Stephen E Livingston

Alaska Native Tribal Health Consortium, Anchorage, Alaska, United States

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Publications (20)102.79 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background & AimsThe Alaska Native population is one of few populations in the world with a high prevalence of autoimmune hepatitis. The objective of this study was to determine the frequency and HLA and clinical associations of autoantibodies in Alaska Native people with autoimmune hepatitis. Methods Alaska Native individuals with autoimmune hepatitis were recruited in clinics conducted statewide. Sera were tested for the presence of autoantibodies described in either autoimmune hepatitis or rheumatic disease. Associations between autoantibodies and HLA alleles and clinical features were assessed. ResultsSeventy-one patients were included. At the study visit, 34 patients (47.9%) had antibodies to double-stranded DNA by immunofluorescence; 27 (38.0%) had anti-neutrophil cytoplasmic antibodies; and 11 (15.5%) had anti-Ro antibodies. Only one person had antibodies against soluble liver antigen, and in that person, anti-Ro was absent. Associations were found between autoantibodies and HLA alleles, including positive associations between HLA DR3 and anti-double-stranded DNA antibodies and between HLA DR14 and antineutrophil cytoplasmic antibodies. There was no association between autoantibodies and clinical outcomes. Conclusions As in other populations, the prevalence of anti-double-stranded DNA antibodies and antineutrophil cytoplasmic antibodies is high in Alaska Native people with autoimmune hepatitis. In contrast to data from other populations, there is a lower prevalence of anti-soluble liver antigen and a lack of association between anti-Ro and anti-soluble liver antigen. In addition, the HLA profile and associations with autoantibodies are unique. No clear prognostic implications of autoantibodies have emerged in this population.
    Liver international: official journal of the International Association for the Study of the Liver 11/2013; · 3.87 Impact Factor
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    ABSTRACT: 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>2,000 IU/ml at 1 or more time point, from 2001 through 2008. Liver biopsies were scored 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 1/16 with ALT levels consistently below twice the ULN and 1/19 with HBV DNA between 2000 and 20,000 IU/ml, vs. 12/22 (55%) with ALT > twice ULN (P=.002) and 11/18 (61%) with 1 or more measurements of HBV DNA > 20,000 IU/ml (P<.001), had moderate or severe hepatitis or fibrosis. In a cohort of Alaska Natives with chronic HBV infection, 25% met criteria for immune active HBV. There is a low probability of advanced fibrosis if levels of HBV DNA never exceed 20,000 IU/ml.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2013; · 5.64 Impact Factor
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    ABSTRACT: Treatment with pegylated interferon and ribavirin may prevent progression of liver disease among patients with chronic hepatitis C virus infection (HCV). Treatment initiation is based on published clinical eligibility criteria, patients' willingness to undergo treatment and likelihood of success. We examined treatment eligibility in a cohort of Alaska Native and American Indian persons with chronic HCV infection. Retrospective cohort study. Medical records of all treatment naïve HCV RNA positive patients given an appointment by hepatology specialty clinic staff in 2003 and 2007 were evaluated by a hepatology provider to investigate documented reasons for treatment deferral. Treatment was initiated in 4 of 94 patients (4%) in 2003 and 14 of 146 patients (10%) in 2007. Major reasons for treatment deferral in 2003 versus 2007 included inconsistent appointment attendance (36% of deferrals vs. 18%), active substance abuse (17% vs. 22%), patient decision (17% vs. 27%), liver biopsy without fibrosis or normal ALT (8% vs. 3%), uncontrolled psychiatric condition (7% vs. 7%) and concurrent medical condition (6% vs. 9%). There was significant improvement in proportion of appointments attended in 2007 versus 2003 (76% vs. 67%, p = 0.04) and the percentage of patients attending at least 1 appointment (84% vs. 66%, p = 0.002). Multiple reasons for treatment deferral were documented. Despite a significant improvement in hepatology clinic attendance and an increase in the number of patients started on treatment in 2007 compared to 2003, the overall percentage of those treated remained low.
    International journal of circumpolar health. 01/2012; 71:1-7.
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    ABSTRACT: The present study describes natural genetic heterogeneity of hepatitis C virus (HCV) p7 protein, the ion channel that plays a critical role in assembly and release of HCV, within 299 variants isolated from serum specimens of 27 chronically infected patients, 12 of whom with human immunodeficiency virus (HIV) co-infection. Liver fibrosis stage was inversely correlated with p7 synonymous substitutions (dS) (p=0.033), and indices of p7 genetic diversity were significantly higher in HIV-negative subjects compared to HIV-positive subjects (dS, p=0.005; non-synonymous substitutions (dN), p=0.002; dN/dS ratio, p=0.024; amino acid distances, p=0.007). Six p7 genes with naturally occurring unique amino acid variations were selected for in vitro study. The variants demonstrated diversified functional heterogeneity in vitro, with one variant from a subject with severe liver disease displaying hyperactive ion channel function, as well as other variants presenting altered pH-activated channel gating activities.
    Virology 12/2011; 423(1):30-7. · 3.35 Impact Factor
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    ABSTRACT: In autoimmune hepatitis (AIH) patients treated with azathioprine, the utility of measuring thiopurine methyltransferase (TPMT) and azathioprine metabolites has been limited. To evaluate the association between TPMT genotype and enzyme activity, and the impact of TPMT enzyme activity on levels of azathioprine metabolites and leukopenia to assess the clinical utility of monitoring azathioprine metabolites in Alaska Native and other non-Caucasian AIH patients. Individuals with AIH were recruited at the Alaska Native Medical Center (Alaska, USA) and the University of Texas Southwestern Medical Center (Texas, USA). Identification of TPMT genotype and measurement of enzyme activity were performed. The metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) were measured in participants who were on azathioprine, and the associations with disease remission and leukopenia were assessed. Seventy-one patients with AIH were included. The distribution of TPMT genotypes was similar to that reported in other populationbased studies. TPMT genotype and phenotype were strongly associated (P<0.0001). Levels of 6-TGN and 6-MMP correlated with azathioprine dose only in individuals with normal TPMT enzyme activity. Patients with leukopenia due to azathioprine were no more likely to have abnormal TPMT enzyme levels than those without leukopenia (P=1.0). No specific level of 6-TGN metabolites was associated with remission or leukopenia. Results of the present study were consistent with previous studies in Caucasian populations. TPMT genotype and phenotype correlated well, and levels of 6-TGN and 6-MMP metabolites were not associated with remission of AIH or toxicity of azathioprine. The present study confirmed the limited utility of monitoring levels of azathioprine metabolites in AIH patients.
    Canadian journal of gastroenterology = Journal canadien de gastroenterologie 01/2011; 25(1):21-7. · 1.53 Impact Factor
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    ABSTRACT: Infection with hepatitis C virus (HCV) is one of the leading causes of chronic hepatitis, liver cirrhosis and end-stage liver disease worldwide. The genetics of HCV infection in humans and the disease course of chronic hepatitis C are both remarkably variable. Although the response to interferon treatment is largely dependent on HCV genotypes, whether or not a relationship exists between HCV genome variability and clinical course of hepatitis C disease still remains unknown. To more thoroughly understand HCV genome evolution over time in association with disease course, near genome-wide HCV genomes present in 9 chronically infected participants over 83 total study years were sequenced. Overall, within HCV genomes, the number of synonymous substitutions per synonymous site (d(S)) significantly exceeded the number of non-synonymous substitutions per site (d(N)). Although both d(S) and d(N) significantly increased with duration of chronic infection, there was a highly significant decrease in d(N)/d(S) ratio in HCV genomes over time. These results indicate that purifying selection acted to conserve viral protein structure despite persistence of high level of nucleotide mutagenesis inherent to HCV replication. Based on liver biopsy fibrosis scores, HCV genomes from participants with advanced fibrosis had significantly greater d(S) values and lower d(N)/d(S) ratios compared to participants with mild liver disease. Over time, viral genomes from participants with mild disease had significantly greater annual changes in d(N), along with higher d(N)/d(S) ratios, compared to participants with advanced fibrosis. Yearly amino acid variations in the HCV p7, NS2, NS3 and NS5B genes were all significantly lower in participants with severe versus mild disease, suggesting possible pathogenic importance of protein structural conservation for these viral gene products.
    PLoS ONE 01/2011; 6(5):e19562. · 3.53 Impact Factor
  • Brian J. McMahon, Brenna C. Simons, Stephen E. Livingston
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    ABSTRACT: Four phases of chronic hepatitis B virus [1] infection have been identified: immune tolerant, immune active, inactive, and hepatitis B surface antigen (HBsAg) clearance. These phases are defined by using a combination of hepatitis B “e” antigen (HBeAg) status, alanine aminotransferase (ALT) level, and HBV DNA level. To determine the extent of liver inflammation and fibrosis needed to decide whether antiviral therapy is necessary often requires a liver biopsy. Recent studies have found that levels of HBsAg can also be used to determine the phase of HBV and can even predict persons who may remain in the inactive phase over time. Non invasive markers including transient elastography can detect a proportion of those with a high probability of severe fibrosis and mild disease but are not yet helpful to determine the status of most chronically infected persons.
    Current Hepatitis Reports 01/2011;
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    ABSTRACT: Various factors influence the development and rate of fibrosis progression in chronic hepatitis C virus (HCV) infection. To examine factors associated with fibrosis in a longterm outcomes study of Alaska Native/American Indian persons who underwent liver biopsy, and to examine the rate of fibrosis progression in persons with subsequent biopsies. A cross-sectional analysis of the demographic, inflammatory and viral characteristics of persons undergoing liver biopsy compared individuals with early (Ishak fibrosis score of lower than 3) with those with advanced (Ishak score of 3 or greater) fibrosis. Persons who underwent two or more biopsies were analyzed for factors associated with fibrosis progression. Of 253 HCV RNA-positive persons who underwent at least one liver biopsy, 76 (30%) had advanced fibrosis. On multivariate analysis, a Knodell histological activity index score of 10 to 14 and an alpha-fetoprotein level of 8 ng/mL or higher were found to be independent predictors of advanced liver fibrosis (P<0.0001 for each). When surrogate markers of liver inflammation (alanine aminotransferase, aspartate aminotransferase/alanine aminotransferase ratio and alpha-fetoprotein) were removed from the model, type 2 diabetes mellitus (P=0.001), steatosis (P=0.03) and duration of HCV infection by 10-year intervals (P=0.02) were associated with advanced fibrosis. Among 52 persons who underwent two or more biopsies a mean of 6.2 years apart, the mean Ishak fibrosis score increased between biopsies (P=0.002), with progression associated with older age at initial biopsy and HCV risk factors. The presence of type 2 diabetes mellitus, steatosis and duration of HCV infection were independent predictors of advanced fibrosis in the present cohort, with significant fibrosis progression demonstrated in persons who underwent serial biopsies.
    Canadian journal of gastroenterology = Journal canadien de gastroenterologie 07/2010; 24(7):445-51. · 1.53 Impact Factor
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    ABSTRACT: 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 < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance. CONCLUSION: HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early.
    Hepatology 05/2010; 51(5):1531-7. · 12.00 Impact Factor
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    ABSTRACT: The factors associated with adverse outcome from hepatitis C virus (HCV) infection are incompletely understood. To determine the incidence and risk factors associated with the development of end-stage liver disease (ESLD) and liver-related death (LRD), we conducted a retrospective/prospective population-based study in a cohort of Alaska Native persons chronically infected with HCV from 1994 to 2005. We followed 960 persons prospectively for an average of 7.2 years and retrospectively for 12.1 years with data from medical records and serum samples. We compared data from subjects that were chronically infected with those who recovered from HCV infection, stratified by alcohol use. Survival models were used to examine factors associated with ESLD and LRD in chronically infected patients. During prospective follow-up, 80 (8.8%) and 47 (5.2%) patients developed ESLD and LRD, respectively. In examining incidence per 100 person-years, no difference was found among heavy alcohol users in the incidence of LRD (2.28 versus 3.50; P = .34) or ESLD (3.21 versus 5.69; P = .13) in persons with chronic HCV compared with those recovered from HCV infection. In subjects that consumed <50 g alcohol/d, the incidences of LRD were 0.77 and 0.09 (P = .01) and of ESLD were 1.58 versus 0.36 (P = .002), respectively, in subjects with chronic infection versus those that recovered. Multivariate analysis showed that older age, heavy alcohol use, and HCV genotype 3 were associated with ESLD. A history of heavy alcohol use is associated with the highest incidence of LRD and ESLD, regardless of whether patients are chronically infected or recover from HCV infection.
    Gastroenterology 11/2009; 138(3):922-31.e1. · 12.82 Impact Factor
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    ABSTRACT: A number of emerging molecules and pathways have been implicated in mediating the T-cell exhaustion characteristic of chronic viral infection. Not all dysfunctional T cells express PD-1, nor are they all rescued by blockade of the PD-1/PD-1 ligand pathway. In this study, we characterize the expression of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) in chronic hepatitis C infection. For the first time, we found that Tim-3 expression is increased on CD4(+) and CD8(+) T cells in chronic hepatitis C virus (HCV) infection. The proportion of dually PD-1/Tim-3-expressing cells is greatest in liver-resident T cells, significantly more so in HCV-specific than in cytomegalovirus-specific cytotoxic T lymphocytes. Tim-3 expression correlates with a dysfunctional and senescent phenotype (CD127(low) CD57(high)), a central rather than effector memory profile (CD45RA(negative) CCR7(high)), and reduced Th1/Tc1 cytokine production. We also demonstrate the ability to enhance T-cell proliferation and gamma interferon production in response to HCV-specific antigens by blocking the Tim-3-Tim-3 ligand interaction. These findings have implications for the development of novel immunotherapeutic approaches to this common viral infection.
    Journal of Virology 08/2009; 83(18):9122-30. · 5.08 Impact Factor
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    ABSTRACT: A higher proportion of deaths among American-Indian/Alaska-Native (AI/AN) people has been attributed to chronic liver disease (CLD) compared with other racial/ethnic groups in the United States. The objectives of this study were to determine CLD prevalence and to define its etiologies and complications among AN and AI people, who received health care from an urban hospital center. We conducted a retrospective, cross-sectional study of AN and AI people > or =18 years old who had at least one patient encounter at the Alaska Native Medical Center during January 2003-December 2004. A total of 1,886 (7.2%) of 26,166 AI/AN people met criteria for having CLD. The most commonly identified etiologies were alcohol-related liver disease (42%), nonalcoholic fatty liver disease (31%), chronic hepatitis C virus infection (26%), and chronic hepatitis B virus infection (8%). Compared with women, men had a higher overall prevalence of CLD (81.9 vs. 64.7 per 1,000), but were less likely to die from a CLD-related cause (1.5 vs. 2.7 per 1,000). These differences in the CLD deaths were mostly attributed to alcohol-related liver disease. This is the first known population-based study to examine the burden and etiology of CLD among AN people. Causes of CLD were similar among AI/AN people as those reported among other racial/ethnic groups in the United States. Identifying specific etiologies of CLD among populations can help target appropriate prevention and treatment strategies as they are specific to the causes of CLD.
    The American Journal of Gastroenterology 02/2009; 104(2):363-70. · 7.55 Impact Factor
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    ABSTRACT: The clinical significance of elevated serum alpha-fetoprotein (AFP) in patients with chronic hepatitis C virus (HCV) infection is not well defined. We analysed data from a population-based cohort of patients with HCV infection to assess the prevalence of elevated serum AFP, to determine its association with clinical and virologic parameters and with clinical outcomes. We defined a slightly elevated serum AFP level as 8 to <15 and a high-AFP level as > or =15 microg/L. Among 541 HCV-RNA-positive persons, 61 (11%) had a slightly elevated or high AFP at the time of consent. AFP > or =8 microg/L was associated with the older age, aspartate aminotransferase/alanine aminotransferase ratio >1, and higher alkaline phosphatase levels, but not with heavy alcohol use, IV drug use, genotype, viral load or duration of HCV infection. Among 192 persons with an AFP at liver biopsy, 17% had an AFP > or =8 microg/L. The sensitivity/specificity of an AFP level > or =8 in detecting Ishak 3-6 fibrosis was 39%/95%. Among 372 persons with a minimum of four AFP measurements over 6 years, 5% had persistently elevated AFP >8 microg/L, 19% had both elevated and normal AFP measurements, and 76% had persistently normal AFP. Elevated AFP at consent was associated with hepatocellular carcinoma (HCC) and end-stage liver disease. Over 6 years of follow-up, persistently elevated AFP was associated with the development of HCC; no person with AFP persistently <8 microg/mL developed HCC. Serial AFP measurements appear to be useful in identifying persons with advanced fibrosis and help to determine who needs periodic screening with liver ultrasound to detect HCC.
    Journal of Viral Hepatitis 04/2008; 15(3):179-87. · 3.08 Impact Factor
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    ABSTRACT: Persistence of hepatitis B e antigen (HBeAg) in chronic hepatitis B has been associated with increased risk for development of cirrhosis and hepatocellular carcinoma. Five hepatitis B virus genotypes were identified in Alaska Native persons; we analyzed clearance of HBeAg by age and genotype. In this prospective cohort study, 1158 Alaska Native persons throughout Alaska were tested serially for HBeAg for a median of 20.5 years and were genotyped. Initial and final HBeAg-positive specimens, time to clearance, age at clearance, and subsequent HBeAg results were analyzed for persons initially HBeAg-positive. Subsequent HBeAg results were analyzed for persons initially negative. Genotypes A, B, C, D, and F were identified. Genotype C persons initially HBeAg-positive were more likely than those with other genotypes to be positive on initial and final specimens (P < .001 for each) and time to HBeAg clearance was longer (P < .001). Age at which 50% of persons cleared HBeAg was <20 years for those infected with genotypes A, B, D, and F and 47.8 years in genotype C (P < .001). After losing HBeAg, those with genotypes C and F were more likely to revert to the HBeAg-positive state (P < .001). Genotype may have a strong effect on mode of transmission and outcome. Genotype C may have been responsible for most perinatal transmission, given that seroconversion from HBeAg occurs decades later than in other genotypes.
    Gastroenterology 11/2007; 133(5):1452-7. · 12.82 Impact Factor
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    ABSTRACT: The highest incidence of hepatitis B virus (HBV)-associated vasculitis in the world has been reported in Alaska Natives. We examined the incidence of HBV-associated vasculitis before and after mass HBV vaccine immunization and the association between HBV genotype and vasculitis in a population-based cohort study in Alaska natives chronically infected with HBV. Genotyping was performed in vasculitis cases and 644 hepatitis B-positive controls without vasculitis using polymerase chain reaction and sequencing of the S gene. Occurrence of HBV vasculitis from 1974 to 2004 was calculated. HBV vasculitis patients and controls were also tested for basal core promoter and precore mutations. Fifteen cases of HBV-associated vasculitis were identified: 13 (86%) had genotype D and one each genotype A and F. Genotype D was more commonly found in patients with vasculitis than controls [odd ratio (OR)=5.9, confidence interval (95% CI) 1.2, 21.8; P<0.015). HBV-associated vasculitis was associated with genotype D.
    Liver international: official journal of the International Association for the Study of the Liver 06/2007; 27(5):627-32. · 3.87 Impact Factor
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    ABSTRACT: The development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection has been associated with specific HBV genotypes and the presence of specific mutations. From a cohort of Alaska Native people with chronic HBV infection, we genotyped 47 patients with HCC and 1129 patients without HCC, and we tested patients with HCC and control patients for mutations in the basal core promoter and precore regions. Genotype F was found in 68% of patients with HCC, versus 18% of those without HCC (P<.001). For patients with genotype F, the median age at diagnosis of HCC was lower than that for patients with other genotypes (22.5 vs. 60 years, respectively; P=.002). Overall, there were no significant differences in the number of basal core promoter and precore region mutations between patients with HCC and control patients. We found a significant association between genotype F and the development of HCC among Alaska Native people with chronic HBV infection but no significant association between HCC and basal core promoter or precore mutations in genotype F.
    The Journal of Infectious Diseases 01/2007; 195(1):5-11. · 5.85 Impact Factor
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    ABSTRACT: Liver biopsy is the primary method of assessing liver injury in hepatitis C patients. FIBROSpect II (FS), a diagnostic panel of three extracellular matrix remodelling markers, may be useful as a noninvasive alternative to this procedure. The purpose of this study was to correlate FS results with liver fibrosis scores to determine if this test is sufficiently accurate to be a viable alternative to liver biopsy. A total of 142 serum specimens were evaluated for fibrosis with FS and were compared with Knodell and Ishak fibrosis scores. FS reports an index score ranging from 0.1 to 1.0, which corresponds to the probability of progressive liver fibrosis. Using a FS index cut-off of 0.42, 50 of 54 patients with Ishak 3-6 were classified as having advanced fibrosis (METAVIR F2-F4) and 58 of 88 patients with Ishak 0-2 as having no/mild fibrosis (METAVIR F0-F1), resulting in a sensitivity of 93%, specificity of 66%, and an overall test accuracy of 76%. With a 38% prevalence of advanced fibrosis, the negative predictive value was 94% and positive predictive value was 63%. A biopsy length of > or = 2 cm was associated with higher concordance between FS results and liver fibrosis scores (P = 0.01). FS was clinically useful in ruling out advanced fibrosis in hepatitis C by identifying patients with mild disease in whom treatment could be deferred. The limitation of this test is its decreased sensitivity and specificity in the middle of the test's reporting range between scores of 0.42 and 0.80.
    Journal of Viral Hepatitis 10/2006; 13(10):652-8. · 3.08 Impact Factor
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    ABSTRACT: An estimated one-third of patients with chronic hepatitis C virus (HCV) infection have persistently normal alanine transaminase (PNALT); however, in many previous studies alanine aminotransferase (ALT) levels were followed for < or = 12 months. We analyzed data from a population-based cohort of 935 Alaska Natives with HCV, recruited from 1994 to 2005, to determine the proportion of persons with PNALT, persistently elevated ALT (PEALT), and fluctuating ALT (FLUXALT) to determine factors for each ALT state. We selected persons with two positive HCV RNA results > or = 1 year apart and > or = 6 ALT levels measured over the subsequent 3 years with at least 1 month between ALT measurements (n = 265). We defined a person as having PNALT, PEALT, or FLUXALT when all six ALT levels were normal, elevated, or did not fit either of the above two categories, respectively, during the 3-year follow-up period. Among 208 persistently HCV RNA-positive persons, 13 had PNALT, 121 PEALT, 74 FLUXALT. Among 77 persons who underwent liver biopsy, those with PEALT were more likely to have Ishak fibrosis scores > 2 compared with persons with FLUXALT (44% vs. 10%, OR 7.0, 95% CI: 1.5-33.2). No statistically significant differences were found in ALT classification by age, gender, infection duration, median body mass index, alcohol consumption, residence, risk behavior, RNA level, or genotype. Only 6% of persons with chronic HCV had PNALT. Persons with PEALT were significantly more likely to have higher fibrosis scores on liver biopsy than those with FLUXALT. Previous studies with short follow-up periods may have overestimated the proportion of persons with normal ALT levels.
    Liver international: official journal of the International Association for the Study of the Liver 08/2006; 26(6):643-9. · 3.87 Impact Factor
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    ABSTRACT: To determine the prevalence and characteristics of steatosis in Alaska Natives/American Indians (AN/AI) with chronic hepatitis C virus (HCV) infection. This outcomes study began in 1994, and 988 AN/AI have been enrolled, including 222 study patients with a positive HCV RNA who underwent liver biopsy. Study patients were analyzed for sex, age at biopsy, estimated length of infection, body mass index (BMI), genotype, ethanol use, HCV RNA and alanine aminotransferase levels. A pathologist blinded to patient identity and clinical data reviewed all biopsy slides for histologic activity and fibrosis. Moderate to severe steatosis was found significantly more often in genotype 3 than in genotypes 1 and 2 (p = 0.008). On multivariate analysis, BMI > 30 and Ishak fibrosis score > or = 2 were significantly associated with steatosis (p = 0.0013 and 0.0002, respectively), but only genotype 3 was associated with presence of moderate to severe steatosis (p = 0.008). Our findings in a cohort of AN/AI are consistent with results of previous studies in other groups that steatosis is associated with fibrosis in HCV and infection with genotype 3 is associated with more severe steatosis.
    International journal of circumpolar health 06/2006; 65(3):253-60. · 1.30 Impact Factor
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    ABSTRACT: Large cohorts of persons infected with hepatitis C virus (HCV) that include patients with multiple risk exposures and behaviors have been rarely reported. We herein describe a population-based cohort of 759 Alaska Natives (AN) with HCV who were recruited into a long-term follow-up study. History of injection drug use (IDU) was reported by 60.1% and blood transfusion by 14.0%. The most common genotype was 1a (42.0%), followed by 1b (20.3%), 2b (14.7%), 3a (14.3%), and 2a (7.8%). By multivariable analysis, risk exposures (blood transfusion vs. other; P < 0.01; odds ratio [OR], 2.87; 95% confidence interval [CI], 1.51-5.45) and year of infection (P < 0.01; OR, 3.47; 95% CI, 1.34-8.96) were significantly associated with HCV RNA-positivity. Having an RNA concentration >/=2 million copies/mL was associated with male gender (OR, 1.94) and genotype (P < 0.01 overall; 1a vs. 3a: OR, 1.92; 2b vs. 3a: OR, 3.17) by multivariable analysis. In conclusion, the two principal risk exposures for AN infected with HCV (IDU and blood transfusion) are the same as the overall U.S. population. Persons with a history of blood transfusion were more likely to be HCV RNA positive than those without such history. Higher RNA levels found in males may explain the more severe disease previously reported in this group.
    Hepatology 03/2004; 39(2):325-32. · 12.00 Impact Factor

Publication Stats

464 Citations
102.79 Total Impact Points

Institutions

  • 2007–2013
    • Alaska Native Tribal Health Consortium
      Anchorage, Alaska, United States
  • 2011
    • University of Washington Seattle
      • Department of Laboratory Medicine
      Seattle, WA, United States
  • 2009
    • Centers for Disease Control and Prevention
      • Division of Viral Hepatitis
      Druid Hills, GA, United States
  • 2004–2009
    • Alaska Native Medical Center
      Anchorage, Alaska, United States