ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Clinical manifestations of hypocalcemia

Clinical manifestations of hypocalcemia
Author:
David Goltzman, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Mar 12, 2021.

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 [1]. 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 [2].

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 [2].

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 [5]. 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 [5].

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 [9] 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 [10].

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 [24].

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 [27].

DISEASE-SPECIFIC MANIFESTATIONS

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 [28]. 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) [29]. 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'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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 clinical manifestations of hypocalcemia depend upon the severity and chronicity of hypocalcemia (table 1). (See 'Introduction' above.)

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'.)

  1. Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain 1991; 114 ( Pt 1B):527.
  2. Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993; 22:363.
  3. Navarro J, Oster JR, Gkonos PJ, et al. Tetany induced on separate occasions by administration of potassium and magnesium in a patient with hungry-bone syndrome. Miner Electrolyte Metab 1991; 17:340.
  4. Cohen L. Potassium replacement associated with the development of tetany in a patient with hypomagnesaemia. Magnes Res 1993; 6:43.
  5. Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298.
  6. Thakker RV. Hypocalcemia: Pathogenesis, differential diagnosis, and management. In: Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th ed, Favus MJ (Ed), American Society of Bone and Mineral Research, Washington, DC 2006. p.213.
  7. Armelisasso C, Vaccario ML, Pontecorvi A, Mazza S. Tonic-clonic seizures in a patient with primary hypoparathyroidism: a case report. Clin EEG Neurosci 2004; 35:97.
  8. Mrowka M, Knake S, Klinge H, et al. Hypocalcemic generalised seizures as a manifestation of iatrogenic hypoparathyroidism months to years after thyroid surgery. Epileptic Disord 2004; 6:85.
  9. Zuckermann EC, Glaser GH. Anticonvulsive action of increased calcium concentration in cerebrospinal fluid. Arch Neurol 1973; 29:245.
  10. Swash M, Rowan AJ. Electroencephalographic criteria of hypocalcemia and hypercalcemia. Arch Neurol 1972; 26:218.
  11. Denlinger JK, Nahrwold ML. Cardiac failure associated with hypocalcemia. Anesth Analg 1976; 55:34.
  12. Ghent S, Judson MA, Rosansky SJ. Refractory hypotension associated with hypocalcemia and renal disease. Am J Kidney Dis 1994; 23:430.
  13. Brunelli SM, Sibbel S, Do TP, et al. Facility Dialysate Calcium Practices and Clinical Outcomes Among Patients Receiving Hemodialysis: A Retrospective Observational Study. Am J Kidney Dis 2015; 66:655.
  14. Thurlow JS, Yuan CM. Dialysate-induced hypocalcemia presenting as acute intradialytic hypotension: A case report, safety review, and recommendations. Hemodial Int 2016; 20:E8.
  15. Shinoda T, Aizawa T, Shirota T, et al. Exacerbation of latent heart failure by mild hypocalcemia after parathyroidectomy in a long-term hemodialysis patient. Nephron 1992; 60:482.
  16. Kazmi AS, Wall BM. Reversible congestive heart failure related to profound hypocalcemia secondary to hypoparathyroidism. Am J Med Sci 2007; 333:226.
  17. Levine SN, Rheams CN. Hypocalcemic heart failure. Am J Med 1985; 78:1033.
  18. Wong CK, Lau CP, Cheng CH, et al. Hypocalcemic myocardial dysfunction: short- and long-term improvement with calcium replacement. Am Heart J 1990; 120:381.
  19. Kudoh C, Tanaka S, Marusaki S, et al. Hypocalcemic cardiomyopathy in a patient with idiopathic hypoparathyroidism. Intern Med 1992; 31:561.
  20. Brunvand L, Hågå P, Tangsrud SE, Haug E. Congestive heart failure caused by vitamin D deficiency? Acta Paediatr 1995; 84:106.
  21. Rimailho A, Bouchard P, Schaison G, et al. Improvement of hypocalcemic cardiomyopathy by correction of serum calcium level. Am Heart J 1985; 109:611.
  22. Benoit SR, Mendelsohn AB, Nourjah P, et al. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005; 12:363.
  23. Meyer T, Ruppert V, Karatolios K, Maisch B. Hereditary long QT syndrome due to autoimmune hypoparathyroidism in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. J Electrocardiol 2007; 40:504.
  24. Bajandas FJ, Smith JL. Optic nueritis in hypoparathyroidism. Neurology 1976; 26:451.
  25. Sheldon RS, Becker WJ, Hanley DA, Culver RL. Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association. Can J Neurol Sci 1987; 14:622.
  26. Hochman HI, Mejlszenkier JD. Cataracts and pseudotumor cerebri in an infant with vitamin D-deficiency rickets. J Pediatr 1977; 90:252.
  27. Lin KF, Chen KH, Huang WL. Organic anxiety in a woman with breast cancer receiving denosumab. Gen Hosp Psychiatry 2015; 37:192.e7.
  28. Tafaj O, Jüppner H. Pseudohypoparathyroidism: one gene, several syndromes. J Endocrinol Invest 2017; 40:347.
  29. Roszko KL, Bi RD, Mannstadt M. Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2. Front Physiol 2016; 7:458.
Topic 833 Version 18.0

References