Alaska Native people have an increased rate of hepatocellular carcinoma compared to the United States population. Viral hepatitis is a risk factor for malignancy and the leading cause of hepatocellular carcinoma in Alaska. With the introduction of hepatitis B immunization in 1982, as well as the emergence of hepatitis C virus in this population, the epidemiology and aetiology of hepatocellular carcinoma in Alaska have changed.
Using the Alaska Native Tumor Registry, all cases of viral and non-viral hepatocellular carcinoma occurring from 1969 through 2013 were identified and reviewed. Incidence rates per 100 000 population were calculated for hepatocellular carcinoma overall and by aetiological category.
One hundred and fifty-two cases of hepatocellular carcinoma were identified in 148 Alaska Native persons. Overall tumour rate was 3.82 per 100 000 and did not change significantly over the study period. Hepatitis B-associated cases decreased significantly over the study period (P = 0.048) and were eliminated in persons under the age of 20. Hepatitis C-associated cases increased significantly (P
Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A, B, C, D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P
Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Disease, U.S. Centers for Disease Control and Prevention (CDC), Anchorage, AK, USA; firstname.lastname@example.org.
The American Association for the Study of Liver Diseases (AASLD) recommends semi-annual hepatocellular carcinoma (HCC) screening using ultrasound (US) in persons with chronic hepatitis B (CHB) virus infection at high risk for HCC such as Asian males aged =40 years and Asian females aged =50 years.
To analyse the cost-effectiveness of 2 HCC screening methods in the Alaska Native (AN) health system: US-alone, or screening by alpha-fetoprotein (AFP) initially and switching to US for subsequent screenings if AFP >10 ng/mL (AFP?US).
A spreadsheet-based model was developed for accounting the costs of 2 hypothetical HCC screening methods. We used epidemiologic data from a cohort of 839 AN persons with CHB who were offered HCC screening by AFP/US semi-annually during 1983-2012. We assumed that compared with AFP?US, US-alone identifies 33% more tumours at an early stage (defined as a single tumour =5 cm or =3 tumours =3 cm in diameter). Years of life gained (YLG) attributed to screening was estimated by comparing additional years of survival among persons with early- compared with late-stage tumours. Screening costs were calculated using Medicare reimbursement rates in 2012. Future screening costs and YLG were projected over a 30-year time horizon using a 3% discount rate.
The total cost of screening for the cohort by AFP?US would have been approximately $357,000 ($36,000/early-stage tumour detected) compared to $814,000 ($59,000/early-stage tumour detected) by US-alone. The AFP?US method would have yielded an additional 27.8 YLG ($13,000/YLG) compared with 38.9 YLG ($21,000/YLG) for US-alone. Screening by US-alone would incur an additional $114,000 per extra early-tumour detected compared with AFP?US and $41,000 per extra YLG.
Although US-alone HCC screening might have yielded more YLG than AFP?US, the reduced costs of the AFP?US method could expand access to HCC screening in resource constrained settings.
Hepatitis B virus (HBV) is a common viral pathogen that currently infects an estimated 4 million people worldwide, including 400 million who have chronic infection. Persons with chronic HBV infection are at a lifelong risk of developing hepatocellular carcinoma (HCC) or cirrhosis, or both. Many persons with HBV are unaware that they carry the infection, and, of those who are chronically infected, only a minority receives routine, scheduled follow-up to monitor their disease status. Persons from high-risk populations, especially immigrants from nations where hepatitis B is highly endemic, should be tested for HBV seromarkers and should be vaccinated if they are found to be negative. The natural history of chronic HBV is a dynamic one: patients can fluctuate between periods of active liver inflammation and periods of inactive disease. Disease progression is influenced by various factors, including viral genotype and specific mutations, demographic features, concurrent viral infections, and social and environmental factors. Recent data suggest that antiviral therapy can decrease the risk of liver decompensation and liver-related death and reduce the risk of HCC in selected individuals with active liver disease and severe fibrosis. Persons identified with chronic HBV infection need lifelong, regular monitoring for the development of active liver disease and HCC.
Most regions of the world have =3 co-circulating hepatitis B virus (HBV) genotypes, which limits direct comparisons of hepatocellular carcinoma (HCC) risk among HBV-infected persons by genotype. We evaluated HCC incidence by HBV genotype in a cohort of Alaska Native (AN) persons where five HBV genotypes (A, B, C, D, F) have been identified.
Our cohort comprised AN persons with chronic HBV infection identified during 1983-2012 who consented to participate in this study. Cohort persons were offered annual hepatitis B e antigen (HBeAg) testing and semi-annual HCC screening. We developed a logistic regression model to compare HCC risk by genotype, adjusting for age, sex, region and HBeAg status.
Among the 1235 consenting study participants, 711 (57.6%) were male, 510 (41.3%) were HBeAg positive at cohort entry and 43 (3.5%) developed HCC. The HBV genotype was known for 1142 (92.5%) persons (13.5% A, 3.9% B, 6.7% C, 56.9% D, 19.0% F). The HCC incidence/1000 person-years of follow-up for genotypes A, B, C, D and F was 1.3, 0, 5.5, 0.4 and 4.2 respectively. Compared with persons with HBV genotype B/D infection, the HCC risk was higher for persons with genotypes A [adjusted odds ratio (aOR): 3.9, 95% confidence interval (CI): 1.14-13.74], C (aOR: 16.3, 95% CI: 5.20-51.11) and F (aOR: 13.9, 95% CI: 5.30-36.69).
HBV genotype is independently associated with HCC risk. AN persons with genotypes A, C and F are at higher risk compared with genotypes B or D.
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Few studies have examined factors associated with disease progression in hepatitis C virus (HCV) infection. We examined the association of 11 risk factors with adverse outcomes in a population-based prospective cohort observational study of Alaska Native/American Indian persons with chronic HCV infection.
We collected data from a population-based cohort study of liver-related adverse outcomes of infection in American Indian/Alaska Native persons with chronic HCV living in Alaska, recruited from 1995 through 2012. We calculated adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for end-stage liver disease (ESLD; presence of ascites, esophageal varices, hepatic encephalopathy, or coagulopathy), hepatocellular carcinoma (HCC), and liver-related death using a Cox proportional hazards model.
We enrolled 1080 participants followed up for 11,171 person-years (mean, 10.3 person-years); 66%, 19%, and 14% were infected with HCV genotypes 1, 2, and 3, respectively. On multivariate analysis, persons infected with HCV genotype 3 had a significantly increased risk of developing all 3 adverse outcomes. Their aHR for ESLD was 2.1 (95% CI, 1.5-3.0), their aHR for HCC was 3.1 (95% CI, 1.4-6.6), and their aHR for liver-related death was 2.4 (95% CI, 1.5-4.0) compared with genotype 1. Heavy alcohol use was an age-adjusted risk factor for ESLD (aHR, 2.2; 95% CI, 1.6-3.2), and liver-related death (aHR, 2.9; 95% CI, 1.8-4.6). Obesity was a risk factor for ESLD (aHR, 1.4; 95% CI, 1.0-1.9), and diabetes was a risk factor for ESLD (aHR, 1.5; 95% CI, 1.1-2.2). Male sex was a risk factor for HCC (aHR, 3.6; 95% CI, 1.6-8.2).
In a population-based cohort study of American Indian/Alaska Native persons with chronic HCV infection, we found those infected with HCV genotype 3 to be at high risk for ESLD, HCC, and liver-related death.
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Anil Suryaprasad and Kathy K. Byrd are with the Division of Viral Hepatitis; National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; Centers for Disease Control and Prevention (CDC); US Department of Health and Human Services; Atlanta, GA. John T. Redd is with the Santa Fe Public Health Service Indian Hospital, Indian Health Service, US Department of Health and Human Services, Santa Fe, NM. David G. Perdue is with the American Indian Cancer Foundation and Minnesota Gastroenterology PA, Minneapolis. M. Michele Manos is with the Kaiser Permanente Division of Research, Oakland, CA. Brian J. McMahon is with the Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, AL.
We compared chronic liver disease (CLD) mortality from 1999 to 2009 between American Indians and Alaska Natives (AI/ANs) and Whites in the United States after improving CLD case ascertainment and AI/AN race classification.
We defined CLD deaths and causes by comprehensive death certificate-based diagnostic codes. To improve race classification, we linked US mortality data to Indian Health Service enrollment records, and we restricted analyses to Contract Health Service Delivery Areas and to non-Hispanic populations. We calculated CLD death rates (per 100,000) in 6 geographic regions. We then described trends using linear modeling.
CLD mortality increased from 1999 to 2009 in AI/AN persons and Whites. Overall, the CLD death rate ratio (RR) of AI/AN individuals to Whites was 3.7 and varied by region. The RR was higher in women (4.7), those aged 25 to 44 years (7.4), persons residing in the Northern Plains (6.4), and persons dying of cirrhosis (4.0) versus hepatocellular carcinoma (2.5), particularly those aged 25 to 44 years (7.7).
AI/AN persons had greater CLD mortality, particularly from premature cirrhosis, than Whites, with variable mortality by region. Comprehensive prevention and care strategies are urgently needed to stem the CLD epidemic among AI/AN individuals.
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Three stages of chronic hepatitis B virus (HBV) infection are recognized: the immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis B carrier phase. Active liver disease is most often found in persons with elevated aminotransferase levels and HBV DNA levels >10(5) copies/mL. Possible risk factors for developing liver disease include older age, male gender, presence of hepatitis B e antigen (HBeAg), HBV genotype, mutations in the precore and core promoter regions of the viral genome, and coinfection with hepatitis D (delta) virus. All persons chronically infected with HBV should be followed every 6 to 12 months with aminotransferase levels. Those with elevated levels should be tested for HBeAg and its antibody (anti-HBe) as well as HBV DNA levels to determine if they are in need of further evaluation with a liver biopsy and are candidates for antiviral therapy. Future research will help clarify the outcome of chronic HBV infection.
Information delineating the possible causes for elevated serum aminotransferase activity among persons with chronic hepatitis B virus (HBV) infection is limited.
We analysed data collected from a population-based cohort of persons with chronic HBV infection followed from 2001 to 2010 to determine the frequency and causes of elevated aminotransferase activity. Any elevation concurrent with an HBV DNA level ?2000 IU/ml was attributed to immune active hepatitis B. Participant medical charts were reviewed by expert clinical staff to determine the presence of additional or alternative attributable causes. For each participant, a serum aminotransferase elevation could be attributed to more than one cause.
Among 1090 persons with chronic HBV infection, the mean follow-up was 7.7 years and the median age in 2001 was 39 (range 19-96) years; 634 (58.2%) had ?1 elevated aminotransferase level during follow-up and 438 (69.1%) of persons with ?1 elevation had at least one cause assigned for the elevation. The most common causes of aminotransferase elevations were immune active hepatitis B (48.4%), alcohol consumption (30.8%), and non-alcoholic fatty liver disease (NAFLD) (24.7%). Among participants with HBV DNA levels persistently less than 2000 IU/ml, the most common causes were NAFLD or alcohol consumption.
In this population-based cohort of persons with chronic HBV infection, the prevalence of elevated aminotransferase activity was high and attributable to immune active chronic hepatitis B in approximately half of the cases; however, NAFLD or alcohol consumption were also common causes for enzyme elevations. These findings underscore the importance of monitoring HBV DNA levels, in addition to aminotransferase activity, among persons with chronic HBV infection so that appropriate interventions, including antiviral therapy, are utilised.
Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska; Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC), Anchorage, Alaska.
There is little information on the proportion of persons with chronic hepatitis B virus (HBV) infection with active hepatitis. We aimed to determine the proportion of persons with hepatitis B e antigen-negative chronic HBV infection who develop immune-active HBV infection over time and the relationship between demographic and viral factors on severity of disease on liver biopsy.
We performed a longitudinal population-based cohort study of 754 Alaska Native patients with chronic HBV infection. Levels of alanine aminotransferase (ALT) were measured every 6 months, and levels of HBV DNA were measured at study entry and whenever ALT levels exceeded the upper limit of normal (ULN). Immune-active chronic HBV infection was defined as levels of ALT = 30 U/L in men and >20 U/L in women and levels of HBV DNA >2000 IU/mL at 1 or more time points from 2001-2008. Liver biopsies were scored by using the modified histology activity index score of Knodell and the Ishak fibrosis score.
Of the study participants, 186 (25%) met the criteria for immune-active HBV, 56% of these initially and 44% later during follow up. Of the 38 patients with liver biopsy results, only 1 of 16 with ALT levels consistently below twice the ULN and 1 of 19 with HBV DNA between 2000 and 20,000 IU/mL, vs 12 of 22 (55%) with ALT > twice ULN (P = .002) and 11 of 18 (61%) with 1 or more measurements of HBV DNA >20,000 IU/mL (P