Chronic hepatitis D virus infection, also known as chronic hepatitis delta, remains the most severe form of chronic viral hepatitis, associated with accelerated liver disease progression, cirrhosis, decompensation, and hepatocellular carcinoma. Recent years have seen major advances in screening strategies and antiviral therapies for hepatitis D. This review discusses evidence supporting broader hepatitis D screening among hepatitis B surface antigen (HBsAg)-positive individuals and practical considerations for implementation across epidemiological settings, and reviews current and emerging treatments—entry inhibition (bulevirtide), prenylation inhibition (lonafarnib), immune-modulatory therapies (pegylated interferons), and HBsAg-targeting approaches (tobevibart, elebsiran, brelovitug, and nucleic acid polymers)—focusing on treatment response and durability of viral suppression. In conclusion, emerging therapies have substantially improved antiviral efficacy, shifting the focus of hepatitis D management from on-treatment suppression toward durable off-treatment control and functional cure, changing the diagnosis, treatment, and long-term management of chronic hepatitis D.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibroinflammatory injury of intrahepatic and extrahepatic bile ducts that may lead to cirrhosis, hepatobiliary malignancy, and death, with liver transplantation representing the only effective intervention in end-stage disease. Rather than a single dominant pathomechanism, the data support a model in which four axes—bile acid metabolism, the intestinal microbiome and gut barrier, biliary epithelial dysfunction, and Th17-skewed immune dysregulation—are reciprocally coupled and converge on a shared periductal fibrogenic output dominated by TGF-β signaling. This review summarizes key mechanistic advances from genetic, epigenomic, single-cell, spatial transcriptomic, and microbiome studies. These investigations implicate antigen presentation pathways, Th17-skewed immune responses, cholangiocyte senescence and profibrotic signaling, and disrupted gut–liver communication as central drivers of chronic biliary injury. Emerging spatial and multi-omics approaches further reveal complex cellular crosstalk among cholangiocytes, immune cells, macrophages, and mesenchymal populations within portal inflammatory niches. We discuss evolving biomarkers and recent clinical trial data targeting bile acid metabolism, fibrosis, the microbiome, and immune pathways. In conclusion, research data suggest viewing PSC as a network disease, which provides a unifying framework for disease pathogenesis and may enable biomarker-guided patient stratification and mechanism-based therapy development targeting distinct pathogenic pathways.
Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic liver disease of the intrahepatic and extrahepatic bile ducts with poor prognosis. The only life-extending treatment for PSC is liver transplantation, with up to 25% of posttransplant patients developing recurrent disease, highlighting an extrahepatic influence on the disease. The gut–liver axis has been widely studied in the development and pathogenesis of PSC, with preclinical and clinical work demonstrating that targeting gut microbiota and its metabolites can elicit therapeutic effects against PSC. This review describes various microbiome-based therapeutics and their effectiveness in treating PSC, including antibiotics, probiotics, fecal microbiota transplantation, and bacteriophages. In conclusion, the use of microbiota-derived metabolites as potential therapeutics is also addressed.
The purpose of these expert practical recommendations is to provide an updated, clinically oriented overview of the screening, diagnosis, treatment, and surveillance of portal hypertension in cirrhosis. Building on recent advances in the understanding and management of portal hypertension, this review summarizes evidence-based strategies for the identification and management of clinically significant portal hypertension in patients with advanced chronic liver disease, in line with the recent Baveno VIII consensus recommendations. It presents practical clinical pathways for risk stratification, the prevention of first and further decompensation, and the longitudinal follow-up focusing on promising non-invasive techniques, also in terms of diagnosing resolution of clinically significant portal hypertension. In addition, the review offers a comprehensive overview of the contemporary management of acute variceal bleeding, including initial resuscitation, pharmacological and endoscopic therapy, and the appropriate use of transjugular intrahepatic portosystemic shunts and other invasive strategies. In conclusion, these expert recommendations offer an updated and practical decision tool for the management of portal hypertension in cirrhosis by combining latest evidence with expert consensus to optimize patient care and improve clinical outcomes.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a driver of metastatic progression in the liver. In addition to its association with hepatocellular carcinoma, the steatotic liver supports metastatic colonization from extrahepatic malignancies by altering hepatic metabolism, stromal organization, vascular architecture, and immune surveillance. Clinical and experimental studies show higher rates of liver metastasis and postoperative recurrence for colorectal, pancreatic, and breast cancers in MASLD. The underlying mechanisms are multifactorial. Hepatocyte lipid overload reshapes lipid metabolism and availability, generating lipotoxic stress signals that support the metabolic adaptation of tumor cells. The steatotic liver also promotes extracellular matrix remodeling, hepatic stellate cell activation, sinusoidal capillarization, and the accumulation of immunosuppressive macrophages and exhausted T cells. Tumor- and liver-derived extracellular vesicles further amplify these changes by transporting lipids, cytokines, and microRNAs that establish a permissive premetastatic niche. Although the contribution of hepatic zonation to metastatic outgrowth is poorly characterized, altered zonation likely enhances metastatic fitness by creating spatial gradients in oxygen tension, lipid metabolism, and immune activity. In conclusion, MASLD can reshape the hepatic metastatic microenvironment, which may lead to metabolic- and immune-targeted therapies to treat liver metastasis in patients with MASLD.
