Short-term reduction of dietary gluten improves metabolic-dysfunction associated steatotic liver disease: A randomised, controlled proof-of-concept study.

BACKGROUND: The current management of metabolic dysfunction-associated steatotic liver disease (MASLD) relies on lifestyle intervention. Prior studies have shown that nutritional wheat amylase trypsin inhibitors (ATI) activate toll-like receptor 4 on intestinal myeloid cells to enhance intestinal and extra-intestinal inflammation, including the promotion of murine MASLD, insulin resistance and liver fibrosis. AIMS: We aimed to assess the impact of ATI (gluten)-free diet in liver as well as metabolic parameters of biopsy-proven MASLD patients. METHODS: We performed a 6-week, proof-of-concept 1:1 randomised controlled trial of an ATI-free diet. The controls followed a balanced diet recommended by the German Nutrition Society. We assessed changes in controlled attenuation parameter (CAP), body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR). Patient-reported outcomes were assessed by the CLDQ-NASH questionnaire. Forty-five patients were consecutively enrolled (21 in the intervention arm and 24 in the control arm). RESULTS: Three patients from each arm discontinued the study. In the ATI-free diet group, a significant decrease in BMI (p = 0.018), CAP (p = 0.018) and HOMA-IR (p = 0.042) was observed at 6 weeks. The mean difference in CAP between the two arms at week 6 was 30.5 dB/m (p = 0.039), with a delta significantly higher in the ATI-free diet group (p = 0.043). Only an ATI-free diet could achieve a significant improvement in CLDQ-NASH domains (p value for total scoring: 0.013). CONCLUSIONS: A short-term ATI-free diet leads to significant improvements in liver and metabolic parameters, as well as patient-reported outcomes with good tolerability. A larger follow-up study is justified to corroborate these findings. CLINICAL TRIAL NUMBER: NCT04066400.

Outcomes in patients receiving palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND & AIMS: Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors. METHODS: From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards. RESULTS: Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels). CONCLUSIONS: Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy. LAY SUMMARY: Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.

Prevalence and Risk Factors of Advanced Liver Fibrosis in a Population-Based Study in Germany.

The prevalence of liver disease, and especially of advanced liver fibrosis, in the German population is poorly defined. The aim of the study was to explore liver enzymes and surrogate scores of hepatic steatosis and advanced hepatic fibrosis in a population-based cohort study in Germany. In the cross-sectional population-based Gutenberg Health study, data of 14,950 participants enrolled between 2007 and 2012 were captured and analyzed. The distribution of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), fatty liver index (FLI), and Fibrosis-4 (FIB-4) score, as well as the underlying risk factors, were assessed by regression models. Elevated liver enzymes in this population-based sample were seen in 19.9% for ALT, 12.8% for AST, and 14% for GGT. Risk factors for liver disease included alcohol use and the presence of the metabolic syndrome, which were both risk factors associated with increased liver enzymes. The FLI suggested that 37.5% of the population exhibited hepatic steatosis and 1.1% of patients exhibited a FIB-4 above the upper cutoff, while 19.2% were in the intermediate range. Interestingly, advanced fibrosis was significantly more frequent in men compared with women (FIB-4: 1.5% vs. 0.6% [P < 0.0001]; NFS: 3.6% vs. 1.9% [P < 0.0001]). In addition, age was a relevant risk factor for exhibiting a noninvasive surrogate score suggestive of advanced fibrosis in the current study population. Conclusion: Elevated liver enzymes were seen in almost a fifth of the German population. At the population-based level, the prevalence of advanced fibrosis was estimated at 1% in Germany.

PuraStat in gastrointestinal bleeding: results of a prospective multicentre observational pilot study.

BACKGROUND: A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting. METHODS: In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application. RESULTS: 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88-99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59-91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation. CONCLUSIONS: PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. METHODS: We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development. RESULTS: The GALAD score identified patients with any stage HCC with an AUC of 0.96 - significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87). AUC values for the GALAD score were consistent in patients with cirrhosis (AUC, 0.93) and without cirrhosis (AUC, 0.98). For detection of HCC within Milan Criteria, the GALAD score achieved an AUC of 0.91, with a sensitivity of 68% and specificity of 95% at a cutoff of -0.63. In a pilot Japanese cohort study, the mean GALAD score was higher in patients with NASH who developed HCC than in those who did not develop HCC as early as 1.5 years before HCC diagnosis. GALAD scores were above -0.63 approximately 200 days before the diagnosis of HCC. CONCLUSIONS: In a case-control study performed in Germany and a pilot cohort study in Japan, we found the GALAD score may detect HCC with high levels of accuracy in patients with NASH, with and without cirrhosis. The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.

Tumor Incidence in Patients with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: The incidence of cancer is increasing worldwide. The role of comorbidities in this development is debated. The aim of this study was to investigate the significance of non-alcoholic fatty liver disease (NAFLD) for the incidence of cancer of various kinds in Germany. METHODS: Between 2000 and 2015, data on 31 587 patients with established NAFLD were collected for analysis. A control group (n = 31 587) assembled for comparison was matched for sex, age, treating physician, and Charlson Comorbidity Index (CCI). RESULTS: By 10 years after the index date, 15.3% of patients with NAFLD and 13.4% of patients in the control group had been diagnosed with cancer (p <0.001). Patients with NAFLD exhibited significantly higher rates of male genital cancers (HR 1.26; 95% confidence interval [1.06; 1.5]; p = 0.008), skin cancer (HR 1.22 [1.07; 1.38]; p = 0.002) and breast cancer (HR 1.2 [1.01; 1.43]; p = 0.036). In this analysis, the rate of hepatocellular carcinoma did not differ between patients with NAFLD and patients without NAFLD (0.19% vs. 0.12%; p = 0.204). CONCLUSION: NAFLD slightly increases the risk of breast cancer in women, genital cancer in men, and skin cancer irrespective of sex. Thus, NAFLD can be considered a marker of increased cancer risk.

Raised serum Interleukin-6 identifies patients with liver cirrhosis at high risk for overt hepatic encephalopathy.

BACKGROUND: Systemic inflammation is a driving force for the development of hepatic encephalopathy and recent studies demonstrated that elevated Interleukin-6 (IL-6) serum levels are associated with the presence of minimal hepatic encephalopathy in patients with liver cirrhosis. AIM: To test the hypothesis that IL-6 is a suitable marker to identify patients with liver cirrhosis at high risk for the development of overt hepatic encephalopathy. METHODS: 201 patients were included into this prospective cohort study and were followed for a mean time of 322 days. Covert hepatic encephalopathy was diagnosed according to the West-Haven criteria (hepatic encephalopathy grade 1) and with the portosystemic encephalopathy (PSE) test. RESULTS: The cumulative incidence of overt hepatic encephalopathy was higher in patients with IL-6 levels above the median of 9 pg/mL than in patients with IL-6 levels at or below the median (35.6% vs 1.9%, P < .001). After adjustment for covert hepatic encephalopathy, history of overt hepatic encephalopathy, C-reactive protein (CRP) and model for end-stage liver disease (MELD), IL-6 levels above the median remained independently associated with the development of overt hepatic encephalopathy. The predictive performance of IL-6 regarding the development of overt hepatic encephalopathy during the next 180 days (AUROC, 0.931) was numerically higher than that of MELD (AUROC, 0.841) or CRP (AUROC, 0.835). In patients without prior overt hepatic encephalopathy, the predictive performance of IL-6 (AUROC, 0.966) was even significantly higher than that of MELD (AUROC 0.843) or CRP (AUROC 0.850). The ideal cut-off for IL-6 in this setting was 23.5 pg/mL with a sensitivity and specificity of 89.3% and 89.5% respectively. CONCLUSION: IL-6 serum levels are closely linked to the development of overt hepatic encephalopathy in patients with liver cirrhosis.

Health-related quality of life in patients with compensated and decompensated liver cirrhosis.

BACKGROUND: Compensated (Child-Pugh [CP] A) and decompensated (CP B/C) liver cirrhosis significantly differs in terms of impairment of health-related quality of life (HRQoL). However, sufficient data on potentially treatable factors associated with HRQoL in both stages of the disease are still lacking. Consequently, aims of this study were to determine differences in HRQoL between patients with compensated and decompensated liver cirrhosis and to identify potentially treatable factors associated with HRQoL. METHODS: 218 patients with liver cirrhosis were enrolled into this study. Chronic Liver Disease Questionnaire (CLDQ) was used to assess HRQoL. Covert hepatic encephalopathy (CHE) was diagnosed according to a combination of Psychometric Hepatic Encephalopathy Score and Critical Flicker Frequency. Frailty was assessed by Clinical Frailty Scale (CFS). RESULTS: HRQoL differed between patients with CP A (n = 133) and CP B/C (n = 85) liver cirrhosis (CLDQ total score: 5.6 vs. 4.8, p < 0.001). Multivariate analysis identified a history of falls in the recent year, presence of CHE, female gender, active smoking, higher CFS, and higher serum levels of CRP as independent predictors of impaired HRQoL (all p < 0.05) in patients with CP A liver cirrhosis. In patients with CP B/C liver cirrhosis, female gender, a history of overt hepatic encephalopathy, and lower hemoglobin were independently associated with impaired HRQoL (all p < 0.05). CONCLUSIONS: Predictors of impaired HRQoL differ in patients with CP A or CP B/C liver cirrhosis. Focusing on treatable factors in routine clinical practice may improve HRQoL in all stages of liver cirrhosis.

Improvement of non-invasive markers of NAFLD from an individualised, web-based exercise program.

BACKGROUND: Lifestyle modifications remain the cornerstone of treatment in non-alcoholic fatty liver disease (NAFLD). However, they requently fail related to the inability of patients to implement lasting changes. AIMS: To evaluate the effects of a short, web-based, individualised exercise program on non-invasive markers of hepatic steatosis, inflammation and fibrosis. METHODS: Patients with histologically confirmed NAFLD underwent an 8-week, web-based, individualised exercise program that contained bidirectional feedback. RESULTS: Forty-four patients entered the study and 41 completed the assigned training goal (93.2%). In the completer population, 8 weeks of individualised exercise increased the VO2peak by 12.2% compared to baseline (P < .001). ALT and AST decreased by 14.3% (P = .002) and 18.2% (P < .001) and remained at this level until follow-up 12 weeks after the intervention. Markers of inflammation including hsCRP, ferritin, and M30 decreased. In parallel, gut microbiota exhibited increased metagenomic richness (P < .05) and at the taxonomic levels Bacteroidetes and Euryarchaeota increased whereas Actinobacteria phylum decreased. Surrogate scores of steatosis and fibrosis including the fatty liver index (FLI), FiB-4, APRI and transient elastography showed significant reductions. In parallel, a marker of procollagen-3 turnover (PRO-C3) decreased while C4M2, reflecting type IV collagen, degradation increased suggesting beneficial hepatic fibrosis remodelling from exercise. Also, an enhancement in health-related quality of life was reported. CONCLUSION: The current study underlines the plausibility and potential of an 8 week individualised web-based exercise program in NAFLD. Clinical trial number: NCT02526732.

Health-related Quality of Life in Nonalcoholic Fatty Liver Disease Associates With Hepatic Inflammation.

BACKGROUND & AIMS: Chronic liver disease has negative effects on health-related quality of life (HRQL). We analyzed data from the European non-alcoholic fatty liver disease (NAFLD) registry to assess the effects of NAFLD on HRQL. METHODS: We collected data from 304 patients (mean age, 52.3 ± 12.9 years) with histologically defined NAFLD enrolled prospectively into the European NAFLD Registry in Germany, the United Kingdom, and Spain. The chronic liver disease questionnaire (CLDQ) was completed within 6 months of liver biopsy collection. RESULTS: The mean CLDQ overall score was 5.0 ± 1.2, with the lowest score in the category fatigue (4.3 ± 1.6) and the highest scores for activity (5.4 ± 1.4). Women had significantly lower CLDQ scores than men (4.6 ± 1.3 vs 5.3 ± 1.1; P < .001). We found negative correlations between CLDQ scores and presence of obesity (P < .001), type 2 diabetes (P < .001), and dyslipidaemia (P < .01). There was a negative correlation between level of aspartate aminotransferase, but not alanine aminotransferase, and HRQL. Higher histological score of steatosis (1 vs 3) resulted in lower mean CLDQ score (5.3 ± 1.1 vs 4.5 ± 1.4; P < .01); higher level of lobular inflammation (0 vs 3) also resulted in lower mean CLDQ score (5.3 ± 1.2 vs 3.9 ± 1.8; P <. 001). In contrast, advanced fibrosis (F3-4) compared to early or intermediate fibrosis (F0-2) had no significant effect on mean CLDQ score (4.9 ± 1.2 vs 5.1 ± 1.3; P = .072). In multivariate analysis, patients sex, age, presence of type 2 diabetes, and inflammation were independently associated with low HRQL. CONCLUSION: In an analysis of data from the European NAFLD registry, we observed a substantial burden of symptoms in patients. In addition to age, sex, and the presence of diabetes, detection of lobular inflammation in biopsies correlated with lower HRQL.

Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany.

BACKGROUND: Advanced fibrosis has been established as the most important predictor of overall mortality in patients with non-alcoholic fatty liver disease (NAFLD). In contrast to cirrhosis, advanced, non-cirrhotic NAFLD is difficult to identify and data from Germany are lacking. AIM: To identify clinical factors associated with advanced, non-cirrhotic fibrosis. METHODS: Patients were recruited in the prospectively enrolling European NAFLD Registry. Clinical characteristics and the performance of non-invasive surrogate scores compared with vibration-controlled transient elastography are reported. RESULTS: Two hundred and sixty-one patients with non-cirrhotic NAFLD on liver biopsy (mean age 51 years, equal sex distribution) were included. The prevalence of stage 3 fibrosis on liver biopsy was 15.7%. These patients were significantly older (57 vs 50 years, P < 0.01), had a higher body mass index (32.3 vs 30.5, P < 0.05), and more frequent arterial hypertension (78% vs 50%, P = 0.001) and type 2 diabetes (61% vs 24.1%, P < 0.001). On multivariate logistic regression, diabetes (OR = 4.68, 95% CI 2.17-10.10) and hypertension (OR = 2.91, 95% CI 1.12-7.18) were independent predictors of advanced fibrosis. Comedication included metformin in 50% and insulin in 33% of patients with diabetes. Despite the presence of cardiovascular risk factors, the use of statins was low. Liver stiffness measurement identified advanced fibrosis with an AUROC of 0.81 (95% CI 0.72-0.91). The performance of NAFLD fibrosis score, Fibrosis-4, and AST to platelet ratio index were lower with AUCs of 0.74, 0.71, and 0.67, respectively. CONCLUSIONS: The prevalence of metabolic comorbidities in a German population with non-cirrhotic biopsy-proven NAFLD is high. While the examined scores exhibit an acceptable specificity, liver stiffness measurement appeared to be superior to blood-based non-invasive surrogate scores in ruling out advanced fibrosis.

Validation of insulin-like growth factor-1 as a prognostic parameter in patients with hepatocellular carcinoma in a European cohort.

BACKGROUND: In hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed. METHODS: IGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS). RESULTS: Liver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC (p < 0.01). A lower serum level of IGF-1 was associated with more advanced stages of liver cirrhosis (p < 0.05) and cancer stages (p < 0.001). Median OS in the cohort was 11.4 months (range 0.5-118.2 months). OS was significantly higher (10.9 vs. 7.9 months; p < 0.05) in patients with a serum IGF-1 level above the median of 43.4 ng/mL. Patient reassignment using IGF-CTP scoring reclassified 35.6% of patients. Through reassignment, stratification regarding OS was comparable to CTP. CONCLUSIONS: This study is the first to investigate IGF-1 and the IGF-CTP classification in a European cohort of HCC patients. Serum IGF-1 correlates with OS in patients with HCC. However, the IGF-CTP classification was not superior compared to CTP score regarding OS.

Applicability of a Web-Based, Individualized Exercise Intervention in Patients With Liver Disease, Cystic Fibrosis, Esophageal Cancer, and Psychiatric Disorders: Process Evaluation of 4 Ongoing Clinical Trials.

BACKGROUND: In the primary and secondary prevention of civilization diseases, regular physical activity is recommended in international guidelines to improve disease-related symptoms, delay the progression of the disease, or to enhance postoperative outcomes. In the preoperative context, there has been a paradigm shift in favor of using preconditioning concepts before surgery. Web-based interventions seem an innovative and effective tool for delivering general information, individualized exercise recommendations, and peer support. OBJECTIVE: Our first objective was to assess feasibility of our Web-based interventional concept and analyze similarities and differences in a sustained exercise implementation in different diseases. The second objective was to investigate the overall participants' satisfaction with our Web-based concept. METHODS: A total of 4 clinical trials are still being carried out, including patients with esophageal carcinoma scheduled for oncologic esophagectomy (internet-based perioperative exercise program, iPEP, study), nonalcoholic fatty liver disease (hepatic inflammation and physical performance in patients with nonalcoholic steatohepatitis, HELP, study), depression (exercise for depression, EXDEP, study), and cystic fibrosis (cystic fibrosis online mentoring for microbiome, exercise, and diet, COMMED, study). During the intervention period, the study population had access to the website with disease-specific content and a disease-specific discussion forum. All participants received weekly, individual tailored exercise recommendations from the sports therapist. The main outcome was the using behavior, which was obtained by investigating the log-in rate and duration. RESULTS: A total of 20 participants (5 from each trial) were analyzed. During the intervention period, a regular contact and a consequent implementation of exercise prescription were easily achieved in all substudies. Across the 4 substudies, there was a significant decrease in log-in rates (P<.001) and log-in durations (P<.001) over time. A detailed view of the different studies shows a significant decrease in log-in rates and log-in durations in the HELP study (P=.004; P=.002) and iPEP study (P=.02; P=.001), whereas the EXDEP study (P=.58; P=.38) and COMMED study (P=.87; P=.56) showed no significant change over the 8-week intervention period. There was no significant change in physical activity within all studies (P=.31). Only in the HELP study, the physical activity level increased steadily over the period analyzed (P=.045). Overall, 17 participants (85%, 17/20) felt secure and were not scared of injury, with no major differences in the subtrials. CONCLUSIONS: The universal use of the Web-based intervention appears to be applicable across the heterogonous collectives of our study patients with regard to age and disease. Although the development of physical activity shows only moderate improvements, flexible communication and tailored support could be easily integrated into patients' daily routine. TRIAL REGISTRATION: iPEP study: ClinicalTrials.gov NCT02478996; https://clinicaltrials.gov/ct2/show/NCT02478996 (Archived by WebCite at http://www.webcitation.org/6zL1UmHaW); HELP study: ClinicalTrials.gov NCT02526732; http://www.webcitation.org/6zJjX7d6K (Archived by WebCite at http://www.webcitation.org/6Nch4ldcL); EXDEP study: ClinicalTrials.gov NCT02874833; https://clinicaltrials.gov/ct2/show/NCT02874833 (Archived by WebCite at http://www.webcitation.org/6zJjj7FuA).

Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND/AIM: Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. METHODS: Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. RESULTS: The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status ≥1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS. CONCLUSIONS: Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib.

Hepatic B cell leukemia-3 suppresses chemically-induced hepatocarcinogenesis in mice through altered MAPK and NF-κB activation.

The transcriptional nuclear factor kappa B (NF-κB)-coactivator B cell leukemia-3 (Bcl-3) is a molecular regulator of cell death and proliferation. Bcl-3 has been shown to be widely expressed in different cancer types including hepatocellular carcinoma (HCC). Its influence on hepatocarcinogenesis is still undetermined. To examine the role of Bcl-3 in hepatocarcinogenesis mice with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) were exposed to diethylnitrosamine (DEN) and phenobarbital (PB). Hepatic Bcl-3 overexpression attenuated DEN/PB-induced hepatocarcinogenesis. Bcl-3Hep mice exhibited a lower number and smaller tumor nodules in response to DEN/PB at 40 weeks of age. Reduced HCC formation was accompanied by a lower rate of cell proliferation and a distinct expression pattern of growth and differentiation-related genes. Activation of c-Jun N-terminal kinase (JNK) and especially extracellular-signal regulated kinase (ERK) was reduced in tumor and tumor-surrounding liver tissue of Bcl-3Hep mice, while p38 and NF-κB p65 were phosphorylated to a higher extent compared to the wild type. In parallel, the absolute number of intrahepatic macrophages, CD8+ T cells and activated B cells was reduced in DEN/PB-treated Bcl-3Hep mice mirroring a reduction of tumor-associated inflammation. Interestingly, at the early time point of 7 weeks following tumor initiation, a higher rate of apoptotic cell death was observed in Bcl-3Hep mice. In summary, hepatocyte-restricted Bcl-3 overexpression reduced hepatocarcinogenesis related to prolonged liver injury early after tumor initiation likely due to decreased survival of DEN/PB-damaged, premalignant cells. Therefore, Bcl-3 could become a novel player in the development of therapeutic and diagnostic tools for HCC.

Voluntary distance running prevents TNF-mediated liver injury in mice through alterations of the intrahepatic immune milieu.

Physical activity confers a broad spectrum of health benefits. Beyond the obvious role in metabolically driven diseases, the role of physical activity in acute liver injury is poorly explored. To study the role of physical activity in acute liver injury, a novel model of voluntary distance running in mice was developed and mice were subjected to acute liver injury induced by N-galactosamine (GalN) and lipopolysaccharide (LPS). Analyses included histological stains, immunoblotting, qRT-PCR and FACS analysis. Voluntary distance running increased to an average of 10.3 km/day after a learning curve. Running lead to a decrease in the absolute numbers of intrahepatic CD4+ T and B lymphocytes and macrophages after 7 weeks. In parallel, hepatic mRNA expression of inflammatory cytokines including IL-6 and IL-1beta, TGF-beta and monocyte chemoattractant protein-1 (MCP-1/CCL2) were suppressed, while TNF-α was not affected by exercise. Likewise, expression of the macrophage-specific antigen F4/80 was downregulated 1.6-fold from exercise. Notably, acute liver injury from GaIN/LPS was significantly blunted following 7 weeks of voluntary exercise as determined by liver histology, a 84.6% reduction of alanine aminotransferase (P<0.01) and a 54.6% reduction of aspartate aminotransferase (P<0.05) compared with sedentary mice. Additionally, proinflammatory cytokines, activation of caspase 3 and JNK were significantly lower, while antiapoptotic protein A20 increased. Voluntary distance running alters the intrahepatic immune phenotype producing an environment that is less susceptible to acute liver injury.

Hepatic B cell leukemia-3 promotes hepatic steatosis and inflammation through insulin-sensitive metabolic transcription factors.

BACKGROUND & AIMS: The pathomechanisms underlying non-alcoholic fatty liver disease (NAFLD) and the involved molecular regulators are incompletely explored. The nuclear factor-kappa B (NF-κB)-cofactor gene B cell leukemia-3 (Bcl-3) plays a critical role in altering the transcriptional capacity of NF-κB - a key inducer of inflammation - but also of genes involved in cellular energy metabolism. METHODS: To define the role of Bcl-3 in non-alcoholic steatohepatitis (NASH), we developed a novel transgenic mouse model with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) and employed a high-fat, high-carbohydrate dietary feeding model. To characterize the transgenic model, deep RNA sequencing was performed. The relevance of the findings was confirmed in human liver samples. RESULTS: Hepatocyte-specific overexpression of Bcl-3 led to pronounced metabolic derangement, characterized by enhanced hepatic steatosis from increased de novo lipogenesis and uptake, as well as decreased hydrolysis and export of fatty acids. Steatosis in Bcl-3Hep mice was accompanied by an augmented inflammatory milieu and liver cell injury. Moreover, Bcl-3 expression decreased insulin sensitivity and resulted in compensatory regulation of insulin-signaling pathways. Based on in vivo and in vitro studies we identified the transcription factors PPARα, PPARγ and PGC-1α as critical regulators of hepatic metabolism and inflammation downstream of Bcl-3. Metformin treatment improved the metabolic and inflammatory phenotype in Bcl-3Hep mice through modulation of PPARα and PGC-1α. Remarkably, these findings were recapitulated in human NASH, which exhibited increased expression and nuclear localization of Bcl-3. CONCLUSIONS: In summary, Bcl-3 emerges as a novel regulator of hepatic steatosis, insulin sensitivity and inflammation in NASH. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is considered the most prevalent liver disease worldwide. Patients can develop end-stage liver disease resulting in liver cirrhosis or hepatocellular carcinoma, but also develop complications unrelated to liver disease, e.g., cardiovascular disease. Still there is no full understanding of the mechanisms that cause NAFLD. In this study, genetically engineered mice were employed to examine the role of a specific protein in the liver that is involved in inflammation and the metabolism, namely Bcl-3. By this approach, a better understanding of the mechanisms contributing to disease progression was established. This can help to develop novel therapeutic and diagnostic options for patients with NAFLD.