Hypercalcemia in Active Pulmonary Tuberculosis ALI A. ABBASI, M.D.; JOSEPH K. CHEMPLAVIL, M.D.; SAMIR FARAH, M.D.; BERNHARD F. MULLER, M.D.; and A. ROBERT ARNSTEIN, M.D.; Allen Park, Detroit, and Royal Oak, Michigan
We ascertained the incidence of hypercalcemia in 7 9 consecutive patients with active pulmonary tuberculosis and a control group of 7 9 patients with chronic obstructive pulmonary disease. Twenty-two patients developed hypercalcemia (serum calcium greater than 10.5 mg/dl) within 4 to 16 weeks after initiation of chemotherapy for tuberculosis. The duration of hypercalcemia ranged from 1 to 7 months, and remission occurred spontaneously in all patients. The mean daily vitamin D supplement was greater in hypercalcemic patients than in the normocalcemic group. There was a positive correlation between daily vitamin D supplement and degree and duration of hypercalcemia. Mean serum calcium in patients with tuberculosis was higher than in patients with chronic obstructive pulmonary disease supplemented with the same dose of vitamin D. Hypercalcemia appears to be related to the activity of pulmonary tuberculosis and the intake of vitamin D; the exact mechanism, however, remains unknown. H Y P E R C A L C E M I A has been known to occur in association with granulomatous diseases. Sarcoidosis is the most common granulomatous disease causing hypercalcemia (1, 2). Tuberculosis, disseminated coccidioidomycosis, histoplasmosis, and chronic beryllium disease have been infrequently reported to be associated with hypercalcemia (3-7). The incidence of hypercalcemia in pulmonary tuberculosis is unknown. In this study, we attempted to ascertain the incidence and investigate the possible cause of hypercalcemia in patients with active pulmonary tuberculosis treated in our hospital over a 5-year period. We present our findings here. Patients Our study design has two components: prospective and retrospective. As we became aware of the association of hypercalcemia with pulmonary tuberculosis, we frequently measured serum calcium levels, monitored other variables for possible side effects of antituberculosis therapy, and thoroughly evaluated hypercalcemic patients encountered during the study. The retrospective part was designed to ascertain the incidence of hypercalcemia among all tuberculosis patients admitted to the hospital during the same period. We reviewed the medical records of all patients with active pulmonary tuberculosis treated in our hospital between 1972 and 1977. The diagnosis of tuberculosis was established from positive sputum smears or cultures for Mycobacterium tuberculosis in all cases. Clinical data of patients, results of their sputum smears and cultures for M. tuberculosis, determinations of serum calcium, phosphorus, alkaline phosphatase, blood urea nitrogen (BUN), bilirubin, and total serum protein, antituber• F r o m t h e Veterans Administration Hospital, Allen Park, the D e p a r t m e n t of Medicine, Wayne State University School of Medicine, Detroit, and William Beaumont Hospital, Royal Oak, Michigan.
324
Annals of Internal Medicine 90:324-328, 1979
culosis drugs used, dietary regimens, and vitamin D supplements were all recorded. The hypercalcemic patients had undergone thorough investigation to exclude other causes of hypercalcemia such as primary and metastatic neoplastic disease, primary hyperparathyroidism, milk-alkali syndrome, adrenal insufficiency, and hyperthyroidism. Serum calcium concentration was measured at admission and at short intervals (1 to 2 weeks) thereafter for most of the period of hospitalization. Hypercalcemia was defined as a serum calcium level greater than 10.5 mg/dl on two or more occasions. Our control subjects included an equal number of agematched patients with chronic obstructive pulmonary disease hospitalized for treatment. We recorded their clinical data, biochemical profile, therapeutic regimens, and vitamin D supplements. Two thirds of patients with pulmonary tuberculosis were age-matched with patients with chronic obstructive pulmonary disease, and one third were matched with the closest age. All patients in both groups were men. Absolute duration of hospitalization for the control group was shorter than that of the study group, but both groups had equal duration of hospitalization during the "risk period" for hypercalcemia. Methods Venous blood was drawn for the determination of serum calcium, phosphorus, alkaline phosphatase, B U N , bilirubin, and total serum proteins after overnight fasting. Serum calcium was measured using the Cresolphthalein Complexon AutoAnalyzer method (Technicon Instruments Corp. Tarrytown, New York). To eliminate false elevation of serum calcium due to binding of calcium to serum proteins in patients with hyperproteinemia, serum calcium was corrected according to the formula (8)
Corrected serum calcium -
0
We ascertained the incidence of hypercalcemia in 7 9 consecutive patients with active pulmonary tuberculosis and a control group of 7 9 patients with chronic obstructive pulmonary disease. Twenty-two patients developed hypercalcemia (serum calcium greater than 10.5 mg/dl) within 4 to 16 weeks after initiation of chemotherapy for tuberculosis. The duration of hypercalcemia ranged from 1 to 7 months, and remission occurred spontaneously in all patients. The mean daily vitamin D supplement was greater in hypercalcemic patients than in the normocalcemic group. There was a positive correlation between daily vitamin D supplement and degree and duration of hypercalcemia. Mean serum calcium in patients with tuberculosis was higher than in patients with chronic obstructive pulmonary disease supplemented with the same dose of vitamin D. Hypercalcemia appears to be related to the activity of pulmonary tuberculosis and the intake of vitamin D; the exact mechanism, however, remains unknown. H Y P E R C A L C E M I A has been known to occur in association with granulomatous diseases. Sarcoidosis is the most common granulomatous disease causing hypercalcemia (1, 2). Tuberculosis, disseminated coccidioidomycosis, histoplasmosis, and chronic beryllium disease have been infrequently reported to be associated with hypercalcemia (3-7). The incidence of hypercalcemia in pulmonary tuberculosis is unknown. In this study, we attempted to ascertain the incidence and investigate the possible cause of hypercalcemia in patients with active pulmonary tuberculosis treated in our hospital over a 5-year period. We present our findings here. Patients Our study design has two components: prospective and retrospective. As we became aware of the association of hypercalcemia with pulmonary tuberculosis, we frequently measured serum calcium levels, monitored other variables for possible side effects of antituberculosis therapy, and thoroughly evaluated hypercalcemic patients encountered during the study. The retrospective part was designed to ascertain the incidence of hypercalcemia among all tuberculosis patients admitted to the hospital during the same period. We reviewed the medical records of all patients with active pulmonary tuberculosis treated in our hospital between 1972 and 1977. The diagnosis of tuberculosis was established from positive sputum smears or cultures for Mycobacterium tuberculosis in all cases. Clinical data of patients, results of their sputum smears and cultures for M. tuberculosis, determinations of serum calcium, phosphorus, alkaline phosphatase, blood urea nitrogen (BUN), bilirubin, and total serum protein, antituber• F r o m t h e Veterans Administration Hospital, Allen Park, the D e p a r t m e n t of Medicine, Wayne State University School of Medicine, Detroit, and William Beaumont Hospital, Royal Oak, Michigan.
324
Annals of Internal Medicine 90:324-328, 1979
culosis drugs used, dietary regimens, and vitamin D supplements were all recorded. The hypercalcemic patients had undergone thorough investigation to exclude other causes of hypercalcemia such as primary and metastatic neoplastic disease, primary hyperparathyroidism, milk-alkali syndrome, adrenal insufficiency, and hyperthyroidism. Serum calcium concentration was measured at admission and at short intervals (1 to 2 weeks) thereafter for most of the period of hospitalization. Hypercalcemia was defined as a serum calcium level greater than 10.5 mg/dl on two or more occasions. Our control subjects included an equal number of agematched patients with chronic obstructive pulmonary disease hospitalized for treatment. We recorded their clinical data, biochemical profile, therapeutic regimens, and vitamin D supplements. Two thirds of patients with pulmonary tuberculosis were age-matched with patients with chronic obstructive pulmonary disease, and one third were matched with the closest age. All patients in both groups were men. Absolute duration of hospitalization for the control group was shorter than that of the study group, but both groups had equal duration of hospitalization during the "risk period" for hypercalcemia. Methods Venous blood was drawn for the determination of serum calcium, phosphorus, alkaline phosphatase, B U N , bilirubin, and total serum proteins after overnight fasting. Serum calcium was measured using the Cresolphthalein Complexon AutoAnalyzer method (Technicon Instruments Corp. Tarrytown, New York). To eliminate false elevation of serum calcium due to binding of calcium to serum proteins in patients with hyperproteinemia, serum calcium was corrected according to the formula (8)
Corrected serum calcium -
0
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