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Abnormal Lipid and Glucose Metabolism in Obesity: Implications for Nonalcoholic Fatty Liver Disease

2007; Elsevier BV; Volume: 132; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2007.03.055

1528-0012

Samir Parekh, Frank A. Anania,

Adipose Tissue and Metabolism

Nonalcoholic fatty liver disease represents a spectrum of histopathologic abnormalities, the prevalence of which may be as high as 24% of the population of the United States. Nonalcoholic fatty liver disease will play a major role in the science and practice of gastroenterology in the near future. The fundamental derangement in nonalcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, hypertriglyceridemia, essential hypertension, low circulating high-density lipoprotein, and obesity. The natural history of fatty liver disease is not always benign, and causality for cirrhosis and chronic liver disease is well-founded in the literature. Treatment strategies are limited and, at present, are primarily focused on weight loss and use of insulin sensitizing agents, including the thiazolidenediones. Recent data clearly implicate hepatic insulin resistance as a culprit in accumulation of free fatty acids as triglycerides in hepatocytes. Hepatic insulin resistance is clearly exacerbated by systemic insulin resistance and impaired handling by skeletal muscle and adipose tissue of both glucose and free fatty acids. The key consequence of hepatic insulin resistance, impaired hepatocyte insulin signal transduction, results in adverse cellular and molecular changes exacerbating hepatocyte triglyceride storage. Cytokines secreted by white adipose tissue, adipokines, have emerged as key players in glucose and fat metabolism previously thought controlled largely by insulin. Modulation of adipokines may aid in further understanding of the pathophysiology and treatment of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease represents a spectrum of histopathologic abnormalities, the prevalence of which may be as high as 24% of the population of the United States. Nonalcoholic fatty liver disease will play a major role in the science and practice of gastroenterology in the near future. The fundamental derangement in nonalcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, hypertriglyceridemia, essential hypertension, low circulating high-density lipoprotein, and obesity. The natural history of fatty liver disease is not always benign, and causality for cirrhosis and chronic liver disease is well-founded in the literature. Treatment strategies are limited and, at present, are primarily focused on weight loss and use of insulin sensitizing agents, including the thiazolidenediones. Recent data clearly implicate hepatic insulin resistance as a culprit in accumulation of free fatty acids as triglycerides in hepatocytes. Hepatic insulin resistance is clearly exacerbated by systemic insulin resistance and impaired handling by skeletal muscle and adipose tissue of both glucose and free fatty acids. The key consequence of hepatic insulin resistance, impaired hepatocyte insulin signal transduction, results in adverse cellular and molecular changes exacerbating hepatocyte triglyceride storage. Cytokines secreted by white adipose tissue, adipokines, have emerged as key players in glucose and fat metabolism previously thought controlled largely by insulin. Modulation of adipokines may aid in further understanding of the pathophysiology and treatment of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease (NAFLD) represents a wide spectrum of disorders, the hallmark of which is hepatic steatosis. NAFLD was thought to be a benign condition but is now increasingly recognized as a major cause of liver-related morbidity and mortality. The disease encompasses not only simple steatosis but also includes nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. The histopathology of NAFLD has a striking resemblance to alcohol-related liver disease but occurs in the absence of significant alcohol consumption. Recent basic and epidemiologic data reveal that the spectrum of NAFLD is closely associated with obesity, diabetes, and hyperlipidemia, a constellation of clinical problems that arise from insulin resistance. This review has 2 components: one is a clinical review of NAFLD and how treatment of obesity can improve this lesion. The second component is a contemporary approach to hepatic insulin resistance. The true prevalence of NAFLD remains unknown. Difficulties in assessing NAFLD prevalence include the absence of signs and symptoms, the poor sensitivity of liver enzymes to indicate disease, and the disputed need for histopathology (and liver biopsy) as a gold standard for diagnosis. When taken together, these barriers may lead to under diagnosis of NAFLD. Depending on which specific diagnostic criteria are used, the prevalence of NAFLD is estimated to range between 10% and 24% of the general population.1Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231Crossref PubMed Scopus (2005) Google Scholar Variability arises from country to country, with a trend toward higher disease burden in developed countries. In the United States, the prevalence of NAFLD is estimated to be 20% and those patients with NASH to be 2% to 3%,2Falck-Ytter Y. Younossi Z.M. Marchesini G. McCullough A.J. Clinical features and natural history of nonalcoholic steatosis syndromes.Semin Liver Dis. 2001; 21: 17-26Crossref PubMed Google Scholar, 3Ruhl C.E. Everhart J.E. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States.Gastroenterology. 2003; 124: 71-79Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 4Ruhl C.E. Everhart J.E. Epidemiology of nonalcoholic fatty liver.Clin Liver Dis. 2004; 8: 501-519Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar a substantially greater prevalence than chronic hepatitis C infection, which is approximately 1.8%5Alter M.J. Kruszon-Moran D. Nainan O.V. McQuillan G.M. Gao F. Moyer L.A. Kaslow R.A. Margolis H.S. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.N Engl J Med. 1999; 341: 556-562Crossref PubMed Scopus (1994) Google Scholar in the United States. These statistics underscore the pressing importance of NAFLD in digestive health. NAFLD is the cause of asymptomatic elevation of aminotransferases in 42%–90% of cases when other known causes of liver disease are excluded.6Daniel S. Ben-Menachem T. Vasudevan G. Ma C.K. Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients.Am J Gastroenterol. 1999; 94: 3010-3014Crossref PubMed Scopus (239) Google Scholar Furthermore, NAFLD is becoming an important concern to pediatricians, affecting 2.6% of children and 22.5% to 52.8% of obese children.7Franzese A. Vajro P. Argenziano A. Puzziello A. Iannucci M.P. Saviano M.C. Brunetti F. Rubino A. Liver involvement in obese children Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population.Dig Dis Sci. 1997; 42: 1428-1432Crossref PubMed Scopus (256) Google Scholar, 8Tominaga K. Kurata J.H. Chen Y.K. Fujimoto E. Miyagawa S. Abe I. Kusano Y. Prevalence of fatty liver in Japanese children and relationship to obesity An epidemiological ultrasonographic survey.Dig Dis Sci. 1995; 40: 2002-2009Crossref PubMed Scopus (245) Google Scholar Initial prevalence studies indicated that NAFLD was most common in middle-aged white women9Angulo P. Keach J.C. Batts K.P. Lindor K.D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.Hepatology. 1999; 30: 1356-1362Crossref PubMed Google Scholar, 10Lee R.G. Nonalcoholic steatohepatitis: a study of 49 patients.Hum Pathol. 1989; 20: 594-598Abstract Full Text PDF PubMed Google Scholar, 11Ludwig J. Viggiano T.R. McGill D.B. Oh B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar; however, subsequent population-based studies indicate that NAFLD is probably more common in men and in those of Hispanic ethnicity compared with non-Hispanic white or non-Hispanic black ethnicity.3Ruhl C.E. Everhart J.E. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States.Gastroenterology. 2003; 124: 71-79Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 12Clark J.M. Brancati F.L. Diehl A.M. The prevalence and etiology of elevated aminotransferase levels in the United States.Am J Gastroenterol. 2003; 98: 960-967Crossref PubMed Scopus (591) Google Scholar Several studies, including the National Health and Nutrition Examination Survey III (NHANES III), suggest a lower prevalence of NAFLD in African Americans.13Browning J.D. Kumar K.S. Saboorian M.H. Thiele D.L. Ethnic differences in the prevalence of cryptogenic cirrhosis.Am J Gastroenterol. 2004; 99: 292-298Crossref PubMed Scopus (100) Google Scholar, 14Caldwell S.H. Harris D.M. Patrie J.T. Hespenheide E.E. Is NASH underdiagnosed among African Americans?.Am J Gastroenterol. 2002; 97: 1496-1500Crossref PubMed Google Scholar, 15Solga S.F. Clark J.M. Alkhuraishi A.R. Torbenson M. Tabesh A. Schweitzer M. Diehl A.M. Magnuson T.H. Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients.Surg Obes Relat Dis. 2005; 1: 6-11Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 16Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).JAMA. 2001; 285: 2486-2497Crossref PubMed Google Scholar Little population-based data are available regarding the change in prevalence of NAFLD with time; however, it is assumed that NAFLD will parallel the growing prevalence of the metabolic syndrome, a condition closely linked to NAFLD. According to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), the metabolic syndrome is defined as the presence of 3 or more of the following: (1) increased waist circumference, (2) hypertriglyceridemia, (3) hypertension, (4) high fasting glucose, and (5) low high-density lipoprotein (HDL) level.16Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).JAMA. 2001; 285: 2486-2497Crossref PubMed Google Scholar Insulin resistance is the pathogenic denominator that links all components of the metabolic syndrome. Insulin resistance is now recognized as the most common risk factor for the development of NAFLD, and steatosis may simply characterize the hepatic manifestation of the metabolic syndrome. A recent study demonstrated that patients with metabolic syndrome have a 4- to 11-fold higher risk of developing NAFLD.17Hamaguchi M. Kojima T. Takeda N. Nakagawa T. Taniguchi H. Fujii K. Omatsu T. Nakajima T. Sarui H. Shimazaki M. Kato T. Okuda J. Ida K. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Google Scholar The prevalence of metabolic syndrome in 304 consecutive NAFLD patients without overt diabetes was found to be 18% in normal weight persons but increased sharply to 67% in obese persons.18Marchesini 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: 917-923Crossref PubMed Scopus (1074) Google Scholar The reported prevalence of obesity in patients with NAFLD also varies widely between 30% and 100% in published reports.1Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231Crossref PubMed Scopus (2005) Google Scholar In those obese individuals with a body mass index (BMI, kg/m2) of at least 30, the prevalence of NAFLD increases by a factor of 4.6.19Bellentani S. Saccoccio G. Masutti F. Croce L.S. Brandi G. Sasso F. Cristanini G. Tiribelli C. Prevalence of and risk factors for hepatic steatosis in Northern Italy.Ann Intern Med. 2000; 132: 112-117Crossref PubMed Google Scholar The presence of NASH has clearly been linked to increasing weight, occurring in 3% of the lean population, 19% of the obese population, and nearly half of the morbidly obese population.20Silverman J.F. O'Brien K.F. Long S. Leggett N. Khazanie P.G. Pories W.J. Norris H.T. Caro J.F. Liver pathology in morbidly obese patients with and without diabetes.Am J Gastroenterol. 1990; 85: 1349-1355PubMed Google Scholar, 21Wanless I.R. Lentz J.S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors.Hepatology. 1990; 12: 1106-1110Crossref PubMed Scopus (713) Google Scholar Distribution of fat may also play an important role in the development of NAFLD because truncal obesity has been associated with NAFLD even in patients with normal BMI.22Ruderman N. Chisholm D. Pi-Sunyer X. Schneider S. The metabolically obese, normal-weight individual revisited.Diabetes. 1998; 47: 699-713Crossref PubMed Scopus (367) Google Scholar The prevalence of type 2 diabetes mellitus (DM) associated with NAFLD ranges from 10% to 75%.1Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231Crossref PubMed Scopus (2005) Google Scholar A recent Japanese study found that the prevalence of NAFLD by ultrasonography rose from 27% among those with normal fasting blood glucose to 43% among those with fasting hyperglycemia and to 62% among patients with type 2 DM.23Jimba S. Nakagami T. Takahashi M. Wakamatsu T. Hirota Y. Iwamoto Y. Wasada T. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults.Diabet Med. 2005; 22: 1141-1145Crossref PubMed Scopus (164) Google Scholar Importantly, type 2 DM is not only associated with NAFLD but may be a risk factor for development of progressive fibrosis. The prevalence of hyperlipidemia associated with NAFLD varies from 20% to 92%, where hypertriglyceridemia rather than hypercholesterolemia appears to be the major risk factor in this association.22Ruderman N. Chisholm D. Pi-Sunyer X. Schneider S. The metabolically obese, normal-weight individual revisited.Diabetes. 1998; 47: 699-713Crossref PubMed Scopus (367) Google Scholar, 24Poonawala A. Nair S.P. Thuluvath P.J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.Hepatology. 2000; 32: 689-692Crossref PubMed Google Scholar In keeping with the criteria of the metabolic syndrome, low HDL levels are also frequently observed in patients with NAFLD.12Clark J.M. Brancati F.L. Diehl A.M. The prevalence and etiology of elevated aminotransferase levels in the United States.Am J Gastroenterol. 2003; 98: 960-967Crossref PubMed Scopus (591) Google Scholar, 18Marchesini 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: 917-923Crossref PubMed Scopus (1074) Google Scholar The importance of hypertension in NAFLD has long been questioned. A recent study examining nonobese, nondiabetic patients with normal liver enzymes and arterial hypertension found a significantly higher prevalence of NAFLD (30.9% vs 12.7%) compared to age- and sex-matched controls not having hypertension.25Donati G. Stagni B. Piscaglia F. Venturoli N. Morselli-Labate A.M. Rasciti L. Bolondi L. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance.Gut. 2004; 53: 1020-1023Crossref PubMed Scopus (103) Google Scholar Regression analyses suggest that the association between hypertension and hepatic steatosis is also mediated by increased insulin resistance. NAFLD is a diagnosis of exclusion that requires the proper context of historical and supporting clinical features including laboratory, imaging, and histologic findings. Because many findings are indistinguishable when compared with alcoholic liver disease, the current definition of NAFLD requires the absence of significant alcohol consumption. The National Institutes of Health (NIH) clinical research network on NAFLD/NASH has defined the maximum allowable level of alcohol intake for NAFLD to be 2 standard drinks per day (140-g ethanol/week) for men and 1 standard drink per day (70-g ethanol/week) for women. Most patients presenting with a new diagnosis of NAFLD are asymptomatic.2Falck-Ytter Y. Younossi Z.M. Marchesini G. McCullough A.J. Clinical features and natural history of nonalcoholic steatosis syndromes.Semin Liver Dis. 2001; 21: 17-26Crossref PubMed Google Scholar Of those who do have symptoms, fatigue, malaise, and right upper quadrant discomfort are the most common complaints. In the absence of cirrhosis, hepatomegaly is the only physical finding in most patients, reported in up to 75% of cases. Laboratory testing reveals a pattern of hepatocellular injury with mild to moderate elevations in liver transaminases (<5× the upper limit of normal); however, aminotransferases may fluctuate, with normal levels present in 78% of patients at any one time.26Ipekci S.H. Basaranoglu M. Sonsuz A. The fluctuation of serum levels of aminotransferase in patients with nonalcoholic steatohepatitis.J Clin Gastroenterol. 2003; 36: 371Crossref PubMed Scopus (16) Google Scholar, 27Yano E. Tagawa K. Yamaoka K. Mori M. Test validity of periodic liver function tests in a population of Japanese male bank employees.J Clin Epidemiol. 2001; 54: 945-951Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Unlike alcohol-related liver disease, the aspartate to alanine aminotransferase ratio is usually less than 1 in NAFLD; however, diagnostic accuracy is lost in patients with cirrhosis because the ratio increases as fibrosis advances.28Sorbi D. Boynton J. Lindor K.D. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease.Am J Gastroenterol. 1999; 94: 1018-1022Crossref PubMed Google Scholar Imaging studies play an important role in diagnosing NAFLD. Ultrasonography produces a diffuse increase in echogenicity of the liver when fatty infiltration is present. Ultrasound is the least costly and invasive imaging modality for evaluating NAFLD, with a sensitivity of 60% to 94% and specificity of 88% to 95%.29Joy D. Thava V.R. Scott B.B. Diagnosis of fatty liver disease: is biopsy necessary?.Eur J Gastroenterol Hepatol. 2003; 15: 539-543PubMed Google Scholar With lesser degrees of fatty infiltration, the sensitivity of ultrasound decreases. In the presence of ≥30% fatty infiltration, ultrasound has a sensitivity of 80% compared with a sensitivity of 55% when hepatic content is 10% to 19%.30Ryan C.K. Johnson L.A. Germin B.I. Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation.Liver Transpl. 2002; 8: 1114-1122Crossref PubMed Scopus (117) Google Scholar Patient body habitus is also an important consideration, with the sensitivity and specificity of ultrasound in morbidly obese patients dropping to 49% and 75%, respectively.31Mottin C.C. Moretto M. Padoin A.V. Swarowsky A.M. Toneto M.G. Glock L. Repetto G. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients.Obes Surg. 2004; 14: 635-637Crossref PubMed Scopus (97) Google Scholar With computed tomography, hepatic fatty infiltration has a low attenuation, and the amount of fat can be estimated by comparing liver density with spleen or paraspinal density. The sensitivity of detecting hepatic steatosis by computed tomography may be as high as 93% with a positive predictive value of 76%.32Saadeh S. Younossi Z.M. Remer E.M. Gramlich T. Ong J.P. Hurley M. Mullen K.D. Cooper J.N. Sheridan M.J. The utility of radiological imaging in nonalcoholic fatty liver disease.Gastroenterology. 2002; 123: 745-750Abstract Full Text Full Text PDF PubMed Scopus (652) Google Scholar These data are comparable, however, to the ultrasound, which is less costly. Magnetic resonance imaging utilizes differences in the precession frequency between water and fat protons in opposed-phase images to diagnose hepatic steatosis and may allow for a quantitative assessment of fatty infiltration within the liver. Magnetic resonance imaging appears to be the most sensitive modality for detecting steatosis but is also the most expensive.33Siegelman E.S. Rosen M.A. Imaging of hepatic steatosis.Semin Liver Dis. 2001; 21: 71-80Crossref PubMed Google Scholar In general, the shortcomings with all 3 radiographic techniques are that they cannot distinguish (1) benign steatosis from steatohepatitis, (2) severity of inflammation or grade, and (3) degree of fibrosis or stage of disease. Clearly, biomarkers to assess adequately such important questions should be forthcoming. Liver biopsy is the only available means to accurately grade and stage NAFLD with certainty. Histologic features of NAFLD include steatosis, mixed inflammatory-cell infiltrates, hepatocyte balloon degeneration, necrosis, glycogen nuclei, Mallory's hyaline, and fibrosis. The value of liver biopsy in establishing the diagnosis of NAFLD in routine clinical practice remains controversial. Opponents argue that although the prevalence of NAFLD in the general population appears to be relatively high, only a very small percentage of patients will have NASH. Thus, most patients will have steatosis alone, generally portending a favorable prognosis. Furthermore, there are currently no approved therapies for NAFLD, and, therefore, management is unlikely to change based on histologic findings. Advocates of liver biopsy argue that histology provides prognostic information and diagnostic confirmation of NAFLD. A recent study revealed that at least one third of patients suspected of having NAFLD on clinical grounds were found to have an alternative diagnosis based on liver biopsy results.34Skelly M.M. James P.D. Ryder S.D. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology.J Hepatol. 2001; 35: 195-199Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar At present, the decision to perform liver biopsy cannot be advocated as standard of care for all patients; however, practitioners must evaluate the need for liver biopsy in patients with NAFLD on a case-by-case basis. Although the prevalence of NAFLD is approximately 20%, best estimates indicate that only 2% to 3% of all adults in the United States have NASH.35McCullough A.J. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease.Clin Liver Dis. 2004; 8: 521-533Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Of those individuals with NASH, approximately 20% will go on to develop cirrhosis.36Hui J.M. Kench J.G. Chitturi S. Sud A. Farrell G.C. Byth K. Hall P. Khan M. George J. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C.Hepatology. 2003; 38: 420-427Crossref PubMed Scopus (233) Google Scholar Historically, the etiology of cirrhosis for many patients has been undetermined and labeled cryptogenic. It is likely that a significant proportion of patients diagnosed with cryptogenic cirrhosis truly had NASH as the etiology and that, at presentation, liver biopsy demonstrates "burned out" cirrhotic histology. This is supported by studies indicating an overrepresentation of metabolic syndrome features in patients with cryptogenic cirrhosis.24Poonawala A. Nair S.P. Thuluvath P.J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.Hepatology. 2000; 32: 689-692Crossref PubMed Google Scholar, 37Caldwell S.H. Oelsner D.H. Iezzoni J.C. Hespenheide E.E. Battle E.H. Driscoll C.J. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.Hepatology. 1999; 29: 664-669Crossref PubMed Google Scholar Compared to age- and sex-matched controls, the prevalence of obesity and diabetes was significantly higher in patients with cryptogenic cirrhosis awaiting liver transplantation.24Poonawala A. Nair S.P. Thuluvath P.J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.Hepatology. 2000; 32: 689-692Crossref PubMed Google Scholar Furthermore, NASH may occur following liver transplantation for cryptogenic cirrhosis as it does in patients with known NASH.38Contos M.J. Cales W. Sterling R.K. Luketic V.A. Shiffman M.L. Mills A.S. Fisher R.A. Ham J. Sanyal A.J. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis.Liver Transpl. 2001; 7: 363-373Crossref PubMed Scopus (189) Google Scholar, 39Ong J. Younossi Z.M. Reddy V. Price L.L. Gramlich T. Mayes J. Boparai N. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease.Liver Transpl. 2001; 7: 797-801Crossref PubMed Scopus (132) Google Scholar Thirty percent to 40% of NASH-related cirrhosis patients receive a liver transplant or die of liver disease-related complications.35McCullough A.J. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease.Clin Liver Dis. 2004; 8: 521-533Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar In Olmstead County, Minnesota, survival for patients with NAFLD was less than that for the age- and sex-matched general population, and liver disease was the third leading cause of death compared with the thirteenth in the general population.40Adams L.A. Lymp J.F. St. Sauver J. Sanderson S.O. Lindor K.D. Feldstein A. Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (832) Google Scholar It is estimated that 10% to 12% of liver transplantations are now performed because of liver disease caused by NASH.35McCullough A.J. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease.Clin Liver Dis. 2004; 8: 521-533Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Importantly, hepatocellular carcinoma is now recognized as a serious potential complication of NAFLD.41Anagnostopoulos G.K. Arvanitidis D. Tsiakos S. Margantinis G. Grigoriadis K. Kostopoulos P. Is hepatocellular carcinoma part of the natural history of nonalcoholic steatohepatitis?.J Clin Gastroenterol. 2003; 37: 88-89Crossref PubMed Scopus (8) Google Scholar, 42El-Serag H.B. Tran T. Everhart J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.Gastroenterology. 2004; 126: 460-468Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 43Nair S. Mason A. Eason J. Loss G. Perrillo R.P. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.Hepatology. 2002; 36: 150-155Crossref PubMed Scopus (156) Google Scholar, 44Ratziu V. Bonyhay L. Di Martino V. Charlotte F. Cavallaro L. Sayegh-Tainturier M.H. Giral P. Grimaldi A. Opolon P. Poynard T. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis.Hepatology. 2002; 35: 1485-1493Crossref PubMed Scopus (298) Google Scholar In 150 consecutive patients with hepatocellular carcinoma, cryptogenic cirrhosis accounted for 29% of cases, with half of the patients having histologic or clinical features of NAFLD.45Marrero J.A. Fontana R.J. Su G.L. Conjeevaram H.S. Emick D.M. Lok A.S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.Hepatology. 2002; 36: 1349-1354Crossref PubMed Scopus (0) Google Scholar Diabetes also appears to be an independent risk factor for hepatocellular carcinoma,46Davila J.A. Morgan R.O. Shaib Y. McGlynn K.A. El-Serag H.B. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population-based, case control study.Gut. 2005; 54: 533-539Crossref PubMed Scopus (267) Google Scholar and chronic hyperinsulinemia as the carcinogenic stimulus has been suggested.42El-Serag H.B. Tran T. Everhart J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.Gastroenterology. 2004; 126: 460-468Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 43Nair S. Mason A. Eason J. Loss G. Perrillo R.P. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.Hepatology. 2002; 36: 150-155Crossref PubMed Scopus (156) Google Scholar, 47Yuan J.M. Govindarajan S. Arakawa K. Yu M.C. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the US.Cancer. 2004; 101: 1009-1017Crossref PubMed Scopus (121) Google Scholar The ability to predict which patients with NAFLD are at greatest risk for progression to cirrhosis and its complications is an important element of optimizing patient care. Progression of fibrosis has been demonstrated histologically in 32% to 37% of patients, but histologic regression may occur in 18% to 29%.48Adams L.A. Sanderson S. Lindor K.D. Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.J Hepatol. 2005; 42: 132-138Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 49Fassio E. Alvarez E. Dominguez N. Landeira G. Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biop