Background & Aims:The Revised Electronic Causality Assessment Method (RECAM), a computerized update of the Roussel Uclaf Causality Assessment Methodology (RUCAM), was recently proposed. In this study, we validated and compared the utility of the RECAM and RUCAM in Chinese patients with a single conventional or herbal agent-induced liver injury.Methods:In this retrospective multicenter cohort of well-established DILI and non-DILI patients from 5 centers in China, the diagnostic performance of the RUCAM and RECAM was compared by AUC analysis. The consistency was evaluated by weighted kappa. The major causes of discrepancy were explored.Results:A total of 481 DILI and 100 non-DILI patients were included. In total, 62.6% of the DILI cases were induced by conventional agents, and 37.4% were induced by herbs. The RECAM had relatively higher AUC than RUCAM for overall [0.947 (0.926-0.964) vs. 0.867 (0.836-0.893), p=0.0016], conventional agents [0.923 (0.890-0.949) vs. 0.819 (0.775-0.858), p=0.0185], and herbs [0.972 (0.941-0.989) vs.0.911 (0.866-0.944), p=0.0199]. Latency, scores associated with hepatitis B, and hepatotoxicity information of the insulting drugs were the 3 main causes for the inconsistency between RECAM and RUCAM scores.Conclusions:The RECAM had relatively better diagnostic performance than RUCAM, with a higher AUC for Chinese DILI patients. Timely updates of the LiverTox category and refinement of serum markers to exclude hepatitis B activity would further improve the applicability of RECAM in areas where the use of herbs and resolution of past HBV infections are common.

Background & Aims: Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. Methods: This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old). Results: Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%). Conclusion: Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices. Impact and implications:: Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.

Abstract Background & Aims Anticoagulation therapy is recommended during the acute or subacute stage for patients with pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome (PAHSOS). Transjugular intrahepatic portosystemic shunt (TIPS) is suggested as step-up treatment when patients have no response to anticoagulants. However, the efficacy of TIPS in patients who do not respond to anticoagulants needs more evidence. The aim of this study was to evaluate the effect of TIPS in PA-HSOS patients with no response to initial anticoagulation treatment. Methods We retrospectively enrolled PA-HSOS patients diagnosed based on the ‘Nanjing criteria’ between January 2013 and September 2020 from four hospitals, and all of them had no response to initial short-term anticoagulation therapy. Then, depending on the next treatment option, these patients were divided into the TIPS treatment group and the anticoagulation therapy group. The baseline information and clinical characteristics were collected and recorded. Liver transplant-free survival in both groups was the primary study endpoint and the risk factors for patient death were further analyzed. Results A total of 473 PA-HSOS patients from four hospitals were included in the study, and 99 patients were enrolled according to the inclusion and exclusion criteria. Of these, 63 patients were in the TIPS group and 36 were in the anticoagulation therapy group. In the anticoagulation therapy group, 25 patients received continuous anticoagulation treatment until the end of the study, and 11 patients did not respond to the prolonged anticoagulation therapy and turned to TIPS therapy halfway through treatment. There were 17 deaths during the median follow-up time of 32.5 months. The different choices of treatment (TIPS or continuous anticoagulation therapy), age, aspartate aminotransferase (AST), and serum total bilirubin (STB) were independent risk factors for predicting death. The patients in the TIPS group had a significantly higher transplant-free survival than those in the continuous anticoagulation therapy group (P=0.028). The prognosis of the mild and moderate patients treated with TIPS was better than that of the severe patients according to Drum Tower Severity Scoring (DTSS), a novel PA-HSOS severity grading criteria, while the severe patients did not show significant benefit with TIPS treatment. Conclusions TIPS treatment can improve the transplant-free survival rate in PA-HSOS patients who have failed short-term anticoagulation therapy, and patients with DTSS of mild and moderate grade could benefit from TIPS.

Abstract Background Drug-induced liver injury (DILI) can present as chronic phenotype as well as acute course. However, the underlying mechanisms of chronic DILI, as well as the definition of cut-off point, are largely less researched. We aimed to profile metabolic characteristics of chronic DILI and provide evidence for the cut-off point by serum metabolomics. Methods & ResultsThe sera of DILI patients were divided into Group Ⅰ (0~6 months), Group Ⅱ (6~12 months) and Group Ⅲ (>12 months), based on the duration of liver injury. Totally 2,105 metabolites associated with the DILI duration were screened out as the holistic metabolomic signature (HMS). By unsupervised principal component analysis on HMS dataset, the samples spontaneously represented a two-cluster pattern of the three groups, i.e. Group I as the first cluster and Group II / III as the second cluster, which suggested six months as the potential metabolomic cut-off point of DILI chronicity. Then the differentiation ability of metabolomic signature was validated in an independent cohort. We further screened out 23 most-associated metabolites as the metabolic fingerprint (MFP) for the DILI duration and constructed an eigenmetabolite by dimension reduction. The eigenmetabolite was significantly different in chronic versus acute DILI and was not related to the severity grade of liver injury. Pathway enrichment analysis underlined the enhanced metabolic pathways of lipids in chronic DILI, which are associated with energy metabolism remodeling and immune regulation balance. ConclusionsMFP was different between chronic and acute DILI. Six months might be the potential metabolomic cut-off point in defining chronicity of DILI.

Background and Aims Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury to sinusoidal endothelial cells in the liver. The intake of pyrrolizidine alkaloids (PAs) in some Chinese herbal remedies/plants remains the major etiology for HSOS in China. Recently, new diagnostic criteria for PA-induced HSOS (i.e. PA-HSOS) have been developed; however, the efficacy has not been clinically validated. This study aimed to assess the performance of the Nanjing criteria for PA-HSOS. Methods Data obtained from consecutive patients in multiple hospitals, which included 86 PA-HSOS patients and 327 patients with other liver diseases, were retrospectively analyzed. Then, the diagnostic performance of the Nanjing criteria and simplified Nanjing criteria were evaluated and validated. The study is registered in www.chictr.org.cn (ID: ChiCTR1900020784). Results The Nanjing criteria have a sensitivity and specificity of 95.35% and 100%, respectively, while the simplified Nanjing criteria have a sensitivity and specificity of 96.51% and 96.33%, respectively, for the diagnosis of PA-HSOS. Notably, a proportion of patients with Budd-Chiari syndrome (11/49) was misdiagnosed as PA-HSOS on the basis of the simplified Nanjing criteria, and this was mainly due to the overlapping features in the enhanced computed tomography/magnetic resonance imaging examinations. Furthermore, most of these patients (10/11) had occlusion or thrombosis of the hepatic vein, and communicating vessels in the liver were found in 8/11 patients, which were absent in PA-HSOS patients. Conclusions The Nanjing criteria and simplified Nanjing criteria exhibit excellent performance in diagnosing PA-HSOS. Thus, both could be valuable diagnostic tools in clinical practice.

Objectives: Autoimmune hepatitis (AIH) can progress into severe outcomes, i.e., decompensated cirrhosis, from remarkable and persistent inflammation in the liver. Considering the energy-expending nature of inflammation, we tried to define the metabolomics signatures of AIH to uncover the underlying mechanisms of cirrhosis development and its metabolic biomarkers. Methods: Untargeted metabolomics analysis was performed on sera samples from 79 AIH patients at the stages (phenotypes) of non-cirrhosis (n = 27), compensated cirrhosis (n = 22), and decompensated cirrhosis (n = 30). Pattern recognition was used to find unique metabolite fingerprints of cirrhosis with or without decompensation. Results: Out of the 294 annotated metabolites identified, 2 metabolic fingerprints were found associated with the development of cirrhosis (independent of the decompensated state, 42 metabolites) and the evolution of decompensated cirrhosis (out of 47 metabolites), respectively. The cirrhosis-associated fingerprints (eigenmetabolite) showed better capability to differentiate cirrhosis from non-cirrhosis patients than the aminotransferase-to-platelet ratio index. From the metabolic fingerprints, we found two pairs of metabolites (Mesobilirubinogen/6-Hydroxynicotinic acid and LysoPA(8:0/0:0)/7alpha-Hydroxycholesterol) calculated as ratio of intensities, which revealed robust abilities to identify cirrhosis or predict decompensated patients, respectively. These phenotype-related fingerprint metabolites featured fundamental energy supply disturbance along with the development of AIH cirrhosis and progression to decompensation, which was characterized as increased lipolysis, enhanced proteolysis, and increased glycolysis. Conclusions: Remodeling of metabolism to meet the liver inflammation-related energy supply is one of the key signatures of AIH in the development of cirrhosis and decompensation. Therefore, drug regulation metabolism has great potential in the treatment of AIH.

Alcohol-associated liver disease (ALD) is caused by alcohol metabolism's effects on the liver. The underlying mechanisms from a metabolic view in the development of alcohol-associated liver cirrhosis (ALC) are still elusive. We performed an untargeted serum metabolomic analysis in 14 controls, 16 patients with ALD without cirrhosis (NC), 27 patients with compensated cirrhosis, and 79 patients with decompensated ALC. We identified two metabolic fingerprints associated with ALC development (38 metabolites) and those associated with hepatic decompensation (64 metabolites) in ALC. The cirrhosis-associated fingerprint (eigenmetabolite) showed a better capability to differentiate ALC from NC than the aspartate aminotransferase-to-platelet ratio index score. The eigenmetabolite associated with hepatic decompensation showed an increasing trend during the disease progression and was positively correlated with the Model for End-Stage Liver Disease score. These metabolic fingerprints belong to the metabolites in lipid metabolism, amino acid pathway, and intermediary metabolites in the tricarboxylic acid cycle. Conclusion: The metabolomic fingerprints suggest the disturbance of the metabolites associated with cellular energy supply as an underlying mechanism in the development and progression of alcoholic cirrhosis.

INTRODUCTION:Previous studies have linked the relationship between ABO blood group and COVID-19 infection. However, existing evidence is preliminary and controversial. This meta-analysis sought to identify studies that describe COVID-19 and ABO blood group.METHODOLOGY:A literature search was conducted from PubMed, Web of Science, MedRxiv, BioRxiv and Google Scholar databases. Members of cases and controls were extracted from collected studies. Pooled Odds ratio (OR) and 95% confidence interval (95%CI) were calculated and interpreted from extracted data. Publication bias and sensitivity analysis were also applied to confirm our discovery.RESULTS:Total 13,600 patients and 3,445,047 controls were included in the study. Compared to other ABO blood group, blood group O was associated with a lower risk of COVID-19 infection (OR = 0.76, 95%CI 0.66-0.84), while blood group A and AB was associated with a higher risk (OR = 1.25, 95%CI 1.10-1.41; OR = 1.13, 95%CI 1.04-1.23, respectively). In the subgroup analysis, the relationship between blood group A, O and COVID-19 infection remained stable among Chinese, European and Eastern Mediterranean populations. In American population, blood groups B was linked with increased risk of COVID-19 infection (OR = 1.21, 95%CI 1.09-1.35).CONCLUSIONS:Our data suggested that individuals with blood types A and AB are more susceptible to COVID-19, while people with blood type O are less susceptible to infection. More research is needed to clarify the precise role of the ABO blood group in COVID-19 infection to address the global question.

AIM To optimize the hepatobiliary phase delay time (HBP-DT) of Gd-EOB-DTPA-enhanced magnetic resonance imaging (GED-MRI) for more efficient identification of hepatocellular carcinoma (HCC) occurring in different degrees of cirrhosis assessed by Child-Pugh (CP) score. METHODS The liver parenchyma signal intensity (LPSI), the liver parenchyma (LP)/HCC signal ratios, and the visibility of HCC at HBP-DT of 5, 10, 15, 20, and 25 min (i.e., DT-5, DT-10, DT-15, DT-20, and DT-25 ) after injection of Gd-EOB-DTPA were collected and analyzed in 73 patients with cirrhosis of different degrees of severity (including 42 patients suffering from HCC) and 18 healthy adult controls. RESULTS The LPSI increased with HBP-DT more significantly in the healthy group than in the cirrhosis group (F = 17.361, P < 0.001). The LP/HCC signal ratios had a significant difference (F = 12.453, P < 0.001) among various HBP-DT points, as well as between CP-A and CP-B/C subgroups (F = 9.761, P < 0.001). The constituent ratios of HCC foci identified as obvious hypointensity (+++), moderate hypointensity (++), and mild hypointensity or isointensity (+/-) kept stable from DT-10 to DT-25: 90.6%, 9.4%, and 0.0% in the CP-A subgroup; 50.0%, 50.0%, and 0.0% in the CP-B subgroup; and 0.0%, 0.0%, and 100.0% in the CP-C subgroup, respectively. CONCLUSION The severity of liver cirrhosis has significant negative influence on the HCC visualization by GED-MRI. DT-10 is more efficient and practical than other HBP-DT points to identify most of HCC foci emerging in CP-A cirrhosis, as well as in CP-B cirrhosis; but an HBP-DT of 15 min or longer seems more appropriate than DT-10 for visualization of HCC in patients with CP-C cirrhosis.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

The amino acid substitution at position 181 of the Hepatitis B virus (HBV) polymerase is a multi-drug resistance affecting both the L-nucleoside and acyclic phosphonate nucleotide groups. Data is limited on the efficacy of entecavir (ETV) rescuing chronic hepatitis B (CHB) patients with rtA181T/V mutation.

The prevalence of hepatitis C virus (HCV) infection in patients on maintenance hemodialysis (MHD) is relatively higher than those without MHD. Chronic HCV infection detrimentally affects the life quality and expectancy, leads to renal transplant rejection, and increases the mortality of MHD patients. With the application of erythropoietin to improve uremic anemia and avoid blood transfusion, the new HCV infections during MHD in recent years are mainly caused by the lack of stringent universal precautions. Strict implementation of universal precautions for HCV transmission has led to markedly decreased HCV infections in many hemodialysis units, but physicians still should be alert for the anti-HCV negative HCV infection and occult HCV infection in MHD patients. Standard interferon alpha and pegylated interferon alpha monotherapies at a reduced dose are currently the main treatment strategies for MHD patients with active HCV replication, but how to increase the sustained virological response and decrease the side effects is the key problem. IFNα-free treatments with two or three direct-acting antivirals without ribavirin in MHD patients are waiting for future investigations.

OBJECTIVE:To analyze the etiology, clinical features and prognosis of liver injuries caused by different drugs.METHODS:The types of suspected drugs related to liver injury, clinical manifestations, liver biochemical parameters, clinical outcomes and other associated data were retrospectively assessed for 140 patients with drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method (RUCAM) was used to assess the causality between drugs and liver injury.RESULTS:The most prevalent agents inducing DILI were Chinese traditional drugs (62.1%), followed by antipyretic analgesic drugs (10%) and antibiotics (5%). The ratio of male to female patients in the study cohort was 1:1.69, with 71 of the total patients (50.7%) being between the ages of 40 and 60 years-old. The RUCAM scale was not less than 3 points for any of the patients.In general, the clinical manifestations and biochemical results were not specific. The percentages of hepatocellular injury type, cholestatic injury type and mixed injury type were 51.4%, 30.7% and 17.9% respectively. The median age of patients with cholestatic liver injury was 55.6 years, which was older than that of patients with hepatocellular injury (47.1 years) or mixed injury (49.9 years).CONCLUSION:Although antipyretic analgesics and antibiotics are considered as common drugs that can induce DILI, Chinese traditional drugs have emerged as another important group of liver injurious agents. Cholestatic DILI was found to occur more often in elderly patients than in younger patients.

Accurate prediction of the sustained virological response (SVR) to antiviral therapy against chronic hepatitis B (CHB) is still a crucial problem needing profound investigation. In recent years, quantification of hepatitis B surface antigen (HBsAg), a reliable predictor of SVR and an ideal endpoint of treatment, has attracted increasing attention. Serum HBsAg titer may reflect the level of intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in most patients, and vary with natural phases of chronic HBV infection, genotypes and variants, antiviral therapy, and other related factors. Serum HBsAg <200 IU/mL or yearly reduction ≥0.5 log10IU/mL may be the optimum cut-off values for prediction of the chance of spontaneous seroclearance of HBsAg. Serum HBsAg <1,000 IU/mL with HBV DNA <2,000 IU/mL may identify most of the inactive HBV carriers from active HBeAg− hepatitis. Interferon-based therapy can lead to more significant HBsAg decline than therapy based on nucleoside and/or nucleotide analogues. Different patterns or kinetics of HBsAg decline during therapy are related to different probabilities of SVR. A low HBsAg level, <3,000 IU/mL at baseline, or HBsAg level, <1,500 IU/mL at week 12, or a rapid on-treatment HBsAg decline of ≥0.5 log10IU/mL at week 12, may predict higher probability of SVR. However these cut-off values must be further validated for larger cohort of patients across genotypes worldwide. Incorporation of serum HBsAg level, HBeAg status, HBV DNA load, HBV genotypes, and other related factors might help establish new concept of more practical “response-guided treatment (RGT)” rules for antiviral therapy.

因尿毒症而接受血液透析治疗、伴有多种并发症、拟择期进行肾移植术、有丙型肝炎病毒(HCV)活跃复制的患者,其抗病毒治疗既是必需的,也是临床一大治疗难点,其抗病毒方案的优化有待探索,疗程中各种并发症的特点、依从性影响因素、疗效等有待深入认识和积累经验.我科最近成功完成1例尿毒症合并肾性高血压、眼底出血、骨髓抑制及其他多种并发症的丙型肝炎患者的抗病毒治疗,取得良好病毒学、血清学、生物化学应答,现将治疗体会和疗效做一总结。

OBJECTIVE:To study the characteristics of the virology background of HLA-A2 restricted HBcAg(18-27) epitope mutations in HBV infected patients in China.METHOD:30 HBV sequences with different genotypes from Genbank were analyzed by bioinformatics and the mismatched primers were designed for constructing a PCR-RFLP method to screen HBcAg(18-27)V/I in China. The distributions of HBcAg(18-27)V/I of 160 samples with HBV genotype B/C infection from 8 areas in China were screened and analyzed by PCR-RFLP and sequencing. The affinity of HBcAg(18-27)V/I to HLA-A0201 was analyzed through referencing the bioinformatics websites.RESULTS:We successfully constructed a PCR-RFLP method for screening HBcAg(18-27)V/I from genotype B/C, and only 3 samples with HBcAg(18-27)V sequence were found in the 160 samples (3/160, 1.88%). The affinity of HBcAg(18-27)I to HLA-A 0201 was lower than the one of HBcAg(18-27)V through bioinformatic analysis (HLA ligand score was 123 vs 156, and the SYFPEITHI score was 22 vs 24).CONCLUSION:The last amino acid of most HBcAg(18-27) sequences of epidemic HBV strains in China is isoleucine, and not valine. Therefore HBcAg(18-27) sequence background in different HBV genotypes should be thoroughly considered when using it as a reference or control in immunological research about HBV.