Hepatology Communications最新文献

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.

Background: Cirrhosis and other chronic liver diseases are the 12th leading cause of death globally and impose a substantial economic burden. Estimating the macroeconomic burden and distribution can provide a policy rationale for the prevention and treatment of these issues. We aimed to estimate and project the macroeconomic burden of cirrhosis and other chronic liver diseases in 190 countries and territories, as well as their distribution across world regions.

Methods: We calculated the macroeconomic burden of cirrhosis and other chronic liver diseases in 190 countries using a health-augmented macroeconomic model that accounts for the impact of morbidity and mortality on labor supply, age differences in education and experience among those affected by cirrhosis and other chronic liver diseases, and reduced investment due to the shifting of costs of these disease-related treatments from savings.

Results: Our findings suggest that cirrhosis and other chronic liver diseases will cost the world economy INT$ 2.649 trillion (2.502-2.827) in 2021-2050. The United States has the largest economic burden of cirrhosis and other chronic liver diseases, followed by China and India. Although low- and middle-income countries have the highest health burdens (91.4% of the global disability-adjusted life years), their share of the economic burden of cirrhosis is only 57.1% of the global loss.

Conclusions: The macroeconomic burden of cirrhosis and other chronic liver diseases is sizeable and distributed unequally across countries and world regions. Our study emphasizes the need for greater investment globally in controlling cirrhosis and other chronic liver diseases and their associated health and economic burdens.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. Measuring the burden of cirrhosis and its complications in people with MASLD is important to inform health care delivery.

Methods: We aimed to quantify the changes in the burden of MASLD-related cirrhosis and hepatocellular carcinoma (HCC) in a nationwide U.S. healthcare system. We used data from the Veterans Health Administration to examine temporal trends between 2010 and 2021 in the annual incidence and prevalence of cirrhosis and HCC in a large cohort of patients with MASLD, and to compare them to those in patients with hepatitis C virus infection (HCV) and alcohol-associated liver disease (ALD).

Results: The MASLD cohort grew from 78,082 in 2010 to 621,400 patients in 2021. The annual age-standardized incidence rates of MASLD-related cirrhosis rose from 1.39 (95% CI, 1.13, 1.65) to 1.91 (95% CI, 1.80, 2.02) per 1000 patients (37.4% increase). HCC incidence increased from 0.08 (95% CI, 0.02, 0.14) to 0.22 (0.18, 0.26) per 1000 patients (175% increase). Cirrhosis and HCC prevalence also increased, particularly among adults older than age 65, Whites, Hispanics, and individuals with diabetes. Temporal trends in the incidence and prevalence of cirrhosis and HCC among patients with ALD were similar to those in MASLD. In contrast, patients with HCV experienced a sharp decline in the incidence of cirrhosis and HCC in this time frame.

Conclusions: The burden of MASLD-related cirrhosis and HCC is growing. While the burden of liver complications is similar between MASLD and ALD, the substantially larger size of the MASLD population means that the modest increases in incidence of cirrhosis and HCC could translate into a large absolute burden.

Background: Obesity impairs liver regeneration by promoting chronic inflammation and metabolic dysfunction, especially in conditions like non-alcoholic fatty liver disease. Portal vein embolization (PVE), used to stimulate liver growth pre-hepatectomy, is less effective in obese subjects. Nicotinamide riboside (NR), a NAD+ precursor, improves mitochondrial function and lipid metabolism, but its role in liver regeneration under obese conditions remains unclear. Our study tried to investigate the effects and underlying mechanisms of NR on liver regeneration after PVE in high-fat diet (HFD)-induced obese rats.

Methods: HFD-fed rats underwent PVE and were treated with or without NR. Liver regeneration was assessed by histology, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, immunohistochemistry, and liver function tests. NAD+ levels were quantified to confirm NR activity. Proteomics, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Ontology (GO) analysis, quantitative real-time PCR (qPCR), and western blotting were used to explore molecular mechanisms, focusing on the MCART1/ASB3 axis.

Results: Obesity impaired liver regeneration post-PVE, as evidenced by lipid accumulation, inflammation, reduced hepatocyte proliferation, and elevated liver enzymes. NR supplementation restored NAD+ levels, improved liver function, increased proliferative activity, and reduced steatosis. Mechanistically, NR upregulated MCART1 and ASB3 expression, promoting energy and lipid metabolism essential for regeneration.

Conclusions: NR promotes liver regeneration after PVE in obese rats by enhancing NAD+-dependent metabolic pathways through the MCART1/ASB3 axis, offering a potential therapeutic strategy for obesity-associated liver dysfunction.

Background: Intrahepatic cholestasis of pregnancy (ICP) is a multifactorial liver disorder associated with adverse pregnancy outcomes. Chronic hepatitis B (CHB) has been reported with increased risk of ICP, while the clinical characteristics and outcomes of isolated ICP compared with ICP involving CHB remain poorly understood.

Methods: ICP involving CHB was defined as the co-concurrence of ICP with CHB, categorized into immune-tolerant CHB (n=44), inactive CHB (n=86), immune-active CHB (n=127), and grey zone CHB (n=89). Isolated ICP (n=826) was defined as ICP without viral hepatitis, while immune-active CHB with normal elevated total bile acid (TBA) (n=87) serves as controls.

Results: Women with ICP involving immune-active CHB experienced the most severe biochemical abnormalities and adverse outcomes, whereas other CHB subgroups exhibited biochemical profiles and outcomes comparable to isolated ICP cases. Assisted reproductive technology (aOR, 1.24), TBA levels (40-99.9 µmol/L-aOR, 1.27, ≥100 µmol/L-aOR, 1.60), and immune-active CHB (aOR, 1.12) were associated with increased risks of composite adverse outcomes. Stratified analysis revealed that TBA ≥40 µmol/L significantly correlated with increased risks of total and iatrogenic preterm birth and neonatal intensive care unit admission (p<0.05); while TBA ≥100 µmol/L was further associated with elevated risks of meconium-stained amniotic fluid and lower Apgar scores (p<0.05). Immune-active CHB women with normal TBA demonstrated relatively higher levels of transaminase but achieved the most favorable pregnancy outcomes.

Conclusions: ICP involving immune-active CHB demonstrated the most severe biochemical abnormalities and adverse pregnancy outcomes, while ICP involving other CHB immune phases showed transient mild biochemical changes and outcomes comparable to isolated ICP. The findings underscore the need to tailor diagnostic, monitoring, and management strategies based on TBA levels and the immune status of CHB.

Background: There is no consensus scoring system for staging and prognosis in hepatocellular carcinoma (HCC), which is the fourth leading cause of cancer-related mortality worldwide. Commonly used systems include the albumin-bilirubin (ALBI) score, the Barcelona staging classification (Barcelona Clinic Liver Cancer, BCLC), the Model for End-Stage Liver Disease (MELD), and the model to estimate survival in ambulatory HCC patients (MESIAH). Liver secretion of pseudocholinesterase (PCHE) has been linked to liver function but is poorly studied in the natural history of HCC. We evaluated whether serum PCHE level predicts HCC mortality and whether it enhances existing scoring systems.

Methods: We conducted a retrospective cohort study of individuals diagnosed with HCC. We collected variables including PCHE level, clinical data used in scoring systems, and time to mortality or liver transplant. We then analyzed the association between these variables and survival using Kaplan-Meier curves, Cox proportional hazards regression models, receiver operating characteristic (ROC) curves, and area under the curve (AUC) calculations.

Results: We identified 420 individuals with HCC who were tested for PCHE levels, with a follow-up time of more than 20 years. There was a strong inverse relationship between PCHE level and overall survival, with the lowest quartile having high mortality and poor outcomes. Low PCHE level was associated with hepatitis C virus (HCV) infection, vascular invasion, poor liver function, and a high likelihood of liver transplant. In contrast, the highest quartile was associated with metabolic dysfunction-associated steatotic liver disease (MASLD) as the underlying cause. Compared with validated scoring systems, ALBI, BCLC, MELD 3.0, and MESIAH, the PCHE level was an independent predictor of mortality. PCHE levels could predict 3-month survival as well as or better than the other scoring systems, with an AUC of 0.74. PCHE level could also predict mortality related to hepatectomy. The addition of PCHE level to MESIAH and ALBI scoring systems could further improve the ability to predict overall mortality in HCC.

Conclusions: PCHE is a reliable stand-alone biomarker of HCC prognosis. It is an independent predictor of mortality and can improve the accuracy of existing scoring systems. Improved risk stratification could improve outcomes by informing treatment decisions regarding hepatectomy or other interventions.