Hepatitis C virus (HCV) is a major cause of chronic liver disease that may progress to cirrhosis. Antiviral treatment is successful in less than 50% of patients, is costly and causes debilitating side effects. For these reasons, additional therapies to limit the progression of liver disease are urgently required. Steatosis is found in 60% of patients with HCV and is strongly associated with more severe fibrosis. Improvements in biochemical parameters may be seen with weight reduction, however

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... e effects on liver histology have not been investigated. We propose that in patients with chronic HCV and steatosis, obesity contributes to fat in the liver, which results in increased fibrosis and progression to cirrhosis. This study investigated the effect of weight reduction on liver biochemistry and histology in patients with HCV and the success of weight maintenance after an intensive intervention. We examined the effect of a 12 week diet and exercise program where all subjects were seen weekly by the Dietician, with the goal of achieving a 0.5 kg weight loss per week. Biochemistry was monitored monthly and a liver biopsy was performed prior to and 3-6 months after the intervention period. Patients then entered a 12 month weight maintenance program with monthly dietetic review. After 12 weeks there was a mean weight loss of 5.9 ± 3.2 kg and a mean reduction in waist circumference of 9.0 ± 5.0 cm. In 16 of the 19 patients, serum ALT levels fell progressively with weight loss. Mean fasting insulin fell from 16 to 11 mmol/L (p<0.002). Nine of the 10 patients with paired liver biopsies had a reduction in steatosis. The degree of reduction in steatosis was significantly associated with the percentage of weight loss (p=0.005). In these subjects the median fibrosis score decreased from 3 to 1 (p=0.01) To date, 12 patients have completed 6-12 months of the maintenance program with a 55% success rate. Those that have maintained weight have sustained improvements in their liver function. A small amount of weight loss may be associated with a reduction in steatosis and abnormal liver enzymes and an improvement in fibrosis, despite the persistence of the virus. 2 Anorexia is a major complication of inflammatory bowel disease (IBD). We postulated that pro-inflammatory cytokines in IBD elevate serum leptin concentration contributing to the anorexia. We showed altered leptin responses in interleukin-2 deficient (IL-2 -/-) mice, a model of IBD, with elevated pro-inflammatory cytokines. Serum leptin concentrations in the IL-2 -/mice in the fed state were lower than controls, but paradoxically increased in the starved state compared to controls. The purpose of this study was to evaluate the role of tumor necrosis factor-α (TNF-α) in these altered leptin responses. Eight-week old, IL-2 -/and wild-type control (IL-2 +/+ ) male mice were compared for food intake, body weight, and serum TNF-α concentrations. The IL-2 -/mice consumed less food and lost weight. Serum concentrations of TNF-α were higher in IL-2 -/mice (0.046 ± 0.01 ng/mL) and did not decline with 24 hr food restriction (0.028 ± 0.01 ng/mL) in contrast to controls (0.015 ± 0.003 ng/mL in fed state vs. 0.005 ± 0.003 ng/mL in starved state, p<0.03). Administering anti-TNF-α antibody to the IL-2 -/mice in the fed state restored the normal fall in serum leptin with 24 hr food restriction. These data confirm altered leptin responses in this IBD model, and correction of the altered leptin response with administration of anti-TNF-α antibody suggesting that elevated TNFα may be one mechanism of sustained elevated leptin during fasting. KY Methallothionein (MT) is a highly conserved low-molecular-weight metal-binding protein with a high cysteine content. MT directly interacts with reactive oxygen species and acts as a scavenger of toxic radicals. There is increased oxidative stress in inflammatory bowel disease (IBD), and this has been postulated to play a pathogenetic role in this chronic intestinal disease. We questioned whether modulation of methallothionein (and subsequent oxidative stress) would influence the development or progression of IBD. In these experiments MT-transgenic mice strain (MT-TG, C57BL/6J background), MT-knock out mice (MT-Ko, 129/SV background), C57BL/6J and 129/SV wild type (WT) mice were used to modulate the status of the MT in a dextran sodium sulfate ulcerative colitis (UC) model. MT-TG mice were grossly similar to nontransgenic mice, however they had 2-4 fold higher basal levels of MT protein in their intestines compared to control mice as determined by the Cd/hemoglobin assay. When MT-TG mice and MT-Ko mice were treated with DSS to induce colitis, they responded in a manner similar to DSS treated WT mice with the development of severe UC. The MT content in intestines of UC animals was increased drastically when compared to untreated control mice. The intestinal antioxidant, glutathione (GSH) was significantly reduced in UC MT-ko mice and UC-WT mice compared to their normal controls. However, there was no significant difference in the GSH level in the MT-TG mice with UC compared to untreated MT-TG mice. MT was evaluated using an immunocytochemical technique in small and large intestines. The subcellular level of MT was highest in intestinal crypts of MT-TG mice and was not observed in MT-Ko mice or in the inflammatory lesions. We conclude that MT does not appear to influence the development or progression of intestinal pathology in this UC model. 4