Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis

anus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo.Jonel Trebicka is supported by the German Research Foundation project ID 403224013–SFB 1382 (A09); by the German Federal Ministry of Education and Research (BMBF) for the DEEP‐HCC project; by the Hessian Ministry of Higher Education, Research, and the Arts (HMWK) for the ENABLE cluster project; and by Eurostars (Grant ID 12350). The MICROB‐PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875), and IHMCSA (project ID 964590) projects have received funding from the European Union's Horizon 2020 research and innovation program. The manuscript reflects only the authors' views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript

Baseline Presence of NAFLD Predicts Weight Loss after Gastric Bypass Surgery for Morbid Obesity

Background. Bariatric surgery is a widely used treatment for morbid obesity. Prediction of postoperative weight loss currently relies on prediction models, which mostly overestimate patients' weight loss. Data about the influence of Non-alcoholic fatty liver disease (NAFLD) on early postoperative weight loss are scarce. Methods. This prospective, single-center cohort study included 143 patients receiving laparoscopic gastric bypass surgery (One Anastomosis-Mini Gastric Bypass (OAGB-MGB) or Roux-en-Y Gastric Bypass (RYGB)). Liver biopsies were acquired at surgery. NAFLD activity score (NAS) assigned patients to No NAFLD, NAFL or NASH. Follow up data were collected at 3, 6 and 12 months. Results. In total, 49.7% of patients had NASH, while 41.3% had NAFL. Compared with the No NAFLD group, NAFL and NASH showed higher body-mass-index (BMI) at follow-up (6 months: 31.0 kg/m(2) vs. 36.8 kg/m(2) and 36.1 kg/m(2), 12 months: 27.0 kg/m(2) vs. 34.4 and 32.8 kg/m(2)) and lower percentage of total body weight loss (%TBWL): (6 months: 27.1% vs. 23.3% and 24.4%; 12 months: 38.5% vs. 30.1 and 32.6%). Linear regression of NAS points significantly predicts percentage of excessive weight loss (%EWL) after 6 months (Cologne-weight-loss-prediction-score). Conclusions. Histopathological presence of NAFLD might lead to inferior postoperative weight reduction after gastric bypass surgery. The mechanisms underlying this observation should be further studied

Effects of ethanol feeding in early-stage NAFLD mice induced by western diet

Background: The prevalence of metabolic liver diseases is increasing and approved pharmacological treatments are still missing. Many animal models of nonalcoholic fatty liver disease (NAFLD) show a full spectrum of fibrosis, inflammation and steatosis, which does not reflect the human situation since only up to one third of the patients develop fibrosis and nonalcoholic steatohepatitis (NASH). Methods: Seven week old C57Bl/J mice were treated with ethanol, Western diet (WD) or both. The animals’ liver phenotypes were determined through histology, immunohistochemistry, Western blotting, hepatic triglyceride content and gene expression levels. In a human cohort of 80 patients stratified by current alcohol misuse and body mass index, liver histology and gene expression analysis were performed. Results: WD diet and ethanol-treated animals showed severe steatosis, with high hepatic triglyceride content and upregulation of fatty acid synthesis. Mild fibrosis was revealed using Sirius-red stains and gene expression levels of collagen. Inflammation was detected using histology, immunohistochemistry and upregulation of proinflammatory genes. The human cohort of obese drinkers showed similar upregulation in genes related to steatosis, fibrosis and inflammation. Conclusions: We provide a novel murine model for early-stage fatty liver disease suitable for drug testing and investigation of pathophysiology

Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in (NAFLD) and (ALD) requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis. steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steato-hepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing. NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development

Myostatin is associated with the presence and development of acute-on-chronic liver failure

Background &amp; Aims: Acute-on-chronic liver failure (ACLF) has been linked to different pathophysiological mechanisms, including systemic inflammation and mitochondrial dysfunction. Sarcopenia has also been proposed as a potential mechanism; myostatin is a key factor inducing sarcopenia. Therefore, this study aimed to evaluate the association of myostatin levels with the development of ACLF and mortality in patients with cirrhosis. Methods: We performed a prospective cohort study, including both outpatient and hospitalized patients with cirrhosis. Clinical, biochemical, and nutritional parameters were evaluated, and the development of acute decompensation (AD) or ACLF during follow-up was recorded. ACLF was defined according to the EASL-CLIF criteria. Receiver-operating characteristic, Kaplan-Meier and Cox regression analyses were performed. Results: A total of 186 patients with the whole spectrum of cirrhosis were included; mean age was 53.4 ± 14 years, mean Child-Pugh score was 8 ± 2.5 and mean MELD score was 15 ± 8. There was a stepwise decrease in myostatin levels from a compensated stage to AD and ACLF. Myostatin correlated positively with nutritional markers and negatively with severity scores. The prevalence of sarcopenia was 73.6%. During follow-up, 27.9% of patients developed AD and 25.8% developed ACLF. Most episodes were grade 2-3, mainly (62.5%) precipitated by infections. The most common organ failures observed were in the liver (63.3%) and the kidney (64.6%). Receiver-operating characteristic analysis yielded <1,280 pg/ml as the best serum myostatin cut-off for the prediction of ACLF. In Kaplan-Meier curves and multivariate analysis, myostatin levels remained independently associated with the incidence of ACLF and survival. Conclusions: There is a progressive decrease in myostatin levels as cirrhosis progresses, demonstrating an association of sarcopenia with the development of ACLF and increased mortality. Impact and implications: Myostatin is a muscle hormone, it is decreased in patients with muscle loss and is a marker of impaired muscle function. In this study we show that myostatin levels are decreased in patients with cirrhosis, with lower levels in patients with acute decompensation and acute-on chronic liver failure (ACLF). Low myostatin levels in cirrhosis predict the development of ACLF and mortality independently of liver disease severity and sex

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease

OBJECTIVE Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients. DESIGN This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation. RESULTS After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM. CONCLUSION The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals