- Email: [email protected]
Are We Overestimating the Risks of NASH?
March 2006
CORRESPONDENCE
7. Elinav E, Ben-Dov IZ, Ackerman E, Kiderman A, Glikberg F, Shapira Y, Ackerman Z. Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern. Am J Gastroenterol 2005;100:2201–2204. 8. Ong JP, Elariny H, Collantes R, Younoszai A, Chandhoke V, Reines HD, Goodman Z, Younossi ZM. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 2005;15:310 –315. 9. Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, Repetto G. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg 2004; 14:635– 637. 10. Mathiesen UL, Franzen LE, Aselius H, Resjo M, Jacobsson L, Foberg U, Fryden A, Bodemar G. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases. Dig Liver Dis 2002;34:516 –522. 11. Jia H, Lubetkin EI. The impact of obesity on health-related qualityof-life in the general adult US population. J Public Health 2005; 2:156 –164. 12. Loria P, Lonardo A, Lombardini S, Carulli L, Verrone A, Ganazzi D, Rudilosso A, D’Amico R, Bertolotti M, Carulli N. Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors. J Gastroenterol Hepatol 2005;20:1176 –1184. doi:10.1053/j.gastro.2006.01.077
Are We Overestimating the Risks of NASH? Dear Sir: We read with interest the article by Adams et al1 in the July 2005 issue and the letter in response to the article by Ioannou2 in the November 2005 issue. Dr. Adam’s group is to be congratulated for this study as further studies on natural history of NAFLD would be difficult without some intervention at least in the form of lifestyle modification. They have shown that NAFLD and NASH are not so sinister diseases contrary to the belief,3 as NAFLD was responsible for only 1.7% of deaths due to liver-related events in their cohort. However, it is stated that liver related mortality is the third important cause of death in their study. In addition to the comments made by Ioannou in his letter, we would like to point out that we do not agree completely with certain conclusions derived by Adams et al. According to them, the mortality of NAFLD is significantly increased compared with the general population of same age and sex. They have included in their analysis 8 patients who had cirrhosis on initial presentation. They also have reported 53 deaths in their cohorts and described liver-related illness as the third most common cause of death (13%) after malignancy (28%) and ischemic heart disease (25%). However, 5 deaths were in patients who had cirrhosis on initial presentation. If this group were excluded from the final analysis, we are left with only 2 patients who died of liver-related illness, which accounts for 4.1% of cause of deaths and 0.5% of all deaths in their cohort. When the various causes of death in their cohort is analyzed after eliminating those who had cirrhosis on initial presentation, another picture will emerge showing liver-related death at much lower level probably nearer to the 13th leading cause of death in their general population. It is also interesting to note that independent risk factors for NAFLD like obesity and metabolic syndrome4 – 6 had no correlation with the mortality in their cohorts and it requires further explanation. This is especially important as 71% of their patients had obesity and 68% had hypertriglyceridemia.
1015
The authors have provided data that 66% of their patients had elevated AST (51 ⫾ 52 U/L). From this it appears that most of their patients had only marginally elevated AST levels and hence it may be presumed that a significant proportion of their patients had only mild form of NAFLD, which may be the reason for the low mortality compared with earlier observations. Earlier studies on natural history of NAFLD based on liver histology had shown that progression of liver disease is related to the severity of liver involvement.7 In contrast, other studies have shown that simple steatosis or steatosis with minimal inflammation is a relatively stable condition.8,9 It would have been appropriate if they had analyzed their cohorts as different groups namely, those with normal liver function tests and those with abnormal liver function tests. Figure 1 in the paper by Adams et al describes the number of patients who had undergone liver biopsy as 70, but they have provided data of 65 patients only. There were 49 confirmed cases of NASH; however, we are not provided with the information as to how many patients had grade 3 and 4 disease. It is also mentioned that there was significant difference in the survival between patients who had a liver biopsy and those who did not have a biopsy. It is evident from their observations that large number of patients who had liver biopsy also had elevated bilirubin, lower albumin and elevated prothrombin time in addition to higher percentage of them having diabetes or impaired glucose tolerance. Eight of these patients had evidence of cirrhosis on presentation. As we have pointed out, these patients (cirrhotics) with evidence of abnormal liver function tests should have been excluded from the analysis of the natural history of NAFLD. As the cohort consisted of patients with cirrhosis, steatohepatitis, bland steatosis, and unclassified NAFLD this study is also fraught with the same pitfalls of earlier studies which included the entire spectrum of NAFLD as one disease and attempted to study its natural history as a whole. If the authors had excluded from their analysis those with cirrhosis on initial presentation, the liver-related mortality in NAFLD would have been shown to be lower than what has been presented. Then the result would be even more unimpressive than what Ioanou has pointed out. VARGHESE THOMAS KAREEM HARISH Department of Gastroenterology Calicut Medical College Hospital Kerala, India 1. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129:113–121. 2. Ioannou GN. The natural history of NAFLD: impressively unimpressive. Gastroenterology 2005;129:1805. 3. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664 – 669. 4. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107:450 – 455. 5. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–923. 6. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106 –1110.
1016
CORRESPONDENCE
7. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116: 1413–1419. 8. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995;22:1714 –1719. 9. Hilden M, Juhl E, Thomsen AC, Christoffersen P. Fatty liver persisting for up to 33 years. A follow-up of the inversen-roholm liver biopsy material. Acta Med Scand 1973;194:485– 489. doi:10.1053/j.gastro.2006.01.078
Reply. I appreciate the interest of Drs. Tarantino, Ioannou, Thomas, and Harish in our paper evaluating the natural history of NAFLD in a community-based study.1 The 124,000 population in Olmsted County was identified at a single point in the year 2000 whereas our study included patients diagnosed with NAFLD during the period 1980 –2000. The study by Browning et al2 reporting that approximately one third of the population had too much fat in the liver used MR spectroscopy without histology to confirm steatosis. Furthermore, that study2 included an age range of 18 – 65 years; the prevalence of NAFLD in youth is much lower, and so the prevalence in the total United States population is lower than 1 in 3. As highlighted in our paper,1 we included every patient with NAFLD from the community who had been diagnosed with the disease. Those individuals with “silent” NAFLD were not included simply because the disease had not been recognized, and whether or not they have a “much lower mortality/morbidity from NAFLD” has yet to be demonstrated. Our study did not capture all cases of NAFLD in Olmsted County, and it is unrealistic to believe every single individual with NAFLD in the community can be identified. To date, there is no test or combination of tests, which can diagnostically provide with 100% accuracy. Liver enzymes and imaging studies may be normal in patients with well-established NAFLD, and even if everybody in the community were to undergo liver biopsy, some cases would still be missed given the patchy distribution of disease.3 We used census data to compare mortality between NAFLD and the general population of the same age and gender, and thus, we were not able to adjust for confounders such as “insulin resistance, central obesity, diabetes, and lipid abnormalities.” All these confounders are well-known risk factors for the development of NAFLD, and thus, if we have had tried to adjust for all of them, most likely we would have ended-up without a control group. I disagree that survival analysis favored overall prognosis for the general Minnesota population. Conversely, as patients with NAFLD were actively investigated, concomitant medical conditions were identified and treated biasing toward a survival advantage for the NAFLD patients. This bias would attenuate the difference in survival between NAFLD and the general Minnesota population, and thus the survival difference we found was conservatively estimated and likely to be more significant than reported. It is intriguing that Thomas and Harish think “patients with marginally elevated AST levels had mild form of NAFLD.” Aminotransferase levels are in the normal range in 79% of individuals with NAFLD in the general population,2 and in some patients whose NAFLD has progressed to advanced disease.4,5 When elevated, aminotransferase levels improve and even normalize as the disease progresses to advanced fibrosis and cirrhosis.6 Prognosis in our patients was not different between those with normal or elevated aminotransferase levels.1 The fact that biopsied patients in our series had more advanced liver disease and a higher proportion of cirrhotics
GASTROENTEROLOGY Vol. 130, No. 3
simply highlights the higher likelihood to perform a biopsy on patients with more advanced disease. Five of the 70 biopsied patients were excluded from analysis as their liver biopsy was performed postmortem. That metabolic syndrome per se is inaccurate in predicting mortality has been reported in several studies.7 A BMI in the obese or overweight category was almost a universal finding in our patients increasing the difficulty in predicting survival.1 Presence of IFG/diabetes which is a component of the metabolic syndrome and often clusters with obesity/overweight was a strong independent predictor of mortality in our series.1 Liver-related mortality in our patients with NAFLD was essentially observed in those whose disease had progressed to cirrhosis, just as occurs among patients with chronic hepatitis C infection. The exclusion of cirrhotic patients with NAFLD from our analysis would have certainly provided a lower, but clearly biased mortality figure, and an incomplete estimate of the real impact of the liver disease on overall mortality. Our results are in agreement with recent series evaluating the long-term mortality in patient with NAFLD.8,9 Those series found a liver-related mortality rate of less than 1% among patients with bland steatosis during an average follow-up of 17 years,8 but as high as 21% liver-related mortality during a 5-year follow-up period among those with cirrhotic-stage NASH.9 However, between bland steatosis and cirrhotic-stage disease there is a wide spectrum of histological damage. The rate of disease progression and prognosis of those patients with intermediate stages has yet to be investigated in large, long-term follow-up studies. Our finding in a communitybased study that most liver-related morbidity and mortality occurred when the disease had progressed to advanced fibrosis and cirrhosis calls for the design of well-controlled treatment trials aimed at preventing NAFLD progression. PAUL ANGULO Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, Minnesota 1. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129:113–121. 2. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–1395. 3. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T, LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898 –1906. 4. Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37: 1286 –1292. 5. Sorrentino P, Tarantino G, Conca P, Perrella A, Terracciano ML, Vecchione R, Gargiulo G, Gennarelli N, Lobello R. Silent nonalcoholic fatty liver disease-a clinical-histological study. J Hepatol 2004;41:751–757. 6. 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: 132–138. 7. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Diabetes Care 2005;28:2289 –2304. 8. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TIA, Becker U, Bendtsen F. Long-term prog-
CORRESPONDENCE
7. Elinav E, Ben-Dov IZ, Ackerman E, Kiderman A, Glikberg F, Shapira Y, Ackerman Z. Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern. Am J Gastroenterol 2005;100:2201–2204. 8. Ong JP, Elariny H, Collantes R, Younoszai A, Chandhoke V, Reines HD, Goodman Z, Younossi ZM. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 2005;15:310 –315. 9. Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, Repetto G. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg 2004; 14:635– 637. 10. Mathiesen UL, Franzen LE, Aselius H, Resjo M, Jacobsson L, Foberg U, Fryden A, Bodemar G. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases. Dig Liver Dis 2002;34:516 –522. 11. Jia H, Lubetkin EI. The impact of obesity on health-related qualityof-life in the general adult US population. J Public Health 2005; 2:156 –164. 12. Loria P, Lonardo A, Lombardini S, Carulli L, Verrone A, Ganazzi D, Rudilosso A, D’Amico R, Bertolotti M, Carulli N. Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors. J Gastroenterol Hepatol 2005;20:1176 –1184. doi:10.1053/j.gastro.2006.01.077
Are We Overestimating the Risks of NASH? Dear Sir: We read with interest the article by Adams et al1 in the July 2005 issue and the letter in response to the article by Ioannou2 in the November 2005 issue. Dr. Adam’s group is to be congratulated for this study as further studies on natural history of NAFLD would be difficult without some intervention at least in the form of lifestyle modification. They have shown that NAFLD and NASH are not so sinister diseases contrary to the belief,3 as NAFLD was responsible for only 1.7% of deaths due to liver-related events in their cohort. However, it is stated that liver related mortality is the third important cause of death in their study. In addition to the comments made by Ioannou in his letter, we would like to point out that we do not agree completely with certain conclusions derived by Adams et al. According to them, the mortality of NAFLD is significantly increased compared with the general population of same age and sex. They have included in their analysis 8 patients who had cirrhosis on initial presentation. They also have reported 53 deaths in their cohorts and described liver-related illness as the third most common cause of death (13%) after malignancy (28%) and ischemic heart disease (25%). However, 5 deaths were in patients who had cirrhosis on initial presentation. If this group were excluded from the final analysis, we are left with only 2 patients who died of liver-related illness, which accounts for 4.1% of cause of deaths and 0.5% of all deaths in their cohort. When the various causes of death in their cohort is analyzed after eliminating those who had cirrhosis on initial presentation, another picture will emerge showing liver-related death at much lower level probably nearer to the 13th leading cause of death in their general population. It is also interesting to note that independent risk factors for NAFLD like obesity and metabolic syndrome4 – 6 had no correlation with the mortality in their cohorts and it requires further explanation. This is especially important as 71% of their patients had obesity and 68% had hypertriglyceridemia.
1015
The authors have provided data that 66% of their patients had elevated AST (51 ⫾ 52 U/L). From this it appears that most of their patients had only marginally elevated AST levels and hence it may be presumed that a significant proportion of their patients had only mild form of NAFLD, which may be the reason for the low mortality compared with earlier observations. Earlier studies on natural history of NAFLD based on liver histology had shown that progression of liver disease is related to the severity of liver involvement.7 In contrast, other studies have shown that simple steatosis or steatosis with minimal inflammation is a relatively stable condition.8,9 It would have been appropriate if they had analyzed their cohorts as different groups namely, those with normal liver function tests and those with abnormal liver function tests. Figure 1 in the paper by Adams et al describes the number of patients who had undergone liver biopsy as 70, but they have provided data of 65 patients only. There were 49 confirmed cases of NASH; however, we are not provided with the information as to how many patients had grade 3 and 4 disease. It is also mentioned that there was significant difference in the survival between patients who had a liver biopsy and those who did not have a biopsy. It is evident from their observations that large number of patients who had liver biopsy also had elevated bilirubin, lower albumin and elevated prothrombin time in addition to higher percentage of them having diabetes or impaired glucose tolerance. Eight of these patients had evidence of cirrhosis on presentation. As we have pointed out, these patients (cirrhotics) with evidence of abnormal liver function tests should have been excluded from the analysis of the natural history of NAFLD. As the cohort consisted of patients with cirrhosis, steatohepatitis, bland steatosis, and unclassified NAFLD this study is also fraught with the same pitfalls of earlier studies which included the entire spectrum of NAFLD as one disease and attempted to study its natural history as a whole. If the authors had excluded from their analysis those with cirrhosis on initial presentation, the liver-related mortality in NAFLD would have been shown to be lower than what has been presented. Then the result would be even more unimpressive than what Ioanou has pointed out. VARGHESE THOMAS KAREEM HARISH Department of Gastroenterology Calicut Medical College Hospital Kerala, India 1. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129:113–121. 2. Ioannou GN. The natural history of NAFLD: impressively unimpressive. Gastroenterology 2005;129:1805. 3. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664 – 669. 4. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107:450 – 455. 5. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–923. 6. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106 –1110.
1016
CORRESPONDENCE
7. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116: 1413–1419. 8. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995;22:1714 –1719. 9. Hilden M, Juhl E, Thomsen AC, Christoffersen P. Fatty liver persisting for up to 33 years. A follow-up of the inversen-roholm liver biopsy material. Acta Med Scand 1973;194:485– 489. doi:10.1053/j.gastro.2006.01.078
Reply. I appreciate the interest of Drs. Tarantino, Ioannou, Thomas, and Harish in our paper evaluating the natural history of NAFLD in a community-based study.1 The 124,000 population in Olmsted County was identified at a single point in the year 2000 whereas our study included patients diagnosed with NAFLD during the period 1980 –2000. The study by Browning et al2 reporting that approximately one third of the population had too much fat in the liver used MR spectroscopy without histology to confirm steatosis. Furthermore, that study2 included an age range of 18 – 65 years; the prevalence of NAFLD in youth is much lower, and so the prevalence in the total United States population is lower than 1 in 3. As highlighted in our paper,1 we included every patient with NAFLD from the community who had been diagnosed with the disease. Those individuals with “silent” NAFLD were not included simply because the disease had not been recognized, and whether or not they have a “much lower mortality/morbidity from NAFLD” has yet to be demonstrated. Our study did not capture all cases of NAFLD in Olmsted County, and it is unrealistic to believe every single individual with NAFLD in the community can be identified. To date, there is no test or combination of tests, which can diagnostically provide with 100% accuracy. Liver enzymes and imaging studies may be normal in patients with well-established NAFLD, and even if everybody in the community were to undergo liver biopsy, some cases would still be missed given the patchy distribution of disease.3 We used census data to compare mortality between NAFLD and the general population of the same age and gender, and thus, we were not able to adjust for confounders such as “insulin resistance, central obesity, diabetes, and lipid abnormalities.” All these confounders are well-known risk factors for the development of NAFLD, and thus, if we have had tried to adjust for all of them, most likely we would have ended-up without a control group. I disagree that survival analysis favored overall prognosis for the general Minnesota population. Conversely, as patients with NAFLD were actively investigated, concomitant medical conditions were identified and treated biasing toward a survival advantage for the NAFLD patients. This bias would attenuate the difference in survival between NAFLD and the general Minnesota population, and thus the survival difference we found was conservatively estimated and likely to be more significant than reported. It is intriguing that Thomas and Harish think “patients with marginally elevated AST levels had mild form of NAFLD.” Aminotransferase levels are in the normal range in 79% of individuals with NAFLD in the general population,2 and in some patients whose NAFLD has progressed to advanced disease.4,5 When elevated, aminotransferase levels improve and even normalize as the disease progresses to advanced fibrosis and cirrhosis.6 Prognosis in our patients was not different between those with normal or elevated aminotransferase levels.1 The fact that biopsied patients in our series had more advanced liver disease and a higher proportion of cirrhotics
GASTROENTEROLOGY Vol. 130, No. 3
simply highlights the higher likelihood to perform a biopsy on patients with more advanced disease. Five of the 70 biopsied patients were excluded from analysis as their liver biopsy was performed postmortem. That metabolic syndrome per se is inaccurate in predicting mortality has been reported in several studies.7 A BMI in the obese or overweight category was almost a universal finding in our patients increasing the difficulty in predicting survival.1 Presence of IFG/diabetes which is a component of the metabolic syndrome and often clusters with obesity/overweight was a strong independent predictor of mortality in our series.1 Liver-related mortality in our patients with NAFLD was essentially observed in those whose disease had progressed to cirrhosis, just as occurs among patients with chronic hepatitis C infection. The exclusion of cirrhotic patients with NAFLD from our analysis would have certainly provided a lower, but clearly biased mortality figure, and an incomplete estimate of the real impact of the liver disease on overall mortality. Our results are in agreement with recent series evaluating the long-term mortality in patient with NAFLD.8,9 Those series found a liver-related mortality rate of less than 1% among patients with bland steatosis during an average follow-up of 17 years,8 but as high as 21% liver-related mortality during a 5-year follow-up period among those with cirrhotic-stage NASH.9 However, between bland steatosis and cirrhotic-stage disease there is a wide spectrum of histological damage. The rate of disease progression and prognosis of those patients with intermediate stages has yet to be investigated in large, long-term follow-up studies. Our finding in a communitybased study that most liver-related morbidity and mortality occurred when the disease had progressed to advanced fibrosis and cirrhosis calls for the design of well-controlled treatment trials aimed at preventing NAFLD progression. PAUL ANGULO Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, Minnesota 1. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129:113–121. 2. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–1395. 3. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T, LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898 –1906. 4. Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37: 1286 –1292. 5. Sorrentino P, Tarantino G, Conca P, Perrella A, Terracciano ML, Vecchione R, Gargiulo G, Gennarelli N, Lobello R. Silent nonalcoholic fatty liver disease-a clinical-histological study. J Hepatol 2004;41:751–757. 6. 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: 132–138. 7. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Diabetes Care 2005;28:2289 –2304. 8. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TIA, Becker U, Bendtsen F. Long-term prog-