NON-ALCOHOLIC STEATOHEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES

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1 NON-ALCOHOLIC STEATOHEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES Preface Zobair M. Younossi xiii Epidemiology and Natural History of NAFLD and NASH 1 Janus P. Ong and Zobair M. Younossi Understanding of the epidemiology and natural history of nonalcoholic fatty liver disease (NAFLD) has increased; it is the most common form of chronic liver disease in the Western world and increasing in importance in other parts of the world. Prevalence is expected to increase as obesity and diabetes epidemics evolve. The natural history of NAFLD depends on the histologic subtype. Those who have simple hepatic steatosis or nonspecific inflammation generally have a benign long-term prognosis, whereas non-alcoholic steatohepatitis (NASH) can progress to cirrhosis. NASH-related cirrhosis may have a similar prognosis as cirrhosis from other causes, leading to liver failure or hepatocellular carcinoma. Pathologic Assessment of Non-alcoholic Fatty Liver Disease 17 Silvia Bondini, David E. Kleiner, Zachary D. Goodman, Terry Gramlich, and Zobair M. Younossi Non-alcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease and is considered the hepatic manifestation of the metabolic syndrome. Within the NAFLD spectrum, simple steatosis is considered benign, whereas non-alcoholic steatohepatitis (NASH) may progress to cirrhosis. The distinction can be made only by liver biopsy. There is not complete agreement on criteria for diagnosis or the features used for grading and staging lesions. This article reviews some of the studies dealing with the histopathology of NAFLD, with attempts to develop a standardized pathologic scoring system for NASH. VOLUME 11 Æ NUMBER 1 Æ FEBRUARY 2007 vii

2 Role of Liver Biopsy and Serum Markers of Liver Fibrosis in Non-alcoholic Fatty Liver Disease 25 Leon A. Adams and Paul Angulo Non-alcoholic fatty liver disease (NAFLD) is common and may progress to end-stage liver disease. Liver-related morbidity and mortality occur almost exclusively in patients whose disease progresses to advanced fibrosis and cirrhosis. Presence and severity of liver fibrosis seem the most important indicators of long-term prognosis. Clinical and biochemical variables may help select NAFLD patients in whom liver biopsy may provide the most prognostic information. Some serum markers of liver fibrosis and imaging techniques aimed at measuring liver stiffness are under investigation as tools to determine severity of liver fibrosis in patients who have NAFLD, but none of them yet can replace liver biopsy. Role of Radiologic Modalities in the Management of Non-alcoholic Steatohepatitis 37 Phunchai Charatcharoenwitthaya and Keith D. Lindor During the last decade, the role of radiologic modalities in management of patients who have fatty liver disease has expanded. Ultrasonography has been used as a noninvasive alternative to biopsy for monitoring patients who have hepatic steatosis, but MRI is more appealing than ultrasonography to denote minor changes in hepatic fat content. Distinguishing patients who have nonalcoholic steatohepatitis from steatosis alone has become of clinical importance; however, the differences are not apparent with any radiologic modalities. Several modalities have been developed to noninvasively and accurately quantify hepatic fat content and diagnose steatohepatitis. In the future, radiologic modalities might be used to monitor the natural history of the disease or evaluate therapeutic interventions in patients who have non-alcoholic fatty liver disease. Pathogenesis of NASH: Animal Models 55 Roslyn M. London and Jacob George The incidence of non-alcoholic steatohepatitis, a disorder linked to visceral adiposity, insulin resistance, dyslipidemia, and type 2 diabetes mellitus, is increasing with the rise in the prevalence of the metabolic syndrome. This review focuses on animal models of steatohepatitis currently used to study (1) the mechanisms regulating hepatic lipid, glucose, and cholesterol homeostasis and (2) inflammatory recruitment and fibrogenesis in the steatotic liver. The ultimate aim of this research is to gain insights into the role of hepatic lipid, inflammation, and fibrosis in human non-alcoholic fatty liver disease. viii

3 Pathogenesis of Non-alcoholic Steatohepatitis: Human Data 75 John Edmison and Arthur J. McCullough Non-alcoholic fatty liver disease (NAFLD) has moved rapidly to the forefront of clinical disease, with a prevalence of 30% in the adult United States population and a definite but yet uncertain rate of progression to cirrhosis and end-stage liver disease. This disease has an impact on all areas of clinical medicine, with increasing prevalence and adversity. It is essential to understand the pathophysiologic mechanisms involved in NAFLD, so that therapeutic strategies can be developed. Although fatty liver may be caused by other factors, this review concentrates on fatty liver associated with insulin resistance, sometimes referred to as the primary form. Metabolic Syndrome and NASH 105 Giulio Marchesini and Rebecca Marzocchi Clinical and epidemiologic studies have associated non-alcoholic fatty liver with the metabolic syndrome, with insulin resistance as the pivotal pathogenic factor. Obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension contribute to risk for liver disease and to disease progression. The presence of multiple metabolic abnormalities is associated with the severity of liver disease. Patients have a high risk for cardiovascular morbidity and mortality, mediated by early atherosclerosis. This evidence has precise therapeutic implications: only a behavioral approach to lifestyle correction will address all alterations characterizing the metabolic syndrome, including metabolic liver disease. Medical Treatment of Non-alcoholic Steatohepatitis 119 Abdurrahman Kadayifci, Raphael B. Merriman, and Nathan M. Bass There is no proven medical treatment of non-alcoholic steatohepatitis (NASH). Most prior therapeutic trials have had methodologic limitations. Insulin sensitizers are the more promising therapeutic candidates among categories that include antioxidants, lipid-lowering agents, and antiobesity drugs. The future will see the evaluation of novel agents and a comprehensive treatment strategy that addresses the risk factors for the metabolic syndrome. This article reviews the current status of medical management options for NASH. Surgical Treatment for Obesity and Its Impact on Non-alcoholic Steatohepatitis 141 John B. Dixon Non-alcoholic steatohepatitis (NASH) in obese and severely obese populations is associated with the metabolic syndrome, with ix

4 features of the syndrome predicting those who will have NASH rather than simple steatosis, a more benign form of non-alcoholic fatty liver disease. Substantial weight loss is proving the most effective therapy for obesity-related conditions. Improvements have seen the development of less invasive procedures. There is growing evidence that laparoscopic adjustable gastric banding and roux-en-y gastric bypass provide effective therapy. Non-alcoholic Steatohepatitis in Children 155 Eve A. Roberts Non-alcoholic steatohepatitis (NASH) is an important liver disease in children; it can cause cirrhosis in children. The disease mechanism involves hepatic insulin resistance with hyperinsulinemia and changes in certain adipocytokines and inflammatory mediators. The differential diagnosis of childhood NASH includes metabolic disorders, drug hepatotoxicity, and alcoholic hepatitis in adolescent patients. The histologic features in childhood NASH often differ from those in adults who have NASH. Treatment is gradual weight loss through changes in food intake patterns and increased levels of physical activity; the role of drug treatment of NASH in children is an area of ongoing research. Steatosis as a Cofactor in Other Liver Diseases: Hepatitis C Virus, Alcohol, Hemochromatosis, and Others 173 Andrew D. Clouston, Julie R. Jonsson, and Elizabeth E. Powell As obesity prevalence rises, there is evidence that fatty liver disease can act synergistically with other chronic liver diseases to aggravate parenchymal injury. This is characterized best in chronic hepatitis C, where steatosis is caused by viral and metabolic effects. There is evidence that steatosis and its metabolic abnormalities also exacerbate other diseases, such as alcoholic liver disease, hemochromatosis, and, possibly, drug-induced liver disease. The pathogenesis seems related to increased susceptibility of steatotic hepatocytes to apoptosis, enhanced oxidative injury, and altered hepatocytic regeneration. Data suggest that active management of obesity may improve liver injury and decrease the progression of fibrosis in patients who have other chronic liver diseases. Non-alcoholic Steatohepatitis and Cancer 191 E. Bugianesi Hepatocellular carcinoma (HCC) is part of the natural history of non-alcoholic steatohepatitis (NASH). A significant proportion of people who have cryptogenic cirrhosis develop HCC. NASHrelated cirrhosis carries a substantial risk for early HCC development. Diagnosis of HCC often is made at first referral; the tumor x

5 usually is large with multiple localizations. Patients who have obesity or diabetes are at risk for HCC and a variety of cancers. Given the epidemic of obesity and diabetes, the incidence of NASHrelated HCC is expected to increase. In addition to developing new diagnostic tools and pharmacologic therapies, efforts should be directed at preventing non-alcoholic fatty liver disease. The Role of Genomics and Proteomics: Technologies in Studying Non-alcoholic Fatty Liver Disease 209 Ancha Baranova, Lance Liotta, Emanuel Petricoin, and Zobair M. Younossi Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are examples of complex diseases accompanied by changes in the expression of thousands of genes and a plethora of proteins encoded by these genes. Before the era of high-throughput analysis, typical translational research initiatives, aimed at defining the molecular targets for complex diseases, were performed on gene-by-gene basis. Innovative technologies, such as expression microarrays, mass spectromety, and reverse proteomics, now allow investigators to reveal complex patterns of the expression of biologically active molecules. For this reason, high-throughput approaches may be well suited for studies designed to untangle the molecular basis of the chronic liver diseases such as NAFLD. Index 221 xi