A practical approach to hypercalcemia

Author: Mary F. Carrol, David S. Schade
Date: May 1, 2003

Hypercalcemia is a disorder commonly encountered by primary care physicians. Approximately one in 500 patients who are treated in a general medicine clinic have undiagnosed primary hyperparathyroidism, the leading cause of hypercalcemia. (1-4) The diagnosis of hypercalcemia most often is made incidentally when a high calcium level is detected in blood samples. The principal challenges in the management of hypercalcemia are distinguishing primary hyperparathyroidism from conditions that will not respond to parathyroidectomy and knowing when it is appropriate to refer the patient for surgery. It is essential that physicians know how to evaluate and optimally manage patients with hypercalcemia, because treatment and prognosis vary according to the underlying disorder.

Pathophysiology of Hypercalcemia

The skeleton contains 98 percent of total body calcium; the remaining 2 percent circulates throughout the body. One half of circulating calcium is free (ionized) calcium, the only form that has physiologic effects. The remainder is bound to albumin, globulin, and other inorganic molecules. Low albumin levels can affect the total serum calcium level. Directly measuring the free calcium level is more convenient and accurate, but the following formula can be used to calculate the corrected total serum calcium level:

Corrected calcium = (4.0 g per dL--[plasma albumin]) 3 0.8 + [serum calcium]

Parathyroid hormone (PTH), 1,25-dihydroxyvitamin [D.sub.3] (calcitriol), and calcitonin control calcium homeostasis in the body (Table 1). Increased bone resorption, increased gastrointestinal absorption of calcium, and decreased renal excretion of calcium cause hypercalcemia. Normal serum calcium levels are 8 to 10 mg per dL (2.0 to 2.5 mmol per L, Figure 1), although the exact range can vary among laboratories. Normal ionized calcium levels are 4 to 5.6 mg per dL (1 to 1.4 mmol per L). Hypercalcemia is considered mild if the total serum calcium level is between 10.5 and 12 mg per dL (2.63 and 3 mmol per L). (5) Levels higher than 14 mg per dL (3.5 mmol per L) can be life threatening.

[FIGURE 1 OMITTED]

PTH is an 84-amino acid hormone produced by the four pea-sized parathyroid glands posterior to the thyroid gland. In response to low serum calcium levels, PTH raises calcium levels by accelerating osteoclastic bone resorption and increasing renal tubular resorption of calcium. It also increases calcitriol, which indirectly raises serum calcium levels. PTH causes phosphate loss through the kidneys. Thus, in patients with PTH-mediated hypercalcemia, serum phosphate levels tend to be low.

Vitamin D is a steroid hormone that is obtained through the diet or produced by the action of sunlight on vitamin D precursors in the skin. Calcitriol, the active form of vitamin D, is derived from successive hydroxylation of the precursor cholecalciferol, first in the liver (25-hydroxylation), then in the kidneys (1-hydroxylation). Adequate vitamin D is necessary for bone formation. However, the principal target for vitamin D is the gut, where it increases the absorption of calcium and phosphate. Thus, in vitamin D-mediated hypercalcemia, serum phosphate levels tend to be high.

Calcitonin is a 32-amino acid hormone produced by the parafollicular C cells of the thyroid. Calcitonin is a weak inhibitor of osteoclast activation and opposes the effects of PTH on the kidneys, thereby promoting calcium and phosphate excretion. Calcitonin levels might be elevated in pregnant patients and in patients with medullary carcinoma of the thyroid. However, there are no direct clinical sequelae, and serum calcium levels usually are normal.

PTH-related peptide (PTHrP) is the principal mediator in hypercalcemia associated with solid tumors. (6) PTHrP is homologous with PTH at the amino terminus, the region that comprises the receptor-binding domain. PTHrP binds the PTH receptor and mimics the biologic effects of PTH on bones and the kidneys.

Clinical Manifestations of Hypercalcemia

The optimal concentration of serum ionized calcium is essential for normal cellular function. Hypercalcemia leads to hyperpolarization of cell membranes. Patients with levels of calcium between 10.5 and 12 mg per dL can be asymptomatic. (7) When the serum calcium level rises above this stage, multisystem manifestations become apparent (Table 2). This constellation of symptoms has led to the mnemonic "Stones, bones, abdominal moans, and psychic groans," which is used to recall the signs and symptoms of hypercalcemia, particularly as a result of primary hyperparathyroidism.

Neuromuscular effects include impaired concentration, confusion, corneal calcification, fatigue, and muscle weakness. (8) Nausea, abdominal pain, anorexia, constipation, and, rarely, peptic ulcer disease or pancreatitis are among the gastrointestinal manifestations. The most important renal effects are polydipsia and polyuria resulting from nephrogenic diabetes insipidus, and nephrolithiasis resulting from hypercalciuria. Other renal effects include dehydration and nephrocalcinosis. Cardiovascular effects include hypertension, vascular calcification, and a shortened QT interval on the electrocardiogram. Cardiac arrhythmias are rare. Bone pain can occur in patients with hyperparathyroidism or malignancy. Osteoporosis of cortical bone, such as the wrist, is mainly associated with primary hyperparathyroidism. (9) Excess PTH also can result in subperiosteal resorption, leading to osteitis fibrosa cystica with bone cysts and brown tumors of the long bones.

Differential Diagnosis for Hypercalcemia

Primary hyperparathyroidism and malignancy account for more than 90 percent of hypercalcemia cases. These conditions must be differentiated early to provide the patient with optimal treatment and accurate prognosis. Humoral hypercalcemia of malignancy implies a very limited life expectancy--often only a matter of weeks. On the other hand, primary hyperparathyroidism has a relatively benign course.

The causes of hypercalcemia can be divided into seven categories: hyperparathyroidism, vitamin D-related causes, malignancy, medications, other endocrine disorders, genetic disorders, and miscellaneous causes (Table 3). Evaluation of a patient with hypercalcemia (Figure 2) should include a careful history and physical examination focusing on clinical manifestations of hypercalcemia, risk factors for malignancy, causative medications, and a family history of hypercalcemia-associated conditions (e.g., kidney stones).

[FIGURE 2 OMITTED]

HYPERPARATHYROIDISM

Increased screening of calcium levels and wide availability of reliable assays for intact PTH levels have led to more frequent and earlier diagnoses of primary hyperparathyroidism. In 80 percent of cases, a single parathyroid adenoma is responsible. However, hyperparathyroidism also can result from hyperplasia of the parathyroid glands or, rarely, parathyroid carcinoma. In primary or tertiary hyperparathyroidism, PTH levels are normal or high in the setting of hypercalcemia (Figure 3).

[FIGURE 3 OMITTED]

In many patients, primary hyperparathyroidism progresses very slowly. Patients should be considered for parathyroidectomy only if they meet criteria recommended by the National Institutes of Health Consensus Development Conference (Table 4). (10) [Evidence level C, consensus opinion] The disease will progress in approximately one fourth of patients who do not undergo surgery. (11) Preoperative nuclear imaging of the parathyroids with a sestamibi scan (Figure 4) allows the surgeon to perform unilateral neck dissection, which results in reduced operative time and less morbidity. (12) Risks of parathyroid surgery include permanent hypoparathyroidism and damage to the recurrent laryngeal nerve.

[FIGURE 4 OMITTED]

Chronic renal failure generally causes hypocalcemia. If untreated, prolonged high phosphate and low vitamin D levels can lead to increased PTH secretion and subsequent hypercalcemia. This is termed tertiary hyperparathyroidism.

VITAMIN D-MEDIATED CAUSES

The most commonly available vitamin D supplements consist of 25-hydroxyvitamin [D.sub.2]. In suspected overdose of over- the-counter vitamin D, the level of 25-hydroxyvitamin [D.sub.3] (not 1,25-dihydroxyvitamin [D.sub.3]) should be measured. Macrophages can cause granuloma-forming (i.e., sarcoidosis, tuberculosis, Hodgkin's lymphoma) increased extra-renal conversion of 25-hydroxyvitamin [D.sub.3] to calcitriol. PTH levels are suppressed, and levels of 1,25-dihydroxyvitamin [D.sub.3] are elevated. Hypercalcemia mediated by excessive vitamin D responds to a short course of glucocorticoids if the underlying disease is treated.

HYPERCALCEMIA OF MALIGNANCY

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

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MARY F. CARROLL, M.D., is director of endocrinology and metabolism at Eastern New Mexico Medical Center, Roswell. She graduated from Trinity College in Dublin, Ireland, and completed a residency in internal medicine and a fellowship in endocrinology and metabolism at the University of New Mexico School of Medicine in Albuquerque.

DAVID S. SCHADE, M.D., is professor of medicine and chief of endocrinology and metabolism at the University of New Mexico School of Medicine and Health Sciences Center. He graduated from Washington University School of Medicine in St. Louis and completed a residency in internal medicine and a fellowship in endocrinology and metabolism at the University of New Mexico School of Medicine.

Address correspondence to David S. Schade, M.D., University of New Mexico Health Sciences Center, Department of Internal Medicine/5-ACC, Division of Endocrinology, 2211 Lomas Blvd. NE, Albuquerque, NM 87131 (dschade@salud.unm.edu). Reprints are not available from the authors.

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