Tuberculosis (TB) remains a major global health challenge and was the leading cause of death by a single infectious agent worldwide in 2023. An estimated 10.8 million people developed TB that year, and 1.25 million died of it.Of those who fell sick with TB in 2023, about 87% were concentrated in 30 high TB burden countries with India being home to one-fourth (26%) of the world’s TB population and the country with highest TB burden.[1,2]The standard first-line regimen—isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E)—is effective but hepatotoxicity is a recognized, clinically important complication, particularly attributable to H, R, and Z. Reported ATT-DILI incidence ranges from approximately 5% to 28%, varying by population risk and monitoring intensity [3–6].Clinical manifestations span from asymptomatic enzyme rises to acute liver failure (ALF) with significant mortality [7,15]. Established risk modifiers include age, sex, malnutrition, alcohol use, viral hepatitis, HIV co-infection, and pre-existing liver disease [3,8,9,11]. This study was conducted at a tertiary care hospital in north India to assess the clinical, demographic and laboratory parameters of patients who developed ATT-induced hepatitis to better understand the patterns and predictors of hepatotoxicity. The hepatotoxicity of first line ATT drugs poses a serious challenge, especially in low resource settings where malnourishment, delayed diagnosis and limiting monitoring facilities are prevalent. This is in addition to the inadequate awareness of early hepatotoxic signs among frontline health workers, which can delay drug withdrawal and worsen outcomes. Indian reports describing the clinical and demographic profile of ATT- induced hepatitis across diverse TB phenotypes in tertiary care are relatively limited [4,12,13]. We therefore characterized patients presenting with ATT-induced hepatitis in a high-volume tertiary center, detailing demographics, clinical features and laboratory patterns.

This was a prospective study conducted at Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar. A total of 103 patients who developed clinical and/or lab features of drug induced hepatitis while receiving  antitubercular treatment were selected for the study, of which 5 were excluded based on exclusion criteria.]

Inclusion criteria

Presence of DILI defined by the presence of any one of the following criteria: [3,14] :

• Elevation of AST and /or ALT ≥ five times the upper limit of normal on one occasion; or ≥ three times the upper limit of normal on three consecutive occasions.
• Elevation of total bilirubin >1.5 mg/dl.
• Elevation of AST and/or ALT above pretreatment levels together with symptoms of nausea, anorexia, vomiting and jaundice.
• Improvement of liver function test (LFTs) after the withdrawal of ATT.

Exclusion criteria:

• Presence of serological evidence of active viral hepatitis (Hepatitis A,B,C,E).
• Known chronic liver disease (CLD).
• Patients with baseline liver function derangements not attributable to ATT.
• Pregnancy or lactation.
• Use of any other hepatotoxic drugs during the treatment period.

Data Collection

Data was collected about the symptoms, the type of tuberculosis (whether pulmonary, extra-pulmonary or disseminated), past history of tuberculosis, family history of tuberculosis and the use of other hepatotoxic drugs was recorded. History about other comorbid conditions like Type 2 Diabetes Mellitus, other liver conditions was noted. Nutritional status was assessed using body mass index (BMI). Lab investigations were done including complete blood counts (CBC), serial Liver function tests (LFTs), coagulation profile, serum protein and serum albumin.

Statistical Analysis

Categorical data was analysed using Pearson’s Chi-square test. Quantitative data was analysed using one way analysis of variance (ANOVA) and independent two sample t-tests. SPSS-22 was used for data analysis.

A total of 103 patients with suspected ATT-induced hepatitis were initially included in the study; 5 were later on excluded (chronic liver disease n=2, concomitant hepatotoxic drug n=1, HCV positive n=2). The analytic cohort comprised 98 patients. Table 1 describes the baseline characteristics of the cohort. Patients were predominantly middle-aged, with a female majority—consistent with several Asian cohorts where sex-related susceptibility has been variably observed [4,8,9]. The rural predominance mirrors catchment patterns and may signal barriers to early monitoring and delayed presentation.

Table 1. Baseline characteristics (N = 98)

Table 2 describes the clinical presentation of patients with gastrointestinal symptoms predominating, providing practical early warning signs for stopping hepatotoxic drugs per ATS guidance [3]. Jaundice in ~29% is slightly lower than some reports [5,13], but encephalopathy in 18% highlights a severe subset, aligned with known risks of progression in hepatocellular DILI [7,16].

Table 2. Clinical presentation (N = 98)

Table 3 shows the type of Tb, with extrapulmonary TB exceeding pulmonary disease—typical for tertiary-care mixes and prolonged/intensive therapy contexts. Frequent pleural and CNS involvement may necessitate longer regimens, potentially increasing exposure to hepatotoxic agents [19,20].

Table 3. Type of tuberculosis at baseline (N = 98)

Table 4 shows the cohort had low alcohol and viral hepatitis confounding after exclusions, strengthening attribution to ATT. Diabetes—though modest—remains relevant as a TB risk factor and potential disease-severity modifier

                                                    Table 4. Comorbidities and history (N = 98)

Baseline LFTs before the start of ATT were largely normal (Table 5), reducing the likelihood of pre-existing hepatic injury. Albumin trended low-normal, consistent with nutritional vulnerability—a recognized ATT-DILI risk factor in regional literature [9,17].

Table 5. Baseline labs before starting ATT (N = 98)

Marked ALT/AST elevations indicate a primarily hepatocellular pattern, with ALP rise pointing to mixed injury in some cases—well-recognized in ATT-DILI [3,10,11]. Albumin reduction from baseline corroborates acute hepatic stress and systemic illness (Table 6).

Table 6. Liver profile at time of ATT-induced hepatitis (N = 98)

This prospective profile of 98 patients with ATT-induced hepatitis highlights a middle-aged, female-predominant, rural cohort, presenting chiefly with gastrointestinal symptoms and hepatocellular-dominant enzyme derangements.

Demographics and symptomatology align with prior South/East Asian studies that report a higher incidence of hepatotoxicity among patients with low BMI, female sex, and extra-pulmonary TB. The high prevalence of under-nutrition and rural background among affected patients highlights the role of socioeconomic, poor access to healthcare  and nutritional vulnerabilities in drug toxicity. [4,8,9,15] Malnutrition impairs hepatic metabolism and protein binding, increasing susceptibility to drug-induced liver injury (DILI). GI symptoms are practical triggers for prompt cessation of hepatotoxic drugs as per ATS guidance [3]. Our encephalopathy rate (~18%) suggests late presentation or severe injury in a subset, consistent with hepatocellular DILI’s risk of progression [7,16].

In our study, the predominance of extra-pulmonary TB (76.5%) might reflect the referral nature of our  centre or indicate the requirement of  longer regimens in such scenarios, potentially increasing exposure to hepatotoxic agents.Earlier Indian data haveshown similar patterns, although large-scalemulticentre validations are lacking [19,20].

Clinical symptoms such as nausea, vomiting, and jaundice typically preceded transaminase elevation,which isconsistentwith the literature. These symptoms are crucial early warning signs and should prompt immediate evaluation. The liver injury pattern was predominantly hepatocellular, as seen in sharp ALT and AST rises, though

Somepatients showed features of amixed pattern. Pyrazinamide, a common culprit, is

knownto cause suchmixed injury profiles [21].

Structured reintroduction of ATT following normalization of liver enzymes was successful inmost patients. Among 98 patients, 85 (86.7%) tolerated standard reintroduction without recurrence of hepatotoxicity. Ten patients developedmild transaminitis upon re-introduction which resolved spontaneously, and three (3.1%) required exclusion of pyrazinamide and a prolonged alternative regimen. These findings reinforce World Health Organization (WHO), British Thoracic Society (BTS) and American Thoracic Society (ATS) guidelines that recommend gradual reintroduction under closemonitoring  [1,3].

From public health perspective , our study has two clinical implications : (1) early symptom evaluation and low-threshold for LFT checks; (2) attention to baseline nutrition given low-normal albumin and regional links between malnutrition and ATT-DILI [9,17]; and closer monitoring of higher-risk groups, particularly during the first 6–8 weeks when DILI risk is highest [3–6,12]. Programmatically, standardized stop-and-reintroduce protocols (ATS/BTS/WHO) with INR/albumin monitoring can mitigate severe events [3,12].

Strengths and limitations:

Our study had some key strength including prospective design, standardized baseline laboratory assessments, and exclusion of key confounders. Limitations include a single-center scope, modest sample size, and absence of time-to-onset and long-term outcomes.

In this prospective tertiary-care cohort, ATT-induced hepatitis was most common among undernourished, middle-aged, rural-residing and female patients; reflecting combined biological susceptibility and healthcare access gaps.Gastrointestinal complaints were the leading presentation, with a hepatocellular injury pattern predominating. Extrapulmonary TB was frequent, likely due to longer treatment courses.Proactive symptom screening in women, nutritional support, early LFT monitoring, and strict adherence to standardized stop–rechallenge protocols—are critical to reducing ATT-related liver injury in high TB-burden settings.

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