Neurologic Symptoms
Cardiovascular Symptoms
Gastrointestinal Symptoms
Renal Symptoms
Bone Symptoms

There is little correlation between the presenting symptoms of hypercalcemia and serum calcium concentrations. Rapid diagnosis of hypercalcemia may be complicated because symptoms associated with hypercalcemia are characteristically nonspecific and are easily attributed to chronic or terminal illness.[1,2] Symptom severity may be caused in part by confounding factors such as previous cancer treatment, drug disease-state interactions, or comorbid pathologies.

Few patients experience all the symptoms that have been associated with hypercalcemia (see the table on Symptom Prevalence Among Patients Treated for Hypercalcemia of Malignancy Stratified by Corrected Serum Total Calcium Concentrations at Presentation ¹, below), and some patients may not experience any symptoms. Patients with corrected total serum calcium concentrations higher than 14 mg/dL (>7.0 mEq/L or 3.49 mmol/L) are generally symptomatic.[1] It must be emphasized that clinical manifestations are closely related to the rapidity of hypercalcemia onset. Some patients develop signs and symptoms when calcium is only slightly elevated, while others with long-standing hypercalcemia may tolerate serum calcium levels higher than 13 mg/dL (>6.5 mEq/L or 3.24 mmol/L) with few symptoms. Neuromuscular manifestations are generally more marked in older patients than in young patients.

One author observed that malaise and fatigue were the most common complaints at patient presentation, followed by (in order of decreasing prevalence rate) varying degrees of obtundation, anorexia, pain, polyuria-polydipsia, constipation, nausea, and vomiting.[3]

Clinical manifestations can be categorized according to body systems and functions.

Calcium ions have a major role in neurotransmission. Increased calcium levels decrease neuromuscular excitability, which leads to hypotonicity in smooth and striated muscle. Symptom severity correlates directly with the magnitude of serum-ionized calcium concentrations and inversely with their rate of change. Neuromuscular symptoms include weakness and diminished deep-tendon reflexes. Muscle strength is impaired, and respiratory muscular capacity may be decreased. Central nervous system impairment may manifest as delirium with prominent symptoms of personality change, cognitive dysfunction, disorientation, incoherent speech, and psychotic symptoms such as hallucinations and delusions. Obtundation is progressive as serum calcium concentrations increase and may progress to stupor or coma.[1,2] Local neurologic signs are not common, but hypercalcemia has been documented to increase cerebrospinal fluid protein, which may be associated with headache. Headache can be exacerbated by vomiting and dehydration.[2] Abnormal electroencephalograms are seen in patients with marked hypercalcemia.[1]

Hypercalcemia is associated with increased myocardial contractility and irritability. Electrocardiographic changes are characterized by slowed conduction, including prolonged P-R interval, widened QRS complex, shortened Q-T interval, shortened or absent S-T segments, and possibly abrupt sloping and early peaking of the proximal limb of T waves. Hypercalcemia enhances patients’ sensitivity to the pharmacologic effects of digitalis glycosides (e.g., digoxin). When serum calcium concentrations exceed 16 mg/dL (>8.0 mEq/L or 3.99 mmol/L), T waves widen, secondarily increasing the Q-T interval. As calcium concentrations increase, bradyarrhythmias and bundle branch block may develop. Incomplete or complete atrioventricular block may develop at serum concentrations around 18 mg/dL (9.0 mEq/L or 4.49 mmol/L) and may progress to complete heart block, asystole, and cardiac arrest.[1,2]

Gastrointestinal symptoms are probably related to the depressive action of hypercalcemia on the autonomic nervous system and resulting smooth-muscle hypotonicity. Increased gastric acid secretion often accompanies hypercalcemia and may intensify gastrointestinal manifestations. Anorexia, nausea, and vomiting are intensified by increased gastric residual volume. Constipation is aggravated by dehydration that accompanies hypercalcemia. Abdominal pain may progress to obstipation and can be confused with acute abdominal obstruction.

Hypercalcemia causes a reversible tubular defect in the kidney, resulting in the loss of urinary concentrating ability and polyuria. Decreased fluid intake and polyuria lead to symptoms associated with dehydration, including thirst, dry mucosa, diminished or absent sweating, poor skin turgor, and concentrated urine. Decreased proximal reabsorption of sodium, magnesium, and potassium occur as a result of salt and water depletion that is caused by cellular dehydration and hypotension. Renal insufficiency may occur as a result of diminished glomerular filtration, a complication observed most often in patients with myeloma.

Although nephrolithiasis and nephrocalcinosis are usually not associated with hypercalcemia of malignancy, calcium phosphate crystals can precipitate within renal tubules to form renal calculi as a consequence of long-standing hypercalciuria. When they occur, coexisting primary hyperparathyroidism should be considered.

Hypercalcemia of malignancy can result from osteolytic metastases or humerally mediated bone resorption with secondary fractures, skeletal deformities, and pain.

References

1. Bajorunas DR: Clinical manifestations of cancer-related hypercalcemia. Semin Oncol 17 (2 Suppl 5): 16-25, 1990.  [PUBMED Abstract]
   
   
2. Mahon SM: Signs and symptoms associated with malignancy-induced hypercalcemia. Cancer Nurs 12 (3): 153-60, 1989.  [PUBMED Abstract]
   
   
3. Ralston SH, Gallacher SJ, Patel U, et al.: Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med 112 (7): 499-504, 1990.  [PUBMED Abstract]