INTRODUCTION — Hypercalcemia can be produced by a variety of disorders, but primary hyperparathyroidism and malignancy account for most cases (see "Etiology of hypercalcemia"). It may be associated with a spectrum of clinical manifestations (table 1), ranging from few (if any) symptoms if the hypercalcemia is mild and/or chronic to obtundation and coma if it is severe and/or acute [1]. The symptoms and signs associated with hypercalcemia are typically independent of the etiology [1].
This topic will review those symptoms directly associated with hypercalcemia. The clinical manifestations more directly associated with hyperparathyroidism and the diagnostic approach to and treatment of hypercalcemia are discussed separately. (See "Primary hyperparathyroidism: Clinical manifestations" and "Diagnostic approach to hypercalcemia" and "Treatment of hypercalcemia".)
GENERAL OVERVIEW — Patients with mild hypercalcemia (calcium above the upper limit of normal but <12 mg/dL [3 mmol/L]) may be asymptomatic, or they may report nonspecific symptoms, such as constipation, fatigue, and depression. A moderately elevated serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) may be well tolerated chronically, while an acute rise to these concentrations may cause marked symptoms, including polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, and changes in sensorium (table 1). In patients with severe hypercalcemia (calcium >14 mg/dL [3.5 mmol/L]), there is often progression of these symptoms [1,2].
NEUROPSYCHIATRIC DISTURBANCES — A number of mild neuropsychiatric disturbances have been associated with hypercalcemia, mostly in patients with primary hyperparathyroidism. The most common symptoms have been anxiety, depression, and cognitive dysfunction. Improvement in some or all of these symptoms has been described after correction of the hyperparathyroidism. (See "Primary hyperparathyroidism: Management", section on 'Neuropsychiatric' and "Primary hyperparathyroidism: Clinical manifestations", section on 'Symptomatic primary hyperparathyroidism'.)
More severe symptoms, including lethargy, confusion, stupor, and coma may occur in patients with severe hypercalcemia (calcium >14 mg/dL [3.5 mmol/L]) from any cause [1]. These symptoms are more likely to occur in older adults and in those with rapidly rising calcium concentrations [2,3].
GASTROINTESTINAL ABNORMALITIES — Gastrointestinal symptoms, such as constipation, anorexia, and nausea, occur commonly. Constipation may be related to decreased smooth muscle tone and/or abnormal autonomic function. Pancreatitis and peptic ulcer disease occur less frequently than other gastrointestinal symptoms [4-8]. Proposed mechanisms for the development of pancreatitis include deposition of calcium in the pancreatic duct and calcium activation of trypsinogen within the pancreatic parenchyma [8-10]. In rats, acute hypercalcemia causes a dose-dependent increase in serum amylase and morphologic characteristics of acute pancreatitis [9].
Peptic ulcer disease has been described in patients with hypercalcemia due to primary hyperparathyroidism [4] and may be caused by calcium-induced increases in gastrin secretion. In patients with multiple endocrine neoplasia type 1 (MEN1) with coexisting Zollinger-Ellison syndrome and hyperparathyroidism, parathyroidectomy alone has led to a significant reduction in serum gastrin concentrations and acid secretion [11].
RENAL DYSFUNCTION — The most important renal manifestations are polyuria (resulting from decreased concentrating ability in the distal tubule), nephrolithiasis, and acute and chronic renal insufficiency.
Nephrogenic diabetes insipidus — Chronic hypercalcemia leads to a defect in concentrating ability that may induce polyuria and polydipsia in up to 20 percent of patients. The mechanism is incompletely understood, but the downregulation of aquaporin-2 water channels and calcium deposition in the medulla with secondary tubulointerstitial injury and impaired generation of the interstitial osmotic gradient may play important roles. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hypercalcemia'.)
In addition, some studies have demonstrated that activation of the normal calcium-sensing receptor by increases in the plasma calcium concentration can directly impair concentrating ability by affecting both the loop of Henle and the collecting tubules. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia" and "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hypercalcemia'.)
The combination of polyuria and diminished fluid intake secondary to gastrointestinal symptoms (nausea) can lead to dehydration, which exacerbates hypercalcemia and related symptoms.
Nephrolithiasis — When hypercalcemia is due to primary hyperparathyroidism or sarcoidosis, it is often longstanding, and the resulting chronic hypercalciuria may cause nephrolithiasis. Increased calcitriol production may also play an important role in both diseases. The occurrence of nephrolithiasis in patients with these disorders is reviewed separately. (See "Kidney disease in sarcoidosis", section on 'Nephrolithiasis and nephrocalcinosis' and "Primary hyperparathyroidism: Clinical manifestations", section on 'Symptomatic primary hyperparathyroidism'.)
Renal tubular acidosis — Chronic hypercalcemia infrequently causes type 1 (distal) renal tubular acidosis [12]. The ensuing hypercalciuria and hypocitraturia can contribute to the development of nephrolithiasis. (See "Nephrolithiasis in renal tubular acidosis".)
Renal insufficiency — The development of renal insufficiency in individuals with hypercalcemia is related to the degree and duration of hypercalcemia.
●Mild hypercalcemia is rarely associated with renal insufficiency. In randomized trials of two to three years duration, there is little evidence that renal function deteriorates in patients with mild chronic hypercalcemia due to hyperparathyroidism. (See "Primary hyperparathyroidism: Management", section on 'Biochemical abnormalities'.)
●Higher elevations in the serum calcium concentration (serum calcium values of 12 to 15 mg/dL [3 to 3.75 mmol/L]) can lead to a reversible fall in glomerular filtration rate that is mediated by direct renal vasoconstriction and natriuresis-induced volume contraction [13,14].
●Longstanding hypercalcemia and hypercalciuria may lead to calcification, degeneration, and necrosis of the tubular cells and eventual tubular atrophy and interstitial fibrosis and calcification (nephrocalcinosis). Nephrocalcinosis, a condition observed in over one-half of hypercalcemic patients with renal insufficiency, is the most common cause of chronic kidney disease in sarcoidosis. In comparison, nephrocalcinosis appears to be uncommon in patients with primary hyperparathyroidism [15]. (See "Kidney disease in sarcoidosis", section on 'Epidemiology' and "Kidney disease in sarcoidosis", section on 'Nephrolithiasis and nephrocalcinosis' and "Nephrocalcinosis".)
CARDIOVASCULAR DISEASE — Acute hypercalcemia directly shortens the myocardial action potential, which is reflected in a shortened QT interval [16]. Although there does not appear to be any clinically important effect of moderate hypercalcemia on cardiac conduction or the prevalence of supraventricular or ventricular arrhythmias [17], arrhythmia has been described in patients with severe hypercalcemia [18,19]. In addition, ST segment elevation mimicking myocardial infarction has been reported in such patients [20-23].
Longstanding hypercalcemia, as occurs in primary hyperparathyroidism, can lead to other cardiac abnormalities, including deposition of calcium in heart valves, coronary arteries, and myocardial fibers; hypertension; and cardiomyopathy. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Cardiovascular'.)
MUSCULOSKELETAL SYMPTOMS — Profound muscle weakness was prominent in the original description of patients with hyperparathyroidism [24]. This is not the case in the majority of such patients today, but mild weakness (due in part to earlier diagnosis) may be apparent if looked for [25]. In one prospective study, for example, nine patients were tested for neuromuscular performance before and four weeks after parathyroid surgery [25]. All had an increase in muscle strength and improvement in fine motor movement, while there was no change in nonoperated patients. Weakness can be an important feature of other causes of hypercalcemia such as malignancy, but this can be a manifestation of the underlying illness rather than from hypercalcemia alone.
Bone pain can occur in individuals with hypercalcemia due to malignancy or primary hyperparathyroidism. A reduction in cortical bone mass may occur in individuals with hyperparathyroidism. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)
PHYSICAL FINDINGS — There are usually no specific physical findings of hypercalcemia other than those that might be related to an underlying disease, such as malignancy, and nonspecific findings related to dehydration. Band keratopathy, a reflection of subepithelial calcium phosphate deposits in the cornea, is a very rare finding [26]. It extends as a horizontal band across the cornea in the area that is exposed between the eyelids; calcium salts probably precipitate in that site because of the higher local pH induced by the evaporation of CO2. It is usually detected by slit-lamp examination.
SUMMARY AND RECOMMENDATIONS
●Hypercalcemia can affect a variety of organ systems (table 1). The symptoms of hypercalcemia depend upon both the degree of hypercalcemia and the rate of onset of the elevation in the serum calcium concentration. In addition, there is individual variation in the manifestation of symptoms. (See 'Introduction' above.)
●Patients with mildly elevated serum calcium concentrations (<12 mg/dL [3 mmol/L]) are often asymptomatic, particularly if the elevation in serum calcium is chronic. Patients with moderately elevated calcium (12 to 14 mg/dL) may have symptoms of polyuria, polydipsia, anorexia, nausea, and constipation. (See 'General overview' above.)
●As the calcium concentration increases, symptoms can become more severe and include weakness, difficulty concentrating, confusion, stupor, and coma. (See 'Neuropsychiatric disturbances' above.)
●The most common renal manifestation of hypercalcemia is polyuria, due to a defect in concentrating ability, leading to dehydration. Chronic hypercalcemia associated with hypercalciuria can lead to nephrolithiasis or nephrocalcinosis. (See 'Renal dysfunction' above.)
●Although uncommon, severe hypercalcemia can be associated with cardiac arrhythmia. Chronic hypercalcemia may lead to deposition of calcium in heart valves, coronary arteries, and myocardial fibers; hypertension; and cardiomyopathy. (See 'Cardiovascular disease' above.)
