nonalcoholic steatohepatitis and the CMS JCMS winter 2006 36 N onalcoholic fatty liver disease (NAFLD) is considered a major cause of liver-related morbidity and mortality, and the prevalence of the disease is estimated at 20%–30% in Western countries. 1–3 NAFLD involves a spectrum of histopathologic changes that range from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. 4 Nonalcoholic steato- sis (NASH) was initially described by Leevy 5 in 1962. NASH was first termed in 1980 by Ludwig and associates 6 to describe biopsy findings in patients with steatohepatitis in the absence of significant alcohol consumption. At the American Association for the Study of Liver Diseases Clinical Single Topic Conference on NASH in 2002, 1 NASH was subcategorized into “primary” and “secondary” disease. Primary NASH is defined as necroinflammatory ste- atohepatitis that is associated with the metabolic syndrome, and secondary NASH is defined as steatohepatitis that accompanies other syndromes, such as lipodystrophy, or is caused by drugs, such as amiodarone and tetracycline. 1 NAFLD/NASH and the Metabolic Syndrome Tere is increasing evidence that NAFLD/NASH is associated with insulin resistance and abnormal glu- cose tolerance, along with features of the metabolic syndrome such as obe- sity, insulin resistance, type 2 diabetes mellitus, dyslipidemia, hypertension, hyperuricemia, and polycystic ovarian syndrome. Consequently, patients with such conditions are also at an increased risk for cardiovascular disease. 1,2,7,8 Te progression of NAFLD is based on a proposed “two-hit” model. Te “first hit,” such as obesity, leads to the devel- opment of steatosis, and the “second hit” leads to hepatocyte injury, inflam- mation, and fibrosis; the best candidates for the second hit are oxidative stress and cytokines, mainly tumor necrosis factor α (TNF-α). 9 However, it must be emphasized that the causative and temporal relationships between oxida- tive stress, insulin resistance, cytokines, and hepatic steatosis remain under investigation and findings may support or challenge the dogma of the two-hit hypothesis. Animal models for NASH have become a great research tool. One such model that simulates the human condition of the metabolic syndrome is leptin-deficient mice, the ob/ob mice, which are genetically obese, insulin- resistant, and develop NASH spontane- ously. 10 Tese mice also have elevated TNF-α and, thus, the hepatocytes gen- erate excessive reactive oxygen species, accumulate lipids, and are resistant to insulin. Inhibition of TNF-α activity has shown improvement of NASH in ob/ob mice. NAFLD/NASH and the CMS Te cardiometabolic syndrome (CMS) is a constellation of metabolic, cardiovascu- lar, renal, and inflammatory abnormali- ties in which insulin resistance is thought to play a key role in end-organ pathogen- esis. 11,12 Te link between insulin resis- tance and NASH has been well estab- lished. NASH and severe hepatic insulin resistance have been demonstrated in the ob/ob mice model and have been reversed with adiponectin and leptin treatment. It has been postulated that hepatic triglyc- eride accumulation is a causative factor in hepatic insulin resistance. 13 Insulin instigates a cascade of intracellular sig- naling by the activation of at least nine postreceptor tyrosine kinase-mediated Nonalcoholic฀fatty฀liver฀disease฀(NAFLD)฀is฀now฀considered฀to฀be฀the฀most฀common฀ liver฀disease฀in฀the฀United฀States฀and฀involves฀a฀spectrum฀of฀progressive฀histopathologic฀ changes.฀Common฀risk฀factors฀associated฀with฀NAFLD฀include฀obesity,฀diabetes,฀and฀ hyperlipidemia.฀Although฀most฀patients฀with฀NAFLD฀have฀simple฀hepatic฀steatosis,฀a฀sig- nificant฀number฀develop฀nonalcoholic฀steatohepatitis,฀which฀may฀progress฀to฀fibrosis,฀cir- rhosis,฀or฀end-stage฀liver฀disease.฀There฀is฀increasing฀evidence฀that฀NAFLD฀is฀a฀common฀ feature฀in฀patients฀with฀the฀cardiometabolic฀syndrome,฀a฀constellation฀of฀metabolic,฀car- diovascular,฀renal,฀and฀inflammatory฀abnormalities฀in฀which฀insulin฀resistance฀is฀thought฀ to฀play฀a฀key฀role฀in฀end-organ฀pathogenesis.฀NAFLD฀is฀usually฀diagnosed฀after฀abnormal฀ liver฀chemistry฀results฀are฀found฀during฀routine฀laboratory฀testing.฀No฀therapy฀has฀been฀ proven฀effective฀for฀treating฀NAFLD/nonalcoholic฀steatohepatitis.฀Expert฀opinion฀empha- sizes฀the฀importance฀of฀exercise,฀weight฀loss฀in฀obese฀and฀overweight฀individuals,฀treat- ment฀of฀hyperlipidemia,฀and฀glucose฀control.฀(JCMS.฀2006;1:36–40)฀ © 2006฀Le฀Jacq฀Ltd. Mohammad฀Basem฀Abdeen,฀MD; 1 ฀Nazif฀A.฀Chowdhury,฀MD; 1 ฀Melvin฀R.฀Hayden,฀ MD; 1,3 ฀Jamal฀A.฀Ibdah,฀MD,฀PhD 1,2,4 From฀the฀Departments฀of฀Internal฀Medicine 1 ฀and฀Physiology฀&฀Pharmacology, 2 ฀ Divisions฀of฀Endocrinology 3 ฀and฀Gastroenterology฀&฀Hepatology, 4 ฀University฀of฀ Missouri-Columbia฀School฀of฀Medicine,฀Columbia,฀MO Address฀for฀correspondence:฀Jamal฀A.฀Ibdah,฀MD,฀PhD,฀Director,฀Division฀of฀ Gastroenterology฀and฀Hepatology,฀University฀of฀Missouri-Columbia,฀฀ One฀Hospital฀Drive,฀Columbia,฀MO฀65212฀ E-mail:฀ibdahj@health.missouri.edu Manuscript฀received฀December฀20,฀2005;฀revised฀January฀18,฀2006;฀accepted฀ January฀30,฀2006 REVIEW PAPER Nonalcoholic Steatohepatitis and the Cardiometabolic Syndrome www.lejacq.com id: 5523 The฀Journal฀of฀Cardiometabolic฀Syndrome฀(ISSN฀1524-6175)฀is฀published฀quarterly฀by฀Le฀Jacq฀Ltd.,฀Three฀Parklands฀Drive,฀Darien,฀CT฀06820-3652.฀Copyright฀©2006฀by฀Le฀Jacq฀Ltd.,฀All฀rights฀reserved.฀No฀part฀of฀this฀publication฀may฀ be฀ reproduced฀ or฀ transmitted฀ in฀ any฀ form฀ or฀ by฀ any฀ means,฀ electronic฀ or฀ mechanical,฀ including฀ photocopy,฀ recording,฀ or฀ any฀ information฀ storage฀ and฀ retrieval฀ system,฀ without฀ permission฀ in฀ writing฀ from฀ the฀ publishers.฀ The฀ opinions฀and฀ideas฀expressed฀in฀this฀publication฀are฀those฀of฀the฀authors฀and฀do฀not฀necessarily฀reflect฀those฀of฀the฀Editors฀or฀Publisher.฀For฀copies฀in฀excess฀of฀25฀or฀for฀commercial฀purposes,฀please฀contact฀Sarah฀Howell฀at฀ showell@lejacq.com฀or฀203.656.1711฀x106.