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NON-ALCOHOLIC STEATOHEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES CONTENTS Preface xiii Zobair M. Younossi Epidemiology and Natural History of NAFLD and NASH 1 Janus P. Ong and Zobair M. Younossi Understanding of the epidemiology and natural history of non- alcoholic 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. Preva- lence 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 spec- trum, 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 sta- ging lesions. This article reviews some of the studies dealing with the histopathology of NAFLD, with attempts to develop a standar- dized pathologic scoring system for NASH. VOLUME 11 NUMBER 1 FEBRUARY 2007 vii

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NON-ALCOHOLIC STEATOHEPATITIS AND NON-ALCOHOLICFATTY LIVER DISEASES

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Preface xiiiZobair M. Younossi

Epidemiology and Natural History of NAFLD and NASH 1Janus P. Ong and Zobair M. Younossi

Understanding of the epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD) has increased; it is themost common form of chronic liver disease in the Western worldand increasing in importance in other parts of the world. Preva-lence is expected to increase as obesity and diabetes epidemicsevolve. The natural history of NAFLD depends on the histologicsubtype. Those who have simple hepatic steatosis or nonspecificinflammation generally have a benign long-term prognosis,whereas non-alcoholic steatohepatitis (NASH) can progress tocirrhosis. NASH-related cirrhosis may have a similar prognosis ascirrhosis from other causes, leading to liver failure or hepatocellularcarcinoma.

Pathologic Assessment of Non-alcoholic FattyLiver Disease 17Silvia Bondini, David E. Kleiner, Zachary D. Goodman,Terry Gramlich, and Zobair M. Younossi

Non-alcoholic fatty liver disease (NAFLD) represents one of themost common forms of liver disease and is considered the hepaticmanifestation of the metabolic syndrome. Within the NAFLD spec-trum, simple steatosis is considered benign, whereas non-alcoholicsteatohepatitis (NASH) may progress to cirrhosis. The distinctioncan be made only by liver biopsy. There is not complete agreementon criteria for diagnosis or the features used for grading and sta-ging lesions. This article reviews some of the studies dealing withthe histopathology of NAFLD, with attempts to develop a standar-dized pathologic scoring system for NASH.

VOLUME 11 Æ NUMBER 1 Æ FEBRUARY 2007 vii

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Role of Liver Biopsy and Serum Markers of Liver Fibrosisin Non-alcoholic Fatty Liver Disease 25Leon A. Adams and Paul Angulo

Non-alcoholic fatty liver disease (NAFLD) is common and mayprogress to end-stage liver disease. Liver-related morbidity andmortality occur almost exclusively in patients whose disease pro-gresses to advanced fibrosis and cirrhosis. Presence and severityof liver fibrosis seem the most important indicators of long-termprognosis. Clinical and biochemical variables may help selectNAFLD patients in whom liver biopsy may provide the most prog-nostic information. Some serum markers of liver fibrosis and ima-ging techniques aimed at measuring liver stiffness are underinvestigation as tools to determine severity of liver fibrosis inpatients who have NAFLD, but none of them yet can replace liverbiopsy.

Role of Radiologic Modalities in the Managementof Non-alcoholic Steatohepatitis 37Phunchai Charatcharoenwitthaya and Keith D. Lindor

During the last decade, the role of radiologic modalities in manage-ment of patients who have fatty liver disease has expanded. Ultra-sonography has been used as a noninvasive alternative to biopsyfor monitoring patients who have hepatic steatosis, but MRI ismore appealing than ultrasonography to denote minor changesin hepatic fat content. Distinguishing patients who have non-alcoholic steatohepatitis from steatosis alone has become of clinicalimportance; however, the differences are not apparent with anyradiologic modalities. Several modalities have been developed tononinvasively and accurately quantify hepatic fat content and di-agnose steatohepatitis. In the future, radiologic modalities mightbe used to monitor the natural history of the disease or evaluatetherapeutic interventions in patients who have non-alcoholic fattyliver disease.

Pathogenesis of NASH: Animal Models 55Roslyn M. London and Jacob George

The incidence of non-alcoholic steatohepatitis, a disorder linked tovisceral adiposity, insulin resistance, dyslipidemia, and type 2 dia-betes mellitus, is increasing with the rise in the prevalence of themetabolic syndrome. This review focuses on animal models of stea-tohepatitis currently used to study (1) the mechanisms regulatinghepatic lipid, glucose, and cholesterol homeostasis and (2) inflam-matory recruitment and fibrogenesis in the steatotic liver. The ulti-mate aim of this research is to gain insights into the role of hepaticlipid, inflammation, and fibrosis in human non-alcoholic fatty liverdisease.

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Pathogenesis of Non-alcoholic Steatohepatitis:Human Data 75John Edmison and Arthur J. McCullough

Non-alcoholic fatty liver disease (NAFLD) has moved rapidly tothe forefront of clinical disease, with a prevalence of 30% in theadult United States population and a definite but yet uncertain rateof progression to cirrhosis and end-stage liver disease. This diseasehas an impact on all areas of clinical medicine, with increasing pre-valence and adversity. It is essential to understand the pathophy-siologic mechanisms involved in NAFLD, so that therapeuticstrategies can be developed. Although fatty liver may be causedby other factors, this review concentrates on fatty liver associatedwith insulin resistance, sometimes referred to as the primary form.

Metabolic Syndrome and NASH 105Giulio Marchesini and Rebecca Marzocchi

Clinical and epidemiologic studies have associated non-alcoholicfatty liver with the metabolic syndrome, with insulin resistanceas the pivotal pathogenic factor. Obesity, type 2 diabetes mellitus,dyslipidemia, and hypertension contribute to risk for liver diseaseand to disease progression. The presence of multiple metabolic ab-normalities is associated with the severity of liver disease. Patientshave a high risk for cardiovascular morbidity and mortality,mediated by early atherosclerosis. This evidence has precise thera-peutic implications: only a behavioral approach to lifestyle correc-tion will address all alterations characterizing the metabolicsyndrome, including metabolic liver disease.

Medical Treatment of Non-alcoholic Steatohepatitis 119Abdurrahman Kadayifci, Raphael B. Merriman,and Nathan M. Bass

There is no proven medical treatment of non-alcoholic steatohepa-titis (NASH). Most prior therapeutic trials have had methodologiclimitations. Insulin sensitizers are the more promising therapeuticcandidates among categories that include antioxidants, lipid-low-ering agents, and antiobesity drugs. The future will see the evalua-tion of novel agents and a comprehensive treatment strategy thataddresses the risk factors for the metabolic syndrome. This articlereviews the current status of medical management options forNASH.

Surgical Treatment for Obesity and Its Impacton Non-alcoholic Steatohepatitis 141John B. Dixon

Non-alcoholic steatohepatitis (NASH) in obese and severely obesepopulations is associated with the metabolic syndrome, with

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features of the syndrome predicting those who will have NASHrather than simple steatosis, a more benign form of non-alcoholicfatty liver disease. Substantial weight loss is proving the most effec-tive therapy for obesity-related conditions. Improvements haveseen the development of less invasive procedures. There is growingevidence that laparoscopic adjustable gastric banding and roux-en-Ygastric bypass provide effective therapy.

Non-alcoholic Steatohepatitis in Children 155Eve A. Roberts

Non-alcoholic steatohepatitis (NASH) is an important liver diseasein children; it can cause cirrhosis in children. The disease mechan-ism involves hepatic insulin resistance with hyperinsulinemia andchanges in certain adipocytokines and inflammatory mediators.The differential diagnosis of childhood NASH includes metabolicdisorders, drug hepatotoxicity, and alcoholic hepatitis in adolescentpatients. The histologic features in childhood NASH often differfrom those in adults who have NASH. Treatment is gradual weightloss through changes in food intake patterns and increased levels ofphysical activity; the role of drug treatment of NASH in children isan area of ongoing research.

Steatosis as a Cofactor in Other Liver Diseases: HepatitisC Virus, Alcohol, Hemochromatosis, and Others 173Andrew D. Clouston, Julie R. Jonsson,and Elizabeth E. Powell

As obesity prevalence rises, there is evidence that fatty liver diseasecan act synergistically with other chronic liver diseases to aggra-vate parenchymal injury. This is characterized best in chronic hepa-titis C, where steatosis is caused by viral and metabolic effects.There is evidence that steatosis and its metabolic abnormalities alsoexacerbate other diseases, such as alcoholic liver disease, hemo-chromatosis, and, possibly, drug-induced liver disease. The patho-genesis seems related to increased susceptibility of steatotichepatocytes to apoptosis, enhanced oxidative injury, and alteredhepatocytic regeneration. Data suggest that active managementof obesity may improve liver injury and decrease the progressionof fibrosis in patients who have other chronic liver diseases.

Non-alcoholic Steatohepatitis and Cancer 191E. Bugianesi

Hepatocellular carcinoma (HCC) is part of the natural history ofnon-alcoholic steatohepatitis (NASH). A significant proportion ofpeople who have cryptogenic cirrhosis develop HCC. NASH-related cirrhosis carries a substantial risk for early HCC develop-ment. Diagnosis of HCC often is made at first referral; the tumor

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usually is large with multiple localizations. Patients who have obe-sity or diabetes are at risk for HCC and a variety of cancers. Giventhe epidemic of obesity and diabetes, the incidence of NASH-related HCC is expected to increase. In addition to developingnew diagnostic tools and pharmacologic therapies, efforts shouldbe directed at preventing non-alcoholic fatty liver disease.

The Role of Genomics and Proteomics: Technologiesin Studying Non-alcoholic Fatty Liver Disease 209Ancha Baranova, Lance Liotta, Emanuel Petricoin,and Zobair M. Younossi

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic stea-tohepatitis (NASH) are examples of complex diseases accompaniedby changes in the expression of thousands of genes and a plethoraof proteins encoded by these genes. Before the era of high-through-put analysis, typical translational research initiatives, aimed at de-fining the molecular targets for complex diseases, were performedon gene-by-gene basis. Innovative technologies, such as expressionmicroarrays, mass spectromety, and reverse proteomics, now allowinvestigators to reveal complex patterns of the expression of biolo-gically active molecules. For this reason, high-throughput ap-proaches may be well suited for studies designed to untangle themolecular basis of the chronic liver diseases such as NAFLD.

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