BACKGROUND: Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis progression. Therefore our aim was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients. METHODS: Liver biopsies from 166 patients were scored for inflammatory activity (A0-4) and hepatic fibrosis (F0-4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing. RESULTS: The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare. In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P < 0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations. For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild-type alleles. C282Y mutations are associated with significantly (P < 0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild-type (P < 0.01). CONCLUSIONS: Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C.
Background/Objectives: Wilson’s disease (WD) is an autosomal recessive disorder characterized by pathological copper accumulation, primarily in the liver and brain. Severe hepatic involvement can be effectively treated with liver transplantation (LT). Geographic variation in ATP7B mutations suggests the presence of regional patterns that may impact disease presentation and management. This study aims to investigate the genetic basis of WD in patients from a major LT center in Iran. Methods: A retrospective analysis was conducted on clinical, biochemical, and pathological data from patients suspected of WD who underwent evaluation for LT between May 2020 and June 2025 at Shiraz University of Medical Sciences. Genetic testing was carried out on 20 patients at the Shiraz Transplant Research Center (STRC). Direct mutation analysis of ATP7B was performed for all patients, and the results correlated with clinical and demographic information. Results: In total, 20 WD patients who underwent liver transplantation (15 males, 5 females) carried 25 pathogenic or likely pathogenic ATP7B variants, 21 of which were previously unreported. Fifteen patients were homozygous, and five were compound-heterozygous; all heterozygous combinations occurred in the offspring of second-degree consanguineous unions. Recurrent changes included p.L549V, p.V872E, and p.P992S/L, while two nonsense variants (p.E1293X, p.R1319X) predicted truncated proteins. Variants were distributed across copper-binding, transmembrane, phosphorylation, and ATP-binding domains, and in silico AlphaMissense scores indicate damaging effects for most novel substitutions. Post-LT follow-up showed biochemical normalization in the majority of recipients, with five deaths recorded during the study period. Conclusions: This single-center Iranian study reveals a highly heterogeneous ATP7B mutational landscape with a large proportion of novel population-specific variants and underscores the benefit of comprehensive gene sequencing for timely WD diagnosis and family counseling, particularly in regions with prevalent consanguinity.
Abstract The molecular mechanisms underlying the transition from nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) are incompletely understood. During the development of NAFLD, Perilipin 5 (PLIN5) can regulate lipid metabolism by suppressing lipolysis and preventing lipotoxicity. Other reports suggest that the lack of PLIN5 decreases hepatic injury, indicating a protective role in NAFLD pathology. To better understand the role of PLIN5 in liver disease, we established mouse models of NAFLD and NAFLD-induced HCC, in which wild-type and Plin5 null mice were exposed to a single dose of acetone or 7,12-dimethylbenz[a]anthracene (DMBA) in acetone, followed by a 30-week high-fat diet supplemented with glucose/fructose. In the NAFLD model, RNA-seq revealed significant changes in genes related to lipid metabolism and immune response. At the intermediate level, pathways such as AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) were blunted in Plin5- deficient mice ( Plin5 − / − ) compared to wild-type mice (WT). In the NAFLD-HCC model, only WT mice developed liver tumors, while Plin5 −/− mice were resistant to tumorigenesis. Furthermore, only 32 differentially expressed genes associated with NALFD progession were identified in Plin5 null mice. The markers of mitochondrial function and immune response, such as the peroxisome proliferator‐activated receptor-γ, coactivator 1‐α (PGC-1α) and phosphorylated STAT3, were decreased. Lipidomic analysis revealed differential levels of some sphingomyelins between WT and Plin5 −/− mice. Interestingly, these changes were not detected in the HCC model, indicating a possible shift in the metabolism of sphingomelins during carcinogenesis.
EDITORIAL article Front. Pharmacol., 05 April 2022Sec. Gastrointestinal and Hepatic Pharmacology https://doi.org/10.3389/fphar.2022.890212
Read moreEinleitung: Es ist bekannt, dass eine erhöhte Expression von TIMP-1 (Tissue inhibitor of metalloproteinases) das Fortschreiten der Fibrose fördert. Die Matrix Metalloproteinasen (MMPs) sind für den Abbau extrazellulärer Matrix verantwortlich, so dass bei einer Inhibition durch TIMP-1 vermehrt Bindegewebe in die Leber eingelagert wird. Zudem hemmt TIMP-1 die Apoptose aktivierter hepatischer Sternzellen. Über den Einfluss von TIMP-1 auf das Protein- Expressionsmuster in Leberzellen ist bisher wenig bekannt.
Read moreWilson disease is a copper overload disease treatable with the chelators D-penicillamine and trientine to enhance urinary excretion or with zinc which predominantly inhibits absorption. By lifelong treatment a normal life expectancy and significant improvement of hepatic injury as well as neurologic manifestation is achievable. Here we evaluate the mode of action for effective therapy of Wilson disease. We postulate that there is no quantitative removal of copper from the liver possible. The therapeutic goal is the removal of toxic free copper (non-ceruloplasmin, but albumin bound copper). This is achievable by the induction of metallothionein which is accomplished by chelators and in particular by zinc. For control of therapy the option of a direct measurement of free copper would be preferable over the less reliable calculation of this fraction. A therapeutic challenge is still the full restoration of neurological deficits which can hardly be reached by the available chelators. Whether bis-choline-tetrathiomolybdate as intracellular copper chelator is an option has to be awaited. It is concluded that the goal of actual drug therapy in Wilson disease is the normalization of free copper in serum.
Read moreLiver fibrosis, the progressive accumulation of scar tissue resulting from chronic liver disease, is increasingly recognized as a multi-system condition whose effects transcend the liver, affecting brain health. In parallel, dementia determining progressively impaired cognition severe enough to impede daily functioning, is a significant global health issue whose risk factors and pathogenic precursors are incompletely defined. Increasing evidence suggests that certain pathophysiological correlates of chronic liver disease may negatively affect neuronal health through incompletely defined pathophysiological mechanisms. With this background, we appraise our current understanding of the relationship between liver fibrosis and cognitive impairment/dementia, using a variety of different methodologies. Firstly, the pathophysiology and clinical significance of liver fibrosis are discussed. Next, we describe the various types of dementia and related risk factors. We then present research evidence supporting the association between cognitive impairment/dementia and liver fibrosis. We highlight both consistency and heterogeneity of findings, including the degree of association being affected by liver fibrosis severity. We thoroughly examine potential causal mechanisms, comprising the role of chronic systemic and neuroinflammation, insulin resistance, vascular dysfunction, and intestinal microbiota-liver-brain axis as potential connectors of liver health with cognitive impairment and dementia. We briefly analyze how sex and age may modify the above associations, how liver fibrosis and cognitive function should be diagnosed, and those potential preventive/treatment strategies based on the shared metabolic/inflammatory pathways associating liver fibrosis, cognitive impairment and dementia. Finally, major research gaps are identified, together with matching proposals for prioritizing advancements in our understanding of the increasingly identified connections between liver fibrosis and dementia/cognitive impairment.
Read moreDer Vitamin A-Rezeptor der retinolspeichernden Ito-Zellen (Sternzellen) ist unbekannt. Das 600 kD Membranprotein Megalin (LDL receptor-related protein 2, Lrp2) wird an der apikalen Membran verschiedener Epithelien exprimiert und vermittelt die Endozytose von Vitaminen sowie multipler weiterer Liganden. Bei homozygot Megalin-defizienten Mäusen treten letale Fehlbildungen der Niere und des Gehirns auf (1). Das Ziel unserer Arbeit war es, die bisher nicht beschriebene hepatische Expression von Megalin zu analysieren und seine potenzielle Funktion in Mausmodellen in vivo zu charakterisieren. Methodik: In aus Rattenleber isolierten Zellpopulationen wurde die Megalin-Expression mit Hilfe von RT-PCR und Immuncytochemie mit Lrp2-spezifischen Antikörpern bestimmt. Als in vivo Modelle wurden weibliche heterozygote Megalin knockout-Mäuse und fibrosesuszeptible BALB/cJ-Inzuchtmäuse, bei denen eine Leberfibrose durch CCl4-Injektionen induziert wurde (1ml/kg i.p., 2 x wöchentlich für 6 Wo.), verwendet. Die Megalinexpression wurde immunhistochemisch ermittelt und mit dem Fibrosestadium in der Siriusrotfärbung und dem hepatischen Kollagengehalt korreliert. Gewebekonzentrationen der Retinole und Retinylester wurden nach Lipidextraktion mittels HPLC bestimmt. Ergebnisse: Die Megalin-mRNA wird sowohl in Ito-Zellen als auch in daraus transdifferenzierten Myofibroblasten exprimiert; in diesen Zellen ließ sich Megalin auch auf Proteinebene nachweisen. Leberhistologien der fibrosesensitiven BALB/cJ-Mäuse zeigen im Gegensatz zu resistenten Mäusen nach CCl4-Behandlung eine starke Immunreaktivität. Die Expression kolokalisierte eng mit den in der Siriusrotfärbung nachgewiesenen Kollagenablagerungen in portoportalen Septen. Bei gleichen Retinylester-Konzentrationen waren die Konzentrationen des freien Retinols in der Gesamtleber bei heterozygoten Megalin knockout-Mäusen im Vergleich zum Wildtyp signifikant (P <0,05) erhöht (73,9±21,8 nmol/g vs. 52,9±14,6 nmol/g). Schlussfolgerungen: Die Ergebnisse verdeutlichen, dass Megalin ein sternzellspezifischer Marker ist, der eine Schlüsselrolle bei der Leberfibrogenese spielen und den bisher unbekannten Vitamin A-Rezeptor der Sternzellen darstellen könnte.
Read moreConsumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.
Read moreMacrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.
Read moreBACKGROUND: Phosphatidylcholine (PC) is intrinsically missing in intestinal mucus of patients with ulcerative colitis. Topical supplementation with delayed intestinal release PC formulations is assumed to compensate this lack. Three monocenter randomized controlled trials (RCTs) with a 30% PC-containing lecithin were successful, whereas 1 trial with >94% PC-containing lecithin failed. OBJECTIVES: Evaluation of 30% PC-containing lecithin provided in a delayed intestinal release formulation for treatment efficacy of ulcerative colitis was evaluated by meta-analysis of 3 RCTs. METHODS: Meta-analysis of 3 studies was performed using RevMan 5.3 software. Odds ratio (OR) and 95% Cl were calculated for remission, clinical and endoscopic improvement, histology, and life quality. p values <0.05 were accepted as significant. RESULTS: The meta-analysis of 3 RTCs with 160 included patients with ulcerative colitis verified that PC improved the rate of remission (OR = 9.68), as well as clinical (OR = 30.58) and endoscopic outcomes (OR = 36.73). Within the available patient population, also histology and quality of life became better. All effects were significant over placebo. Achieved remission was maintained in a higher percentage of patients under intestinal-release PC formulation than placebo. The profile of adverse events was identical to the placebo population. CONCLUSIONS: A 30% PC-containing lecithin in delayed intestinal release formulation improves clinical and endoscopic outcomes, histologic activity, and quality of life in patients with ulcerative colitis. For the patients, lack of adverse events is an important consideration.
Read moreLiver diseases, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), have emerged as a major global health concern, affecting millions of individuals and leading to increased morbidity and mortality [...].
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