American Gastroenterological AssociationAGA technical review on nonalcoholic fatty liver disease*,**
Section snippets
Methods
This report is based on the following: (1) a formal review and analysis of the literature on NAFLD (Index Medicus, 1950–1966; MEDLINE, 1966–2001), (2) several published guidelines and meta-analyses, including the American Gastroenterological Association's policy statement on guidelines, (3) the Manual for Guideline Development (American Gastroenterological Association: Clinical Practice and Practice Economics Committee)1 as well as the policy statement on the development and use of practice
History of discovery of NAFLD
The association of macrovesicular steatosis of the liver with inflammatory changes and fibrosis in obese subjects has been known for several decades.4 However, it was largely ignored as a clinical entity until several reports5, 6, 7 documented the development of liver failure in some patients following surgical jejunoileal bypass for morbid obesity. The hepatic histology in such patients was indistinguishable from that seen in alcoholic hepatitis and included macrovesicular steatosis, Mallory
Nomenclature
A complete diagnosis of fatty liver disease ideally should define the histology, including the stage and grade of the disease as well as its etiology (Table 1).Traditionally, fatty disorders of the liver have been classified as alcoholic or nonalcoholic. NAFLD includes both nonalcoholic fatty liver and NASH. NAFLD is associated with numerous etiologies (Table 2), and the underlying mechanisms as well as the natural history of the disease may vary with the specific etiology.
Histologic criteria for the diagnosis of fatty liver and steatohepatitis
The principal histologic feature of NAFLD is the presence of macrovesicular fatty change in hepatocytes with displacement of the nucleus to the edge of the cell.18, 19, 20, 21 The original descriptions of steatohepatitis included the additional presence of Mallory bodies, ballooning degeneration, predominantly lobular neutrophilic inflammation, and Rappaport zone III perisinusoidal fibrosis.9, 13, 15, 18 It is now appreciated that, in a given patient, only some of these features may be present.
Grading and staging of steatohepatitis
An universally accepted histologic grading and staging system for steatohepatitis does not exist. The histologic grade indicates the activity of the steatohepatitic lesion, whereas the stage reflects the degree of fibrosis (Table 1). In a retrospective analysis,26 those with florid steatohepatitis characterized by fat, ballooning degeneration, Mallory bodies, or perisinusoidal fibrosis had a poorer long-term outcome than those with fat and only nonspecific lobular inflammation. Based on these
Clinical spectrum of NAFLD
NAFLD is a heterogeneous disorder. The heterogeneity stems from the variability in the definitions of the term “steatohepatitis” as well as its varied clinical associations. The epidemiology, clinical associations, and clinical features of NAFLD are reviewed below.
How good are the diagnostic criteria?
Powell et al.48 originally proposed 3 criteria for the diagnosis of NASH: (1) a histologic picture of steatohepatitis, (2) convincing evidence of minimal or no alcohol consumption (<40 g/wk), and (3) absence of serologic evidence of viral hepatitis. Although these criteria are used widely in clinical practice, each criterion has specific limitations that bear discussion.
The variability in the histologic expression of NASH has been a source of debate and has prevented the development of a
What is the natural history of NAFLD?
Only limited data are available on the natural history of the spectrum of histologic lesions seen in macrovesicular fatty disorders of the liver that are not associated with the use of alcohol. It is generally believed that there are several distinct histologic states in the natural history of these disorders that indicate progression of the lesion (Figure 2).These include a fatty liver alone, steatohepatitis, steatohepatitis with fibrosis, and eventually
NAFLD in children
NAFLD has been reported in the pediatric population. In a retrospective review of liver biopsy specimens, Baldridge et al.47 found that 82 of 650 cases had hepatic steatosis, of which 14 were considered to have NASH with varying degrees of fibrosis. Similar data have been reported by others.30, 39, 155 Although most reported cases of fatty disorders of the liver in children have been noted around the age of puberty, isolated instances have been reported in those as young as 7–8 years of age.33
Treatment of NAFLD
The treatment of any condition requires consideration of the natural history of the condition, the relative efficacy and safety of the therapeutic options, and cost. As previously noted, NASH can progress to cirrhosis.22, 75, 199 This is particularly true in the presence of bridging fibrosis.26 Also, those with fat and ballooning degeneration or fat, ballooning degeneration and Mallory bodies or perisinusoidal fibrosis may be at greater risk for progression.26 Older subjects and those with
Summary
NAFLD is a major cause of liver-related morbidity in North America. It is frequently associated with the presence of insulin resistance. There is increasing evidence that NAFLD can progress to cirrhosis and liver failure. Physicians should actively check for the presence of NAFLD in those who are overweight and/or diabetic. There is no established treatment for NAFLD. Treatment usually is directed toward optimizing body weight. The role of pharmacologic agents remains to be established, and
Acknowledgements
The Clinical Practice Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the author: Alfred Baker, M.D., Helen Te, M.D., Karen Eun-Young Kim, M.D., and J. Sumner Bell, M.D. The members of the American Association for the Study of Liver Diseases Practice Guidelines Committee who contributed to the development of these papers include Henry Bodenheimer, M.D., David E. Bernstein, M.D., Gary L. Davis, M.D., James Everhart, M.D., Thomas
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Address requests for reprints to: Chair, Clinical Practice Committee, AGA National Office, c/o Membership Department, 7910 Woodmont Avenue, 7th Floor, Bethesda, Maryland 20814. Fax: (301) 654-5920.
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This literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice Committee and the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines Committee. The paper was approved by the Clinical Practice Committee on March 3, 2002, and by the AGA Governing Board on May 19, 2002. It was approved by the AASLD Governing Board and AASLD Practice Guidelines Committee on May 24, 2002.