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Asymptomatic Hypercalcemia in a 51-Year-Old Woman

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Asymptomatic Hypercalcemia in a 51-Year-Old Woman IM BOARD REVIEW DAVID L. LONGWORTH, MD, JAMES K STOLLER, MD, EDITORS A SELF-TEST OF CLINICAL WIAM I. HUSSEIN, MD ANGELO A. LICATA, MD, PHD Department of Endocrinology, Cleveland Clinic Head, Calcium and Metabolie Bone RECOGNITION Osteoporosis Section, Department of Endocrinology, Cleveland Clinic Asymptomatic hypercalcemia in a 51 -yearmold woman 51 -"YEAR-OLD white woman has a serum TABLE 1 calcium level of 11.6 mg/dL (normal Laboratory studies on admission range: 8.5-10.5) on a routine blood chemistry test; TABLE 1 shows her other laboratory values. STUDY RESULT NORMAL RANGE She had normal calcium levels 2 years ago, when she suffered a kidney stone. Total calcium 11.6 mg/dL (8.5-10.5) The patient says she experiences arthral- Total protein 6.5 g/dL (6.0-8.4) gia, which she attributes to aging, but she denies having fractures, constipation, Albumin 4.3 g/dL (3.5-5.0) polyuria, or weakness. No one in her family has ever had hypercalcemia or kidiiey stones. Phosphorus 1.8 mg/dL (2.5-4.5) She takes atenolol 50 mg daily for hyperten- Magnesium mg/dL (1.6-2.4) sion, cimetidine for dyspepsia, and estrogen 1.9 as postmenopausal hormone replacement Blood urea nitrogen 20 mg/dL (10-25) therapy. A physical examination is normal. Her Creatinine 0.8 mg/dL (0.7-1.4) pulse is 78 per minute and regular, and her Chloride 110 mmol/L (98-110) blood pressure is 134/70 mm Hg. Carbon dioxide 23 mmol/L (24-32) CAUSES OF HYPERCALCEMIA Intact parathyroid hormone 95 pg/mL (10-60) What is the most likely cause of this 1 patient's hypercalcemia? • Humoral hypercalcemia of malignancy • Familial hypocalciuric hypercalcemia Primary hyperparathyroidism is mainly a • Primary hyperparathyroidism biochemical diagnosis, because it causes no • Drug-induced hypercalcemia symptoms in more than 50% of cases. In the days before routine calcium determinations All of these choices are well-recognized caus- by automatic analyzing machines, this condi- es of hypercalcemia, but primary hyper- tion was thought to be rare, and was discov- parathyroidism is the most likely cause in this ered only after it progressed to severe hyper- case. calcemia and bone disease (osteitis fibrosa Primary hyperparathyroidism accounts cystica). Usually, there are no findings on for more than 70% of cases of asymptomatic examination that are diagnostic. hypercalcemia in ambulatory patients. The The serum calcium level is generally mild- incidence is one case per 800 persons per year. ly elevated (< 12.0 mg/dL), but can be much It is most common in the fifth and sixth higher. The serum phosphorus level is low. decades, and three times more common in The level of intact parathyroid hormone women than in men. (PTH) is elevated in 90% of cases, but is inap- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • NUMBER 5 MAY 1998 233 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. IM BOARD REVIEW propriately normal in the rest. (In a normal fractional excretion of calcium is very low parathyroid gland, PTH secretion is sup- (ie, < 0.01); in contrast, patients with pri- pressed and unmeasurable when calcium rises mary hyperparathyroidism usually have a to the high end of the normal range.) Mild value greater than 0.02. hyperchloremia with metabolic acidosis is No treatment is required for familial common. hypocalciuric hypercalcemia, and parathy- Humoral hypercalcemia of malignancy roidectomy does not reverse the hypercal- accounts for more than 50% of cases of hyper- cemia. calcemia in hospitalized patients. The most Drug-induced hypercalcemia can be common malignant diseases that cause hyper- asymptomatic. Several drugs and vitamins can calcemia are lung cancer, breast cancer, cause hypercalcemia, including: myeloma, lymphoma, and renal cell carcino- • Estrogen and antiestrogen (tamox- ma. Most of these tumors increase the calcium ifen), in patients with bone metastases due to level by secreting PTH-related peptide, others breast cancer. An "estrogen flare" may happen secrete lymphotoxins and interleukin-1, and in one third of patients with breast cancer and certain lymphomas produce an excess of 1,25 skeletal metastases. vitamin D. • Lithium Nothing in our patient's history, physi- • Theophylline cal examination, or laboratory data suggests • Thiazide diuretics an underlying malignant condition. In most • Vitamin A cases the malignant disease is already • Vitamin D advanced by the time the hypercalcemia is Some of these drugs increase serum cal- found; hypercalcemia precedes the diagno- cium by increasing bone resorption, renal sis of malignancy in fewer than 20% of calcium reabsorption, or gut absorption; cases. Intact PTH is usually suppressed. Of however, the exact mechanisms are not fully note: the new immunoradiometric assay of understood for all of them. A history of the the entire PTH molecule is the best assay to medications and vitamins that the patient is use to measure intact PTH, since it is not taking should be an essential part of the PTH is high affected by metabolic fragments of PTH evaluation. in primary (which may be increased in renal dysfunc- tion) and does not cross-react with PTH- • CAUSES OF PRIMARY hyperpara- related peptide. HYPERPARATHYROIDISM thyroidism, Familial hypocalciuric hypercalcemia is caused by decreased renal clearance of calci- What is the most likely cause of primary but low in um. It is a benign autosomal dominant con- 2 hyperparathyroidism ? hypercalcemia dition that occurs at an early age, without symptoms, signs, or complications of hyper- • Solitary parathyroid adenoma of malignancy calcemia. There may be a family history of • Generalized hyperplasia of all parathyroid hypercalcemia. Patients have normal or glands mildly elevated intact PTH levels, mild • Multiple parathyroid adenomas hypermagnesemia, and normal serum phos- • Parathyroid carcinoma phorus levels. One way to distinguish familial hypocal- Solitary benign parathyroid adenomas ciuric hypercalcemia from primary hyper- account for 80% to 85% of cases of primary parathyroidism is to measure the concentra- hyperparathyroidism. Removing the adenoma tions of calcium and creatinine in a sample produces a long-term remission in nearly all of urine and blood, and from these values patients. The recurrence rate of new adeno- calculate the fractional excretion of calcium: mas is 0.6% at 8 to 10 years. (urine calcium concentration x serum creati- Diffuse hyperplasia of all parathyroid nine concentration) / (urine creatinine con- glands is less common, occurring in only 15% centration x serum calcium concentration). of patients with primary hyperparathyroidism. In familial hypocalciuric hypercalcemia, the This condition can occur sporadically or as 238 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • NUMBER 5 MAY 1998 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. • part of the syndrome of multiple endocrine neoplasia (MEN), either type 1 (Wermer syn- Indications for surgery drome, with tumors of the pituitary gland, for primary hyperparathyroidism parathyroid gland, and pancreas) or type 2a (Sipple syndrome, with medullary thyroid car- Serum calcium level > 1 mg/dL above upper limit of normal cinoma, pheochromocytoma, and hyper- (ie, >11.5 mg/dL, depending on the laboratory) parathyroidism). MEN syndrome is found in about half of cases of diffuse hyperplasia. Marked hypercalciuria (> 400 mg/day) Treatment consists of removal of all glands Any overt manifestation of primary hyperparathyroidism except for remnant parathyroid tissue left in Classic neuromuscular disease situ or autotransplanted in the nondominant Nephrocalcinosis forearm. Nephrolithiasis Multiple parathyroid adenomas are Osteitis fibrosa cystica found in only 1% to 2% of all cases of pri- mary hyperparathyroidism. These can be Cortical bone density in the distal radius < 2 standard deviations below age- and sex-matched control values (radial Z score < -2 SD) sporadic or, rarely, part of familial syn- dromes. Reduced creatinine clearance in the absence of other cause Parathyroid carcinoma is very rare, occurring in fewer than 0.5% of patients. Age < 50 years The average serum calcium level in patients with parathyroid carcinoma is 14 mg/dL, SOURCE: ADAPTED FROM CONSENSUS DEVELOPMENT CONFERENCE PANEL. DIAGNOSIS AND MANAGEMENT OF ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM: CONSENSUS with marked elevations in intact PTH lev- DEVELOPMENT CONFERENCE STATEMENT. ANN INTERN MED 1991; 114:593-597 els. Parathyroid carcinoma may be very dif- ficult to diagnose histologically unless it invades the capsule or lymph nodes. The cancer may also be detected when hypercal- cemia recurs after apparently successful toms—and there are no indices that can pre- surgery. Aggressive surgical resection of the dict who will develop complications from tumor and lymph nodes is important to max- the disease. To address this issue, the Surgery cures imize survival. National Institutes of Health convened a hyperpara- consensus committee in 1991 to draft a set • SURGERY FOR PRIMARY of guidelines (TABLE2). However, the commit- thyroidism, HYPERPARATHYROIDISM tee emphasized that these recommendations but not all are not exact, and that clinicians should use Which erf the following is an indication their own judgment. patients 3 for surgery in primary hyperparathy- Our patient underwent surgery, and a require roidism? large adenoma was found. Afterward, her serum calcium level returned to the normal surgery • Urinary calcium excretion > 400 mg/day range,
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