Abstract and Introduction
Abstract
Background: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI.
Aims: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI.
Methods: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety.
Results: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial.
Conclusion: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT 02651350).
Introduction
The incidence of drug- or herb-induced liver injury (DILI/HILI) is 19.1–23.8 per 100,000 person globally.[1] DILI can be caused by synthetic drugs, biological preparations, herbs, dietary supplements and toxins. HILI specifically indicates liver injury caused by herbs and dietary supplements.[2–4] The majority of DILIs present as acute and self-limiting episodes that resolve after withdrawal of the offending agent, although some acute DILI cases can be serious, resulting in hospitalisation and even life-threatening outcomes.[5] In a substantial proportion of patients, liver injury persists with prolonged recovery[6,7] after withdrawing the offending agents. The initial acute injury progresses to chronic DILI with the prevalence ranging from 10% to 24%.[8,9] The American College of Gastroenterology (ACG) guidelines define chronicity as evidence of continued liver injury more than 6 months after drug withdrawal following the diagnosis of acute DILI.[6] In addition to unresolved liver biochemistry, histological and/or radiological evidence of persistent liver damage can also be observed in these cases.[10] The spectrum of liver injury patterns in patients with chronic DILI is broad, ranging from autoimmune-like DILI[11] with or without autoantibodies to chronic hepatitis and resolving bile duct syndrome.[12–15] The severity spectrum ranges from mild chronic injury to cirrhosis, liver failure and death.[14,16] According to the Spanish DILI Registry study,[17] 8% of patients with DILI had sustained liver injury for >1 year, among which 64% did not show resolution even after 3 years. More importantly, 44% of patients with long-term unsolved DILI exhibited progression to cirrhosis. Collectively, withdrawal of the offending drug, a common strategy for the treatment of DILI/HILI, may not be sufficient to benefit patients with chronic DILI/HILI, and a new treatment approach is warranted.
The European Association for the Study of the Liver (EASL) guidelines suggest the use of corticosteroid therapy in patients who do not show recovery despite drug cessation, with the intention of preventing progression of persistent liver injury.[18] Steroids have been used to treat DILI in acute liver failure (ALF), although evidence does not support their use.[19] Corticosteroid treatment for suspected autoimmune hepatitis (AIH), such as DILI and immune checkpoint inhibitor-induced liver injury, is much more common in clinical practice;[18,20–25] however, its efficacy still lacks high-level clinical evidence. In the four clinical guidelines from the United States,[6] Europe,[18] Asia,[26] and China,[27] no consensus has been recommended regarding the use of steroids for the treatment and management of chronic DILI/HILI, especially for non-AIH, such as chronic DILI/HILI.
This randomised open-label trial was initiated to determine the efficacy and safety of 48-week stepwise dose reduction of corticosteroid plus glycyrrhizin therapy (48w-SRCT) for these patients.
Aliment Pharmacol Ther. 2022;55(10):1297-1310. © 2022 Blackwell Publishing
