Approach to the Patient with Hypercalcemia

David M. Slovik

The advent of automated laboratory screening has led to an increased recognition of asymptomatic persons with hypercalcemia, with an estimated annual incidence of 51/100,000. In addition, outpatients with nonspecific complaints, such as fatigue, weakness, abdominal discomfort, or constipation, may have hypercalcemia discovered during biochemical testing. Mild hyperparathyroidism is usually the explanation for these often inadvertently recognized elevations in calcium levels. Hypercalcemia may also herald other important underlying diseases, such as malignancy or sarcoidosis. Asymptomatic hyperparathyroidism is not necessarily a benign condition. The effect of excessive levels of parathyroid hormone (PTH) for prolonged periods on target organs, such as bone and the kidney, may lead to skeletal loss and impaired renal function. Primary hyperparathyroidism and malignancy account for more than 90% of cases of hypercalcemia.

The primary physician must be able to interpret an abnormal calcium value and diagnose its cause. If primary hyperparathyroidism is present, one needs to know the basics of medical management and recognize when referral for consideration of surgical intervention is indicated. The treatment of hypercalcemia resulting from malignancy can improve quality of life and deserves consideration.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14)

The serum calcium concentration is maintained within narrow limits by PTH. Precise calcium homeostasis is necessary because of the vital role of calcium in membrane function, hormonal secretion and action, and neuromuscular function. The free or ionized portion of serum calcium is responsible for its physiologic actions. Slightly less than 50% of serum calcium is in the form of free calcium ions; the remainder is bound to plasma proteins, mostly albumin. Globulins can also bind serum calcium. Calcium binding by serum proteins is pH dependent. Increased binding at
alkaline pH explains the common symptom of paresthesias that occur in conjunction with hyperventilation. The normal range for serum calcium is generally 8.5 to 10.4 mg/dL, or 2.1 to 2.6 mmol/L, although this may vary slightly. The normal range for ionized serum calcium is 4.6 to 5.3 mg/dL or 1.1 to 1.3 mmol/L; this too may vary slightly. True hypercalcemia requires an increase in the ionized fraction of serum calcium. An increase in protein binding can cause an elevation in the serum total calcium concentration without an increase in the serum ionized calcium. Patients with hyperalbuminemia (e.g., due to severe dehydration) may have pseudohypercalcemia with an elevated total calcium but normal ionized calcium. A rough convenient correction factor to apply to the total serum calcium is the subtraction or addition of 0.8 mg/dL for the calcium concentration for every 1.0 g/dL of serum albumin greater or less than 4.0 g/dL, respectively.

Primary Hyperparathyroidism

In the ambulatory setting, primary hyperparathyroidism is the most common cause of hypercalcemia. It is caused by an increase in osteoclastic bone resorption, mediated by the binding of excess PTH to receptors on osteoblasts, in addition to an increase in gut calcium absorption. PTH also increases renal tubular reabsorption of calcium and decreases renal tubular phosphate reabsorption, which results in phosphate wasting. Pathologically, approximately 80% to 85% of patients are found to have a single parathyroid adenoma, whereas 15% to 20% have four-gland hyperplasia; the latter is more common in younger patients and is sometimes associated with the syndrome of multiple endocrine neoplasia (MEN). Parathyroid cancer accounts for less than 1% of all cases of hypercalcemia attributed to excess PTH secretion.

The incidence of hyperparathyroidism increases with age, peaking in the fifth and sixth decades of life, and hyperparathyroidism occurs more commonly in women than men by approximately a 2:1 ratio. It is not certain whether the increased recognition of the disease relates to multiphasic biochemical screening or the number of cases of the disease has increased, possibly as a result of head and neck irradiation in infancy or other environmental factors that affect parathyroid cell proliferation.

Hereditary hyperparathyroidism may be observed in familial settings, such as the autosomal dominant syndromes of MEN types 1 and 2. In MEN 1, parathyroid hyperplasia occurs in conjunction with adenomas of the pituitary and pancreas. In MEN 2, parathyroid hyperplasia may occur with medullary cancer of the thyroid and bilateral adrenal pheochromocytoma. Both MEN 1 and MEN 2 are associated with mutations in the RET protooncogene.

The clinical presentation ranges from the asymptomatic to the classic. The majority of patients with hyperparathyroidism do not have symptoms, and some do not even present with persistently elevated serum calcium. Normocalcemic hyperparathyroidism, characterized by normal serum calcium levels and elevated PTH levels, sometimes precedes onset of primary disease. If the serum calcium level fluctuates around the upper limit of normal, it is likely that the patient has or will develop frank primary hyperparathyroidism, although the time frame is unclear. Thiazide diuretics may unmask such early disease by transiently elevating serum calcium through reduction in urinary calcium excretion. More sustained elevations suggest mild underlying hyperparathyroidism.

The classic presentation of stones, bones, abdominal groans, and psychic moans has been replaced by a more subtle and nonspecific presentation. Fatigue, weakness, mild gastrointestinal symptoms (constipation, abdominal pain), changes in intellectual performance, and depression may all be manifestations of hypercalcemia or excessive PTH. Often, such nonspecific symptoms are recognized only after successful parathyroid surgery has been performed, when the patient describes an improved sense of well-being. With higher levels of serum calcium, more classic symptoms of polyuria, polydipsia, anorexia, nausea, muscle weakness, and changes in sensorium occur.

The complications resulting from the hypercalcemia of hyperparathyroidism include nephrogenic diabetes insipidus, characterized by a renal concentrating defect and increased urination. Hyperparathyroidism is also associated with an increase in calcium oxalate stones, particularly in patients with elevated levels of 1,25-dihydroxyvitamin D₃ and urinary calcium excretion in excess of 300 to 350 mg/24 hour. Chronic hypercalciuria can cause a type 1 (distal) renal tubular acidosis. With longer duration and a marked degree of hypercalcemia, renal insufficiency may ensue, although unlikely with mild hypercalcemia. As noted, bone pain and muscle weakness occur. Some of the bone pain may result from skeletal fracture and osteitis fibrosa cystica, although the latter is quite uncommon now. A possible but somewhat controversial increase in peptic ulcer disease and pancreatitis has been noted, as well as a spectrum of psychiatric disease. In persons with mild disease, survival appears to be unaffected.

Malignancy

Malignancy is the other major cause of hypercalcemia and the most common cause of hypercalcemia among hospitalized patients. Cancers of the breast, lung, and kidney lead the list of malignant causes, accounting for 50% to 60% of such cases. The incidence of hypercalcemia during the course of breast cancer ranges from 18% to 42%, and that in lung cancer ranges from 6% to 16%. Other malignancies associated with hypercalcemia include multiple myeloma (incidence of 30% to 100%), squamous cell carcinomas of the head and neck (2%), lymphoma and leukemia (1%), and genitourinary cancer (1%).

Several mechanisms for the hypercalcemia of malignancy have been identified, with a common theme being increased osteoclastic bone resorption. Such resorption and resultant hypercalcemia can occur with or without bony metastasis, and many tumors that commonly metastasize to bone do not cause hypercalcemia. Squamous cell cancers produce a parathyroid hormone-related protein, a PTH-like peptide with an aminoterminal structure similar to that of PTH and a nearly identical effect on mineral ion homeostasis. Myeloma cells produce interleukin-1β and interleukin-6, which stimulate osteoclastmediated bone resorption. In some patients with lymphoma and leukemia, an increase in 1,25-dihydroxyvitamin D₃ is implicated.

Hypercalcemia is rarely the sole presenting manifestation of an underlying malignancy. The presence of hypercalcemia in association with malignancy indicates a poor prognosis. Very high levels of serum calcium (>14 mg/dL) are most often associated with malignancy, but levels up to 20 mg/dL may be seen in acute primary hyperparathyroidism caused by large parathyroid adenomas.

Other Causes

Granulomatous Disease

In sarcoidosis, tuberculosis, and berylliosis, enhanced conversion of inactive vitamin D to its active 1,25-dihydroxy form by granulomatous tissue increases absorption of calcium from the gut and resorption of bone, raising serum calcium.

Vitamin D Intoxication

Hypercalcemia from vitamin D intoxication can result from ingesting very high doses of vitamin D, 25-hydroxyvitamin D, or 1,25-dihydroxyvitamin D. Hypercalcemia may occur when an excess of 10,000 U of vitamin D is consumed daily along with high doses of calcium supplements. There are reports of severe hypercalcemia in patients taking over-the-counter vitamins
or supplements that contain very high amounts of vitamin D. Levels of 25-hydroxy vitamin D above 150 mg/dL are considered in the toxic range. Increases in 1,25-dihydroxy vitamin D, the active form of vitamin D, can be seen with ingesting large amounts of this vitamin, extrarenal production in granulomatous tissue, and in primary hyperparathyroidism.

The Milk-Alkali Syndrome

The milk-alkali syndrome is the third highest cause of hypercalcemia because of the high intake of calcium carbonate preparations for osteoporosis treatment. High intakes, often greater than 3 to 4 g of calcium, can lead to hypercalcemia, metabolic alkalosis, and renal insufficiency.

Medications

Thiazide diuretics cause a transient, mild increase in serum calcium, generally within the normal range. As noted earlier, a sustained increase in serum calcium implies underlying metabolic bone disease, usually hyperparathyroidism. Mild hypercalcemia may be seen in the osteoporotic hypertensive patient on high-dose calcium along with high-dose vitamin D for osteoporosis and a thiazide diuretic for hypertension. Lithium can cause hypercalcemia by altering the calcium setpoint for PTH secretion, thus requiring higher concentrations of calcium to suppress PTH; it also reduces urinary calcium. Some patients have elevated PTH levels with the hypercalcemia. Stopping the lithium may allow the calcium and PTH to return to normal, but some have concomitant primary hyperparathyroidism; the longer the lithium treatment, the less likely these parameters will normalize. Theophylline excess can lead to hypercalcemia, as can high intake of vitamin A analogues for treatment of acne and vitamin A intoxication.

Hyperthyroidism

Hyperthyroidism is associated with mild elevations in serum calcium in approximately 15% to 20% of patients because of increased skeletal turnover.

Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia is an autosomal dominant disorder characterized by mild hypercalcemia, hypocalciuria, normal-to-elevated serum magnesium concentrations, and normal or slightly increased PTH levels. The primary defect is a loss-of-function mutation in the calcium-sensing receptor in the parathyroid glands and kidney, resulting in higher-than-normal serum calcium concentrations being needed to suppress PTH. Urinary calcium excretion is often less than 100 mg/24 hour and the calcium/creatine clearance less than 0.01. Parathyroid surgery does not cure this problem.

Uncommon Causes

Immobilization in young persons who have not completed skeletal growth and in patients with Paget disease may cause severe hypercalcemia due to a high-bone-turnover state. During the recovery phase of rhabdomyolysis, the serum calcium may rise. Addison disease is another uncommon cause of hypercalcemia.

DIFFERENTIAL DIAGNOSIS (TABLE 96-1)

Hyperparathyroidism accounts for most cases of hypercalcemia in the asymptomatic healthy-appearing patient, with primary disease found to be the cause in more than 60% and most likely when encountering hypercalcemia dating back several years. Malignancy, granulomatous disease, hyperthyroidism, Addison disease, and excess ingestion of vitamin D and calcium are the causes of most other cases. Occasionally, an underlying MEN syndrome or hypocalciuric hypercalcemia is present.

TABLE 96-1 Important Causes of Hypercalcemia

Hyperparathyroidism
	Primary (sporadic or familial due to MEN I or II)
	Tertiary due to chronic renal failure
Other Endocrine Conditions
	Hyperthyroidism
	Addison disease
	Acromegaly
	Pheochromocytoma
Dietary and Supplements
	Vitamin D intoxication
	Milk-alkali syndrome
	Vitamin A intoxication
Malignancy
	Due to local osteolysis (multiple myeloma, breast cancer)
	Due to production of PTH-related peptide: small-cell cancers of the lung; squamous-cell cancers of head and neck
	Hodgkin disease and lymphoma
Granulomatous Disease
	Sarcoidosis
	Berylliosis
	Tuberculosis
Medications
	Thiazides
	Lithium
	Theophylline
Other Conditions
	Familial hypocalciuric hypercalcemia
	Immobilization in setting of high bone turnover
	Recovery phase of rhabdomyolysis