A Practical Approach to Hypercalcemia - Drsarma

1 A Practical Approach to Hypercalcemia MARY F. CARROLL, , Eastern New Mexico Medical Center, Roswell, New Mexico DAVID S. SCHADE, , University of New Mexico School of Medicine and Health Sciences Center, Albuquerque, New Mexico Hypercalcemia is a disorder commonly encountered by primary care physicians. The diag- nosis often is made incidentally in asymptomatic patients. Clinical manifestations affect the neuromuscular, gastrointestinal, renal, skeletal, and cardiovascular systems. The most com- mon causes of Hypercalcemia are primary hyperparathyroidism and malignancy. Some other important causes of Hypercalcemia are medications and familial hypocalciuric hyper- calcemia. An initial diagnostic work-up should include measurement of intact parathyroid hormone, and any medications that are likely to be causative should be discontinued. Parathyroid hormone is suppressed in malignancy-associated Hypercalcemia and elevated in primary hyperparathyroidism.

2 It is essential to exclude other causes before considering parathyroid surgery, and patients should be referred for parathyroidectomy only if they meet certain criteria. Many patients with primary hyperparathyroidism have a benign course and do not need surgery. Hypercalcemic crisis is a life-threatening emergency. Aggressive intravenous rehydration is the mainstay of management in severe hypercal- cemia, and antiresorptive agents, such as calcitonin and bisphosphonates, frequently can alleviate the clinical manifestations of hypercalcemic disorders. (Am Fam Physician 2003;67:1959-66. Copyright 2003 American Academy of Family Physicians). H. ypercalcemia is a disorder other inorganic molecules. Low albumin lev- commonly encountered by els can affect the total serum calcium level. primary care physicians. Directly measuring the free calcium level is Approximately one in 500 more convenient and accurate, but the follow- patients who are treated in a ing formula can be used to calculate the cor- general medicine clinic have undiagnosed pri- rected total serum calcium level: mary hyperparathyroidism, the leading cause Corrected calcium = ( g per dL.)

3 Of The diagnosis of hyper- [plasma albumin]) + [serum calcium]. calcemia most often is made incidentally Parathyroid hormone (PTH), 1,25-dihy- when a high calcium level is detected in blood droxyvitamin D3 (calcitriol), and calcitonin samples. The principal challenges in the man- control calcium homeostasis in the body agement of Hypercalcemia are distinguishing (Table 1). Increased bone resorption, increased primary hyperparathyroidism from condi- gastrointestinal absorption of calcium, and tions that will not respond to parathyroidec- decreased renal excretion of calcium cause tomy and knowing when it is appropriate to Hypercalcemia . Normal serum calcium levels refer the patient for surgery. It is essential that are 8 to 10 mg per dL ( to mmol per L, physicians know how to evaluate and opti- Figure 1), although the exact range can vary mally manage patients with Hypercalcemia , among laboratories.

4 Normal ionized calcium because treatment and prognosis vary accord- levels are 4 to mg per dL (1 to mmol per ing to the underlying disorder. L). Hypercalcemia is considered mild if the total serum calcium level is between and Pathophysiology of Hypercalcemia 12 mg per dL ( and 3 mmol per L).5 Levels The skeleton contains 98 percent of total higher than 14 mg per dL ( mmol per L). body calcium; the remaining 2 percent circu- can be life threatening. lates throughout the body. One half of circu- PTH is an 84-amino acid hormone pro- See page 1853 for lating calcium is free (ionized) calcium, the duced by the four pea-sized parathyroid glands definitions of strength- only form that has physiologic effects. The posterior to the thyroid gland. In response to of-evidence levels. remainder is bound to albumin, globulin, and low serum calcium levels, PTH raises calcium MAY 1, 2003 / VOLUME 67, NUMBER 9 AMERICAN FAMILY PHYSICIAN 1959.

5 TABLE 1. Actions of the Hormones Involved in Calcium Homeostasis Hormone Effect on bones Effect on gut Effect on kidneys Parathyroid hormone Ca , ++. Supports osteoclast Indirect effects via Supports Ca++ resorption PO4 levels in blood resorption calcitriol from and PO4 excretion, activates 1-hydroxylation 1-hydroxylation Calcitriol (vitamin D) Ca++, No direct effects Ca++ and PO4 No direct effects PO4 levels in blood Supports osteoblasts absorption Calcitonin causes Ca++, PO4 Inhibits osteoclast No direct effects Promotes Ca++ and PO4. levels in blood when resorption excretion Hypercalcemia is present Ca++ = calcium; PO4 = phosphate radical. levels by accelerating osteoclastic bone resorp- the precursor cholecalciferol, first in the liver tion and increasing renal tubular resorption of (25-hydroxylation), then in the kidneys calcium. It also increases calcitriol, which indi- (1-hydroxylation).

6 Adequate vitamin D is nec- rectly raises serum calcium levels. PTH causes essary for bone formation. However, the prin- phosphate loss through the kidneys. Thus, in cipal target for vitamin D is the gut, where it patients with PTH-mediated Hypercalcemia , increases the absorption of calcium and phos- serum phosphate levels tend to be low. phate. Thus, in vitamin D-mediated hypercal- Vitamin D is a steroid hormone that is cemia, serum phosphate levels tend to be high. obtained through the diet or produced by the Calcitonin is a 32-amino acid hormone pro- action of sunlight on vitamin D precursors in duced by the parafollicular C cells of the thy- the skin. Calcitriol, the active form of vitamin roid. Calcitonin is a weak inhibitor of osteoclast D, is derived from successive hydroxylation of activation and opposes the effects of PTH on the kidneys, thereby promoting calcium and phosphate excretion.

7 Calcitonin levels might be Spectrum of Hypercalcemia elevated in pregnant patients and in patients with medullary carcinoma of the thyroid. Total serum calcium level, mg/dL (mmol/L) However, there are no direct clinical sequelae, 8 (2) 10 ( ) 12 (3) 14 ( ) 16 (4) and serum calcium levels usually are normal. PTH-related peptide (PTHrP) is the princi- pal mediator in Hypercalcemia associated with Hypercalcemic crisis solid PTHrP is homologous with PTH. at the amino terminus, the region that com- prises the receptor-binding domain. PTHrP. Moderate Hypercalcemia binds the PTH receptor and mimics the bio- logic effects of PTH on bones and the kidneys. Mild Hypercalcemia Clinical Manifestations of Hypercalcemia The optimal concentration of serum ionized calcium is essential for normal cellular func- Normocalcemia tion. Hypercalcemia leads to hyperpolariza- tion of cell membranes. Patients with levels of calcium between and 12 mg per dL can be 4 (1) ( ) 8 (2) 10 ( ) 12 (3).

8 When the serum calcium level Ionized serum calcium level, mg/dL (mmol/L) rises above this stage, multisystem manifesta- tions become apparent (Table 2). This constel- FIGURE 1. Spectrum of Hypercalcemia indicated by serum total and lation of symptoms has led to the mnemonic ionized calcium levels. Stones, bones, abdominal moans, and psychic 1960 AMERICAN FAMILY PHYSICIAN VOLUME 67, NUMBER 9 / MAY 1, 2003. TABLE 2. Clinical Manifestations of Hypercalcemia Renal stones Neuromuscular psychic groans . Nephrolithiasis Impaired concentration and memory Nephrogenic diabetes insipidus Confusion, stupor, coma Dehydration Lethargy and fatigue groans, which is used to recall the signs and Nephrocalcinosis Muscle weakness symptoms of Hypercalcemia , particularly as a Skeleton bones Corneal calcification (band result of primary hyperparathyroidism. Bone pain keratopathy). Neuromuscular effects include impaired Arthritis Cardiovascular concentration, confusion, corneal calcifica- Osteoporosis Hypertension tion, fatigue, and muscle Nausea, Osteitis fibrosa cystica in Shortened QT interval on abdominal pain, anorexia, constipation, and, hyperparathyroidism (subperiosteal electrocardiogram rarely, peptic ulcer disease or pancreatitis are resorption, bone cysts) Cardiac arrhythmias among the gastrointestinal manifestations.

9 Gastrointestinal abdominal Vascular calcification The most important renal effects are polydip- moans Other sia and polyuria resulting from nephrogenic Nausea, vomiting Itching diabetes insipidus, and nephrolithiasis result- Anorexia, weight loss Keratitis, conjunctivitis ing from hypercalciuria. Other renal effects Constipation include dehydration and nephrocalcinosis. Abdominal pain Cardiovascular effects include hypertension, Pancreatitis vascular calcification, and a shortened QT Peptic ulcer disease interval on the electrocardiogram. Cardiac arrhythmias are rare. Bone pain can occur in patients with hyperparathyroidism or malig- nancy. Osteoporosis of cortical bone, such as TABLE 3. the wrist, is mainly associated with primary Causes of Hypercalcemia Excess PTH also can result in subperiosteal resorption, leading to Parathyroid hormone-related Medications osteitis fibrosa cystica with bone cysts and Primary hyperparathyroidism* Thiazide diuretics (usually mild)*.

10 Brown tumors of the long bones. Sporadic, familial, associated with Lithium multiple endocrine neoplasia I or II Milk-alkali syndrome (from calcium Differential Diagnosis for Hypercalcemia antacids). Tertiary hyperparathyroidism Primary hyperparathyroidism and malig- Associated with chronic renal failure Vitamin A intoxication (including nancy account for more than 90 percent of or vitamin D deficiency analogs used to treat acne). Hypercalcemia cases. These conditions must be Vitamin D-related Other endocrine disorders differentiated early to provide the patient with Vitamin D intoxication Hyperthyroidism optimal treatment and accurate prognosis. Usually 25-hydroxyvitamin D2 in Adrenal insufficiency Humoral Hypercalcemia of malignancy implies over-the-counter supplements Acromegaly Granulomatous disease sarcoidosis, a very limited life expectancy often only a mat- Pheochromocytoma berylliosis, tuberculosis ter of weeks.