Natural History of NAFLD: Remarkably Benign in the Absence of Cirrhosis
2005; Elsevier BV; Volume: 129; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2005.05.041
ISSN1528-0012
Autores Tópico(s)Alcohol Consumption and Health Effects
ResumoStudies based on “cryptogenic” abnormal liver blood tests,1Clark 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 (1076) Google Scholar ultrasonography,2Bellentani 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 Scopus (1055) Google Scholar and more recently, proton nuclear magnetic resonance spectroscopy3Browning A.J. Szcepaniak L.S. Dobbins R. Nurember P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2880) Google Scholar have suggested that the prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States may be as high as 30%. This, together with an accumulating body of evidence that some patients with NAFLD can progress to cirrhosis, liver failure, and hepatocellular cancer (HCC)4Caldwell S.H. Crespo D.M. The spectrum expanded cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.J Hepatol. 2004; 40: 578-584Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar has emphasized the need for detailed information on the natural history of NAFLD both to guide patient management and to enable rational public health care planning. Natural history studies reported to date can be divided into 2 main categories-serial biopsy studies looking for evidence of histological progression in patients with different stages of NAFLD-and cohort studies examining the clinical outcomes of patients with NAFLD diagnosed histologically or ultrasonographically. The principal limitations of the majority of these studies have been their relatively short-term follow-up, and for the serial biopsy studies in particular, a high degree of selection bias in patients undergoing repeat biopsy.Within these limitations our current knowledge of the natural history of the different stages of NAFLD can be summarized as follows: (1) contrary to previous dogma, simple steatosis can progress to steatohepatitis, fibrosis, cirrhosis, and even liver-related death but progression occurs in less than 5% of patients over a 5–17 year follow-up with no impact on overall mortality.5Teli M.R. James O.F.W. Burt A.D. Bennett M.K. Day C.P. The natural history of non alcoholic fatty liver a follow up study.Hepatology. 1995; 22: 1714-1719Crossref PubMed Google Scholar, 6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar, 7Harrison S.A. Torgerson S. Hayashi P.H. The natural history of non alcoholic fatty liver disease a clinical histopathological study.Am J Gastroenterol. 2003; 98: 2042-2047Crossref PubMed Scopus (408) Google Scholar, 8Adams L.A. Sanderson S. Lindor K.D. Angulo P. The histological course of non alcoholic 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 (743) Google Scholar, 9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar The lack of impact on mortality of simple steatosis, initially observed in a Danish study, has recently been confirmed by 10-year follow-up data from the Dionysos Study in Northern Italy10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar; (2) patients with non-alcoholic steatohepatitis (NASH), with or without fibrosis, can progress to cirrhosis assessed histologically or clinically over a 3–8 year follow-up, with proportions ranging from 0% in the least selected follow-up studies11Fassio E. Alvarez E. Dominguez N. Landeira G. Longo C. Natural history of non alcoholic steatohepatitis a longitudinal study of repeat liver biopsies.Hepatology. 2004; 40: 820-826Crossref PubMed Scopus (419) Google Scholar to 25% in the largest clinical follow-up study performed to date,6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar although this study may have included patients with NASH and cirrhosis in the “NASH” group12Gramlich T. Kleiner D.E. McCullough A.J. Matteoni C.A. Boparai N. Younossi Z.M. Pathologic features associated with fibrosis in non alcoholic fatty liver disease.Hum Pathol. 2004; 35: 196-199Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar; (3) once cirrhosis develops in patients with NAFLD the prognosis appears to be poor with 2 studies reporting that up to a third of patients develop liver-related morbidity or mortality over a relatively short follow-up period13Ratziu 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 (435) Google Scholar, 14Hui 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 non alcoholic steatohepatitis compared with hepatitis C.Hepatology. 2003; 38: 420-427Crossref PubMed Scopus (390) Google Scholar with one reporting a high rate (27%) of HCC,13Ratziu 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 (435) Google Scholar consistent with a several other reports of HCC developing in patients with NASH cirrhosis.15Bugianesi E. Leone N. Vanni E. Marchesini G. Brunello F. Carucci P. Musso A. De Paolis P. Capussotti L. Salizzoni M. Rizzetto M. Expanding the natural history of non alcoholic steatohepatitis from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1250) Google Scholar This high liver-associated death rate in NASH cirrhosis presumably accounts for the 10% liver-related death rate reported in the only “NASH” follow-up study given the inclusion of cirrhotic patients in the NASH cohort.6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar The lack of any evidence of increased non-liver-related mortality in NAFLD patients9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar, 10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar is perhaps surprising given that many of these patients will be obese, have type 2 diabetes and other features of the metabolic syndrome. Both diabetes and the metabolic syndrome are clearly associated with an increased risk of death from all causes, as well as from cardiovascular diseases in particular,16Hu G. Qiao Q. Tuomilehto J. Balkau B. Borch-Johnsen K. Pyotala K. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women.Arch Intern Med. 2004; 164: 1066-1076Crossref PubMed Scopus (901) Google Scholar, 17De Marco R. Locatelli F. Zoppini G. Verlato G. Bonora E. Muggeo M. Cause-specific mortality in Type 2 diabetes.Diabetes Care. 1999; 22: 756-761Crossref PubMed Scopus (335) Google Scholar and both diabetes and obesity are associated with an increased risk of death from various malignancies.18Verlato G. Zoppini G. Bonora E. Muggeo M. Mortality from site-specific malignancies in Type 2 diabetic patients from Verona.Diabetes Care. 2003; 26: 1047-1051Crossref PubMed Scopus (118) Google Scholar, 19Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity and mortality from cancer in a prospectively studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5839) Google Scholar Further evidence that NAFLD, through its association with the metabolic syndrome might be expected to increase the death rate from cardiovascular disease has come from a recent study demonstrating increased carotid artery intimal media thickness as an index of subclinical arthrosclerosis in patients with simple NAFLD.20Targher G. Bertolini L. Padovani R. Zenari L. Zoppini G. Falezza G. Relation of non alcoholic hepatic steatosis to early carotid atherosclerosis in healthy men.Diabetes Care. 2004; 27: 2498-2500Crossref PubMed Scopus (152) Google ScholarThe study published by Adams et al21Adams 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 (2235) Google Scholar in this current issue of GASTROENTEROLOGY is an important addition to the literature on the natural history of NAFLD. They report on the survival and liver-related morbidity of 420 patients with NAFLD in Olmsted County Minnesota21Adams 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 (2235) Google Scholar using the Rochester Epidemiology Project (REP), NIH funded, data linkage system. The REP indexes all medical diagnoses made by health care providers in Olmsted County, with 87% of residents being seen once a year by the 2 main health care providers and 95% of residents being seen at least once over a 4-year period. The main finding of the study is that the overall death rate in patients with NAFLD is higher than expected (standardized mortality ratio [SMR] 1.34, 95% CI 1.003–1.76, P .03), with increased mortality associated with age, impaired fasting glucose/diabetes, and cirrhosis. Liver disease was the third leading cause of death and the mean length of follow-up was 7.6 years. Liver histology was adequate for accurate staging in 61 patients, with 49 fulfilling the histological criteria for NASH, 10 having simple steatosis, and 8 having established cirrhosis. Patients undergoing liver biopsy were more likely to have symptoms, diabetes, and clinical evidence of advanced liver disease and also had a significantly lower survival than those who did not undergo liver biopsy (10-year survival 55% versus 90%). The main strengths of this study are that it is by far the largest natural history study performed thus far in patients with NAFLD, it is community-based, rather than including patients referred to specialist liver centres, and includes a large proportion (if not all) cases of NAFLD in a well-defined population. Given these strengths does it change the current state-of-the-art of the natural history of NAFLD outlined above?First, none of the 10 patients with histologically proven, simple, (“bland”) steatosis developed clinical evidence of cirrhosis or died from a liver-related cause, confirming the relatively benign natural history of the mildest form of NAFLD demonstrated in previous studies. Second, the 8% liver-related mortality, in the 49 patients with histologically proven NASH is similar to the 10% reported in the only equivalent study reported to date.6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar As in this previous study, however, it seems likely that the liver-related deaths were confined to the 8 of 49 NASH patients with established cirrhosis at trial entry given that 5 of 7 liver-related deaths occurred in these 8 patients. Third, the outcome in patients either with biopsy-confirmed cirrhosis at entry or developing clinical cirrhosis during follow-up, confirms the poor prognosis of patients with NASH cirrhosis, with 33% dying from a liver-related cause and one patient developing HCC, consistent with the 2 previous studies examining the natural history of NASH-related cirrhosis.13Ratziu 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 (435) Google Scholar, 14Hui 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 non alcoholic steatohepatitis compared with hepatitis C.Hepatology. 2003; 38: 420-427Crossref PubMed Scopus (390) Google Scholar The most novel observation from this study is the increased overall mortality in the NAFLD patients. On first consideration this may seem discordant from the normal mortality ratios reported previously9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar, 10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar; however, it seems probable that the increased SMR in this patient cohort was largely attributable to an increased mortality in patients with cirrhosis. Of these 21 patients 33% died a liver-related death and patients with cirrhosis may also have contributed to deaths from bleeding causes and deaths attributable to infection (4% and 11% of deaths respectively). The effect of including cirrhosis patients in the survival analysis is clearly demonstrated in Figure 4, with the biopsied patients having a markedly higher death rate than the non-biopsied patients, most likely attributable to their increased liver disease severity and accordingly higher death rate from liver-related causes. Although none of the 13 patients developing “clinical” cirrhosis during follow up underwent liver biopsy at trial entry, it seems likely that a vast proportion of them had histological cirrhosis at entry to the study rather than cirrhosis developing de novo in patients with steatosis or NASH considering the low risk of progression from NASH to cirrhosis reported in previous serial biopsy studies. Given the high death rate in the cirrhotic patients, and the confidence intervals of the increased SMR in the NAFLD patients (1.003– 1.76) it appears that the SMR in non-cirrhotic NAFLD patients is unlikely to be increased, consistent with data from patients with pure fatty liver9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar or with NAFLD detected ultrasonographically10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar; and therefore likely to include a lower proportion of patients with advanced disease than the current study. The observation that cirrhosis was an independent predictor of mortality on multivariate analysis further supports the impact of the cirrhotic patients on the SMR and the predictive values of age and diabetes could also be explained by their known adverse impact on the prognosis of patients with cirrhosis.22Bianchi G.P. Marchesini G. Zoli M. Bugianesi E. Fabbri A. Pisi E. Prognostic significance of diabetes in patients with cirrhosis.Hepatology. 1994; 20: 119-125PubMed Google ScholarIn summary therefore, from this and previous studies, it would appear that the natural history of NAFLD depends critically on disease stage. Patients with simple steatosis have a relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%. Patients with NASH and fibrosis can progress to cirrhosis, defined histologically or clinically, with the risk varying from 0% at 5 years to 12% over 8 years.6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar, 11Fassio E. Alvarez E. Dominguez N. Landeira G. Longo C. Natural history of non alcoholic steatohepatitis a longitudinal study of repeat liver biopsies.Hepatology. 2004; 40: 820-826Crossref PubMed Scopus (419) Google Scholar Once cirrhosis develops, patients are at high risk of developing hepatic decompensation and of dying from a liver-related cause including HCC. Despite the high prevalence of obesity, diabetes, and the metabolic syndrome there is, as yet, no evidence that patients with NAFLD have an increased risk of death from either malignancy or cardiovascular disease. The lack of increased death rate from malignancy may simply be due to the still relatively small studies that have not examined cause-specific SMRs, while the lack of increased mortality from cardiovascular disease may be attributable to the putative “cardioprotective” effects of chronic liver disease including reduced arterial pressure, an improved lipid profile or prolonged coagulation parameters.23Marchesini G. Ronchi M. Forlani G. Bugianesi E. Bianchi G. Fabbri A. Zoli M. Melchionda N. Cardiovascular disease in cirrhosis-a point-prevalence study in relation to glucose tolerance.Am J Gastroenterol. 1999; 94: 655-662PubMed Google Scholar Clearly, what is required are larger and longer follow-up studies in patients with histologically defined NAFLD, ideally comprising of both serial biopsies and clinical observations to include a detailed examination of the incidence/prevalence of malignancy and cardiovascular disease. Only with this sort of information, likely to emerge from initiatives such as the NIH-funded NASH Clinical Research Network, will we be able to provide patients with accurate prognostic information, initiate treatment trials on a more rational basis and predict the likely burden of NAFLD-related end-stage liver disease on health care systems. The impact of NAFLD on the well established obesity- and diabetes-related risks of malignancy and cardiovascular disease deserves particular attention in view of the implications for screening/surveillance strategies in this growing number of patients. Studies based on “cryptogenic” abnormal liver blood tests,1Clark 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 (1076) Google Scholar ultrasonography,2Bellentani 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 Scopus (1055) Google Scholar and more recently, proton nuclear magnetic resonance spectroscopy3Browning A.J. Szcepaniak L.S. Dobbins R. Nurember P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2880) Google Scholar have suggested that the prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States may be as high as 30%. This, together with an accumulating body of evidence that some patients with NAFLD can progress to cirrhosis, liver failure, and hepatocellular cancer (HCC)4Caldwell S.H. Crespo D.M. The spectrum expanded cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease.J Hepatol. 2004; 40: 578-584Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar has emphasized the need for detailed information on the natural history of NAFLD both to guide patient management and to enable rational public health care planning. Natural history studies reported to date can be divided into 2 main categories-serial biopsy studies looking for evidence of histological progression in patients with different stages of NAFLD-and cohort studies examining the clinical outcomes of patients with NAFLD diagnosed histologically or ultrasonographically. The principal limitations of the majority of these studies have been their relatively short-term follow-up, and for the serial biopsy studies in particular, a high degree of selection bias in patients undergoing repeat biopsy. Within these limitations our current knowledge of the natural history of the different stages of NAFLD can be summarized as follows: (1) contrary to previous dogma, simple steatosis can progress to steatohepatitis, fibrosis, cirrhosis, and even liver-related death but progression occurs in less than 5% of patients over a 5–17 year follow-up with no impact on overall mortality.5Teli M.R. James O.F.W. Burt A.D. Bennett M.K. Day C.P. The natural history of non alcoholic fatty liver a follow up study.Hepatology. 1995; 22: 1714-1719Crossref PubMed Google Scholar, 6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar, 7Harrison S.A. Torgerson S. Hayashi P.H. The natural history of non alcoholic fatty liver disease a clinical histopathological study.Am J Gastroenterol. 2003; 98: 2042-2047Crossref PubMed Scopus (408) Google Scholar, 8Adams L.A. Sanderson S. Lindor K.D. Angulo P. The histological course of non alcoholic 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 (743) Google Scholar, 9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar The lack of impact on mortality of simple steatosis, initially observed in a Danish study, has recently been confirmed by 10-year follow-up data from the Dionysos Study in Northern Italy10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar; (2) patients with non-alcoholic steatohepatitis (NASH), with or without fibrosis, can progress to cirrhosis assessed histologically or clinically over a 3–8 year follow-up, with proportions ranging from 0% in the least selected follow-up studies11Fassio E. Alvarez E. Dominguez N. Landeira G. Longo C. Natural history of non alcoholic steatohepatitis a longitudinal study of repeat liver biopsies.Hepatology. 2004; 40: 820-826Crossref PubMed Scopus (419) Google Scholar to 25% in the largest clinical follow-up study performed to date,6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar although this study may have included patients with NASH and cirrhosis in the “NASH” group12Gramlich T. Kleiner D.E. McCullough A.J. Matteoni C.A. Boparai N. Younossi Z.M. Pathologic features associated with fibrosis in non alcoholic fatty liver disease.Hum Pathol. 2004; 35: 196-199Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar; (3) once cirrhosis develops in patients with NAFLD the prognosis appears to be poor with 2 studies reporting that up to a third of patients develop liver-related morbidity or mortality over a relatively short follow-up period13Ratziu 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 (435) Google Scholar, 14Hui 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 non alcoholic steatohepatitis compared with hepatitis C.Hepatology. 2003; 38: 420-427Crossref PubMed Scopus (390) Google Scholar with one reporting a high rate (27%) of HCC,13Ratziu 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 (435) Google Scholar consistent with a several other reports of HCC developing in patients with NASH cirrhosis.15Bugianesi E. Leone N. Vanni E. Marchesini G. Brunello F. Carucci P. Musso A. De Paolis P. Capussotti L. Salizzoni M. Rizzetto M. Expanding the natural history of non alcoholic steatohepatitis from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1250) Google Scholar This high liver-associated death rate in NASH cirrhosis presumably accounts for the 10% liver-related death rate reported in the only “NASH” follow-up study given the inclusion of cirrhotic patients in the NASH cohort.6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar The lack of any evidence of increased non-liver-related mortality in NAFLD patients9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar, 10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar is perhaps surprising given that many of these patients will be obese, have type 2 diabetes and other features of the metabolic syndrome. Both diabetes and the metabolic syndrome are clearly associated with an increased risk of death from all causes, as well as from cardiovascular diseases in particular,16Hu G. Qiao Q. Tuomilehto J. Balkau B. Borch-Johnsen K. Pyotala K. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women.Arch Intern Med. 2004; 164: 1066-1076Crossref PubMed Scopus (901) Google Scholar, 17De Marco R. Locatelli F. Zoppini G. Verlato G. Bonora E. Muggeo M. Cause-specific mortality in Type 2 diabetes.Diabetes Care. 1999; 22: 756-761Crossref PubMed Scopus (335) Google Scholar and both diabetes and obesity are associated with an increased risk of death from various malignancies.18Verlato G. Zoppini G. Bonora E. Muggeo M. Mortality from site-specific malignancies in Type 2 diabetic patients from Verona.Diabetes Care. 2003; 26: 1047-1051Crossref PubMed Scopus (118) Google Scholar, 19Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity and mortality from cancer in a prospectively studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5839) Google Scholar Further evidence that NAFLD, through its association with the metabolic syndrome might be expected to increase the death rate from cardiovascular disease has come from a recent study demonstrating increased carotid artery intimal media thickness as an index of subclinical arthrosclerosis in patients with simple NAFLD.20Targher G. Bertolini L. Padovani R. Zenari L. Zoppini G. Falezza G. Relation of non alcoholic hepatic steatosis to early carotid atherosclerosis in healthy men.Diabetes Care. 2004; 27: 2498-2500Crossref PubMed Scopus (152) Google Scholar The study published by Adams et al21Adams 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 (2235) Google Scholar in this current issue of GASTROENTEROLOGY is an important addition to the literature on the natural history of NAFLD. They report on the survival and liver-related morbidity of 420 patients with NAFLD in Olmsted County Minnesota21Adams 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 (2235) Google Scholar using the Rochester Epidemiology Project (REP), NIH funded, data linkage system. The REP indexes all medical diagnoses made by health care providers in Olmsted County, with 87% of residents being seen once a year by the 2 main health care providers and 95% of residents being seen at least once over a 4-year period. The main finding of the study is that the overall death rate in patients with NAFLD is higher than expected (standardized mortality ratio [SMR] 1.34, 95% CI 1.003–1.76, P .03), with increased mortality associated with age, impaired fasting glucose/diabetes, and cirrhosis. Liver disease was the third leading cause of death and the mean length of follow-up was 7.6 years. Liver histology was adequate for accurate staging in 61 patients, with 49 fulfilling the histological criteria for NASH, 10 having simple steatosis, and 8 having established cirrhosis. Patients undergoing liver biopsy were more likely to have symptoms, diabetes, and clinical evidence of advanced liver disease and also had a significantly lower survival than those who did not undergo liver biopsy (10-year survival 55% versus 90%). The main strengths of this study are that it is by far the largest natural history study performed thus far in patients with NAFLD, it is community-based, rather than including patients referred to specialist liver centres, and includes a large proportion (if not all) cases of NAFLD in a well-defined population. Given these strengths does it change the current state-of-the-art of the natural history of NAFLD outlined above? First, none of the 10 patients with histologically proven, simple, (“bland”) steatosis developed clinical evidence of cirrhosis or died from a liver-related cause, confirming the relatively benign natural history of the mildest form of NAFLD demonstrated in previous studies. Second, the 8% liver-related mortality, in the 49 patients with histologically proven NASH is similar to the 10% reported in the only equivalent study reported to date.6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar As in this previous study, however, it seems likely that the liver-related deaths were confined to the 8 of 49 NASH patients with established cirrhosis at trial entry given that 5 of 7 liver-related deaths occurred in these 8 patients. Third, the outcome in patients either with biopsy-confirmed cirrhosis at entry or developing clinical cirrhosis during follow-up, confirms the poor prognosis of patients with NASH cirrhosis, with 33% dying from a liver-related cause and one patient developing HCC, consistent with the 2 previous studies examining the natural history of NASH-related cirrhosis.13Ratziu 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 (435) Google Scholar, 14Hui 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 non alcoholic steatohepatitis compared with hepatitis C.Hepatology. 2003; 38: 420-427Crossref PubMed Scopus (390) Google Scholar The most novel observation from this study is the increased overall mortality in the NAFLD patients. On first consideration this may seem discordant from the normal mortality ratios reported previously9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar, 10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar; however, it seems probable that the increased SMR in this patient cohort was largely attributable to an increased mortality in patients with cirrhosis. Of these 21 patients 33% died a liver-related death and patients with cirrhosis may also have contributed to deaths from bleeding causes and deaths attributable to infection (4% and 11% of deaths respectively). The effect of including cirrhosis patients in the survival analysis is clearly demonstrated in Figure 4, with the biopsied patients having a markedly higher death rate than the non-biopsied patients, most likely attributable to their increased liver disease severity and accordingly higher death rate from liver-related causes. Although none of the 13 patients developing “clinical” cirrhosis during follow up underwent liver biopsy at trial entry, it seems likely that a vast proportion of them had histological cirrhosis at entry to the study rather than cirrhosis developing de novo in patients with steatosis or NASH considering the low risk of progression from NASH to cirrhosis reported in previous serial biopsy studies. Given the high death rate in the cirrhotic patients, and the confidence intervals of the increased SMR in the NAFLD patients (1.003– 1.76) it appears that the SMR in non-cirrhotic NAFLD patients is unlikely to be increased, consistent with data from patients with pure fatty liver9Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. Becker U. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (413) Google Scholar or with NAFLD detected ultrasonographically10Bellantani S. Bedogni G. Miglioli L. Masutti F. Croce L.S. Castiglione A. Goldoni C. Tiribelli C. Natural history and incidence of non alcoholic and alcoholic fatty liver disease (NAFLD, AFLD) in general population with alteration of liver enzymes.J Hepatol. 2005; 42: 3PubMed Google Scholar; and therefore likely to include a lower proportion of patients with advanced disease than the current study. The observation that cirrhosis was an independent predictor of mortality on multivariate analysis further supports the impact of the cirrhotic patients on the SMR and the predictive values of age and diabetes could also be explained by their known adverse impact on the prognosis of patients with cirrhosis.22Bianchi G.P. Marchesini G. Zoli M. Bugianesi E. Fabbri A. Pisi E. Prognostic significance of diabetes in patients with cirrhosis.Hepatology. 1994; 20: 119-125PubMed Google Scholar In summary therefore, from this and previous studies, it would appear that the natural history of NAFLD depends critically on disease stage. Patients with simple steatosis have a relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%. Patients with NASH and fibrosis can progress to cirrhosis, defined histologically or clinically, with the risk varying from 0% at 5 years to 12% over 8 years.6Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Non alcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2750) Google Scholar, 11Fassio E. Alvarez E. Dominguez N. Landeira G. Longo C. Natural history of non alcoholic steatohepatitis a longitudinal study of repeat liver biopsies.Hepatology. 2004; 40: 820-826Crossref PubMed Scopus (419) Google Scholar Once cirrhosis develops, patients are at high risk of developing hepatic decompensation and of dying from a liver-related cause including HCC. Despite the high prevalence of obesity, diabetes, and the metabolic syndrome there is, as yet, no evidence that patients with NAFLD have an increased risk of death from either malignancy or cardiovascular disease. The lack of increased death rate from malignancy may simply be due to the still relatively small studies that have not examined cause-specific SMRs, while the lack of increased mortality from cardiovascular disease may be attributable to the putative “cardioprotective” effects of chronic liver disease including reduced arterial pressure, an improved lipid profile or prolonged coagulation parameters.23Marchesini G. Ronchi M. Forlani G. Bugianesi E. Bianchi G. Fabbri A. Zoli M. Melchionda N. Cardiovascular disease in cirrhosis-a point-prevalence study in relation to glucose tolerance.Am J Gastroenterol. 1999; 94: 655-662PubMed Google Scholar Clearly, what is required are larger and longer follow-up studies in patients with histologically defined NAFLD, ideally comprising of both serial biopsies and clinical observations to include a detailed examination of the incidence/prevalence of malignancy and cardiovascular disease. Only with this sort of information, likely to emerge from initiatives such as the NIH-funded NASH Clinical Research Network, will we be able to provide patients with accurate prognostic information, initiate treatment trials on a more rational basis and predict the likely burden of NAFLD-related end-stage liver disease on health care systems. The impact of NAFLD on the well established obesity- and diabetes-related risks of malignancy and cardiovascular disease deserves particular attention in view of the implications for screening/surveillance strategies in this growing number of patients. The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort StudyGastroenterologyVol. 129Issue 1PreviewBackground & Aims: The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. Methods: Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. Full-Text PDF
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