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Go Back       Himalayan Journal of Community Medicine and Public Health | Volume:3 Issue:1 | Jan. 10, 2022
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DOI : 10.47310/Hjcmph.2022.v03i01.011       Download PDF       HTML       XML

To Estimate Baseline Liver Injury in New Tuberculosis Patients Initiated On Daily DOTS from Indira Gandhi Medical College Shimla

Kheora S1 and Rana A*2

1Dr Siddhartha Kheora, Department of Medicine, IGMC Shimla, India

2Dr Aman Rana, Department of Pediatrics,IGMC Shimla, India

*Corresponding Author

Dr Aman Rana

Article History: | Received: 20.12.2021 | Accepted: 30.12.2021 | Published: 10.01.2022|

Abstract: It has been hypothesised that various factors can lead to this diversity like age, sex, baseline liver function tests, underlying liver diseases, malnutrition and severity of tuberculosis disease. Also genetic susceptibility of the patients to drug liver injury has been identified such as NAT2 polymorphism. We conducted a cross sectional study to estimate the baseline liver injury in newly diagnosed tuberculosis patients before the initiation of anti tubercular drugs. There were a total of 312 participants in our study . The mean age of all patients was 40.26±17.82 years. All patients had normal liver function tests before the initiation of therapy. Liver function tests were monitored at initiation, 2ndand 4th week of the treatment to note the elevation in serum bilirubin and liver transaminase levels which indicate the anti-tuberculosis treatment induced hepatotoxicity.

Keywords: Liver injury, Tuberculosis, Anti tubercular therapy.

Copyright @ 2022: This is an open-access article distributed under the terms of the Creative Commons Attribution license which permits unrestricted use, distribution, and reproduction in any medium for non commercial use (NonCommercial, or CC-BY-NC) provided the original author and source are credited.


As per the global burden of disease report of world health organisation in 1990, tuberculosis ranked as the 7th most common disease in world causing morbidity globally.i It affects nearly eight million new people yearly and causes two million deaths each year.ii,iii This can be interpreted as that in every 4 seconds one person becomes a case of tuberculosis and in every 10 seconds one person dies because of tuberculosis. Tuberculosis was declared as a global emergency in 1993 by world health organisation and is still an emergency and every year the cases are increasing.iv,v

First line anti-tuberculosis drugs are Isoniazid (INH), Rifampicin (RMP), Pyrazinamide (PZA), Ethambutol (E) and Streptomycin (S).vi,vii These drugs were recommended by WHO under brand name of Directly observed treatment short-course (DOTS) to control tuberculosis. Use of DOTS by healthcare providers was a vital step in controlling tuberculosis under the framework of Revised National Tuberculosis Control Programme (RNTCP).

The incidence of Anti- tuberculosis Drug induced Hepatitis varies from 3 -28% in various studies with higher incidence in Asian countries.viii Reason for the development of this hepato-toxicity despite all patients receives same doses of drugs is still unclear.

Drug induced liver injury or DILI, one of the leading causes of acute liver failure in US, accounts for 13% of cases of acute liver failure posing a major challenge for drug development and safety.ix

In India and other developing countries, ATT is the most important drug implicated in DILI. .Anti Tuberculosis drug induced liver injury is mostly due to inadequate evaluation of risk factors and “inappropriate dosing”. Worldwide, incidence of Anti Tuberculosis DILI ranges between 5 to 33%.x

India which contributes significant proportion of TB cases, the incidence of ATT DILI ranges between 33 to 35%. In India, approximately 70% cases are ATT induced Acute Liver Failure.xi

There are studies about risk factors and predisposing factors for DILI. But there are only few studies about the frequency of monitoring LFT in patients with these risk factors. WHO, which has put monumental effort in eradicating TB , says, frequent LFT monitoring in all cases are far from reality due to financial drawbacks. The pathogenesis of DILI and contributory factors and mechanisms are not well established till now.

DILI may occur in all currently recommended regimes for treatment of TB. Pyrazinamide, INH, followed by Rifampicin in order, are the most common drugs causing DILI. DILI is most common among first line ATT drugs. Pyrazinamide with Rifampicin appears more toxic than INH alone. A higher risk of hepatotoxicity has been reported in Indian patientsxii,xiii,xiv,xvthan in their western counterparts.xvi,xvii,xviii

Alcoholics with baseline minor elevations of enzymes have to be closely monitored. Other patients who need close monitoring are underlying chronic liver disease like NASH, concomitant hepatotoxic drugs, other systemic diseases like autoimmune diseases, esp. SLE, or metabolic diseases. Age, sex, co-morbid illness, nutritional status, socioeconomic status, literacy, staff education, infrastructure, available lab resources and other possible confounding factors play a statistically significant role. Careful patient selection, adequate basic screening for underlying liver diseases, careful selection of regime according to underlying risk factors and appropriate follow up may reduce serious DILI. A patient with underlying liver disease, need safer regimes and frequent monitoring. This is based on the prognostic scores of the underlying liver disease.

Screening for risk factors, based on the epidemiology, endemicity and prevalence of disease may help avoid unnecessary elaborate investigations. Screening for chronic viral hepatitis in risk groups, according to the endemic prevalence and region wise investigation panels may help overcome the financial constraints in applying all these tests. Anti-tuberculosis therapy is the commonest type of acute liver failure in South Asia followed by Hepatitis B related Acute Liver Failure and alcohol related Acute Liver Failure.

TB drugs can be continued till AST/ALT is 5 × ULN, in the absence of hyper-bilirubinemia or symptoms; or up to 3 × ULN in the presence of symptoms or hyper-bilirubinemia (bilirubin 2 × ULN).

The present study was carried out to estimate the prevalence of DILI in both in patients and out patients on FDC DOTS regime..


Study Design: Prospective cohort study.

Study Period: One year from the protocol approval

Study Population: The study was conducted in all patients presented in the Department of Medicine IGMC Shimla who satisfied the inclusion criteria.

Inclusion Criteria:

1. Age ≥ 15 years

2. Registered on Daily DOTS at IGMC Shimla

Exclusion Criteria:

1. Non-consenting patients

2. Severe liver injury needing modified ATT at baseline

Recruitment strategy/Sampling:

All consecutive patients presented in the DOTS centre of IGMC Shimla were recruited after proper counselling and written informed consent. Baseline liver function were done before initiation of first dose of anti-tubercular treatment. The patient was then followed at 2 and 4 weeks for repeat liver function tests. The test results were obtained telephonically if the patient was unable to visit at 2 and 4 weeks.

In case of significant alteration of liver functions at follow-up, the patient was requested to visit the treating physician for modification of the treatment on the lines of drug induced liver injury. The details of intervention for drug induced liver injury were recorded.

Diagnosis of drug induced liver injury (DILI)

DILI was defined as alteration of liver function after initiation of all anti-tuberculosis drugs, and the presence of at least one of the following criteria

1. A rise of three times the baseline levels of serum aspartate aminotransferase (AST) and/or alanine amino-transaminase (ALT)

2. A three times rise in the level of serum total bilirubin from baseline levels.

Laboratory monitoring:

Liver function tests were performed on all patients before anti-tuberculosis therapy. During treatment, liver enzymes and bilirubin were measured at initiation, 2nd week and 4th week of treatment.

The patients who developed drug induced liver damage in the form of asymptomatic elevation of liver enzymes and bilirubin, were grouped as “DILI Present” and others who did not show any significant change in liver enzymes and bilirubin were classified as “DILI Absent”.

In the DILI group, medications were stopped and serum transaminases were measured weekly until they returned to normal levels. Thereafter, anti TB drugs were gradually reintroduced.

Statistical Analysis

The data was entered in Microsoft excel sheet and was analysed using Epi-info software. Descriptive statistical analysis has been carried out in the present study. Results on continuous measurements are presented on Mean ± SD (Min-Max) and results on categorical measurements are presented in Number (%). Chi-square and fisher exact test were used to find the significance of drug induced liver damage for various risk factors. Significance is assessed at 5% level of significance.


There were a total of 312 patients in our study. Out of them there were 179 (57.4%) males and 133 (42.6%) females. There were 149/179 (83.3%) males of age less than 60 years while 114/133 (85.7%) females were of age less than 60 years. The mean age of all patients was 40.26±17.82 years and that of males and females was 43.25±17.02 years and 36.23±18.14 years respectively.

Table 1: Age and Gender Wise Distribution of Patients
































Liver function tests were done of patients on ATT. The total bilirubin levels of patients at baseline, 2nd week and 4th week were 0.9±0.63, 1.24±1.84 and 1.3±2.85mg/dl respectively with significant association of total bilirubin levels with treatment duration. Likewise SGOT, SGPT and ALP levels increased from baseline to 2nd week and then decreased at 4th week with significant association of all parameters with duration of treatment.

Table 2: Effect of anti TB drugs on liver








































P value (Friedman test)





Figure Image is Available in PDF Format

Figure 1: Pattern of rise of total bilirubin (mg/dl) during the course of RX


In this study, 312 patients who were started on ATT under Revised National Tuberculosis Control Programme (RNTCP) in Indira Gandhi Medical College, Shimla were studied for adverse effects of anti-tuberculosis drugs. Data was collected for one year and analysed with clinical data, haematological and biochemical investigation.

All patients had normal liver function tests before the initiation of therapy. Liver function tests were monitored at initiation, 2ndand 4th week of the treatment to note the elevation in serum bilirubin and liver transaminase levels which indicate the anti-tuberculosis treatment induced hepatotoxicity.

There were 179 (57.4%) males and 133 (42.6%) females in the study group. The age of the group ranges from 15-88 years with mean age of 40.29±17.72 years. There were more number of patients was in age group of ≤60 years (263 cases). In males 149/179 (83.24%) and 30/179 (16.75%) cases were in age groups of ≤60 years and >60 years respectively. In females 114/133 (85.71%) and 19/133 (14.2%) were in age group of of ≤60 years and >60 years respectively. The mean age of males was 43.25±17.02 years and of females was 36.31±18.04 years.

These findings were close to the study done by Daphne yee et al xix which had 65% males and 35% females. They had maximum number of cases between age group of 17-34 years (51%) with mean age of 40.3 years.

The mean age of cases in similar study done by JN Pande et alxx was 39 years with range from 15-70 years.These finding suggest that tuberculosis affects economically productive age group and also affects significantly larger number of males than females. This can be due to either tuberculosis affects men more than women or men tend to use the medical services, such as RNTCP services more readily.


In our study we found that advancing age is independent risk factor for development of anti-tuberculosis treatment induced hepatotoxicity.

It can be concluded that monitoring of LFTs during the first 2 months of ATT should identify the majority of DILI earlier, possibly shortening treatment interruption and reducing mortality.

Hence, every patient of tuberculosis should be given Anti-tubercular drugs under direct supervision, as it increases the patient adherence to treatment regimens, less increase of SGOT and SGPT, thus less prone to develop hepatotoxicity, more compliant to patient, increased effectiveness with easy availability in all government hospitals and awareness of patient about the disease.


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