The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association (2012)

Preamble These recommendations are based on the following: (i) a formal review and analysis of the recently published world literature on the topic (Medline search up to June 2011); (ii) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines; (1) (iii) guideline policies of the three societies approving this document; and (iv) the experience of the authors and independent reviewers with regards to non-alcoholic fatty liver disease (NAFLD). Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) workgroup with minor modifications (Table 1) (2). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B), or low quality (C) (2). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently (3,4,5,6,7,8).Table 1: Grading of recommendations, assessment, development, and evaluation (GRADE)Definitions The definition of NAFLD requires that (i) there is evidence of hepatic steatosis, either by imaging or by histology and (ii) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication, or hereditary disorders (Table 2). In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically further categorized into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) (Table 3). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis.Table 2: Common causes of secondary hepatic steatosisTable 3: Nonalcoholic fatty liver disease and related definitionsIncidence and prevalence in the general population The incidence of NAFLD has been investigated in a limited number of studies. Two Japanese studies (9,10) reported an incidence rate of 31 and 86 cases of suspected NAFLD per 1,000 person-years, respectively, whereas another study from England showed a much lower incidence rate of 29 cases per 100,000 person-years (11). More studies are needed to better understand the incidence of NAFLD across different age, ethnic, and geographic groups. The reported prevalence of NAFLD varies widely depending on the population studied and the definition used. The prevalence of histologically defined NAFLD was 20 and 51% in two different studies comprised of potential living liver donors (12,13). The reported prevalence of NAFLD when defined by liver ultrasound (US) ranged between 17 and 46% depending on the population studied (4). In a study consisting of nearly 400 middle-aged individuals, the prevalence of NAFLD defined by ultrasonography was 46% and the prevalence of histologically confirmed NASH was 12.2% (14). In the Dallas Heart Study, when assessed by magnetic resonance (MR) spectroscopy, the prevalence of NAFLD in the general population was 31% (15). The prevalence of suspected NAFLD when estimated using aminotransferases alone without imaging or histology ranged between 7 and 11%, but aminotransferases can be normal in individuals with NAFLD (4). In summary, estimates of the worldwide prevalence of NAFLD ranges from 6.3 to 33%, with a median of 20% in the general population, based on a variety of assessment methods (4). On the other hand, the estimated prevalence of NASH is lower, ranging from 3 to 5% (4). The prevalence of NASH cirrhosis in the general population is not known. Prevalence of NAFLD in high-risk groups (Table 4) Obesity is a common and well-documented risk factor for NAFLD. Both excessive body mass index (BMI) and visceral obesity are recognized risk factors for NAFLD. In patients with severe obesity undergoing bariatric surgery, the prevalence of NAFLD can exceed 90% and up to 5% of patients may have unsuspected cirrhosis (4,16,17,18,19,20). There is a very high prevalence of NAFLD in individuals with type 2 diabetes mellitus (T2DM) (4). An ultrasonographic study of patients with T2DM showed a 69% prevalence of NAFLD (21). In another study, 127of 204 diabetic patients displayed fatty infiltration on US, and 87% of the patients with fatty infiltration who consented to biopsy had histologic confirmation of NAFLD (22). High serum triglyceride levels and low serum HDL levels are very common in patients with NAFLD. The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics was estimated to be 50% (23). Age, gender, and ethnicity are also associated with a differential prevalence for NAFLD (4). A number of studies have shown that the prevalence of NAFLD increases with age (24,25,26,27,28). The likelihood of disease progression to advanced fibrosis or mortality increases in older patients with NAFLD (29,30,31). Many recent studies have reported that male gender is a risk factor for fatty liver disease (4). For example, in a study of 26,527 subjects undergoing medical checkups, the prevalence of NAFLD was 31% in men and 16% in women (32). Compared with non-Hispanic whites, Hispanic individuals have significantly higher and non-Hispanic blacks have significantly lower prevalence of NAFLD (15,33,34,35). The prevalence of NAFLD in American-Indian and Alaskan-Native populations appears lower, ranging from 0.6 to 2.2%, although the lack of histologic definition makes it likely that is an underestimate (36,37). There are data to suggest that hypothyroidism, hypopituitarism, hypogonadism, sleep apnea, and polycystic ovary syndrome independent of obesity are important risk factors for the presence of NAFLD (Table 4) (3).Table 4: Risk factors associated with NAFLDNatural history The evolution of hepatic histologic changes in patients with NAFL and NASH has been investigated by several studies, but these generally included smaller number of patients and had relatively modest duration of follow-up (4,7). Nonetheless, it is generally agreed that patients with simple steatosis have very slow, if any, histological progression, while patients with NASH can exhibit histological progression to cirrhotic-stage disease (4,7). The long-term outcomes of patients with NAFLD and NASH have been reported in several studies (31,38,39,40,41,42,43,44,45). Their detailed discussion is beyond the scope of this guideline, but their findings can be summarized as follows: (i) patients with NAFLD have increased overall mortality compared with matched control populations; (ii) the most common cause of death in patients with NAFLD, NAFL, and NASH is cardiovascular disease; and (iii) patients with NASH (but not NAFL) have an increased liver-related mortality rate. Another piece of indirect evidence that supports the progressive nature of NASH is in the features of cryptogenic is related to NAFLD with cryptogenic cirrhosis have high prevalence of metabolic risk factors obesity, metabolic of patients with NAFLD, their liver one or features of and studies have the of histological features of NASH with the of cirrhosis with NAFLD are increased risk for but this risk is likely limited to with advanced fibrosis and cirrhosis studies investigated the history of NASH cirrhosis in to patients with cirrhosis study a lower rate of and mortality in patients with NASH cirrhosis as compared with patients with a recent study of NAFLD patients with advanced fibrosis and cirrhosis a duration of showed an overall of that was not different from matched patients with studies have shown that patients with NASH cirrhosis are significantly lower risk for than patients with cirrhosis and definition of NAFLD NAFLD the lack of evidence of or recent of significant of the definition of significant alcohol in patients with suspected NAFLD is A recent consensus for NASH significant alcohol be defined as per in men and per in women a liver this that be used to the of alcohol in the of The definition of significant alcohol in the published NAFLD literature has been and ranged from of alcohol per one per to per and published studies have not used alcohol are not with when a with suspected NAFLD, confirmation with a or a be of hepatic steatosis patients undergoing and imaging for other than liver or may unsuspected hepatic this is not in studies have not the or history of NAFLD in this in and obesity clinics can be that there be for NAFLD, individuals attending diabetes and obesity there are significant in the and of NAFLD. liver can be normal ranges in patients with NAFLD and may not be to as whereas liver is but it is and as a of experience and published studies suggest and of NAFLD but studies are In a study, that of patients with NASH have a A study that patients with NAFLD have a significantly higher number of with cirrhosis and a of NAFLD or cryptogenic cirrhosis than matched In another study of with and without NAFLD, for age, gender, and the of liver fat was and fatty liver was in of of with NAFLD normal and lack of evaluation The of NAFLD requires that (i) there is hepatic steatosis by imaging or (ii) there is no significant alcohol consumption, (iii) there are no for hepatic steatosis, and (iv) there are no causes for liver Common causes of hepatic steatosis are significant alcohol consumption, and severe (Table 2). a with suspected NAFLD, it is important to for liver disease liver and disease serum is common in patients with NAFLD and it not increased serum and in patients with suspected NAFLD to for in the with in patients with NAFLD and their is a liver biopsy to hepatic and to significant hepatic injury and fibrosis in a with suspected NAFLD with serum and a or in the serum are common in patients with NAFLD and are generally to be an In a recently published study from the NASH serum defined as or in of patients with NAFLD and not associated with advanced histologic features assessment of steatohepatitis and advanced fibrosis in NAFLD The history of NAFLD is is generally whereas NASH can to liver and liver that liver biopsy is the most for the presence of steatohepatitis and fibrosis in patients with NAFLD, but it is generally that biopsy is limited by and and levels and imaging such as US, and not steatohepatitis and fibrosis in patients with NAFLD. there has been significant in and for steatohepatitis in patients with NAFLD but their detailed discussion is beyond the scope of this practice The presence of metabolic syndrome is a strong for the presence of steatohepatitis in patients with NAFLD and may be used to best patients with liver who and from a liver There has been in methods to advanced fibrosis in patients with NAFLD these the NAFLD liver and The NAFLD is based on available and it is using the 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support from and in the 3 the 3 has for related to from and has from and has for related to NAFLD from and has from and for NASH has from and for has from and for related to NAFLD and has for related to NAFLD from and and support from in the 3 has as an to and as the for for and