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 Table 2), 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. 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.
Table 2. Symptom Prevalence Among Patients Treated for Hypercalcemia of Malignancy Stratified by Corrected Serum Total Calcium Concentrations at Presentationa
|Symptoms||Prevalence (%) by Serum Calcium Concentration|
|a Adapted from Ralston et al.|
| ||<3.5 mmol/L||≥3.5 mmol/L|
|Central nervous system symptoms||41||80|
|Nausea and/or vomiting||22||30|
|Polyuria and/or polydipsia||34||35|
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. Abnormal electroencephalograms are seen in patients with marked hypercalcemia.
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]