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3 Fisher B, Redmond C, Poisson R, Margolese R, Wolmark N, Wickerham L, et al. Eight-year results ofa randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in thetreatment of breast cancer. N Engl 1 Med 1989;320:822-8.

4 Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickerham L, el al. A randomizedclinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl 1 Med 1989;320:473-8.

5 Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomised clinical trialevaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl 1 Med 1989;320:479-84.

6 Fisher B, Redmond CK. Fraud in breast cancer trials. N Engl 1 Med 1994;330:1458--60.7 Angell M, Kassirer JP. Setting the record straight in the breast cancer trials. N Eng/.J Med 1994;330:1448--50.8 Rennie D. Breast cancer: How to mishandle misconduct. lAMA 1994;271:1205-7.9 Crewdson J. Fraud in breast cancer study: Doctor lied on data for decade. Chicago Tribune 1994Mar 13:I.

10 Poisson R. Fraud in breast cancer trials. N Engl 1 Med 1994;330:1460.II Gavaghan H. Cancer institute to tighten control of trials. Nature 1994;368:679.12 Greenberg DS. Dingell and the breast cancer trials. Lancet 1994;343:1089.13 Anonymous. Breast cancer: Clearing trails in the forest without losing our way. Lancell994;343: 1049-50.

1. MITTRA

Tata MemoriaL HospitaLBombay

Maharashtra

Tuberculosis and Adrenal FunctionChemotherapy has reduced the mortality due to tuberculosis but its prevalencecontinues to be high in many developing countries, including India.' Increasingurbanization has led to pulmonary tuberculosis becoming a major disease inour country.? Tuberculosis can also involve the adrenal gland, identificationof which may have prognostic and therapeutic implications.

In developed countries tuberculosis was the most frequent cause of Addison'sdisease but has been replaced by autoimmune adrenalitis. However, it remainsthe major cause of Addison's disease in India.'

Is the adrenal gland predisposed to tuberculous infection? The extent orduration of infection are logical predisposing factors. Studies have shown thatthe duration of illness is related to adrenal involvement' but there is nocorrelation with the extent or type of lesion. 5However, patients with adv~nceddisease have decreased diurnal changes in serum cortisol. 4 It is also possiblethat associated immunosuppression renders the adrenal susceptible totuberculous infection. Reports on patients with the acquired immunodeficiencysyndrome (AIDS) have corroborated this-mycobacteria, especially atypicalmycobacteria, were present throughout the adrenal gland in 1% to 12% ofpatients dying from AIDS.5 However, histological studies probably under-estimate the true prevalence of adrenal involvement and cultures were notdone in most studies."

Is the immunosuppression in patients with tuberculosis independent of thepresence of AIDS? Although the latter was not specifically excluded, a recentstudy has shown that patients with pulmonary tuberculosis had decreasedCD4 and increased CD8 counts. The CD4/CD8 ratio was reduced in theperipheral blood showing thereby that T cells which mount a cellular immuneresponse are diminished, while simultaneously higher levels of suppressor Tcells are present. This ratio is reversed by antituberculous chemotherapyimplying that the immunosuppression is due to tuberculosis per se.! Otherfactors could also immunocompromise patients with tuberculosis. Tuberculosishas been shown to be associated with a high degree of undernutrition" whichin turn leads to impaired cell mediated immunity and cytokine production."Immunosuppression renders the adrenal susceptible to tuberculosis and thisexplains in part why it seems to be prone to tuberculous infection.

258 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 7, NO.6, 1994

Does antituberculous therapy affect adrenocortical hormone metabolism?Rifampicin, the sheet-anchor of most regimens, induces the hepatic mixedfunction oxygenases which are involved -in drug metabolism. 10Thus patientswho are already in a pre-Addisonian state may not improve as expected withchemotherapy, as rifampicin enhances the metabolism of corticosteroids.!'Cortisol levels can also be decreased by the use of drugs for associated AIDSincluding phenytoin sodium which increases the cortisol clearance rate andketoconazole which inhibits cortisol synthesis." In addition, opiates such asmethadone also suppress the adrenal gland and may be partly responsible forthe hypocortisolism seen in intravenous drug abusers with AIDS.

Adrenal insufficiency can be suspected by the presence of certain clinicalfeatures and is confirmed by laboratory investigations. Advances in the abilityto measure circulating hormones have also helped in assessing the hypoadrenalstate. When the adrenal cortex is totally destroyed, cortisol is undetectablein the serum. Milder deficiency may alter the circadian hormone secretion.

In clinical practice, adrenal reserve is assessed by the adrenocorticotropin(ACTH) stimulation test where a compromised adrenal gland is unable toproduce more than 20 ILg/dl of cortisol after administration of exogenousACTH.12 Other sophisticated though conceptually simple methods fordiagnosis include measuring serum ACTH levels" (which begin to rise evenbefore the cortisol level falls), and the corticotropin releasing hormone (CRF)stimulation test to distinguish primary from secondary adrenocorticalinsufficiency.P Adrenal autoantibodies may be detected in the serum inautoimmune adrenalitis.

Many of the above methods have been used to assess adrenal function inpatients with tuberculosis and a spectrum of adrenal abnormalities has beenreported. Newly diagnosed patients with pulmonary tuberculosis have higherbasal levels of serum cortisol suggesting a 'stress phenomenon' similar to thatseen in patients with other acute illnesses." The adrenal reserve is oftencompromised as shown by a subnormal cortisol response to ACTH challenge. 16Adrenal hypofunction can occur either by a direct effect on the adrenals'? orvia suppression at the adenohypophyseal level.l''

It may be difficult to diagnose adrenal insufficiency in a patient with tuber-culosis as infected patients have anorexia, fatigue, debility and weight loss.However, if in the absence of gastrointestinal tuberculosis there is excessivenausea and vomiting, Addison's disease should be suspected especially ifthere is pigmentation of the skin and mucosa, postural hypotension andhypoglycaernia.? Adrenal hypofunction should also be considered in a patientwho responds poorly to chemotherapy.'?

The duration of adrenal disease, adrenal size and presence of adrenalcalcification are indications that tuberculosis might be the cause of Addison'sdisease.P In tuberculous adrenalitis, the adrenals are enlarged-! for the firsttwo years followed by atrophy.F In autoimmune adrenalitis, the adrenals arenearly always small and atrophic.

Adrenal involvement with tuberculosis is usually insidious but may occasionallypresent as an Addisonian crisis, either spontaneously or after the administrationof rifampicin.P Thus, patients with Addison's disease on rifampicin shouldhave their corticosteroid dose increased to avoid hypoadrenocortism. Anabnormally low cortisol response to ACTH has been seen in some patientswho deteriorated while on antitubercular chemotherapy. 24 This has led to thesuggestion that patients with extensive active tuberculosis not responding wellto chemotherapy alone should be given a small dose of corticosteroids, 10 anda recent study has shown that 15 mg of prednisolone given daily with anti-tubercular drugs improved the efficacy of treatment. 25 However, other studieshave shown that antitubercular chemotherapy does not affect adrenal functionadversely. 12,14

What does this mean in India? With the increasing availability of assay

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 7, NO.6, 1994 259

technology, it has now become possible to generate Indian data. We shoulddevelop normal ranges for our population-for different ages and sexes-andthen study the multiple bioreactive and immunoreactive forms of hormonesthat circulate and the possibility that commonly used drugs alter thehypothalamo-pituitary-adrenal axis. We should also develop methods tooptimize available resources for testing adrenocortical reserve.

It may also be possible to forestall adrenal insufficiency in a person under-going antitubercular therapy, considering that successful chemotherapyimproves the cell mediated immune status. Since tuberculosis continues tobe common and adrenocortical insufficiency is easily treated if identified, itis important that we work out clear and simple guidelines on how to managepatients with tuberculosis who have compromised adrenal function.

REFERENCES1 Anonymous. Antituberculous chemotherapy in India. Natl Med J India 1991 ;4:1-2.2 De 1, Gollerkeri RS. Pulmonary tuberculosis and its socio-cultural setting in Vadodara, Geogr Med

1987;17:161-76.3 Guleria IS. Tuberculosis in relation to other diseases. In: Rao KN, Viswanathan R, Deshmukh MD,

Pampra SP, Sen PK, Bordia NL, et al. Textbook of tuberculosis. New Delhi:Vikas, 1981:270-6.4 York EL, Enarson DA, Nohert EJ, Fanning FA, Sproule Bl. Adrenocortical function in patients investigated

for active tuberculosis. Chest 1992;101:1338-41.5 Glasgow Bl , Steinsapir KD, Anders K, Layfield LJ. Adrenal pathology in the acquired immune deficiency

syndrome. Am} Clin PathoI1985;84:594-7.6. Donovan DS, Dluhy RG. AIDS and its effect on the adrenal gland. The Endocrinologist 1991 ;1:227-32.7 Singhal M, Banavalikar IN, Sharma S, Saha K. Peripheral blood T lymphocyte subpopulations in patients

with tuberculosis and the effect of chemotherapy. Tubercle 1989;70:171-8.8 Harries AD, Nkhoma WA, Thompson JP, Nyangulu DS, Wirima JJ. Nutritional status in Malawian

patients with pulmonary tuberculosis and response to chemotherapy. Eur J Clin Nutr 1988;42:445-50.9 Yoneda T. Relation between malnutrition and cell-mediated immunity in pulmonary tuberculosis. Kekkaku

1989;64:633-40.10 Mehta PJ, Hakim A, Kamath S. Pre-Addisonian state: Does it exist?} Assoc Physicians India 1992;40:511.11 Ellis ME, Tayoub F. Adrenal function in tuberculosis. Br} Dis Chest 1986;80:7-12.12 Clayton RN. Diagnosis of adrenal insufficiency. BM} 1989;298:271-2.13 Muir A, Maclaren NK. Autoimmune diseases of the adrenal glands, parathyroid glands, gonads and

hypothalamic-pituitary axis. Endocrinol Metab Clin North Am 1991;20:619-44.14 Orth DN. Corticotropin-releasing hormone in humans. Endocr Rev 1992;13:164-91.15 Spratt DI, Cox P, Orav J, Moloney J, Bigos T. Reproductive axis suppression in acute illnesses related

to disease severity. } Clin Endocrinol Metab 1993;76:1548-54.16 Immanuel C, Sarma GR, Krishnamurthy PV, Ramachandran G, Kumaraswami V. Salivary cortisol in the

assessment of adrenocortical function in patients with pulmonary tuberculosis. Indian J Med Res 1992;95: 1-7.17 Behera D, Dash RJ. Adreno-cortical reserve in pulmonary tuberculosis. } Assoc Physicians India

1992 ;40:520-1.18 Hafiez AR, el Kamma B, Abdel-Hafez MA, el-Nady E, Abdou MA, Abdel Hakim AH, et al.

Adenohypophyseal activity in relation to suprarenal function in tuberculosis. Kekkaku 1992;67:363-7.19 Mugusi F, Swai AB, Turner SJ, Alberti KG, McLarty DG. Hypoadrenalism in patients with pulmonary

tuberculosis in Tanzania: An undiagnosed complication? Trans R Soc Trop Med Hyg 1990;84:849-51.20 Vita JA, Silverberg SJ, Goland RS, Austin JH, Knowlton AI. Clinical clues to the cause of Addison's

disease. Am} Med 1985;78:461--<i.21 Buxi TB, Vohra RB, Sujatha, Byotra SP, Mukherji S, Daniel M. CT in adrenal enlargement due to

tuberculosis: A review of literature with five new cases. Clin Imaging 1992;16:102-8.22 Sun ZH, Nomura K, Toraya S, Ujihara M, Horiba N, Suda T, et al. Clinical significance of adrenal

computed tomography in Addison's disease. Endocrinol Jpn 1992;39:563-9.23 Benini F, Savarin T, Senna GE, Durigato S, Vettore L. Diagnostic and therapeutic problems in a case of

adrenal tuberculosis. I Endocrinol Invest 1990;13:597--<iOO.24 Scott GM, Murphy PH, Gemidjioglu MF. Predicting deterioration of treated tuberculosis by corticosteroid

reserve and C-reactive protein. } Infect 1990;21:61-9.25 Iareshko AG. The optimization of the corticosteroid therapy of patients with destructive pulmonary

tuberculosis. Vrach Delo 1989;11:39-40.

G.R. SRIDHAREndocrine and Diabetes Centre

VisakhapatnamAndhra Pradesh