Search Results (30)

Renin–angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), have been associated with improved outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess the differential impact of ACEIs versus ARBs on survival and cardiovascular outcomes in individuals with MASLD. Using data from the UK Biobank, we identified 52,143 participants with exclusive use of either an ACEI or ARB. Individuals with viral, autoimmune, cholestatic, or alcohol-related liver disease were excluded. MASLD was defined as fatty liver index ≥ 60 with ≥1 cardiometabolic risk factor. Inverse probability of treatment weighting (IPTW) was used to adjust for confounders. Outcomes included all-cause mortality, cardiovascular events, hepatic decompensation, and hepatocellular carcinoma (HCC), analyzed using Cox proportional hazards models. Among MASLD participants, ARB use was associated with significantly lower all-cause mortality compared to ACEI use (HR, 0.94; 95% CI, 0.90–1.00; p = 0.031) after IPTW adjustment. Cardiovascular risk was also lower with ARBs (HR, 0.92; 95% CI, 0.89–0.96; p < 0.001), particularly in subgroups with BMI ≥ 25 kg/m², no diabetes, and advanced fibrosis. No differences in hepatic decompensation or HCC incidence were observed. Benefits of ARBs were not significant in participants without steatotic liver disease. ARB use was associated with improved survival and reduced cardiovascular events in individuals with MASLD, whereas ACEIs expressed no comparable benefit. These findings suggest that ARBs might be a more effective RAS inhibitor subclass in MASLD and support their preferential use in patients with steatotic liver disease requiring antihypertensive therapy. Full article

Background/Objectives: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with limited epidemiological data from Central–Eastern Europe. This study characterized a Hungarian PSC cohort, comparing patients with and without inflammatory bowel disease (IBD), and longitudinally evaluated the predictive efficacy of established prognostic scores (Mayo Risk Score, Amsterdam-Oxford Model [AOM], UK-PSC short/long). Methods: Data from 135 PSC patients (median diagnosis age 31 years, 57.7% male) were collected yearly at two Hungarian centers, with a median follow-up of 8.8 years. Outcomes included liver transplantation (LT) and liver-related death. Prognostic value of baseline clinical scores was assessed for 2-, 5-, 8-, and 10-year composite outcome. Results: PSC-IBD patients (54.1%) were younger with higher baseline Mayo and AOM scores, and had increased rates of colorectal carcinoma (8.22% vs. 0.00%) and liver transplantation (26.03% vs. 9.68%) within 10 years than PSC-only patients. There were no differences in liver-related mortality or composite outcomes between the groups. All prognostic scores showed good short-term predictive ability for poor outcomes (AUROC at 2 years: 0.858–0.958), which diminished over time (AUROC at 10 years: 0.708–0.756). The AOM demonstrated the most consistent performance. Persistent alkaline phosphatase (ALP) elevation (≥2.2×ULN) 2 years post-diagnosis, despite ursodeoxycholic acid therapy, strongly predicted 10-year adverse outcomes (HR: 3.927, p < 0.001), outperforming formal scoring systems (HR: 2.688–1.522). Conclusions: While PSC-IBD patients had more CRC and liver transplantation, overall transplantation-free survival was similar to PSC-only patients. Prognostic utility of current scores declines with longer follow-up; AOM was most stable. Sustained ALP elevation is a robust long-term prognostic indicator. Full article

Background: Autoimmune cholestatic liver diseases (AICLDs), including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by progressive biliary injury and cholestasis, leading to an impaired quantity/quality of life. Pruritus affects 20–70% of patients and is often refractory to current treatments. Ileal bile acid transporter (IBAT) inhibitors reduce bile acid reabsorption and may alleviate cholestatic pruritus. This systematic review and meta-analysis evaluates their efficacy and safety in adults with AICLD. Methods: Following PRISMA guidelines, we systematically searched PubMed, Embase, and Cochrane-CENTRAL for studies assessing IBAT inhibitors in adult AICLD patients with pruritus for ≥12 weeks. The primary outcome was the change in the 5-D Pruritus Scale. Secondary outcomes included sleep quality, serum bile acids, liver biochemistry, and safety. Heterogeneity was assessed using Cochrane Q and I² statistics. Results: Three studies (n = 180) met inclusion criteria, including two RCTs and one single-arm study. Patients (78% female; 85% PBC; 77% linerixibat) showed a significant pruritus reduction (MD = −4.93, 95%CI [−6.26, −3.59], p < 0.0001), accompanied by improved sleep quality (MD = −8.12, 95%CI [−13.54, −2.70], p = 0.0033). Serum bile acids, FGF19, and autotaxin decreased significantly, with increased C4 levels. AST and GGT declined, while ALP, ALT, and bilirubin remained stable. Adverse events occurred in 89.7%, mainly diarrhea (22.7%), nausea (12.2%), and abdominal pain (18.2%); serious events were rare (2.2%). Conclusions: IBAT inhibitors significantly reduce pruritus and improve sleep in AICLD, with a favorable safety profile. These findings support their potential as a novel therapeutic option for cholestatic pruritus in adults with AICLD. Full article

Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated with impaired bile flow due to autoimmune or congenital conditions. Despite diverse etiologies, liver fibrosis exhibits conserved biological processes, including hepatocyte death, chronic inflammation, disruption of epithelial or endothelial barriers, and excessive deposition of extracellular matrix (ECM) components. These coordinated events reflect the complex interplay among parenchymal damage, immune activation, and fibrogenic signaling pathways. If unresolved, fibrosis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In the pursuit of non-invasive biomarkers for early detection and monitoring of fibrosis, extracellular vesicles (EVs) have garnered significant attention. Among the diverse cargoes within EVs, microRNAs (miRNAs) have emerged as particularly promising due to their stability, disease-specific expression patterns, and involvement in fibrogenic signaling. This review explores the role of EV-associated miRNAs in liver fibrosis, highlighting key candidates implicated in hepatocellular and cholestatic injury and their clinical potential as diagnostic and prognostic biomarkers, with special focus on MAFLD/MASH, primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia as representatives. Full article

Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct damage and cholestasis. While ursodeoxycholic acid (UDCA) is the first-line therapy, approximately 40% of patients have incomplete responses, necessitating alternative treatments. This systematic review and meta-analysis evaluate the efficacy and safety of novel oral anti-cholestatic agents for PBC. Methods: A systematic literature search was conducted in electronic databases up to September 2024. Randomized controlled trials, cohort studies, and case-control studies evaluating novel oral anti-cholestatic agents in adult PBC patients were included. The primary outcome was a change in alkaline phosphatase (ALP) levels. Safety was assessed by the incidence of serious adverse events. Random-effect meta-analyses were performed. Results: Ten studies involving 878 patients were analyzed. Novel agents included seladelpar, fenofibrate, saroglitazar, bezafibrate, elafibranor, and budesonide. The meta-analysis showed significant reductions in ALP levels with novel agents compared to the controls (SMD −2.80; 95% CI −3.56, −2.03; p < 0.00001), with high heterogeneity (I² = 93%). Saroglitazar achieved the largest effect size. There was no significant difference in serious adverse events between novel agents and controls (OR 1.21; 95% CI 0.81, 1.83; p = 0.35). Conclusions: Novel oral anti-cholestatic agents show promise in improving biochemical markers in PBC patients with suboptimal UDCA responses, with a safety profile comparable to controls. However, study heterogeneity and limited long-term data restrict direct comparisons. Larger standardized trials with extended follow-up are needed to confirm long-term efficacy and safety. Full article

Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), are immune-mediated conditions associated with significant hepatic and systemic manifestations. Among these, cytopenias—defined as reductions in blood cell counts affecting single or multiple lineages—represent a clinically important, though often under-recognized, complication. Cytopenias in AiLDs arise from diverse mechanisms, including immune-mediated destruction, hypersplenism due to portal hypertension, bone marrow suppression, and nutritional deficiencies. These abnormalities can exacerbate bleeding, infections, or fatigue, complicating the disease course and impacting therapeutic strategies. Immune-mediated cytopenias, such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), and autoimmune neutropenia (AIN), are more frequently associated with AIH, whereas cytopenias in PBC and PSC are largely attributed to hypersplenism. Diagnostic evaluation involves a systematic approach combining clinical history, laboratory testing (e.g., complete blood counts, Coombs tests, and nutritional assessments), imaging studies, and bone marrow evaluation in complex cases. Treatment strategies aim to address the underlying cause of cytopenias, including immunosuppressive therapy for autoimmune mechanisms, beta-blockers or splenectomy for hypersplenism, and supplementation for nutritional deficiencies. Challenges include distinguishing between immune- and hypersplenism-related cytopenias, managing drug-induced cytopenias, and optimizing care in transplant candidates. The recently recognized IgG4-related disease, often mimicking cholestatic AiLDs, adds another layer of complexity, given its association with autoimmune cytopenias and hypersplenism. This review aims to act as a guide for the clinician dealing with patients with AiLDs with respect to the occurrence of cytopenias, with a specific focus on pathophysiology and management of these cytopenias. Furthermore, there need to be enhanced multidisciplinary discussions about those patients between the hematologists and hepatologists, with a maintenance of a high index of suspicion for the rarer causes of cytopenias in AiLDs on the part of the treating physician, and there is a need for further studies to elucidate the mechanisms behind the occurrence of cytopenias in AiLDs. Full article

Microbial transglutaminase (mTG) is a bacterial survival factor, which is frequently used as a food additive. This results in the formation of immunogenic epitopes that may cause autoimmunity. Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease characterized by the presence of characteristic autoantibodies. The aim of this work was to determine epitope similarity and cross-reactivity between mTG- and PBC-specific antigens and to investigate whether the microbial enzyme may be associated with the induction of autoimmunity due to epitope similarity and cross-reactivity. Monoclonal and polyclonal antibodies against mTG were applied to nine different PBC-specific antigens using ELISA technique. They reacted significantly with four out of nine antigens. This reaction was most pronounced for gp210 and PML protein. We also performed in vitro studies on the impact of the mTG on the specific antigen–antibody binding using sera of PBC patients. We found four PBC-specific antigens that share homology with mTG sequences. We noticed inhibition of this specific binding by the mTG to the PDC M2, gp210, PML, and KLHL12 protein. Microbial mimics may be the major targets of cross-reactivity with human-specific antigens. Cross-reactivity may indicate a link between mTG and the development of autoimmune diseases. Full article

Hepatic fibrosis (HF) is an important pathological state in the progression of chronic liver disease to end-stage liver disease and is usually triggered by alcohol, nonalcoholic fatty liver, chronic hepatitis viruses, autoimmune hepatitis (AIH), or cholestatic liver disease. Research on novel therapies has become a hot topic due to the reversibility of HF. Research into the molecular mechanisms of the pathology of HF and potential drug screening relies on reliable and rational biological models, mainly including animals and cells. Hence, a number of modeling approaches have been attempted based on human dietary, pathological, and physiological factors in the development of HF. In this review, classical and novel methods of modeling HF in the last 10 years were collected from electronic databases, including Web of Science, PubMed, ScienceDirect, ResearchGate, Baidu Scholar, and CNKI. Animal models of HF are usually induced by chemical toxicants, special diets, pathogenic microorganisms, surgical operations, and gene editing. The advantages and limitations of hepatic stellate cells (HSCs), organoids, and 3D coculture-based HF modeling methods established in vitro were also proposed and summarized. This information provides a scientific basis for the discovery of the pathological mechanism and treatment of HF. Full article

Background/Objectives: Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic disease of the liver that symptomatically can present with pruritus and fatigue. Its established first- and second-line therapies are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) although they provide limited symptom management. Liver transplantation offers a potentially curative therapeutic option in refractory cases progressing to cirrhosis. Novel research published after the current guidelines highlights the importance of providing an up-to-date analysis of treatment options available. Methods: In this study, we conducted a literature search using Pubmed, Ovid Medline, and SCOPUS to provide a narrative review of first-line, second-line, and emerging therapies in PBC. Results: UDCA has been well established as a long-term, safe therapy within the literature although it is possible that treatment dosage can be further optimised in refractory patients. It has a favourable side effect profile. Despite improving biochemical markers, histopathological profile, and overall outcomes, up to 30–40% of patients are refractory to it. Age and sex are highlighted as independent indicators of non-responsiveness. This necessitates effective second-line therapies. Future trials could aim to investigate UDCA as a co-first-line therapy. Further supporting results for OCA were found in the interim extension trial of the seminal POISE study. The long-term phase 4 COBOLT trial is still awaiting results to further assess the complications, adherence, and potential adverse effects. It is a viable option in UDCA-refractory patients. The high incidence rate of dose-related pruritis indicates that alternative second-line options are needed. Bezafibrate is an off-label antilipemic agent that shows promise as a prospective second-line therapy option. The landmark BEZURSO trial alleviated some efficacy and safety concerns, but it remains associated with elevated serum creatinine; thus, it should be considered with caution. Other prospective second-line therapies are budesonide, triple therapy, and novel agents such as seladelpar and elafibranor. Conclusions: UDCA should remain the treatment of choice for PBC, though perhaps not as monotherapy. With further investigation, BF shows promise as a new second-line therapy alongside OCA, which it may outperform. Full article

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches. Full article

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8–12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3⁺ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20⁺, CD38⁺, or CD68⁺ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant. Full article

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut–liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota–bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors. Full article

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intra- and/or extrahepatic bile ducts leading to the formation of multifocal strictures alternated to bile duct dilatations. The diagnosis of the most common subtype of the disease, the large duct PSC, is based on the presence of elevation of cholestatic indices, the association of typical cholangiographic findings assessed by magnetic resonance cholangiography and the exclusion of causes of secondary sclerosing cholangitis. Liver biopsy is not routinely applied for the diagnosis of large duct PSC but is mandatory in the case of suspicion of small duct PSC or overlap with autoimmune hepatitis. Full article

Introduction: Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that is characterized by an inflammatory and fibrotic process affecting bile ducts which eventually develops into liver cirrhosis and liver failure. The aim of this study was to investigate serum IgG subclass distribution in patients with PSC and its possible association with PSC outcomes. Patients and methods: We performed a retrospective analysis of 181 patients who had been diagnosed with PSC between January 1970 and December 2015 and followed at our outpatient clinic. Their demographic, immunological, and clinical characteristics were recorded and analyzed. Results: This study included 181 patients with PSC (120 males, 61 females). There was no association between IgGs and the development of autoimmune hepatitis, cirrhosis, cholangiocarcinoma, liver transplantation, inflammatory bowel disease, and colectomy. Patients with elevated IgG4 had statistically significant higher rates of cholangitis (p = 0.02) and endoscopic retrograde cholangiopancreatography (ERCP) (p = 0.009). High IgG4 values were observed in nine patients who underwent ERCP. In these nine patients, on average, IgG4 was evaluated 5 years after ERCP (min 3 days, max 11 years). Subanalysis considering only IgG4 values evaluated before ERCP showed no significant difference but remains significant if we consider IgG4 values after ERCP. Conclusion: Elevated IgG4 in our study showed a possible association with higher rates of cholangitis and ERCP among patients with primary sclerosing cholangitis. It seems that IgGs may be a useful tool for the prediction of outcomes in patients with PSC. A prospective study is necessary, especially to study the trends of IgGs values during disease as well as the role of possible seroconversion. Full article

Primary biliary cholangitis (PBC) is a slowly progressive cholestatic autoimmune liver disease which leads to fibrosis, cirrhosis, and liver failure. Oxidative stress seems to play an important role in the pathogenesis of chronic liver diseases. The serum level of 8-isoprostane is a marker of oxidative stress in vivo. Oxidative stress causes the production of interleukin 8 (IL-8), which belongs to pro-inflammatory cytokines. The aim of the study was to determine whether the degree of lipid peroxidation determined by measuring the serum level of 8-isoprostane and the elevated concentration of IL-8 influences the progression of PBC. In the study, 72 PBC patients, 15 pathological controls (patients with other autoimmune liver diseases), and 15 healthy blood donors were enrolled. Serum levels of IL-8 and 8-isoprostane in PBC patients were significantly higher compared with the control groups: 91.1 ± 20.1 vs. 4.8 ± 0.6 pg/mL, p = 0.0077; 238.9 ± 226.9 pg/mL vs. 12.3 ± 11.9 pg/mL, p < 0.001, respectively. Serum 8-isoprostane values were positively correlated with a higher concentration of IL-8, bilirubin concentration, and severe liver fibrosis. A correlation between the concentration of IL-8, 8-isoprostane, and specific autoantibodies was observed. The results show that IL-8 and 8-isoprostane may be an important factor in liver pathologies in patients with PBC, especially in the development of inflammatory processes. Serum 8-isoprostane might be a promising marker for the prediction of the degree of liver fibrosis. Full article