Dr.Ajay Emani
December 2025-Issue 1
ABSTRACT
Background: Tuberculosis (TB) is a significant public health concern in developing countries like India. Central nervous system (CNS) tuberculosis, a severe extrapulmonary TB, is generally treated with first-line anti-tubercular therapy (ATT). Drug-induced liver injury (DILI) is a very frequent side effect, which can compromise treatment adherence and outcomes. Although DILI in pulmonary TB has been described in the literature, little is known about its incidence and predictors in the spectrum of CNS TB.
Objectives: To determine the incidence, clinical and biochemical predictors, and radiological correlates of DILI in patients undergoing ATT for CNS tuberculosis.
Methods: This prospective observational study was conducted in the Department of Neurology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, from August 2021 to February 2023. 104 patients with recent diagnosis of CNS TB were included. DILI was classified according to American Thoracic Society guidelines. Demographic, clinical, biochemical, and radiological information was recorded and compared. Statistical significance was compared using parametric as well as non-parametric tests.
Results: The incidence of DILI was 23.1%. Altered sensorium (p=0.08), elevated ESR (p=0.05), hydrocephalus (p=0.03), cerebrovascular accident (p=0.03), and myelitis (p=0.02) were the predictors. Most of the patients improved on withdrawal of the offending drug and could tolerate later rechallenge.
Conclusion: DILI is a frequent complication of CNS TB. Early identification of high-risk patients on the basis of clinical and radiological presentation can improve management and treatment outcomes.
Keywords: Anti-tubercular therapy, CNS tuberculosis, drug-induced liver injury, hepatotoxicity, predictors of DILI, tuberculous meningitis.
INTRODUCTION
Tuberculosis (TB) is a powerful worldwide health problem, disproportionately occurring in low- and middle-income nations in the world even in the presence of effective antimicrobial treatment. India alone carries nearly 20% of the world's TB burden and, therefore, is the nation with the greatest number of cases in the world.1 Although pulmonary TB is more common, extrapulmonary expressions are more and more recognized, especially in immunocompromised hosts and in young children. Of these, central nervous system (CNS) tuberculosis is the most serious form, with significant morbidity and mortality secondary to the life-threatening nature of the involved structures.2
Central nervous system (CNS) tuberculosis ranges from tuberculous meningitis (TBM), intracranial tuberculomas, to spinal tuberculosis. However, TBM is the most frequent and fatal manifestation that typically is a subacute presentation with fever, headache, altered mental status, and neurological deficits.3 Early diagnosis and the start of anti-tubercular therapy (ATT) are crucial to survival. Even with proper treatment, the progress of CNS TB is often marred by side effects of drugs, the most serious of which is drug-induced hepatitis (DIH).3 Thus, DIH can lead to interruption of treatment, prolongation of the course of the disease, augmented risk of developing resistance, and finally, poor outcome clinically.4
The typical first-line ATT treatment includes rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E). Of these, rifampicin and isoniazid are the major drugs involved in hepatotoxicity.3,4 In a systematic meta-analysis of hepatotoxicity related to ATT, it was found that hepatotoxicity in 0.6% of the patients receiving isoniazid monotherapy, 1.6% of the patients receiving multidrug combinations without rifampicin, 1.1% receiving monotherapy with rifampicin, and 2.73% receiving a combination of rifampicin and isoniazid. In children, the rate was even greater at 6.9%, suggesting heightened vulnerability in the pediatric population.5 The pathophysiology of DIH is complex, and suggested mechanisms include direct hepatocellular injury, immune-mediated responses, and idiosyncratic reactions.6
A variety of host-related risk factors have been uniformly linked with a heightened risk of DIH.7 These are older age, female sex, malnutrition, pre-existing liver disease, chronic alcohol use, HIV infection, slow acetylator status, and co-prescription of hepatotoxic medication.8,9 Aside from individual vulnerabilities, geographic and ethnic elements also seem to be involved. Indeed, DIH has been reported at higher frequencies in Asian groups than in Western groups. The prevalence varies from 3% in the United States to up to 36% in Japan and 8–36% in India.10,11 The geographic variation can be attributed to variation in nutritional status, drug-metabolizing enzyme pharmacogenetic polymorphisms, and background rates of hepatitis B or C infection.11
In addition, patients with disseminated or advanced forms of TB, including CNS disease, seem to be at risk of developing DIH. This could be due to increased systemic inflammatory responses, excess disease-related stress, and slow hepatic clearance of drugs with multiorgan dysfunction.11,12 Yet, much literature that has assessed the risk and predictors of DIH in CNS TB is lacking. The majority of existing studies have addressed pulmonary TB or lumped extrapulmonary TB together as a uniform group, thus missing the spectrally varying risk profile among CNS TB patients.12
Thus, the current study seeks to assess frequency, clinical and biochemical profile, predictors, and outcomes of drug-induced hepatitis among patients with CNS tuberculosis. The primary objective is to determine clinical and lab parameters that can predict development of DIH in early stages of treatment. And the secondary objective is to determine the effect of DIH on treatment discontinuation, therapy duration, and neurological outcome.
1. Alnour TM. Smear microscopy as a diagnostic tool of tuberculosis: Review of smear negative cases, frequency, risk factors, and prevention criteria. indian journal of tuberculosis. 2018;65(3):190-194. 10.1016/j.ijtb.2018.02.001
2. Chauhan A, Parmar M, Dash GC, et al.: The prevalence of tuberculosis infection in India: a systematic review and meta-analysis. Indian J Med Res. 2023, 157:135-51. 10.4103/ijmr.ijmr_382_23
3. Rajpal S, Arora VK: Latent TB (LTBI) treatment: challenges in India with an eye on 2025: "to treat LTBI or not to treat, that is the question". Indian J Tuberc. 2020, 67:S43-7. 10.1016/j.ijtb.2020.09.028
4. Zhao H, Wang Y, Zhang T, Wang Q, Xie W: Drug-induced liver injury from anti-tuberculosis treatment: a retrospective cohort study. Med Sci Monit. 2020, 26:e920350. 10.12659/MSM.920350
5. Liu Q, Huang L, Yan H, et al.: Clinical risk factors for moderate and severe antituberculosis drug-induced liver injury. Front Pharmacol. 2024, 15:1406454. 10.3389/fphar.2024.1406454
6. Mehra A, Semwal P, Bhat NK, Bolia R: A prospective observational study of hepatic dysfunction in children on antitubercular drugs. Indian J Pediatr. 2022, 89:1126-8. 10.1007/s12098-022-04317-7
7. Xu N, Yang JX, Yang J: Incidence and associated risk factors of antituberculosis drug-induced hepatotoxicity among hospitalised patients in Wuhan, China. Eur J Hosp Pharm. 2022, 29:217-21. 10.1136/ejhpharm-2020-002433
8. Song JH, Yoon SY, Park TY, Heo EY, Kim DK, Chung HS, Lee JK: The clinical impact of drug-induced hepatotoxicity on anti-tuberculosis therapy: a case control study. Respir Res. 2019, 20:283. 10.1186/s12931-019-1256-y
9. Naidoo K, Hassan-Moosa R, Mlotshwa P, et al. High rates of drug-induced liver injury in people living with HIV coinfected with tuberculosis (TB) irrespective of antiretroviral therapy timing during antituberculosis treatment: results from the starting antiretroviral therapy at three points in TB trial. Clin Infect Dis. 2020;70(12):2675–2682. doi:10.1093/cid/ciz732
10. Kumar R, Kumar A, Patel R, Prakash SS, Kumar S, Surya H, Marrapu S: Incidence and risk factors of antituberculosis drug-induced liver injury in India: a systematic review and meta-analysis. Indian J Gastroenterol. 2025, 44:35-46. 10.1007/s12664-024-01643-w
11. Jiang F, Yan H, Liang L, et al.: Incidence and risk factors of anti-tuberculosis drug induced liver injury (DILI): large cohort study involving 4652 Chinese adult tuberculosis patients. Liver Int. 2021, 41:1565-75. 10.1111/liv.14896
12. Kim JH, Lee H, Oh IS, et al. Comparative safety of bedaquiline and delamanid in patients with multidrug resistant tuberculosis: a nationwide retrospective cohort study. J Microbiol Immunol Infect. 2023;56(4):842–852. 10.1016/j.jmii.2023.04.009
13. P, Das A, Gupta D, et al.: Malnutrition and risk of antituberculosis drug-induced hepatotoxicity in children. Indian Pediatr. 2021, 58:22-6. 10.4081/pr.2011.e16
14. Abbara A, Chitty S, Roe JK, et al. Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK. BMC Infect Dis. 2017, 17:231. 10.1186/s12879-017-2330-
15. He Q, Li Y, Liu S, et al. Drug-induced liver injury associated with pretomanid, bedaquiline, and linezolid: insights from FAERS database analysis. Br J Clin Pharmacol. 2024;91(3):799–807. doi:10.1111/bcp.16318
16. Low EXS, Zheng Q, Chan E, Lim SG. Drug induced liver injury: east versus west - a systematic review and meta-analysis. Clin Mol Hepatol. 2020;26(2):142–154. doi:10.3350/cmh.2019.1003z
17. Lim WS, Avery A, Kon OM, Dedicoat M: Anti-tuberculosis drug-induced liver injury. BMJ. 2023, 383:e074866. 10.1136/bmj-2023-074866
18. Brennan PN, Cartlidge P, Manship T, Dillon JF: Guideline review: EASL clinical practice guidelines: drug-induced liver injury (DILI). Frontline Gastroenterol. 2022, 13:332-6. 10.1136/flgastro-2021-101886
19. Elsebaie EM, Abdel-Fattah AN, Bakr NA, et al.: Principles of nutritional management in patients with liver dysfunction—a narrative review. Livers. 2023, 3:190-218. 10.3390/livers3020013