Physical activity and liver diseases

Regular physical activity beneficially impacts the risk of onset and progression of several chronic diseases. However, research regarding the effects of exercising on chronic liver diseases is relatively recent. Most authors focused on non-alcoholic fatty liver disease (NAFLD), in which increasing clinical and experimental data indicate that skeletal muscle cross-talking to the adipose tissue and the liver regulates intrahepatic fat storage. In this setting physical activity is considered required in combination with calories restriction to allow an effective decrease of intrahepatic lipid component, and despite that evidence is not conclusive, some studies suggest that vigorous activity might be more beneficial than moderate activity to improve NAFLD/NASH. Evidence regarding the effects of exercise on the risk of hepatocellular carcinoma is scarce; some epidemiological studies indicate a lower risk in patients regularly and vigorously exercising. In compensated cirrhosis exercise acutely increases portal pressure, but in longer term it has been proved safe and probably beneficial. Decreased aerobic capacity (VO2) correlates with mortality in patients with decompensated cirrhosis, who are almost invariably sarcopenic. In these patients VO2 is improved by physical activity, which might also reduce the risk of hepatic encephalopathy through an increase in skeletal muscle mass. In solid organ transplantation recipients exercise is able to improve lean mass, muscle strength and as a consequence, aerobic capacity. Few data exist in liver transplant recipients, in whom exercise should be object of future studies given its high potential of providing long-term beneficial effects. Despite evidence is far from complete, physical activity should be seen as an important part of the management of patients with liver disease in order to improve their clinical outcome. This article is protected by copyright. All rights reserved.

Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared to their pre-treatment values (within 6 six months prior to the start of therapy). All registered platelet count measurements from 24 week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 x10(9) /L (IQR 7-62, p<0.001). In comparison, patients without SVR showed a median decline of 17 x10(9) /L (IQR -5-47, p<0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, p<0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R=-0.41, p<0.001). CONCLUSIONS Among chronic HCV-infected patients with advanced hepatic fibrosis the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure. This article is protected by copyright. All rights reserved.

The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment.

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies.

Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: A Problem of Growing Magnitude.

Hepatocellular carcinoma (HCC) is a cancer with globally rising incidence. Growing evidence supports associations between metabolic syndrome and diabetes as well as obesity and HCC arising in patients with nonalcoholic fatty liver disease (NAFLD). This constitutes a problem of alarming magnitude given the rising epidemic of these conditions. The role of diabetes seems to be particularly important when associated with obesity or cirrhosis. Excess hepatic iron may be another potential risk factor for the development of NAFLD-associated HCC. In the context of NAFLD, HCC frequently develops in a not-yet cirrhotic liver. As there are no surveillance programs for these patients, diagnosis often occurs at a tumor stage beyond curative options. Clinical, tumor, and patient characteristics in NAFLD-associated HCC differ from other etiologies. Older age and cardiovascular comorbidities may limit treatment options further. The outcome in patients with NAFLD-associated early HCC is excellent and therefore aggressive treatment should be pursued in appropriate patients. Population-based prevention to reduce the culprit-NAFLD-early recognition through targeted surveillance programs in risk-stratified patients and effective treatment of HCC associated with NAFLD are urgently needed. In this review, the authors summarize the epidemiology, risk factors, features, and prevention of NAFLD-associated HCC.

Hepatocellular carcinoma and lifestyles.

The majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to non-alcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and non-alcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.

Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials

BACKGROUND & AIMS Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials. METHODS Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I(2) as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing. RESULTS Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8-82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference -0.026; 95% CI-0.052 to -0.001; number needed to treat 38 patients). There was no heterogeneity (I(2) = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD -0.011; 95% CI -0.040 to 0.017). CONCLUSIONS Non-selective beta-blockers may prevent HCC in patients with cirrhosis.

Results of the Questionnaire

Early diagnosis of patients with compensated advanced chronic liver disease (cACLD) and portal hypertension is challenging in clinical practice. A growing amount of evidence regarding noninvasive diagnostic methods, and in particular liver stiffness measurement (LSM), suggests that these tools could be used in clinical practice and might potentially limit the use of invasive, reference diagnostic tools (HVPG measurement and endoscopy). Our panel aimed at better understanding the opinion of the Baveno faculty regarding the current practice and use of invasive and noninvasive methods in the field of screening and surveillance of varices; a specific questionnaire was electronically sent to all the faculty members. The results suggested that the experts agreed on the use of noninvasive methods to rule out/identify patients with cACLD. They also indicated that the persistence or removal of the causal agent which led to cirrhosis should guide the choice of using the shortest or the longest interval among those recommended for surveillance endoscopies. Finally, the use of noninvasive methods in these clinical scenarios was pointed out as a relevant field for future research.

ENaC activity in collecting ducts modulates NCC in cirrhotic mice.

Cirrhosis is a frequent and severe disease, complicated by renal sodium retention leading to ascites and oedema. A better understanding of the complex mechanisms responsible for renal sodium handling could improve clinical management of sodium retention. Our aim was to determine the importance of the amiloride-sensitive epithelial sodium channel (ENaC) in collecting ducts in compensate and decompensate cirrhosis. Bile duct ligation was performed in control mice (CTL) and collecting duct-specific αENaC knockout (KO) mice, and ascites development, aldosterone plasma concentration, urinary sodium/potassium ratio and sodium transporter expression were compared. Disruption of ENaC in collecting ducts (CDs) did not alter ascites development, urinary sodium/potassium ratio, plasma aldosterone concentrations or Na,K-ATPase abundance in CCDs. Total αENaC abundance in whole kidney increased in cirrhotic mice of both genotypes and cleaved forms of α and γ ENaC increased only in ascitic mice of both genotypes. The sodium chloride cotransporter (NCC) abundance was lower in non-ascitic KO, compared to non-ascitic CTL, and increased when ascites appeared. In ascitic mice, the lack of αENaC in CDs induced an upregulation of total ENaC and NCC and correlated with the cleavage of ENaC subunits. This revealed compensatory mechanisms which could also take place when treating the patients with diuretics. These compensatory mechanisms should be considered for future development of therapeutic strategies.

Bayesian joint modeling of longitudinal and survival data

The joint modeling of longitudinal and survival data is a new approach to many applications such as HIV, cancer vaccine trials and quality of life studies. There are recent developments of the methodologies with respect to each of the components of the joint model as well as statistical processes that link them together. Among these, second order polynomial random effect models and linear mixed effects models are the most commonly used for the longitudinal trajectory function. In this study, we first relax the parametric constraints for polynomial random effect models by using Dirichlet process priors, then three longitudinal markers rather than only one marker are considered in one joint model. Second, we use a linear mixed effect model for the longitudinal process in a joint model analyzing the three markers. In this research these methods were applied to the Primary Biliary Cirrhosis sequential data, which were collected from a clinical trial of primary biliary cirrhosis (PBC) of the liver. This trial was conducted between 1974 and 1984 at the Mayo Clinic. The effects of three longitudinal markers (1) Total Serum Bilirubin, (2) Serum Albumin and (3) Serum Glutamic-Oxaloacetic transaminase (SGOT) on patients' survival were investigated. Proportion of treatment effect will also be studied using the proposed joint modeling approaches. ^ Based on the results, we conclude that the proposed modeling approaches yield better fit to the data and give less biased parameter estimates for these trajectory functions than previous methods. Model fit is also improved after considering three longitudinal markers instead of one marker only. The results from analysis of proportion of treatment effects from these joint models indicate same conclusion as that from the final model of Fleming and Harrington (1991), which is Bilirubin and Albumin together has stronger impact in predicting patients' survival and as a surrogate endpoints for treatment. ^

Hepatitis B vaccination of high risk pregnant women: A clinical trial at Parkland Memorial Hospital

Hepatitis B infection is a major public health problem of global proportions. It is estimated that 2 billion people worldwide are infected by the Hepatitis B virus (HBV) at some point, and 350 million are chronic carriers. The Centers for Disease Control and Prevention (CDC) report an incidence in the United States of 140,000–320,000 infections each year (asymptomatic and symptomatic), and estimate 1–1.25 million people are chronically infected. Hepatitis B and its chronic complications (cirrhosis of the liver, liver failure, hepatocellular carcinoma) responsible for 4,000–5,000 deaths in America each year. ^ One quarter of those who become chronic carriers develop progressive liver disease, and chronic HBV infection is thought to be responsible for 60 million cases of cirrhosis worldwide, surpassing alcohol as a cause of liver disease. Since there are few treatment options for the person chronically infected with Hepatitis B, and what is available is expensive, prevention is clearly best strategy for combating this disease. ^ Since the approval of the Hepatitis B vaccine in 1981, national and international vaccination campaigns have been undertaken for the prevention of Hepatitis B. Despite encouraging results, however, studies indicate that prevalence rates of Hepatitis B infection have not been significantly reduced in certain high risk populations because vaccination campaigns targeting those groups do not exist and opportunities for vaccination by individual physicians in clinical settings are often missed. Many of the high-risk individuals who go unvaccinated are women of childbearing age, and a significant proportion of these women become infected with the Hepatitis B virus (HBV) during pregnancy. Though these women are often seen annually or for prenatal care (because of the close spacing of their children and their high rate of fertility), the Hepatitis B vaccine series is seldom recommended by their health care provider. In 1993, ACOG issued a statement recommending Hepatitis B vaccination of pregnant women who were defined as high-risk by diagnosis of a sexually transmitted disease. ^ Hepatitis B vaccine has been extensively studied in the non-pregnant population. The overall efficacy of the vaccine in infants, children and adults is greater than 90%. In the small clinical trials to date, the vaccine seemed to be effective in those pregnant women receiving 3 doses; however, by using the usual 0, 1 and 6 month regimen, most pregnant women were unable to complete a full series during pregnancy. There is data now available supporting the use of an "accelerated" dosing schedule at 0, 1 and 4 months. This has not been evaluated in pregnant women. A clinical trial proving the efficacy of the 0, 1, 4 schedule and its feasibility in this population would add significantly to the body of research in this area, and would have implications for public health policy. Such a trial was undertaken in the Parkland Memorial Hospital Obstetrical Infectious Diseases clinic. In this study, the vaccine was very well tolerated with no major adverse events reported, 90% of fully vaccinated patients achieved immunity, and only Body Mass Index (BMI) was found to be a significant factor affecting efficacy. This thesis will report the results of the trial and compare it to previous trials, and will discuss barriers to implementation, lessons learned and implications for future trials. ^

Cost-effectiveness analysis of a 2-stage community-based hepatocellular carcinoma screening program in Taiwan

Hepatocellular carcinoma (HCC) has been ranked as the top cause of death due to neoplasm malignancy in Taiwan for years. The high incidence of HCC in Taiwan is primarily attributed to high prevalence of hepatitis viral infection. Screening the subjects with liver cirrhosis for HCC was widely recommended by many previous studies. The latest practice guideline for management of HCC released by the American Association for the Study of Liver Disease (AASLD) in 2005 recommended that the high risk groups, including cirrhotic patients, chronic HBV/HCV carriers, and subjects with family history of HCC and etc., should undergo surveillance.^ This study aims to investigate (1) whether the HCC screening program can prolong survival period of the high risk group, (2) what is the incremental cost-effectiveness ratio of the HCC screening program in Taiwan, as compared with a non-screening strategy from the payer perspective, (3) which high risk group has the lowest ICER for the HCC screening program from the insurer's perspective, in comparison with no screening strategy of each group, and (4) the estimated total cost of providing the HCC screening program to all high risk groups.^ The high risk subjects in the study were identified from the communities with high prevalence of hepatitis viral infection and classified into three groups (cirrhosis group, early cirrhosis group, and no cirrhosis group) at different levels of risk to HCC by status of liver disease at the time of enrollment. The repeated ultrasound screenings at an interval of 3, 6, and 12 months were applied to cirrhosis group, early cirrhosis group, and no cirrhosis group, respectively. The Markov-based decision model was constructed to simulate progression of HCC and to estimate the ICER for each group of subjects.^ The screening group had longer survival in the statistical results and the model outcomes. Owing to the low HCC incidence rate in the community-based screening program, screening services only have limited effect on survival of the screening group. The incremental cost-effectiveness ratio of the HCC screening program was $3834 per year of life saved, in comparison with the non-screening strategy. The estimated total cost of each group from the screening model over 13.5 years approximately consumes 0.13%, 1.06%, and 0.71% of total amount of adjusted National Health Expenditure from Jan 1992 to Jun 2005. ^ The subjects at high risk of developing HCC to undergo repeated ultrasound screenings had longer survival than those without screening, but screening was not the only factor to cause longer survival in the screening group. The incremental cost-effectiveness ratio of the 2-stage community-based HCC screening program in Taiwan was small. The HCC screening program was worthy of investment in Taiwan. In comparison with early cirrhosis group and no cirrhosis group, cirrhosis group has the lowest ICER when the screening period is less than 19 years. The estimated total cost of providing the HCC screening program to all high risk groups consumes approximately 1.90% of total amount of adjusted 13.5-year NHE in Taiwan.^

Hepatitis B and C infections in U.S. incarcerated populations: Prevalence and related mortality

Published reports have consistently indicated high prevalence of serologic markers for hepatitis B (HBV) and hepatitis C (HCV) infection in U.S. incarcerated populations. Quantifying the current and projected burden of HBV and HCV infection and hepatitis-related sequelae in correctional healthcare systems with even modest precision remains elusive, however, because the prevalence and sequelae of HBV and HCV in U.S. incarcerated populations are not well-studied. This dissertation contributes to the assessment of the burden of HBV and HCV infections in U.S. incarcerated populations by addressing some of the deficiencies and gaps in previous research. ^ Objectives of the three dissertation studies were: (1) To investigate selected study-level factors as potential sources of heterogeneity in published HBV seroprevalence estimates in U.S. adult incarcerated populations (1975-2005), using meta-regression techniques; (2) To quantify the potential influence of suboptimal sensitivity of screening tests for antibodies to hepatitis C virus (anti-HCV) on previously reported anti-HCV prevalence estimates in U.S. incarcerated populations (1990-2005), by comparing these estimates to error-adjusted anti-HCV prevalence estimates in these populations; (3) To estimate death rates due to HBV, HCV, chronic liver disease (CLD/cirrhosis), and liver cancer from 1984 through 2003 in male prisoners in custody of the Texas Department of Criminal Justice (TDCJ) and to quantify the proportion of CLD/cirrhosis and liver cancer prisoner deaths attributable to HBV and/or HCV. ^ Results were as follows. Although meta-regression analyses were limited by the small body of literature, mean population age and serum collection year appeared to be sources of heterogeneity, respectively, in prevalence estimates of antibodies to HBV antigen (HBsAg+) and any positive HBV marker. Other population characteristics and study methods could not be ruled out as sources of heterogeneity. Anti-HCV prevalence is likely somewhat higher in male and female U.S. incarcerated populations than previously estimated in studies using anti-HCV screening tests alone without the benefit of repeat or additional testing. Death rates due to HBV, HCV, CLD/cirrhosis, and liver cancer from 1984 through 2003 in TDCJ male prisoners exceeded state and national rates. HCV rates appeared to be increasing and disproportionately affecting Hispanics. HCV was implicated in nearly one-third of liver cancer deaths. ^

Hepatitis C and human immunodeficiency virus infections in injecting drug users in drug treatment centers in Vietnam

Background. Injecting drug users (IDUs) are at risk of infection with Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Independently, each of these viruses is a serious threat to health, with HIV ravaging the body’s immune system, and HCV causing cirrhosis, liver cancer and liver failure. Co-infection with HIV/HCV weakens the response to antiretroviral therapy in HIV patients. IDUs with HIV/HCV co-infection are at a 20 times higher risk of having liver-related morbidity and mortality than IDUs with HIV alone. In Vietnam, studies to ascertain the prevalence of HIV have found high rates, but little is known about their HCV status. ^ Purpose. To measure the prevalence of HCV and HIV infection and identify factors associated with these viruses among IDUs at drug treatment centers in northern Vietnam. ^ Methods. A cross-sectional study was conducted from November 2007 to February 2008 with 455 injecting drug users aged 18 to 39 years, admitted no more than two months earlier to one of four treatment centers in Northern Vietnam (Hatay Province) (response rate=95%). Participants, all of whom had completed detoxification and provided informed consent, completed a risk assessment questionnaire and had their blood drawn to test for the presence of antibody-HCV and antibody-HIV with enzyme immuno assays. Univariate and multivariable logistic regression models were utilized to explore the strength of association using HIV, HCV infections and HIV/HCV co-infection as outcomes and demographic characteristics, drug use and sexual behaviors as factors associated with these outcomes. Unadjusted and adjusted odds ratios and 95% confidence intervals were calculated. ^ Results. Among all IDU study participants, the prevalence of HCV alone was 76.9%, HIV alone was 19.8%. The prevalence of HIV/HCV co-infection was 92.2% of HIV-positive and 23.7% of HCV-positive respondents. No sexual risk behaviors for lifetime, six months or 30 days prior to admission were significantly associated with HCV or HIV infection among these IDUs. Only duration of injection drug use was independently associated with HCV and HIV infection, respectively. Longer duration was associated with higher prevalence. Nevertheless, while HCV infection among IDUs who reported being in their first year of injecting drugs were lower than longer time injectors, their rates were still substantial, 67.5%. ^ Compared with either HCV mono-infection or HIV/HCV non-infection, HIV/HCV co-infection was associated with the length of drug injection history but was not associated with sexual behaviors. Higher education was associated with a lower prevalence of HIV/HCV co-infection. When compared with HIV/HCV non-infection, current marriage was associated with a lower prevalence of HIV/HCV co-infection. ^ Conclusions. HCV was prevalent among IDUs from 18 to 39 years old at four drug treatment centers in northern Vietnam. Co-infection with HCV was predominant among HIV-positive IDUs. HCV and HIV co-infection were closely associated with the length of injection drug history. Further research regarding HCV/HIV co-infection should include non-injecting drug users to assess the magnitude of sexual risk behaviors on HIV and HCV infection. (At these treatment centers non-IDUs constituted 10-20% of the population.) High prevalence of HCV prevalence among IDUs, especially among HIV-infected IDUs, suggests that drug treatment centers serving IDUs should include not only HIV prevention education but they should also include the prevention of viral hepatitis. In addition, IDUs who are HIV-positive need to be tested for HCV to receive the best course of therapy and achieve the best response to HIV treatment. These data also suggest that because many IDUs get infected with HCV in the first year of their injection drug career, and because they also engaged in high risk sexual behaviors, outreach programs should focus on harm reduction, safer drug use and sexual practices to prevent infection among drug users who have not yet begun injecting drugs and to prevent further spread of HCV, HIV and co-infection. ^

2005 ACIP recommendations effect on newborn hepatitis B vaccination rates and the factors affecting the successful implementation of the recommendations in the US

Background. Hepatitis B virus infection is one of major causes of acute and chronic hepatitis, cirrhosis of the liver, and primary hepatocellular carcinoma. Hepatitis B and its long term consequences are major health problems in the United States. Hepatitis B virus can be vertically transmitted from mother to infant during birth. Hepatitis B vaccination at birth is the most effective measure to prevent the newborn from HBV infection and its consequences, and is part of any robust perinatal hepatitis B prevention program following ACIP recommendations. Universal vaccination of the new born will prevent HBV infection during early childhood and, assuming that children receive the three dosages of the vaccine, it will also prevent adolescent and adult infections. Hepatitis B vaccination is now recommended as part of a comprehensive strategy to eliminate HBV transmission in the United States. ^ Objective. (1)To assess if the hepatitis B vaccination rates of newborn babies have improved after the 2005 ACIP recommendations. (2) To identify factors that affects the implementation of ACIP recommendation for hepatitis B vaccination in newborn babies. These factors will encourage ongoing improvement by identifying successful efforts and pinpointing areas that fall short and need attention. Additional focus areas may be identified to accelerate progress in eliminating perinatal HBV transmission.^ Methods. This review includes information from all pertinent articles, reviews, National immunization survey (NIS) surveys, reports, peer reviewed literature and web sources that were published after 1991.The key words to be used for selecting the articles are: "Perinatal Hepatitis B Prevention program", "Universal Hepatitis B vaccination of newborn babies", "ACIP Recommendations." The data gathered will be supplemented with an analysis of vaccination rates using the National Immunization Survey (NIS) birth dose coverage data.^ Results. The data collected in the NIS of 2009 reveals that the national coverage for birth dose of HepB increased to 60.8% from 50.1% in 2006. The largest increase observed for the birth dose in the past 5 years is from 2008 which increased from 55.3 % to 60.8% in 2009. By state, coverage ranged from 22.8% in Vermont to 80.7% in Michigan. %. Overall, in 2009 the estimated vaccination rates are in higher ranges for most states compared to the estimated vaccination rates in 2006. States vary widely in hepatitis B vaccination rates and in their compliance with the 2005 ACIP recommendation. There are many factors at various stages that might affect the successful implementation of the new ACIP recommendation as revealed in literature review. ^ Conclusions. HBV perinatal transmission can be eliminated, but it requires identifying the gaps and measures taken to increase the current vaccination coverage, ensuring timely administration of post exposure immunoprophylaxis and continued evaluations of the impact of immunization recommendations.^

Pathway analysis of genome-wide association study data in primary biliary cirrhosisa

Genome-wide association studies (GWAS) have successfully identified several genetic loci associated with inherited predisposition to primary biliary cirrhosis (PBC), the most common autoimmune disease of the liver. Pathway-based tests constitute a novel paradigm for GWAS analysis. By evaluating genetic variation across a biological pathway (gene set), these tests have the potential to determine the collective impact of variants with subtle effects that are individually too weak to be detected in traditional single variant GWAS analysis. To identify biological pathways associated with the risk of development of PBC, GWAS of PBC from Italy (449 cases and 940 controls) and Canada (530 cases and 398 controls) were independently analyzed. The linear combination test (LCT), a recently developed pathway-level statistical method was used for this analysis. For additional validation, pathways that were replicated at the P <0.05 level of significance in both GWAS on LCT analysis were also tested for association with PBC in each dataset using two complementary GWAS pathway approaches. The complementary approaches included a modification of the gene set enrichment analysis algorithm (i-GSEA4GWAS) and Fisher's exact test for pathway enrichment ratios. Twenty-five pathways were associated with PBC risk on LCT analysis in the Italian dataset at P<0.05, of which eight had an FDR<0.25. The top pathway in the Italian dataset was the TNF/stress related signaling pathway (p=7.38×10 -4, FDR=0.18). Twenty-six pathways were associated with PBC at the P<0.05 level using the LCT in the Canadian dataset with the regulation and function of ChREBP in liver pathway (p=5.68×10-4, FDR=0.285) emerging as the most significant pathway. Two pathways, phosphatidylinositol signaling system (Italian: p=0.016, FDR=0.436; Canadian: p=0.034, FDR=0.693) and hedgehog signaling (Italian: p=0.044, FDR=0.636; Canadian: p=0.041, FDR=0.693), were replicated at LCT P<0.05 in both datasets. Statistically significant association of both pathways with PBC genetic susceptibility was confirmed in the Italian dataset on i-GSEA4GWAS. Results for the phosphatidylinositol signaling system were also significant in both datasets on applying Fisher's exact test for pathway enrichment ratios. This study identified a combination of known and novel pathway-level associations with PBC risk. If functionally validated, the findings may yield fresh insights into the etiology of this complex autoimmune disease with possible preventive and therapeutic application.^