Search Results (107)

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts. PBC encompasses several clinical subtypes, including classical AMA-positive PBC (90–95% of cases), AMA-negative PBC (5–10%), and overlap syndromes such as AIH-PBC. These subtypes exhibit distinct serological profiles, with AMA-negative cases often presenting PBC-specific antinuclear antibodies (anti-gp210, anti-sp100) and overlap syndromes demonstrating combined autoantibody patterns characteristic of both conditions. Autoantibodies serve as central biomarkers for diagnosis, prognosis, and understanding disease pathogenesis. This review provides a comprehensive overview of classical and emerging autoantibodies associated with PBC, including AMA-M2, anti-gp210, anti-sp100, anti-KLHL12, and anti-RPL30. We discuss their diagnostic significance across PBC subtypes, pathogenic implications, and potential utility in patient stratification and therapeutic monitoring. Recent evidence suggests that bile acid-induced neoantigen formation, rather than classical loss of immune tolerance, may drive AMA production. Advances in autoantibody profiling, including subclass-specific analysis and multi-marker panels, may pave the way for personalized medicine and improved outcomes in PBC. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly attracting growing concern around the world. While there has been progress in the development of pharmacologic treatments, lifestyle and dietary interventions remain as the first-line approach for management. This scoping review aimed to identify dietary strategies for managing MASLD and to highlight current research gaps and challenges. Methods: A systematic search of PubMed and Science Direct was conducted up to 10 July 2025, for relevant studies on dietary modifications and MASLD. Data extracted included types of interventions, outcomes related to liver health, and research limitations. Results: Dietary interventions were shown to consistently improve hepatic and metabolic outcomes. In a randomized controlled trial of 12 weeks (n = 259), a Mediterranean diet reduced hepatic steatosis by 39% and improved insulin sensitivity. A calorie-restricted lifestyle program in adults with MASLD (n = 196) reduced liver fat by 25% over 52 weeks. Resistant starch supplementation (n = 200) lowered intrahepatic triglyceride content by 8% through gut microbiome modulation. A pilot RCT of medically tailored meals in cirrhosis (n = 40) reduced ascites symptoms and improved quality of life. Finally, prebiotic supplementation in MASLD (n = 200) lowered systemic inflammation and increased immune-regulating microbes. In contrast, Western dietary patterns and ultra-processed foods were consistently linked to lipotoxicity and inflammation. Conclusions: Dietary interventions remain critical for the management of chronic liver disease and continue to play a vital role even as pharmacotherapy options emerge. Further research should explore precision nutrition and microbiome-based therapies while also addressing the methodological limitations like the underutilization of causal inference frameworks. Finally, it is also important to consider culturally tailored interventions to account for barriers in access and equity in underserved populations. Full article

Background: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to late-stage presentation and ineffective systemic therapies. Targeting the tumor microenvironment (TME) in ICC offers new therapeutic possibilities, particularly through tumor-associated macrophages (TAM), which can both promote and inhibit tumor progression. The current study utilized multi-omics analysis to characterize the gene signature of TAM and explore its therapeutic potential in ICC. Methods: Public GEO datasets provided the basis for analysis. Single-cell RNA sequencing (scRNA-seq) data from five ICCs, three adjacent non-tumorous tissues (ANTs), and four healthy liver samples were examined with Python. To validate scRNA-seq findings, bulk RNA-seq data from 27 ICC and 27 matched ANT samples were assessed using R. Differentially expressed genes were identified with adjusted p-values <0.01 and log2-fold changes >1 or <−1. CIBERSORT pipeline analyzed 22 immune cell subtypes in bulk RNA-seq data. STRING database analyzed the contribution of unique TAM-related genes to networks of protein–protein interactions. Results: TAM population demonstrated phenotypic heterogeneity exhibiting partial gene signatures of inflammatory (MS1) and anti-inflammatory (MS2) macrophages. Unique TAM-associated markers, TREM2, CD9, and PRMT10, showed variable expression within the TAM subpopulation. Bulk RNAseq analysis confirmed the scRNA-seq results, highlighting overexpression of TREM2 and CD9 in most ICC samples versus ANT. Immune cell deconvolution revealed decreased MS1 and MS2 macrophages in ICC, and alterations in adaptive immune profile, suggesting immunotolerant TME. STRING database defined TREM2-LGALS3 axis as a potential target for anti-tumor therapies. Conclusions: TAM represents a unique heterogenous population which is primarily found in ICC TME versus ANT or healthy liver tissue The non-uniform expression of unique gene signature demonstrates additional heterogeneity in the TAM subpopulation and suggests that TREM2+ TAM may be desirable targets for anti-TREM2-LGALS3 immunotherapy. Full article

Ascites and renal dysfunction are among the most frequent and severe complications of decompensated advanced chronic liver disease (dACLD), often representing two interrelated manifestations of a shared pathophysiological continuum. Recurrent ascites and refractory ascites pose significant therapeutic challenges and are frequently associated with kidney impairment, particularly hepatorenal syndrome. Recent advances have reshaped the understanding of the underlying mechanisms, moving beyond the classical paradigm of peripheral arterial vasodilation to encompass systemic inflammation, gut dysbiosis, and cirrhosis-associated immune dysfunction (CAID). These insights have prompted a shift from uniform treatment protocols toward personalized, multidisciplinary strategies. Therapeutic innovations such as long-term albumin infusion, a transjugular intrahepatic portosystemic shunt, and the Alfapump^® system offer promising options, though each requires careful patient selection. Emerging approaches—including fecal microbiota transplantation and peritoneal dialysis—further expand the therapeutic landscape. Ultimately, early risk stratification, the integration of non-invasive tools, and individualized care models are essential to improving outcomes in this high-risk population. This review synthesizes current evidence and highlights future directions for the tailored management of dACLD patients with ascites and renal dysfunction. Full article

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive and heterogeneous malignancy characterized by marked resistance to standard chemotherapy and poor prognosis. While the advent of immunotherapy has revolutionized the management of several solid tumors, including melanoma, breast cancer, and non-small cell lung cancer, its efficacy in iCCA remains limited. Recent clinical trials have demonstrated the efficacy of durvalumab in combination with chemotherapy for iCCA, leading to its approval as a first-line treatment. However, overall response rates remain low, largely due to its immunosuppressive tumor immune microenvironment (TIME). The immune-cold nature of iCCA is typified by a dominant presence of immunosuppressive cell populations, including M2-polarized tumor-associated macrophages, myeloid-derived suppressor cells, and T regulatory cells. In addition, traditional biomarkers such as PD-L1 expression, tumor mutational burden, and microsatellite instability have shown limited predictive value in iCCA, highlighting the need for novel biomarkers and immunotherapeutic strategies. Emerging approaches aimed at reprogramming the TIME, including combination therapies targeting suppressive cells, stromal remodeling, and novel immune effectors like CAR-T and cancer vaccines, hold significant promise for enhancing therapeutic efficacy. This review summarizes the distinct features of iCCA TIME, key mechanisms of immune evasion, current challenges, and future directions to overcome immune resistance, with the aim of developing personalized immunotherapies to improve patient outcomes. Full article

Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterized by progressive destruction of the small intrahepatic bile ducts, leading to cholestasis, inflammation, and ultimately fibrosis and cirrhosis. This review emphasizes the central role of bile acids in PBC pathogenesis, exploring how disruptions in their synthesis, transport, and detoxification contribute to cholangiocyte damage and disease progression. In addition to discussing the autoimmune features of PBC, including the presence of specific autoantibodies and cellular immune responses, we examine how bile acid dysregulation exacerbates cholestasis and promotes lipid metabolic disturbances. Particular attention is given to the “bicarbonate umbrella” hypothesis, which describes a protective mechanism by which cholangiocytes resist bile acid–induced injury—an essential factor disrupted in PBC. The aim of this review is to summarize current knowledge gaps in the pathophysiology of PBC, with a focus on the role of bile acids not only as key drivers of disease mechanisms, but also as potential biomarkers of disease progression and treatment response. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) play a crucial role in trophoblast invasion, immune tolerance, and placental angiogenesis. To delineate their diagnostic and pathological significance, we critically evaluated the evidence for correlations between circulating or placental lncRNA profiles with pregnancy complications. Methods: Five databases were searched from inception through September 2024. We included only the studies that assessed the expression of the lncRNA-complicated pregnancies versus a control group. Results: Three single-center case–control studies fulfilled the inclusion criteria. Eight serum lncRNAs that present <20 weeks of gestation were elevated in subsequent pregnancy-induced hypertension or preeclampsia. The three lncRNAs in intrahepatic cholestasis of pregnancy were consistently decreased with a negative correlation with bile acids. Gestational diabetes was characterized by the elevation of MALAT1. Conclusions: Different lncRNAs showed a potential for use as non-invasive markers as well as for risk stratification for pregnancy-induced hypertension or preeclampsia, metabolic, and hepatobiliary pregnancy complications. There is a need for large-scale, multi-ethnic, prospective cohorts to include lncRNA as screening or therapeutic targeting in obstetric practice. Full article

Background: Chronic hepatitis B (CHB) remains being a major public health threat, and currently existing CHB therapies have limited efficacy and side effects. We have recently developed a vaccine termed VVX001 based on a recombinant fusion protein consisting of the preS domain of the large surface protein of hepatitis B virus (HBV) fused to grass pollen allergen peptides. VVX001 has been shown to induce preS-specific antibodies in grass pollen allergic patients, and sera of immunized subjects inhibited HBV infection in vitro. Methods: In this study we investigated if immunization with VVX001 can induce preS-specific antibodies in CHB using the adeno-associated virus (AAV)-HBV murine model of CHB. Six groups of C57BL/6 female mice (n = 6) were transduced with AAV-HBV or AAV-Empty, and after six weeks, they were immunized five times with 20 µg of aluminum hydroxide-adsorbed VVX001 or preS or vehicle (Alum alone). Serum samples were taken continuously. Two weeks after the last immunization, spleen and liver mononuclear cells were collected. Serum reactivity to preS and preS-derived peptides was assessed by ELISA. B-cell responses were measured by ELISPOT assay, and intrahepatic lymphocyte (ILH) counts were determined by FACS. HBV DNA, HBsAg, HBeAg, ALT, and AST were assessed using commercial kits. Results: Our results show that VVX001 induces preS-specific IgG antibodies that cross-react with different HBV genotypes A-H and are directed against the sodium taurocholate co-transporting polypeptide (NTCP) receptor binding site of preS both in mice with and without HBV. Actively immunized AAV-HBV-treated mice had a higher number of intrahepatic lymphocytes than vehicle-vaccinated and mock-transduced animals. Conclusions: These findings encourage performing further trials to study the potential of VVX001 for therapeutic vaccination against CHB. Full article

Background/Objectives: The TOPAZ-1 phase III trial reported a survival benefit of using durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with gemcitabine and cisplatin (GCD) treatment in patients with advanced biliary tract cancer. This retrospective study investigated the efficacy and safety of GCD treatment for advanced biliary tract cancer in real-world conditions. Methods: The study subjects were 52 patients with biliary tract cancer who received GCD therapy between January 2023 and May 2024. The observation parameters included the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), tumor markers (CEA, CA19-9), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: The cohort included 36 men and 16 women, with a median age of 73.0 years. There were 36 cases of cholangiocarcinoma (distal: 10, perihilar: 19, intrahepatic: 7), 13 cases of gallbladder cancer, and 3 cases of ampullary carcinoma. The stages were locally advanced in 30 cases and metastatic in 22 cases. Biliary drainage was performed in 30 cases. There were 38 cases receiving first-line therapy and 14 cases receiving second-line or later treatments. The median values at the start of GCD therapy were ALB 3.7 g/dL, CRP 0.39 mg/dL, NLR 2.4, PLR 162.5, CEA 4.8 ng/mL, and CA19-9 255.9 U/mL. The mGPS distribution was 0:23 cases, 1:18 cases, and 2:11 cases. The treatment outcomes were ORR 25.0% (CR 2 cases, PR 11 cases), DCR 78.8% (SD 28 cases, PD 10 cases, NE 1 case), median PFS 8.6 months, and median OS 13.9 months. The PLR was suggested to be useful for predicting PFS. A decrease in CEA at six weeks after the start of treatment was a significant predictor of PFS and OS. Gallbladder cancer had a significantly poorer prognosis compared to other cancers. The immune-related adverse events included hypothyroidism in two cases, cholangitis in one case, and colitis in one case. Conclusions: The ORR, DCR, and PFS were comparable to those in the TOPAZ-1 trial. Although limited by its retrospective design and small sample size, this study suggests that GCD therapy is an effective treatment regimen for unresectable biliary tract cancer in real-world clinical practice. Full article

Background: Although immune complex formation is widely acknowledged as the etiological agent for the development of systemic lupus erythematosus, polyarteritis nodosa, reactive arthritis, etc., its roles in chronic hepatitis are less understood. This study aims to compare the immunohistochemistry profile of immune complex deposition in patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH). Methods: Immunohistochemistry of C4d, a widely used marker for complement deposition was employed on liver biopsies from 72 and 15 patients with CHB and AIH, respectively. Statistical analysis was performed to analyze its prevalence and its association with a range of clinical and histological parameters. Results: Among the 15 AIH biopsies examined, C4d deposition was observed in 11 cases (73.3%), the majority of which showed a periportal staining pattern (10/11). In CHB, 61 (84.7%) of 72 cases tested positive for C4d, which did not differ significantly with that of AIH. While the periportal pattern was predominantly observed in CHB cases, positive staining in central veins, sinusoids, and hepatic parenchyma were also documented. In particular, C4d deposition is significantly associated with elevated serum ALT and liver inflammation in CHB. Of note, in specimens with a patchy parenchymal C4d staining pattern, a spatially correlated HBsAg IHC signal was observed in adjacent sections from the same tissue. Conclusions: These data suggest an involvement of immune complex-mediated immunopathy in autoimmune hepatitis and HBV-induced hepatitis. The positive intrahepatic C4d signal was associated with heightened liver inflammation. The colocalization of the C4d signal on hepatocytes with HBsAg strongly suggests a causal relationship between viral activity and complement deposition. These observations align with our recent evidence implicating the contribution of capsid–antibody complexes in the pathogenesis of CHB. Full article

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no reports on tumor immune microenvironment (TIME) analyses based on iCCA subclassifications. This study investigated subclassification-specific TIMEs in iCCAs for the purpose of establishing appropriate pharmacotherapy. Methods: A total of 131 resected iCCA cases were analyzed, comprising 73 tumors classified as small-duct-type and 58 as large-duct-type based on pathological evaluation. Immunohistochemical analyses targeting CD8, PD-1, PD-L1, CTLA-4, and S100 protein (a dendritic cell [DC] marker) were performed to investigate the immune-cell status in each subclassification. Results: Large-duct-type iCCA had a significantly higher CD8 expression in tumor-infiltrating cells than small-duct-type ICC. However, the expression of other molecules did not significantly differ between the two tumor types. The proportion of tumors with a high level of S100 protein expression (DC-high group) in tumor-infiltrating cells was significantly higher in small-duct-type ICCs than in large-duct-type iCCAs (30% vs. 1.7%). In small-duct-type iCCAs, the expression levels of CD8, PD-1, PD-L1, and CTLA-4 were significantly higher in the DC-high group than in the DC-low group. Conclusions: We revealed subclassification-specific TIMEs in iCCAs. A subset of small-duct-type iCCAs exhibited strong DC infiltration. In these patients, the tumors may establish an immunosuppressive TIME to evade antitumor immunity triggered by DC-mediated antigen presentation. These findings may contribute to the development of tailored pharmacotherapy for each iCCA subclassification. Full article

Isolated intrahepatic lymphoid follicles (ILFs), also referred to as reactive lymphoid hyperplasia, are rare benign lymphoid proliferations that can closely mimic hepatocellular carcinoma (HCC) on imaging. This case highlights the diagnostic complexity of hepatic mass lesions in chronic hepatitis B patients, particularly when radiologic and serologic features raise concern for malignancy. A 60-year-old man with chronic hepatitis B presented with a liver mass, elevated alpha-fetoprotein levels, and imaging findings of heterogeneous arterial enhancement, all suggestive of HCC. Despite initial treatment with atezolizumab plus bevacizumab, the lesion progressed, leading to an extended left hepatectomy. Histopathological examination revealed well-formed lymphoid follicles with reactive germinal centers, without evidence of malignancy or granulomatous inflammation. Serum IgG was elevated, and ANA was positive, supporting the possibility of an underlying immune-mediated process. The patient showed clinical and serologic improvement following corticosteroid therapy, with no evidence of recurrence at 10-month follow-up. This case underscores the importance of histopathological confirmation in hepatic masses with atypical features and highlights the need to consider benign immune-related mimickers in the differential diagnosis, particularly in the era of immunotherapy. Full article

Objectives: The distinction of clinically uncertain, poorly differentiated liver masses into primary liver cancer (PLC) of cholangiocytic origin (intrahepatic cholangiocarcinoma; CCA) or hepatocellular origin (hepatocellular carcinoma; HCC) vs. metastasis is highly relevant to guiding patient treatment. Protocols differ in terms of resection, local ablation, liver transplantation, or systemic therapies with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Methods: This retrospective case series exemplifies a multidisciplinary, practical guide to clinically uncertain liver masses using imaging, histomorphology, immune phenotyping, and mutational testing of telomerase promoter (TERT) combined with a literature review. Results: In 2/3 patients with uncertain liver masses and inconclusive immunohistochemistry profiles, TERT testing supported the diagnosis of poorly differentiated hepatocellular carcinoma. The third case with a history of sclerosing cholangitis and vague adenoid morphology yielded mutations in ARID1a and TP53 and was identified as primary liver cancer, consistent with poorly differentiated intrahepatic cholangiocarcinoma or mixed hepatocellular cholangiocarcinoma (cHCC/CCA). Conclusions: Finding HCC-typical TERT promoter mutations is a useful diagnostic tool in poorly differentiated primary liver cancer. Full article

Background: Synchronous small- and large-duct intrahepatic cholangiocarcinoma (iCCA) represents a rare and heterogeneous entity, posing challenges for diagnosis, prognosis, and treatment selection. The pathological and molecular diversity between these subtypes influences tumor behavior and therapeutic response, necessitating a personalized approach. This study investigates the molecular and pathological heterogeneity of synchronous iCCA and its clinical implications. Methods: This prospective case series included six patients diagnosed with synchronous small- and large-duct iCCA at the Military Medical Academy, Sofia, between January 2023 and January 2025, with a median follow-up of 15 months. Tumor classification was based on histopathological examination, immunohistochemical analysis, and next-generation sequencing (NGS)-based genomic profiling. Radiological and clinical data were analyzed to assess tumor growth patterns, treatment response, and progression-free survival (PFS). Results: Small-duct-predominant iCCA was associated with IDH1/2 mutations and FGFR2 fusions, a mass-forming growth pattern, and longer PFS. In contrast, large-duct-predominant iCCA exhibited KRAS, TP53, and NF1 mutations, an infiltrative periductal growth pattern, and a more aggressive clinical course with shorter PFS. Tumor mutational burden-high (TMB-H) and microsatellite instability-high (MSI-H) were observed in a subset of large-duct iCCA cases, suggesting potential benefit from immune checkpoint inhibitors (ICIs). Conclusions: Synchronous small- and large-duct iCCA demonstrates distinct molecular, histopathological, and clinical features, necessitating individualized treatment strategies. Targeted therapies for IDH1/2- and FGFR2-altered small-duct iCCA have shown efficacy, whereas large-duct iCCA remains more aggressive and treatment-resistant, requiring novel therapeutic approaches. Future research should focus on adaptive treatment strategies that account for tumor heterogeneity and dominant molecular drivers. Full article

Background and Aims: According to a recent study on the immunomodulatory activity of Atractylodes lancea (Thunb.) DC. (AL) in healthy Thai subjects, AL significantly inhibited the production of key pro-inflammatory cytokines while stimulating the production of immune cells. However, no maximum tolerated dose (MTD) and phase 2A dosage regimens were reported. The study aimed to evaluate the immunomodulatory effects of Atractylodes lancea (Thunb.) DC. (AL) in healthy subjects, and to recommend optimal dose regimens for intrahepatic cholangiocarcinoma (iCCA) based on toxicity criteria. Methods: A physiologically based pharmacokinetic (PBPK) model, combined with the toxicological approach and the immunomodulatory effect, was used for dose-finding. The safety and efficacy of each AL regimen were evaluated based on the previous study. At least a once-daily dose of 1000 mg AL significantly suppressed the production of all pro-inflammatory cytokines while significantly increasing the number of peripheral immune cells. Results: The developed PBPK model predicted the clinically observed data well. No significant differences in SII index values were found, but a difference in the lymphocyte-monocyte ratio was found on day 4. The dosage regimen for phase 2A is a once-daily dose of 1500 or 2000 mg. Preliminary results in phase 2A revealed that a once-daily dose of 2000 mg had a significantly higher median overall survival, progression-free survival, disease control rate, and inhibition of increased tumor size without toxicities compared with control. Conclusions: A PBPK model, in conjunction with a toxicological approach, could assist in finding the potential dosage regimens for a clinical study, including herbal medicine. Full article