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Background: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown., Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and non-obese subjects with chronic HCV., Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment., Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index > or = 30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014)., Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.

Background and Aim: Obesity is a risk factor for progression of fibrosis in chronic liver diseases such as non-alcoholic fatty liver disease and hepatitis C. The aim of this study was to investigate the longer term effect of weight loss on liver biochemistry, serum insulin levels, and quality of life in overweight patients with liver disease and the effect of subsequent weight maintenance or regain., Patients: Thirty one patients completed a 15 month diet and exercise intervention., Results: On completion of the intervention, 21 patients (68%) had achieved and maintained weight loss with a mean reduction of 9.4 (4.0)% body weight. Improvements in serum alanine aminotransferase (ALT) levels were correlated with the amount of weight loss (r = 0.35, p = 0.04). In patients who maintained weight loss, mean ALT levels at 15 months remained significantly lower than values at enrollment (p = 0.004), while in regainers (n = 10), mean ALT levels at 15 months were no different to values at enrollment (p = 0.79). Improvements in fasting serum insulin levels were also correlated with weight loss (r = 0.46, p = 0.04), and subsequent weight maintenance sustained this improvement. Quality of life was significantly improved after weight loss. Weight maintainers sustained recommended levels of physical activity and had higher fasting insulin levels (p = 0.03) at enrollment than weight regainers., Conclusion: In summary, these findings demonstrate that maintenance of weight loss and exercise in overweight patients with liver disease results in a sustained improvement in liver enzymes, serum insulin levels, and quality of life. Treatment of overweight patients should form an important component of the management of those with chronic liver disease.

Objective: To determine the influence of an elevated body mass index (BMI) on cardiovascular outcomes and survival in peritoneal dialysis (PD) patients., Design: Prospective, observational study of a prevalent PD cohort at a single center., Setting: Tertiary care institutional dialysis center., Patients: The study included all patients with a BMI of at least 20 who had been receiving PD for at least 1 month as of 31 January 1996 (n = 43). Patients were classified as overweight [BMI > 27.5; mean +/- standard error of mean (SEM): 32.1 +/- 1.1; n = 14] or normal weight (BMI 20-27.5; mean +/- SEM: 23.8 +/- 0.4; n = 29)., Outcome Measures: Patient survival and adverse cardiovascular events (myocardial infarction, congestive cardiac failure, cerebrovascular accident, and symptomatic peripheral vascular disease) were recorded over a 3-year period., Results: At baseline, no significant differences were seen between the groups in clinical, biochemical, nutritional, or echocardiographic parameters, except for a lower dietary protein intake (0.97 +/- 0.10 g/kg/day vs 1.44 +/- 0.10 g/kg/day, p = 0.004) and a higher proportion of well-nourished patients by subjective global assessment (100% vs 72%, p < 0.05) in the overweight group. After 3 years of follow-up, 29% of overweight patients and 69% of normal-weight patients had died (p < 0.05). Using a Cox proportional hazards model, a BMI greater than 27.5 was shown to be an independent positive predictor of patient survival, with an adjusted hazard ratio (HR) of 0.09 [95% confidence interval (CI): 0.01-0.85; p < 0.05]. However, being overweight did not significantly influence myocardial infarction-free survival (adjusted HR: 0.33; 95% CI: 0.07-1.48; p = 0.15) or combined adverse cardiovascular event-free survival (adjusted HR: 0.67; 95% CI: 0.23-1.93; p = 0.46)., Conclusions: Obesity conferred a significant survival advantage in our PD population. Obese patients should therefore not be discouraged from receiving PD purely on the basis of BMI. Moreover, maintaining a higher-than-average BMI to preserve "nutritional reserve" may help to reduce the mortality and morbidity rates associated with PD.

Type II (non-insulin-dependent) diabetes mellitus has a substantial genetic component; however, its molecular basis remains largely unknown. The mode of inheritance is likely to be polygenic, with penetrance influenced by environmental factors. Although the familial aggregation of Type II diabetes is acknowledged, there is little data concerning the prevalence of diabetes in the relatives of subjects with diabetes in comparison with the general population, and our objective was to address this question in the defined geographic region of Oxfordshire, England. We studied 139 first degree relatives of 90 probands with Type II diabetes who attended routine diabetes clinics in Oxfordshire and documented the fasting plasma glucose, triglyceride and HDL-cholesterol concentrations and BMI of these subjects. The probands were selected without regard to family history of diabetes. The control population data were derived from two large-scale Oxford community studies which documented the prevalences of known and newly diagnosed diabetes. The prevalences of newly diagnosed and known diabetes were calculated for each group. The mean BMI, and concentrations of fasting glucose, triglyceride and HDL-cholesterol were compared and prevalence ratios for obesity (defined as BMI > 30 kg/m2), hyperglycaemia (defined as fasting plasma glucose > or = 6.1 mmol/l), and dyslipidaemia (defined as triglyceride > 2.0 mmol/l, HDL < 1.0 mmol/l) were calculated. There was a fourfold higher prevalence of hyperglycaemia in the first degree relatives of subjects with Type II diabetes compared with the control population: the prevalence ratio after adjustment for age, sex and BMI was 4.32 (95 % confidence interval 2.29-8.17). The relatives had a considerably higher fasting plasma glucose concentration than the control population (5.18+/-0.67 mmol/l (mean +/- 1 SD) vs 4.76+/-1.59 mmol/l, p = 0.0001), and this difference remained statistically significant after adjustment for age, sex and obesity. The relatives were significantly more obese, had higher fasting plasma insulin concentrations and had lower HDL-cholesterol concentrations. In conclusion, there is a strong familial aggregation of hyperglycaemia and obesity in the relatives of subjects with Type II diabetes and these subjects have higher fasting plasma insulin concentrations and lower HDL-cholesterol than the general population. These data indicate the particular relevance of screening the first degree relatives of subjects with Type II diabetes, as intervention strategies which aim to improve the metabolic profile are indicated for a large proportion of these subjects.

Objectives: In view of previous studies demonstrating hyperleptinemia in uremic and hemodialysis patients, the aims of the present study were to determine whether serum leptin levels are elevated in peritoneal dialysis (PD) patients, to establish whether leptin is significantly removed by PD, and to elucidate the relationship of plasma leptin to body composition, dietary intake, nutritional indices, and dialysis adequacy., Design: Cross-sectional analysis of PD patients and matched healthy controls., Setting: Tertiary-care institutional dialysis center., Participants: The study included 49 PD patients [35 women and 14 men; median age 63 years, interquartile range (IQR) 49.5-68.5 yr; body mass index (BMI) 25.5 +/- 0.8] and 27 controls (11 men and 16 women; median age 42 years, IQR 34.8-51; BMI 27.2 +/- 0.9). For evaluation of leptin clearance, 8 patients receiving nocturnal intermittent PD were also evaluated., Main Outcome Measures: The primary outcome measure was plasma leptin concentration. Dialysate leptin concentration was also measured in 7 patients., Results: Serum leptin levels were significantly higher (p < 0.01) in patients (males: median 11 ng/mL, IQR 9-19 ng/mL; females: 53 ng/mL, 19.5-128 ng/mL) compared with controls (males: 5.5 ng/mL, 4-9.5 ng/mL; females: 12 ng/mL, 9.8-17.3 ng/mL). Leptin levels in both groups correlated positively with BMI (r = 0.64 and 0.60, respectively; p < 0.0001) and with percentage body fat determined by dual-energy x-ray absorptiometry (r = 0.86 and 0.82, respectively; p < 0.01). Dialysis patients exhibited a greater increase in serum leptin for any given increase in BMI. No significant correlation was observed between leptin concentration and residual renal function, dialysis adequacy (Kt/V), dietary protein or caloric intake, or serum levels of albumin, prealbumin, C-reactive protein, glucose, and insulin-like growth factor-I. Although leptin was detectable in peritoneal dialysate after a 6-hour dwell (median 4.2 ng/mL, IQR 1.1-8.5 ng/mL, n = 8), serum leptin levels were not appreciably lowered following intermittent PD via an automated cycler (63.9 +/- 19.3 ng/mL vs 57.6 +/- 20.5 ng/mL, p = NS, n = 8)., Conclusions: Serum leptin levels are elevated in PD patients and are not appreciably cleared by PD. Although hyperleptinemia correlates poorly with dialysis adequacy and protein intake, a strong and significant relationship was maintained between serum leptin and fat mass. Serum leptin could therefore serve as a useful clinical marker of body fat content in PD patients.