Semin Liver Dis 2004; 24(4): 333-334
DOI: 10.1055/s-2004-837862
FOREWORD

Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Obesity and the Liver

Lee M. Kaplan1  Guest Editor 
  • 1Associate Chief, Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
Further Information

Publication History

Publication Date:
16 December 2004 (online)

Within the past decade, the growing epidemic of obesity has taken center stage as a clinical, scientific, and public health issue. More than 30% of adults in the United States have obesity, defined as a body mass index (BMI) of at least 30 kg/m2 (∼30 or more pounds overweight). This is double the rate of obesity as recently as thirty years ago. Obesity in children is growing even faster-3-fold in the past generation-suggesting that this epidemic will not abate in the foreseeable future.

Obesity contributes to the development of more than 50 distinct medical disorders and alters the response to the treatment of many others, thus each discipline must evaluate the impact of obesity on the biological processes and diseases within its purview. This issue of Seminars in Liver Disease is devoted to the relationship between obesity and hepatobiliary physiology and disease. We begin with an overview by Scharf and Ahima on the important role of the gastrointestinal tract and liver in monitoring energy balance and food intake, thereby contributing to the overall regulation of body weight. The remaining articles examine the effect of obesity on the liver, with a particular focus on fatty liver disease and the hepatotoxic effects of drugs used to treat obesity and its complications.

Nonalcoholic fatty liver disease (NAFLD), first described less than 25 years ago, is now recognized as one of the most prevalent manifestations of the obesity-related metabolic syndrome. It includes a spectrum of disease, from hepatic steatosis to hepatitis and progressive fibrosis. It reflects abnormal fat deposition in hepatocytes as a result of dysregulation of lipid metabolism, and occurs most commonly in the setting of systemic or hepatic insulin resistance. Progression beyond steatosis appears to reflect the development of an inflammatory response to one or more neoantigens within fat-laden hepatocytes. Candidate antigens include lipid metabolites generated by the action of intracellular free radicals, whose accumulation may be another effect of hepatic insulin resistance. While obesity and type 2 diabetes mellitus are its primary precursors, NAFLD also occurs in the setting of innate or acquired lipodystrophy and consequent severe insulin resistance. Choudhury and Sanyal, in their clinical overview article, describe the important epidemiological and diagnostic considerations in patients with NAFLD. Suriawinata and Fiel explore the pathological findings in NAFLD, which cover a wide spectrum from “simple” steatosis to steatohepatitis, various patterns of fibrosis, and cirrhosis. These changes mimic those seen in alcohol- and drug-associated fatty liver disease, and epidemiological and molecular studies have suggested that common pathophysiological mechanisms contribute to these different types of fatty liver disease. In this context, it is worth comparing the clinical, pathological, and pathophysiological characteristics of alcoholic liver disease-described in the previous issue of Seminars-with those of NAFLD described in this issue.

Our appreciation of the clinical impact of NAFLD has grown steadily over the past several years. Initially considered a benign pathological finding, we have learned that in a subset of people, NAFLD progresses to steatohepatitis (NASH) and even cirrhosis. Many people with “cryptogenic” cirrhosis are now thought to have end-stage, burnt-out NASH, and NAFLD-related cirrhosis is estimated to be the third or fourth leading cause of liver transplantation. Over the last several years, we have learned that even “benign” hepatic steatosis has significant adverse effects on health. Transplanted steatotic livers have a substantially higher primary failure rate than nonsteatotic donor organs. Ramesh and Sanyal describe the important interaction between NAFLD and chronic hepatitis C infection, underscoring the more rapid and severe progression of chronic hepatitis C infection in steatotic livers, as well as lower rates of response to antiviral therapy in this setting.

Ghali and Lindor describe the increased predilection for drug-related hepatotoxicity in patients with obesity. Several of the drugs used to treat obesity and its most common complications-diabetes, hypertension, and hyperlipidemia-can promote liver damage, either in a dose-related or idiosyncratic manner. These authors also describe the apparent increased sensitivity of steatotic livers to the toxic effects of a wide variety of drugs, underscoring the adverse metabolic and inflammatory effects of excess hepatocyte lipid deposition.

Finally, the problem of obesity-associated liver disease is not limited to adults. As described by Hoppin, the rapidly growing epidemic of obesity in children and adolescents has led to dramatic increases in the incidence of diabetes and fatty liver disease in this population.

Current treatment options for fatty liver disease are described in the articles by Choudhury and Sanyal, and Blackburn and Mun. Unfortunately, information about medical therapies for NAFLD remains limited. A few small trials have suggested that insulin-sensitizing agents, such as thiazolidinediones and metformin, may lead to improvement in liver enzymes and pathological manifestations. The clinical value of antioxidants and anti-inflammatory agents is even less clear. Blackburn and Mun explore the effect of gastric weight loss surgery on NAFLD, concluding that in most cases, profound weight loss is accompanied by amelioration of the liver pathology. The response in individual patients is widely variable, however, and accurate predictors of outcome remain elusive.

Taken together, the articles in this issue of Seminars in Liver Disease describe the profound effect of obesity on liver physiology and the important role of the liver in the metabolic response to obesity and hyperlipidemia. Better understanding of these interactions and their underlying mechanisms will facilitate the development of more effective strategies for treating NAFLD, alcoholic liver disease, drug-induced hepatotoxicity, and viral hepatitis. Given the central role of the liver in lipid metabolism, exploration of these mechanisms will also contribute to our understanding of the metabolic syndrome more broadly, providing much-needed insight into the prevention and control of obesity itself.

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