Hepatology Communications最新文献

Background: The incidence of cancer and the prevalence of metabolic disease and metabolic dysfunction-associated steatotic liver disease is increasing in young adults. However, updated global data on metabolic dysfunction-associated steatohepatitis (MASH)-associated primary liver cancer (PLC) in young adults remains scarce.

Methods: This study analyzed data from the Global Burden of Disease study between 2000 and 2021 to assess the age-standardized incidence, mortality, and disability-adjusted life years rates from MASH-associated PLC in young adults (15-49 y).

Results: In 2021, there were 4300 incidence cases, 3550 deaths, and 179,340 disability-adjusted life years from MASH-associated PLC in young adults. Among various etiologies of PLC in young adults, only MASH-associated PLC had increased incidence rates (annual percent change: +0.26, 95% CI: 0.16%-0.35%), with the Eastern Mediterranean region having the largest observed increase (annual percent change: 1.46%, 95% CI: 1.40%-1.51%). In 2021, MASH-associated PLC in young adults made up 6% (+1% from 2000) incident cases, 6% (+2% from 2000) deaths, and 6% (+2% from 2000) disability-adjusted life years of all PLC in this age group. Over half of the countries exhibited an increase in age-standardized incidence rate from MASH-associated PLC in young adults from 2000 to 2021.

Conclusions: The incidence of MASH-associated PLC in young adults is significantly increasing, signaling likely future increases in PLC incidence among older adults as this cohort ages. This trend necessitates urgent strategies worldwide to mitigate the epidemics of MASH-associated PLC in young adults.

Introduction: Liver transplantation (LT) provides significant survival benefits to patients with unresectable HCC. In the United States, organ allocation policies for HCCs within the United Network for Organ Sharing criteria do not prioritize patients based on their differences in oncological characteristics. This study assessed whether transplant-associated survival benefits (TASBs) vary among patients with different tumor burden scores (TBS) measured at the time of listing.

Methods: We analyzed data from adults applying for HCC MELD exception points between 2002 and 2019, with follow-up until December 2023, using the Scientific Registry of Transplant Recipients. TBS was determined based on the largest tumor diameter and number of HCCs. Patients were categorized into low (≤3), intermediate (3.1-5), and high (>5) TBS groups. TASB was measured as the difference in 5-year survival with and without LT.

Results: This study included 36,634 LT candidates. High-TBS patients had higher waitlist dropout rates and marginally lower post-transplant survival, resulting in a significantly greater TASB. The 5-year TASB for the low, intermediate, and high TBS groups were 15.7, 22.1, and 25.0 months, respectively. The adjusted survival benefit expressed in 5-year survival differences was 21.9%, 34.5%, and 39.4% in the low, intermediate, and high TBS groups, respectively (p<0.001).

Conclusions: Higher TBS during listing correlates with greater LT benefits for patients with unresectable HCC within UNOS criteria. We conclude that organ allocation policies in the United States should prioritize patients with high TBS due to their increased risk of dropout and comparable post-transplant survival when compared to patients with less advanced tumors.

Histopathologic evaluation of liver biopsy has played a longstanding role in the diagnosis and management of liver disease. However, the utility of liver biopsy has been questioned by some, given the improved imaging modalities, increased availability of noninvasive serologic tests, and development of artificial intelligence over the past several years. In this review, we discuss the current and future role of liver biopsy in both non-neoplastic and neoplastic liver diseases in the era of improved noninvasive laboratory, radiologic, and digital technologies.

Background: Acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are rare inherited sphingolipid disorders with multisystemic manifestations, including liver disease and dyslipidemia. Despite effective treatments, insufficient disease awareness frequently results in diagnostic delays during which irreversible complications occur. We delineated the shared and distinctive features of hepatic, splenic, and lipoprotein phenotypes in ASMD and GD1.

Methods: We analyzed baseline hepatic, splenic, and lipoprotein phenotypes of untreated adults in pivotal trials of ASMD (ASCEND, N=36) and GD1 (ENGAGE, N=40).

Results: The mean cohort ages were 34.8 years in ASMD and 31.8 years in GD1. Most patients had normal or low body mass index. Moderate hepatosplenomegaly (mean volume in multiples of normal) was common in both cohorts (hepatomegaly 1.53±0.42 and 1.40±0.32, respectively; splenomegaly 11.45±4.36 and 13.20±5.91, respectively). Liver function tests were mildly elevated in ASMD but normal in GD1. In both disorders, mean HDL cholesterol (mg/dL) was profoundly low (22.23±9.14 ASMD; 26.25±8.08 GD1) and correlated inversely with liver volume (r=-0.45 ASMD, p=0.005; r=-0.50 GD1, p=0.001) and spleen volume (r=-0.60 ASMD, p=0.0001; r=-0.63 GD1, p<0.0001). Mean LDL cholesterol (mg/dL) was elevated in ASMD (145.86±49.80) but low in GD1 (68.85±22.53). HDL cholesterol correlated inversely with serum concentrations of lyso-sphingomyelin in ASMD (r=-0.48, p=0.003) and glucosylsphingosine in GD1 (r=-0.63, p<0.0001).

Conclusions: ASMD and GD1 should be considered in differential diagnosis of patients with unexplained liver and lipid abnormalities, especially young, lean adults with very low HDL and hepatosplenomegaly. HDL emerged as a potential biomarker of disease activity in these sphingolipid disorders.

Background: Liver fibrosis could lead to serious secondary diseases, including osteodystrophy. The interaction between liver and bone has not been fully elucidated, thus existing therapies for osteodystrophy secondary to liver fibrosis are often ineffective. FGF23 was initially found as an endocrine regulator of phosphate homeostasis, but recently, its involvement in fibrosis has been suggested. In this study, we hypothesized that the FGF23 level increases with liver injury, which in turn induces liver fibrosis and osteodystrophy.

Methods: Liver fibrosis model mice were generated via carbon tetrachloride administration and bile duct ligation. Fibrosis was assessed using Masson trichrome staining and hydroxyproline assay. The bone structure was evaluated using dual-energy x-ray absorptiometry and microcomputed tomography. Human HSC lines LX-2 and primary rat HSCs were used for in vitro analyses.

Results: Carbon tetrachloride-induced and bile duct ligation-induced liver injury increased the serum FGF23 level compared with that in control mice. RNA sequencing analysis of FGF23-treated LX-2 showed that FGF23 promotes the production of matrisome, which helps in forming the extracellular matrix. The FGF receptor antagonist pemigatinib alleviated carbon tetrachloride-induced and bile duct ligation-induced liver fibrosis and the deleterious alterations in bone density and microstructure in mice.

Conclusions: The serum FGF23 level increased with liver injury, and FGF23 promoted liver fibrosis. Moreover, pemigatinib alleviated liver fibrosis and hepatic osteodystrophy. These findings suggest that FGF23 mediates the communication between the liver and bone and that FGF23 may be a new therapeutic target for liver fibrosis and subsequent osteodystrophy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.

Objective: Accumulating evidence suggests that microRNAs derived from macrophage exosomes can regulate the stemness and progression of cancer. However, the interaction mechanisms between HCC cells and tumor-associated macrophages remain unclear.

Methods: Exosomes were extracted from control or CD63 overexpression macrophages and co-cultured with HCC cells. The stemness, proliferation, epithelial-mesenchymal transition, and in vivo tumorigenicity of HCC cells were assessed to determine the role of CD63-high macrophage-derived exosomal miR-6876-5p in HCC. The binding relationship between miR-6876-5p and the PTEN/Akt axis was also investigated.

Results: Elevated CD63 expression was associated with increased tumor-associated macrophage infiltration and poorer prognosis in HCC. CD63-high macrophage-derived exosomes enhanced HCC cell proliferation, stemness, and epithelial-mesenchymal transition. miR-6876-5p within these exosomes was identified as a key mediator, promoting HCC progression by targeting PTEN and activating the Akt signaling pathway. In vivo studies confirmed that CD63-high macrophage-derived exosomal miR-6876-5p accelerated tumor growth and enhanced stemness in HCC cells.

Conclusions: CD63-high macrophage-derived exosomes, particularly those enriched with miR-6876-5p, play a pivotal role in HCC progression by enhancing stemness and promoting epithelial-mesenchymal transition through the PTEN/Akt pathway. Targeting these exosomes and their microRNAs offers a promising therapeutic strategy forHCC.

Background: Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune-mediated liver inflammation. Despite its global prevalence, the pathogenesis of AIH remains poorly understood, and there is a lack of specific biomarkers and targeted treatments. This study aimed to investigate the role of hsa_circ_0109623, hsa-miR-146b-3p, and Sortilin 1 (SORT1) in AIH and their potential as therapeutic targets.

Methods: We collected liver tissue samples and peripheral blood mononuclear cells from patients with AIH and healthy controls and performed RT-PCR, western blotting, flow cytometry, and other molecular biology techniques to analyze the expression of hsa_circ_0109623, hsa-miR-146b-3p, and SORT1. We also used bioinformatics tools to predict the interaction between these molecules and conducted luciferase reporter assays to confirm their binding.

Results: hsa_circ_0109623 was significantly upregulated in patients with AIH and positively correlated with inflammatory activity. We also found that hsa_circ_0109623 could enhance CD4+ T-cell activation and promote the expression of proinflammatory cytokines. Conversely, hsa-miR-146b-3p was downregulated in patients with AIH and negatively correlated with the expression of hsa_circ_0109623 and SORT1. In addition, hsa-miR-146b-3p acted as a sponge for hsa_circ_0109623, inhibiting CD4+ Th1 cell polarization and cytokine production. SORT1 was also upregulated in patients with AIH and acted as a sponge for hsa-miR-146b-3p, promoting CD4+ Th1 cell polarization and cytokine expression. Furthermore, hsa_miR_146b-3p/SORT1 can regulate the STAT1/STAT4 signaling pathway mediating the progression of AIH.

Conclusions: The hsa_circ_0109623/hsa-miR-146b-3p/SORT1 axis plays a crucial role in the pathogenesis of AIH by regulating CD4+ T-cell activation and cytokine production. These molecules may serve as potential biomarkers and therapeutic targets for AIH. Further research is needed to validate these findings and explore their clinical applications.

Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein with the ability to bind to multiple ligands and perform diverse functions. Through the recognition of long-chain fatty acids, proteins containing thrombospondin structural homology repeat domains such as thrombospondin-1, and molecules with molecular structures consistent with danger- or pathogen-associated molecular patterns, CD36 participates in various physiological and pathological processes of the body. CD36 is widely expressed in various cell types, including hepatocytes and KCs in the liver, where it plays a pivotal role in lipid metabolism, inflammation, and oxidative stress. Accumulating evidence suggests that CD36 plays a complex role in the development of nonalcoholic simple fatty liver disease and NASH and contributes to the pathogenesis of inflammatory liver injury, hepatitis B/hepatitis C, liver fibrosis, and liver cancer. This review summarizes the current understanding of the structural properties, expression patterns, and functional mechanisms of CD36 in the context of liver pathophysiology. Furthermore, the potential of CD36 as a therapeutic target for the prevention and treatment of liver diseases is highlighted.

Neurogastroenterology and motility disorders are complex gastrointestinal conditions that are prevalent worldwide, particularly affecting women and younger individuals. These conditions significantly impact the quality of life of people suffering from them. There is increasing evidence linking these disorders to cirrhosis, with a higher prevalence compared to the general population. However, the link between neurogastroenterology and motility disorders and cirrhosis remains unclear due to undefined mechanisms. In addition, managing these conditions in cirrhosis is often limited by the adverse effects of drugs commonly used for these disorders, presenting a significant clinical challenge in the routine management of patients with cirrhosis. This review delves into this connection, exploring potential pathophysiological links and clinical interventions between neurogastroenterology disorders and cirrhosis.