In consideration to the global tuberculosis epidemic India has a unique position as in 1992 in a comprehensive review it was observed that less than half of tuberculosis patients received an accurate diagnosis and of them less than half were treated effectively [1].

        It is one of the foremost public health problems and causes enormous burden of combined suffering and death. One of the basic approach to control clinical tuberculosis is chemotherapy also known as DOTS, directly observed treatment short course, or FDC, fixed dose combination [2].

        Anti-tuberculosis Dili has a wide spectrum of presentations, ranging from asymptomatic mild rise in liver biochemical tests to acute hepatitis and acute liver failure. The mild increase in amino-transferases experienced by ~20% of patients is usually asymptomatic.

To prevent serious complications of drug induced acute liver injury, the most important step is to withdraw all hepatotoxic drugs when values of liver enzymes reach critical levels. A feature peculiar to anti-TB drugs is the development of adaptation or tolerance to the drugs. Indeed, adaptation during INH or anti-TB use is an illustrative example for adaptation. The present study was conducted to estimate the proportion and describing the magnitude of drug induced liver injury in patients started on anti-tubercular drugs

Methodology      

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 

• Age ≥ 15 years          
• Registered on Daily DOTS at IGMC Shimla

Exclusion Criteria 

• Non-consenting patients 
• 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 

• A rise of three times the baseline levels of serum aspartate aminotransferase (AST) and/or alanine amino-transaminase (ALT) 
• 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 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 4: Age distribution of Dili

        There were 56 cases of Dili reported in our study out of which both males and females were in equal proportion (28.50%). There were 41/56 (73.21%) cases of Dili in participants of age less than 60 years followed by 15/56 (26.78%) cases amongst >60 years age group cases. The overall prevalence of Dili cases was found to be 17.95% in our study.

Table 5: Serum bilirubin and liver enzymes in elevated group (Dili)

        Table 5 shows the liver enzymes levels in patients of Dili. The mean serum bilirubin level was 0.76±0.48 at baseline and increased to 2.33±3.29 at 2nd week and to 3.41±6.96 at 4th week of treatment. The mean levels of SGOT and SGPT increased to more than 5 times the baseline values at 2nd week of treatment and then decreased by 4th week.

        Albumin levels were evaluated in 256 patients at start of treatment. Out of 56 patients of Dili, albumin levels were evaluated in 46 patients and out of them 29 had albumin levels of less than 3.5

 Table 6: Baseline albumin levels in patients with Dili and without Dili

In our study, 56 (17.94%) cases showed the evidence of anti-tuberculosis treatment (ATT) induced liver damage in the form of elevation of serum bilirubin and transaminase levels three times above normal. The remaining 256 (82%) cases didn’t show any significant change in their serum bilirubin and/or transaminase levels as compared to pre-treatment levels.

Our findings are comparable with similar study done by SK Rajan et al   which considered 50 cases and among these 11 (22%) cases developed drug induced liver damage. 

The relatively higher incidence of hepatotoxicity in the developing countries has been attributed to various factors. There is no consensus as which one of these factors, whether alone or in combination is involved in the development of DIH and whether they could be used as markers to identify patients at high risk.

In our study 41/263 (15.58%) cases in the age group of ≤60 years and 15/49 (30.61%) cases in the age group of > 60 years developed ATT induced liver damage. These results indicate that advancing age is an independent risk factor for drug induced hepatotoxicity consistent with previous reports. 

Many studies have shown that advancing age is an independent predictor of ATT induced liver damage. A study done by SK Sharma et al  found that older age (OR=1.2) is a risk factor for Dili (p<0.05) as compared to non-DIH group.

In our study, among 56/312 (17.9%) patients who had asymptomatic elevation of liver enzymes, 28/179 (15.6%) cases were males and 28/133 (21%) were females with equal proportion (50%) of males and females with Dili

According to Dili by Naga Chalasani, –women have a slightly higher risk of liver injury due to “certain medications” and not “all cause Dili”. This study has also come out with similar results.

However, some studies suggest that males are more likely to have Dili, as the other risk factors like advancing age, high alcohol intake, radio-logically extensive disease were present significantly in males as confounding factors, giving an impression that liver damage is more common in males as compared to females.

However, some workers believe that the incidence of DIH due to anti tuberculosis drugs is not influenced by the sex of the patient.

We observed that, 29 (25%) cases in elevated group (n=116) had pre-treatment serum albumin < 3.5gm/dl as compared to 87 (75%) cases in non-elevated group (p<0.008). In a study by SK Sharma et al, pre-treatment serum albumin of <3.5gm/dl was present in 32% of DIH group compared with 16% of non-DIH group (p<0.01, OR=2.3). They concluded that patients with pre-treatment hypo-albuminemia had a twofold higher risk of developing DIH.  In a study by JN Pande et al   the serum albumin was significantly lower in the cases during hepatitis than in the controls (p<0.001).there was no significant difference in the serum albumin among the patients with extensive or limited disease.

In our study the liver enzyme levels were measured at baseline, 2nd week and 4th week. The levels increased from baseline value to significant levels at 2nd week and then were restored to normal levels later due to hepatic adaptation. Rao R et al   in their study observed that the mean levels of liver enzymes increased in 2nd and 4th week and then decreased in 6th week of treatment and further decrease was seen in 8th week but in our study the mean level of enzymes raised in 2nd week and then in 4th week decreased to normal levels.

Mathew S observed that there was significant increase in the total Bilirubin, SGOT, SGPT in the first week after the onset of treatment. The pair wise comparison done among the pre-treatment values, 1st week, 1st month and 4th month values also showed that there was significant increase in the total Bilirubin, SGOT, SGPT in the first week after the onset of treatment and later the values decreased at 4th week and further decrease was seen on 16th month.

Liver function tests were measured before initiation of therapy and repeated at 2nd and 4th week of treatment to look for asymptomatic elevation of liver enzymes and overt drug induced hepatitis. 56 cases who showed abnormality in their liver function were grouped as elevated group and remaining 256 cases as non-elevated group. 

The characteristics of both groups were analyzed and results were observed. In our study 17.9% of cases developed Dili. 15.38% of the cases in the age group of 20-59 years and 32.69% of cases in the age group of >60 years showed the evidence of liver damage, concluding that patients in the age group of >60 years are double times more likely to develop drug induced liver damage. 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.

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