Hepatology Communications最新文献

Background: Predicting liver-related events (LREs) in stable cirrhosis is crucial; however, traditional scoring methods perform poorly. Ammonia, due to its pathophysiological integration, may prognosticate LRE. This study tests the hypothesis that hyperammonemia can predict LRE and evaluates the AMMON-OHE score in a prospective cohort.

Methods: A total of 280 patients with cirrhosis were prospectively enrolled and followed until LRE, liver transplant, or death. Ammonia was measured at enrollment and periodically, along with other parameters. LRE at 1 year was defined as hospitalization for ascites, variceal bleeding, hepatic encephalopathy, or bacterial infection. AMN ≥ULN was calculated by adjusting ammonia to the lab's upper normal limit. Cox regression and time-dependent analyses were performed. AMMON-OHE was validated using TRIPOD+AI and decision curve analysis.

Results: Most patients were male (60.7%), with a mean age of 66.1±10.3 years. MASLD was the commonest etiology (43.7%). Median CTP and MELD scores were 6 (IQR: 5-7) and 8 (IQR: 6-11). Overall, 60 (21.4%) developed LRE at 1 year, and 23 (8.2%) died. In multivariable analysis, AMN ≥ULN was an independent predictor of LRE (HR: 4.92; 95% CI: 2.80-8.64). The AMMON-OHE score predicted LRE with a time-dependent AUROC of 0.859 (CI: 0.810-0.907), outperforming MELD (p=0.014) but similar to CTP (p=NS). The AMMON-OHE score underestimated the risk of LRE in our cohort.

Conclusions: AMN ≥ULN in stable outpatients with cirrhosis can predict LRE. Although the AMMON-OHE score has a high AUROC, it underestimates the risk of LRE in this cohort.

Background: Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide.

Methods: To explore the role of mitogen-activated protein kinase 15 (MAPK15) in mammalian lipid homeostasis, we created and characterized the first knockout mouse model for this gene. Hepatocellular in vitro models were also used to further investigate molecular mechanisms underlying MAPK15-dependent regulation of lipid metabolism in the liver.

Results: We observed that Mapk15-/- mice exhibited liver steatosis in the context of a MASLD-like phenotype while hepatocellular in vitro models allowed to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a steatohepatitis-like phenotype. Importantly, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, suggesting a compensatory role in disease progression. In this context, overexpression of this kinase efficiently opposed lipid accumulation in a MASLD hepatocellular model, opening to the possibility of counteracting hepatic steatosis in humans by pharmacologically or genetically activating this MAP kinase.

Conclusions: Presented data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintaining physiological intracellular levels of lipids in this tissue.

Background: To enhance early liver disease detection, a clinical pathway integrating reflex AST testing and automated AAR reporting was implemented. We aim to evaluate the long-term effectiveness of introducing reflex AST testing by assessing its impact after implementation in 2 regions of Wales.

Methods: We applied a quasi-experimental, Difference-in-Difference approach to evaluate the introduction of the reflex AST:ALT pathway in Wales (January 2010 to December 2023). Outcomes were the monthly incidence rate of (1) chronic liver disease (including cirrhosis) and (2) cirrhosis in the 2 intervention regions versus the control regions.

Results: In total, 78,917 individuals with liver disease were included in the study. A significant increase in cirrhosis diagnoses was observed in both regions (first region: incidence rate ratio=1.24, 95% CI: 1.15-1.34, p<0.001; second region: incidence rate ratio=1.16, 95% CI: 1.02-1.33, p=0.028). The incidence of composite chronic liver disease (including cirrhosis) increased transiently in the second region only (incidence rate ratio=1.35, 95% CI: 1.16-1.56, p<0.001).

Conclusions: In this long-term, population-level evaluation, reflex AST:ALT testing increased cirrhosis detection in both regions and produced a short-term rise in chronic liver disease (including cirrhosis) diagnoses one region, strengthening the evidence of the pathway's effect on cirrhosis detection. Further study is warranted to understand regional variation.

Background: Treatment algorithms for hepatocellular carcinoma (HCC) account for tumor burden/stage and severity of liver disease. There are conflicting data on the differential benefit of curative versus non-curative treatments based on BCLC stage. Therefore, we sought to leverage a nationally representative sample of patients in the Veterans Health Administration (VHA) to address this question.

Methods: We performed a retrospective cohort study of patients with cirrhosis and HCC in the VHA. We conducted a landmark analysis and fit survival models, censored at 3 years, to evaluate the association of treatment type based on the highest level (non-curative vs. curative vs. combination), stratified by BCLC stage, for patients with early-stage to intermediate-stage HCC.

Results: We evaluated 1191 patients with confirmed HCC (535 received only non-curative treatment, 227 only curative, and 429 received a combination of curative and non-curative). Among BCLC-0 patients, patients who received curative-intent therapy had significantly better survival at all time points compared with patients receiving non-curative treatment only (HR ranging from 0.53 at 6 months to 0.77 at 3 years). In contrast, for patients with BCLC-A stage disease, receiving either curative treatment alone or combination therapy was associated with significantly better survival compared with non-curative treatment (HR ranged from 0.41 to 0.76 over the study period). However, for BCLC-B stage disease, only combination therapy had significantly better survival (HR 0.44 at 6 months to 0.65 at 3 years).

Conclusions: Our real-world data demonstrate that among patients with early-stage to intermediate-stage HCC, curative-intent treatment is associated with the best survival for patients with BCLC-0 and BCLC-A stage disease, while combination therapy yields the best outcomes in patients with BCLC-B stage disease.

Background: Rifaximin treatment is associated with reduced rates of overt hepatic encephalopathy (OHE) hospitalization relative to lactulose alone. This real-world study evaluated the impact of treatment on rehospitalizations following an initial OHE hospitalization among commercial, Medicare, and Medicaid patients treated with rifaximin±lactulose or lactulose only.

Methods: Claims data from January 1, 2016, to September 30, 2023, were used to identify adults with an initial OHE hospitalization under commercial, Medicare, and/or Medicaid coverage (index date was the day following discharge). Patients were stratified into either the rifaximin cohort (±lactulose) or the lactulose-only cohort based on treatments received within 30 days following discharge. The 30-day OHE rehospitalization rate and OHE rehospitalization rate per-patient-per-year were compared between cohorts using adjusted logistic regression and negative binomial regressions, respectively. Subgroup analyses were conducted based on the timing of rifaximin treatment and adherence to treatment guidelines.

Results: The study included 7880 patients with an OHE hospitalization with commercial insurance (rifaximin: 5997; lactulose only: 1883), 4131 patients with Medicare insurance (rifaximin: 2419; lactulose only: 1712), and 2924 patients with Medicaid insurance (rifaximin: 1854; lactulose only: 1070). After adjustment, rifaximin was associated with a lower risk of 30-day OHE rehospitalization and lower OHE rehospitalization rates per-patient-per-year than lactulose in commercial (OR=1.75, incidence rate ratio [IRR]=1.67, respectively), Medicare (OR=1.61, IRR=1.51), and Medicaid (OR=1.50, IRR=1.54; all p<0.05) populations. Patients immediately receiving rifaximin and those with AASLD guideline-adherent escalation to rifaximin had the fewest rehospitalizations.

Conclusions: Timely treatment with rifaximin in adherence with clinical practice guidelines following an initial OHE hospitalization was associated with improved short-term and longer-term rehospitalization outcomes, regardless of insurance type.

Introduction: HFE genetic variants, especially C282Y homozygosity (C282Y+/+), can increase systemic iron and cause hemochromatosis, though expression varies. Excess iron can lead to liver disease and liver cancer, yet factors influencing liver iron beyond HFE genotype remain unclear. We investigated genetic/environmental factors influencing liver iron, including HFE genotype and hemochromatosis diagnosis.

Methods: We analyzed 37,287 European ancestry UK Biobank participants (mean age 64.1, SD: 7.6) with HFE genotypes and MRI-estimated liver iron concentrations (MRLIC). Linear regression assessed MRLIC associations with genetic and environmental factors, adjusting for age, sex, and genetic covariates.

Results: Mean MRLIC was highest in undiagnosed C282Y+/+ males and females (2.56 and 2.31 mg/g) versus diagnosed (1.23 and 1.51 mg/g, p=0.0001 and 0.0004). Other HFE genotypes had nominal increases versus those without HFE genetic variants. Higher MRLIC was associated with higher alcohol intake (β=0.11, 95% CI: 0.09-0.11, p=6.0×10-128; >30 vs. 1-14 units/wk), frequent red/processed meat consumption (β=0.08, 95% CI: 0.07-0.09, p=3.7×10-54; ≥3 times/week vs. none), high waist-height ratio (β=0.01, 95% CI: 0.006-0.02, p=6.4×10-5; although magnitude was weak) and genetically predicted transferrin saturation (β=0.22, 95% CI: 0.19-0.26, p=3.8×10-46). Lower MRLIC was associated with underweight body mass index (β=-0.06, 95% CI: -0.09 to -0.03, p=1.1×10-4) and proton pump inhibitor use (β=-0.03, 95% CI: -0.04 to -0.03, p=3.5×10-17).

Conclusions: Undiagnosed C282Y+/+ individuals had excess liver iron versus diagnosed, likely due to treatment. Genetic and environmental factors influence liver iron beyond C282Y+/+. Tailored lifestyle advice could benefit those at risk of hemochromatosis.

Background: Long-term survivors of biliary atresia (BA) require liver transplantation owing to cholestasis-associated complications. Bezafibrate (BZF), an antihyperlipidemic agent, can improve cholestasis-induced liver damage. Herein, we evaluated the cholestasis-reducing effect of BZF on survivors of BA with native livers, a condition that has not been previously assessed in any study.

Methods: In this single-center, single-arm, open-label, uncontrolled, prospective phase II trial, patients were enrolled from a central registry system at the Chiba University Data Center. Postoperative patients (n=10) aged older than 18 years (median age, 29 y) with BA and increased serum ALP levels were enrolled between July 2021 and March 2022. Patients with high total bilirubin or alanine aminotransferase levels, recent changes in BA medication, cholangitis within 3 months, renal dysfunction, or liver transplantation were excluded. Participants were administered 400 mg BZF orally in 2 daily doses for 12 weeks and subsequently underwent a 12-week observation. Other drugs were continued. The primary endpoint was the change in ALP levels after 12 weeks of oral BZF administration. The secondary and exploratory endpoints were changes in gamma-glutamyl transpeptidase and triglyceride levels, fecal microbiota, and bile acids.

Results: The mean change in the ALP level was -67 U/L (±20 U/L; p=0.0042). Changes in ALP and gamma-glutamyl transpeptidase levels differed between week 0 and week 6. Adverse events occurred in 5 patients. BZF administration increased the number of Fusicatenibacter without affecting microbiome diversity or bacterial phylum abundance while decreasing lithocholic acid levels and increasing chenodeoxycholic acid levels.

Conclusions: BZF decreased cholestasis markers in survivors of BA with native livers, indicating its potential as an alternative to delayed liver transplantation for this population.

Background: An overdose of acetaminophen (APAP) can cause severe liver injury and may even lead to death. However, the mechanisms that underlie APAP-induced liver injury (AILI) are not fully understood. The extensive liver necrosis resulting from APAP overdose aggravates the sterile inflammatory response by activating resident macrophages and recruiting various immune cells. Numerous studies have highlighted the crucial role of lipid metabolism in macrophage function. This study investigated fatty acid metabolism in hepatic macrophages and its impact on the progression of AILI.

Methods: We administered APAP intraperitoneally to C57/B6L mice to induce acute liver injury and studied lipid changes in hepatic macrophages. We treated hepacytes with APAP and collected the conditioned medium to stimulate macrophages. Moreover, we generated a myeloid-specific knockout of Fasn mice to validate the role of de novo lipogenesis in macrophages during AILI.

Results: We stained liver tissue sections with Bodipy493/503 lipid dye and observed elevated lipid levels in hepatic macrophages after AILI. Mechanistically, HMGB1 released from necrotic hepatocytes increases FASN expression by activating the PI3K/AKT/sterol regulatory element-binding protein-1 (SREBP1) signaling pathway in macrophages. The enhanced de novo lipogenesis increased inflammatory factor expression in macrophages and facilitated their migratory ability. Conversely, myeloid-specific knockout of Fasn reduced the inflammatory response of macrophages and inhibited their chemotaxis in vivo and in vitro. Furthermore, either myeloid-specific knockout of Fasn or treatment with orlistat, a FASN inhibitor, notably improved liver necrosis and accelerated injury resolution following AILI in mice.

Conclusions: Our findings suggest that targeting de novo lipogenesis in hepatic macrophages may represent a novel strategy for treating AILI.