Liver Dysfunction in Pulmonary Tuberculosis Patients on DOTS: A Study and Review

Abha Pandit, Abhay Kumar Pandey


Context: Phenomenal number of people suffers tuberculosis and is prescribed primary line DOTS antitubercular chemotherapy. Evidence based clinical practice to minimize risk of hepatotoxicity is primary imperative.

Aim: Study generates evidence for predicting individual hepatotoxic risk using patient’s constitutional and health parameters and disease characteristics and adopting right course of management. It is observational study in patients consecutively selected by defined inclusion and exclusion criteria.

Methods: Newly enrolled pulmonary tuberculosis patients for DOTS were studied to examine host and disease specific predictors of hepatotoxicity risk. Pretreatment baseline liver function tests and eGFR were done. Development of hepatotoxicity was watched by monthly monitoring of liver enzymes and bilirubin serum profiles.

Result: The selected 148 patients were older and four fifths were males. 16 patients developed ATT-DIH at first or second month monitoring following DOTS. They were more undernourished, hypoproteinaemic, bore more extensive disease and were sputum AFB positive. Their eGFR profiles were normal but significantly lower and plasma antioxidant capacity significantly reduced. Oxidative stress marker levels also were insignificantly raised. They exhibited subclinical elevation of serum enzymes AST and ALT .No significant influence of age and gender was seen on incidence of ATT-DIH.

Conclusion: Frailty with extensive disease constituted phenotype vulnerable to ATT-DIH. Hypoalbuminaemia, reduced plasma antioxidant capacity, subclinical elevated profile of transaminases before starting DOTS were forewarning laboratory indices. LFT ought to be monitored at fortnight, a month and at 2 months in such patients as minimum necessity to timely detect and address hepatotoxicity.


DOTS; Primary antitubercular drugs; Hepatotoxicity; transaminases; monitoring in tuberculosis


Pandit A., Tuberculosis: A basic discourse Apollo medicine, 2016; 13:86-90.

Pandit A., Tuberculosis control: Perspective and programmes, Mintage Journal of Pharmaceutical and Medical Research, 2016; 5:7-10.

Pratt DS, Kaplan MM, Evaluation of abnormal liver-enzyme results in asymptomatic patients, N Engl J Med 2000; 342(17):1266-71.

Chitturi S, Ferrell G, Drug induced liver disease. In Schiff ER, Sorrell MF, Maddrey WC, eds. Schiffs Diseases of Liver, 9th ed. Philadelphia. Lippincott Williams and Wilkins, 2002; 1059-1128.

Pessayre D, Bentata M, Degott C, Nouel O, Miguet JP, Rueff B, Benhamou JP. Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction, Gastroenterology, 1977; 72(2): 284-9.

Kulkarni A, Madrasi NA, Relationship of nitric oxide and protein carbonyl in tuberculosis, Indian J Tuberc, 2008; 55(3): 138-44.

Rai RR, Phadke MS. Plasma oxidant-antioxidant status in different respiratory disorders, Indian J Clin Biochem, 2006; 21(2):161-4.

Mitchell JR, Thorgeirsson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ, Jollow HR, Keiser HR, Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites, Clin Pharmacol Ther, 1975; 18(1):70-9.

Sarma GR, Immanuel C, Kailasam S, Narayana AS, Venkatesan P, Rifampin-induced release of hydrazine from isoniazid- A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin, Am Rev Respir Dis., 1986; 133(6):1072-5.

Kopanoff DE, Snider DE Jr, Caras GJ, Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study, Am Rev Respir Dis., 1978; 117(6):991-1001.

Snider DE Jr, Caras GJ, Isoniazid-associated hepatitis deaths: a review of available information, Am Rev Respir Dis., 1992; 145: 494-7.

Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ, The human bile salt export pump: characterization of substrate specificity and identification of inhibitors, Gastroenterology, 2002; 123(5):1649-58.

Martínez E, Collazos J, Mayo J, Hypersensitivity reactions to rifampin. Pathogenetic mechanisms, clinical manifestations, management strategies, and review of the anaphylactic-like reactions. Medicine (Baltimore), 1999; 78(6):361-9.

Rae JM, Johnson MD, Lippman ME, Flockhart DA, Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays, J Pharmacol Exp Ther 2001; 299(3):849-57.

Centers for Disease Control and Prevention (CDC). Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection, MMWR Morb Mortal Wkly Rep. 2002; 51(44):998-9.

Lee WM. Drug-induced hepatotoxicity. N Engl J Med, 2003 Jul 31; 349(5):474-85.

Ferrell GC, Drug induced liver disease, Edinburgh. Churchill Livingstone 1993. P 1-673.

Sharma SK, Mohan A, Antitubercular drug induced hepatotoxicity, In Venkataraman GS ed. Medicine Update, Vol. 14 Mumbai.Association of Physicians of India, 2004 p 298-306.

Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN et al American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis, Am J Respir Crit Care Med. 2003; 167(4):603-62.

Sangeetha P, Das UN, Koratkar R, Suryaprabha P. Increase in free radical generation and lipid peroxidation following chemotherapy in patients with cancer, Free Radic Biol Med, 1990; 8(1):15-9.

Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power" the FRAP assay, Anal Biochem, 1996; 239(1):70-6.

Leavy AS, Greene T, Kusek JW, Beck GJ, A simplified equation to predict glomerular filtration rate from serum creatinine, J Am Soc Nephrol, 2000;11:A0828.

Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK, Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment, Am J Respir Crit Care Med. 2002; 166(7):916-9.

Mehta S, Malnutrition and drugs: clinical implications. Dev Pharmacol Ther, 1990; 15(3-4):159-65.

Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK, Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study, Thorax, 1996; 51(2):132-6.

Gangadharam PR. Isoniazid, rifampi, and hepatotoxicity, Am Rev Respir Dis, 1986; 133(6): 963-5.

Garg PK, Tandon RK, Antituberculosis treatment induced hepatotoxicity, in Sharma SK, Mohan A, eds. Tuberculosis. 2nd ed. New Delhi, Jaypee Bros Medical Publ., 2009; 783-795

Anand CAC, Risk Factors of Hepatotoxicity during Anti-tuberculosis treatment, MJAFI (Medical Journal of the Armored Forces India), 2006; 62: 45-49.

Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB, Diagnosis and monitoring of hepatic injury-I, Performance characteristics of laboratory tests, Clin Chem, 2000; 46(12):2027-49.

Marvin W, Impacts of gender on drug responses, Drug Top, 1998; 591–600

Shakya R, Rao BS, Shrestha B, Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors, Ann Pharmacother, 2004; 38(6):1074-9.

Mahmood K, Hussain A, Jairamani KL, Talib A, Abbasi B, Salkeen S, Hepatotoxicity with Antituberculosis Drugs: The risk factors, Pak J Med Sci, 2007, 23: 33-38

Makhlouf HA, Helmy A, Fawzy E, El-Attar M, Rashed HA, A prospective study of antituberculous drug-induced hepatotoxicity in an area endemic for liver diseases, Hepatol Int., 2008; 2(3):353-60.

Grönhagen-Riska C, Hellstrom PE, Fröseth B., Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis, Am Rev Respir Dis, 1978; 118(3): 461

Girling DJ. Adverse effects of antituberculosis drugs, Drugs. 1982 ;23(1-2):56-74

Singh J, Garg PK, Tandon RK, Hepatotoxicity due to antituberculosis therapy, Clinical profile and reintroduction of therapy, J Clin Gastroenterol, 1996; 22(3):211-4.

Krishnaswamy K, Prasad CE, Murthy KJ, Hepatic dysfunction in undernourished patients receiving isoniazid and rifampicin, Trop Geogr Med, 1991; 43(1-2):156-60.

Buchanan N, Eyberg C, Davis MD, Isoniazid pharmacokinetics in Kwashiorkor, S Afr Med J, 1979; 56(8):299-300.

Paton NI, Chua YK, Earnest A, Chee CB. Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting, Am J Clin Nutr., 2004; 80(2):460-5.

Burman WJ, Reves RR, Hepatotoxicity from rifampin plus pyrazinamide: lessons for policymakers and messages for care providers, Am J Respir Crit Care Med, 2001; 164(7):1112-3.

Pandit A, Treatment outcomes in tuberculosis at TB/DOTS unit of tertiary care centre, Mintage Journal of Pharmaceutical and Medical Research, 2016; 5:15-16

Tost JR, Vidal R, Caylà J, Díaz-Cabanela D, Jiménez A, Broquetas JM, Study Group for Severe Hepatotoxicity due to Anti-tuberculosis Drug,. Severe hepatotoxicity due to anti-tuberculosis drugs in Spain., Int J Tuberc Lung Dis., 2005; 9(5):534-40

Steele MA, Burk RF, DesPrez RM, Toxic hepatitis with isoniazid and rifampin. A meta-analysis, Chest, 1991; 99(2):465-71.

[No authors listed] Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society, Thorax. 1998; 53(7):536-48.

Migliori GB, Raviglione MC, Schaberg T, Davies PD, Zellweger JP, Grzemska M,et al Tuberculosis management in Europe. Task Force of the European Respiratory Society (ERS), the World Health Organisation (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD) Europe Region, Eur Respir J., 1999; 14(4):978-92.

Agal S, Baijal R, Pramanik S, Patel N, Gupte P, Kamani P, Amarapurkar D. Monitoring and management of antituberculosis drug induced hepatotoxicity, J Gastroenterol Hepatol., 2005; 20(11):1745-52.

Byrd RB, Horn BR, Solomon DA, Griggs GA, Toxic effects of isoniazid in tuberculosis chemoprophylaxis. Role of biochemical monitoring in 1,000 patients, JAMA, 1979; 241(12):1239-41.

Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Sub-committee, An official ATS statement: hepatotoxicity of antituberculosis therapy., Am J Respir Crit Care Med, 2006; 174(8):935-52.

Xia YY, Hu DY, Liu FY, Wang XM, Yuan YL, Tu DH, et al. Design of the anti-tuberculosis drugs induced adverse reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS), BMC Public Health. 2010; 21,10:267.

Raghu G, Wells AU, Nicholson AG, Richeldi L, Flaherty KR, Le Maulf F et al. Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria, Am J Respir Crit Care Med, 2016 Jun 22.

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