An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

Aripiprazole-induced liver injury: a spontaneous reporting database study.

Background: There have been individual case reports of aripiprazole in recent years, both domestically and internationally, but no analysis of the characteristics of the occurrence of adverse reactions/events of drug-induced liver injury with aripiprazole using spontaneous reports has been seen. Methods: Using a retrospective study approach, the 452 adverse reaction/event reports of aripiprazole-induced liver injury collected by the China Adverse Drug Reaction Monitoring System from 1 January 2012 to 31 December 2016 were analyzed and evaluated, and exploring it's the clinical characteristics and related risk factors for liver injury occurrence. Results: Among 452 cases of aripiprazole-induced liver injury ADR/ADE reports, there were 121 cases classified as serious, accounting for 26.8% of the total. There were 250 male and 202 female patients, with a male-to-female ratio of 1.24:1. The age of patients ranged from 11 to 77 years old, with an average age of (34.56 ± 12.81) years old, and a high proportion of young adults in the total population. Some patients had used the drug off-label or at a higher than recommended dosage. The onset of liver injury was generally within 15-90 days after continuous use, while some patients are also accompanied by nausea, vomiting, and weight gain. 70% of the combined drug instructions listed that may cause liver injury. Conclusion: In clinical practice, healthcare professionals should pay closely attention to the adverse reactions and risk factors of liver injury caused by aripiprazole. If there are potential risk factors for liver injury, early and regular monitoring of liver function should be carried out to reduce the occurrence of adverse reactions.

Pyroptotic MAITs link microbial translocation with severity of alcohol-associated liver disease.

BACKGROUND: Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying MAITs' loss remains elusive. Hence, we aimed to explore what induced MAITs' loss and its clinical significance. METHODS: The characteristics of pyroptotic MAITs were evaluated in a cohort of patients with ALD, including 41 patients with alcohol-associated liver cirrhosis (ALC) and 21 patients with ALC complicated with severe alcoholic hepatitis (ALC + SAH). RESULTS: In patients with ALD, blood MAITs were significantly decreased, hyperactivated, and displayed enhanced cell death through pyroptosis. The frequencies of pyroptotic MAITs increased with disease severity in patients with ALC and patients with ALC + SAH. These frequencies were negatively associated with the frequencies of MAITs and positively correlated with the levels of MAITs' activation, plasma levels of intestinal fatty acid-binding protein (a marker of intestinal enterocyte damage), soluble CD14, lipopolysaccharide-binding protein, and peptidoglycan recognition proteins (surrogate markers of microbial translocation). Pyroptotic MAITs were also found in the liver of patients with ALD. Interestingly, MAITs underwent further activation and pyroptosis in vitro under stimulation by Escherichia coli or direct bilirubin. Notably, blocking IL-18 signaling reduced the activation and frequencies of pyroptotic MAITs. CONCLUSIONS: The loss of MAITs in patients with ALD is, at least in part, due to cell death from pyroptosis and is associated with the severity of ALD. Such increased pyroptosis may be affected by dysregulated inflammatory responses to intestinal microbial translocation or direct bilirubin.

A Lower HCC Incidence in Chronic HBV-Infected Patients Recovered from Acute-on-Chronic Liver Failure: A Prospective Cohort Study.

Background: Activation of chronic hepatitis B virus (HBV) infection is an important cause of acute-on-chronic liver failure (ACLF). However, the effect of HBV-ACLF episode on hepatocellular carcinoma (HCC) occurrence remains largely unknown. Methods: A total of 769 HBV-ACLF patients and 2114 HBV-related chronic liver disease (HBV-CLD) patients diagnosed between August 1998 and December 2011 were enrolled in this prospective cohort study. Of the HBV-CLD patients, 380 received lifetime antiviral treatment with nucleos(t)ide analogues. Propensity score matching was applied to reduce baseline differences between HBV-ACLF and HBV-CLD cohorts. Results: The survival rate of HBV-ACLF patients was 53.6%, 50.3%, 47.8%, and 46.2% at 90-day, 1-year, 5-year, and 10-year, respectively. The cumulative incidence of HCC was lower in HBV-ACLF cohort with 369 eligible patients survived for >90 days than in HBV-CLD cohort with the 380 patients (5.77/1,000 vs. 9.78/1,000 person-years, p = 0.0497). HBV-ACLF episode decreased HCC risk regardless of liver cirrhosis, and in patients without family history of HCC. Multivariate Cox analyses indicated that male, increasing age, liver cirrhosis, and platelet count (≤100 × 109/L) increased, whereas HBV-ACLF episode decreased, HCC risk independently. In the propensity score-matched cohorts, HBV-ACLF episode reduced HCC incidence (10.20/1,000 vs. 4.66/1,000 person-years, p = 0.0326). The area under curve of nomogram was 0.812 for 3-year HCC probability. Conclusions: HBV-ACLF episode decreases HCC occurrence in chronic HBV patients. Older age and liver cirrhosis independently increased HCC occurrence. A nomogram-enrolled episode of ACLF reliably predicts the occurrence of HCC.

Reversibility of acute-on-chronic liver failure syndrome in hepatitis B virus-infected patients with and without prior decompensation.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome associated with high short-term mortality and reversibility. This study aimed to compare the characteristics of survival and reversibility in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) patients with and without previous decompensation. Overall, 1044 patients who fulfilled the acute hepatic insult criteria of the APASL-ACLF Research Consortium (AARC) definition were enrolled from a prospectively established cohort of HBV-related liver failure patients. These patients were divided into the AARC ACLF group and the non-AARC ACLF group according to prior decompensation. Mortality, reversibility of ACLF syndrome, and predicted factors associated with reversibility were evaluated. Liver transplantation-free mortality of the AARC ACLF group was significantly lower than that of the non-AARC ACLF group (28 days: 28.2% vs. 40.3%, p = .012; 90 days: 41.7% vs. 65.4%, p < .001). The 5-year cumulative reversal rates of ACLF syndrome were 88.0% (374/425) and 66.0% (31/47) in the AARC and non-AARC ACLF groups, respectively, (p = .039). Following reversibility of ACLF syndrome, 340/374 (90.9%) and 21/31 (67.7%) patients in the AARC and non-AARC ACLF groups, respectively, maintained a stable status within 5 years. Although prior decompensation indicated poor reversibility of ACLF syndrome, HBV-infected patients with prior decompensation who fulfilled the acute hepatic insult criteria of the AARC definition showed favourable reversibility and maintained a stable status after receiving nucleoside analogues. The AARC ACLF definition identified HBV-ACLF as a distinct syndrome with good reversibility. HBV-infected patients with prior decompensation could be included in the AARC ACLF management.

Relationship between the Level of Serum Golgi Protein 73 and the Risk of Short-term Death in Patients with ALD-ACLF.

Background and Aims: As a hepatocellular carcinoma biomarker, serum Golgi protein 73 (GP73) is reportedly related to inflammation. Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation. In this study, we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF (ALD-ACLF). Methods: This retrospective cohort study involved 126 Chinese adults with ALD-ACLF. Baseline serum GP73 level was measured using enzyme-linked immunosorbent assay. Patients were followed-up for 90 d and outcomes were assessed. Data were analyzed using multivariate Cox regression and piecewise linear regression analyses. The predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic curves. Results: The serum GP73 level was independently associated with an increased mortality risk in patients with ALD-ACLF. Compared with the lowest tertile, the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model [at 28 days: hazard ratio (HR): 4.29 (0.99-18.54), p=0.0511; at 90 days: HR: 3.52 (1.15-10.79), p=0.0276]. Further analysis revealed a positive linear association. GP73 significantly improved the accuracy of the Child-Turcotte-Pugh score, model for end-stage liver disease score, and model for end-stage liver disease-sodium score in predicting short-time prognosis of patients with ALD-ACLF. Conclusions: The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ALD-ACLF. GP73 improved the predictive value of classic prognostic scores.

Herb-Induced Liver Injury Related to Reynoutria multiflora (Thunb.) Moldenke: Risk Factors, Molecular and Mechanistic Specifics.

Herbal medicine is widely used in Asia as well as the west. Hepatotoxicity is one of the most severe side effects of herbal medicine which is an increasing concern around the world. Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb., PM) is the most common herb that can cause herb-induced liver injury (HILI). The recent scientific and technological advancements in clinical and basic research are paving the way for a better understanding of the molecular aspects of PM-related HILI (PM-HILI). This review provides an updated overview of the clinical characteristics, predisposing factors, hepatotoxic components, and molecular mechanisms of PM-HILI. It can also aid in a better understanding of HILI and help in further research on the same.

World Gastroenterology Organisation classification and a new type-based prognostic model for hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: The acute-on-chronic liver failure (ACLF) classification, proposed by the World Gastroenterology Organisation (WGO), attempts to cover all ACLF patients diagnosed in the East and West. This study aimed to explore and establish a prognostic model based on this classification. METHODS: A total of 1159 hepatitis B virus-ACLF patients, enrolled with 90-day follow-up data, were divided into three groups (type A, B, and C) according to WGO ACLF classification and analyzed. A model of ACLF prognosis based on type (MAPT) was developed in a derivation cohort (n = 566); its reproducibility was tested in a validation cohort (n = 593). RESULTS: A significant difference in 90-day mortality among the three groups was observed (31.1%, type A; 40.9%, type B; 61.4%, type C, P < 0.001). ACLF type was determined to be an independent risk factor of 90-day mortality in HBV-ACLF patients. An MAPT, inclusive of type and five other variables, was built and validated; it was found to be superior to the Chronic Liver Failure (CLIF) Consortium ACLF score, Model for End-Stage Liver Disease, CLIF-Sequential Organ Failure, and Child-Turcotte-Pugh scores in predicting 90-day mortality, with an area under the receiver operating characteristic curve of 0.802 (95% CI [0.763-0.836]), sensitivity of 71.77%, and specificity of 75.82%. CONCLUSIONS: The MAPT model showed excellent predictive value for 90-day mortality in HBV-ACLF and can likely expand the clinical application of WGO ACLF classification.

Infection deteriorating hepatitis B virus related acute-on-chronic liver failure: a retrospective cohort study.

BACKGROUND: Infection is common in acute-on-chronic liver failure (ACLF), which may worsen the clinical condition and prognosis. However, the characteristics of infection and its influence on prognosis in hepatitis B virus related ACLF (HBV-ACLF) as defined by the European Association for the Study of the Liver (EASL) have not been clarified. We aimed to investigate the characteristics of infection and its influence on mortality in patients with HBV-ACLF defined by EASL in China. METHODS: We performed a retrospective cohort study in patients with HBV-ACLF defined by EASL in a single center from January 2015 to December 2017. These patients were divided into two groups with and without infection. The incidence, sites of infection, isolated strains, and risk factors associated with mortality were evaluated. RESULTS: A total of 289 patients were included, among them 185 (64.0%) were diagnosed with an infection. The most common type of infection was pneumonia (55.7%), followed by spontaneous bacterial peritonitis (47.6%) and others. The gram-negative bacteria were the most frequent (58.3%). Patients with one, two, and three or more infection sites had a gradually increasing incidence of sepsis (P < 0.01), septic shock (P < 0.001), and ACLF-3 (P < 0.05). Also, patients with infection isolated one, two, and three or more strains showed a growing incidence of sepsis (P < 0.01) and septic shock (P < 0.001). Patients with infection showed a significantly higher 28-day mortality than those without (P < 0.01), especially in patients with ACLF-3. Infection was identified as an independent risk factor for 28-day mortality in all HBV-ACLF patients. Pneumonia and sepsis were identified as independent predictors of 28-day mortality for patients with infection. CONCLUSIONS: Infection is associated with severe clinical course and high mortality in HBV-ACLF defined by EASL. The increased number of infection sites or isolated strains was associated with the occurrence of sepsis and septic shock. Pneumonia and sepsis were independent predictors for mortality in HBV-ACLF patients with infection.

Predictive value of the Chinese group on the study of severe hepatitis B-acute-on-chronic liver failure score in the short-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: As a large, prospective, multicenter study-based prognostic score for hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), the Chinese group on the study of severe hepatitis B-acute-on-chronic liver failure score (COSSH-ACLFs), has been approved by some foreign scholars; however, its predictive value needs to be verified. This study investigated the predictive value of COSSH-ACLFs for short-term prognosis in Chinese patients with HBV-ACLF. METHODS: This retrospective cohort study included 751 patients with HBV-ACLF admitted to the Fifth Medical Center of Chinese PLA General Hospital between January 2011 and December 2014. Spearman method was used to assess the correlation of COSSH-ACLFs with classical scores. Different COX multivariate regression models were used to confirm the relationship between COSSH-ACLFs and short-term prognosis in patients with HBV-ACLF, and stratified analysis was used to further verify the stability of this relationship. We compared the predictive powers of COSSH-ACLFs and other classical scores using area under the receiver operating characteristic curve (AUROC) and Z-test. RESULTS: A total of 975 patients with HBV-ACLF were screened, and 751 were analyzed (623 male and 128 female). COSSH-ACLFs was the highest in patients with end-stage ACLF, followed by those with middle- and early-stage ACLF (H = 211.8, P < 0.001). In the fully adjusted model, COX multivariate regression analysis revealed that COSSH-ACLFs (as a continuous variable) was independently and positively correlated with mortality risk in patients with HBV-ACLF at 28 days (hazard ratio [HR]: 1.37 [1.22, 1.53], P < 0.001) and 90 days (HR: 1.43 [1.29, 1.58], P < 0.001). The same trend could be observed in the crude model and minimally adjusted model. The AUROCs of COSSH-ACLFs for 28-day and 90-day prognoses in patients with HBV-ACLF were 0.807 and 0.792, respectively, indicating a stronger predictive accuracy than those of classic models. CONCLUSIONS: COSSH-ACLFs, with a superior predictive accuracy compared with other classical scores, can strongly predict short-term prognosis in Chinese patients with HBV-ACLF.