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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 1  |  Page : 5-8

Prevalence of drug-induced liver injury in patients on antitubercular therapy


1 Department of Medicine, Army Hospital RR, New Delhi, India
2 Department of Internal Medicine, Military Hospital, Dehradun, Uttarakhand, India
3 Department of Preventive and Social Medicine, Armed Forces Medical College, Pune, Maharashtra, India
4 Department of Medicine, Armed Forces Medical College, Pune, Maharashtra, India
5 Medical Cadet, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission24-Dec-2020
Date of Decision27-Jan-2021
Date of Acceptance06-Feb-2021
Date of Web Publication18-May-2021

Correspondence Address:
Dr. Sonal Singh
Military Hospital, Garhi Cantt, Dehradun - 248 003, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amjm.amjm_74_20

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  Abstract 


Background: As per the World Health Organization Global Tuberculosis (TB) Report 2019, there were an estimated 10.0 million new TB cases worldwide in 2018, with India (27%) having the maximum burden of the disease. Drug-induced liver injury (DILI) due to antitubercular treatment (ATT) is a serious adverse effect and a major cause of discontinuation of ATT, leading to increased drug resistance, morbidity, and mortality. Methodology: This was an observational study that was conducted at a tertiary care center in South Maharashtra having a dedicated TB nodal center. All newly detected cases of pulmonary and extrapulmonary TB and cases of TB after relapse/failure/treatment after default, who reported to this nodal center from January 2019 to June 2019 and in whom Category 1 and Category 2 ATT was started as per the Revised National Tuberculosis Programme protocol, were enrolled in this study. Results: Out of 100 enrolled patients, 10 (10%) were diagnosed to have ATT-induced DILI, which is concordant with other studies. No deaths were recorded. However, there was no statistically significant difference between male and female patients who developed DILI (12% males vs. 8% females). No correlation was found with body mass index or alcohol consumption. Conclusion: A fine balance should be struck between unnecessary discontinuation of ATT and continued safe treatment. Patient and staff education, careful selection of regimen, and close monitoring of risk factors will minimize cases of DILI.

Keywords: Antitubercular treatment, drug-induced liver injury, prevalence


How to cite this article:
Singhal A, Singh S, Yadav AK, Atal AT, Shukla S. Prevalence of drug-induced liver injury in patients on antitubercular therapy. Amrita J Med 2021;17:5-8

How to cite this URL:
Singhal A, Singh S, Yadav AK, Atal AT, Shukla S. Prevalence of drug-induced liver injury in patients on antitubercular therapy. Amrita J Med [serial online] 2021 [cited 2021 Jul 31];17:5-8. Available from: https://www.ajmonline.org.in/text.asp?2021/17/1/5/316321




  Introduction Top


As per the World Health Organization Global Tuberculosis (TB) Report 2019, there were an estimated 10.0 million new TB cases worldwide in 2018, with India (27%) having the maximum burden of the disease. According to the report, there were an estimated 26.9 million new cases of TB in India in 2018. The backbone of antitubercular treatment (ATT) under Revised National Tuberculosis Programme (RNTCP) in India is formed by and includes hepatotoxic drugs, namely isoniazid (INH), pyrazinamide, and rifampicin. Drug-induced liver injury (DILI) due to ATT is a serious adverse effect and a major cause of discontinuation of ATT, leading to increased drug resistance, morbidity, and mortality.

DILI secondary to ATT varies widely and is reported in 2%–39% of cases worldwide.[1] The reported mortality from DILI after development of jaundice varies from 4% to 12%.[2] From an analysis of pooled data from four prospective Indian studies with directly observed therapy short,[3],[4] the risk of DILI was found to be 11.5%. The incidence of DILI varies with the definition, study population, and treatment regimen. There is no agreed definition of DILI and most definitions focus on alanine aminotransferase (ALT). Different recommendations have been made for monitoring liver tests in patients on ATT by the British Thoracic Society, the American Thoracic Society, and the European Respiratory Society, with some favoring a risk factor-based approach. Despite this, DILI remains a diagnosis of exclusion and rechallenge with suspected offending agent with more than two-fold elevation in ALT, and fall in ALT after discontinuation is the strongest diagnostic confirmation of DILI.[5]

With these background data, an observational study was conducted in South Maharashtra to study the incidence of ATT-induced DILI in patients on the first-line ATT.


  Methodology Top


This was an observational study that was conducted at a tertiary care center in South Maharashtra having a dedicated TB nodal center. All newly detected cases of pulmonary and extrapulmonary TB and cases of TB after relapse/failure/treatment after default, who reported to this nodal center from January 2019 to June 2019 and in whom Category 1 and Category 2 ATT was started as per the RNTCP protocol, were enrolled in this study. Both outpatients and inpatients were enrolled. Ethical clearance was obtained from the Institutional Ethical Committee, and written informed consent was taken from the patients.

For the purpose of this study, recommendations from the Indian Network for DILI 2012 were used for the diagnosis of DILI. DILI was defined as (a) aspartate aminotransferase (AST) or ALT levels >5 times the upper limit of normal (ULN), regardless of symptoms, or (b) total bilirubin >2 mg/dL and rise in AST or ALT or alkaline phosphatase levels >2 times the ULN or (c) AST or ALT >3 times ULN, if symptomatic with nausea, vomiting, abdominal pain, anorexia, skin rash, etc.

A thorough history was taken regarding comorbidities, ingestion of alcohol and/or hepatotoxic drugs or complementary and alternative medications, and any previous underlying liver disease. Serological testing for hepatitis A, B, C, and E was carried out. All patients presenting with DILI underwent abdominal ultrasound to rule out biliary obstruction. Other investigations such as serum ceruloplasmin, antinuclear antibody, and antismooth muscle antibody were done if clinically indicated to rule out other causes of abnormal liver function tests (LFTs). Baseline LFT was carried out and then repeated at weekly interval for 2 weeks, followed by fortnightly and monthly intervals for a total duration of 6 months. All the patients were followed up for 6 months once started on ATT.

Patients with underlying liver disease, on other hepatotoxic drugs, and on abnormal baseline LFTs were excluded from the study. The demographic profile, comorbidities, symptoms and timing of onset of DILI, and resolution of symptoms following withdrawal of ATT were recorded.

The data were collected in MS Excel. The continuous variable was defined as mean and standard deviation. The qualitative variables were described as frequency and percentage. StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP was used for statistical analysis. A P < 0.05 was taken statistically significant.


  Results Top


A total of 100 patients were enrolled in the study, 50 female and 50 males, who satisfied the inclusion and exclusion criteria. The demographic and clinical profile of these patients is shown in [Table 1].
Table 1: Demographic and clinical profile of enrolled patients (n=100)

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Out of 100 enrolled patients, 10 (10%) were diagnosed to have ATT-induced DILI. No deaths were recorded. The demographic and clinical profile of these patients is depicted in [Table 2]. Out of 10 patients who developed DILI, two had HIV coinfection, both of which were not initiated on highly active antiretroviral therapy yet. Of these 10 patients, one patient had HIV and hepatitis B virus (HBV) coinfection. However, on further evaluation, his HBeAg was negative and HBV-DNA was undetectable. There was no evidence of chronic liver disease on abdominal ultrasound. Therefore, the patient was labeled as chronic HBV carrier. Concomitant alcohol consumption was noted in four patients. Patients who developed DILI had statistically higher age as compared to patients who did not have DILI [Figure 1]. However, there was no statistically significant difference between male and female patients who developed DILI (12% male vs. 8% females). No correlation was found with body mass index (BMI) or alcohol consumption.
Figure 1: Graph depicting relationship between development of DILI and age

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Table 2: Demographic and clinical profile of patients who developed drug-induced liver injury (n=10)

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Five (50%) out of 10 patients reported to have symptoms at 4 weeks of initiation of therapy, 3 (30%) after 2 weeks of therapy, and 2 (20%) after a week of therapy. The time taken for the serum bilirubin to settle down after ATT was stopped is depicted in [Figure 2]. ATT was stopped for the average period of 3 weeks following which all of them recovered.
Figure 2: Kaplan- Meier survival estimate

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  Discussion Top


Hepatotoxicity due to ATT drugs includes a wide spectrum of liver injury which ranges from asymptomatic elevation of liver enzymes to acute liver failure requiring liver transplant and death. Approximately, 20% of the patients on ATT have transient elevation of liver enzymes which is self-limiting.[1] This phenomenon is attributed to adaptation or tolerance to ATT drugs. In our study, 10% of the patients were diagnosed to have ATT-induced DILI. In a large series from New Delhi, involving a total of 1223 patients with acute liver failure, anti-TB drugs contributed to 5.7% (70) patients with ALF, with 67% mortality.[6] In another study conducted at CMC, Vellore, the prevalence of ATT-induced DILI was found to be 9.48%.[7] Our results are in concordance with these studies.

In our study, advanced age was associated with higher incidence of DILI. Recent studies have noted that patients older than 35 years of age are at 4 times increased risk of developing TB DILI.[3] In our study, female sex was not associated with a higher risk of DILI. For women, several studies have shown increased risk of hepatotoxicity,[8],[9] but this was not always treatment limiting.[9] One study did show four times higher risk of treatment-limiting hepatotoxicity in women but with an overall incidence of only 2%.[8] In our study, BMI and alcohol consumption were not associated with DILI. Malnutrition and hypoalbuminemia have been shown to be associated with DILI in several studies from India.[10],[11] The effect of alcohol as a risk factor for DILI has been ascribed to under-nutrition and depleted glutathione stores.[12]

Our studies had a few limitations. First, causality due to HBV, hepatitis C virus, or HIV coinfection could not be established due to low sample size. There was only one case of hepatitis B in our study and only two cases of HIV-positive patients who developed DILI. As shown in previous Indian studies, patients with HIV infection are prone to DILI due to concomitant use of protease inhibitors.[13] Few studies[14],[15] suggest that hepatitis B carriers may have more severe liver injury secondary to ATT. Second, patients with baseline abnormal LFT and underlying liver disease were eliminated from the study.


  Conclusion Top


Understanding the basic mechanism, genetic factors, and risk factors associated with ATT-induced DILI is crucial in the management and effective treatment of TB. In many instances, data regarding the risk factors are conflicting or insufficient. A fine balance should be struck between unnecessary discontinuation of ATT and continued safe treatment. Patient and staff education, careful selection of regimen, and close monitoring of risk factors will minimize cases of DILI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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Pessayre D, Bentata M, Degott C, Nouel O, Miguet JP, Rueff B, et al. Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction. Gastroenterology 1977;72:284-9.  Back to cited text no. 2
    
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Saha A, Shanthi FX, Winston AB, Das S, Kumar A, Michael JS, et al. Prevalence of hepatotoxicity from antituberculosis therapy: A five-year experience from South India. J Prim Care Community Health 2016;7:171-4.  Back to cited text no. 7
    
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Schaberg T, Rebhan K, Lode H. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 1996;9:2026-30.  Back to cited text no. 9
    
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Krishnaswamy K, Prasad CE, Murthy KJ. Hepatic dysfunction in undernourished patients receiving isoniazid and rifampicin. Trop Geogr Med 1991;43:156-60.  Back to cited text no. 10
    
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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;166:916-9.  Back to cited text no. 11
    
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Senousy BE, Belal SI, Draganov PV. Hepatotoxic effects of therapies for tuberculosis. Nat Rev Gastroenterol Hepatol 2010;7:543-56.  Back to cited text no. 12
    
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Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998;157:1871-6.  Back to cited text no. 13
    
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Wu JC, Lee SD, Yeh PF, Chan CY, Wang YJ, Huang YS, et al. Isoniazid-rifampin-induced hepatitis in hepatitis B carriers. Gastroenterology 1990;98:502-4.  Back to cited text no. 14
    
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Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000;31:201-6.  Back to cited text no. 15
    


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