The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study

Background & 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. Results: Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1–23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003–1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7–2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3–5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2–7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. Conclusions: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low. Background & 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. Results: Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1–23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003–1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7–2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3–5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2–7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. Conclusions: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low. With the increasing prevalence of obesity, diabetes, and the metabolic syndrome in the general population,1Mokdad A.H. Ford E.S. Bowman B.A. Dietz W.H. Vinicor F. Bales V.S. Marks J.S. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.JAMA. 2003; 289: 76-79Crossref PubMed Scopus (4561) Google Scholar, 2Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5772) Google Scholar, 3Flegal K.M. Carroll M.D. Ogden C.L. Johnson C.L. Prevalence and trends in obesity among US adults, 1999–2000.JAMA. 2002; 288: 1723-1727Crossref PubMed Scopus (5360) Google Scholar nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease. A recent population-based cohort study found that 34% of the adult population in the United States has excessive fat accumulation in the liver, mostly unrelated to alcohol abuse.4Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg 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 (2934) Google Scholar This suggests that over 60 million adult Americans and an unknown proportion of children in this country suffer from NAFLD. This is alarming because NAFLD may progress to cirrhosis, liver failure, and hepatocellular carcinoma.5Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231Crossref PubMed Scopus (4171) Google Scholar, 6Caldwell 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 Scopus (969) Google Scholar, 7Bugianesi 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 nonalcoholic steatohepatitis from cryptogenic cirrhosis to heptocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1264) Google Scholar Despite being common and potentially serious, the natural history of NAFLD remains poorly defined. The few studies reported to date have limited numbers of highly selected patients, ie, patients with histologically proven NAFLD who have been referred to specialized tertiary care centers.8Lee R.G. Nonalcoholic steatohepatitis a study of 49 patients.Hum Pathol. 1989; 20: 594-598Abstract Full Text PDF PubMed Scopus (505) Google Scholar, 9Powell E.E. Cooksley W.G. Hanson R. Searle J. Halliday J.W. Powell L.W. The natural history of nonalcoholic steatohepatitis a follow-up study of forty-two patients for up to 21 years.Hepatology. 1990; 11: 74-80Crossref PubMed Scopus (1328) Google Scholar, 10Teli M.R. James O.F. Burt A.D. Bennett M.K. Day C.P. The natural history of nonalcoholic fatty liver a follow-up study.Hepatology. 1995; 22: 1714-1719Crossref PubMed Google Scholar, 11Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Nonalcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2809) Google Scholar, 12Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I. Becker U. Bendtsen F. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (421) Google Scholar, 13Evans C.D. Oien K.A. MacSween R.N. Mills P.R. Non-alcoholic steatohepatitis a common cause of progressive chronic liver injury?.J Clin Pathol. 2002; 55: 689-692Crossref PubMed Scopus (93) Google Scholar Accurate data are clearly needed as to the extent to which NAFLD causes morbidity and mortality in the general population. Population-based studies to determine the long-term prognosis of NAFLD have not been conducted, and, thus, it remains uncertain whether morbidity and mortality rates reported to date can be generalized to community-based practice where patients may have a milder disease. Furthermore, the relatively small number and/or only modest length of follow-up in all these studies8Lee R.G. Nonalcoholic steatohepatitis a study of 49 patients.Hum Pathol. 1989; 20: 594-598Abstract Full Text PDF PubMed Scopus (505) Google Scholar, 9Powell E.E. Cooksley W.G. Hanson R. Searle J. Halliday J.W. Powell L.W. The natural history of nonalcoholic steatohepatitis a follow-up study of forty-two patients for up to 21 years.Hepatology. 1990; 11: 74-80Crossref PubMed Scopus (1328) Google Scholar, 10Teli M.R. James O.F. Burt A.D. Bennett M.K. Day C.P. The natural history of nonalcoholic fatty liver a follow-up study.Hepatology. 1995; 22: 1714-1719Crossref PubMed Google Scholar, 11Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Nonalcoholic fatty liver disease a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2809) Google Scholar, 12Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I. Becker U. Bendtsen F. Long term prognosis of fatty liver risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (421) Google Scholar, 13Evans C.D. Oien K.A. MacSween R.N. Mills P.R. Non-alcoholic steatohepatitis a common cause of progressive chronic liver injury?.J Clin Pathol. 2002; 55: 689-692Crossref PubMed Scopus (93) Google Scholar have prohibited detection of prognostic factors for patients with NAFLD. Knowledge of the natural history of NAFLD and the factors that predict outcomes is vital to guide individual patient prognosis with implications for management decisions regarding further invasive investigation, need for treatment, and ongoing monitoring. In addition, quantification of the disease burden in the community has important public health ramifications. The Rochester Epidemiology Project (REP) is a unique data linkage system funded by the National Institutes of Health to investigate disease in a population setting. The REP indexes all medical diagnoses made by health care providers in Olmsted County, Minnesota.14Melton III, L.J. History of the Rochester Epidemiology Project.Mayo Clin Proc. 1996; 71: 266-274Abstract Full Text Full Text PDF PubMed Scopus (1343) Google Scholar The 2 main providers of health care in Olmsted County (Mayo Clinic and Olmsted Medical Center) as well as local private physicians are indexed, allowing coverage of primary, secondary, and tertiary health care. Subsequently, all diagnoses made in outpatient office or clinic visits, hospitalizations, emergency room visits, nursing home care, surgical procedures, autopsies, and death certificates are recorded. Each year, 87% of the Olmsted County residents are seen at least once at Mayo or the Olmsted Medical Center, and, in any given 4-year period, at least 1 health encounter is recorded in over 95% of county residents.14Melton III, L.J. History of the Rochester Epidemiology Project.Mayo Clin Proc. 1996; 71: 266-274Abstract Full Text Full Text PDF PubMed Scopus (1343) Google Scholar This allows evaluation of the health status of what is effectively the entire county. Using the resources of the REP, we conducted a population-based cohort study to examine the natural history of patients diagnosed with NAFLD in Olmsted County. We sought to determine (1) overall mortality in comparison with the Minnesota general population of the same age and sex and (2) liver-related morbidity and mortality. The study population consisted of residents of Olmsted County, located in southeastern Minnesota. According to census data, the total population in the year 2000 was 124,000 people, with 81% of these living in urban areas and the remainder in rural farming areas.15Evans D.L. Price J.L. Barron W.G. United States Census BureauProfiles of demographic characteristics, 2000 Census of Population and Housing, Minnesota. 2001; Google Scholar The proportion of whites in the population was 90.3%, compared with the general US population of 75.1%. The proportion of people with college education was 34.7%, compared with the general US population proportion of 24.4%. Patients residing in Olmsted County who had been diagnosed with NAFLD, fatty liver, hepatic steatosis, steatohepatitis, or cryptogenic cirrhosis over a 20-year period between January 1, 1980, and January 1, 2000, were ascertained from the REP master diagnostic index. Although fatty liver was recognized prior to 1980, this liver condition was better characterized in 198016Ludwig 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; therefore, we chose to identify patients after this date. The date January 1, 2000, was chosen to allow a 20-year ascertainment period. Follow-up was extended to December 31, 2003. All medical records were reviewed in detail, and patients were included only if fatty infiltration of the liver was confirmed on imaging studies (ultrasound, computed tomography, or magnetic resonance imaging) or liver biopsy. In addition, because a sizable proportion of cryptogenic cirrhosis is due to NAFLD,17Caldwell 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 (237) Google Scholar we included patients diagnosed with cryptogenic cirrhosis who also had the metabolic syndrome prior to diagnosis. The metabolic syndrome was defined using the criteria proposed by the National Cholesterol Education Program (ATP III), ie, at least 3 of the 5 following features: fasting glucose ≥110 mg/dL; blood pressure ≥130/≥85 mm Hg; fasting triglyceride ≥150 mg/dL; low, high-density lipoprotein (HDL) cholesterol (<40 mg/dL for males, <50 mg/dL for females); and obesity (body mass index [BMI] ≥30 [kg/m2]).18Executive 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 Scopus (24336) Google Scholar Because waist circumference to determine central obesity was not measured for most of our patients, we used BMI ≥30 to define obesity.19World Health OrganizationReport of a WHO consultation. World Health Organization, Department of Noncommunicable Disease Surveillance, Geneva1999Google Scholar Patients were excluded if there was evidence of other liver disease on clinical history or examination, laboratory studies, imaging, or biopsy. Patients at risk of viral hepatitis because of intravenous drug use or blood product transfusion prior to 1992 were excluded if they had not had hepatitis B or C serology performed after their exposure. In addition, patients with secondary causes of fatty liver (medications, human immunodeficiency virus, gastrointestinal bypass surgery) were excluded. Patients with an average weekly ethanol consumption ≥140 grams were excluded. During the study period, information on alcohol consumption (type, amount, frequency, duration as well as alcohol abuse screening questions) was prospectively collected as part of the medical record by a patient history form filled out by the patient and reviewed by a nurse and/or physician at each visit. Initial search of the REP diagnostic index identified 620 patients. By chart review, 86 patients had evidence or risk factors for other liver disease; 46 had a history of excessive alcohol ingestion; 41 had secondary causes of fatty liver; 5 were nonresidents of Olmsted County; 4 were initially diagnosed pre-1980; 2 denied research authorization for use of their medical records for research; and 1 had cryptogenic cirrhosis but only 2 features of the metabolic syndrome. The remaining 435 patients formed the study population. Fifteen of these patients were first diagnosed with fatty liver at time of postmortem and were therefore excluded from the survival analysis. The following baseline information was recorded at time of either radiographic or histologic confirmation of NAFLD diagnosis: age, sex, ethnicity, BMI, average weekly alcohol intake, history of diabetes (fasting glucose ≥126 mg/dL or under treatment), impaired fasting glucose (IFG; fasting glucose ≥110 mg/dL), hypertriglyceridemia (fasting triglyceride ≥ 150 mg/dL), low fasting HDL cholesterol (<40 mg/dL for men and <50 mg/dL for women), hypertension (BP ≥ 130/≥85 mm Hg or under treatment), and ischemic heart disease (defined as prior myocardial infarct or angina pectoris) or cerebrovascular disease (defined as prior cerebrovascular accident or transient ischemic attack). In addition, symptoms of fatigue, abdominal pain, or discomfort were noted. The following laboratory values within 1 month of diagnosis were obtained; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, albumin, platelet count, prothrombin time, fasting glucose, and lipids (triglyceride, HDL cholesterol, total cholesterol) in addition to date of first documented abnormal aminotransferase level. The following information was recorded if performed within 6 months of diagnosis (number of patients with results available in parentheses); hepatitis B (332) and C serology (307), antinuclear antibody (190), γ-globulin (170), antismooth muscle antibody (95), antimitochondrial antibody (120), ferritin and transferrin saturation (257), ceruloplasmin (135), α-1 antitrypsin level and phenotype (124), and radiologic findings (415). Liver histology was scored according to the schema developed by Brunt et al20Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3152) Google Scholar by a single liver pathologist, who was unaware of the patient details. Nonalcoholic steatohepatitis (NASH) was defined as the presence of steatosis plus lobular inflammation plus hepatocellular ballooning in accordance with recent conference guidelines21Neuschwander-Tetri B.A. Caldwell S.H. Nonalcoholic steatohepatitis summary of an AASLD Single Topic Conference.Hepatology. 2003; 37: 1202-1219Crossref PubMed Scopus (1796) Google Scholar or steatosis plus any stage of fibrosis. Follow-up was obtained from medical charts and death certificates. Subsequent diagnoses of cirrhosis, ascites, hepatorenal syndrome, variceal hemorrhage, jaundice, encephalopathy, hepatocellular carcinoma, liver transplantation, diabetes, hypertension, hypertriglyceridemia, or low HDL were recorded. In addition, date and cause of death were determined. The results are displayed in Tables with categoric variables presented as number and percentage and continuous variables presented as mean and standard deviation. Observed survival of NAFLD patients was compared with the expected survival of the Minnesota population calculated using the method of Ederer, based on age- and sex-specific conditional probabilities of death in the subsequent year from published census tables.22Ederer F. The relative survival rate a statistical methodology.Natl Cancer Inst Monograph. 1961; 6: 101-121PubMed Google Scholar One-sample log-rank tests were used for comparison with the Minnesota population. Cox proportional hazards modeling was used to evaluate overall mortality. Variables that were significant at the .05 level in separate Cox proportional hazard models were considered for the multivariable model. Analysis was performed using SAS Release 8.2 (SAS Institute Inc., Cary, NC). The 435 patients were predominantly middle-aged whites with an equal sex distribution (Table 1). Of the nonwhite patients, 20 (5%) were Asian, 6 (1%) Arabic, 5 (1%) Hispanic, and 2 (0.5%) African American. Features of metabolic syndrome were common. In particular, obesity was present in over two thirds of the population. IFG (glucose ≥110 mg/dL) was present in 159 (37%) patients, with 112 (26%) of these being diabetic.Table 1Baseline Clinical and Laboratory Features of Patients Diagnosed with NAFLD in Olmsted County During 1980 to 2000 (n = 435)VariableTotal cohort (n = 435)Age (y)49 ± 15Male213/435 (49%)White402/435 (92%)Abdominal pain/fullness115/420 (27%)Fatigue54/419 (13%)BMI (kg/m2)33.5 ± 6.5Obesity299/420 (71%)Glucose (mg/dL)119 ± 49Diabetes112/435 (26%)Impaired fasting glucose159/435 (37%)Hypertension155/431 (36%)Triglyceride (mg/dL)227 ± 161Hypertriglyceridemia263/389 (68%)HDL cholesterol (mg/dL)41 ± 12Low HDL cholesterol117/359 (33%)AST (U/L)51 ± 52Elevated AST276/418 (66%)Bilirubin (mg/dL)0.8 ± 1.1Elevated bilirubin48/393 (12%)Alkaline phosphatase (mg/dL)199 ± 115Elevated alkaline phosphatase344/404 (85%)Prothrombin time (s)10.6 ± 1.2Elevated prothrombin20/208 (10%)Platelet count (×109/L)245 ± 66Low platelet count14/407 (3%)NOTE. Data provided as mean ± standard deviation or number (percentage) with patients with missing data excluded from denominator. Obesity defined as BMI ≥30; diabetes as fasting glucose ≥126 mg/dL or requiring treatment; impaired fasting glucose as fasting glucose ≥110 mg/dL; hypertension as blood pressure ≥130/85 mm Hg or requiring treatment; hypertriglyceridemia as fasting triglyceride ≥150 mg/dL; low HDL cholesterol as <40 mg/dL in men, <50 mg/dL in women; elevated AST as >31 U/L; elevated alkaline phosphatase >115 U/L in males and >108 in females; elevated prothrombin time >12.0 seconds; low platelet count <150 × 109/L. Open table in a new tab NOTE. Data provided as mean ± standard deviation or number (percentage) with patients with missing data excluded from denominator. Obesity defined as BMI ≥30; diabetes as fasting glucose ≥126 mg/dL or requiring treatment; impaired fasting glucose as fasting glucose ≥110 mg/dL; hypertension as blood pressure ≥130/85 mm Hg or requiring treatment; hypertriglyceridemia as fasting triglyceride ≥150 mg/dL; low HDL cholesterol as <40 mg/dL in men, <50 mg/dL in women; elevated AST as >31 U/L; elevated alkaline phosphatase >115 U/L in males and >108 in females; elevated prothrombin time >12.0 seconds; low platelet count <150 × 109/L. The adjusted incidence rate of NAFLD diagnosis increased significantly over the study period, from an average of 4.2/100,000/year during 1980–1985 to 38.0/100,000/year during 1995–1999 (P <.001). Patients diagnosed with NAFLD in the first decade were more commonly cirrhotic (3 of 58 vs 5 of 362, respectively, P < .05) and had significantly lower albumin levels (4.0 ± 0.5 vs 4.3 ± 0.4 gm/dL, respectively, P < .001) and higher prothrombin time (11.5 ± 0.7 vs 10.6 ± 1.1 seconds, respectively, P < .001) compared with those diagnosed in the second decade. Diagnosis was confirmed by imaging in the majority of cases (Figure 1), either by abdominal ultrasound (n = 350), computed tomography (n = 62), or magnetic resonance imaging (n = 1). Of the patients undergoing liver biopsy, the most common indication was for investigation of abnormal liver tests (n = 43), followed by postmortem biopsies (n = 20), suspicion of cirrhosis (n = 6), unexplained hepatomegaly (n = 4), and staging for malignancy (n = 4). Seven patients had “other” indications, including premethotrexate therapy and investigation of suspected masses. Five patients who underwent postmortem biopsies were diagnosed with NAFLD prior to death by imaging studies. Only 2 patients in the cohort were diagnosed with cryptogenic cirrhosis and metabolic syndrome. One of these was an obese (BMI, 52.2) 44-year-old male with diabetes for 14 years as well as hypertension, hypertriglyceridemia, and low HDL cholesterol. The other patient was a 71-year-old obese (BMI, 30.8) hypertensive female with low HDL cholesterol and IFG. A history of ischemic heart disease was present in 39 (9%) patients and cerebrovascular disease in 14 (3%). Two hundred sixty-three (60%) patients were lifetime nonsmokers, whereas 171 (40%) were current or previous smokers (minimum of 1 cigarette per day). Survival analysis was performed on 420 patients after excluding 15 patients whose initial diagnosis of NAFLD was at postmortem. From time of diagnosis of NAFLD, mean follow-up was 7.6 ± 4.0 years (range, 0.1–23.5 years), culminating in a total of 3192 person-years. Overall, 53 (12.6%) patients had died by the end of follow-up (Table 2). Follow-up to within 6 months of the study end (December 31, 2003) was available in a further 281 (67%) patients, equaling a total of 334 (80%) patients who were either censored because of death or had complete follow-up.Table 2Cause of DeathEtiologyN (%) (N = 53)Malignancy15 (28%) Bowel5 (9%) Pancreas3 (8%) Breast2 (4%) Other5 (9%)Ischemic heart disease13 (25%)Liver disease7 (13%) Liver failure4 (7%) Variceal hemorrhage2 (4%) Hepatocellular carcinoma1 (2%)Infection6 (11%) Pneumonia5 (9%) Sepsis1 (2%)Obstructive lung disease2 (4%)Congestive cardiac failure2 (4%)Cerebrovascular accident1 (2%)Gastrointestinal bleed1 (2%)Pulmonary embolus1 (2%)Aortic aneurysm dissection1 (2%)Smoke inhalation1 (2%)Retroperitoneal hemorrhage1 (2%)Unknown2 (4%) Open table in a new tab Survival among NAFLD patients was significantly less than the expected survival of the general Minnesota population of similar age and sex, with a standardized mortality ratio (SMR) of 1.34 (95% CI: 1.003–1.76, P = .03) as shown in Figure 2. To examine patients with at least 10 years of follow-up, the subset of 161 subjects diagnosed with NAFLD between 1980 and 1994 were analyzed (Figure 3). As follow-up lengthened, survival worsened compared with the general population (SMR, 1.55; 95% CI: 1.11–2.11; P = .005). At 10 years, the survival in this subgroup of NAFLD patients was significantly lower compared with the Minnesota population (77% vs 87%, respectively, P < .005, log-rank test).Figure 3Survival of patients diagnosed with NAFLD in Olmsted County, Minnesota, between January 1, 1980, and January 1, 1994. Survival is compared with the general population of Minnesota of the same age and sex.View Large Image Figure ViewerDownload (PPT) By univariate Cox regression analysis, an increased risk of death was associated with hypertension (P < .05), smoking (P < .05), age (P < .0001), ischemic heart disease (P < .0001), baseline diagnosis of cirrhosis (P < .0001), and IFG/diabetes (P < .0001). Risk of death was not significantly associated with the presence of metabolic syndrome (P = .9) or obesity (P = .8). In a multivariable Cox regression model, only IFG/diabetes, cirrhosis, and age remained significantly associated with death (Table 3).Table 3Baseline Predictors of Mortality by Multivariate Proportional Hazard ModelingVariableParameter estimateStandard errorHazard ratio (95% CI)P valueAge (per decade)0.080.012.2 (1.7–2.7)<.0001IFG/diabetes0.970.342.6 (1.3–5.2).005Cirrhosis at baseline1.130.483.1 (1.2–7.8).02Smoking0.350.291.4 (0.8–2.5).2Hypertension−0.320.290.7 (0.4–1.3).3Ischemic heart disease0.080.371.1 (0.5–2.3).8NOTE. IFG, Impaired fasting glucose (fasting glucose ≥110 mg/dL); diabetes defined as fasting glucose ≥126 mg/dL or requiring treatment; hypertension defined as blood pressure ≥130/≥85 mm Hg or requiring treatment. Open table in a new tab NOTE. IFG, Impaired fasting glucose (fasting glucose ≥110 mg/dL); diabetes defined as fasting glucose ≥126 mg/dL or requiring treatment; hypertension defined as blood pressure ≥130/≥85 mm Hg or requiring treatment. Cirrhosis was diagnosed in 21 (5%) patients, with 8 (2%) diagnosed at initial presentation and 13 (3%) during follow-up. Thirteen (3.1%) patients developed cirrhosis-related complications, including ascites in 10 (2%), jaundice in 8 (2%), portosystemic encephalopathy in 7 (2%), variceal bleeding in 5 (1%), and HCC in 2 (0.5%) (1 of whom had cryptogenic cirrhosis plus metabolic syndrome). One patient underwent liver transplantation. Median (50%) survival of patients diagnosed with cirrhosis was 6.8 years. Liver-related death occurred in 7 (1.7%) patients and was the third leading cause of death after malignancy and ischemic heart disease (Table 2). Four (1%) patients died of liver failure, 2 (0.5%) of variceal hemorrhage, and 1 (0.25%) of HCC. If patients with cirrhosis on presentation were excluded from the analysis, then only 2 liver-related deaths occurred in the remaining 412 patients, although 13 developed cirrhosis. Only one of the liver-related deaths occurred in a patient previously diagnosed with cryptogenic cirrhosis plus metabolic syndrome. During follow-up, 91 (22%) people were diagnosed with diabetes after a mean of 4.6 ± 3.2 years from their diagnosis of NAFLD. Ninety-six (23%) people were diagnosed with either hypertriglyceridemia and/or low HDL cholesterol 4.7 ± 3.8 years after initial NAFLD diagnosis, and 94 (22%) patients were diagnosed as having hypertension after a mean of 5.2 ± 3.1 years. These conditions were not routinely screened for in all patients, and, thus, the proportion of patients developing metabolic complications after the diagnosis of NAFLD may be higher. The histologic features of the 65 patients who underwent liver biopsy (excluding the 20 postmortem biopsies) are shown in Table 4. Patients with NAFLD who underwent liver biopsy had a significantly shorter survival compared with those who did not (Figure 4), although no patient died from a liver biopsy complication. Patients undergoing liver biopsy were more likely to be symptomatic, have IFG/diabetes or more advanced liver disease as evidenced by laboratory markers of portal hypertension, and impaired hepatic synthetic function (Table 5). In concordance with this, significantly more patients who underwent liver biopsy had cirrhosis at presentation compared with those who did not undergo liver biopsy (6 of 65 vs 2 of 355, respectively, P < .001).Table 4Histologic Features of Patients With NAFLD