Dual-Ligand Europium-Organic Gels as a Highly Efficient Anodic Annihilation Electrochemiluminescence Emitter for Ultrasensitive Detection of MicroRNA.

In this study, a novel europium dual-ligand metal-organic gel (Eu-D-MOGs) with high-efficient anodic annihilation electrochemiluminescence (ECL) was synthesized as an ECL emitter to construct a biosensor for ultrasensitive detection of microRNA-221 (miR-221). Impressively, compared to the ECL signal of europium single-ligand metal-organic gels (Eu-S-MOGs), the ECL signal of Eu-D-MOGs was significantly improved since the two organic ligands could jointly replace the H2O and coordinate with Eu3+, which could remarkably reduce the nonradiative vibrational energy transfer caused by the coordination between H2O and Eu3+ with a high coordination demand. In addition, Eu-D-MOGs could be electrochemically oxidized to Eu-D-MOGs•+ at 1.45 V and reduced to Eu-D-MOGs•- at 0.65 V to achieve effective annihilation of ECL, which overcame the side reaction brought by the remaining emitters at negative potential. This benefited from the annihilation ECL performance of the central ion Eu3+ caused by its redox in the electrochemical process. Furthermore, the annihilation ECL signal of Eu3+ could be improved by sensitizing Eu3+ via the antenna effect. In addition, combined with the improved rolling circle amplification-assisted strand displacement amplification strategy (RCA-SDA), a sensitive biosensor was constructed for the sensitive detection of miR-221 with a low detection limit of 5.12 aM and could be successfully applied for the detection of miR-221 in the lysate of cancer cells. This strategy offered a unique approach to synthesizing metal-organic gels as ECL emitters without a coreactant for the construction of ECL biosensing platforms in biomarker detection and disease diagnosis.

Prevalence and clinical profiles of primary sclerosing cholangitis in China: Data from electronic medical records and systematic literature retrieval.

BACKGROUND & AIMS: Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. METHODS: We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. RESULTS: A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. CONCLUSION: Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.

Long-term antiviral therapy is associated with changes in the profile of transcriptionally active HBV integration in the livers of patients with CHB.

Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.

PRTA:Joint extraction of medical nested entities and overlapping relation via parameter sharing progressive recognition and targeted assignment decoding scheme.

Nested entities and relationship extraction are two tasks for analysis of electronic medical records. However, most of existing medical information extraction models consider these tasks separately, resulting in a lack of consistency between them. In this paper, we propose a joint medical entity-relation extraction model with progressive recognition and targeted assignment (PRTA). Entities and relations share the information of sequence and word embedding layers in the joint decoding stage. They are trained simultaneously and realize information interaction by updating the shared parameters. Specifically, we design a compound triangle strategy for the nested entity recognition and an adaptive multi-space interactive strategy for relationship extraction. Then, we construct a parameter-shared information space based on semantic continuity to decode entities and relationships. Extensive experiments were conducted on the Private Liver Disease Dataset (PLDD) provided by Beijing Friendship Hospital of Capital Medical University and public datasets (NYT, ACE04 and ACE05). The results show that our method outperforms existing SOTA methods in most indicators, and effectively handles nested entities and overlapping relationships.

SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway.

Pathogenic variants in HFE and non-HFE genes have been identified in hemochromatosis in different patient populations, but there are still a certain number of patients with unexplained primary iron overload. We recently identified in Chinese patients a recurrent p.(Arg639Gln) variant in SURP and G-patch domain containing 2 (SUGP2), a potential mRNA splicing-related factor. However, the target gene of SUGP2 and affected iron-regulating pathway remains unknown. We aimed to investigate the pathogenicity and underlying mechanism of this variant in hemochromatosis. RNA-seq analysis revealed that SUGP2 knockdown caused abnormal alternative splicing of CIRBP pre-mRNA, resulting in an increased normal splicing form of CIRBP V1, which in turn increased the expression of BMPER by enhancing its mRNA stability and translation. Furthermore, RNA-protein pull-down and RNA immunoprecipitation assays revealed that SUGP2 inhibited splicing of CIRBP pre-mRNA by a splice site variant at CIRBP c.492 and was more susceptible to CIRBP c.492 C/C genotype. Cells transfected with SUGP2 p.(Arg639Gln) vector showed up-regulation of CIRBP V1 and BMPER expression and down-regulation of pSMAD1/5 and HAMP expression. CRISPR-Cas9 mediated SUGP2 p.(Arg622Gln) knock-in mice showed increased iron accumulation in the liver, higher total serum iron, and decreased serum hepcidin level. A total of 10 of 54 patients with hemochromatosis (18.5%) harbored the SUGP2 p.(Arg639Gln) variant and carried CIRBP c.492 C/C genotype, and had increased BMPER expression in the liver. Altogether, the SUGP2 p.(Arg639Gln) variant down-regulates hepcidin expression through the SUGP2/CIRBP/BMPER axis, which may represent a novel pathogenic factor for hemochromatosis.

Multiscale X-ray phase-contrast CT unveils the evolution of bile infarct in obstructive biliary disease.

Bile infarct is a pivotal characteristic of obstructive biliary disease, but its evolution during the disease progression remains unclear. Our objective, therefore, is to explore morphological alterations of the bile infarct in the disease course by means of multiscale X-ray phase-contrast CT. Bile duct ligation is performed in mice to mimic the obstructive biliary disease. Intact liver lobes of the mice are scanned by phase-contrast CT at various resolution scales. Phase-contrast CT clearly presents three-dimensional (3D) images of the bile infarcts down to the submicron level with good correlation with histological images. The CT data illustrates that the infarct first appears on day 1 post-BDL, while a microchannel between the infarct and hepatic sinusoids is identified, the number of which increases with the disease progression. A 3D model of hepatic acinus is proposed, in which the infarct starts around the portal veins (zone I) and gradually progresses towards the central veins (zone III) during the disease process. Multiscale phase-contrast CT offers the comprehensive analysis of the evolutionary features of the bile infarct in obstructive biliary disease. During the course of the disease, the bile infarcts develop infarct-sinusoidal microchannels and gradually occupy the whole liver, promoting the disease progression.

Liver fibrosis showed a two-phase regression rate during long-term anti-HBV therapy by three-time biopsies assessments.

BACKGROUND: Evidence has proven that liver fibrosis or even cirrhosis can be reversed by anti-HBV treatment. However, the difference of fibrosis regression rates in short-term and long-term antiviral therapy remain unclear. Therefore, we aimed to identify the dynamic changes in fibrosis regression rate in patients with three-time liver biopsies during 5 years antiviral therapy. METHODS: CHB patients with three times of liver biopsies (baseline, after 1.5-year and 5-year antiviral therapy) from a prospective cohort were enrolled. All patients were biopsy-proved Ishak stage ≥ 3 at baseline (n = 92). Fibrosis regression was defined as Ishak stage decreased ≥ 1 or predominantly regressive categorized by P-I-R score. RESULTS: Totals of 65.2% (60/92) and 80.4% (74/92) patients attained fibrosis regression after 1.5-year and 5-year therapy, respectively. Median HBV DNA level declined from 6.5 log IU/ml (baseline) to 0 log IU/ml (1.5 years and 5 years, P < 0.001). The mean level of Ishak fibrosis stage in all patients decreased from stage 4.1 (baseline) to 3.7 (1.5 years) then 3.2 (5 years). Fibrosis regression rates were 0.27 stage/year between baseline to year 1.5 and 0.14 stage/year between year 1.5 and year 5. Furthermore, for patients who attained fibrosis regression after 5-year antiviral therapy, the two-phase regression rates were 0.39 stage/year (0 year-1.5 years) and 0.20 stage/year (1.5 years-5 years). This two-phase feature of regression rate was further confirmed by fully-quantification assessment of liver fibrosis based on SHG/TPEF. CONCLUSION: During the 5 years of long-term antiviral treatment, liver fibrosis rapidly regresses in the first 1.5 years before slowing down in the following 3.5 years.

Obliteration of portal venules contributes to portal hypertension in biliary cirrhosis.

The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, n = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the 'territory' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.

Intravoxel incoherent motion assessment of liver fibrosis staging in MASLD.

PURPOSE: Partial correlation analysis was performed to account for the interference of steatosis changes and inflammatory factors, to determine the true correlation between fibrosis and IVIM parameters (Dfast, Dslow, and F), and to evaluate the diagnostic efficacy of IVIM for liver fibrosis. METHODS: A total of 106 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) examined by IVIM from November 2016 to November 2023 at our hospital were retrospectively included. Preliminary analysis of each IVIM parameter and correlations with pathological findings were performed using Spearman correlation analysis, and partial correlation analysis was used to exclude the interference of other pathological factors, thus yielding the true correlations between IVIM parameters (Dfast, Dslow, and F) and pathology. The diagnostic efficacy of IVIM parameters for diagnosing MASLD was assessed via receiver operating characteristic (ROC) curve analysis. RESULTS: Spearman correlation analysis of all the IVIM parameters revealed correlations with steatosis, lobular inflammation, and ballooning. Partial correlation analysis indicated that Dfast was correlated with the pathological fibrosis stage (r = - 0.593, P < 0.001), Dslow was correlated with the pathological steatosis score (r = - 0.313, P < 0.05), and F was correlated with the pathological fibrosis stage and steatosis score (r = - 0.456 and 0.255, P < 0.001 and P < 0.05). In the diagnosis of hepatic fibrosis, significant hepatic fibrosis, advanced liver fibrosis and cirrhosis, Dfast achieved areas under the ROC curve of 0.763, 0.801, 0.853, and 0.897, respectively. The threshold values for diagnosing different fibrosis stages using Dfast (10-3 mm2/s) were 57.613, 54.587, 52.714, and 51.978, respectively. CONCLUSION: According to our partial correlation analysis, there was a moderate correlation between Dfast and F according to fibrosis stage, and Dfast was not influenced by inflammation or steatosis when diagnosing fibrosis in MASLD patients. A relatively close Dfast threshold is insufficient for accurately and noninvasively assessing various stages of MASLD fibrosis. In clinical practice, this approach can be considered an alternative method for the preliminary assessment of fibrosis in MASLD patients.

Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients.

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.

The staging of nonalcoholic fatty liver disease fibrosis: A comparative study of MR elastography and the quantitative DCE-MRI exchange model.

Objectives: To evaluate the efficacy and image processing time of the dynamic contrast-enhanced MRI (DCE-MRI) exchange model in liver fibrosis staging and compare it to the efficacy of magnetic resonance elastography (MRE). Methods: The subjects were 45 patients with nonalcoholic fatty liver disease (NAFLD) who underwent MRE and DCE-MRI in our hospital. Liver biopsy results were available for all patients. Spearman rank correlation coefficients were used to compare the correlations among MRE, DCE-MRI and liver fibrosis parameters. Quantitative DCE-MRI parameters, MRE-derived liver stiffness measurement (LSM), and the results of a combined DCE-MRI + MRE logistic regression model were compared in terms of the area under the receiver operating characteristic curve (AUC). We also compared the scanning and postprocessing times of the MRE and DCE-MRI techniques. Results: The correlation coefficients between the following parameters of interest and liver fibrosis were as follows: capillary permeability-surface area product (PS; DCE-MRI parameter), -0.761; portal blood flow (Fp; DCE-MRI parameter), -0.754; MRE-LSM, 0.835. Some DCE-MRI parameters (PS, Fp) had slightly greater AUC values than MRE-LSM for diagnosing the presence or absence of liver fibrosis, and the combined model had the highest AUC value for all stages except F4, but there was no significant difference in the diagnostic efficacy of the DCE-MRI, MRE, and combined models for any stage of fibrosis. The average scanning times for MRE and DCE-MRI were 17 s and 330 s, respectively, and the average postprocessing times were 45.5 s and 342.7 s, respectively. Conclusions: In the absence of MRE equipment, DCE-MRI represents an alternative technique. However, MRE is a quicker and simpler method for assessing fibrosis than DCE-MRI in the clinic.

Comprehensive approach to controlling chronic hepatitis B in China.

Hepatitis B virus (HBV) infection was highly endemic in China, where the prevalence of HBsAg was 9.7% in 1992. Comprehensive strategies, including universal infant hepatitis B vaccination with emphasis on timely birth-dose and 3-dose coverage, dramatically reduced the mother-to-infant transmission and early childhood acquisition of HBV, resulting in estimated HBsAg prevalence rates of 5.6% and 0.1% in the general population and among children aged <5 years in 2022, respectively. Clinical guidelines on the prevention and treatment of chronic hepatitis B have been periodically updated based on emerging evidence from clinical research. The continuously improved reimbursement policy and the massively reduced price of antiviral drugs through government negotiation and central procurement have increased treatment accessibility and affordability. However, due to the low rates of diagnosis and treatment, China still faces a large challenge in achieving the 2030 goal of lowering HBV-related mortality by 65%. A public health approach involving concerted efforts from the government, medical community, industry, and society as a whole would be necessary to increase the uptake of HBV tests and treatment to achieve the global goal of eliminating viral hepatitis as a public health threat by 2030.

Add-on immunosuppressive therapy may benefit selected patients with primary biliary cholangitis and autoimmune phenomena.

Background: Mildly elevated levels of transaminase and/or immunoglobulin G (IgG) are common in patients with primary biliary cholangitis (PBC). It is still unclear whether adding immunosuppressive therapy to ursodeoxycholic acid (UDCA) benefits those patients who are not fulfilling the diagnostic criteria of PBC with autoimmune hepatitis (AIH) features. Objectives: To assess the efficacy of adding immunosuppressive therapy to UDCA for patients with PBC and autoimmune phenomena but not fulfilling the diagnostic criteria of PBC with AIH features. Design: This is a retrospective-prospective cohort study in a tertiary medical center. Methods: Patients with PBC and autoimmune phenomena were defined by the elevation of IgG and/or transaminase but did not fulfill the diagnostic criteria of PBC with AIH features. We grouped these patients based on with and without add-on immunosuppressive therapy and balanced their baseline characteristics using inverse probability treatment weighting (IPTW). Results: A total of 652 patients with PBC and autoimmune phenomena were included, with a median follow-up of 4.08 years. After IPTW, the pseudo sample size in the add-on therapy and monotherapy groups was 558 and 655, respectively. After 1 year of observation, patients in the add-on therapy group had a higher biochemical response rate (normalization of transaminase and IgG levels) (49% versus 17%, p < 0.001). Furthermore, add-on therapy improved the transplant-free survival in the subgroup of patients with PBC and transaminase ⩾3 × upper limit of normal (ULN) or IgG ⩾1.3 × ULN (p = 0.033). Conclusion: Add-on immunosuppressive therapy may improve the normalization rates of transaminase and IgG levels in all patients with PBC and mildly elevated transaminase and IgG levels and the long-term outcomes in the subgroup of the patients with transaminase ⩾3 × ULN or IgG ⩾1.3 × ULN.

A look at add-on immunosuppressive therapy in primary biliary cholangitis patients Adding immunosuppressive therapy may enhance the normalization of ALT, AST and IgG levels in all PBC patients with mild elevation and improve long-term outcomes in those with more severe elevation of ALT, AST and IgG. These findings contribute to our understanding of treatment options for PBC patients with autoimmune phenomena.

Market or regulation? The competition effect between green finance and environmental enforcement on environmental quality and its "dominate-follow" pattern.

Current research on environmental instruments often isolates the two mainstream types, market-based and regulation-based, overlooking their real-world interactions. In response, the intensity gap variable (EII_GAP) is constructed to link various instruments into a united system. Thus, based on the spatial econometrics of the spatial panel Durbin model (SPDM), the collective effects between market- and regulation-based environmental instruments on environmental quality are explored. Moreover, the political strategies for maximizing environmental benefits are discussed. Results show that the interaction pattern between market- and regulation-based environmental instruments on environmental quality is characterized by competition rather than cooperation. A unit widening in the intensity gap leads to 17 to 18% and 12 to 18% units of environmental quality improvement in local and adjacent areas, respectively. Furthermore, the "dominate-follow" approach as the most effective mode for maximizing environmental effects is proposed. This study recommends employing one type of instrument as the dominant while the other as the auxiliary. In provinces where one kind of environmental instrument takes domination, the environmental quality could be increased by around 8 to 113% after taking another contrary instrument as the auxiliary.

How People Process Different Types of Health Misinformation: Roles of Content Falsity and Evidence Type.

Emerging communication technologies have seen the proliferation of misleading claims, untruthful narratives, and conspiracies. To understand how people perceive and act on different types of misinformation, this study examines how health misinformation varying in falsity (fabrication versus misuse) and evidence type (statistical versus narrative) affects sharing and verification intentions. Using COVID-19 vaccines as cases, the results from an online experiment showed that misused misinformation was perceived as less false than fabricated misinformation and resulted in higher sharing intentions for the issue of vaccine efficacy. Misinformation with narrative evidence, as compared to that with statistical evidence, was perceived as less false and led to lower verification intentions. These findings can be explained by psychological processes such as counterarguing and narrative engagement. Our results can help practitioners develop dedicated misinformation literacy programs.

Health discussion network characteristics among a sample of people with inflammatory bowel disease.

OBJECTIVES: This study examined the health discussion networks (HDNs) of people with inflammatory bowel disease (IBD). We sought to test if HDN characteristics were associated with IBD management self-efficacy outcomes. METHODS: We recruited a sample of adults with IBD (N = 112) in December 2020 to take an online survey. Participants listed up to five people (alters) who they discussed their health with, and we used those data to construct individual HDNs. Participants provided demographic information about alters, and characterized alter by relationship, closeness, and support provided. We used multivariable regression to examine associations of HDN characteristics with IBD symptoms, remission, and emotions management self-efficacy outcomes. RESULTS: Participants reported data for 412 alters (mean HDN size: 3.68). Alters were mostly friends (40%) or family members (36%); few were healthcare workers (6%). In multivariable analyses, HDN size was associated with remission and emotions management self-efficacy (ps < .05), and the amount of support offered by alters was associated with emotions management self-efficacy (p < .05). DISCUSSION: HDN size and alter support variables were associated with some IBD management self-efficacy outcomes among our study sample. These findings provide empirical evidence about HDNs among people with IBD and support the notion that disease management is a collective effort.

Histopathological characteristics of liver biopsy performed at different time points in drug-induced liver injury.

BACKGROUND AND AIMS: Liver biopsy can provide critical information in patients with drug-induced liver injury (DILI). Our study aimed to compare the histopathological features of DILI at different time points from the onset to liver biopsy. METHODS: We conducted a single-centre retrospective observational study. The clinical and follow-up data were extracted, and the pathological slides were reviewed. RESULTS: 129 patients were included. The median age was 52 and 75% were women. They were divided into <1 month, 1-3 months, and >3 months groups according to the durations from onset of the disorder to liver biopsy. The aminotransferase, alkaline phosphatase, and bilirubin levels showed no significant differences at onset but significantly decreased with time among the three groups (all p<0.05) at the time of liver biopsy. Histological injury patterns were significantly different among the three groups (p<0.01). Hepatocellular, canalicular, and cholestasis of Kupffer cells were significantly less frequent in the >3 months group (p<0.01). For patients taking herbs, bridging necrosis and cholestatic injury were significantly more frequent in the <1 month group (p<0.01). Furthermore, ductopenia, cholate stasis, and foam-like cells were equally distributed in the three groups but were significantly associated with poor prognosis. CONCLUSIONS: Biopsy time significantly affects liver pathology: the earlier, the more acute cholestatic-hepatitic pattern, the later, the more chronic injury patterns. The prognostic features (ductopenia, cholate stasis, and foam-like cells) occurred equally in all three groups. Our study provides valuable information for liver pathologists aiding in their better interpretation of the liver biopsy from patients with DILI.

Association of BMI with mortality in drug-induced liver injury.

BACKGROUND: To clarify the associations between BMI and the incidences of all-cause death or liver-related death (LRD)/liver transplantation (LT) in drug-induced liver injury (DILI). METHODS: DILI patients from three hospitals were retrospectively retrieved and follow-up from 2009 to 2021. They were categorized into underweight (BMI < 18.5 kg/m 2 ), normal weight (BMI of 18.5-23.9 kg/m 2 ), overweight (BMI of 24-27.9 kg/m 2 ) and obese (BMI ≥ 28 kg/m 2 ) groups. Cox regression models were conducted to reveal the effect of BMI on all-cause death or LRD/LT. RESULTS: A total of 1469 eligible DILI patients were included: underweight 73 (4.97%), normal weight 811 (55.21%), overweight 473 (32.20%) and obese 112 (7.62%). Eighty-nine patients (6.06%) had all-cause death, of which 66 patients (4.49%) had LRD/LT. The median age was 52 years old, and females were 1039 (70.73%). The associations between BMI and all-cause mortality ( nonlinear test P <  0.01) or liver-related mortality/LT ( nonlinear test P  = 0.01) were J-shaped. Multivariate Cox regression analysis showed that underweight (HR: 3.02, 95% CI: 1.51-6.02) was significantly associated with all-cause mortality after adjusting for age and sex. Furthermore, obese males were significantly associated with liver-related mortality/LT (HR: 3.49, 95% CI: 1.13-10.72) after additional adjustment for serological indices and comorbidities. CONCLUSION: Association between BMI and mortality is a J-shape. The overall mortality was significantly higher in underweight and obese group. Male obesity is independently associated with LRD/LT. These findings indicate that DILI patients with extreme BMI would have a high risk of dismal outcomes, which warrants extra medical care.

Regression of Liver Fibrosis in Patients on Hepatitis B Therapy Is Associated With Decreased Liver-Related Events.

BACKGROUND & AIMS: Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients. METHODS: Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs. RESULTS: A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 109/L). CONCLUSIONS: Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis.

Autoimmune hepatitis with confluent necrosis indicates severe liver injury but responds well to standard immunosuppressive therapy.

We aimed to study the effects of different extensive confluent necrosis on complete biochemical remission, side effects of immunosuppressants, and outcomes in patients with autoimmune hepatitis (AIH). Patients with liver biopsy, receiving standard immunosuppressive therapy (IST), and regular follow-up were retrospectively recruited. Demographic and clinicopathological characteristics between Ishak confluent necrosis scores ≤4 (the non-severe AIH group) and ≥5 (the severe AIH group) were compared. The Kaplan-Meier Survival analysis, Cox regression analysis, and log-rank test were performed. Bilateral p<0.05 was considered statistical significance. One hundred and forty-two patients were enrolled, the median age was 56.0, and 83.8% were female. There were no significant differences in aminotransferases and immunological markers between the two groups. Patients in the severe AIH group had significantly worse liver synthetic function, a higher proportion of cirrhosis, and histologically a higher degree of portal inflammation, interface hepatitis, fibrosis stage, and a higher histological activity index score (all p<0.05). Patients in the severe AIH group had a lower response than the other group after four weeks (57.1% vs. 86.3%, p=0.002). However, differences in complete biochemical remission (CBR) were insignificant. Eight patients experienced end-point events. Kaplan-Meier survival analysis showed no significant difference between the two groups (p=0.343). For adverse effects of IST, patients in the severe group tended toward a higher incidence of corticosteroid adverse effects without statistical significance. Our study indicated that patients with histologically severe confluent necrosis (Ishak score≥5) had significantly worse liver synthetic function and a higher degree of liver fibrosis before IST. Compared with their counterparts, this subgroup of patients showed delayed biochemical response but eventually comparable CBRs, side effects, and long-term outcomes.