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• W2192736005 abstract "Original ArticlesHypercalcemia in Active Pulmonary Tuberculosis Sulaiman A. Al-Majed, FRCP(C), FCCP Riad Sulimani, FRCP(C), FACP Faisal Al-Kassimi, MRCP, FCCP Lalit Pandya, MSc, MD, MRCP Sameer Huraib, and FRCP(C) Nasser Al-SharifMD, DTM Sulaiman A. Al-Majed Address reprint requests and correspondence to Dr. Al-Majed: Department of Medicine, Division of Respiratory Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia From the Division of Respiratory Medicine, King Khalid University Hospital, Riyadh Search for more papers by this author , Riad Sulimani From the Division of Endocrinology, King Khalid University Hospital, Riyadh Search for more papers by this author , Faisal Al-Kassimi From the Division of Respiratory Medicine, King Khalid University Hospital, Riyadh Search for more papers by this author , Lalit Pandya From the Sahary Chest Hospital, Riyadh Search for more papers by this author , Sameer Huraib From the Division of Nephrology, King Khalid University Hospital, Riyadh Search for more papers by this author , and Nasser Al-Sharif From the Sahary Chest Hospital, Riyadh Search for more papers by this author Published Online:1 May 1991https://doi.org/10.5144/0256-4947.1991.289SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractIn a retrospective review of 241 patients with active pulmonary tuberculosis, hypercalcemia was found in 62 (26%). It was detected on presentation in 48 patients and developed in 14 patients 4 to 6 weeks after the start of antituberculous chemotherapy. The mean (± SD) serum calcium level in those cases was 2.78 (± 0.137) mmol/L. The majority of cases (67.6%) had a mild rise in the calcium level that remained below 2.8 mmol/L but 35% had a level that ranged between 2.8 and 3.0 mmol/L. Only 2.4% had serum level higher than 3.0 mmol/L, which could explain the predominant absence of hypercalcemia-related symptoms. Hypercalcemia was more common in patients older than 50 years (P < 0.05), but this did not correlate with the extent of the tuberculosis shown on radiological evaluation. Spontaneous return to normocalcemia occurred in all 42 patients who underwent serial assessments of their serum calcium concentration, 6 to 8 weeks after the start of chemotherapy. Saudi Arabia is known to have a high prevalence of vitamin D deficiency, but none of our patients were immobilized or had received vitamin D supplements or multivitamins. This supports the view that vitamin D intake does not play a major role in inducing hypercalcemia in cases of active pulmonary tuberculosis, as has been suspected.IntroductionHypercalcemia has been reported to occur in conjunction with various granulomatous diseases, such as tuberculosis[1–5], sarcoidosis[6], disseminated fungal infection[7,8], and berylliosis[9]. However, some studies failed to detect any significant hypercalcemia associated with tuberculosis[10–12]. As in sarcoidosis, hypersensitivity to vitamin D was considered the likely mechanism for hypercalcemia in tuberculosis[13], and some studies documented the occurrence of hypercalcemia in patients given vitamin D supplements[14].Although Saudi Arabia is a sunny country, vitamin D deficiency is common[15] and is attributed to dietary habits and an actual lack of exposure to the sun. The present study was therefore designed to analyze retrospectively the effects of tuberculosis on calcium homeostasis in this environment, and to discover whether a correlation existed between the presence of hypercalcemia and patient age, as well as between the extent and severity of the disease.PATIENTS AND METHODSWe retrospectively reviewed the records of 241 patients with smear- and culture-positive pulmonary tuberculosis. All patients had been seen at the Chest Hospital and King Khalid University Hospital, Riyadh, between July 1986 and October 1989. None of the patients were on diuretics, vitamin D, or calcium supplements or suffered from renal failure; all were fully ambulatory. Bed-ridden or immobilized patients were excluded. All patients were followed clinically for a minimum of 9 months. The extent of tuberculosis on admission was determined radiologically, using the classification of the National Tuberculosis Association of the USA[16], and graded as advanced, moderate, or minimal.In addition, the following information was recorded: antituberculous drugs given, and values noted for serum urea, creatinine and electrolytes, serum albumin, alkaline phosphatase, serum calcium, and phosphate, before and during chemotherapy. A tourniquet was used to draw blood in all cases. The serum calcium value was corrected to the serum albumin value using the formula described by Kleeman et al[17]. This was done to compensate for the mild increase in calcium level which can result from tourniquet application, as venous stasis is known to falsely raise the serum calcium level due to a hemoconcentration of albumin[18]. Hypercalcemia was defined as a serum calcium level higher than 2.6 mmol/L, which is the upper limit of normal for Saudis[19,20].RESULTSTable 1 gives the age and sex characteristics of the normocalcemic and hypercalcemic groups. We studied a total of 241 patients, of whom 148 were males and 93, females. Sixty-two patients (26%) had a calcium level higher than 2.6 mmol/L, though other biochemical variables were normal. There were 40 males and 22 females with an age of 6 to 80 years. Hypercalcemia was detected on presentation in 48 patients, but in 14 others developed 4 to 6 weeks after starting antituberculous chemotherapy. The mean (± SD) serum calcium concentration in those cases was 2.78 (± 0.137) mmol/L. The majority of cases (67.6%) had a mild rise in the serum calcium level below 2.8 mmol/L; in 35% the level was below 3.0 mmol/L. Only 2.4% had a serum calcium level higher than 3.0 mmol/L. None of the patients had symptoms attributable to hypercalcemia.Table 1. Sex and age characteristics of the patients.For analysis purposes, the patients were divided into two main groups: those who were below the age of 50 and those above. Hypercalcemia was found in 47 of the 203 (23%) patients younger than 50 years, compared with 15 to 38 (39%) 50 years and older, and the difference was significant at P < 0.05. Twelve of the 36 (33%) patients with advanced disease had hypercalcemia, whereas 50 of 205 (24%) patients with moderate or mild disease had hypercalcemia, though the difference between the two groups was not significant at P > 0.05.Of the 62 patients with hypercalcemia, 42 underwent serial estimations of serum calcium, which reverted to normal within 6 to 8 weeks following the start of chemotherapy.DISCUSSIONWe found a 26% prevalence of hypercalcemia in patients with active pulmonary tuberculosis. This agrees with observations from previous studies of between 26 and 48%[5,14,21]. The resolution of hypercalcemia after institution of tuberculous chemotherapy in our patients makes unlikely other causes of hypercalcemia, such as the application of a tourniquet or existence of malignancy. Also, all patients were followed for 9 months, and during that time showed no clinical evidence of malignancy. Hyperparathyroidism, which occurs in 1 to 6.2 per thousand in the general population[22], could not account for the high prevalence recorded in our study. A survey by the British Thoracic Society[12] found no hypercalcemia in a group of 287 patients with active tuberculosis. Other workers have also failed to detect any hypercalcemia at the time of diagnosis of tuberculosis[10,11]. The discrepency between various studies is difficult to explain, but may represent differences in calcium intake in the diet as well as differences in the population studied. Similar to the findings of Kitrou et al[20], we found hypercalcemia was significantly more frequent in subjects older than 50 years (P < 0.05). This could not be attributed to an effect resulting from immobilization, as all our patients were fully ambulatory. Although there was a trend for a correlation between the radiological extent of tuberculosis and the presence of hypercalcemia, the trend was not statistically significant (P > 0.05). This agrees with the findings of previous studies[5,21,23].Hypercalcemia was documented at presentation in 48 of our patients, but appeared only 4 to 6 weeks after the start of chemotherapy in another 14. This finding militates against Ketrou et al's[20] view that hypercalcemia is triggered by antituberculosis chemotherapy. The hypercalcemia appears to be influenced in some way by the tuberculosis, as it cleared with the continuation of chemotherapy.The lack of symptoms of hypercalcemia in our study and others[5,14] reflects the predominantly mild rise of serum calcium in our patients. However, symptomatic hypercalcemia was reported in two of 24 patients[21], with serum calcium of 3 to 3.5 mmol/L, and in several case reports[5,24,25].The mechanism of hypercalcemia in active tuberculosis is still not clearly understood. The general opinion is that it represents a hypersensitivity to vitamin D that is further aggravated by high vitamin D intake[14,26]. This view is supported by Shai et al[27] who documented hypercalcemia in eight of ten tuberculous patients given vitamin D supplements. Isaacs et al[24] found raised serum levels of 1,25-dihydroxy vitamin D3 in tuberculous patients. The link between the clinical activity of tuberculosis and the presence of hypercalcemia could be clarified by the work of Cadranel et al[28] who found that inflammatory alveolar cells, obtained by bronchoalveolar lavage, have the capacity to synthesize 1,25 dihydroxy vitamin D3. This was associated with a persistent lymphocytic alveolitis in the lung. However, the extrarenal production of 1,25 (OH)2 D3 was not considered the principal mechanism of the hypercalcemia[28]. Both Cipola et al[25] and Sullivan et al[29] found normal serum levels of 1,25 (OH)2 D3 in cases of hypercalcemia secondary to active tuberculosis. It is postulated that the inflammatory cells of tuberculous alveolitis release osteoclast-activating factor and prostaglandins which, in turn, mobilize calcium from the bones[28].Our finding of hypercalcemia despite a well-documented prevalence of vitamin D deficiency in Saudi Arabia[15] supports the view that the hypercalcemia does not result from an increased dietary intake of vitamin D.ARTICLE REFERENCES:1. Johnson NM, Shneerson G. Hypercalcemia and hypercaleiuria associated with pulmonary tuberculosis . Br J Dis Chest. 1980; 74: 201–2. Google Scholar2. Gerritson J, Knol K. Hypercalcemia in a child with miliary tuberculosis . Eur J Pediatr. 1989; 148: 650–1. Google Scholar3. Sharma OP, Lamon J, Winsor D. 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Am J Med. 1969; 46: 545–61. Google Scholar10. Diaz-Curiel M, Fernandez-Guerrero M, Rapado A, Castrillo JM. Hypercalcemia in pulmonary tuberculosis (letter) . Ann Intern Med. 1982; 97 (1): 143. Google Scholar11. Gwinup G, Randazzo G, Elias A. The influence of Vitamin D intake on serum calcium in tuberculosis . Acta Endocrinol. 1981; 97: 114–7. Google Scholar12. British Thoracic Association. A controlled trial of six months chemotherapy in pulmonary tuberculosis. First Report: result during chemotherapy . Br J Dis Chest. 1981; 75: 141–53. Google Scholar13. Bell NH, Stern PH, Pantzer E, Sinha TK. Evidence that increased circulating la, 25-dehydroxy vitamin D is the probable cause of abnormal calcium metabolism in sarcoidosis . J Clin Invest. 1979; 64: 218–25. Google Scholar14. Abbasi AA, Chemplavil JK, Farah S, et al. Hypercalcemia in active pulmonary tuberculosis . Ann Intern Med. 1979; 90: 324–8. Google Scholar15. Sedrani SH. Are Saudis at risk of developing vitamin D deficiency? Saudi Med J. 1986; 7 (5): 427–33. Google Scholar16. National Tuberculosis Association of the USA. Diagnostic standards and classification of tuberculosis. New York: National Tuberculosis Association, 1961. Google Scholar17. Kleeman CR, Massry SG, Coburn JW. The clinical physiology of calcium homeostasis, parathyroid hormone and calcitonine . Calcif Med. 1971; 114: 16–21. Google Scholar18. Baron DN, ed. A short textbook of chemical pathology. London: Hodder and Stoughton, 1973;138–9. Google Scholar19. Bacchus RA, Kilshaw BH, Madkour MM, et al. Establishment of male Saudi Arabian reference ranges for biochemical analytes . Saudi Med J. 1982; 3 (4): 249–58. Google Scholar20. El-Hazmi MAF, Al-Faleh FZ, Al-Mofleh IA, et al. Establishment of normal “reference” ranges for biochemical parameters for healthy Saudi Arabs . Trop Geogr Med. 1982; 34: 323–2. Google Scholar21. Kitrou MP, Phytou-Pallikari A, Tzannes SE, et al. Serum calcium during chemotherapy for active pulmonary tuberculosis . Eur J Respir Dis. 1983; 64: 347–54. Google Scholar22. Christensson T. Familial hyperparathyroidism . Ann Intern Med. 1976; 85: 614–5. Google Scholar23. Epstein S, Stern PH, Bell NH, et al. Evidence for abnormal regulation of circulating 12, 25 dihydroxy vitamin D in patients with pulmonary tuberculosis and normal calcium metabolism . Calcif Tissue Int. 1984; 36: 541–4. Google Scholar24. Isaacs RD, Nicholson GI, Holdaway IM. Miliary tuberculosis with hypercalcemia and raised vitamin D concentrations . Thorax. 1987; 42: 555–6. Google Scholar25. Cipola L, Roy TM, Gardner RP. Symptomatic hypercalcemia in active pulmonary tuberculosis . J Ky Med Assoc. 1989; 87: 13–6. Google Scholar26. Bradley GW, Sterling GM. Hypercalcemia and hypokalemia in tuberculosis . Thorax. 1978; 33: 464–7. Google Scholar27. Shai F, Baker RK, Addrizzo JR, Wallach S. Hypercalcemia in mycobacterial infection . J Clin Endocrinol. 1972; 34: 251–6. Google Scholar28. Cadranel J, Hance AJ, Milleron B, et al. Vitamin D metabolism in tuberculosis. Production of 1, 25 (OH2) D3 by cells recovered by bronchoalveolar lavage and the role of this metabolite in calcium homeostasis . Am Rev Respir Dis. 1988; 138: 984–9. Google Scholar29. Sullivan JN, Salmon WD. Hypercalcemia in active pulmonary tuberculosis . South Med J. 1987; 80: 572–6. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 11, Issue 3May 1991 Metrics History Accepted12 June 1990Published online1 May 1991 InformationCopyright © 1991, Annals of Saudi MedicinePDF download" @default.
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