Background and Aims: Wilson disease (WD) is an inherited disorder of copper metabolism, and an international group for the study of WD (IGSW) has proposed three phenotypes for its initial presentation: acute hepatic, chronic hepatic, and neurologic phenotypes. Characterization of the acute hepatic phenotype may improve our understanding of the disease. Methods: Clinical features of 10 WD patients with the acute hepatic phenotype and characteristics of chronic lesions remaining in survivors were assessed by the European Association for the Study of the Liver (EASL) guidelines. Results: All six patients younger than 30 years had survived an acute episode of hemolytic anemia with residual liver disease of cirrhosis or chronic hepatitis. The acute episode was self-limiting in two of the four patients over the age of 30 years and progressed to acute liver failure in the other two patients. One of the two survivors had residual liver disease of chronic hepatitis, while the other had chronic hepatitis and neurologic disease. Neurologic disease remained in a patient who successfully received a liver transplantation. During acute episodes, serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) changed rapidly along with anemia. Liver-specific ALT levels were age-dependently correlated with hemoglobin (Hb) concentrations. Enzyme reduction was milder for AST than ALT, which resulted in a high AST/ALT ratio in the anemic stage. The anemic stage in two patients transformed to acute liver failure. Conclusions: All survivors of an acute episode of the acute hepatic phenotype had residual liver disease or both liver and neurologic diseases. The rapid changes in liver enzymes during the acute episode and the liver and neurologic diseases remaining in survivors may provide a better understanding of WD.

Liver transplantation is the definitive therapy for patients with advanced liver disease and its complications. Patients who are transplanted with a diagnosis of hepatocellular carcinoma (HCC) are at risk of recurrent cancer, and these patients are monitored on a regular basis for recurrence. In contrast, de novo HCC following liver transplantation is a very rare complication, and recipients without HCC at the time of transplantation are not screened. We describe the clinical features of de novo HCC over a decade after achieving a sustained viral response with treatment of hepatitis C and two decades after liver transplantation. Our case highlights the necessity of screening for HCC in the post-transplant patient with advanced liver disease even after viral clearance.

Background and Aims: Gastric antral vascular ectasia (GAVE) is commonly found in patients with cirrhosis, but it is also associated with other diseases in the absence of cirrhosis. Whether GAVE confers a different severity of gastrointestinal (GI) bleeding between patients with and without cirrhosis remains unknown. We aim to examine whether there is a difference in clinically significant GI bleeding due to GAVE in patients with or without cirrhosis. Methods: This is a retrospective case-control study of patients who were diagnosed with GAVE between January 2000 and June 2014. Patients were categorized into cirrhosis and noncirrhosis groups, and those with an additional GI bleeding source were excluded. Univariate comparisons and multivariable models were constructed using logistic regression. Results: In total, 110 patients diagnosed with GAVE on esophagogastroduodenoscopy (EGD) were included in our analysis; 84 patients had cirrhosis (76.4%) and 26 (23.6%) did not. Active GI bleeding was more prevalent in patients without cirrhosis (63.4% vs. 32.1%, p=0.003) despite similar indications for EGD, and endoscopic treatment with argon plasma coagulation (APC) was required more often in this group, approaching statistical significance (27% vs. 10.7%, p=0.056). There was no difference in bleeding severity, as evidenced by similar re-bleeding rates, surgery, or death attributed to uncontrolled bleeding. The strongest independent risk factor for GI bleeding was the absence of cirrhosis (odds ratio (OR): 5.151 (95% confidence interval (CI): 1.08-24.48, p=0.039). Conclusions: Patients with GAVE in the absence of cirrhosis are at higher risk for active GI bleeding and require more frequent endoscopic treatment than similar patients with cirrhosis. It may be worthwhile to treat GAVE in this population even in the absence of active bleeding.

Interleukin-6 (IL-6), a cytokine mainly produced by activated monocytes, has broad pleiotropic actions that affect the functions of a variety of lymphoid cells. The roles of IL-6 in regulating immunity to infections are currently being defined. Remarkably, IL-6-mediated cellular and humoral immune responses play a crucial role in determining the outcome of viral infection. This article reviews the current knowledge on the critical role of IL-6 in hepatitis B virus (HBV) infection. As a competent intermediary, IL-6 derived from activated monocytes plays an important role in promoting lymphocytes responses that are essential for effective viral control. However, as a mediator of inflammation, IL-6 is also involved in the development of HBV-induced liver cirrhosis and exacerbating liver injury. Overall, the current data point to IL-6 as an immunoregulatory cytokine in HBV infection. Immunotherapeutic strategies aimed at optimizing the beneficial effects of IL-6 in HBV infection may prove to be an ordeal in the future, as they should foster the strengths of IL-6 while circumventing potential drawbacks.

Background and Aims: While traditional risk factors for the development of nonalcoholic fatty liver disease (NAFLD) relate to metabolic syndrome, several Asian studies have suggested a high rate of de novo NAFLD following pancreaticoduodenectomy (PD). The aim of this study is to identify de novo NAFLD after pancreatic surgery and its associated risk factors. Methods: A retrospective cohort of patients at a single center that underwent PD or distal pancreatectomy (DP) over 7 years was identified. Pre- and postoperative contrast-enhanced computed tomography scans of the abdomen were reviewed, including attenuation measurements of the liver, spleen, and muscle. Primary outcomes included hepatic attenuation, liver to muscle ratio (LMR), and liver to spleen ratio (LSR). Results: Of the 96 patients (mean age 64.3) included, 70% underwent PD, and 30% underwent DP. The mean LMR decreased significantly from 1.81 to 1.66 (p=0.02), noted only in men. No interaction effect with LMR was observed with surgical type, chemotherapy, blood loss, pancreatic enzyme replacement, or transaminases. LMR decreased in 55% of subjects. Conclusions: Increased fatty infiltration, as evidence by decreased LMR, was found among men that underwent PD and DP within a year of surgery. This may be related to weight loss and malabsorption and deserves further investigation.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver dysfunction worldwide, and its prevalence is highly associated with genetic susceptibility. The transmembrane 6 superfamily member 2 (TM6SF2) E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation, and its presence appears to be directly involved in the pathogenesis and development of NAFLD. Although this variant appears to be a novel powerful modifier in the development of NAFLD, whether it is associated with an increased risk of NAFLD-related liver fibrosis and hepatocellular carcinoma (HCC) remains to be determined. The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD, with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD. Additionally, the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed.

Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses are important factors that determine whether HBV infection is cleared or persists. After infection, viral replication occurs inside hepatocytes, and the secretion of infectious virions can take place at high rates for decades. Consequently, HBV DNA and viral proteins, like HBV early antigen (HBeAg) and HBV surface antigen (HBsAg), can be easily detected in serum. Chronic infection with HBV is the result of an ineffective antiviral immune response towards the virus. In this review, we discuss the role of immune cells in chronic HBV infection.

Although hepatitis E virus (HEV) is the primary cause of enterically transmitted acute hepatitis and jaundice in developing countries, locally acquired HEV infections are increasing in nonendemic countries. As such, HEV is emerging as an underdiagnosed cause of infection. This report describes three clinically variable cases of HEV infection with unusual clinical presentations. These cases highlight the fact that HEV should be considered in the differential diagnosis of patients with unexplained hepatitis (acute or chronic) with or without extrahepatic manifestations. HEV should also be considered in patients with persistently elevated liver enzymes who have not travelled to known HEV-endemic regions. Lack of knowledge among physicians and an absence of standardized diagnostic tests may result in increased morbidity and mortality from HEV infection.

Background and Aims: Schistosomiasis is a major chronic disease of humans in endemic regions, and infected individuals may develop a spectrum of pathology, including hepatic fibrosis, hepatosplenomegaly, and portal hypertension. Hepatocellular carcinoma (HCC) is considered the fifth most common cancer in the world, and there is limited and controversial evidence suggesting that Schistosoma mansoni infection may be a possible risk factor for HCC. The aim of this study was to report a case series of patients with HCC and S. mansoni infection and to conduct a literature review on the topic. Methods: From January 2002 to January 2015, an institutional database was screened retrospectively to identify patients with HCC and S. mansoni infection at a single center in the Department of Gastroenterology of University of São Paulo School of Medicine and Hospital das Clínicas, Brazil. Results: Seven cases were included. The mean age of patients was 62.1±10.3 years; six (85.7%) were male and one (14.3%) was female. All cases had positive epidemiology, coming from endemic areas of S. mansoni infection in Brazil, and four (57.1%) had previous complications (upper gastrointestinal bleeding) related to portal hypertension or surgery intervention (splenectomy) performed more than 10 years before the HCC diagnosis. Nontumoral portal vein thrombosis was identified in five (71.4%) patients. All patients had negative serology for HCV, and four (57.1%) had positivity of HBVcore antibodies without evidence of viral replication. According to BCLC staging, one (14.3%) patient was BCLC A and received TACE instead of RFA because HCC size was >30 mm; three (42.8%) BCLC B patients received sorafenib instead of local regional treatment due to the presence of nontumoral TPV. During follow-up, all patients developed tumoral progression and died. Conclusions: It remains unclear if S. mansoni infection alone has carcinogenic potential. The available literature indicates that S. Mansoni, in the presence of HBV and HCV infections, likely acts as a cofactor for the hepatic lesion and potentiates injury.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions.

Tumors of the liver and biliary tree, mainly hepatocellular carcinoma and cholangiocarcinoma, are the second leading cause of cancer related death worldwide and the sixth leading cause of cancer related death among men in developed countries. Recent developments in biomarkers and imaging modalities have enhanced early detection and accurate diagnosis of these highly fatal malignancies. These advances include serological testing, micro-ribonucleic acids, fluorescence in situ hybridization, contrast-enhanced ultrasound, and hepatobiliary-phase magnetic resonance imaging. In addition, there have been major developments in the surgical and nonsurgical management of these tumors, including expansion of the liver transplantation criteria, new locoregional treatments, and molecularly targeted therapies. In this article, we review various types of hepatobiliary tumors and discuss new developments in their diagnosis and management.

Background and Aims: African Americans (AA) historically have a low response rate to hepatitis C therapies, and there is limited information available for this patient population regarding the development and treatment of chronic hepatitis C (CHC). The aim of this study was to evaluate liver disease progression and hepatocellular carcinoma (HCC) development in AA with CHC. Methods: Between 1995 and 2008, 246 AA patients with CHC were identified from a database of patients and followed until 2012-2013 (average 8 years) or the development of HCC after 2008. Results: Viral clearance (intent to treat; sustained virus response (SVR)) was achieved in 15% of patients with interferon based therapies with or without ribavirin. AA patients who achieved an SVR (n=22) did not develop HCC or new onset cirrhosis, whereas the HCC incidence in untreated AA patients was 23% (51/203). Patients who achieved an SVR also had improved fibrosis, as defined by the AST Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) score, relative to nonresponders and untreated patients. Conclusions: The severity of liver disease at the first visit (except for cirrhosis) correlated with the development of HCC, but because of the overlap in values between patients, these measurements were not useful for predicting individual risk. Since cirrhosis at the first visit was not a predictive factor, treatment with newer antiviral therapies is the best option for reducing the incidence of advanced liver disease and its harmful outcomes in the AA population.

Thrombotic venous diseases of the liver do not occur frequently, but when they do, they can present as difficult diagnostic and therapeutic challenges. The aim of this article is to review the epidemiology, pathogenesis, diagnosis, and therapeutic options of these serious vascular problems.

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries. Although effective vaccines for HAV are available, the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists, such as Japan. There are two forms of antiviral agents against HAV: direct-acting antivirals (DAAs) and host-targeting agents (HTAs). Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection. Among the HTAs, amantadine and interferon-lambda 1 (IL-29) inhibit HAV IRES-mediated translation and HAV replication. Janus kinase (JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication. Based on this review, both DAAs and HTAs may be needed to control effectively HAV infection, and their use should continue to be explored.