Natural history and epidemiology of non-alcoholic fatty liver disease in Korea

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1 Natural history and epidemiology of non-alcoholic fatty liver disease in Korea Tae Yeob Kim and Joo Hyun Sohn Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disease that may range from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) which can progress to advanced fibrosis and cirrhosis and is currently one of the most common chronic liver diseases in Korea and worldwide. Furthermore, in parallel with the increasing prevalence of obesity, type 2 diabetes and metabolic syndrome, the prevalence of NAFLD is expected to increase. However, data about the incidence, prevalence and natural history of NAFLD are diverse depending on the charcteristics of study population and screening tests - hepatic imaging studies, histology and liver enzymes. Herein, the natural history and epidemiology of NAFLD are shortly reviewed and summarized using many recent articles, esp. Korean data. Keywords: Non-alcoholic fatty liver disease; epidemiolgoy; incidence; prevalence; natural history Introduction Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disease that may range from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) which can progress to advanced fibrosis and cirrhosis. 1 NAFLD is one of the most common liver diseases in Korea nowadays affecting % of the nondiabetic general population. 2-5 The major risk factors for NAFLD are central obesity, type 2 diabetes mellitus, dyslipidemia, and the associated metabolic syndrome. The prevalence of obesity and metabolic syndrome in Korea National Health and Nutrition Examination Survey (KNHANES) has substantially increased during the past decade, 6-8 and so the prevalence of NAFLD in Korea is expected to increase. Furthermore, the increasing prevalence of NAFLD will increase clinical burden with extra-hepatic health problems because patients with NAFLD have the positive relation to cardiovascular risk factors and Framingham risk score. 9 Therefore, the acquisition of knowledge about the natural history and epidemiology of NAFLD is an important issue, and we will review shortly the recent data regarding this issue, esp. including Korean data. SYMPOSIUM 1 Natural History of NAFLD The natural history of NAFLD is not yet fully demonstrated but recent data have added a tantalizing clue on it

2 SYMPOSIUM 1. Nonalcoholic Fatty Liver Disease in 2012 It is generally accepted that the majority of patients with NAFLD may have stable course or remission and only a small portion of patients may progress and the disease progression depends on the histological status of NAFLD at the time of presentation. As aforementioned, NAFLD can be histologically divided into NAFL and NASH. Generally, patients with NAFL have a benign prognosis, whereas patients with NASH can have progressive liver disease, finally leading to cirrhosis and hepatocellular carcinoma (HCC). 15 It is notable that according to a report, even most patients with NASH have relatively benign course, with 10-15% histological progression and only about 2% progressing to decompensated cirrhosis. 16 However, the proportion of patients with progressive disease varies depending on the data. It is also well recognized that several risk factors such as obesity, diabetes mellitus, degree of inflammation and fibrosis on initial biopsy, weight gain and age, have been associated with disease progression, whereas controlled weight reduction has been associated with disease regression. 16 A very recent report showed that of the 66 patients who have NAFLD by ultrasonography at baseline, as many as 24 patients (36.4%) had no evidence of NAFLD at 7 years follow-up, even though mostly depending on modest weight reduction. 17 According to a paired biopsy study with 103 patients and mean interval between biopsies of 3.2 years, liver fibrosis stage apparently progressed in 37%, remained stable in 34% and regressed in 29%. 18 Furthermore, 12.6% (13/103) patients with fibrosis had no fibrosis. In this study, diabetes and initial fibrosis stage were the independent risk factors associated with higher rate of fibrosis progression. A systematic review of risk factors for fibrosis progression in 221 NASH patients showed that 37.6% had progressive fibrosis over a mean follow-up interval of 5.3 years. In this study, age and inflammation on initial biopsy are independent predictors of progression to advanced fibrosis and other traditional parameters (e.g. obesity, diabetes, hypertension) were not statistically significant predictors. 19 Other long-term follow-up study of patients with NAFLD and elevated liver enzymes covered most aspects of natural history of NAFLD. 20 In this study, about 20% among patients with NAFL will progress to NASH with early fibrosis and about 15% among patients with NASH and early fibrosis will progress to cirrhosis and/or decompensation over the 8-13 years. The predictors of fibrosis progression are weight gain and presence of portal tract fibrosis. 20 About 7% of patients with compensated cirrhotic NASH will develop HCC within 10 years. In patients with NASH and cirrhosis, the 10-year liver related mortality is around 15% and all-cause mortality about 20% (Fig. 1). 20 This study demonstrated that patients with NASH progressed to cirrhosis have a substantial risk for hepatic decompensation, development of HCC and death. Another study showed that liver-related mortality of NASH patients were 17.5% compared to only 2.7% in patients with NAFL over a median follow-up of 18.5 years. 11 Figure 1. Natural history of NAFLD. 17,20,21,22,27 NAFL, non-alcoholic fatty liver (simple steatosis); NASH, non-alcoholic steatohepatitis; HCC, Hepatocellular carcinoma. The risk of HCC development seems to be somewhat lower in NASH-related cirrhotic patients than in those with HCV-re

3 Tae Yeob Kim / Natural history and epidemiology of non-alcoholic fatty liver disease in Korea lated cirrhosis, with 11.3% for NASH and 30.5% for HCV at 5 years and 12.8% for NASH and 20.3% for HCV at 3.2 years. 21,22 However, the overall survival is similar, probably associated with increased cardiovascular death in patients with NASH (the 5-year survival rates were 75.2% for NASH and 73.8% for HCV, respectively). 21 In western countries, a rise in incidence of HCC associated with NAFLD has been observed in recent years. Although data about the natural history of NAFLD in Korea is lacking, a retrospective and hospital-based study of Korean patients with HCC compared etiologies between two periods ( and ) demonstrated that the prevalence of cryptogenic HCC was increased from 2.3% to 5.4% during the observational period, and from this study it might be carefully inferred that NAFLD and/or its risk factors contribute to the recent increase of cryptogenic HCC prevalence in Korea. 23 A long-term follow-up study of Swedish patients with biopsy proven NAFLD demonstrated that survival of patients with NASH was lower than expected in comparison with general population. 12 Recent meta-analysis found that NAFLD was associated with increased overall mortality, originated from cardiovascular disease (CVD) and liver-related disease, and an increased risk of type 2 diabetes. 24 In this meta-analysis, however, CVD mortality was not different between NAFL and NASH. Epidemiology of NAFLD 1. Incidence The incidence of NAFLD is not yet clearly determined because of difficulties in estimation, esp. for general population. Several reasons for difficulties are a substantial loss in long-term follow-ups of healthy people from general population, insufficiency of a reference method for the assessment of NAFLD, and a paucity of information of metabolic parameters. So, only a few studies are available about the incidence of NAFLD. Susuki et al 25 prospectively investigated the incidence of NAFLD based on elevated liver enzymes from data obtained as part of routine health care for employees in a Japanese government office and they reported that the incidence of high aminotransferases was 31 per 1,000 person-years. Hamaguchi et al 26 performed a prospective observational study in the setting of a medical health checkup program in a general hospital, and they observed 308 (9.8%) new cases of NAFLD among 3147 participants who did not have NAFLD at baseline during follow-up for a mean time of only 1.1 years. The incidence of fatty liver in the general Italian population was estimated by the Dionysos study at two new cases/100 people/year, indicating the 15.3% incidence rate among 144 patients without NAFLD at baseline during a follow-up period of 8.5 years. 27 Zelber-Sagi et al 17 evaluated a representative sample of the general population without alchol related liver disease and primary NAFLD. During the 7-year follow-up, they onserved 28 (19.0%) new cases of NAFLD among 147 subjects. 17 Recently three Korean studies evaluated the incidence of NAFLD defined by ultrasonographic examination. Kim et al 28 investigated the incidence of NAFLD in 2895 healthy subjects (1502 men, 1393 women) with mean age of 47 years attending medical check-up, and they obsereved 374 (19.3%) new cases of NAFLD among 1938 subjects during 5 years. In a cohort of Korean male workers aged years attending health check-ups, an incidence rate of 37 per 1000 person-years was reported. 29 In a large cohort of non-diabetic healthy Korean adults participated in a health SYMPOSIUM

4 SYMPOSIUM 1. Nonalcoholic Fatty Liver Disease in 2012 check-up program, new cases of NAFLD are developed in 13% (644/4954) during a 5-year follow-up. 30 According to these data, metabolic syndrome, weight gain, or insulin resistance were associated with NAFLD incidence. According to these data, the current incidence of NAFLD in Korea is about 13-19% in general population. 2. Prevalence There are relatively large data available about the prevalence of NAFLD despite it varies depending on charcteristics of study population and screening tests - hepatic imaging studies, histology and liver enzymes and it is clear that NAFLD is an increasing common problem in Korea and worldwide. The results of recent epidemiologic Korean studies about the prevalence of NAFLD are summarized in Table 1. It showed that the current prevalence of NAFLD in Korea was % in general population and 51.4% in living liver donors. A systematic review revealed that the estimated worldwide prevalence of NAFLD ranges form 3.1 to 51% in general populations. 31 Using proton magnetic resonance spectrography in the United States, the prevalence of hepatic steatosis (5.5% or more fat) was estimated 31%. 32 The several population based studies using ultrasonography demonstrasted that the prevalence of NAFLD in general population from 9.3 to 29.5% in Asia, 33, % in Mexico, 35 30% in Israel, 36 20% in Romania, % in Italy. 38 The prevalence of NAFLD diagnosed by elevated liver enzymes was much lower than by imaging studies, ranged from 2.8% in United States 39 to 9.3% in Japan. 25 In patients with morbid obesity (body mass index 35kg/m 2 ), type 2 diabetes, and dyslipidemia, the prevalence of NAFLD is much higher than in general population. Two studies of morbidly obese patients undergoing bariatric surgery revealed that the prevalence of NAFL was 47%, NASH 27-42% and cirrhosis %. 40,41 Two review articles showed that among patients who were morbidly obese and undergoing bariatric surgery the prevalence of NAFLD was about 76% (range 33-99%), NASH 37% (range %), fibrosis 23% (range %), and cirrhosis 5.8% (1.6-10%). 42,43 Among diabetic patients, the prevalence of ultrasonographic NAFLD was % In addition to a higher prevalence of NAFLD in patients with type 2 diabetes, they appear to have more advanced liver disease, including NASH and cirrhosis. 42 Dyslipidemia including hypertriglyceridemia, hypercholesterolemia, or both is also associated with NAFLD, found in 20%-92% of patients with NAFLD. It is notable that most of these patients had other components of the metabolic syndrome. 16 On the other hand, there is no information available on the prevalence of NASH in general population, as large population-based studies can be hardly performed, because a liver biospy, the current gold standard of NASH diagnsosis and staging, is invasive and cannot be applied as a screening tools. For lacking anything better, we can estimate the Table 1. The Prevalence of Nonalcoholic Fatty liver Disease (NAFLD) in Korean Population Reference, Year Population (n) Prevalence of NAFLD (%) Diagnosis of NAFLD, by ultrasound Kim (2004) 2 General population (N=768) 23.4 Park (2006) 3 General population (N=6648) 18.7 Bae (2010) 4 General population (N=99969) 28.1 Sinn (2012) 5 General population (N=5878) 27.4 Diagnosis of NAFLD, by biopsy Lee (2007) 48 Living liver donors (N=589) 51.4, (2.2% NASH)

5 Tae Yeob Kim / Natural history and epidemiology of non-alcoholic fatty liver disease in Korea prevalence of NAFL and NASH using liver biospy in general population or low-risk groups from reports of biospy samples of apparently healthy liver transplant donors or series of autopsy with non-liver related death. Studies of living liver donors showed the prevalence of NAFLD ranged from about 15% to 52% similar in both Eastern and Western population, 47,48 but that of NASH was somwhat lower in Eastern countries ( %) including Korea 48,49 than in Western countires (3-15%) An autopsy study of 351 non-alcoholic patients showed that a prevalence of NASH was 2.7% among normal weight subjects, while it increased to 12.2% among diabetic patients and 18.5% among severely obese patients. 52,53 3. Risk factors associated with NAFLD Well-known risk factors related to NAFLD are age, sex, race, obesity (esp. central obesity), type 2 diabetes, dyslipidemia and metabolic syndrome. A part of them will be shortly described herein and some parts are above-mentioned. The prevalence of NAFLD among adults increases with age. This may be parallel with increasing prevalence of insulin resistance and metabolic syndrome with age. The peak prevalence of NAFLD was earlier in men (fourth decade) than women (sixth decade). 54 Similarly to Western studies, Park et al 3 showed that the prevalence of NAFLD increased gradually among Korean women aged years and spiked suddenly once age exceed 50 years. Earlier studies of patients with NAFLD suggested a female preponderance but more recent studies, including population-based studies, showed that NAFLD affects both genders equally or a higher proportion of men. 54 A Korean study showed the prevalence of NAFLD were higher in men than in women below 50 years, but the prevalence did not differ significantly according to gender above 50 years. 3 The difference with regards to the influence of age on the prevalence of NAFLD between the genders may be attributed by protective effects of estrogen and less visceral fat in women. 42 Racial and ethinic difference in prevalence of NAFLD are evaluated in some reports. In a study using proton magnetic resonance spectrography, Browning et al 32 found a lower prevalence of NAFLD among African Americans (median 24%) than non-hispanic whites (median 33%) or Hispanics (45%). Caldwell et al 55 showed the prevalence of NASH is much lower in African American decent than in Europian American descent. These differences may be explained less viseceral fat and a different lipoprotein metabolism in African Americans. 56 Obesity and metabolic syndrome including diabetes were closely linked to prevalence of NAFLD. Sinn et al showed the prevalence of NAFLD increased ranging from 15.2% to 100% in accordance with the increased numbers of observed metabolic components of the Adult Treatment Panel III criteria. 5 As described previously, in Korean population the prevalence of obesity and type 2 diabetes is increasing, and so the prevalence of NAFLD appears to increase. SYMPOSIUM 1 Conclusion Korean data about the natural history of NAFLD is not yet available, so we have no choice but to infer from data of other countries. Even though the majority of patients with NAFLD may have stable course or remission and only a small portion of patients may progress, patients with NASH progressed to cirrhosis have a substantial risk for hepatic decompensation, development of HCC and death. It is also notable that NAFLD itself is associated with increased cardiovascular death. Well-known risk factors associated with NAFLD progression include obesity, diabetes mellitus, degree

6 SYMPOSIUM 1. Nonalcoholic Fatty Liver Disease in 2012 of inflammation and fibrosis on initial biopsy, weight gain and age, whereas controlled weight reduction has been associated with disease regression. The natural history of NAFLD is summarized in Figure 1. Nowadays, NAFLD is one of the most common liver diseases in Korea and worldwide and the prevalence of NAFLD is expected to increase further in parallel with increasing prevalence of obesity, type 2 diabetes and metabolic syndrome. The prevalence of NAFLD and NASH is much higher in patients who have the metabolic syndrome than in general population and the risk to disease progression is increasing in accordance with the increasing numbers of metabolic components. Overall, the current incidence and prevalence of NAFLD in Korea is about 13-19% and 19-28% in general population respectively, and the prevalence of NASH in Korea is 2.2% in living liver donors but is not determined yet in general population. Further well-designed prospective studies about the natural history and epidemiology of NAFLD, esp. in general Korean population, are required. References 1. Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001;21: Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, Lim SK, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004;164: Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 2006;21: Bae JC, Cho YK, Lee WY, Seo HI, Rhee EJ, Park SE, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am J Gastroenterol 2010;105: Sinn DH, Gwak GY, Park HN, Kim JE, Min YW, Kim KM, et al. Ultrasonographically detected non-alcoholic Fatty liver disease is an independent predictor for identifying patients with insulin resistance in non-obese, non-diabetic middle-aged asian adults. Am J Gastroenterol 2012;107: Kim DM, Ahn CW, Nam SY. Prevalence of obesity in Korea. Obes Rev 2005;6: Khang YH, Yun SC. Trends in general and abdominal obesity among Korean adults: findings from 1998, 2001, 2005, and 2007 Korea National Health and Nutrition Examination Surveys. J Korean Med Sci 2010;25: Lim S, Shin H, Song JH, Kwak SH, Kang SM, Won Yoon J, et al. Increasing prevalence of metabolic syndrome in Korea: the Korean National Health and Nutrition Examination Survey for Diabetes Care 2011;34: Sung KC, Ryan MC, Wilson AM. The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects. Atherosclerosis 2009;203: de Alwis NM, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol 2008;48 Suppl 1:S Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009;7: Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51: Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol 2008;49: Angulo P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance? Hepatology 2010;51: Ratziu V, Poynard T. Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious. Hepatology 2006;44: Kopec KL, Burns D. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract 2011;26:

7 Tae Yeob Kim / Natural history and epidemiology of non-alcoholic fatty liver disease in Korea 17. Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012;56: Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42: Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009;51: Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44: Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009;24: Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51: Oh KC, Park SH, Park JC, Jin DK, Park CS, Kim KO, et al. [Is the prevalence of cryptogenic hepatocellular carcinoma increasing in Korea?]. Korean J Gastroenterol 2005;45: Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43: Suzuki A, Angulo P, Lymp J, St Sauver J, Muto A, Okada T, et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 2005;41: Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143: Bedogni G, Miglioli L, Masutti F, Castiglione A, Croce LS, Tiribelli C, et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology 2007;46: Kim HK, Park JY, Lee KU, Lee GE, Jeon SH, Kim JH, et al. Effect of body weight and lifestyle changes on long-term course of nonalcoholic fatty liver disease in Koreans. Am J Med Sci 2009;337: Chang Y, Ryu S, Sung E, Woo HY, Cho SI, Yoo SH, et al. Weight gain within the normal weight range predicts ultrasonographically detected fatty liver in healthy Korean men. Gut 2009;58: Rhee EJ, Lee WY, Cho YK, Kim BI, Sung KC. Hyperinsulinemia and the development of nonalcoholic Fatty liver disease in nondiabetic adults. Am J Med 2011;124: Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34: Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40: Omagari K, Kadokawa Y, Masuda J, Egawa I, Sawa T, Hazama H, et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 2002;17: Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol 2005;11: Lizardi-Cervera J, Laparra DI, Chavez-Tapia NC, Ostos ME, Esquivel MU. [Prevalence of NAFLD and metabolic syndrome in asymtomatics subjects]. Rev Gastroenterol Mex 2006;71: Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z, Oren R. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver Int 2006;26: Radu C, Grigorescu M, Crisan D, Lupsor M, Constantin D, Dina L. Prevalence and associated risk factors of non-alcoholic fatty liver disease in hospitalized patients. J Gastrointestin Liver Dis 2008;17: Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005;42: Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase SYMPOSIUM

8 SYMPOSIUM 1. Nonalcoholic Fatty Liver Disease in 2012 activity in the United States. Gastroenterology 2003;124: Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137: Kallwitz ER, Guzman G, TenCate V, Vitello J, Layden-Almer J, Berkes J, et al. The histologic spectrum of liver disease in African-American, non-hispanic white, and Hispanic obesity surgery patients. Am J Gastroenterol 2009;104: Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008;28: Levene AP, Goldin RD. The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30: Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Fiorello S, et al. Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2005;90: Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003;285:E Amarapurkar A, Ghansar T. Fatty liver: experience from western India. Ann Hepatol 2007;6: Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47: Yamamoto K, Takada Y, Fujimoto Y, Haga H, Oike F, Kobayashi N, et al. Nonalcoholic steatohepatitis in donors for living donor liver transplantation. Transplantation 2007;83: Nadalin S, Malago M, Valentin-Gamazo C, Testa G, Baba HA, Liu C, et al. Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits. Liver Transpl 2005;11: Minervini MI, Ruppert K, Fontes P, Volpes R, Vizzini G, de Vera ME, et al. Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests. J Hepatol 2009;50: Smith BW, Adams LA. Non-alcoholic fatty liver disease. Crit Rev Clin Lab Sci 2011;48: Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12: Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 2007;11:1-16, vii. 55. Caldwell SH, Harris DM, Patrie JT, Hespenheide EE. Is NASH underdiagnosed among African Americans? Am J Gastroenterol 2002;97: Caldwell SH, Ikura Y, Iezzoni JC, Liu Z. Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver)? J Gastroenterol Hepatol 2007;22 Suppl 1:S