria, urolithiasis, nephrolithiasis, nephrocalcinosis, renal impairment, GI disorders (anorexia, constipation, ileus, nausea, vomiting), pruritus, hypertension, and soft tissue deposition.

Neurologically, CNS symptoms predominate and can include headache, fatigue, apathy, depression, agitation, insomnia, hallucinations, psychosis, confusion, lethargy, obtundation, coma, and, rarely, seizures. The mental status changes are directly related to the degree of hypercalcemia and are more frequent at Ca levels exceeding 14 mg/dl. All CNS signs are reversible with treatment. PNS manifestations reflect decreased neuromuscular excitability, and although they are common, these manifestations are nonspecific. Weakness is generally subjective with few objective signs. y

Differential Diagnosis and Evaluation. Before the realization that the observed clinical features reflect hypocalcemia, other etiologies must be considered. The particular cerebral manifestations, such as seizures and encephalopathic features, also dictate specific evaluation. The differential diagnoses of these central manifestations are lengthy and not addressed here (see Chapter.52 ). In the clinical setting of tetany, consideration should be given to disorders associated with cramping such as congenital myopathies and dystrophies (e.g., Duchenne's muscular dystrophy), cramp-myalgia syndrome (a dystrophinopathy), benign cramp syndrome (pseudotetanus), disorders producing contractures (e.g., McCardle's disease), and disorders producing continuous muscle activity (neuromyotonia).

The differential diagnosis of hypercalcemia is extensive. Frequently, the history, physical examination, initial laboratories, and routine radiographs identify the cause of hypercalcemia. A thorough examination may disclose features indicating the underlying disorder (e.g., breast mass, lymphadenopathy). Important laboratory evaluations include PTH, urine Ca, CBC, chemistries (ionized Ca, Mg, P), urinalysis, stool for occult blood, EKG, and chest x-ray study. Other considerations include tests of adrenal and thyroid function, serum and urinary immunoelectrophoresis (for myeloma), vitamin D metabolite levels, and immunoassay for PTH-related peptide. A bone scan may be required in some patients, including those with suspected multiple myeloma (e.g., abnormal serum protein electrophoresis, anemia, increased plasma cells on blood smear).

Management. Prevention of hypercalcemia in immobilized patients includes early mobilization and hydration, which increases calciuresis and dilutes the urine. High Ca containing dietary products should be avoided. Although the underlying cause is the most important consideration for definitive treatment, the initial management of hypercalcemia depends on its magnitude and symptoms and may need to be initiated without a specific diagnosis. The major treatment modalities act by decreasing bone resorption,

decreasing GI absorption, and increasing calciuresis. Mild hypercalcemia (< 11.5 mg/dl) may require only recognition of the underlying disorder, recommendations to increase fluid intake, and careful follow-up. Conversely, in the setting of severe hypercalcemia (> 15 mg/dl or severe clinical signs), urgent treatment is usually required and, in the setting of normal renal function, typically consists of volume replacement using IV normal saline, furosemide, and careful monitoring of therapy.

Prognosis and Future Perspectives. The prognosis for patients with hypercalcemia is related to the underlying disorder resulting in the hypercalcemia. Although cancer patients with hypercalcemia have a poor prognosis and usually die within a few months, hypercalcemic treatment usually improves their quality of life.

The opinions and assertions contained herein are the private views of the author, and are not to be construed as the official policy or position of the U. S. Government, the Department of Defense, or the Department of the Air Force.

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