Background and Aims: Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer worldwide. Knowledge and adherence to HCC surveillance guidelines has been associated with earlier detection. We sought to evaluate characteristics and outcomes following HCC diagnosis in patients screened for HCC in a large academic liver center versus patients diagnosed and referred from the community.

Methods: We reviewed the records of patients diagnosed with HCC in the liver center of an academic institution from January 1999 till December 2013. Patients were classified into two groups: patients followed in our hepatology clinic and patients with HCC recently referred to our center. Univariate analysis was performed using chi-squared test and multivariate analysis was performed using SPSS 22.0.

Results: The records of 410 patients were reviewed, and included 77.3% of patients referred from the community and 22.7% of patients followed in our clinic. In the clinic group, 75.6% were identified with one nodule at initial diagnosis, compared to 65.6% in the referral group. Patients in the referral group were more likely to present with tumors ≥5 cm at diagnosis, with 28.7% compared to 5.4% in the clinic group (p < 0.0001). Patients referred from the community were also less likely to undergo transplant, with 32.2% as compared to 48.4% of the clinic group (p < 0.004).

Conclusion: Patients with chronic liver disease managed in an academic liver center present in the early stage of HCC diagnosis and are more likely to meet the Milan criteria and undergo transplant. Early referral to a specialized transplant center, if feasible, where a multidisciplinary approach is utilized might be essential in the management of chronic liver disease.

Background and Aims: Cloning of ATP7B provided evidence that Wilson’s disease is a hepatic copper toxicosis with a variety of extrahepatic complications. Affected siblings with the same genetic background and exposure to similar environmental factors may be a good model for the study of genotype-phenotype correlation.

Methods: Twenty-three affected siblings in 11 families were selected from a database. The first phenotypes were determined according to the international proposal. The final types of chronic organ damage were re-evaluated for life-long management.

Results: Phenotypes were identical in 5 of the families and different in 6 of the families. The acute hepatic phenotype H1 was found in 3 younger siblings and 1 older sibling. All survived an acute episode of hemolysis with underlying chronic liver disease. One also presented complication with neurological disease. The neurological phenotype N1 with neuropsychiatric symptoms and hepatic disease was found in 2 aged siblings of 1 family, in an older sibling in 3 families and in the oldest sibling in 1 family. Phenotypes in siblings were mainly split by either H1 occurring in random order or age-dependent N1. Types of chronic organ damage were identical in 8 of the families and different in 3 of the families. The same combination of chronic liver disease was found in 6 families and chronic liver disease complicated with neurological disease in 2 families. Split organ damage in siblings was found when an older sibling was complicated by neurological disease. There was no reverse combination of a younger sibling being complicated by neurological disease in any of the families.

Conclusion: Phenotype combinations of siblings were mainly modified by externally-induced hemolytic episodes, while chronic organ damage in siblings was split by age-dependent neurological complications.

Background and Aims: Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) who are dialysis-dependent form a unique group, in which safety, tolerability and efficacy of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) need further evaluation.

Methods: We performed a retrospective analysis of 14 patients with CHC and ESRD on dialysis who received 15 courses of SOF-based therapy. We evaluated dose escalation to standard-dose SOF in this proof-of-principle experience.

Results: Sustained virological response (defined as undetectable viral load at 12 weeks, SVR-12) was achieved in 13 out of the 15 (86.7%) treatment courses. Seven (46.6%) patients received reduced half dose as conservative proof-of-principal to mitigate potential toxicity. In 13 out of 15 treatment courses, patients completed the designated treatment duration. One patient was treated twice and developed SVR-12 with the retreatment. One patient was lost to follow-up and counted as a non-responder. Premature discontinuations were not due to DAA-related adverse effects. There were no reports of severe adverse effects or drug interactions.

Conclusion: We treated CHC patients with ESRD using dose escalation to standard-dose SOF in this proof-of-principle experience and achieved SVR rates comparable to general population.

Background: Impairment of the ability to adapt to stress in animals may contribute to some stress-related psychiatric disorders, such as anxiety and depression. A growing body of evidence has suggested that the brain’s serotonin (5-HT) nervous system may play an important role in the etiology, expression and treatment of anxiety and depression. The aim of the present study was to examine whether brain 5-HT7 receptors are involved in the formation of stress adaptation.

Methods: Male ICR mice were either exposed to repeated restraint stress for 60 or 240 min/day (stressed group) or left in their home cage (non-stressed group) for 1 or 14 days. The emotionality of mice was estimated by the hole-board test. The levels of 5-HT7 receptor expression and extracellular signal-regulated kinase 1/2 (ERK) phosphorylation were assessed by western blot analysis.

Results: A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response was not observed in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. Increases in 5-HT7 receptor protein and ERK phosphorylation were observed in the frontal cortex and hippocampus of stress-adaptive, but not stress-maladaptive, mice. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with LP-12, a selective 5-HT7 receptor agonist, immediately after daily exposure to stress.

Conclusion: The present findings suggest that the brain 5-HT7 receptor-ERK system may play an important role in the formation of stress adaptation. Furthermore, stimulation of 5-HT7 receptors may have a beneficial effect on stress adaptation and alleviate the emotional abnormality observed under conditions of excessive stress.

In the United States, chronic infection with the hepatitis C virus (HCV) affects an estimated 0.1–2% of the pediatric population, who are consequently at risk for major complications, including cirrhosis, hepatocellular carcinoma, and death. The current standard of treatment for chronic hepatitis C (CHC) in children is pegylated-interferon-alpha (PEG-IFN) in combination with ribavirin. PEG-IFN/ribavirin therapy is approved for children ages 3 and older; however, it is often held from use until adulthood because of its extensive list of potential side effects and high likelihood of causing adverse symptoms. While CHC is usually indolent in children and adolescents, immediately treating and curbing the spread of HCV before adulthood is important, as there can be transmission to other individuals via sexual activity and infected females can later vertically transmit the infection during pregnancy, the latter representing the most common means of transmission for children in the United States. The recent development of direct-acting antivirals has shown promising results in clinical trials for use in children and has dramatically increased the rates of sustained virological response in adults while improving side effect profiles as compared to interferon-based treatments. Given the usually indolent course of CHC in children, significant side effects of the currently-approved PEG-IFN/ribavirin therapy, and likely availability of all-oral interferon-free regimens for children within a few years, deferring treatment in clinically-stable children with CHC in anticipation of upcoming superior treatment modalities may be justified.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are national and global epidemics. The disease is characterized by a spectrum of liver steatosis (fat deposition), inflammation (in NASH) and fibrosis. NAFLD and specifically NASH can lead to cirrhosis, which carry risks of progression to portal hypertension and hepatocellular carcinoma (HCC). NASH is also associated with higher mortality from cardiovascular causes. Most of the data for NAFLD has been obtained from the perspective of developed nations, although the disease is increasing and threatening to reach epidemic proportions across the world. Emerging data is notable for high prevalence of NAFLD in South Asian populations, presumably resulting from a combination of underlying genetic polymorphisms and changes in socio-economic status. It is also notable that an ‘Asian Paradox’ has been defined for NAFLD based upon the observation of lower than pre-defined body mass index (BMI), otherwise termed as “lean NAFLD”, among this population. Yet, data remains limited in regards to the characteristics of NAFLD/NASH in this population. In this article, we present a review of the literature and discuss the prevalence, associated risk factors and burden of HCC in South Asians with NAFLD.

Background and Aims: The current paradigm of specialist physician-managed treatment of chronic hepatitis C virus infection (HCV) is inefficient in absorbing the approximately 3 million patients awaiting treatment in the United States. Task shifting—whereby specialist physicians screen patients for treatment eligibility but on-treatment monitoring is devolved to more abundant non-physician clinicians—achieves non-inferior treatment outcomes with second generation direct-acting antivirals (2nd Gen DAAs), may increase treatment capacity, and may facilitate greater treatment access. We determined the cost effectiveness of 2nd Gen DAAs with respect to interferon-based first-generation DAAs (1st Gen DAAs) within a task-shifted treatment model.

Methods: Using a previously described decision-analytic Markov structure, we modeled a hypothetical cohort of 1,000 patients with HCV genotype 1 infection over a lifetime horizon, based upon our outreach clinic’s HCV treatment protocol. Treatment-naïve and treatment-experienced HCV cohorts were modeled separately, based upon our outr8each clinic’s demographics. Treatment response to 2nd Gen DAAs was modeled based on our outreach clinic’s data. Adverse events, utility, costing, and transition probabilities were sourced from the literature.

Results: Driven by improved effectiveness and safety, as well as an expected increase in treatment capacity, 2nd Gen DAAs treatment monitored by non-physician clinicians was projected to improve health outcomes and be dominant from a cost-effective perspective versus that of 1st Gen DAAs. Trends were consistent across all assessed patient subpopulations.

Conclusions: Based on an assumption of increased treatment capacity accompanying a task-shifted treatment model, 2nd Gen DAAs-based treatment was cost effective and cost saving as compared to 1st Gen DAAs-based treatment for all HCV patient subgroups assessed.

In 1978, the idea of making a baby on a petri dish generated worldwide media attention as scientific and social controversy. On July 25th of that year, the world’s first human in vitro fertilization (IVF) was accomplished in England, and Louise Brown was the first ‘test-tube’ baby. Once Louise was shown to be a healthy infant the protests subsided, and since then the IVF technique has gradually become accepted as an alternative to the ‘natural’ way for infertile couples to have a child. However, IVF is not without risks and possible disappointment, and for 37 years there has been no significant change in technique. However, in 2006 two colleagues in England developed a novel method for IVF that will eliminate inherited disease by using a woman’s donated, healthy mitochondrial (mt) organelles (oxygen-energy cells), euginizing the mother’s unhealthy mt cells that carry inherited chronic and/or serious disease. The transfer of these powerful, healthy cells into the mother’s egg cell represents a 3-person IVF process by which many chronic and serious diseases are eliminated that would otherwise have been passed on by the mother to her child. In cytoplasmic (mt) implantation, the mother’s cell nucleus is not affected and any characteristics of the child, for example hair and eye color, are from the mother and father. This technique has been successfully researched in mice, but to date not in humans. This year, the United Kingdom petitioned Parliament and was granted approval to research on humans. In the United States, the Food and Drug Association (FDA) has been reluctant to give human research approval to our own scientists, citing the factors of unknown physical risk, ethics and legalities. These issues will again be discussed in a 2016 symposium.

Designer babies? Or healthier generations to come? This article explains 3-person IVF process to our current and future nurses as the FDA will raise both sides of this argument within the next year for consideration to resume research with human subjects. In this day, clinicians, government employees, the public, and our media (including social media) contribute to the weighing of the value of eliminating any given inherited disease and increasing long-term family health versus the risks of physical, ethical and legal complications.

Avian influenza viruses (AIVs) have been recorded in a broad variety of hosts, including humans, terrestrial and marine mammals, and domestic and wild birds. Wild aquatic birds are recognized as the chief natural reservoirs of AIV, and their migratory flyways can serve as routes for the dispersion of the virus across countries and continents. Although AIV is one of the most studied pathogens in the world, studies on the ecology and epidemiology of this virus in South America are few and fragmented. In this review, we examine the current state of the art on the epidemiology of AIV in wild birds in South America. Current evidence corroborates that many of the broad epidemiological patterns that have been documented in other continents, such as the role played by Anseriformes and Charadriiformes in the maintenance and spread of AIV, are also true in South America. On the other hand, the fact that AIV prevalence in South American studies appears to be remarkably lower than that observed in other continents, along with the presence of endemic taxa of birds that may be highly susceptible to AIV, indicates that South America may have distinct characteristics that modulate the epidemiology of AIV in unique ways. However, our knowledge on the occurrence of AIV in South America is still limited and there are important gaps in the species and geographic distribution of the sampling effort.

Although duodenal biopsy is suggested as the gold standard method for diagnosis of coeliac disease (CD), high levels of immunoglobulin A anti-tissue transglutaminase (IgA anti-TTG) followed by positivity for immunoglobulin A anti-endomysial (IgA anti-EMA) have been used widely for the diagnosis. In this study, we tested the hypothesis that IgA anti-TTG and IgA anti-EMA tests are useful for diagnosis of CD, without need for endoscopy and duodenal biopsy.

CD diagnosis was made with IgA anti-TTG >10 U/mL and IgA anti-EMA positivity in presence of villous atrophy. Receiver operating characteristic (ROC) analysis was performed to establish the cut-off values of the IgA anti-TTG that could predict the presence of IgA anti-EMA positivity and villous atrophy from histology results.

The cut-off values for IgA anti-TTG that predict positivity for IgA anti-EMA (sensitivity: 89.7%; specificity: 82%; positive predictive value: 92.4%) and villous atrophy (sensitivity: 88.9%; specificity: 78.5%; positive predictive value: 92.9%) were 17 and 30 U/mL, respectively.

Serological testing can be used with high sensitivity and specificity for diagnosis of CD, without biopsy and histology. This significantly improves the timeliness and effectiveness of CD diagnosis.

Background and Aims: The role of miR-34a in hepatocellular carcinoma (HCC) is controversial and several unresolved issues remain, including its expression pattern and relevance to tumor etiology, tumor stage and prognosis, and finally, its impact on apoptosis.

Methods: miR-34a expression was assessed in hepatitis C virus (HCV)-induced non-metastatic HCC tissues by RT-Q-PCR. Huh-7 cells were transfected with miR-34a mimics and the impact of miR-34a was examined on 84 pro-apoptotic/anti-apoptotic genes using PCR array; its net effect was tested on cell viability via MTT assay.

Results: miR-34a expression was up-regulated in HCC tissues. Moreover, miR-34a induced a large set of pro-apoptotic/anti-apoptotic genes, with a net result of triggering apoptosis and repressing cell viability.

Conclusions: HCC-related differential expression of miR-34a could be etiology-based or stage-specific, and low expression of miR-34a may predict poor prognosis. This study’s findings also emphasize the role of miR-34a in apoptosis.

Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease.

Methods: We performed a cross-sectional study of patients with liver disease at the Pfleger Liver Institute at the University of California, Los Angeles between June 2015 and August 2016. Patients completed a demographic questionnaire and an acetaminophen knowledge survey. Additional information was obtained from the medical record.

Results: Of 401 patients with liver disease, 30 (15.7%) were able to correctly identify that people without liver disease can safely take up to 4 g/day of acetaminophen. The majority of patients (79.9%–86.8%) did not know that Norco® (hydrocone/acetaminophen), Vicodin® (hydrocone/acetaminophen) and Percocet® (oxycodone/acetaminophen) contained acetaminophen. Only 45.3% of the patients knew that Tylenol® #3 contained acetaminophen.

Conclusions: We conclude that patients with liver disease have critically low levels of knowledge of acetaminophen, putting them at risk both of acetaminophen overdose, as well as undermedication, and inadequate management of chronic pain. We recommend an increase in education efforts regarding acetaminophen dosage and its safety in the setting of liver disease. Increasing education for those at risk of low acetaminophen knowledge is essential to minimizing acetaminophen overdose rates and optimizing pain management.

Background and Aims: During recent years, the relationship between vitamin D levels and chronic hepatitis B (CHB) infection has attracted many researchers’ attention. However, the results relating to the association of vitamin D levels and HBV infection have been conflicting and there remains a lack of knowledge about the effects of antiviral treatments on vitamin D level.

Methods: Eighty-four patients with CHB were assessed and divided into three groups: inactive carriers (n = 28), treated (n = 34), and new (treatment-naïve) cases (n = 22). Thirty-two healthy controls (HCs) were included to enable comparison with the CHB groups. The levels of vitamin D3 were measured and statistically compared among the various groups.

Results: Male subjects had higher levels of vitamin D3 (41.25 vs 28.85, p < 0.01). No association was found among any of the groups when compared with the HC group. Despite the significant association, the HCs demonstrated a higher level of vitamin D3, which was lower in the treated group, the inactive carrier group, and the new cases group (new case [29.82] < inactive carrier [32.91] < treated [39.56] < control [44.88]). The HBV DNA levels were not associated with vitamin D3 levels in the inactive carriers (p = 0.171), the treated groups (p = 0.192), and the new cases (p = 0.369). Moreover, the alanine transaminase and aspartate transaminase levels were not associated with vitamin D3 levels for any of the HBV-infected groups.

Conclusions: Vitamin D3 contributes to the clinical statues of CHB patients. There is also a possible correlation between clinically healthy CHB patients and vitamin D3 level.

Background and Aims: Intermediate stage hepatocellular carcinoma (HCC) can be treated by transarterial chemoembolization (TACE). However, there appear to be side effects, such as induction of proangiogenic factors, e.g. vascular endothelial growth factor (VEGF), which have been shown to be associated with a poor prognosis. This prospective study was designed to compare serum VEGF level response after TACE with different embolic agents in patients with HCC.

Methods: Patients were assigned to one of three different TACE regimens: degradable starch microspheres (DSM) TACE, drug-eluting bead (DEBDOX) TACE or Lipiodol TACE (cTACE). All patients received 50 mg doxorubicin/m2 body surface area (BSA) during TACE. Serum VEGF levels were assessed before TACE treatment, 24 h post-treatment and 4 weeks later.

Results: Twenty-two patients with 30 TACE treatments were enrolled. Compared to baseline VEGF levels, a marked increase was observed for 24 h post-TACE (164% of baseline level) and during the 4-week follow-up (170% of baseline level) only for the cTACE arm (p < 0.05). In contrast, the increase of serum VEGF levels were only 114% and 123% for DEBDOX and 121% and 124% for DSM, respectively.

Conclusions: Conventional TACE using Lipiodol shows marked increase in blood levels of the proangiogenic factor VEGF, while DEBDOX and DSM TACE induce only a moderate VEGF response.

Prevalence of hepatitis C virus (HCV) infection is high in patients with end-stage renal dysfunction, including patients undergoing hemodialysis (HD). The HCV infection itself can cause glomerulonephritis and puts individuals at increased risk of developing end-stage renal disease; fortunately, successful HCV eradication sometimes restore HCV-related renal dysfunction. Moreover, the prognosis of dialysis patients infected with HCV is significantly worse and the renal allograft survival in HCV-infected patients is also worse than in dialysis patients without HCV infection. If life prognosis is favorable, therefore, anti-HCV therapy is strongly recommended for HCV-infected patients with severe renal dysfunction. The standard therapy for HCV-infected patients with severe renal dysfunction has historically been interferon-based therapy. However, this therapy remains ineffective in achieving high, sustained viral response rates and the rate of adverse events and treatment discontinuation due to treatment-induced adverse events continues to be high in patients with severe renal dysfunction. Safe and effective anti-HCV therapies are urgently needed, and crucial, for patients with severe renal dysfunction. Recently, direct-acting antivirals (DAAs) that specifically target viral proteins have been developed, and these targets include the NS3, NS5A, and NS5B of HCV. Clinical trials have revealed high efficacy and safety of the DAA-based therapies, but patients with severe renal dysfunction were not included in the majority of these trials. However, several recent reports have shown high efficacy and safety for some regimens of DAA combination therapy for HCV-infected patients with severe renal dysfunction. In this review, we discuss novel treatments for HCV-infected patients with severe renal dysfunction and the pharmacokinetics of these drugs.

Aims: To examine the regulation of SREBP-1c and CAV1 by microRNA-29a (miR-29a) in cells infected with hepatitis C virus (HCV) in an attempt to control HCV-induced non-alcoholic fatty liver disease.

Methods: In order to examine the manipulation of SREBP-1c and CAV1 by miR-29a, oleic acid (OA)-treated JFH-I-infected Huh-7 cells were used. OA was added 24 h post-transfection and gene expression was investigated by qRT-PCR at 48 h post treatment. The functional impact of the observed alteration in SREBP-1c and CAV1 expression was analyzed by examining lipid droplet (LD) and triglyceride (TG) content at 72 h post-OA treatment using light microscopy and spectrophotometry, respectively. Viral load was quantified by qRT-PCR at 72 h post-transfection.

Results: OA treatment induced the expression of miR-29a and SREBP-1c, as compared to untreated cells. Forced miR-29a expression led to a significant up-regulation of SREBP-1c as well as CAV1 compared to mock untransfected cells. Ectopic expression of miR-29a resulted in a marked increase in LDs and their respective TGs, while miR-29a antagomirs decreased both the LD and TG content compared to mock untransfected cells. Moreover, forcing the expression of miR-29a in JFH-1 HCV-infected Huh-7 cells resulted in 53% reduction in viral titers compared to mock untransfected Huh-7 cells.

Conclusion: Inducing miR-29a expression significantly induces SREBP-1c and CAV1 expression, thereby increasing LDs as well as their respective TGs. Nonetheless, forcing the expression of miR-29a resulted in reduction of HCV RNA levels in Huh-7 cells.