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Journal: Journal of clinical and translational hepatology

139

Background and Aims: There has been increasing evidence that vitamin D deficiency may increase the risk of metabolic syndrome. Since metabolic syndrome is a major risk factor for non-alcoholic fatty liver disease (NAFLD), we aimed to investigate the association between vitamin D and the severity and mortality of NAFLD. Methods: Data was obtained from the United States Third National Health and Nutrition Examination Survey conducted in 1988-1994, with follow-up mortality data through 2011. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases and categorized as normal, mild, moderate or severe. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). ANOVA (F-test) was used to evaluate the association between vitamin D level and degree of NAFLD, and Cox proportional hazards regression analysis was used for survival analyses. Results: Vitamin D levels for normal, mild, moderate and severe steatosis were 25.1 ± 0.29 ng/mL, 24.7 ± 0.42 ng/mL, 23.7 ± 0.37 ng/mL and 23.6 ± 0.60 ng/mL, respectively (trend p < 0.001). Likewise, vitamin D levels for low, intermediate and high NFS categories were 24.7 ± 0.38 ng/mL, 23.4 ± 0.42 ng/mL and 21.5 ± 0.57 ng/mL, respectively (trend p < 0.001). After median-follow up over 19 years, vitamin D deficiency was significantly associated with diabetes- and Alzheimer's disease-related mortality (hazard ratio (HR): 3.64, 95%CI: 1.51-8.82 and HR: 4.80, 95%CI: 1.53-15.1, respectively), with a borderline significance in overall mortality (HR: 1.16, 95%CI: 0.99-1.36, p = 0.06). Conclusions: Vitamin D level was inversely related to the degree of liver steatosis and fibrosis. Moreover, vitamin D deficiency was associated with diabetes- and Alzheimer's disease-related mortality in NAFLD patients.

Concepts: Vitamin D, Nutrition, Obesity, Cirrhosis, Metabolic syndrome, Non-alcoholic fatty liver disease, Fatty liver, Steatosis

139

Hepatocarcinogenesis is a multistep process, heralded by abnormalities in cell differentiation and proliferation and sustained by an aberrant neoangiogenesis. Understanding the underlying molecular pathogenesis leading to hepatocellular carcinoma is a prerequisite to develop new drugs that will hamper or block the steps of these pathways. As hepatocellular carcinoma has higher arterial vascularization than normal liver, this could be a good target for novel molecular therapies. Introduction of the antiangiogenic drug sorafenib into clinical practice since 2008 has led to new perspectives in the management of this tumor. The importance of this drug lies not only in the modest gain of patients' survival, but in having opened a roadmap towards the development of new molecules and targets. Unfortunately, after the introduction of sorafenib, during the last years, a wide number of clinical trials on antiangiogenic therapies failed in achieving significant results. However, many of these trials are still ongoing and promise to improve overall survival and progression-free survival. A recent clinical trial has proven regorafenib effective in patients showing tumor progression under sorafenib, thus opening new interesting therapeutic perspectives. Many other expectations have been borne from the discovery of the immune checkpoint blockade, already known in other solid malignancies. Furthermore, a potential role in hepatocellular carcinoma therapy may derive from the use of branched-chain amino acids and of nutritional support. This review analyses the biomolecular pathways of hepatocellular carcinoma and the ongoing studies, the actual evidence and the future perspectives concerning drug therapy in this open field.

Concepts: Immune system, Pharmacology, Clinical trial, Cancer, The Canon of Medicine, Therapy, Classification of Pharmaco-Therapeutic Referrals, Clinical trial protocol

139

Although a vaccine against hepatitis B virus (HBV) has been available since 1982, the prevalence of adults with chronic HBV infection in sub-Saharan Africa and East Asia is still estimated at 5-10%. A high rate of chronic infections is also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and the Indian subcontinent, the prevalence is 2-5%. Less than 1% of the population of Western Europe and North America is chronically infected. Given the high prevalence of infections (such as hepatitis) among inmates, prison is considered a reservoir for facilitating such infections. Based on these premises, this current review examines and discusses emerging trends in the epidemiology of HBV infection, with particular attention to HBV infection in prison. The hepatitis B surface antigen (HBsAg) prevalence in prisoners in west and central Africa is very high (23.5%). The Centers for Disease Control and Prevention has highlighted the importance of HBV blood screening and subsequent anti-HBV vaccination in the prison population. The vaccination was recommended for all inmates, representing an opportunity to prevent HBV infection in a high-risk population. In these subjects, an accelerated hepatitis B immunisation schedule may result in rapid seroconversion for early short-term protection. Therefore, it is necessary to seek collaboration among public health officials, clinicians and correctional authorities to implement a vaccination programme.

Concepts: Immune system, Disease, North Africa, Middle East, Europe, Hepatitis B, Asia, Central Asia

2

Infections account for significant morbidity and mortality in liver cirrhosis and most are related to the gut microbiome. Fecal dysbiosis, characterized by an overgrowth of potentially pathogenic bacteria and a decrease in autochthonous non-pathogenic bacteria, becomes prominent with the progression of liver cirrhosis. In cirrhotic patients, disruption of the intestinal barrier causes intestinal hyperpermeability (i.e. leaky gut), which is closely related to gut dysmotility, dysbiosis and small intestinal bacterial overgrowth and may induce pathological bacterial translocation. Although the involved microbial taxa are somewhat different between the cirrhotic patients from the East and the West, the common manifestation of a shortage of bacteria that contribute to the production of short-chain fatty acids and secondary bile acids may facilitate intestinal inflammation, leaky gut and gut dysbiosis. Translocated endotoxin and bacterial DNA are capable of provoking potent inflammation and affecting the metabolic and hemodynamic systems, which may ultimately enhance the progression of liver cirrhosis and its various complications, such as hepatic encephalopathy (HE), variceal bleeding, infection and renal disturbances. Among studies on the microbiome-based therapeutics, findings of probiotic effects on HE have been contradictory in spite of several supportive results. However, the effects of synbiotics and prebiotics are substantially documented. The background of their effectiveness should be evaluated again in relation to the cirrhosis-related changes in gut microbiome and their metabolic effects. Strict indications for the antibiotic rifaximin remain unestablished, although its effect is promising, improving HE and other complications with little influence on microbial populations. The final goal of microbiome-based therapeutics is to adjust the gut-liver axis to the maximal benefit of cirrhotic patients, with the aid of evolving metagenomic and metabolomic analyses.

Concepts: Bacteria, Ammonia, Microbiology, Cirrhosis, Liver, Bile, Pathogenic bacteria, Hepatic encephalopathy

0

Background and Aims: Hypercholesterolemia is a common finding in patients with primary biliary cholangitis (PBC) and is a well-defined risk factor for cardiovascular disease. However, studies have been mixed on whether PBC patients do, in fact, have higher cardiovascular risk. The aim of this study is to review the current literature and provide an evidence-based assessment of cardiovascular risk in PBC patients. Methods: We performed a systematic literature search on PubMed regarding patients with PBC and cardiovascular events from the database inception to July 1, 2017. A total of 33 articles fulfilling our inclusion criteria were found. Results: The majority of the studies evaluated yielded no statistically significant difference in cardiovascular disease in the PBC population compared to the general public. However, some reports found a statistically significantly increase in coronary artery disease. Several studies have looked at the specific lipid profile of patients with PBC with hypocholesteremia. While these lipid abnormalities differ by stage of disease, there is evidence to suggest that the specific lipid profile in PBC may have lower atherogenicity than in patients with hypercholesterolemia without PBC. Studies looking at patients with PBC with other risk factors for cardiovascular disease, such as hypertension and metabolic syndrome, have consistently found a higher risk for cardiovascular disease in these patients. Statin treatment is effective in reducing lipid levels and possibly improving endothelial inflammation in patients with PBC with hypercholesterolemia. Conclusions: There is not enough evidence to suggest an increased risk of cardiovascular disease in patients with PBC with hypercholesterolemia, except for those individuals with concomitant features of metabolic syndrome. In patients with PBC with no additional cardiovascular risk factors, individual risk/benefit discussion on lipid-lowering treatment should be considered.

0

Background and Aims: Acetaminophen (APAP) and HMG-CoA reductase inhibitors are common causes of drug-induced liver injury (DILI). This study aimed to determine the ability to reduce APAP- and statins-mediated liver injury by using formulations that combine glycosphingolipids and vitamin E. Methods: Mice were injected with APAP or with statins and treated before and after with β-glucosylceramide (GC), with or without vitamin E. Mice were followed for changes in liver enzymes, liver histology, hepatic expression of JNK, STAT3 and caspase 3, as well as intrahepatic natural killer T cells (NKT) and the serum cytokine levels by flow cytometry. Results: Administration of GC before or after APAP alleviated the liver damage, as noted by a reduction of the liver enzymes, improvement in the liver histology and decreased hepatic caspase 3 expression. Beneficial effect was associated with a reduction of the intrahepatic NKT, JNK expression in the liver, and increased glutathione in the liver, and decreased TNF-α serum levels. Synergistic effect of co-administration of GC with vitamin E was observed. Similar protective effect of GC on statin-mediated liver damage was documented by a reduction in liver enzymes and improved liver histology, which was mediated by reduction of NKT, increased STAT3 expression in the liver, and reduced the TGF-β and IL17 levels. Conclusions: β-glycosphingolipids exert a hepatoprotective effect on APAP- and statins-mediated liver damage. Vitamin E exerted a synergistic effect to that of GC. The generation of “safer drug” formulations, which include an active molecule combined with a hepatoprotective adjuvant, may provide an answer to the real unmet need of DILI.

0

Background and Aims: Skeletal manifestation in liver diseases represents the minimally scrutinized part of the disease spectrum. Vitamin D deficiency has a central role in developing hepatic osteodystrophy in patients with chronic liver disease. This study aimed to investigate vitamin D levels and their relationship with disease advancement in these patients. Methods: Vitamin D levels were checked in 125 chronic liver disease patients. The patients were classified in three stages according to Child-Pugh score: A, B and C. The relationship of vitamin D levels with Child-Pugh score and other variables in the study was assessed by the contingency coefficient. Correlation and logistic regression analyses were also carried out to find additional predictors of low vitamin D levels. Results: Among the patients, 88% had either insufficient or deficient stores of vitamin D, while only 12% had sufficient vitamin D levels (p >0.05). Vitamin D levels were notably related to Child-Pugh class (contingency coefficient = 0.5, p <0.05). On univariate and multinomial regression analyses, age, female sex, MELD and Child-Pugh class were predictors of low vitamin D levels. Age, model of end-stage liver disease score and Child-Pugh score were negatively correlated to vitamin D levels (p <0.05). Conclusions: Vitamin D deficiency is notably related to age, female sex and model of end-stage liver disease score, in addition to Child-Pugh class of liver cirrhosis. Vitamin D levels should be routinely checked in patients with advanced liver cirrhosis (Child-Pugh class B and C) and this deficiency must be addressed in a timely manner to improve general well-being of cirrhotic patients.

0

Background and Aims: DNA methylation and histone modification are epigenetic modifications essential for normal function of mammalian cells. The processes are mediated by biochemical interactions between DNA methyltransferases (DNMTs) and histone deacetylases. Promoter hypermethylation and deacetylation of tumor suppressor genes play major roles in cancer induction, through transcriptional silencing of these genes. DNA hypermethylation is carried out by a family of DNMTs including DNMT1, DNMT3a and DNMT3b. In hepatocellular carcinoma, a significant positive correlation between over-expression of these genes and cancer induction has been reported. The DNA demethylating agent genistein (GE) has been demonstrated to reduce different cancers. Previously, we reported that GE can induce apoptosis and inhibit proliferation in hepatocellular carcinoma PLC/PRF5 and HepG2 cell lines. Besides, histone deacetylase inhibitors, such as trichostatin A (TSA), were successfully used to inhibit cancer cell growth. The present study was designed to assess the effect of GE in comparison with TSA on DNMT1, DNMT3a and DNMT3b gene expression, cell growth inhibition and apoptosis induction in the HepG2 cell line. Methods: Cells were seeded and treated with various doses of GE and TSA. The MTT assay, flow cytometry assay, and real-time RT-PCR were used to determine viability, apoptosis, and DNMT1, DNMT3a and DNMT3b gene expression respectively. Results: Both agents inhibited cell growth, induced apoptosis and reactivated DNMT1, DNMT3a and DNMT3b gene expression. Furthermore, TSA demonstrated a significantly greater apoptotic effect than the other agent, whereas GE improved gene expression more significantly than TSA. Conclusions: Our findings suggest that GE and TSA can significantly inhibit cell growth, induce apoptosis and restore DNMT1, DNMT3a and DNMT3b gene reactivation.

0

Background and Aims: Sustained virologic response is evaluated by single-step reverse transcription (SRT) PCR assay, which assesses hepatitis C virus (HCV) clearance from plasma but not from tissues such as peripheral blood mononuclear cells (PBMCs). Persistence of HCV RNA in PBMCs beyond end of treatment (EOT) is associated with nonresponse. Our goal was to measure intra-PBMC HCV RNA levels during oral antiviral therapy according to the HCV therapy follow-up fractionation (CTF2) protocol. Methods: Compensated chronic HCV patients (n = 2 78 SRT-PCR positive) were scheduled to receive oral antiviral therapy. Subjects were followed-up by SRT and intra-PBMCs HCV RNA PCR at the end of the 2nd, 6th, 10th, 14th, 18th and 24th weeks to evaluate virus clearance from plasma and PBMCs, respectively. The CTF2 protocol evaluated SRT and PBMC PCR status at each follow-up point for determining therapy continuation or interruption to address cost effectiveness. Results: All patients tested negative by SRT PCR after therapy for 2 weeks. Application of the CTF2 protocol revealed: a) increasing HCV clearance rate from 75.9% at the end of 10th week to 90.3% at the end of 24th week (p < 0.00001); b) faster clearance of HCV from plasma compared to PBMCs at each point of follow-up until the 18th week (p < 0.05); c) higher viral elimination rates diagnosed by PBMC HCV RNA PCR(-) compared to PBMC HCV RNA PCR(+) from the 6th to 24th week of treatment (p < 0.0001); d) higher over-time increase curve of combined plasma and PBMC HCV RNA determined negativity compared to the decline in positivity curves by PBMC PCR at the 6th-18th week compared to the 24th week (p < 0.01)-these results validated treatment continuation; and e) solitary evaluation of EOT sustained HCV infection and relapses by PBMC HCV RNA (p < 0.001). Conclusions: Early elimination of serum and tissue (PBMC) HCV infection by oral antiviral therapy can be achieved and evaluated during a cost-effective CTF2 protocol application.

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Occult hepatitis C virus (HCV) infection (OCI), first described in 2004, is defined as the presence of HCV RNA in hepatocytes or peripheral blood mononuclear cells without detectable HCV RNA in the serum. Here, we aimed to review the epidemiology, diagnostic methods, clinical implications and potential management recommendations currently described in the literature, as well as the future directions for investigation of this entity. PubMed and Cochrane databases were searched with combination of the following keywords: “occult”, “hepatitis C virus”, and “occult HCV infection”. There are data to support OCI as a potential culprit in cryptogenic liver disease. There are also consistent data demonstrating the existence of OCI in specific populations, such as dialysis, human immunodeficiency virus-infected and hepatitis B virus-infected patients, and also in the general population. While the gold standard for diagnosis is liver biopsy, examination of peripheral blood mononuclear cells may be a reliable, safer alternative method of diagnosis. Occult HCV infection is likely associated with liver fibrosis and progression of liver disease. Additional studies are required to determine the infectivity of OCI patients, as well as clarify the natural course and specific clinical implications of OCI. Lastly, studies are needed to determine whether treatment of OCI leads to decreased morbidity and/or mortality.