Search Results (163)

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect 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

Objective: Yinchenhao decoction (YCHD), a classical herbal formula comprising Artemisia capillaris, Gardenia jasminoides, and Rheum palmatum, has been clinically used for over 1000 years to treat cholestasis. However, its mechanism of action remains undefined. This study aimed to elucidate YCHD’s therapeutic mechanisms against cholestasis, with a focus on the gut microbiota-mediated regulation of the farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) pathway. Methods: An alpha-naphthyl isothiocyanate (ANIT)-induced cholestasis mouse model was established. Mice received YCHD (3/9 g/kg) for 7 days. 16S rRNA sequencing, targeted LC/MS (bile acid (BA) quantification), untargeted GC/MS (fecal metabolite detection), qPCR/Western blot (FXR pathway analysis), fecal microbiota transplantation (FMT), and antibiotic depletion were employed to dissect the gut–liver axis interactions. Results: YCHD alleviated cholestatic liver injury by reducing serum biomarkers, restoring BA homeostasis via FXR-FGF15 activation, and suppressing hepatic Cyp7a1-mediated BA synthesis. It remodeled gut microbiota, enriched FXR-activating secondary BAs (CDCA, DCA, CA), and restored the intestinal barrier integrity. Antibiotic cocktail abolished YCHD’s efficacy, while FMT from YCHD-treated mice enhanced its therapeutic effects, confirming microbiota dependency. Conclusions: YCHD mitigates cholestasis through gut microbiota-driven FXR activation and direct hepatobiliary regulation. These findings bridge traditional medicine and modern pharmacology, highlighting microbiome modulation as a therapeutic strategy for cholestatic liver diseases. Full article

Cholestasis is an uncommon but potentially life-threatening clinical condition in the neonatal period, leading to maldigestion/malabsorption of fats and fat-soluble components of the diet. Thus, nutritional management is crucial for the cholestatic newborn in order to sustain growth and development. Even if it can be recognized a wide variety of diseases underlying neonatal cholestasis, from a nutritional point of view, patients can be categorized into two main groups, according to their intestinal integrity in length and function, which influences the nutritional strategies to be used: patients with intestinal failure-associated liver disease (IFALD) and those suffering from liver dysfunction without intestinal impairment (NOT IFALD). For both groups, enteral nutrition is widely considered a cornerstone of their care. In this narrative review, we summarize the evidence that guides neonatologists in the complex management of enteral nutrition in a cholestatic newborn, such as the choice of type of milk to be used or of any supplementation needed, focusing on preventive and curative strategies including their effects on sustaining growth. Analyzing data published over a period of more than 50 years, despite the agreement of experts and societies in many aspects of management of both IFALD and NOT IFALD cholestatic newborns, we found that robust evidence behind clinical practice is still lacking. This underscores the urgent need for well-designed multicenter randomized controlled trials to optimize the nutritional care of this vulnerable patient population. 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

Background/Objectives: Paraneoplastic syndromes (PNS), characterized by a large diversity of symptoms, may sometimes be the first clinical feature of a severe underlying disorder such as cancer. Methods: We report the case of a middle-aged male patient with no significant previous medical history, a nonsmoker or alcohol heavy drinker, complaining about generalized, recently onset itch. Given no reasonable explanation of pruritus after dermatological consultation and the unsatisfactory response to treatment, the patient was referred to gastroenterology with the suspicion of a cholestatic liver disease. Results: The abdominal ultrasound examination revealed gallstones and no dilation of the biliary tree. Numerous tests were run and came out negative, except for the slight elevation of C-reactive protein, mild dyslipidemia, and positivity for H. pylori antigen. The gut microbiota displayed important dysbiosis with a significant increase in the histamine-producing bacteria. Given this chronic pruritus became suspicious, thorax and abdominal CT were recommended and performed soon after. A large right mid-thoracic tumor image was found. Bronchoscopy came out negative for a tumor. After the CT-guided biopsy, the tumor turned out not to be a lymphoma, but a non-small cell lung carcinoma (NSCLC). Conclusions: Chronic pruritus was not associated with cholestasis in a patient with gallstone disease, but rather with a PNS, as the first clinical manifestation of NSCLC, triggering many diagnostic and therapeutic challenges. Full article

Background/Objectives: Liver transplantation is a life-saving procedure for patients with end-stage liver disease. In recent years, the demand for liver transplantation has surpassed the supply of available donor organs. Utilizing extended-criteria donors (ECDs) alleviates the scarcity of suitable donor livers for transplantation. One of the ECD was donors with a history of alcohol abuse. Liver grafts from donors with a history of chronic and active alcohol abuse are typically promptly excluded, diminishing the available organ pool. This highlights the need to re-evaluate the donor exclusion criteria and expand the organ pool to address the ongoing shortage. Methods: We examined adult (>18 years) liver transplant recipients who received deceased donor livers and had a documented history of alcohol abuse between 2011 and 2024. Liver transplant indications were conventional and included hepatitis C virus (HCV), non-alcoholic steatohepatitis, alcoholic liver disease, alcoholic liver disease coexisting with HCV, cryptogenic cirrhosis, chronic cholestatic liver disease, primary biliary cholangitis, primary sclerosing cholangitis, metabolic liver disease, hepatocellular carcinoma, and alcoholic hepatitis. We compared the 1-year, 5-year, and 9-year survival rates with those of liver recipients from non-alcohol-consuming donors. Results: In total, 370 liver recipients from deceased donors with a documented history of alcohol abuse were included. At 1 year post-transplant, survival was comparable between the two groups. Conclusions: Liver transplantation from deceased donors with a history of alcohol abuse yielded survival rates and liver function outcomes comparable to those from non-alcohol-using donors. By expanding the criteria to include carefully screened alcohol-using donors, transplant programs can improve access to life-saving transplantations. Full article

Chronic liver disease (CLD) in children poses significant challenges, necessitating timely management to mitigate morbidity and mortality. Liver transplantation (LT) has emerged as a transformative intervention, offering improved long-term survival for paediatric patients with CLD. This review explores the evolving landscape of liver transplantation, focusing on indications and timing considerations. The aetiology of CLD is diverse, encompassing intrahepatic, extrahepatic cholestatic conditions, metabolic diseases, malignancy, and drug-induced liver injury. LT is indicated when children exhibit signs of hepatic decompensation, necessitating a comprehensive evaluation to assess transplant suitability. Indications for LT include biliary atresia, inborn errors of metabolism, hepatocellular carcinoma, and emerging indications such as mitochondrial hepatopathies and acute on chronic liver failure. The timing of transplantation is critical, emphasizing the need for early recognition of decompensation signs to optimise outcomes. Advancements in LT techniques and immunosuppressive therapies have enhanced patient and graft survival rates. Various transplant modalities, including reduced-size LT and living-related LT, offer tailored solutions to address the unique needs of paediatric patients. While LT represents a cornerstone in the management of paediatric CLD, careful patient selection, multidisciplinary collaboration, and ongoing refinements in transplant protocols are imperative for optimizing outcomes and addressing the evolving landscape of paediatric liver disease management. Full article

Congestion is a key clinical feature of heart failure (HF), contributing to hospitalizations, disease progression, and poor outcomes. While traditionally considered a hemodynamic issue, congestion is now recognized as a systemic process affecting multiple organs. Renal dysfunction arises from impaired perfusion and sodium retention, leading to maladaptive left ventricular remodeling. Hepatic congestion contributes to cholestatic liver injury, while metabolic disturbances drive anemia, muscle wasting, and systemic inflammation. Additionally, congestion disrupts the intestinal barrier and immune function, exacerbating HF progression. Given its widespread impact, effective congestion management requires a shift from a cardiovascular-centered approach to a comprehensive, multidisciplinary strategy. Targeted decongestive therapy, metabolic and nutritional optimization, and immune modulation are crucial in mitigating congestion-related organ dysfunction. Early recognition and intervention are essential to slow disease progression, preserve functional capacity, and improve survival. Addressing HF congestion through personalized, evidence-based strategies is vital for optimizing long-term care and advancing treatment paradigms. 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

Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases. Full article

Background/Objectives: Liver elastography is increasingly used in neonatal intensive care units (NICUs) as a non-invasive, radiation-free, reproducible technique for assessing liver stiffness. This technique demonstrates substantial advantages over conventional ultrasound in diagnosing diffuse liver diseases by providing quantitative measures of tissue elasticity. This article aims to describe the most critical milestones for performing liver elastography ultrasound point-of-care, a tool increasingly used to complement traditional ultrasound in the study of the liver in intensive care units where the population is very susceptible to manipulation. Methods: Techniques such as point-shear wave elastography (pSWE) and two-dimensional shear wave elastography (2D-SWE) have become key in evaluating conditions such as hypoxic-ischemic liver disease, cholestatic diseases, storage and metabolic disorders, or infectious liver conditions. However, despite its usefulness, performing elastography in neonates, particularly in those weighing less than 1000 g or in high-frequency oscillatory ventilation, presents notable challenges, including the extreme sensitivity of neonates to touch, noise, and temperature changes and the difficulty in obtaining accurate measurements due to limited hepatic depth. Results: Key factors for the success of sonoelastography in this population include minimizing contact time, adjusting mechanical and thermal indices to meet biosecurity guidelines, and ensuring patient comfort and stability during the procedure. Despite these challenges, elastography has proven helpful in routine clinical practice. Conclusions: The growing evidence on elastography has provided standardized reference values, further enhancing its clinical applicability in NICU settings. Full article

Background and Aim: Biliary atresia is a rare, progressive disease that affects the bile ducts in newborns. Persistent bile duct obstruction induces various pathological conditions, including jaundice, inflammation, and liver fibrosis; however, the exact pathogenesis of biliary atresia is not yet fully understood. Nuclear factor-κB (NF-κB) is widely acknowledged as a key regulator in the pathogenesis of hepatitis and liver fibrosis, and extensive research has been conducted to develop strategies to effectively inhibit its activity to mitigate liver damage. Exosome-based therapeutic platforms offer targeted NF-κB inhibition with low immunogenicity and enhanced liver-specific delivery. This study aimed to evaluate the therapeutic efficacy of Exo-SrIκB in treating cholestatic liver fibrosis using experimental animal models. Methods: Exo-SrIκB (an exosome-based therapy containing the super-repressor IκB protein) using EXPLOR technology (Exosome engineering for Protein Loading via Optically Reversible protein-protein interactions) to encapsulate the super repressor IκB (SrIκB) within exosomes. The therapeutic efficacy of Exo-SrIκB was assessed in minipig and mouse models with experimentally induced cholestatic liver disease. Results: Administration of Exo-SrIκB significantly attenuated liver fibrosis progression in both animal models by inhibiting NF-κB nuclear translocation and reducing the expression of fibrotic markers. Treated animals exhibited reduced collagen deposition, lower α-SMA levels, and improved hepatic function compared to untreated controls. Conclusion: Exo-SrIκB effectively suppressed NF-κB signaling and alleviated liver fibrosis in experimental cholestatic liver disease models, suggesting that exosome-based therapeutics may offer a targeted and biocompatible application to managing liver fibrosis and other chronic liver diseases. 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