Metabolic effects of hypoxia and chronic hepatitis C

Hypoxia has been linked to the pathogenesis of hepatic steatosis in murine and human models. There is an abundance of data suggesting that HIFs play a central role in regulating hepatic lipid metabolism. This study suggested that hypoxia-induced hepatic lipid accumulation is through de novo lipogenesis and free fatty acid uptake, and is dependent on hypoxia inducible factors la and 2a. On the contrary, hepatitis C infection reduced de novo lipogenesis and free fatty acid uptake in both normoxic and hypoxic conditions in vitro, and this inhibition is viral strain-dependent. In the clinical setting, chronic hepatitis C {CHC) and non-alcoholic fatty liver diseases {NAFLD) are associated with hepatic steatosis and insulin resistance. Using an integrative physiological approach that measures lipid and carbohydrate flux in vivo we demonstrated that patients with CHC had modest increase in insulin resistance and that the relative contribution of tissue specific insulin sensitivity in patients with CHC and NASH varied. Furthermore, curing HCV infection improved hepatic and subcutaneous adipose tissue insulin resistance. The improvement in hepatic and adipose tissue insulin resistance was more pronounced in patients infected with genotype 3 HCV, whilst the improvement in skeletal muscle insulin resistance was more evident in genotype 1 infection, demonstrating a genotype-specific effect in the metabolic perturbation in CHC. Further studies are required to confirm that genotype specific effect of HCV on insulin resistance and its link with NASH

Cystic lymphangioma of the lesser sac presenting as acute appendicitis: A case report

Intra-abdominal lymphangiomas usually present by 2 years of age and are uncommon in adults. Cystic lymphagiomas arising from the lesser sac are even more uncommon. We report an unusual case of a lesser sac cystic lymphangioma presenting as acute appendicitis. A 21 year old female was admitted with pyrexia, right iliac fossa tenderness and an elevated C-reactive protein (CRP). At laparotomy, a large fluid filled cystic lesion was observed occupying the right side of the abdominal cavity. The lesion was excised in its entirety and histological diagnosis confirmed lymphangioma. The patient remains well with no evidence of recurrence 1 year post resection

Endoscopic mucosal resection of colorectal polyps in typical UK hospitals

AIM: To evaluate the outcomes of endoscopic mucosal resection (EMR) for colorectal polyps, with particular regard to procedural complications and recurrence rate, in typical United Kingdom (UK) hospitals that perform an average of about 25 colonic EMRs per year

Economic modelling of early transjugular intrahepatic portosystemic shunt insertion for acute variceal haemorrhage

Introduction: Early insertion of transjugular intrahepatic portosystemic shunt (TIPS) in high-risk patients with acute variceal haemorrhage reduces rebleeding and mortality. However, the economic benefit of utilizing this approach remains unclear. We evaluated the economic implications of introducing early TIPS into routine algorithms for the management of variceal bleeding. Methods: Consecutive patients admitted in 2009 with variceal haemorrhage to two liver units and eligible for early TIPS insertion were identified retrospectively. The costs of a 12-month follow-up from index bleeding admission were calculated--the actual cost of follow-up and rebleeding in this cohort was compared with the theoretical 12-month follow-up costs of instead inserting an early TIPS at index admission. Our findings were subjected to a sensitivity analysis to assess the cost effectiveness of early TIPS insertion compared with standard care. Results: In 2009, 78 patients were admitted to our units with variceal haemorrhage; 27 patients (35%) were eligible for early TIPS insertion. The actual cost of a 12-month follow-up was £138 473.50. Early TIPS insertion, assuming a 3.2% rebleeding rate, would save £534.70 per patient per year (P<0.0001). On sensitivity analysis, early TIPS dominated standard care up to an early TIPS rebleeding rate of 6% and remained cost-effective up to a rebleeding rate of 12%. Conclusion: Early TIPS insertion for high-risk patients with acute variceal bleeding is a cost-efficient intervention. This has important implications for the introduction of early TIPS as standard care and the organization of interventional radiology services

Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. METHODS: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. RESULTS: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. CONCLUSIONS: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD