Recently, the Liver Disease Department and Pathology Department at the Fifth Medical Center of the People’s Liberation Army General Hospital (formerly the PLA Third O2 Hospital) collaborated to achieve a new breakthrough in the clinical treatment of Chronic Drug-Induced Liver Injury (DILI). The research teams, led by Dr. Zhengsheng Zou, Jingmin Zhao, and Dong Ji, previously pioneered the establishment of a 48-week Steroid Stepwise Reduction (48w-SSR) treatment plan for chronic recurrent DILI, demonstrating its efficacy and safety through rigorous Randomized Controlled Trials (RCTs). The results were published in the prestigious journal Alimentary Pharmacology & Therapeutics (a TOP journal in the 1st area of the Chinese Academy of Sciences).
In order to enhance patient compliance in the treatment of chronic DILI and reduce potential side effects associated with steroid therapy, the Liver Disease Department of the Fifth Medical Center, in collaboration with the Liver Disease Research Team from the Department of Gastroenterology at the First Medical Center of the PLA General Hospital, conducted a six-year study. This study aimed to optimize the treatment duration, comparing a 36-week optimized treatment group with a 48-week treatment group through an RCT (see Figure 1). The research findings were presented at the 2023 American Association for the Study of Liver Diseases (AASLD) Annual Meeting and were recognized as a Poster TOP 5%, receiving special commendation on November 10 in the poster hall.
DILI Overview:
Drug-Induced Liver Injury (DILI) is one of the most globally recognized drug-related diseases, with over 1100 marketed drugs known to have potential hepatotoxicity. Despite the biochemical relief that most DILI patients experience after discontinuing the suspected drug, 8%-25% progress to chronic DILI. This chronic condition may lead to recurrent episodes, potentially advancing to liver cirrhosis or failure, imposing significant psychological and economic burdens on patients and their families. Existing guidelines mention the potential efficacy of steroid therapy for chronic recurrent DILI but lack clear treatment plans and high-quality evidence.
Building upon the previously established 48w-SSR treatment plan, the researchers conducted a new RCT to optimize the duration of steroid therapy and achieved positive results.
Through a prospective RCT registered internationally (ClinicalTrials.gov, NCT03266146), liver biopsy was performed twice on enrolled cases before and after treatment. The study confirmed a biochemical continuous response rate of 92.9% and 95.2% in the two study cohorts (P=1.000), a 2-point decrease in liver tissue inflammation scores of 93.1% and 92.9% (P=1.000), and a 1-point decrease in fibrosis scores of 41.4% and 46.4% (P=0.701) (see Figures 2 and 3).
After discontinuation, a 24-week follow-up revealed no significant (Grade 3 or above) steroid-related side effects in either group. The study results indicated that the 36-week steroid group and the 48-week steroid treatment group showed consistent efficacy, with good biochemical response rates and improvement in liver tissue inflammation and fibrosis rates (no statistical difference). Additionally, both groups exhibited good safety, suggesting that the 36-week steroid treatment plan could replace the 48-week plan, resulting in a 12-week shorter course.
Crucially, this study optimized the indications for steroid use in chronic DILI patients, including the presence of one of the following four conditions: 1) ALT or AST ≥ 10×ULN; 2) ALT or AST ≥ 5×ULN and TBIL ≥ 2×ULN; 3) Liver tissue pathology showing significant liver inflammation, fused necrosis, or bridging necrosis, or liver inflammation grading ≥ G3; 4) Moderate/high-risk Biochemical Non-response (BNR) rate (BNR-6 score ≥ 28).
This study, once again optimizing the steroid treatment duration (36 weeks, a 12-week reduction), significantly reduces liver function fluctuations in patients with chronic DILI, effectively preventing and halting the development of liver cirrhosis or failure. It provides high-level evidence for the steroid treatment of chronic DILI, contributing a replicable and scalable Chinese solution to the standardization of international chronic DILI diagnosis and treatment.
Initiated by Chinese scientists, this research involved the collaboration of several top international experts in the field of drug-induced liver injury. Dr. Guru P. Aithal, the President of the International Drug-Induced Liver Injury Alliance and a professor at the University of Nottingham, UK, participated in the optimization of clinical trial design and manuscript improvement. Director Zhengsheng Zou, Director Jingmin Zhao, Director Dong Ji, and Dr. Guru P. Aithal are the co-corresponding authors. Deputy Director Ang Huang, Deputy Director Yun Zhu, Deputy Director Shuhong Liu, and Director Ying Sun are the co-first authors.
Reference:
[Huang A, Zhu Y, Liu S, et al. An optimized steroid stepwise dose reduction therapy for chronic drug-Induced liver injury with or without AIH-like features: a randomized prospective open-label trial. AASLD 2023. Poster 1701-A.]
