Jill Kuzniarek

Higher Serum Testosterone is associated with Increased Risk of Advanced Hepatitis C-related Liver Disease in Males

Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)‐related advanced liver disease is unknown. We performed a cross‐sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE‐ActiTest. Other risk‐factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., body mass index), and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by the FibroSURE‐ActiTest was evaluated with logistic regression. A total of 308 eligible study participants were prospectively recruited (mean age: 57; 52% African‐American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls as well as 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases, compared to mild disease controls (6.0 versus 5.3 ng/mL and 5.9 versus 5.4 ng/mL, respectively). We observed a significant 25% increase in advanced fibrosis risk and 15% increase in advanced inflammatory activity risk for each 1‐ng/mL increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (odds ratio [OR]adjusted advanced fibrosis = 3.74; 95% CI: 1.86‐6.54 versus ORadjusted advanced inflammatory activity = 2.23; 95% CI: 1.07‐4.93, respectively). Conclusions: Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV‐infected men. Testosterone may be important in the pathogenesis of HCV‐related advanced liver disease in males. (Hepatology 2011)

Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C

BACKGROUND & AIMS Coffee or caffeine has been proposed to protect against hepatic fibrosis, but few data are available on their effects in patients with chronic hepatitis C virus (HCV) infection. METHODS We conducted a cross-sectional study of veterans with chronic HCV infection to evaluate the association between daily intake of caffeinated and decaffeinated coffee, tea, and soda, and level of hepatic fibrosis, based on the FibroSURE test (BioPredictive, Paris, France) (F0-F3, mild [controls] vs. F3/F4-F4, advanced). Models were adjusted for multiple potential confounders including age, alcohol abuse, and obesity. RESULTS Among 910 patients with chronic HCV infection, 98% were male and 38% had advanced hepatic fibrosis. Daily intake of caffeinated coffee was higher among controls than patients with advanced fibrosis (1.37 vs. 1.05 cups/d; P = .038). In contrast, daily intake of caffeinated tea (0.61 vs. 0.56 cups/d; P = .651) or soda (1.14 vs. 0.95 cans/d; P = .106) did not differ between the groups. A higher percentage of controls (66.0%) than patients with advanced fibrosis (57.9%) consumed 100 mg or more of caffeine daily from all sources (P = .014); controls also received a larger proportion of their caffeine from coffee (50.2% vs. 43.0%; P = .035). Hepatoprotective effects of an average daily intake of 100 mg or more of caffeine (adjusted odds ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .020) and 1 cup or more of caffeinated tea by non-coffee drinkers (adjusted odds ratio, 0.56; 95% confidence interval, 0.34-0.94; P = .028) persisted after adjustment for confounders, including insulin resistance. CONCLUSIONS A modest daily caffeine intake (as little as 100 mg) may protect against advanced hepatic fibrosis in men with chronic HCV infection. Additional research is needed to confirm these findings in women and in people with other chronic liver diseases.

WNT Signaling Pathway Gene Polymorphisms and Risk of Hepatic Fibrosis and Inflammation in HCV-Infected Patients

Background Chronic hepatitis C infection is the leading cause of hepatocellular carcinoma (HCC), a highly lethal malignancy with rapidly increasing prevalence in the United States. Little is known about genetic variations and HCC risk. This study aimed to determine if genetic variation in Wnt signaling pathway genes are associated with advanced hepatic fibrosis and inflammation risk in a hepatitis C virus (HCV) infected population. Methods We performed a genetic association cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 58 candidate genes and risk of FibroSURE-Acti Test determined advanced fibrosis (F3/F4-F4 advanced cases vs. F0-F3 mild controls) and inflammation (A2/A3-A3 advanced cases vs. A0-A2 mild controls). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) employing multivariate logistic regression. Haplotypes were inferred by the HAPLO.STAT program, interactions were evaluated using multifactor dimensionality reduction (MDR) analysis. Results Among 425 chronically HCV-infected male veterans, 155 (37%) had advanced fibrosis and 180 (42%) had advanced inflammation. Of 3016 SNPs evaluated, eight were significantly associated with fibrosis risk (e.g., SFRP2 rs11937424: OR = 2.19, 95% CI 1.48-3.23, P = 0.00004), and seven were significantly associated with inflammation risk (e.g., SFRP1 rs16890282: OR = 2.15, 95% CI 1.39-3.16, P = 0.0004). MDR analysis identified overweight/obese, SOST rs1405952, SFRP2 rs11937424, and FZD4 rs11234870 as the best interaction model for predicting risk of fibrosis; whereas race/ethnicity, FZD1 rs1346665, and TBX3 rs1520177 as the best interaction model for predicting risk of inflammation. Conclusions Polymorphisms in several genes involved in the Wnt signaling pathway were associated with hepatic fibrosis or inflammation risk in HCV-infected males. Additional studies in other multi-ethnic HCV cohorts are needed to validate our findings in males and to assess if similar associations exist in chronically HCV-infected females.

The association between serological and dietary vitamin D levels and hepatitis C-related liver disease risk differs in African American and white males

Vitamin D may affect the severity of HCV‐related liver disease.

Dietary fructose intake and severity of liver disease in hepatitis C virus-infected patients.

Background and Goals: Dietary fructose intake in the United States has been increasing, and fructose intake has been associated with the metabolic syndrome and hepatic steatosis. This study aimed to determine whether dietary fructose intake is associated with advanced hepatic fibrosis and inflammation in an hepatitis C virus (HCV)-infected male population. Study: We conducted a cross-sectional study of HCV-infected male veterans. The main exposure variable was daily dietary fructose calculated from the National Cancer Institute Diet History Questionnaire and the main outcome variables were FibroSURE-ActiTest determined hepatic fibrosis (F0-F3=mild vs. F3/F4-F4=advanced) and inflammation (A0-A2=mild vs. A2/A3-A3=advanced). We examined this association in logistic regression adjusting for demographic, clinical, and other dietary variables. Results: Among 313 HCV+ males, 103 (33%) had advanced fibrosis and 89 (28%) had advanced inflammation. Median daily fructose intake was 46.8 g (interquartile range, 30.4 to 81.0). Dietary fructose intake across quartiles among males with advanced versus mild fibrosis was 21.4% versus 25.2%, 32.0% versus 24.8%, 24.3% versus 25.2%, and 22.3% versus 24.8%, respectively, and among males with advanced versus mild inflammation was 20.2% versus 25.5%, 41.6% versus 21.4%, 22.5% versus 25.9%, and 15.7% versus 27.2%, respectively. In multivariate analysis, there were no significant associations between daily fructose intake and advanced fibrosis. There was a significant association only between the second quartile of daily fructose intake (30 to 48 g) and advanced inflammation. Conclusions: There were no significant associations between dietary fructose intake and hepatic fibrosis risk, as assessed by FibroSURE, in HCV-infected males. Additional research is needed to clarify the potential role of fructose intake and HCV-related hepatic inflammation.

Su1033 Sex Hormone Pathway Gene Polymorphisms Are Associated With Risk of Advanced Hepatitis C-Related Liver Disease in Males

BACKGROUND Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear. GOAL To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males. METHODS We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction. RESULTS Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation. CONCLUSIONS The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.

Racial differences in the association between adiposity measures and the risk of hepatitis C-related liver disease.

Background: African Americans have lower reported likelihood of hepatitis C virus-related cirrhosis than whites. It is unknown whether relative differences in the distribution of adipose tissue, lean mass, and other anthropometric measurements may explain these observed interethnic differences in disease risk. Aim: To evaluate the association between anthropometric measurements and advanced liver disease in a cross-sectional study of African American and white male veterans. Methods: We used the validated FibroSURE-ActiTest to assess hepatic pathology, and direct segmental multichannel bioelectric impedance analysis for anthropometric measurements. Race-stratified logistic regression was employed to evaluate risk of high fibrosis progression rate (FPR) and advanced inflammation (A2 to A3). Results: Among 330 eligible males (59% African American), there were 43 white and 57 African American males with high FPR, and 70 African American and 59 white with advanced inflammation. Percentage body fat (%BF) was a stronger predictor of high FPR risk than was a high body mass index in African Americans [odds ratio (OR)adj=2.08; 95% confidence interval (CI),0.83-5.23 for highest %BF vs. lowest tertile and ORadj=1.50; 95% CI,0.60-3.75 for obese vs. normal body mass index, respectively], but not in whites. Highest lean leg mass was associated with a nonsignificant increased risk of both high FPR and advanced inflammation in African Americans (ORhighFPRadj=1.73; 95% CI, 0.73-4.10; ORAdvancedinflammationAdj=1.65; 95% CI, 0.76-3.56) versus a decreased risk of both in whites (ORhighFPRadj=0.62; 95% CI, 0.21-1.79; ORAdvancedinflammationAdj=0.58; 95% CI, 0.22-1.48). Conclusions: Interethnic differences in nontraditional anthropometric measurements like %BF suggests their potential role in understanding interethnic differences in hepatitis C virus-related liver disease risk in males.

Sa1071 Military Sexual Trauma in Veterans With Hepatitis C: Gender-Based Prevalence and Association With Conditions That Impact Treatment Eligibility

Some co-morbidities of interest included type II diabetes (13.3%), depression (11.7%), and substance abuse (14.5%). Preand post-diagnosis, type II diabetes increased with disease severity (NCD=11.5% pre; 13.5% post) (CC=16.2% pre; 19.9% post) (ESLD=21.7% pre; 26.8% post.. Similarly, substance abuse increased with disease severity (NCD=14.1% pre; 20.4% post) (CC=15.1% pre; 22.3% post) (ESLD=16.5% pre; 26% post). Depression also increased from 11.7% pre-diagnosis to 16.3% following diagnosis, but was fairly evenly distributed across disease severity cohorts. Anemia was highly prevalent following diagnosis (12.3%), especially in the ESLD cohort (28.3%). Only 10.9% of the population received treatment for HCV, the majority (83.1%) with dual therapy compared to 13.2% with telaprevir and 3.4% with boceprevir based triple therapy. The modest use of the protease inhibitors likely reflects their coming to market in 2011. In the six months following diagnosis, utilization of inpatient, hospital outpatient, emergency room, physician office, and pharmacy services increased significantly. Utilization and costs increased with disease severity and treatment rate was highest among CC patients. CONCLUSIONS: A small percentage of HCV patients receive treatment. Type II diabetes, depression, and substance abuse are common among patients with HCV. Healthcare utilization and cost increased after diagnosis and were highest among those with the most severe disease.

Sa1092 Higher Total Serum Testosterone Level is Associated With Increased Risk of Biopsy-Confirmed Advanced Hepatic Fibrosis and Inflammation but Not Advanced Steatosis in Male Veterans With Chronic Hepatitis C

consent were evaluated with a minucious questionaring and were retested for HCV RNA. Results Between January 2011and October 2011, 61 patients (49 males/12 females, mean age 37,5 years, range 20-61) were included in the present study. 67,7% had genotype 3a. The mean time between the end of treatment and re-evaluation was 2,5 years (range 1-7). At the day of re-evaluation, 37/61 (60%) patients reported active drug use and 21/37 (56,8%) were injected drug users. 27/61 (43,5%) patients were on methadone / buprenorphine substistution. Only 5/61 (8,1%) cases of reinfection were observed. They were all injected drug users and 4 of whom were infected with another HCV genotype from the initial, while one patient was reinfected with the same (genotype 3a). Two of these 5 patients were lost from the supervised program. Conclusion Our study showed that the rate of reinfection after successful treatment of HCV infection in past or current users is very low. In IVDUs, treatment of hepatitis C is feasible, when a multidisciplinary team is willing to provide the appropriate care.

High Total Serum Testosterone is Associated With Increased Risk of Advanced Hepatic Fibrosis and Inflammatory Activity in Male Veterans With Chronic Hepatitis C

Background: Increased relative adiposity, measured as BMI or waist circumference, is a recognized risk factor for HCV-related liver disease. Bioelectric impedance analysis (BIA)based measurements of adiposity offer advantages including less inter-observer variability compared with widely used anthropometric calculations. There have been no studies of BIA in association with HCV-related liver disease. Methods: HCV+ male veterans with confirmed HCV viremia and without ascites or decompensated disease were recruited at a single VA medical center. We obtained direct 8-segment multi-frequency BIA measurements of body composition with Biospace Inbody scale (98% correlation with DXA, 99% reproducibility). BIA measurements (<5 minutes in duration) were taken after entering study measured height, gender and age. Fibrosure test was used to assess grade of fibrosis and inflammation. We also obtained other conventional anthropometric measurements (waist, hips). ANOVA was employed to compare mean BIA and anthropometric measurements with advanced compared to mild fibrosis (F3-F4, F4 vs. F0-F3), and with advanced compared to mild inflammatory activity (A2, A2-A3, A3 vs. A0, A1, A1-A2). Logistic regression was employed to evaluate these factors and risk of advanced liver disease after adjusting for ethnicity, age and current alcohol use. Results: We recruited 198 HCV+ male veterans (mean age 56 yrs; 52% AfricanAmerican; 43% non-Hispanic White). BIA-measured body fatness (%BF) and BMI were significantly associated with advanced hepatic fibrosis in univariate (Table 1) and multivariate (Table 2) analyses. Similar associations were observed with advanced inflammation (data not shown). However, waist and hip circumference obtained from conventional tapemeasurements were not significantly associated with fibrosis in univariate or multivariate analyses, though both were marginally significant for inflammation. There were no significant differences in total body water or lean body mass among groups with advanced and mild hepatic disease (Tables 1, 2). This indicates that the observed associations with %BF and BMI are primarily related to differences in relative fatness and not in water retention or muscular atrophy. The correlation between BMI and %BF was significant and moderately strong (Kendal tau-b=64%), with similar correlation observed for both BMI and %BF with waist and hip circumference respectively. Conclusion: Bioimpedance analysis (BIA) measured %BF and BIA calculated BMI both predict the presence of advanced hepatic fibrosis and inflammation in HCV+ male veterans. BIA measurements were easy, quick, and highly reproducible. Given the degree of correlation among these measures, additional research is needed to clarify their joint and individual contributions in risk of advanced liver disease. Table 1. Univariate assessment of bioelectric impedance analysis (BIA)and anthropometricbased measurements in 198 male veterans with chronic HCV.