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Journal: Journal of clinical and translational hepatology


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


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


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


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


Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality. The principal treatment is surgical resection or liver transplantation, depending on whether the patient is a suitable transplant candidate. However, in most patients with HCC the diagnosis is often late, thereby excluding the patients from definitive surgical resection. Medical treatment includes sorafenib, which is the most commonly used systemic therapy; although, it has been shown to only minimally impact patient survival by several months. Chemotherapy and radiotherapy are generally ineffective. Due to the poor prognosis of patients with HCC, newer treatments are needed with several being in development, either in pre-clinical or clinical studies. In this review article, we provide an update on the current and future medical and surgical management of HCC.

Concepts: Medicine, Cancer, Patient, Surgery, Radiation therapy, Hepatocellular carcinoma, Physician, Organ transplant


Hepatocellular carcinoma (HCC) is a leading cause of liver-related death worldwide. Hepatitis C virus (HCV) infection is a major cause of advanced hepatic fibrosis and cirrhosis, with significantly increased risk for development of HCC. The morbidity and mortality of HCV-related HCC remains high, as rates of HCV cirrhosis continue to increase. The long-term goal of antiviral therapy for chronic HCV is to reduce complications from cirrhosis, including HCC. The advent of new direct-acting antivirals with high rates of virological clearance has revolutionized cure of HCV infection. While the development of HCC in HCV patients who achieve disease sustained virologic response is reduced, these patients remain at risk for HCC, particularly those patients with advanced fibrosis and cirrhosis. This review outlines the epidemiology of HCC in chronic HCV, various mechanisms, risk factors and pathophysiology that contribute to this disease process, screening recommendations, and the available data on the impact of new direct-acting antiviral treatment on the development on HCC.

Concepts: Epidemiology, Cancer, Virus, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B


Background and Aims: Few previous studies have reported on a combination response (hepatitis B virus (HBV) DNA undetected, alanine aminotransferase normalization and hepatitis B e antigen (HBeAg) seroconversion) following nucleos(t)ide analogue (NAs) long-term therapy in patients with chronic hepatitis B (CHB). This study aimed to investigate the combination response on long-term NAs therapy in patients with HBeAg-positive CHB and to determine whether prolonged therapy is beneficial for combination response, particularly in optimal patients (baseline alanine aminotransferase level ≥5 upper limit of normal and HBV DNA level <109copies/mL). Methods: In total, 280 HBeAg-positive CHB patients were enrolled in this study. Among them, 190 were treated with entecavir and 90 were treated with telbivudine. Results: The cumulative rates of combination response in the total number of patients were 8.6% at 1 year, 13.2% at 2 years, 19.1% at 3 years, 24.2% at 4 years and 26.0% at 5 years. In optimal patients, the cumulative rate of combination response was significantly higher than that in the non-optimal patients at 3 years (p= 0.043); the trend of the cumulative rate was not strong at the later time. Interestingly, in optimal patients, combination response mainly occurred in the first 3 years. Multivariate analysis identified HBeAg/anti-HBe seroconversion at 1 year as the only factor for combination response in optimal patients (hazard ratio: 16.321;p= 0.000). During the 3 years, the proportion with aspartate aminotransaminase to platelet ratio index ≤0.5 increased from 15.6% at baseline to 71.3% at year 3. Conclusions: Upgrading the rate of combination response is limited by prolonging the treatment duration of NAs from 3 years to 5 years in HBeAg-positive CHB patients; a new switch treatment strategy modification should be considered, particularly in optimal patients.

Concepts: Cirrhosis, Hepatitis, Alanine transaminase, Hepatitis C, Hepatitis B, Hepatitis A


Background and Aims: The use of additional nucleos(t)ide analogues (NAs) without cross-resistance to previously used NAs as a rescue therapy is recommended by most international guidelines for chronic hepatitis B patients with NA-resistance. We aimed to investigate the efficacy and safety of combination therapy of peg-interferon (PegIFN) alfa-2a and NA in these patients, comparing to those who switch to an alternative NA therapy without cross-resistance. Methods: In this prospective, comparative and cohort study, data were collected from the patients' hospital records. Eligible patients were those with hepatitis B e antigen (HBeAg) positivity and resistance to one or more NAs. All patients were treated with alternative NA alone or in combination with PegIFN alfa-2a for 52 weeks or 72 weeks, respectively. HBeAg seroconversion was measured at the end of follow-up (EOF; more than 104 weeks after the end of treatment). Results: Sixty-three patients were recruited to the cohort study (NA-therapy group = 31 patients; combination therapy group of NA and PegIFN alfa-2a = 32 patients). At the EOF, significantly more patients in the combination therapy group (13/27, 48.2%) achieved primary outcome of HBeAg seroconversion than those in the NA therapy group (4/32, 12.5%) (p= 0.003). Four patients (14.8%) in the combination therapy group achieved hepatitis B surface antigen (HBsAg) loss and HBsAg seroconversion, but none in the NA therapy group did (p= 0.039). In the combination therapy group, 16 patients (51.6%) achieved HBeAg seroconversion at the end of treatment, of which, 11 patients (68.8%) maintained the response until EOF. Conclusions: Adding on PegIFN alfa-2a in combination with NA therapy might be an appropriate rescue treatment option for patients who have prior NA resistance. In addition, combination therapy induced sustained off-treatment biochemical responses in these patients.

Concepts: Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B, Hepatitis A


Background and Aims : Acute calculous cholecystitis with impending gall bladder perforation in severe liver diseases including decompensated cirrhosis and acute-on-chronic liver failure (ACLF) is difficult to manage, due to the procedures such as cholecystectomy and per cutaneous cholecystostomy being associated with high risk and complications in these patients. Methods :Four cases of severe liver disease with acute calculous cholecystitis who presented to the Institute of Liver and Biliary Sciences (New Delhi, India) for further management were included in the study if they underwent endoscopic ultrasound-guided gall bladder drainage (EUS-GBD). The patients were followed up for a minimum of 3 months and outcomes were recorded. Results :Four cases of severe liver disease (three ACLF and one decompensated cirrhosis), with model for end-stage liver disease scores of 24, 26, 23 and 25 respectively, presented with acute calculous cholecystitis (Tokyo grade III) and systemic sepsis (high total leukocyte counts). Their international normalized ratios were 2.3, 2.6, 2.2 and 2.9 respectively, and two were in shock, requiring inotropes at presentation. Ultrasonography of the abdomen confirmed hugely distended gall bladder with stone impacted at the neck and moderate ascites. All these cases underwent EUS-GBD by linear echo endoscope, and had the gastric wall punctured in the antrum using a 19G access needle followed by dilatation of the tract using controlled radial expansion balloon and Sohendra dilator. In three cases, the plastic stents were placed. In the fourth case, a Nagi stent was placed. All the patients recovered and were discharged within a week. Conclusions :EUS-GBD is challenging in severe liver disease but represents a life-saving procedure, and hence can be attempted in such critically ill patients with utmost care and precaution.

Concepts: Systemic inflammatory response syndrome, Cirrhosis, Liver, Hepatology, Bile, Abdomen, Liver disease, Cholecystitis


Hepatitis E is an infectious inflammatory disease of the liver caused by the hepatitis E virus (HEV), a single-stranded RNA virus. Today, it is estimated that there are more than 20 million HEV infections every year, leading to 3.3 million symptomatic cases and more than 56,000 deaths. For a long time it was believed that HEV was a travel-associated disease, endemic in developing countries with poor hygienic standards and unsafe water supply. However, over the past years, publications have demonstrated that autochthonous HEV infections in industrialized countries are far more common than previously thought. Awareness for HEV amongst health care practitioners in industrialized countries is still limited. This relatively rare disease is of great importance, especially in immunocompromised patients where it can cause chronic liver disease. This article comprehensively reviews current literature to give an overview on clinically important topics. It will focus on epidemiological aspects, acute and chronic HEV infection as well as extra-hepatic manifestations, diagnostic approach and treatment options. Furthermore, the article is concluded with a brief outlook on perspectives and urgent problems to be addressed in the future.

Concepts: Inflammation, Epidemiology, Disease, Infectious disease, Genome, RNA, Infection, Hepatitis A