Harshad Devarbhavi1, Tarun Joseph1, Nanjegowda Sunil Kumar2, Chetan Rathi3, Varghese Thomas2, Shivaram Prasad Singh4, Prabha Sawant3, Ashish Goel5, Chundamannil E Eapen5, Prakash Rai6, Anil Arora7, Venkatakrishnan Leelakrishnan8, Gayathri Gopalakrishnan9, Vishnu Vardhan Reddy1, Rajvir Singh10, Bhabadev Goswami11, Jayanthi Venkataraman12, Girisha Balaraju13, Mallikarjun Patil1, Rakesh Patel14, Sunil Taneja15, Abraham Koshy16, Padaki Nagaraja Rao17, Shiv Kumar Sarin18, Pravin Rathi19, Radhakrishna Dhiman20, Ajay K Duseja15, Joy Vargese12, Ajay Kumar Jain21, Manav Wadhawan22, Piyush Ranjan7, Dheeraj Karanth23, Panchapakesan Ganesh24, Sandeep Nijhawan25, Gopal Krishna Dhali26, Channagiri K Adarsh27, Ajay Jhaveri28, Aabha Nagral28, Prasanna Rao29. 1. Department of Gastroenterology, St. John's Medical College Hospital, Bangalore, India. 2. Department of Gastroenterology, Government Medical College, Kozhikode, India. 3. Department of Gastroenterology, LTM Medical College Hospital, Mumbai, India. 4. Department of Gastroenterology, S.C.B Medical College Hospital, Cuttack, India. 5. Department of Gastroenterology, Christian Medical College, Vellore, India. 6. Department of General Medicine, Holy Spirit Hospital, Mumbai, India. 7. Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India. 8. Department of Gastroenterology, P.S.G Institute of Medical Sciences, Coimbatore, India. 9. Department of Gastroenterology, Narayana Hrudayalaya Hospitals, Bangalore, India. 10. Acute Care Surgery, HGH, Hamad Medical Corporation, Doha, Qatar. 11. Department of Gastroenterology, Dispur Hospitals, Guwahati, India. 12. Department of Hepatology, Gleneagles Global Health City, Chennai, India. 13. Department of Gastroenterology, Kasturba Medical College Hospital, Manipal, India. 14. Department of Gastroenterology, Suyash Endoscopy Centre, Thane, India. 15. Department of Hepatology, Post Graduate Institute of Medical Education & Research, Chandigarh, India. 16. Department of Gastroenterology, Lakeshore Hospital, Kochi, India. 17. Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India. 18. Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. 19. Department of Gastroenterology, B.Y.L. Nair Hospital, Mumbai, India. 20. Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. 21. Department of Gastroenterology, Choithram Hospital and Research Centre, Indore, India. 22. Department of Gastroenterology, BLK Super Speciality Hospital, New Delhi, India. 23. Department of Gastroenterology, Vikram Hospital, Bangalore, India. 24. Department of Gastroenterology, Sri Ramachandra Hospital, Chennai, India. 25. Department of Gastroenterology, Sawai Man Singh Medical College, Jaipur, India. 26. School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, India. 27. Department of Gastroenterology, BGS Gleneagles Global Hospitals, Bangalore, India. 28. Department of Gastroenterology, Jaslok Hospital and Research Center, Mumbai, India. 29. Department of Gastroenterology, Apollo Hospitals, Bangalore, India.
Abstract
BACKGROUND: Etiology of and outcomes following idiosyncratic drug-induced liver injury (DILI) vary geographically. We conducted a prospective study of DILI in India, from 2013 to 2018 and summarize the causes, clinical features, outcomes and predictors of mortality. METHODS: We enrolled patients with DILI using international DILI expert working group criteria and Roussel Uclaf causality assessment method. Follow-up was up to 3 months from onset of DILI or until death. Multivariate logistics regression was carried out to determine predictors of non-survival. RESULTS: Among 1288 patients with idiosyncratic DILI, 51.4% were male, 68% developed jaundice, 68% required hospitalization and 8.2% had co-existing HIV infection. Concomitant features of skin reaction, ascites, and encephalopathy (HE) were seen in 19.5%, 16.4%, and 10% respectively. 32.4% had severe disease. Mean MELD score at presentation was 18.8 ± 8.8. Overall mortality was 12.3%; 65% in those with HE, 17.6% in patients who fulfilled Hy's law, and 16.6% in those that developed jaundice. Combination anti-TB drugs (ATD) 46.4%, complementary and alternative medicines (CAM) 13.9%, anti-epileptic drugs (AED) 8.1%, non-ATD antimicrobials 6.5%, anti-metabolites 3.8%, anti-retroviral drugs (ART)3.5%, NSAID2.6%, hormones 2.5%, and statins 1.4% were the top 9 causes. Univariate analysis identified, ascites, HE, serum albumin, bilirubin, creatinine, INR, MELD score (p < 0.001), transaminases (p < 0.04), and anti-TB drugs (p = 0.02) as predictors of non-survival. Only serum creatinine (p = 0.017), INR (p < 0.001), HE (p < 0.001), and ascites (p = 0.008), were significantly associated with mortality on multivariate analysis. ROC yielded a C-statistic of 0.811 for MELD and 0.892 for combination of serum creatinine, INR, ascites and HE. More than 50 different agents were associated with DILI. Mortality varied by drug class: 15% with ATD, 13.6% with CAM, 15.5% with AED, 5.8% with antibiotics. CONCLUSION: In India, ATD, CAM, AED, anti-metabolites and ART account for the majority of cases of DILI. The 3-month mortality was approximately 12%. Hy's law, presence of jaundice or MELD were predictors of mortality.
BACKGROUND: Etiology of and outcomes following idiosyncratic drug-induced liver injury (DILI) vary geographically. We conducted a prospective study of DILI in India, from 2013 to 2018 and summarize the causes, clinical features, outcomes and predictors of mortality. METHODS: We enrolled patients with DILI using international DILI expert working group criteria and Roussel Uclaf causality assessment method. Follow-up was up to 3 months from onset of DILI or until death. Multivariate logistics regression was carried out to determine predictors of non-survival. RESULTS: Among 1288 patients with idiosyncratic DILI, 51.4% were male, 68% developed jaundice, 68% required hospitalization and 8.2% had co-existing HIV infection. Concomitant features of skin reaction, ascites, and encephalopathy (HE) were seen in 19.5%, 16.4%, and 10% respectively. 32.4% had severe disease. Mean MELD score at presentation was 18.8 ± 8.8. Overall mortality was 12.3%; 65% in those with HE, 17.6% in patients who fulfilled Hy's law, and 16.6% in those that developed jaundice. Combination anti-TB drugs (ATD) 46.4%, complementary and alternative medicines (CAM) 13.9%, anti-epileptic drugs (AED) 8.1%, non-ATD antimicrobials 6.5%, anti-metabolites 3.8%, anti-retroviral drugs (ART)3.5%, NSAID2.6%, hormones 2.5%, and statins 1.4% were the top 9 causes. Univariate analysis identified, ascites, HE, serum albumin, bilirubin, creatinine, INR, MELD score (p < 0.001), transaminases (p < 0.04), and anti-TB drugs (p = 0.02) as predictors of non-survival. Only serum creatinine (p = 0.017), INR (p < 0.001), HE (p < 0.001), and ascites (p = 0.008), were significantly associated with mortality on multivariate analysis. ROC yielded a C-statistic of 0.811 for MELD and 0.892 for combination of serum creatinine, INR, ascites and HE. More than 50 different agents were associated with DILI. Mortality varied by drug class: 15% with ATD, 13.6% with CAM, 15.5% with AED, 5.8% with antibiotics. CONCLUSION: In India, ATD, CAM, AED, anti-metabolites and ART account for the majority of cases of DILI. The 3-month mortality was approximately 12%. Hy's law, presence of jaundice or MELD were predictors of mortality.
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