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.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a silent disease; its spectrum includes simple steatosis, nonalcoholic steatohepatitis and fibrosis. Pro- and anti-inflammatory cytokines play roles in the pathogenesis of NAFLD and insulin resistance (IR). Moreover, plasma cell antigen-1 (PC-1) is related to IR and associated with NAFLD progression. Therefore, we aimed to detect biomarkers, ultrasonographic and anthropometric findings capable of differentiating NAFLD grades, since most previous investigators were concerned more with NAFLD patients without classifying them into grades.

Methods: A total of 87 NAFLD patients (31 with grade 1 (mild NAFLD), 26 with grade 2 (moderate NAFLD) and 30 with grade 3 (severe NAFLD) were included in the study, in addition to 47 controls (grade 0). All subjects underwent ultrasonographic examination for NAFLD diagnosis. Serum interleukin-10 (IL-10), plasma interleukin-18 (IL-18) and plasma PC-1 levels were determined using enzyme-linked immunosorbent assay.

Results: Homoeostasis model assessment (HOMA)-IR was higher in different NAFLD grades than in controls. Ultrasonographic and anthropometric findings and lipid profile indices (except for high-density lipoprotein cholesterol, which was decreased) were increased with NAFLD progression. Grade 3 patients showed significant increase in levels of IL-18 and significant decrease in IL-10 and PC-1 levels when compared to grade 1 patients.

Conclusion: Anthropometric and ultrasonographic findings were valuable in differentiating NAFLD grades. IR is very important in NAFLD pathogenesis. IL-18, HOMA-index and PC-1 levels could be used to differentiate between NAFLD grades, together with other measurements.

Vertical transmission (VT) is the primary route of transmission of viral hepatitis in children. The rate of VT ranges from 1–28% with hepatitis B virus (HBV) and 3–15% with hepatitis C virus (HCV). VT for both viruses can occur during the intrauterine or peripartum period. VT of HBV primarily occurs by intrauterine transmission (IUT). Hepatitis B surface antigen is unable to cross the placenta and, therefore, relies on processes like transplacental leakage, placental infection, cellular transmission by peripheral blood mononuclear cells, and germline transmission. HCV can also infect the fetus by IUT. Both viruses also have the potential for transmission during delivery, when there is increase chance of maternal–fetal blood exposure. HBV and HCV share some common risk factors for VT, including maternal viral load, human immunodeficiency virus co-infection and neonatal sex. Prevention of VT differs greatly between HBV and HCV. There are several alternatives for prevention of HBV VT, including antiviral medications during the third trimester of pregnancy and HBV vaccine, as well as hepatitis B immunoglobulin administration to infants post-partum. In contrast, there are no preventative interventions available for HCV. Despite these differences, the key to prevention with both viruses is screening women prior to and during pregnancy.

Background and Aims: Both alcoholic drinks and high sugar-containing soft drinks cause major health problems worldwide. Oral administration of OS and M1 soy-derived extracts has been shown to alleviate liver injury in animal models. The aim of the present study was to determine the liver- and sugar-protective effect of OS and M1 soy-derived extracts when added to alcohol and sugar-enriched drinks.

Methods: Mice were treated with alcohol or high sugar-containing drinks, with and without administration of a combination of OS and M1 soy extracts. Mice were observed for the effects on liver injury, glucose metabolism, and the immune system.

Results: Co-administration of the soy extracts OS and M1 significantly alleviated the liver injury induced by acute alcohol, as evidenced by decreased liver enzymes. These beneficial effects were associated with promotion of subsets of regulatory T lymphocytes and with a trend towards a pro-inflammatory to an anti-inflammatory cytokine shift. Co-administration of OS M1 soy extracts with sugar-sweetened beverages significantly alleviated the increases in serum sugar levels.

Conclusions: OS and M1 extracts exert a synergistic hepato- and glucose-protective effect in models of alcohol-induced liver damage and soft drinks-associated increases in serum glucose. These extracts may provide a solution to the two pressing health problems.

Background and Aims: Nonalcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation (LT) in the United States and is on a trajectory to become the leading indication for LT in the next decade. We aimed to study the trends in NASH-related LT among persons born between 1945 and 1965, the baby boomer (BB) generation.

Methods: We performed a retrospective cohort analysis using population-based data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry from 2004–2015 to evaluate the birth cohort-specific trends in liver transplant waitlist registrations and liver transplant surgeries in patients with NASH. We stratified our study population into three birth cohorts: 1) birth before 1945, 2) birth between 1945 and 1965, and 3) birth after 1965.

Results: The overall rates of NASH-related waitlist registrations and liver transplant surgeries steadily increased from 2004 to 2015 and were reflective of a sharp rise noted in the NASH BB sub-group. From 2004 to 2015, the proportion of BB patients with NASH added to LT waitlist demonstrated an incremental growth, 60.6% in 2004 versus 83.2% in 2015 (p < 0.01). Among the liver transplant recipients with NASH, the proportion represented by the BB cohort increased from 56.3% in 2004 to 80.0% in 2015 (p < 0.01).

Conclusions: We report rising rates of waitlist registration and LT for the indication of NASH. More importantly, the BB sub-cohort was mainly responsible for these alarming trends.

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.

Plants have been employed as medicine since time immemorial, and there has been a recent resurgence in the use of plants as medicines due to their little or no toxicity at the doses used for treatment of different ailments. This review discusses in detail the phytochemical and pharmacological activities of Jamun (Syzygium cumini), a tree belonging to family Myrtaceae, which has been credited with several medicinal properties in the traditional system of medicine, the Ayurveda. The different properties attributed to Jamun are sweet, sour, astringent, acrid, refrigerant, carminative, diuretic, and digestive. Research and practical use in traditional medicinal systems have found Jamun to be effective in treating leucorrhoea, gastric disorders, fever, diabetes, piles, stomachache, wounds, and dental, digestive and skin disorders. Some compounds in Jamun have antioxidant, antimicrobial, antiallergic, antidiabetic, antihyperlipidemic, anticancer, gastroprotective, hepatoprotective, cardioprotective and radioprotective activity. Finally, Jamun has been found to contain phytochemicals including anthroquinones, alkaloids, catechins, flavonoids, glycosides, steroids, phenols, tannins, saponins and cardiac glycosides. The diverse activities of Jamun may be due to its abilities to scavenge free radicals, increase antioxidant status of cells by increasing glutathione, glutathione peroxidase, catalase and/or superoxide dismutase, and to attenuate lipid peroxidation. In addition, it also suppresses the transcription of peroxisome proliferator-activated receptor, Nuclear factor kappa B, cyclooxygenase, inducible nitric oxide synthase, tumor necrosis factor alpha and other proinflammatory cytokines, accompanied by the up-regulation of nuclear factor erythroid 2-related factor 2 transcription, which is involved in regulating the antioxidant status of the cells.

The growing issue of clinical obesity has led to increased consumption of weight-loss dietary supplements containing hydroxycitric acid (HCA) derived from the fruit rind of Garcinia cambogia, a plant widely distributed in Asia and Africa. It is often consumed in an unregulated manner, beyond the permissible dose, to achieve the target weight-loss. However, its safety/efficacy is controversial and reports on cytotoxicity and genotoxicity are limited and inconsistent. Hence, we aimed to study the putative effects of HCA on genotoxicity in human peripheral blood cells.

Human lymphocytes and erythrocytes were treated with HCA (0, 10, 20, 40 or 100 µg/mL) for 3 h or 24 h and processed for cytotoxicity and genotoxicity analyses.

Initial phytochemical assessment of HCA revealed the presence of high flavonoid content. Subsequent multi-endpoint cyto-genotoxicity studies in human lymphocytes displayed low cytotoxicity but significant genotoxicity at higher concentrations of 40 and 100 µg/mL; these concentrations are approximately equivalent to and double the maximum permissible dose (∼2800 mg/day), respectively. Flow cytometric estimation of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and mode of cell death revealed significant ROS generation at the higher concentrations, but no effect on ΔΨm and apoptosis/necrosis. Insignificant hemolysis was observed in erythrocytes.

High flavonoid content of HCA potentially imparts pro-oxidant property, facilitating DNA damage at high concentrations. However, such genotoxicity does not lead to cell death. Therefore, HCA can be recommended for safe consumption within the permissible dose limit.

Treatment of arterial lesions using drug-eluting stent is now a gold standard method, however, the mechanisms of drug uptake and its retention is not well understood. In most of the computational studies, only the binding of drug to specific receptor is considered; but it is well established that when the drug binds to the specific receptor, there is also occurrence of non-specific binding caused by the trapping of drug in the extracellular matrix. When non-specific binding is not subtracted from total binding to give receptor-mediated binding, a description of receptor/ligand requires that effects of non-specific binding be considered.

We construct a computational model of the drug transport within the arterial wall. The governing equations, along with the suitable boundary conditions, are solved numerically in an explicit manner. Necessary stability criteria have been checked in our in-house FORTRAN code.

The simulated results in this study predict that the penetration length of both free and non-specific bound drug increases with increase in time, and ultimately saturation of binding sites takes place; however, specific bound drug becomes totally absorbed at the adventitial boundary. The concentration of free drug is always higher in the case of the single bound phase model than that of the double bound phase model.

Because local concentration of free drug is inextricably linked to the binding and saturation of binding, our results provide a potential explanation for the success of stent-based delivery.

Acute intermittent porphyria (AIP) is a rare and potentially life-threatening metabolic disorder. It is characterized by an autosomal dominant enzymatic deficiency in porphobilinogen deaminase, which is a critical enzyme in the heme biosynthesis pathway. This deficiency leads to an overproduction of porphyrin precursors that can lead to acute attacks that can be severe and affect overall quality of life. These attacks can be precipitated by factors such as medications, nutritional changes, infection and environmental exposures. Liver transplantation is a potential cure for patients who have evidence of end-stage liver disease or are experience multiple life-threatening attacks. This article presents the case of a patient with AIP, who was successfully treated with liver transplantation. The article also provides a review of the epidemiology/pathophysiology of AIP, and its diagnosis and precipitating factors leading to exacerbation of symptoms, as well as its treatment options, with an emphasis on use of liver transplantation to achieve cure.

Background and Aims: Hepatitis C virus (HCV) cirrhosis is the leading indication for liver transplantation in the United States and recurrent HCV following liver transplantation is a major cause of allograft loss and mortality. Liver biopsies are commonly used to identify recurrent HCV and determine the need for antiviral therapy. The introduction of direct-acting antiviral agents (DAAs) has changed the management of recurrent HCV infection. This study aimed to describe the role of liver biopsies in liver transplant recipients with HCV after the introduction of DAAs.

Methods: A retrospective analysis was performed looking at the rate of liver biopsies post-liver transplantation for HCV. The analysis included 475 adult liver transplants for hepatitis C performed at the University of California, Los Angeles from January 1, 2006 to October 1, 2015. Patients were divided into two eras, pre- and post-introduction of DAAs on December 1, 2013.

Results: In the era before the introduction of DAAs, the percentage of patients biopsied was significantly higher compared to the era after the introduction of DAAs (56.1% vs. 26.9%, p < 0.001).

Conclusions: The introduction of DAAs has changed the management of liver biopsy following liver transplantation and the management of recurrent HCV. Given that DAAs are well tolerated and have high efficacy, liver biopsies are no longer routinely used to justify the use antiviral therapy following liver transplantation.

Background and Aims: Non-Hodgkin lymphoma (NHL) of the liver is a rare lymphoid malignancy, accounting for less than 1% of extranodal lymphomas.

Methods: I conducted an analysis of the U.S Surveillance, Epidemiology, and End Results (SEER) database to evaluate the histological subtypes and the survival outcomes of 785 cases with hepatic NHL between 1973 and 2012.

Results: There were 785 of 312 459 cases with NHL had a first primary hepatic NHL (0.25%). Of the total 785 cases, the median age at diagnosis was 61 years (range 3–95 years) and male-female ratio of 1.7:1. The most common subtype was diffuse large B cell lymphoma (63.2%). In all patients, the median overall survival (OS) was 33 months (95%CI, 22–48 months). The 5-year OS rate for indolent B-cell NHLs was 62%, compared with 44% for an aggressive B-cell NHLs and 42% for T-cell NHLs. The median OS improved from 19 months in patients diagnosed in a period 1996–2000 to 60 months when diagnosed between 2006 and 2012 (p < .001). In a multivariable Cox regression analysis, the age ≥80 years (adjusted hazard ratio [aHR] 3.21, p < .001), male gender (aHR 1.26, p = .02), Black race (aHR, 1.70, p < .001), and T-cell NHL variants (aHR 1.73, p = .03) were unfavourable prognostic factors.

Conclusion: NHL of the liver comprises about 0.3% of all NHLs and survival was improved in the recent calendar period.

Background and Aims: Recurrent infection of hepatitis C virus (HCV) in liver transplant (LT) recipients is universal and associated with significant morbidity and mortality.

Methods: We retrospectively evaluated the safety and efficacy of ledipasvir/sofosbuvir with and without ribavirin in LT recipients with recurrent genotype 1 hepatitis C.

Results: Eighty-five LT recipients were treated for recurrent HCV with ledipasvir/sofosbuvirwith and without ribavirin for 12 or 24 weeks. The mean (± standard deviation [SD]) time from LT to treatment initiation was 68 (±71) months. The mean (± SD) age of the cohort was 63 (±8.6) years old. Most recipients were male (70%). Baseline alanine transaminase, total bilirubin, and HCV ribonucleic acid (RNA) values (± SD) were 76.8 (±126) mg/dL, 0.8 (±1.3) U/L, and 8,010,421.9 (±12,420,985) IU/mL, respectively. Five of 43 recipients who were treated with ribavirin required drug cessation due to side effects, with 4 of those being anemia complications. No recipient discontinued the ledipasvir/sofosbuvir. Eighty-one percent of recipients had undetectable viral levels at 4 weeks after starting therapy, and all recipients had complete viral suppression at the end of therapy. The sustained viral response at 12 weeks after completion of therapy was 94%.

Conclusion: Ledipasvir and sofosbuvir with and without ribavirin therapy is an effective and well-tolerated interferon-free treatment for recurrent HCV infection after LT. Anemia is not uncommon in LT recipients receiving ribavirin.

Hepatic resection (HR) and radiofrequency ablation (RFA) are popular local therapies for early-stage hepatocellular carcinoma (HCC). Alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-c-carboxy prothrombin are well-known and useful tumor markers for HCC. The positive number status of these tumor markers has recently been demonstrated as beneficial for predicting outcome for HCC patients treated with local therapy. Although the normal ranges reported have differed by institution, the positivity of tumor markers is consistent and can easily be assessed. Kumamoto and Wakayama’s group clearly demonstrated the following: 1) Regardless of the degree of tumor stage, a triple-positive tumor marker profile can predict poor outcome in HCC patients undergoing HR; 2) For RFA alone, HCC patients with double- and triple-positive status, having less than three lesions and lesions ≤3 cm in diameter show comparably insufficient outcomes; 3) For HCC patients with lesions ≤5 cm in Child–Pugh grade A, HR is preferred over RFA; 4) Microvascular invasion rates increased even in the double-positive patients, while poorly differentiated HCC was frequently observed only in the triple-positive patients; and 5) RFA with chemoembolization, anatomical liver resection, and postoperative adjuvant chemoembolization or hepatic arterial chemotherapy might improve the outcome for patients with highly malignant HCC with multiple positive tumor markers. However, the impacts of these therapies still need to be evaluated in prospective comparative studies.

Nonalcoholic fatty liver disease (NAFLD) is a pathologic condition frequently observed in clinical practice. To date, the prevalence of NAFLD is approximately 25–30% among adults of the general population in Western countries but increases to approximately 70–75% among patients with type 2 diabetes mellitus. In the last decade, accumulating evidence has clearly demonstrated that patients with NAFLD have not only an increased liver-related morbidity and mortality but also an increased risk of fatal and non-fatal cardiovascular events. In particular, several studies have documented the existence of an independent association among NAFLD and cardiac changes in structure and function in both non-diabetic and diabetic patients. In addition, mounting evidence also suggests that there is a strong relationship between NAFLD and cardiac arrhythmias, such as atrial fibrillation, QTc prolongation and ventricular arrhythmias. This is of clinical interest, as it could explain, at least in part, the increased risk of death for cardiovascular disease in patients with NAFLD. Therefore, seeing that cardiovascular disease complications are the leading cause of disability and death in NAFLD patients, the recent European clinical practice guidelines advised to check the cardiovascular system in all patients with NAFLD. This clinical mini review will briefly describe the increasing body of evidence regarding the association between NAFLD and cardiac arrhythmias, and discuss the potential biological mechanisms underlying this association.

Hepatic encephalopathy is a spectrum of reversible neuropsychiatric abnormalities, seen in patients with liver dysfunction and/or portosystemic shunting. One of the most debilitating complications of cirrhosis, encephalopathy affects 30–45% of cirrhotics. In addition to significantly affecting the lives of patients and their caregivers, it is also associated with increased morbidity and mortality as well as significant utilization of health care resources. In this paper, we provide an overview on the pathophysiology, diagnosis, management and newer therapies of hepatic encephalopathy.

Background and Aims: The role of bile cast nephropathy (BCN) in pathogenesis of hepatorenal syndrome (HRS) in decompensated cirrhosis and acute on chronic liver failure (ACLF) is unknown. This study aimed to determine the frequency of BCN detected on postmortem renal biopsy among patients with decompensated cirrhosis and ACLF who had been admitted with acute kidney injury due to HRS (HRA-AKI) and expired during that hospitalization.

Methods: One-hundred-twenty-seven postmortem renal biopsies with adequate size (>1 cm in length) were included for analysis. These were obtained from 84 patients with decompensated cirrhosis and 43 patients with ACLF.

Results: BCN was detected in 57 of the total 127 (44.8%) renal biopsy specimens. Patients with BCN had significantly higher levels of serum total bilirubin, total leukocyte count and model for end-stage liver disease score, as compared to those without BCN. BCN was detected in 32/43 (74.4%) of the patients with ACLF, as compared to 25/84 (29.7%) of the patients with decompensated cirrhosis (p < 0.001). On multivariate analysis, direct bilirubin (OR (95% CI): 1.27 (1121–1.698); p < 0.001) and presence of ACLF (OR (95% CI): 2.603 (1.054–7.111); p = 0.041) were found to be significant predictors of BCN on postmortem renal biopsy.

Conclusion: BCN was found in 72.1% of patients with ACLF and 27.4% patients with decompensated cirrhosis who had been hospitalized with an admitting diagnosis of HRS-AKI and who expired during that hospitalization and underwent postmortem renal biopsy. Direct serum bilirubin and presence of ACLF were found to be significant predictors of BCN on postmortem renal biopsy.