Samuel So

The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013

BACKGROUND With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013. METHODS We estimated mortality using natural history models for acute hepatitis infections and GBDs cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs). FINDINGS Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86-0·94) to 1·45 million (1·38-1·54); YLLs from 31·0 million (29·6-32·6) to 41·6 million (39·1-44·7); YLDs from 0·65 million (0·45-0·89) to 0·87 million (0·61-1·18); and DALYs from 31·7 million (30·2-33·3) to 42·5 million (39·9-45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990. INTERPRETATION Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health. FUNDING Bill & Melinda Gates Foundation.

An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation.

The incidence of Epstein-Barr virus (EBV) infection and lymphoproliferative disorder (LPD) was determined in a pediatric liver transplant population consisting of 51 children treated with FK506 and 91 treated with cyclosporine. The incidence of symptomatic EBV infection was 21.9% (23 of 105 cases) in children < 5 yr old and 10.8% (4 of 37 cases) in children 5 to 17 yr old as compared with 2.7% (9 of 323 cases) in adults (P < 0.0001). In the under 5 yr old group on cyclosporine, the incidences of EBV infection and LPD were 9 of 68 (13.2%) and 2 of 68 children, (2.9%), respectively. In contrast, in children under 5 yr old group on FK506, the incidences of EBV infection and LPD in the FK506 group were 14 of 37 (37.8%) and 7 of 37 children (18.9%), respectively. The difference between these two groups was statistically significant (P < 0.02). There were no cases of LPD in the 5-17 yr-old children on either cyclosporine (n = 23) or FK506 (n = 14). The incidence of EBV infections in the 5 to 17 yr age group, 17.4% on cyclosporine and 0% on FK506, was less than for the younger children on FK506 (37.8%). A total of 39% (9 of 23) of children under 5 yr old who had symptomatic EBV infections developed LPD, and 44% (4 of 9) with LPD died. The higher incidence of EBV infections and LPD in the younger children treated with FK506 was probably related to a greater intensity of immunosuppression for patients on FK506 than those on cyclosporine.

Why we should routinely screen Asian American adults for hepatitis B: A cross‐sectional study of Asians in California

Chronic hepatitis B virus (HBV) infection is a serious liver disease that, if left undiagnosed or without appropriate medical management, is associated with a 25% chance of death from cirrhosis or liver cancer. To study the demographics and prevalence of chronic HBV infection and HBV vaccination in the Asian American population, we provided free HBV serological screening and administered a survey to 3163 Asian American adult volunteers in the San Francisco Bay Area between 2001 and 2006. Of those screened, 8.9% were chronically infected with HBV. Notably, one‐half to two‐thirds (65.4%) of the chronically infected adults were unaware that they were infected. Of those who were not chronically infected, 44.8% lacked protective antibodies against HBV and were likely susceptible to future infection. Men were twice as likely as women to be chronically infected (12.1% versus 6.4%). Asian Americans born in East Asia, Southeast Asia, or the Pacific Islands were 19.4 times more likely to be chronically infected than those born in the United States. Self‐reporting of prior vaccination was unreliable to assess protection against HBV. Among the 12% who reported having been vaccinated, 5.2% were chronically infected, and 20.3% lacked protective antibodies. Conclusion: Given the high prevalence of unrecognized chronic HBV infection in the Asian American population, we call for healthcare providers to routinely screen Asian adults for HBV, regardless of their vaccination status. Those who test positive should be provided with culturally appropriate information to prevent disease transmission and proper medical management to reduce their risk of liver disease. (HEPATOLOGY 2007.)

Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis

We analyzed gene expression patterns in human gastric cancers by using cDNA microarrays representing ≈30,300 genes. Expression of PLA2G2A, a gene previously implicated as a modifier of the ApcMin/+ (multiple intestinal neoplasia 1) mutant phenotype in the mouse, was significantly correlated with patient survival. We confirmed this observation in an independent set of patient samples by using quantitative RT-PCR. Beyond its potential diagnostic and prognostic significance, this result suggests the intriguing possibility that the activity of PLA2G2A may suppress progression or metastasis of human gastric cancer.

FK506 (tacrolimus) compared with cyclosporine for primary immunosuppression after pediatric liver transplantation: Results from the U.S. multicenter trial

We report on the efficacy and safety of FK506 (tacrolimus) compared with a cyclosporine (CsA)-based immunosuppressive regimen after 1 year of treatment in pediatric liver allograft recipients (< 12 years) participating in a multicenter U.S. randomized trial. Patients received either FK506 or CsA as primary immunosuppression following a first ABO-compatible liver transplant. Intravenous FK506 was initiated at 0.1 mg/kg per day, followed by oral FK506 beginning at 0.3 mg/kg per day. The dose was adjusted to maintain plasma trough levels of 0.5-2.0 ng/ml. The CsA group was treated according to each centers usual protocol. Both groups received the same initial doses of corticosteroids. All rejection episodes were biopsy-proven and a standardized algorithm was adopted for the treatment of rejection. Thirty patients were randomized to the FK506 group and 20 to the CsA group. After twelve months of follow-up 20 patients remained in the FK506 group and 13 in the CsA group. Patient survivals were 80% and graft survival 70% in the FK506 group compared with 81% and 71% respectively, in the CsA group. 48% of the FK506 group remained rejection-free compared with 21% of the CsA group, and 79% of FK506-treated patients did not require OKT3 compared with 68% of CsA treated patients. The cumulative corticosteroid dose was less at each time point throughout the first year in the FK506 group. The incidence of serious and minor infections was similar in both groups. Nephrotoxicity, neurotoxicity, and gastrointestinal disturbances were the major toxicities reported. Differences did not reach statistical significance between the two groups although major neurologic events, diarrhea and dyspepsia were more often reported in the FK506 group. There was no difference in mean serum creatinine at 12 months between the two groups. There was a tendency toward lower mean serum cholesterol in the FK506 group. There was no hirsuitism in the FK506 group compared with a 30% incidence in the CsA group. In conclusion, compared with CsA, there is a trend toward less rejection in FK506-treated pediatric allograft recipients, while both drugs have a similar spectrum of side effects.

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Cost-effectiveness of screening and vaccinating Asian and Pacific Islander adults for hepatitis B.

Context About 10% of Asian and Pacific Islander adults in the United States are chronically infected with hepatitis B virus (HBV). Many are unaware of their infection and do not receive antiviral treatment. Contribution This analysis assesses the incremental cost-effectiveness of alternative strategies for voluntary screening for HBV in Asian and Pacific Islander adults. Compared with voluntary screening only, a strategy of screening and then treating infected persons and a strategy of screening and treating infected persons and ring vaccinating close contacts were cost-effective (about

Sprouty 2, an Inhibitor of Mitogen-Activated Protein Kinase Signaling, Is Down-Regulated in Hepatocellular Carcinoma

36000 to

Factors affecting survival after orthotopic liver transplantation in infants.

40000 per quality-adjusted life-year gained). Implication Programs to screen and treat Asian and Pacific Islander adults for HBV infection are probably cost-effective. The Editors Despite tremendous success in reducing the occurrence of acute and chronic hepatitis B virus (HBV) infection in U.S. children and adolescents (1), chronic HBV infection continues to be a serious health threat to Asian and Pacific Islander adults in the United States (defined here as persons having origins in East, South, and Southeast Asia or in the Pacific Islands [2]). Approximately 10% of Asian and Pacific Islander adults are chronically infected with HBV (37), compared with less than 0.5% of the overall U.S. population (8, 9). If unmonitored and untreated, chronic HBV infection results in death from liver failure or liver cancer in up to 1 in 4 people (10, 11); an estimated 3000 to 5000 such deaths occur annually in the United States (12). The striking racial and ethnic disparity in chronic HBV infection in the United States is largely ascribed to the fact that 67% of the Asian and Pacific Islander population is foreign born (13), originating from countries where HBV is endemic and the majority of chronic infections are acquired before adulthood (9). Because of the high prevalence of chronic HBV infection in this population, the incidence of liver cancer is more than 3 times higher among Asian and Pacific Islander males than among white males (14, 15), and 60% to 80% of cases of liver cancer in the Asian and Pacific Islander populations are attributable to HBV infection (16, 17). To reduce their risk for dying of liver cancer, patients must first know that they are chronically infected with HBV and then be regularly screened for liver cancer (18). Recently developed antiviral therapies have been shown to be cost-effective in extending life and reducing morbidity for patients with HBV (1922). However, as many as two thirds of chronically infected Asian and Pacific Islander adults are unaware of their infection and thus cannot benefit from treatment (6). Incomplete screening coverage also prevents unprotected persons from knowing that they should be vaccinated against HBV and leaves close contacts of chronically infected persons uninformed that they are at increased risk for infection (23). To date, the national strategy for eliminating HBV transmission has largely focused on vaccinating newborns, children, and adolescents and screening pregnant women (24). The U.S. Advisory Committee on Immunization Practices first recommended HBV vaccination of all infants and children in 1982 (25). Subsequent recommendations were issued to implement catch-up vaccination in most Asian and Pacific Islander children (26) and, later, among all children and adolescents (27). However, a 1998 survey of Asian and Pacific Islander children in 6 major U.S. cities found that completion rates for the 3-dose series were only 14% to 67% (28). In addition, an estimated 40000 legal immigrants who are chronically infected with HBV enter the United States each year; more than 50% of these individuals are Asian (29). The Advisory Committee on Immunization Practices recently issued screening recommendations that extend to all children and adults born in high-prevalence areas (for example, Asia and the Pacific Islands), regardless of previous HBV vaccination status (24, 30). We conducted a cost-effectiveness analysis of HBV screening and vaccination strategies targeted to all (U.S.-born and foreign-born) Asian and Pacific Islander adults in the United States. Methods We used a Markov model of acute HBV infection and disease progression to assess the clinical and economic consequences of alternative HBV screening and vaccination strategies in a hypothetical cohort of 10000 Asian and Pacific Islander adults 20 to 60 years of age (Appendix). We considered the status quo (voluntary screening only and no incremental screening or vaccination) and 4 incremental strategies: a universal vaccination strategy, in which all individuals are given a 3-dose vaccination series; a screen-and-treat strategy, in which individuals are given hepatitis B surface antigen (HBsAg) blood tests to determine whether they are chronically infected with HBV; a screen, treat, and ring vaccinate strategy, in which all individuals are given HBsAg blood tests to determine whether they are chronically infected, and close contacts of persons found to be infected are also screened with HBsAg and hepatitis B surface antibody blood tests and vaccinated if needed; and a screen, treat, and vaccinate strategy, in which all individuals are given HBsAg and hepatitis B surface antibody blood tests to determine whether they are chronically infected or should be vaccinated, and are then vaccinated with a 3-dose vaccination series if needed. In all cases, chronically infected persons are monitored and treated. We selected these 4 incremental strategies because they are the most clinically relevant. We did not consider all possible combinations of tests, vaccines, and treatments. We took a societal perspective and included all health care costs and savings, regardless of payer or beneficiary. We estimated costs and benefits of the interventions (deaths averted and quality-adjusted life-years [QALYs] gained) over the lifetime of the cohort, including the lives of infants born to women in the cohort. We assumed that all interventions take place at the start of the time horizon. We discounted all future costs and benefits to the present at 3% (31). Decision Tree and Markov Model We accounted for the dynamics of HBV infection, screening, and vaccination as follows. We start with a cohort of 10000 persons who may be immune to, susceptible to, or chronically infected with HBV. For simplicity, all persons in the cohort are assumed to be the same age. We assumed age 40 years in the base case and varied age from 20 to 60 years in sensitivity analysis. At the beginning of the time horizon, individuals are screened and vaccinated, based on estimated rates of compliance with the intervention. They then progress through the Markov model on the basis of epidemiologic variables. Acute infections among newborns born to women in the cohort are modeled in a similar manner to that for adults, but with different disease progression variables (Appendix). The model was intended to capture the high-level costs and effectiveness of screening and treating a large cohort. We did not incorporate all clinical characteristics of disease progression and therapies (such as viral load and hepatitis B e antigen status) that would be important for a model focused on clinical treatment recommendations. In sensitivity analysis, we considered a range of values for treatment cost and effectiveness to account for the broad range of therapies (and hepatitis B e antigen status) mentioned in the literature (1922, 30, 3237). The model structure was based in part on other models in the literature (21, 22, 3840) and was reviewed by clinicians involved in the care and treatment of patients with chronic HBV. We implemented the model in Microsoft Excel (Microsoft Corp., Redmond, Washington), with the software add-in Sensit (Decision Support Services, San Francisco, California) to perform 1-way sensitivity analyses. Data and Sources We estimated values for the model variables (Table 1 and Appendix) on the basis of the medical literature and expert sources (1, 37, 10, 11, 1922, 3171). We examined 13 articles on the cost-effectiveness of HBV vaccination (3840, 43, 57, 62, 7278). Many of these studies focused on infants and children or high-risk groups. Few studies examined screening, and those that did focused on cost savings without examining the health benefits that could accrue from monitoring and treatment of previously unidentified disease (43, 7577, 79). Many studies have examined the cost-effectiveness of interferon treatment for HBV infection, but few have examined the cost-effectiveness of more recent antiviral therapies (such as adefovir, entecavir, and telbivudine) (1922, 3236, 8082). In sensitivity analysis, we considered low and high values for all variables. Where data were available, low and high values were chosen to reflect ranges in the literature. Table 1. Values for Model Variables Compliance and Vaccine Effectiveness We assumed 70% compliance with each intervention. We assumed that in the screen, treat, and vaccinate strategy, all persons who are tested and found to be already infected will accept medical management, and those who are tested and found to be uninfected will be vaccinated. Only persons tested and found to be susceptible are vaccinated. In the universal vaccination strategy, we assumed that all persons who complied were vaccinated, regardless of whether they were already infected or already immune. In the screen, treat, and ring vaccinate strategy, we assumed that public health officials could reach and test, and vaccinate if needed, 70% of an infected persons close contacts. We assumed that the HBV testing program would increase awareness of HBV and thus would increase the proportion of newborns who complete HBV prophylaxis compared with the status quo. We assumed that all persons who are vaccinated would adhere to the full 3-dose vaccination series, and that vaccine protection lasts for a lifetime. The protection rate after all 3 dos

An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma.

The Sprouty proteins are increasingly being recognized to be deregulated in various types of cancers. This deregulation is often associated with aberrant signaling of receptor tyrosine kinases and its downstream effectors, leading to the mitogen-activated protein kinase (MAPK) signaling pathway. In human hepatocellular carcinoma, where the MAPK activity is enhanced via multiple hepatocarcinogenic factors, we observed a consistent reduced expression of the sprouty 2 (Spry2) transcript and protein in malignant hepatocytes compared with normal or cirrhotic hepatocytes. The expression pattern of Spry2 in hepatocellular carcinoma resembles that of several potential tumor markers of hepatocellular carcinoma and also that of several angiogenic factors and growth factor receptors. In contrast to previous studies of Spry2 down-regulation in other cancers, we have ruled out loss of heterozygosity or the methylation of promoter sites, two common mechanisms responsible for the silencing of genes with tumor suppressor properties. Functionally, we show that Spry2 inhibits both extracellular signal-regulated kinase signaling as well as proliferation in hepatocellular carcinoma cell lines, whereas knocking down Spry2 levels in NIH3T3 cells causes mild transformation. Our study clearly indicates a role for Spry2 in hepatocellular carcinoma, and an understanding of the regulatory controls of its expression could provide new means of regulating the angiogenic switch in this hypervascular tumor, thereby potentially controlling tumor growth.