WHO GRADING OF DILI

DILI patients were classified according to WHO criteria for grading of DILI according to ALT levels.

ATT and altered Baseline LFT values

With the prevalence of alcoholism and diabetes more in developing countries, a significant proportion of patients has baseline altered LFT values. There are no clear cut evidence-based guidelines exist for the use prescribing ATT, in patients with cirrhosis. When no other alternatives are advisable, close monitoring is needed and risk factors should also be evaluated. In patients with history of alcohol intake and cirrhosis, ATT is associated with hepatotoxicity in 10%. “Recommended ATT in Child class A cirrhosis is the same as a noncirrhotic population but strict follow up is required. In Child class B Pyrazinamide should be avoided”. Isoniazid and Rifampicin may be avoided. Medications should be individualized depending upon various factors. Surveillance using liver enzymes is recommended with use of INH but still it can cause acute liver failure. The cause for the underlying liver enzyme abnormality or the liver disease must be established before starting ATT [1]. 

        In a retrospective study by Abbara A et al   there were 105 (6.9%) cases of ATT-associated DILI amongst 1529 patients diagnosed with active TB between April 2010 and May 2014. Risk factors for DILI were: low patient weight, HIV-1 co-infection, higher baseline ALP, and alcohol intake. Half (53%) of the cases occurred within 2 weeks of starting ATT and 87.6% occurred within 8 weeks. Five (4.8%) of seven deaths were attributable to DILI.

        In another retrospective study by Jeong I (2015) et al   among the 195 patients, 17 (8.7%) developed hepatotoxicity, and their mean AST/ALT values (mean± SD) were 249±229/249±250 IU/L. Among the 17 patients who developed hepatotoxicity, 5 were excluded for having anti-TB DIH. Acetaminophen (2 patients) and alcohol (2 patients) were the other putative causes of hepatotoxicity, and viral hepatotoxicity was presumed to be the cause in 1 patient. The median latent period for developing DIH was 37 days (range 13-112) in anti-TB DIH group. Thirty other    patients   showed   mild   LFT   abnormality, as defined previously (60 IU/L≤serum AST or ALT level<120 IU/mL).

        In a study by Ramanadougar et al [4]  the study group of 100 pulmonary tuberculosis patients consisted of 67 males and 33 females. Age varied from 15 – 80 years. Twenty eight patients (28%) developed anti-tuberculosis treatment induced liver damage which included 23 (23%) patients who had asymptomatic elevation of liver enzymes and 5 (5%) patients who developed overt drug induced hepatotoxicity. Among patients who developed ATT induced liver damage 46.4% patients had history of high alcohol intake, 50% patients had BMI < 18, 53.6% patients had radio logically severe disease and 78.6% patients had pre-treatments albumin < 3.5% gm/dl.

Figure 1: Mechanism of DILI

In a study analyzing the pattern of ADRs caused by the anti-tubercular drugs. Inpatient files of all the TB patients during the period from 1st January 2001 till 31st December 2006. 326 patients were identified among which 40 (females 24, males 16) experienced at least one ADR. The most common ADR was elevated liver enzymes [24 (57.14%)] and hepato-biliary system was the most common system affected. More than half the ADRs [21 (52.55%)] developed within 20 days of initiation of therapy. Isoniazid and Pyrazinamide were the suspected drugs. The most common laboratory abnormality observed was elevated SGOT level in 21 patients (52.5%)]. Seven (17.5%) patients needed specific drug treatment for managing the ADRs and 10 (25%) needed symptomatic management. Thirty five (87.5%) patients recovered following the ADR. 

        A study regarding incidence of anti-tuberculosis drug induced hepatotoxicity and associated risk factors among the patients in Dawro Zone, South Ethiopia: A Cohort Study was conducted. 124 new tuberculosis positive individual available from Tercha Hospital and Five health Centre’s during data collection were consecutively included. The socio-demographic data and anthropometric measurement were obtained. The incidence of anti- TB-DIH was found to be 8%. The drug responsible for hepato-toxicity was not known. Chronic high alcohol intake was associated with development of anti-TB-DIH. 

        In another prospective study to determine the clinical profile in patients with ATT-induced hepatotoxicity and to test a predefined strategy of reintroduction of ATT. 72 consecutive patients with clinical evidence of ATT-induced hepatotoxicity were included. Jaundice was the presenting symptom in 44 (61%) patients; prodromal symptoms were present in 28 (39%). Serious complications developed in 12 (16.6%) patients (fulminant hepatic failure in seven, sub acute hepatic failure in four, hepatic encephalopathy in one). Nine patients (three males, six females) died from these complications. The mean duration of treatment before the onset of hepatitis was significantly longer in the group that died than in the rest of the patients. Malnutrition was present in 37 of the 72 patients. After resolution of drug induced hepatitis, reintroduction of Isoniazid and Rifampicin was possible in 41 of 44 patients. Thus, results showed that ATT-induced hepatitis carried significant morbidity and mortality, that malnutrition was common in patients with ATT-related hepatitis, and that potentially hepatotoxic anti-tuberculosis agents could be safely reintroduced after recovery from hepatitis. 

        In a study by Buntoro IF et al [8] in Indonesia in which they compared liver function test after treatment with FDC in tuberculosis patients. They observed a rise of 54.69±37.66 % in SGPT levels as compared to baseline levels in patients who were not malnourished and a rise of 135.05±117.45 in patients with malnutrition. In younger patients the rise was of 9.1±12.7 IU/L and in older patients the rise observed was 15.5±12.6 IU/l.

        No further studies are available or conducted in India regarding FDC induced hepatitis/ DILI in Indian population and hence this study was planned to find the incidence and risk of DILI in tuberculosis patients receiving FDC DOTS.

Advanced age, female sex, moderately/far advanced/extensive disease, hypo-albuminemia, malnutrition, alcoholism, underlying liver disease, Hepatitis B virus infection, Hepatitis C virus infection, HIV infection, acetylator phenotype, N-acetyl transferase(NAT) activity and Glutathione s-transferase activity are the factors responsible for drug induced liver injury in the patients receiving anti tubercular treatment.

1. Vaishnavi Priyaa, C. A Study on LFT Monitoring in ATT and the Spectrum of Anti-Tuberculosis Drug-Induced Liver Injury [MD thesis]. Guindy, Chennai, Tamil Nadu: Dr. MGR Medical University, 2015.

2. Abbara, A., et al. "Drug-Induced Liver Injury from Antituberculous Treatment: A Retrospective Study from a Large TB Centre in the UK." BMC Infectious Diseases, vol. 17, 2017, Article ID 231.

3. Jeong, I., et al. "Drug-Induced Hepatotoxicity of Anti-Tuberculosis Drugs and Their Serum Levels." Journal of Korean Medical Science, vol. 30, 2015, pp. 167–172.

4. Ramanagoudar, P.S. Effect of Anti-Tubercular Treatment on Liver in Freshly Diagnosed Pulmonary Tuberculosis Patients Receiving DOTS Therapy [MD thesis]. Bangalore, Karnataka: Rajiv Gandhi University of Health Sciences.

5. Alam, K., et al. "Reporting Adverse Drug Reactions Among Hospitalized Medical Patients: A Prospective Study from Tertiary Care Hospital in Western Nepal." Nepal Journal of Epidemiology, vol. 4, no. 1, 29 Mar. 2014, pp. 330–336.

6. Abera, W., et al. "Incidence of Anti-Tuberculosis Drug-Induced Hepatotoxicity and Associated Risk Factors Among Tuberculosis Patients in Dawro Zone, South Ethiopia: A Cohort Study." International Journal of Mycobacteriology, vol. 5, no. 1, Mar. 2016, pp. 14–20.

7. Singh, J., et al. "Hepatotoxicity Due to Anti-Tuberculosis Therapy: Clinical Profile and Reintroduction of Therapy." Journal of Clinical Gastroenterology, vol. 22, no. 3, Apr. 1996, pp. 211–214

8. Buntoro, If., et al. "Decrease of Liver Function After Treatment of Anti-Tuberculosis Drugs in Tuberculosis Patients with Malnutrition and Alcohol Consumption." International Journal of Pharmacy and Pharmaceutical Sciences, vol. 8, no. 7, 2016, pp. 269–273