Viral hepatitis remains a significant worldwide threat, in spite of the availability of several successful therapeutic and vaccination strategies. Complications associated with acute and chronic infections, such as liver failure, cirrhosis and hepatocellular carcinoma, are the cause of considerable morbidity and mortality. Given the significant burden on the healthcare system caused by viral hepatitis, it is essential that novel, more effective therapeutics be developed. The present review attempts to summarize the current treatments against viral hepatitis, and provides an outline for upcoming, promising new therapeutics. Development of novel therapeutics requires an understanding of the viral life cycles and viral effectors in molecular detail. As such, this review also discusses virally-encoded effectors, found to be essential for virus survival and replication in the host milieu, which may be utilized as potential candidates for development of alternative therapies in the future.

Background and Aims: Utilization of living donor liver transplantation (LDLT) and its relationship with recipient Model for End-Stage Liver Disease (MELD) needs further evaluation in the United States (U.S.). We evaluated the association between recipient MELD score at the time of surgery and survival following LDLT.

Methods: All U.S. adult LDLT recipients with MELD < 25 were evaluated using the 1995–2012 United Network for Organ Sharing registry. Survival following LDLT was stratified into three MELD categories (MELD < 15 vs. MELD 15–19 vs. MELD 20–24) and evaluated using Kaplan-Meier methods and multivariate Cox proportional hazards models.

Results: Overall, 2,258 patients underwent LDLT. Compared to patients with MELD < 15, overall 5-year survival following LDLT was similar among patients with MELD 15–19 (80.9% vs. 80.3%, p = 0.77) and MELD 20–24 (81.2% vs. 80.3%, p = 0.73). When compared to patients with MELD < 15, there was no significant difference in long-term post-LDLT survival among those with MELD 15–19 (HR: 1.11, 95% CI: 0.85−1.45, p = 0.45) and a non-significant trend towards lower survival in patients with MELD 20–24 (HR: 1.28, 95% CI: 0.91−1.81, p = 0.16). Only 14% of LDLTs were performed in patients with MELD 20–24 and the remaining 86% in patients with MELD < 20.

Conclusion: LDLT is underutilized in patients with MELD 20 and higher.

Folate is a UV-labile vitamin, critical to maintenance of DNA synthesis and repair mechanisms. Evidence supports a number of folate-dependent enzymes as being UV-responsive, suggesting that the activity of pathways operating through such enzymes may differ between geographic areas of varied UV exposure. Therefore, we explored the possible association of global UV levels with the prevalence of common polymorphisms in folate-metabolism enzymes.

Data from the PubMed electronic database was collated for the polymorphisms MTHFR-C677T, MTHFR-A1298C, cSHMT-C1420T, TYMS 28bp 2R>3R, TYMS 3′UTR ins/del and DHFR 19bp deletion. Data extracted were analysed by the latitude of the study locations, as a surrogate measure of population UV exposure.

Frequency of the MTHFR-C677T and MTHFR-A1298C polymorphisms was positively associated with latitude, while a negative association was observed between latitude and frequency of the cSHMT-C1420T and TYMS 28bp 2R>3R variants.

These findings provide novel evidence suggestive of folate genotypes being selected to maintain homeostasis between folate-dependent de novo thymidylate synthesis and methylation pathways in environments of differing UV levels. To the authors’ knowledge, this is the first study to report significant associations between latitude and the occurrence of MTHFR-A1298C, TYMS 28bp 2R>3R and cSHMT-C1420T polymorphisms. On-going studies are required to further explore the biological significance of these findings.

Diabetes is growing as an epidemic, with around 250 million diabetics estimated globally and which is expected to rise up to 380 million in the next 15 years. Differences in the efficacy and toxicity of various antidiabetic drugs have been linked to polymorphisms in various drug metabolizing enzymes. In this study we have investigated the frequency of occurrence of two single nucleotide polymorphisms in the CYP gene (CYP2C8*3 and CYP2C9*2) in type 2 diabetes mellitus (T2DM) patients from North India.

This study included 360 T2DM patients from North India. Real-time polymerase chain reaction was carried out for the evaluation of specific CYP450 gene polymorphisms via the specific TaqMan® SNP genotyping assays (Applied Biosystems Inc.) for detection of CYP2C8*3 (rs10509681) and CYP2C9*2 (rs1799853) polymorphisms in the CYP450 gene.

For the CYP2C8*3 polymorphism, the genotype frequencies detected were 0%, 92.78% and 7.22% for CC, TT and CT genotypes while the frequency of the C allele was 3.61% and that of the T allele was 96.39%. For the CYP2C9*2 (rs1799853) polymorphism, the frequencies were 3.1%, 12.5% and 84.44% for CC, AA and CA genotypes. The frequency of occurrence of A and C alleles were 54.72% and 45.28% respectively.

Frequency of occurrence of the T and A alleles of CYP2C8*3 (rs10509681) and CYP2C9*2 (rs1799853) polymorphisms was higher in T2DM patients from North India.

Hypoxic hepatitis (HH), also known as ischemic hepatitis or shock liver, is characterized by a massive, rapid rise in serum aminotransferases resulting from reduced oxygen delivery to the liver. The most common predisposing condition is cardiac failure, followed by circulatory failure as occurs in septic shock and respiratory failure. HH does, however, occur in the absence of a documented hypotensive event or shock state in 50% of patients. In intensive care units, the incidence of HH is near 2.5%, but has been reported as high as 10% in some studies. The pathophysiology is multifactorial, but often involves hepatic congestion from right heart failure along with reduced hepatic blood flow, total body hypoxemia, reduced oxygen uptake by hepatocytes or reperfusion injury following ischemia. The diagnosis is primarily clinical, and typically does not require liver biopsy. The definitive treatment of HH involves correction of the underlying disease state, but successful management includes monitoring for the potential complications such as hypoglycemia, hyperglycemia, hyperammonemia and hepatopulmonary syndrome. Prognosis of HH remains poor, especially for cases in which there was a delay in diagnosis. The in-hospital mortality rate is >50%, and the most frequent cause of death is the predisposing condition and not the liver injury itself.

From an epidemiological point of view, hepatitis E is an old infection in Iran, but only recently has its importance as a public health concern been considered from research and public health standpoints. As such, there is still a long road ahead to clarify the real burden of hepatitis E virus (HEV) infection in Iran. According to the available epidemiological studies, the seroprevalence of HEV infection among pregnant women is between 3.6% and 7.4%, and among Iranian children is between 0.9% to 8.5%, varying by geographic regions within the country and directly dependent upon the sanitary status of each. In addition to evaluating the sanitation level of a society, community-based seroprevalence studies of HEV infection demonstrate the most prevalent risk factors, the major routes of transmission, and the epidemiological patterns of HEV among that country’s population. In this review, the current knowledge about the pathogenesis and epidemiology of HEV infection in pregnant women and children in Iran, as well as the recent advances in diagnosis, prevention and treatment of HEV infection have been summarized.

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease caused by diffuse inflammation, destruction and fibrosis of the intrahepatic bile ducts, ultimately leading to cirrhosis, portal hypertension and liver failure. The pathogenesis of PBC is incompletely understood, but current data suggest roles for genetic susceptibility and environmental factors. PBC is often thought of as an organ-specific autoimmune disease, which mainly targets the liver; however, lung tissue is also a site for autoimmune involvement of PBC. The pulmonary manifestations of PBC include abnormalities in gas transfer and pulmonary function, subclinical alveolitis, interstitial lung disease, granulomatous lung disease, airway disease, pulmonary hypertension, pulmonary hemorrhage and pleural effusion.

With 185 million people chronically infected globally, hepatitis C is a leading bloodborne infection. All-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more tolerable. However, trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ transplantation. Yet, these patients—most often suffering from malignancy or autoimmune diseases—could stand to benefit from these treatments. In this study, we systematically review the literature on the treatment of hepatitis C in these neglected populations. Research on patients with organ transplants is more robust and this literature is reviewed here non-systematically. Our systematic review produced 2273 unique works, of which 56 met our inclusion criteria and were used in our review. The quality of data was low; only 3 of the 56 studies were randomized controlled trials. Sustained virologic response was reported sporadically. Interferon-containing regimens achieved this end-point at rates comparable to that in immunocompetent individuals. Severe adverse effects and death were rare. Data on all-oral regimens were sparse, but in the most robust study, rates of sustained virologic response were again comparable to immunocompetent individuals (40/41). Efficacy and safety of interferon-containing regimens and all-oral regimens were similar to rates in immunocompetent individuals; however, there were few interventional trials. The large number of case reports and case series makes conclusions vulnerable to publication bias. While firm conclusions are challenging, given the dearth of high-quality studies, our results demonstrate that antiviral therapy can be safe and effective. The advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side effects. Preliminary data reveal that these regimens may confer such benefits in immunosuppressed individuals as well. More prospective interventional trials would greatly benefit the many patients with chronic hepatitis C on immunosuppressive therapies.

Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions.

Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles.

Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited to minor gastrointestinal complaints (most often, diarrhea) and did not occur at increased frequency as compared to controls. As administration of bile acids was often limited to durations of 12 months or less, long-term side effects for non-cholestatic indications cannot be excluded.

Conclusions: Based on the available literature, bile acids cannot be widely recommended for non-cholestatic liver diseases at present.

Hepatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM) present a significant health burden, with increasing complications and mortality rates worldwide. Pycnogenol® (PYC), a natural product, possesses antidiabetic and antiviral properties that may improve HCV-associated T2DM. In this review, we present previously published data on the effectiveness of PYC against HCV replication and T2DM. We believe that supplementing conventional treatment with PYC may improve the current HCV therapy, attenuate HCV-associated T2DM, and reduce the risk of complications such as cirrhosis or hepatocellular carcinoma and cardiovascular disease.

Drug-induced liver injury is a rare but clinically important diagnosis. Vedolizumab is an α4β7 integrin inhibitor recently approved for use in patients with moderate-to-severe inflammatory bowel disease. Cases of hepatoxicity due to vedolizumab in the pre-marketing stage were rare, and all cases resolved upon drug withdrawal. We present here the first reported case of hepatotoxicity attributable to vedolizumab, which despite drug cessation persisted with chronic cholestatic liver injury.

Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease. Methods: Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) and NAFLD were included. Pooled data are reported as odds ratios (ORs) with 95% confidence intervals. Results: Of 393 potentially relevant studies, 35 on NAFLD were included in the analysis. Compared to healthy controls, the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL) were 1.46 (1.16–1.85) and 2.76 (2.30–3.13), and were 1.75 (1.24–2.46) and 4.44 (2.92–6.76) among patients with non-alcoholic steatohepatitis respectively. The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90–6.13) and 5.05 (1.47–17.29) when comparing non-alcoholic hepatocellular carcinoma to NAFL patients. Among the NAFLD patients, the ORs for G allele frequency when comparing steatosis grade 2–3 to grade 0–1 NAFL, when comparing the NAFLD activity score of ≥ 4 to score ≤ 3, when comparing NASH to NAFLD, when comparing the presence of lobular inflammation to absence, and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43–3.80), 1.80 (1.36–2.37), 1.66 (1.42–1.94), 1.58 (1.19–2.10), and 2.63 (1.87–3.69) respectively. Subgroup analysis based on ethnicity showed similar results. Conclusions:PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs. PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.

Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. It encompasses a spectrum of disease, including fatty liver disease, alcoholic hepatitis (AH), and alcoholic cirrhosis. AH can range from mild to severe disease, with severe disease being defined as: Discriminant Function (DF) ≥ 32, or Model for End-stage Liver Disease (MELD) ≥ 21, or presence of hepatic encephalopathy. Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. Besides alcohol cessation, corticosteroids have been used with conflicting results and are associated with an inherent risk of infection. Overall steroids have shown short term benefit when compared to placebo, but they have no obvious long term benefits. Pentoxifylline does not improve survival in patients with severe AH and is no longer recommended based on the results of the STOPAH (Steroid Or Pentoxifylline for Alcoholic Hepatitis) trial. Anti-tumor necrosis factor (TNF) agents are associated with increased risk of life threatening infections and death. Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). Future treatment may lie in human induced pluripotent stem cell (iPSC) technology, which is currently under investigation for the study of pathogenesis, drug discovery, and stem cell transplantation. Liver transplantation has been reported with good results in highly selected patients but is controversial due to limited organ supply.

Background: Hepatitis C (HCV) direct acting antiviral agents (DAAs) are safe, effective, and tolerable. Most contraindications to interferon-based treatment are no long applicable. The aims of this study were to understand the predictors of approval to drug accessibility.

Methods: We studied all consecutive patients with HCV prescribed DAAs between October 2014 and July 2015. Data on demographic, socio-economic status, comorbidities, baseline laboratory values, and assessment of liver disease severity, insurance, and specialty pharmacy type were collected. Multivariate analyses were performed to identify predictors of prescription approval.

Results: In total, 410 patients were prescribed DAAs between October 2014 and July 2015. Of those, 332 (81%) patients were insurance approved for therapy. Of the 332 patients accepted, 251 were accepted after the first prescription attempt, and 38 were accepted after the second and third attempts. The number of attempts for the other 43 approved patients was unknown. Older age (p = 0.001), employment (p = 0.001), lack of comorbidities (p = 0.02), liver transplantation (p = 0.018), and advanced liver disease (p = 0.001) were more likely associated with obtaining approval. Household income was not associated with insurance approval. In the multivariate analysis, Medicare insurance (odds ratio [OR]) 2.67, 95% confidence interval [CI] 0.96–7.20), lack of nonliver comorbidities (OR 2.72, 95% CI 1.35–5.43), and the presence of advanced liver disease (OR 1.82, 95% CI 1.04–3.24) independently predicted drug approval.

Conclusion: Despite the availability of DAAs for HCV, barriers from insurance carriers continue to impair widespread use. Patients with advanced liver disease, Medicare, and without comorbidities are most likely to be insurance approved for DAAs.

Hepatic abscess (HA) remains a serious and often difficult to diagnose problem. HAs can be divided into three main categories based on the underlying conditions: infectious, malignant, and iatrogenic. Infectious abscesses include those secondary to direct extension from local infection, systemic bacteremia, and intra-abdominal infections that seed the portal system. However, over the years, the etiologies and risks factors for HA have continued to evolve. Prompt recognition is important for instituting effective management and obtaining good outcomes.

Background and Aims: Previous studies have shown increased hepatic decompensation in patients with cirrhosis undergoing surgery. However, there are little data available in cirrhotics undergoing orthopedic surgery compared to cirrhotics who did not undergo surgery. The aim of this study was to examine the demographics, comorbid conditions, and clinical factors associated with hepatic decompensation within 90 days in cirrhotics who underwent orthopedic surgery. Methods: This is a retrospective matched cohort study. Inclusion criteria were cirrhosis diagnosis, age > 18 years, ≥ 6 months continuous health plan membership, and a procedure code for orthopedic surgery. Up to five cirrhotic controls without orthopedic surgery were matched on age, gender, and cirrhosis diagnosis date. Data abstraction was performed for demographics, socioeconomics, clinical, and decompensation data. Chart review was performed for validation. Multivariable analysis estimated relative risk of decompensation. Results: Eight hundred fifty-three orthopedic surgery cases in cirrhotics were matched with 4,263 cirrhotic controls. Among the cases and matched controls, the mean age was 60.5 years, and 52.2% were female. Within 90 days after surgery, cases had more decompensation compared to matched controls (12.8% vs 4.9%). Using multivariable analysis, orthopedic surgery, a 0.5 g/dL decrease in serum albumin, and a 1-unit increase in Charlson Comorbidity Index were associated with a significant increase in decompensation within 90 days of surgery. Diabetes, chronic obstructive pulmonary disease, and chronic kidney disease were seen with increased frequency in cases vs. matched controls. Conclusions: Cirrhotics who underwent orthopedic surgery had a significant increase in hepatic decompensation within 90 days of surgery compared to matched controls. An incremental decrease in serum albumin and an incremental increase in the Charlson Comorbidity Index were significantly associated with hepatic decompensation after surgery.

Viral infection in the liver, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, is a major health problem worldwide, especially in developing countries. The infection triggers a pro-inflammatory response in patients that is crucial for host defense. Recent studies have identified multiple transmembrane and cytosolic receptors that recognize pathogen-derived nucleic acids, and these receptors are essential for driving immune activation in the liver. In addition to sensing DNA/RNA from pathogens, these intracellular receptors can be activated by nucleic acids of host origin in response to sterile injuries. In this review, we discuss the expanding roles of these receptors in both immune and nonimmune cells in the liver.