Correlates of adiponectin in hepatitis C-infected children: the importance of body mass index.

OBJECTIVES: Adiponectin is a regulator of cytokines that, in turn, play a vital role in inflammatory and immune responses. Adiponectin is therefore likely to have a contributory role in hepatitis C virus (HCV) infection. We sought to characterize adiponectin levels and examine correlates in a pediatric HCV-infected cohort. METHODS: We performed a cross-sectional study in children (5-17 years of age, n = 86) in the Pediatric Study of Hepatitis C (PEDS-C) trial. Adiponectin levels were univariately correlated with patient demographics, anthropometrics, and viral and histological measures. Multivariate regression models were used to identify the unique (ie, nonconfounded) associations with adiponectin concentrations. RESULTS: Body mass index (BMI) had the highest univariate inverse correlation with log(e) adiponectin (r = -0.5, P < 0.0001). In multivariate analysis, BMI remained inversely correlated with log(e) adiponectin after accounting for age and route of HCV transmission (r = -0.38, P = 0.0003). Steatosis and fibrosis were inversely related to log(e) adiponectin in univariate analysis, but these associations were not statistically significant after multivariate adjustments (P ≥ 0.1827). CONCLUSIONS: High BMI among HCV-infected children is associated with lower adiponectin levels. Practitioners should be cognizant of the possible risks of low adiponectin when managing HCV-infected children who are overweight. Further studies are indicated to determine the impact of having low adiponectin on HCV infection in youth.

Expected and actual case ascertainment and treatment rates for children infected with hepatitis C in Florida and the United States: epidemiologic evidence from statewide and nationwide surveys.

OBJECTIVE: To evaluate the rate of pediatric hepatitis C virus (HCV) case ascertainment relative to the estimated number of actual cases. STUDY DESIGN: Data from Florida and United States health departments were used to assess pediatric HCV case ascertainment rates in Florida and nationwide. The percentage of children infected with HCV from Miami-Dade County receiving medical care by a pediatric gastroenterologist was estimated based on data obtained from physician questionnaires. RESULTS: From 2000 through 2009, 2007 children were identified as having positive HCV antibody tests in Florida, only 12% of the expected number (n = 12 155). An estimated 1.6% of the expected children with HCV who tested Ab-positive (37 of 1935) were actively followed by a pediatric gastroenterologist in Miami-Dade County, Florida. Across the United States, only 4.9% of the expected cases have been identified. CONCLUSIONS: The identification of children infected with HCV in the nation as a whole is grossly inadequate. Only a small fraction of cases are identified. In Florida, less than 2% of children identified receive treatment. Lack of identification and lack of treatment of children infected with HCV constitute critical public health problems. Strategies to increase awareness of HCV infection and to screen at-risk individuals could substantially improve morbidity and mortality while reducing health care costs.

Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is associated with an increased prevalence of diabetes and insulin resistance (IR); whether this is a causal relationship has not been established. METHODS: We performed a longitudinal study within the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial to evaluate whether suppression of hepatitis C is associated with improvement in IR. Participants had advanced hepatic fibrosis and carried non-3 HCV genotypes (n = 96). Patients underwent 24 weeks of pegylated interferon and ribavirin therapy and were categorized into HCV clearance groups at week 20 on the basis of HCV RNA levels; null responders had <1 log(10) decline (n = 38), partial responders had >or=1 log(10) decline (n = 37) but detectable HCV RNA, and complete responders had no detectable HCV RNA (n = 21). The primary outcome was change (week 20 minus week 0) in IR by using the homeostasis model assessment (HOMA2-IR). RESULTS: Adjusting only for baseline HOMA2-IR, mean HOMA2-IR differences were -2.23 (complete responders), -0.90 (partial responders), and +0.18 (null responders) (P = .036). The observed differences in mean HOMA2-IR scores were ordered in a linear fashion across response groups (P = .01). The association between HCV clearance and improvement in HOMA2-IR could not be accounted for by adiponectin or tumor necrosis factor-alpha and was independent of potential confounders including age, gender, ethnicity, body mass index, duration of infection, medications used, and fibrosis. CONCLUSIONS: HCV suppression correlates with improvement in IR. These data provide further support for a role of HCV in the development of insulin resistance.

Influence of body mass index on outcome of pediatric chronic hepatitis C virus infection.

BACKGROUND AND AIMS: Evidence demonstrates that obesity is associated with progression of chronic hepatitis C virus (HCV) infection and poor response to interferon therapy among HCV-infected adults. However, this evidence has been confounded by multiple comorbidities present in adult cohorts and the use of single adult doses. PATIENTS AND METHODS: We performed a retrospective investigation to evaluate the role of body mass index (BMI) in chronic HCV progression and response to therapy in the children. One hundred twenty-three children and teenagers studied at Children's Hospital Boston for HCV infection between 1998 and 2007 were included. Patients' weight and height at the time of liver biopsy or before and after HCV therapy were obtained and BMI was calculated. RESULTS: The presence of steatosis was statistically associated with higher mean (+/-SE) BMI percentiles (72nd +/- 5.8 vs 58th +/- 3.5) percentile; F(1,101) = 4.2, P = 0.04. Nonresponders to treatment had a higher mean (+/-SE) BMI percentile (70th +/- 7.4) when compared with responders (50th +/- 6.5) in univariate and multivariate analyses (P = 0.04, P = 0.02, respectively). Using a multivariate model, it was calculated that 1 standard deviation (1 z-score unit) increase in baseline BMI z score is associated with a 12% decrease in the probability of sustained virologic response. CONCLUSIONS: Overweight adversely affects the progression of chronic HCV liver disease and is associated with diminished response to antiviral therapy using weight-based dosing in a cohort with minimal comorbidities.

Extrahepatic hepatitis C virus after transplantation: diabetes and renal dysfunction.

1. Insulin resistance is associated with hepatitis C virus infection and plays a role in the progression of hepatitis C virus-related liver disease and fibrosis. 2. Treating insulin resistance and achieving glycemic control will be important for improving post-liver transplant morbidity and mortality: control of the hepatitis C virus will help to accomplish this. 3. The main renal complication of hepatitis C virus is membranoproliferative glomerulonephritis, and this occurs most commonly in the setting of mixed cryoglobulinemia.

Hepatitis C virus is independently associated with increased insulin resistance after liver transplantation.

BACKGROUND AND AIMS: There is a strong epidemiologic association between diabetes mellitus (DM) and hepatitis C virus (HCV) infection. However, the pathogenetic basis for this association has not been established. We sought to evaluate the association between insulin resistance (IR), beta-cell dysfunction, and HCV among orthotopic liver transplant (OLT) recipients. METHODS: We performed a cross sectional analysis comparing 39 HCV(+) with 60 HCV(-) OLT recipients. IR and beta-cell function were calculated using validated measures and were correlated with clinical variables. RESULTS: By multivariate analysis of the entire cohort, HCV infection and body mass index (BMI) were independent predictors of IR (P =0.04 and 0.0006, respectively). HCV infection was associated with 35% increase in IR. Because the model used to calculate IR was derived from nondiabetic subjects, we performed additional analysis of patients who did not meet criteria for diabetes at the time of their study evaluation. In this analysis, HCV(+) subjects had greater fasting insulin and homeostasis model assessment (HOMA) IR (15.3 mu U/mL and 3.8) compared with HCV(-) patients (10.7 mu U/mL and 2.5) (P =0.03, 0.03). There was no difference in beta-cell function or hepatic insulin extraction between the HCV (+) and (-) groups. HCV (P =0.0005), BMI (P <0.0001), and high high-density lipoprotein (P =0.039) were the only independent predictors of IR. The presence of HCV infection and a 10-fold increase in HCV RNA were associated with a 62% and 8% increase in IR, respectively. CONCLUSIONS: HCV is independently associated with increased IR after OLT. These findings provide a possible pathogenetic basis for the association of DM with HCV.

Serum vitamin D levels are not predictive of the progression of chronic liver disease in hepatitis C patients with advanced fibrosis.

In animal models and human cross-sectional studies, vitamin D deficiency has been associated with liver disease progression. Vitamin D supplementation has been suggested as a treatment to prevent disease progression. We sought to evaluate the role of vitamin D levels in predicting chronic liver disease development. We conducted a nested case-control study of vitamin D levels in subjects with (cases) and without (controls) liver histologic progression or clinical decompensation over the course of the HALT-C Trial. Vitamin D levels were measured at 4 points over 45 months. 129 cases and 129 aged-matched controls were included. No difference in baseline vitamin D levels were found between cases and controls. (44.8 ng/mL vs. 44.0 ng/mL, P = 0.74). Vitamin D levels declined in cases and controls over time (P = 0.0005), however, there was no difference in the level of decline (P = 0.37). Among study subjects with diabetes mellitius, baseline vitamin D levels were higher in cases, 49.9 ng/mL, than controls, 36.3 ng/mL. (P = 0.03) In addition, baseline vitamin D levels were higher in black case subjects, 32.7 ng/mL, than in black control subjects, 25.2 ng/mL (P = 0.08) No difference in vitamin D levels was found between patients with and without progression of hepatitis C-associated liver disease over 4 years. Our data do not suggest any role for vitamin D supplementation in patients with advanced chronic hepatitis C and raise the possibility that higher vitamin D levels may be associated with disease progression.

Prospective study of liver transplant recipients with HCV infection: evidence for a causal relationship between HCV and insulin resistance.

An association between hepatitis C virus (HCV) infection and insulin resistance (IR) has been recently reported. However, causality has not been established. The cross-sectional nature of most reported studies and varying degrees of fibrosis have limited definitive conclusions about the independent role of HCV in development of IR. We sought to evaluate whether HCV induces IR by prospectively analyzing a cohort of adult liver transplant (LT) recipients. A total of 34 adults (14 HCV(+) and 20 HCV(-)) who underwent consecutive LT were followed during the first year posttransplantation. IR was estimated using the homeostasis model assessment (HOMA). Univariate and multivariate repeated measures analyses and Cox regression models were used. There were no significant differences between the groups with respect to age, body mass index (BMI), family history of diabetes, alcohol consumption, or laboratory indices. The cohort had no or minimal fibrosis. There was lower prednisone use in the HCV(+) group, and no difference in the use of tacrolimus between the two groups was found. IR was 77% higher in HCV(+) subjects during the first year post-LT when controlling for BMI (P = 0.035). Subjects with high HCV ribonucleic acid (RNA) levels reached high HOMA-IR significantly earlier than those with lower HCV RNA (P = 0.03). Following the first month post-LT, HCV(+) subjects were 4 times more likely to become diabetic than HCV(-) controls (P < 0.01). In conclusion, there is significantly higher IR in the HCV(+) group during the first year post-LT. This cannot be explained by differences in BMI, medications used, alcohol consumption, or degree of fibrosis. Higher HCV RNA levels were associated with earlier elevations in HOMA-IR. Collectively, these results provide strong evidence that HCV induces the development of IR.

Treatment Options for Hepatitis C Infection in Children.

Multiple factors support treatment of hepatitis C virus (HCV) infection in children. These factors include the anticipated long duration of infection after early acquisition, relatively good tolerance of antiviral medications, and avoidance of social stigmatization. Nevertheless, careful selection of appropriate candidates for therapy is important. If a contraindication to current therapeutic agents is present, treatment should be withheld until this has resolved or until new agents are available. Children without contraindications to the medications used for HCV should undergo liver biopsy to determine the presence and degree of fibrosis. In the absence of fibrosis, treatment may be deferred. If any degree of hepatic fibrosis is present, antiviral therapy for HCV should be considered. At present, in the United States, the only therapy approved for children by the Food and Drug Administration (FDA) is a combination of interferon (IFN) alfa-2b and ribavirin. No safe therapies have been established for children younger than 3 years of age. Pegylated interferon in combination with ribavirin may be considered in adolescents older than 16 years of age who are post-pubertal, or in younger children in the context of clinical trials. Multicenter trials are currently underway to determine the safety and effectiveness of other forms of therapy for HCV infection in children.