INTRODUCTION — Hypocalcemia may be associated with a spectrum of clinical manifestations (table 1), ranging from few (if any) symptoms if the hypocalcemia is mild to life-threatening seizures, refractory heart failure, or laryngospasm if it is severe. In addition to severity, the rate of development of hypocalcemia and chronicity determine the clinical manifestations.
Among the symptoms of hypocalcemia, tetany, papilledema, and seizures may occur in patients who develop hypocalcemia acutely. By comparison, ectodermal and dental changes, cataracts, basal ganglia calcification, and extrapyramidal disorders are features of chronic hypocalcemia. These last findings are most common in patients with hypoparathyroidism.
The clinical manifestations of hypocalcemia are discussed here. The etiology of, diagnostic approach to, and treatment of hypocalcemia are discussed separately. (See "Etiology of hypocalcemia in adults" and "Diagnostic approach to hypocalcemia" and "Treatment of hypocalcemia" and "Hypoparathyroidism".)
ACUTE MANIFESTATIONS — The hallmark of acute hypocalcemia is tetany, which is characterized by neuromuscular irritability. The symptoms of tetany may be mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) or severe (carpopedal spasm, laryngospasm, and focal or generalized seizures, which must be distinguished from the generalized tonic muscle contractions that occur in severe tetany) (table 1). Other patients have less specific symptoms, such as fatigue, hyperirritability, anxiety, and depression, and some patients, even with severe hypocalcemia, have no neuromuscular symptoms.
Tetany — Acute hypocalcemia directly increases peripheral neuromuscular irritability . As measured electromyographically, tetany consists of repetitive, high-frequency discharges after a single stimulus. Hyperexcitability of peripheral neurons is probably the most important pathophysiologic effect of hypocalcemia, but hyperexcitability occurs at all levels of the nervous system, including motor endplates, the spinal reflexes, and the central nervous system.
Tetany is uncommon unless the serum ionized calcium concentration falls below 4.3 mg/dL (1.1 mmol/L), which usually corresponds to a serum total calcium concentration of 7.0 to 7.5 mg/dL (1.8 to 1.9 mmol/L). Patients in whom the onset of hypocalcemia is gradual tend to have fewer symptoms at the same serum calcium concentration .
Other factors that determine the variation in frequency and severity of symptoms include acid-base status, hypomagnesemia, and potassium balance [3,4]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)
Hypocalcemia and alkalosis act synergistically to cause tetany. Although alkalosis can directly reduce serum ionized calcium, the ability of alkalosis to enhance tetany is only partly due to this effect since the decrease is relatively small. Respiratory alkalosis alone (eg, hyperventilation) can cause tetany, even in the absence of underlying hypocalcemia. By contrast, tetany is unusual among patients with chronic renal failure and hypocalcemia (occasionally severe) because of the protective effect of concurrent metabolic acidosis.
Tetany is manifested clinically by both sensory and muscular dysfunction .
●Symptoms typically begin with perioral and acral paresthesias. These symptoms can cause hyperventilation, leading to respiratory alkalosis and an elevation in arterial pH, which in turn exacerbate the paresthesias.
●The motor symptoms of tetany include stiffness and clumsiness, myalgia, and muscle spasms and cramps. In the hands, the result is forced adduction of the thumb, flexion of the metacarpophalangeal joints and wrists, and extension of the fingers (carpal spasm). Spasm of the respiratory muscles and of the glottis (laryngismus stridulus) can cause cyanosis.
●Autonomic manifestations include diaphoresis, bronchospasm, and biliary colic.
The classic physical findings in patients with neuromuscular irritability due to latent tetany are Trousseau's and Chvostek's signs.
Trousseau's sign — Trousseau's sign is the induction of carpal spasm by inflation of a sphygmomanometer above systolic blood pressure for three minutes [5,6]. Carpal spasm, as indicated above, is characterized by adduction of the thumb, flexion of the metacarpophalangeal joints, extension of the interphalangeal joints, and flexion of the wrist (figure 1). It may also be induced by voluntary hyperventilation for one to two minutes after release of the cuff.
Trousseau's sign depends upon the effect of ischemia to increase excitability of the nerve trunk under the cuff, rather than at the motor endplate; excitability is maximal at three minutes and returns to normal even if ischemia is maintained for a longer period.
Chvostek's sign — Chvostek's sign is contraction of the ipsilateral facial muscles elicited by tapping the facial nerve just anterior to the ear . The response ranges from twitching of the lip to spasm of all facial muscles and depends upon the severity of the hypocalcemia (figure 2). Chvostek's sign occurs in approximately 10 percent of normal subjects [5,6].
Although Trousseau's sign is more specific than Chvostek's sign, both may be negative in patients with hypocalcemia .
Seizures — Generalized tonic-clonic, generalized absence, and focal seizures can occur in hypocalcemia and may be the sole presenting symptom [2,7,8]. The presence of seizures without tetany in patients with hypocalcemia may be explained by the observation that low cerebrospinal fluid ionized calcium concentrations may have a convulsive  but not a direct tetanic effect. In patients with seizures caused by hypocalcemia, the electroencephalogram (EEG) shows both spikes ("convulsive effect") and bursts of high-voltage, paroxysmal slow waves .
Cardiovascular — Hypotension may complicate acute hypocalcemia, particularly when rapidly induced by ethylenediaminetetraacetic acid (EDTA), transfusion of citrated blood, or with use of low calcium dialysate in patients undergoing renal replacement therapy [11-14]. In addition, decreased myocardial performance and even congestive heart failure (with or without hypotension) have been reported [15-20]. Myocardial dysfunction is reversible with calcium repletion [18,21]. Although the mechanism is undefined, calcium plays a critical role in excitation-contraction coupling and is required for epinephrine-induced glycogenolysis in the heart. (See "Excitation-contraction coupling in myocardium".)
Hypocalcemia characteristically causes prolongation of the QT interval in the electrocardiogram (waveform 1) [22,23]. Hypocalcemia prolongs phase 2 of the action potential with the impact modulated by the rate of change of serum calcium concentration and function of the myocyte calcium channels. Prolongation of the QT interval is associated with early after-depolarizations and triggered dysrhythmias. Torsades de pointes (polymorphic ventricular tachycardia associated with a prolonged QT interval) can potentially be triggered by hypocalcemia but is much less common than with hypokalemia or hypomagnesemia. Although electrocardiographic conduction abnormalities are common, serious hypocalcemia-induced dysrhythmias, such as heart block and ventricular dysrhythmias, are infrequent.
Papilledema — Papilledema can occur in patients with hypocalcemia of any cause [24-26]. It occurs only when hypocalcemia is severe, and it usually improves with reversal of hypocalcemia. It may or may not be accompanied by high cerebrospinal fluid pressure (benign intracranial hypertension). Rarely, optic neuritis (distinguished by decreased visual acuity) rather than papilledema is present .
Psychiatric manifestations — Hypocalcemia can cause psychological symptoms, particularly emotional instability, anxiety, and depression. Less common are confusional states, hallucinations, and frank psychosis. All are reversible with treatment .
Hypoparathyroidism — Although the signs and symptoms of acute hypocalcemia are similar regardless of the etiology, there are several clinical manifestations that are unique to chronic hypoparathyroidism. These include basal ganglia calcifications, cataracts, dental abnormalities, and ectodermal manifestations (table 1). These clinical features are reviewed in more detail separately. (See "Hypoparathyroidism", section on 'Chronic manifestations'.)
Pseudohypoparathyroidism — Pseudohypoparathyroidism (PHP) refers to a group of heterogeneous disorders defined by renal unresponsiveness to parathyroid hormone (PTH) and characterized biochemically by hypocalcemia, hyperphosphatemia, and elevated PTH concentrations. There are several subtypes of PHP, based upon genetic and clinical characteristics . Some variants of PHP are associated with skeletal abnormalities, intellectual impairment, and resistance to other hormones. PHP is discussed in detail elsewhere. (See "Etiology of hypocalcemia in infants and children", section on 'End-organ resistance to PTH (pseudohypoparathyroidism)'.)
Vitamin D deficiency — Vitamin D deficiency or resistance can cause hypocalcemia and, if severe, lead to rickets and osteomalacia. In addition to the classic radiographic signs of vitamin D deficiency rickets, children may have muscle weakness and hypotonia, motor retardation, and stunted growth. Children with vitamin D receptor mutations may also have alopecia, multiple milia, epidermal cysts, and oligodontia. (See "Causes of vitamin D deficiency and resistance", section on 'Vitamin D resistance' and "Overview of rickets in children", section on 'Clinical manifestations'.)
Osteomalacia may be asymptomatic and present radiologically as osteopenia. It can also produce characteristic symptoms including diffuse bone pain and tenderness and muscle weakness. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Clinical features'.)
Autosomal dominant hypocalcemia — Autosomal dominant hypocalcemia (ADH) is caused by an activating mutation of the calcium-sensing receptor (CaSR) gene (ADH type 1) or by gain-of-function mutations of G-alpha-11, a key mediator of CASR signaling (ADH type 2) . In ADH1 and ADH2, there is a downward resetting of the PTH-calcium relationship, such that PTH is not released at serum calcium concentrations that normally trigger PTH release, thereby causing hypocalcemia with low or inappropriately normal PTH levels. The majority of patients with ADH are asymptomatic and, therefore, are not diagnosed until adulthood, when hypocalcemia is incidentally noted. A few patients, however, have symptomatic hypocalcemia. The major clinical clue to this syndrome is its familial nature and the tendency of patients to develop renal complications during treatment with calcium and vitamin D supplementation.
Some patients also have potassium wasting, hypokalemia, and metabolic alkalosis, creating a phenotype similar to Bartter syndrome. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Autosomal dominant hypocalcemia'.)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hypoparathyroidism (The Basics)")
SUMMARY AND RECOMMENDATIONS
●The symptoms of acute hypocalcemia are characterized by neuromuscular irritability or tetany. Symptoms range from mild paresthesias to carpopedal spasm to seizures (figure 1 and figure 2). (See 'Acute manifestations' above.)
●Chronic hypocalcemia from hypoparathyroidism may be associated with cataract formation, ectopic calcification (basal ganglia), and occasionally parkinsonism and dementia. (See "Hypoparathyroidism", section on 'Clinical features'.)
●Pseudohypoparathyroidism (PHP) refers to a group of heterogeneous disorders defined by renal unresponsiveness to parathyroid hormone (PTH) and characterized biochemically by hypocalcemia and hyperphosphatemia with elevated PTH concentrations. Some variants of PHP are associated with skeletal abnormalities, intellectual impairment, and resistance to other hormones. (See "Etiology of hypocalcemia in infants and children", section on 'End-organ resistance to PTH (pseudohypoparathyroidism)'.)
●Vitamin D deficiency or resistance can cause hypocalcemia and, if severe, rickets and osteomalacia. In addition to the classic radiographic signs of vitamin D deficiency rickets, children with rickets may have muscle weakness and hypotonia, motor retardation, and stunted growth. Osteomalacia may be asymptomatic and present radiologically as osteopenia. It can also produce characteristic symptoms including diffuse bone pain and tenderness and muscle weakness. (See "Overview of rickets in children", section on 'Clinical manifestations' and "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Clinical features'.)
●Autosomal dominant hypocalcemia (ADH) is caused by an activating mutation of the calcium-sensing receptor (CaSR) gene or a gain-of-function mutation in an important molecule in the CASR signaling pathway. The majority of patients with ADH are asymptomatic and, therefore, are not diagnosed until adulthood, when hypocalcemia is incidentally noted. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Autosomal dominant hypocalcemia'.)