The advent of specific antiviral therapy for chronic hepatitis C has increased the importance of establishing the correct etiology of chronic hepatitis in patients, especially because interferon alfa (IFN-alpha) has been reported to exacerbate autoimmune hepatitis (AIH), whereas corticosteroids increase viral replication in chronic hepatitis C. In our medical center, we have treated many patients with apparent chronic hepatitis C and serological or clinical evidence of autoimmunity. Our aim was to estimate the prevalence of this association and to learn whether demographic or clinical features distinguished between patients with or without autoimmune markers. We performed a retrospective review of the records of 244 unselected patients seen at the Clinics and Hospital of the University of Massachusetts between May 1991 and November 1993, who had elevated serum aminotransferases. One hundred seventeen patients had chronic hepatitis C defined by elevations of serum alanine transaminase (ALT) for at least 6 months, positive serum antibodies to hepatitis C virus (HCV; second-generation enzyme immunoassay [EIA2] or recombinant immunoblot assay [RIBA]), and absence of hepatitis B surface antigen in the serum. Records were reviewed for results of autoimmune markers in sera, including anti-nuclear antibodies (ANAs), anti-smooth muscle antibodies (SMAs), rheumatoid factor (RF), antimitochondrial antibodies (AMAs), anti-liver and kidney microsomal (LKM) antibodies, and cryoglobulins. We found a high prevalence of positivity, particularly for anti-SMAs (66%) and RF (76%) in both men and women. Forty of 41 patients tested negative for anti-LKM antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TR␤ isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TR␤-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonatecontaining TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic

Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, with a prevalence ranging from 10% to 30%. The use of thyroid hormone receptor (TR) agonists for the treatment of NAFLD has not been considered viable because thyroid hormones increase free fatty acid (FFA) flux from the periphery to the liver, induce hepatic lipogenesis, and therefore could potentially cause steatosis. MB07811 is an orally active HepDirect prodrug of MB07344, a liver-targeted TR-␤ agonist. The purpose of these studies was to assess the effects of MB07811 on whole body and liver lipid metabolism of normal rodents and rodent models of hepatic steatosis. In the current studies, MB07811 markedly reduced hepatic steatosis as well as reduced plasma FFA and triglycerides. In contrast to MB07811, T 3 induced adipocyte lipolysis in vitro and in vivo and had a diminished ability to decrease hepatic steatosis. This suggests the influx of FFA from the periphery to the liver may partially counteract the antisteatotic activity of T 3 . Clearance of liver lipids by MB07811 results from accelerated hepatic fatty acid oxidation, a known consequence of hepatic TR activation, as reflected by increased hepatic mitochondrial respiration rates, changes in hepatic gene expression, and increased plasma acyl-carnitine levels. Transaminase levels remained unchanged, or were reduced, and no evidence for liver fibrosis or other histological liver damage was observed after treatment with MB07811 for up to 10 weeks. Additionally, MB07811, unlike T 3 , did not increase heart weight or decrease pituitary thyroid-stimulating hormone beta (TSH␤) expression. Conclusion: MB07811 represents a novel class of liver-targeted TR agonists with beneficial low-density lipoprotein cholesterollowering properties that may provide additional therapeutic benefit to hyperlipidemic patients with concomitant NAFLD. (HEPATOLOGY 2009;49:407-417.)

MR imaging with these parameters is a rapid, noninvasive, and accurate modality for estimation of hepatic iron concentration; it is sufficiently accurate and precise to obviate liver biopsy for the purpose of measuring hepatic iron concentration.

AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 μM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.