Andreas Geier

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.

Hepatocyte-Specific Smad7 Expression Attenuates TGF-β–Mediated Fibrogenesis and Protects Against Liver Damage

BACKGROUND & AIMS The profibrogenic role of transforming growth factor (TGF)-beta in liver has mostly been attributed to hepatic stellate cell activation and excess matrix synthesis. Hepatocytes are believed to contribute to increased rates of apoptosis. METHODS Primary hepatocyte outgrowths and AML12 cells were used as an in vitro model to detect TGF-beta effects on the cellular phenotype and expression profile. Furthermore, a transgenic mouse model was used to determine the outcome of hepatocyte-specific Smad7 expression on fibrogenesis following CCl(4)-dependent damage. Samples from patients with chronic liver diseases were assessed for (partial) epithelial-to-mesenchymal transition (EMT) in hepatocytes. RESULTS In primary cell cultures and in vivo, the majority of hepatocytes survive despite activated TGF-beta signaling. These cells display phenotypic changes and express proteins characteristic for (partial) EMT and fibrogenesis. Experimental expression of Smad7 in hepatocytes of mice attenuated TGF-beta signaling and EMT, resulted in less accumulation of interstitial collagens, and improved CCl(4)-provoked liver damage and fibrosis scores compared with controls. CONCLUSIONS The data indicate that hepatocytes undergo TGF-beta-dependent EMT-like phenotypic changes and actively participate in fibrogenesis. Furthermore, ablation of TGF-beta signaling specifically in this cell type is sufficient to blunt the fibrogenic response.

Are There Better Guidelines for Allocation in Liver Transplantation? A Novel Score Targeting Justice and Utility in the Model for End-Stage Liver Disease Era

Objectives:To design a new score on risk assessment for orthotopic liver transplantation (OLT) based on both donor and recipient parameters. Background:The balance of waiting list mortality and posttransplant outcome remains a difficult task in the era of the model for end-stage liver disease (MELD). Methods:Using the United Network for Organ Sharing database, a risk analysis was performed in adult recipients of OLT in the United States of America between 2002 and 2010 (n = 37,255). Living donor-, partial-, or combined-, and donation after cardiac death liver transplants were excluded. Next, a risk score was calculated (balance of risk score, BAR score) on the basis of logistic regression factors, and validated using our own OLT database (n = 233). Finally, the new score was compared with other prediction systems including donor risk index, survival outcome following liver transplantation, donor-age combined with MELD, and MELD score alone. Results:Six strongest predictors of posttransplant survival were identified: recipient MELD score, cold ischemia time, recipient age, donor age, previous OLT, and life support dependence prior to transplant. The new balance of risk score stratified recipients best in terms of patient survival in the United Network for Organ Sharing data, as in our European population. Conclusions:The BAR system provides a new, simple and reliable tool to detect unfavorable combinations of donor and recipient factors, and is readily available before decision making of accepting or not an organ for a specific recipient. This score may offer great potential for better justice and utility, as it revealed to be superior to recent developed other prediction scores.

Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis.

Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis. This article gives a comprehensive overview of the molecular and cellular mechanisms of sepsis-associated cholestasis. Recent advances in the understanding of intrahepatic cholestasis have allowed us to delineate the molecular mechanisms that underlie sepsis-associated cholestasis and to describe their potential clinical and therapeutic applications. The mechanisms and clinical presentation of sepsis-associated liver injury vary according to the severity of the bacterial infection. Proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. Ischemic liver injury and, rarely, progressive sclerosing cholangitis can also be found in patients with septic shock, or major trauma with systemic inflammatory response syndrome. Treatment is mainly focused on eradication of the underlying infection and managing the sepsis. The use of ursodeoxycholic acid or extracorporeal liver support as treatments for sepsis-associated cholestasis is under investigation, but neither can be recommended in routine clinical practice at present. Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation.

Spontaneous cholecysto‐ and hepatolithiasis in Mdr2−/− mice: A model for low phospholipid‐associated cholelithiasis

Previously, we identified needle‐like and filamentous, putatively “anhydrous” cholesterol crystallization in vitro at very low phospholipid concentrations in model and native biles. Our aim now was to address whether spontaneous gallstone formation occurs in Mdr2 (Abcb4) knockout mice that are characterized by phospholipid‐deficient bile. Biliary phenotypes and cholesterol crystallization sequences in fresh gallbladder biles and non‐fixed liver sections were determined by direct and polarizing light microscopy. The physical chemical nature and composition of crystals and stones were determined by sucrose density centrifugation and before mass and infrared spectroscopy. Gallbladder biles of Mdr2−/− mice precipitate needle‐like cholesterol crystals at 12 weeks of age on chow. After 15 weeks, more than 50% of Mdr2−/− mice develop gallbladder stones, with female mice displaying a markedly higher gallstone‐susceptibility. Although gallbladder biles of Mdr2−/− mice contain only traces (≤ 1.1 mM) of phospholipid and cholesterol, they become supersaturated with cholesterol and plot in the left 2‐phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. Furthermore, more than 40% of adult female Mdr2−/− mice show intra‐ and extrahepatic bile duct stones. In conclusion, spontaneous gallstone formation is a new consistent feature of the Mdr2−/− phenotype. The Mdr2−/− mouse is therefore a model for low phospholipid‐associated cholelithiasis recently described in humans with a dysfunctional mutation in the orthologous ABCB4 gene. The mouse model supports the concept that this gene is a monogenic risk factor for cholesterol gallstones and a target for novel therapeutic strategies. (HEPATOLOGY 2004;39:117–128.)

Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the “European Network for the Study of Cholangiocarcinoma” (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.

Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid‐induced liver injury in superobese patients with nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)‐induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high‐affinity Na+/taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha‐hydroxylase (CYP7A1) were significantly up‐regulated in obese patients and hepatoma cells exposed to FFA. Up‐regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. Conclusion: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP‐mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin‐receptor agonists might prevent NASH. (HEPATOLOGY 2013;57:1394–1406)

The model for end-stage liver disease allocation system for liver transplantation saves lives, but increases morbidity and cost: a prospective outcome analysis

We analyzed the first 100 patients who underwent liver transplantation by Model for End‐Stage Liver Disease (MELD) allocation, and compared the outcome of patients on the waiting list and after orthotopic liver transplantation with the last 100 patients who underwent transplantation prior to the introduction of the MELD system in July 2007. MELD allocation resulted in decreased waiting list mortality (386 versus 242 deaths per 1000 patient‐years, P < 0.0001) and the transplantation of sicker recipients (uncorrected median MELD score 13.5 versus 20, P = 0.003). Recipient posttransplant morbidity was significantly higher, mainly caused by increased percentage of renal failure requiring renal replacement therapy (13 versus 46%, P < 0.0001). However, kidney function recovered in most cases within 6 months after OLT. Hospital mortality remained similar in both groups (6% versus 9%). Patient 1‐year survival was 91% versus 83% (pre‐MELD versus MELD era, P = 0.2154), graft 1‐year survival was 88% versus 78% (P = 0.1013), respectively. Costs accumulated were significantly higher after introduction of the MELD policy (US

Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver

81,967 versus US

Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride

127,453, a 55% increase, P = 0.02) with a strong correlation with the individual MELD score (P < 0.0001). The MELD system addresses the goal of fairness well. However, the postoperative course appears more difficult in the MELD era with increased financial burden, but reasonable patient and graft survival. This is the inevitable price to balance justice and utility in liver graft allocation. Liver Transpl 17:674–684, 2011.