Hypercalcemia in Pulmonary TB

Chou Chien-Wen M.D.Endocrine and Metabolism SectionChi-Mei Medical Center 8 Aug 2003

Case Report

• Name: 王 x 賜 • Sex: Male• Age: 87y/o• Admission Date: 92/6/20-92/7/3• PI: intermittent conscious disturbance

with irrelevant speech, poor appetite, general malaise and weakness for 1-2 days

• PH: COPD BPH with TURP in 90-8

Laboratory Datas (1)

• WBC 11700, HB 14.2, Pl 27 x 10^3

• U/A: WBC 8-10/HPF

• BUN 38.6, Cr 3.01, Glu 91.5,

• Na 138, K 3.78, Ca 12.88, P 3.1,

• Alb 3.2, Alk.p 225, CRP 141

• 24 hours urine Ca 425 mg, P 622 mg

Laboratory Datas (2)• CXR: bronchiectasis superimposed

infection over both lungs, emphysematous change of both lungs

• Sputum culture: K-P.• B/C: no growth • U/C: Pseudomonas Aeruginosa >10000• T4 6.52, TSH 2.03, CEA 6.2, PSA 4.57,

i-PTH 6.8 pg/ml (normal 10-65)• Skull X ray: small geographic lucencies at right

frontal region• Bence-Jones protein: negative

Laboratory Datas (3)

• Sputum cytology: negative

• 92/6/22 Sputum smear: Acid-fast stain ++

• 92/6/25 Vit D1,25-OH 136 pg/ml (normal 15.9-55.6)

• 92/6/26 Serum Ca 11.3

• 92/6/30 Serum Ca 9.4, BUN 20.8, Cr 1.97

• 92/6/30 Sputum smear: Acid-fast stain negative

Treatment

• Normal saline iv 80 cc/h

• Bonefos 300 mg in 500 cc N/S iv 6 h for 2 days

• Haldol 1 amp stat

• 92/6/20 Cefazolin 1 gm iv q8h, GM 80 mg iv qd

• 92/6/23 Rifater 5# qd, EMB 2# qd, vit B6 1# qd till discharge

Hypercalcaemia and hypokalaemia in tuberculosis

• In two patients with extensive pulmonary tuberculosis who developed hypercalcaemia and hypokalaemia

• the hypercalcaemia appeared related to the use of small doses of vitamin D, which suggested patients with tuberculosis were hypersensitive to vitamin D.

• The hypercalcaemia was quickly suppressed with steroids.

• The hypokalaemia was associated with increased renal excretion of potassium, and was probably due to distal tubular damage from hypercalcaemia.

Bradley GW. Thorax. 33(4):464-7, 1978 Aug.

Hypercalcemia in active pulmonary tuberculosis

• 79 consecutive patients with active pulmonary tuberculosis and a control group of 79 patients with COPD

• 22 patients developed hypercalcemia (serum calcium > 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.

Abbasi AA. Annals of Internal Medicine. 90(3):324-8, 1979 Mar.

Evidence for abnormal regulation of circulating 1 alpha, 25-dihydroxyvitamin D in patients with pulmonary tuberculosis and normal calcium metabolism

• vitamin D, 100,000 units a day for 4 days, were compared in 25 normal subjects and 11 patients with active pulmonary tuberculosis who were normocalcemic

• Whereas vitamin D increased mean serum 25-OHD from 20 +/- 2 (+/- SE) to 40 +/- 5 ng/ml (P less than 0.001) and did not change mean serum 1 alpha, 25(OH)2D in the normals (33 +/- 2 vs. 31 +/- 2 pg/ml), it increased mean serum 25-OHD from 21 +/- 4 to 55 +/- 13 ng/ml (P less than 0.05) and mean serum 1 alpha, 25(OH)2D from 28 +/- 2 to 35 +/- 3 pg/ml (P less than 0.05) in the patients.

• Serum calcium was normal and remained within the normal range in all subjects and patients.

• significant abnormality in the regulation of circulating 1 alpha, 25(OH)2D in normocalcemic patients with pulmonary tuberculosis.

Epstein S. Calcified Tissue International. 36(5):541-4, 1984 Sep

Hypercalcemia associated with increased circulating 1,25 dihydroxyvitamin D in a patient with pulmonary tuberculosis.

• a 53-year-old man with far-advanced pulmonary tuberculosis who developed transient increases in circulating 1,25 dihydroxyvitamin D (1,25(OH)2D) and hypercalcemia while on antituberculous treatment.

• Serum 25-hydroxyvitamin D (25OHD) was suppressed during the abnormal elevation of serum 1,25(OH)2D.

• It is concluded that tuberculosis is a chronic granulomatous disease in which hypercalcemia may result from abnormal metabolism of vitamin D.

Bell NH. Calcified Tissue International. 37(6):588-91, 1985 Dec.

Are tuberculous patients at a great risk from hypercalcemia?.

• The risk of tuberculous was investigated in 33 patients aged 19 to 80. • 22 of the 33 received no vitamin D supplements. • After 17 to 34 days of chemotherapy serum calcium corrected for albu

min and 1,25(OH)2D levels were lower without change in serum D-binding protein.

• In 11 patients 25(OH)D, 50 micrograms/day, was given orally for two months. 25(OH)D given three days before chemotherapy in five patients induced an increase of levels of 1,25(OH)2D which was greater than in 10 control patients with similar serum levels of 25(OH)D.

• When chemotherapy was added to 25(OH)D, the five patients showed high normal 1,25(OH)2D levels.

• The last six patients received 25(OH)D together with or after starting chemotherapy.

• None of the 33 patients developed hypercalcemia, even when supplemented with 25(OH)D for two months.

• It appears that hypercalcemia is uncommon in tuberculosis.

Fuss M. Quarterly Journal of Medicine. 69(259):869-78, 1988 Nov.

Hypercalcemia in pulmonary tuberculosis

• The incidence of hypercalcemia among unselected patients with active pulmonary tuberculosis was investigated, retrospectively, during a ten-year period.

• Among 67 patients, the mean serum calcium concentration on admission was significantly raised compared to healthy controls (2.51 +/- 0.16 (SD) vs 2.43 +/- 0.07 mmol/l; p less than 0.001) and 25% of the patients had hypercalcemia.

• After one year of successful tuberculostatic treatment the serum calcium values had normalized

Lind L. Upsala Journal of Medical Sciences. 95(2):157-60, 1990

Hypercalcemia in active pulmonary tuberculosis and its occurrence in relation to the radiographic extent of disease

• The prevalence of hypercalcemia in tuberculosis in Hong Kong and its occurrence in relation to the radiographic extent of disease were studied in 57 patients with sputum smear (n = 44) and/or culture positive (n = 13) pulmonary tuberculosis and in five patients with military tuberculosis prior to treatment.

• Only one (1.6%) patient had a corrected plasma calcium level above the reference range for our laboratory.

• There was a positive relationship between the corrected plasma calcium levels and the radiographic extent of disease (r = 0.37), p < 0.01).

• a low prevalence of "absolute" hypercalcemia in Hong Kong could be related to the low dietary calcium intake in these subjects.

Chan TY Southeast Asian Journal of Tropical Medicine & Public Health. 23(4):702-4, 1992 Dec.

Ketoconazole decreases the serum ionized calcium and 1,25-dihydroxyvitamin D levels in tuberculosis-associated hypercalcemia

• Two boys (aged 10.5 years and 14.7 years) with active tuberculosis and hypercalcemia.

• At admission, serum 1,25-dihydroxyvitamin D levels were elevated. Oral ketoconazole administration (3.0 mg/kg every 8 hours) decreased 1,25-dihydroxyvitamin D levels within the first week of therapy (from 208.8 to 57.6 pmol/L 72.4% in one boy and from 321.6 to 115.2 pmol/L 64.2% in the other).

• coincident normalization of serum ionized calcium concentration (from 1.45 to 1.24 mmol/L 13.0% in one boy and from 1.55 to 1.26 mmol/L 17.0% in the other).

• CONCLUSIONS--Abnormal elevated levels of 1,25-dihydroxyvitamin D caused hypercalcemia in our patients; ketoconazole administration may be effective in the treatment of hypercalcemia in patients with tuberculosis, which decreases 1,25-dihydroxyvitamin D synthesis

Saggese G. American Journal of Diseases of Children. 147(3):270-3, 1993 Mar

The prevalence of hypercalcaemia in pulmonary and miliary tuberculosis--a longitudinal study.

• We studied the prevalence of hypercalcaemia in 34 Chinese patients with pulmonary (n = 32) or miliary (n = 2) tuberculosis.

• None of these subjects were given vitamin D or calcium supplements. .

• During the 6-month study period, two patients (6%) developed hypercalcaemia (plasma calcium greater than 2.51 mmol/l), as compared to figures of 16% to 28% in the United States and India.

• By correcting the plasma calcium to a normal albumin, five (15%) of our patients were hypercalcaemic, as compared to a figure of 48% in Greece.

• Apart from variations in methodology, discrepancies in the reported prevalence of hypercalcaemia in tuberculosis may be due to differences in sun exposure, and vitamin D and calcium intake.

Chan TY. Singapore Medical Journal. 35(6):613-5, 1994 Dec

Hypercalcemic crisis in a patient with pulmonary tuberculosis

• Hypercalcemia occurs in 16% to 28% of patients with pulmonary tuberculosis.

• Rarely, however, does the calcium rise to a level that requires emergency management.

• In this report, a 49-year-old woman undergoing treatment for pulmonary tuberculosis presented with vomiting and weakness secondary to severe hypercalcemia. .

• Physicians must maintain a high index of suspicion since prompt recognition and therapy will ensure a successful outcome.

Pruitt B. Journal - Oklahoma State Medical Association. 88(12):518-20, 1995 Dec

Hypercalcemia and pulmonary tuberculosis in east Tennessee

• In a study of 83 patients with active pulmonary tuberculosis who were treated in East Tennessee, only three developed hypercalcemia.

• The incidence of hypercalcemia in East Tennessee is markedly lower than that quoted in earlier studies performed in the United States.

• The explanation for the infrequent occurrence of elevated serum calcium in our population is probably multifactorial, but does not appear to be related to the selection of antituberculous agents.

Hourany J. Tennessee Medicine. 90(12):493-5, 1997 Dec

Hypercalcemia, inappropriate calcitriol levels, and tuberculosis on hemodialysis.

• a female patient undergoing hemodialysis who developed tuberculosis, hypercalcemia, and inappropriately elevated calcitriol levels.

• These findings suggest ectopic production of calcitriol by tuberculous granulomas.

• Successful treatment of tuberculosis led to a substantial decrease in the levels of calcium and calcitriol

Peces R. Scandinavian Journal of Urology & Nephrology. 34(4):287-8, 2000 Aug

Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment

• We prospectively evaluated all patients with newly-diagnosed TB presenting, either as inpatients or as outpatients, to our hospital, during a 3-year period.

• We evaluated 88 patients with TB (50 males and 38 females), aged between 23 and 89 years (mean age+/-SD: 46.4+/-19 years), and 65 age- and sex-matched controls with chronic obstructive pulmonary disease (36 males and 29 females), aged between 28 and 88 years (mean age+/-SD: 47.2+/-18 years).

• Among TB patients, 56 had pulmonary TB, 20 had pleural TB without evidence of pulmonary parenchyma involvement, eight had pulmonary and pleural TB, and four had disseminated disease.

Roussos A. Respiratory Medicine. 95(3):187-90, 2001 Mar

Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment

• The mean (+/-SD) albumin-adjusted serum calcium concentration and the mean ionized calcium concentration were significantly higher in the TB group (2.49+/-0.21 mmol l(-1) and 1.27+/-0.02 mmol l(-1) respectively) than in the control group (2.36+/-0.11 mmol l(-1) and 1.19+/-0.02 mmol l(-1), P<0.05).

• In the TB group no correlation between type of disease and albumin-adjusted or ionized calcium concentration was seen.

• Hypercalcaemia was detected in 22 patients with TB (25%) but only three showed symptoms associated with it.

• We conclude that, although hypercalcaemia is a common laboratory finding among Greek patients with TB before anti-TB chemotherapy, it is usually asymtomatic.

Roussos A. Respiratory Medicine. 95(3):187-90, 2001 Mar

Sarcoidosis and other granulomatous diseases

• Unregulated synthesis of 1,25(OH)2D3, found even in an anephric patient

• Isolated sarcoid macrophages express the gene encoding the identical 25(OH)d 1 alfa-hydroxylase

• Unusual sensitivity to b\vitamin D and become hypercalcemic in response to ultraviolet radiation or oral vitamin D intake

• Also associated with other granulomatous diseases, such as tuberculosis, fungal infections. and berylliosis, Wegener’s granulomatosis, AIDS-related Pneumocystitis carinii and extensive granulomatous foreign body reactios

Williams Textbook of Endocrinology, Tenth Edition