Signaling Induced by Chronic Viral Hepatitis: Dependence and Consequences.

Chronic viral hepatitis is a main cause of liver disease and hepatocellular carcinoma. There are striking similarities in the pathological impact of hepatitis B, C, and D, although these diseases are caused by very different viruses. Paired with the conventional study of protein-host interactions, the rapid technological development of -omics and bioinformatics has allowed highlighting the important role of signaling networks in viral pathogenesis. In this review, we provide an integrated look on the three major viruses associated with chronic viral hepatitis in patients, summarizing similarities and differences in virus-induced cellular signaling relevant to the viral life cycles and liver disease progression.

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK.

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.

Variation in the Viral Hepatitis and HIV Policies and Practices of Methadone Maintenance Programs.

OBJECTIVE: Patients prescribed methadone maintenance treatment (MMT) demonstrate elevated prevalence of hepatitis B virus (HBV), hepatitis C virus, and HIV. Government agencies recommend testing for these infections in MMT programs, but uptake is limited. METHODS: We audited infection-related policies and practices of all 14 MMT programs in Philadelphia, Pennsylvania, in 2015. Results were tabulated and compared with the results from a 2010 audit of 10 of 12 MMT programs. The audit focused on which patients are tested, timing and frequency, specific tests ordered, vaccination, and communication of test results. RESULTS: Written policies were nonspecific, offering little guidance on appropriate testing. The principal change in policy between 2010 and 2015 involved adding clearer guidance for communication of results to patients. In 2010 and 2015, all MMT programs tested new patients for hepatitis C virus antibodies, although retesting of existing patients varied. HBV testing increased from 2010 to 2015, though it was not uniform, with 5 programs testing for HBV surface antibodies and 10 programs testing for HBV surface antigens. Six programs assessed hepatitis vaccination status, but only 1 administered vaccines. In 2010, city-sponsored HIV antibody testing was available at all MMT programs. Without this program in 2015, few MMT programs conducted HIV testing. CONCLUSIONS: Despite limited hepatitis and HIV screening in MMT programs nationally, this study shows that testing can be incorporated into routine procedures. MMT programs are positioned to play an integral role in the identification of patients with chronic infections, but additional guidance and resources are required to maximize their impact.

Impact of Cirrhosis on Resource Use and Inpatient Complications in Patients Undergoing Total Knee and Hip Arthroplasty.

BACKGROUND: Cirrhosis is a major cause of morbidity and mortality and is an important risk factor for complications in surgical patients. The purpose of this study was to investigate the association of cirrhosis with postoperative complications, length of stay (LOS), and costs among patients who underwent total knee arthroplasty (TKA) or total hip arthroplasty (THA). METHODS: Using the Nationwide Inpatient Sample between 2000 and 2011, we identified patients who had a primary TKA or primary THA. TKA patients were divided into 2 groups: (1) cirrhosis (n = 41,464) and (2) no cirrhosis (n = 5,721,297) and THA patients were divided into 2 groups: (1) cirrhosis (n = 27,401) and (2) no cirrhosis (n = 2,622,539). Patient demographics, comorbidities, perioperative complications, LOS, and incremental costs were analyzed. An additional subgroup analysis by cirrhosis etiology was performed. RESULTS: Multivariable analysis revealed cirrhosis was associated with 1.55 (95% confidence interval: 1.47-1.63) times higher odds of any complication after TKA and 1.59 (1.50-1.69) higher odds after THA. Adjusted outcomes showed cirrhotic TKA patients had $1857 higher costs and 0.30 days longer LOS and THA cirrhotic patients had $1497 higher costs and 0.48 longer LOS. We found similar results for each cirrhosis subtype but alcohol-related had the highest resource use and complication rate. CONCLUSION: Patients with cirrhosis who are undergoing TKA or THA are at a significantly increased risk for perioperative complications, increased LOS, and higher costs. The perioperative complications and costs were highest among patients with alcohol-related cirrhosis.

Effect of socioeconomic status on hepatocellular carcinoma incidence and stage at diagnosis, a population-based cohort study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) incidence is increasing worldwide and cirrhosis is the most important risk factor predominantly caused by chronic viral hepatitis infection. We studied the impact of socioeconomic status (SES) on HCC incidence and stage at diagnosis among viral hepatitis cases. METHODS: A population-based retrospective cohort study was conducted through the Ontario Cancer Registry linked data. Incidence rates were calculated using person-time methodology. Association between SES (income quintile) and HCC incidence was assessed using proportional-hazards regression. The impact of SES on HCC stage was investigated using logistic regression. RESULTS: Among 11 350 individuals diagnosed with viral hepatitis between 1991 and 2010, a crude HCC incidence rate of 21.4 cases per 1000 person-years was observed. Adjusting for age, gender, urban/rural residence and year of viral hepatitis diagnosis, a significant association was found between SES and HCC incidence, with an increased risk among individuals in the lowest three income quintiles (incidence rate ratio, IRR = 1.235; 95% CI: 1.074-1.420; IRR = 1.183; 95% CI: 1.026-1.364; IRR = 1.158; 95% CI: 1.000-1.340 respectively). No significant association between SES and HCC incidence was found after additionally adjusting for risk factors associated with HCC. However, HCC risk factors such as cirrhosis and HIV are associated with SES. Furthermore, no association was found between SES and HCC stage. CONCLUSIONS: The association between SES and HCC incidence is likely because of differences in risk factors across income quintiles. Investigating how SES affects HCC incidence facilitates an understanding of which populations are at elevated risk for HCC.

Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan.

UNLABELLED: A national viral hepatitis therapy program was launched in Taiwan in October 2003. This study aimed to assess the impact of the program on reduction of end-stage liver disease (ESLD) burden. Profiles of national registries of households, cancers, and death certificates were used to derive incidence and mortality of ESLDs from 2000 to 2011. Age-gender-adjusted incidence and mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) and cirrhosis of adults ages 30-69 years were compared before and after launching the program using Poisson's regression models. A total of 157,570 and 61,823 patients (15%-25% of those eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011. There were 42,526 CLDs and cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person-years from 2000 to 2011. Male gender and elder age were associated with a significantly increased risk of CLDs and cirrhosis and HCC. Mortality and incidence rates of ESLDs decreased continuously from 2000 to 2003 (before therapy program) through 2004-2007 to 2008-2011 in all age and gender groups. The age-gender-adjusted rate ratio (95% confidence interval; P value) in 2008-2011 was 0.78 (0.76-0.80; P < 0.001) for CLDs and cirrhosis mortality, 0.76 (0.75-0.78; P < 0.005) for HCC mortality, and 0.86 (0.85-0.88; P < 0.005) for HCC incidence using 2000-2003 as the reference period (rate ratio = 1.0). CONCLUSIONS: The national viral hepatitis therapy program has significantly reduced the mortality of CLDs and cirrhosis and incidence and mortality of HCC.

Assessment of the sexual functions of males with chronic liver disease in South West Nigeria.

BACKGROUND: Patients with chronic liver disease (CLD) have been reported to have sexual dysfunction irrespective of etiology. There is little or no report from Nigeria on this disorder. This study looked at sexual dysfunction among male patients with CLD. MATERIALS AND METHODS: Patients with chronic viral hepatitis B, liver cirrhosis (LC) and hepatocellular carcinoma (HCC) were interviewed using the international index of erectile function questionnaire. Their responses were compared with an age and sex matched healthy controls. Bio-data and body mass index were obtained for both groups and liver disease severity was graded for patients using the Child-Pugh score. Analysis was done using SPSS (SPSS Inc., Chicago, IL, USA, 2004) for frequencies and means while comparison of means was done using Student's t-test. Significance level was put at P < 0.05. RESULTS: There were 120 subjects consisting of 60 patients aged from 28 to 71 years; mean (SD) 45. 3 ± 9.4 and 60 controls aged from 29 to 79 years with mean (SD) 45.5 ± 10.1 years. Sexual dysfunctions were seen in patients with HCC and LC in the domains of sexual desire and sexual satisfaction respectively when compared with controls. When patients were divided into the various liver disease severities, patients in Child-Pugh Grade B scored low in the domain of arousal, whereas the domains of erectile functions, orgasm, resolution and satisfaction were affected in patients in Grade C when compared with controls. CONCLUSIONS: Male patients with CLD have significant sexual dysfunctions when compared with controls. The dysfunctions are more pronounced in those with Grade C liver disease. Sexual concerns of CLD should be inquired of in those with advanced liver disease.

Prevention of hepatocellular carcinoma: a concise review of contemporary issues.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer deaths in men. Due to differences in the prevalence of viral hepatitis, the incidence of HCC in low and middle income countries is much higher than that of high income countries. Strategies to limit the impact of HCC include primary prevention against new cases of viral hepatitis, secondary prevention of HCC in susceptible individuals, and early HCC detection. Universal hepatitis B vaccination has resulted in dramatic reduction in incident cases of chronic hepatitis B and HCC in children and adolescents, and the full effect is expected in the next 20 years. The key hurdle for universal vaccination is the cost and the accessibility in low and middle income countries. Randomized controlled trials and meta-analyses showed that successful treatment of chronic hepatitis B and C can reduce the risk of HCC and cirrhotic complications. HCC surveillance by regular ultrasound examination and alpha fetoprotein testing leads to early cancer detection and offers the opportunity for curative treatment. Since all these measures are costly and require manpower and infrastructure support, the implementation should rely on the liaison among healthcare providers and policymakers. The cost-effectiveness of various strategies should also be studied based on local situations.

[Assessment and reversibility of liver fibrosis in viral hepatitis]. / Evaluation et réversibilité de la fibrose hépatique au cours des hépatites virales.

The evaluation of liver fibrosis in chronic viral hepatitis is of paramount importance since secondary complications, including hepatocellular carcinoma, occur in patients with extensive fibrosis and cirrhosis. Clinical examination and some simple biological and morphological tests represent the first step to appraise liver fibrosis in viral hepatitis. Biochemical (Fibrotest, Hepascore, Fibrometre) or morphological (Fibroscan) methods have emerged over the past ten years to avoid--in more than half of patients--the systematic use of the liver biopsy to appraise liver fibrosis in chronic hepatitis C virus infection. The liver biopsy remains however essential in many situations--especially for demonstrating regression of cirrhosis after viral inactivation. Regression of cirrhosis is now a recognized concept, thanks to the next generation of antiviral treatments. Today, the inactivation of viral hepatitis is an achievable primary goal and regression of cirrhosis becomes a reasonable secondary goal.

Combined effect of socioeconomic status, viral hepatitis, and lifestyles on hepatocelluar carcinoma risk in Korea.

BACKGROUND: The independent and combined effects of socioeconomic status (SES), viral hepatitis, and other lifestyle factors on hepatocellular carcinoma (HCC) risk have not been investigated among Koreans. METHODS: From the National Cancer Center Hospital, 207 HCC cases and 828 age- and gender-matched controls aged 30 years or older were recruited. Socio-demographic and behavioural risk factors were ascertained through personal interview, and infection with hepatitis B and C viruses was determined by their serologic markers. Multivariate logistic regression and synergy index methods were applied for statistical analysis. RESULTS: HB surface antigen (HbsAg) and anti-HCV-positive rates were 149.3 and 185.1 times higher in cases than controls, respectively. Lifetime alcohol consumption (odds ratio: 2.96, 95% CI: 1.29-6.79), cigarette smoking (OR: 3.53, 95% CI: 1.31-9.52), and family income (OR: 17.07, 95% CI: 4.27-68.25) were independently associated with the risk of HCC in subjects with or without viral hepatitis. Synergistic interaction on HCC risk was observed between low income and HBsAg positivity (SI: 3.12, 95% CI: 1.51-6.47) and between low income and heavy alcohol intake (SI: 2.93, 95% CI: 1.24-6.89). CONCLUSION: The inverse association with SES suggests SES as an independent and synergistic predictor of HCC. Heavy alcohol intake also showed a combined effect with low SES on HCC risk.

Fertility needs and funding in couples with blood-borne viral infection.

BACKGROUND: Couples infected with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) are increasingly seeking assisted conception. These couples avoid unprotected intercourse and use condoms at all times in order to minimize the risk of infecting their partner. As this practice inhibits pregnancy, assisted procreation is generally required for safe conception. For many couples, access to such services is restricted on ethical, geographical and financial grounds. OBJECTIVE: The aim of the study was to assess the fertility needs, geographical origin and state funding of patients with blood-borne viral infection. METHODS: A retrospective review of the medical records of couples referred for fertility treatment between January 1999 and December 2006, where one or both partners were infected with HIV, HBV and/or HCV, was carried out. RESULTS: Of the 205 couples included in the study, 44% lived in London, 51% came from elsewhere in the United Kingdom and 5% travelled from outside the United Kingdom to seek treatment. Genitourinary medicine clinics were the main source of referral. 85.8% of couples had HIV infection, 15.1% were infected with HBV and 13.6% had HCV infection. Fertility screening identified a high incidence of male factor infertility (33.3%) in HIV-infected men and tubal disease (40.8%) in HIV-infected women. Only 23.6% of HIV-infected couples, 20% of HBV-infected couples and 12.5% of HCV-infected couples obtained state funding for assisted conception. CONCLUSION: Fertility screening identified a high incidence of male and tubal factor subfertility among couples living with HIV, HBV and HCV. Limited access to specialist clinics equipped to cater for these couples and restricted funding may impact negatively on couples obtaining risk-reducing assisted reproduction treatment. This may have long-term public health implications as individuals attempt to conceive through unprotected intercourse.

Assessment of validity of INR system for patients with liver disease associated with viral hepatitis.

International Normalized Ratio (INR), which standardizes prothrombin time (PT) during oral anticoagulation, has been extended to standardize PT in liver diseases and is included in all prognostic models of survival, the classification of CHILD-Pugh or Meld. However, the mechanisms of PT prolongation in liver diseases differ from those involved in oral anticoagulation. Our aim was to assess the validity of the INR system for patients with liver disease associated with viral hepatitis. We prospectively collected blood samples from 61 patients with liver disease associated with viral hepatitis; control patients were on warfarin (n = 20). PTs were measured on a STA-R coagulometer with six thromboplastin reagents, and INRs were calculated using instrument-specific ISIs. Simultaneously, we selected 15 pairs of patients in the study population and in the control population such that INR values for each patient pair are almost equal. For these 15 pairs of patients, we performed factor assays and measured the coagulant activities of factors II, V, VI, and X and fibrinogen. Analysis of results for the control population confirms the validity of the INR system for patients on oral anticoagulants in that there was no significant difference between the reported INRs for the six different thromboplastin reagents. Conversely, for the study population, there was a significant difference between the INR results using the different reagents. Results for fibrinogen and factors V, VII, and X showed significant differences between the two groups; however, control and patient results for factor II were not statistically different. The INR system is not valid for comparison of patients with liver disease associated with viral hepatitis because different reagents do not yield the same INR for the same sample.

Does integrating viral hepatitis services into a public STD clinic attract injection drug users for care?

OBJECTIVE: Injection drug users (IDUs) are at high risk for multiple health problems, including human immunodeficiency virus (HIV), viral hepatitis, and sexually transmitted diseases (STDs), and are likely to have poor access to health care. To more effectively serve high-risk clients, experts recommend that programs accessed by such client populations offer integrated services. In 2000, the New York City Department of Health and Mental Hygiene integrated viral hepatitis services (vaccine and screening) into a publicly funded STD clinic. We evaluated integrated service delivery to high-risk IDUs at this clinic. METHODS: Hepatitis data were reviewed to identify clients who self-reported as IDUs. STD medical records of these clients were abstracted to ascertain primary reason for clinic visit, STD/HIV services received, and diagnoses made. RESULTS: Between May 2000 and March 2004, 8,778 individuals received hepatitis services, of whom 3% (279/8,778) reported injection drug use. Nearly 60% (161/279) of IDUs reported availability of hepatitis services as the primary reason for the clinic visit. Of these 161 clients, 103 (64%) also received other services; 54% (55/103) had an STD exam (yielding 12 new STD diagnoses), and 59% (61/103) had HIV counseling and testing (yielding two new HIV cases). Of these 103 clients, 31 (30%) were referred to the clinic for hepatitis services from a drug treatment center, and 77% (24/31) tested positive for the antibody to hepatitis C virus. CONCLUSIONS: Integrated hepatitis services appeared to attract IDUs to this STD clinic, where many also benefited from STD/HIV exams, testing, treatment, and referrals they may not have received otherwise.

Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for End-Stage Liver Disease (MELD) and King's College Hospital criteria.

While King's Hospital Criteria (KCH) criteria are used worldwide, the Model for End-Stage Liver Disease (MELD) is a more recently developed scoring system that has been validated as an independent predictor of patient survival in conditions for liver transplantation (LT). The aim of the present study was to compare MELD and KCH criteria with other early clinical prognostic indicators (CPI) in a cohort of patients with fulminant hepatic failure (FHF). A total of 144 patients (mean age 31.7 +/- 14.7 yr; range 12-82 yr; 62 males) with FHF due to acute viral hepatitis were included into the study. Variables found significant on univariate analysis were entered into a multivariate logistic regression analysis. A total of 52 (36.1%) patients survived, the remaining 92 (63.9%) died. Univariate analysis showed that age, duration of jaundice, jaundice-encephalopathy interval (JEI), grade of encephalopathy, presence of cerebral edema, bilirubin, prothrombin time, creatinine, and MELD score were significantly different between survivors and nonsurvivors. Multivariate logistic regression identified 6 independent CPI of adverse outcome on admission: age >or=50 yr, JEI >7 days, grade 3 or 4 encephalopathy, presence of cerebral edema, prothrombin time >or=35 seconds, and creatinine >or=1.5 mg/dL. Presence of any 3 of 6 CPI was optimum in identifying survivors and nonsurvivors. A MELD score of >or=33 was found to be best discriminant between survivors and nonsurvivors by the construction of receiver operating characteristic (ROC) curves. Any 3 CPI were superior to MELD and KCH criteria in predicting the outcome (c-statistic [95% confidence interval]: CPI 0.802 [0.726-0.878], MELD 0.717 [0.636-0.789], and KCH criteria 0.676 (0.588-0.764); P values: CPI vs. MELD 0.045, CPI vs. KCH criteria 0.019, and MELD vs. KCH criteria 0.472). In conclusion, MELD and KCH criteria are not as useful as a combination of other early CPI in predicting adverse outcome in patients with FHF due to acute viral hepatitis.