Liver disease is a major cause of mortality and morbidity

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9: Changes in the Prevalence of the Most Common Causes of Chronic Liver Diseases in the United States From 1988 to 2008 ZOBAIR M. YOUNOSSI,*, MARIA STEPANOVA,* MARIAM AFENDY,* YUN FANG, YOUSSEF YOUNOSSI, HESHAM MIR,* and MANIRATH SRISHORD*, *Center for Liver Diseases, Inova Fairfax Hospital, Falls Church; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia This article has an accompanying continuing medical education activity on page e60. Learning Objectives At the end of this activity, the learner will recognize the increasing prevalence of nonalcoholic fatty liver disease in the United States, understand the implications of the rising obesity epidemic on the prevalence of nonalcoholic fatty liver disease, and learn that the rates of other important causes of chronic liver disease such as viral hepatitis and alcoholic liver disease have remained stable. BACKGROUND & AIMS: Chronic liver diseases (CLDs) are major causes of morbidity and mortality worldwide. We assessed changes in the prevalence of different types of CLD in the United States. METHODS: National Health and Nutrition Examination Surveys conducted between 1988 and 2008 were used to estimate changes in the prevalence and predictors of CLDs. Serologic and clinical data were used to establish the diagnoses of CLDs in 39,500 adults. Statistical analyses were conducted with SUDAAN 10.0 (SAS Institute, Inc, Cary, NC). RESULTS: The prevalence rates for CLD were 11.78% ( ), 15.66% ( ), and 14.78% ( ). During the same period, the prevalence of hepatitis B virus infection (0.36%, 0.33%, and 0.34%), hepatitis C virus (1.95%, 1.97%, and 1.68%), and alcoholic liver disease (1.38%, 2.21%, and 2.05%) remained generally stable. In contrast, the prevalence of nonalcoholic fatty liver disease (NAFLD) increased from 5.51% to 9.84% to 11.01%. From 1988 to 1994, NAFLD accounted for 46.8% of CLD cases; from 1994 to 2004 its prevalence increased to 62.84%, and then to 75.1% from 2005 to During these time periods, steady increases were observed in obesity (21.74%, 30.02%, and 33.22%), visceral obesity (35.18%, 48.16%, and 51.43%), type II diabetes (5.55%, 7.88%, and 9.11%), insulin resistance (23.29%, 32.50%, and 35.00%), and hypertension (22.68%, 33.11%, and 34.08%). A multivariate analysis showed that during all time periods, obesity was an independent predictor of NAFLD. CONCLU- SIONS: National Health and Nutrition Examination Surveys data collected from 1988 to 2008 show that the prevalence of major causes of CLD remained stable, except for NAFLD, which increased steadily, along with the prevalence of metabolic conditions. Given the increasing rates of obesity, NAFLD prevalence is expected to contribute substantially to the burden of CLD in the United States. Keywords: Epidemiology; Population; Incidence. View this article s video abstract at Liver disease is a major cause of mortality and morbidity worldwide. 1 Recent data from the Centers for Disease Control and Prevention show that liver disease is currently the 12th leading cause of death in the United States. 1 In most cases, liver-related mortality results from complications of chronic liver disease (CLD) including advanced cirrhosis and hepatocellular carcinoma (HCC). Despite a recent decline in a number of other cancers, the incidence of HCC continues to increase, especially in men. 2,3 CLD and complications of cirrhosis also are associated with severe impairments in health-related quality of life. 4,5 Furthermore, CLD influences resource use, negatively contributing to well-being of the individual patient and society. 6 Understanding the causes of CLD and its future projections is critically important from a public health perspective in the United States. Of major causes of CLD, chronic hepatitis C (CH-C) has been widely implicated for the recent increases in the incidence of HCC and is currently the main etiologic indication for liver transplantation in the United States. 6 On the other hand, accumulating evidence suggests that nonalcoholic liver disease (NAFLD)-related cirrhosis is rapidly becoming another important cause of CLD and HCC. 2,7 10 In addition, individuals with NAFLD-related cirrhosis are less likely to undergo HCC screening and tend to present with larger tumors. 11 Furthermore, a recent study suggested that patients with NAFLD and cirrhosis are less likely to be listed for orthotopic liver transplantation or to receive an orthotopic liver transplantation, even if they are listed. 12 Together, these studies indicate that NAFLD is poised to become the most important cause of CLD with a substantial clinical and economic impact. In this study, we used population-based data to assess the changes in the prevalence of CLD over the past 2 decades. The major aim of this study, however, was to assess whether the recent epidemics of obesity has affected the pattern of CLD in the United States. Abbreviations used in this paper: ALD, alcoholic liver disease; CH-B, chronic hepatitis B; CH-C, chronic hepatitis C; CLD, chronic liver disease; DM, diabetes mellitus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IR, insulin resistance; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NHANES, National Health and Nutrition Examination Survey by the AGA Institute /$36.00 doi: /j.cgh

2 June 2011 PREVALENCE OF CHRONIC LIVER DISEASES 525 Methods Study Population This study was based on data obtained from the National Health and Nutrition Examination Survey (NHANES), a nationwide survey representing the health and nutritional status of the noninstitutionalized civilian US population. The data were collected by the US National Center for Health Statistics of the Centers for Disease Control and Prevention via household interviews, physical examinations, and laboratory data including blood and urine samples collected in designated examination centers. We used NHANES III data collected between 1988 and 1994, as well as data obtained in 5 continuous cycles of NHANES conducted from 1999 to Data from these 5 NHANES cohorts were combined into 2 larger periods from 1999 to 2004, and from 2005 to These surveys were based on similar questionnaires and similar methods for serum and blood assays. After weighting on the basis of age, sex, level of education, and race or ethnic group, the distribution of participants was representative of that of the US population. Stratification and sampling units describing the design stages of NHANES were used to account for the complex, multistage probability sample design of these data. 13 Inclusion criteria for this study were as follows: age 18 years or older, availability of complete demographics (age, sex, and ethnicity), social history (history of injection drug use and smoking and alcohol consumption within the past year), and clinical data (history of hypertension and type II diabetes). Additional data included body mass index, waist circumference, and blood pressure, which were measured at the time of examination. Several additional laboratory tests also were collected: fasting serum glucose and insulin levels, triglyceride levels, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, aspartate aminotransferase level, alanine transaminase level, transferrin saturation, and serologies for hepatitis B virus, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and hepatitis C virus (HCV) (anti-hcv by enzyme-linked immunosorbent assay and HCV RNA by polymerase chain reaction). Participants with data insufficient for ruling in or ruling out CLD (as described later) were excluded from the study. Adult participants who were excluded from the study were similar to the final study cohort. Definitions Diabetes mellitus (DM) was defined as a fasting glucose level of 126 mg/dl or greater or the history of oral hypoglycemics or insulin use or both. For the NHANES cycle, relevant history was collected from the adult data file; in the other cycles, the diabetes questionnaires were used. Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, diastolic blood pressure of 90 mm Hg or greater, or history of oral antihypertensive medications. For the NHANES cycle, relevant history was collected from the adult data file; in the other cycles, data from the Medical Conditions questionnaires were used. Hypercholesterolemia was defined as an increased cholesterol level of greater than 200 mg/dl, low-density lipoprotein level as 139 mg/dl or greater, or high-density lipoprotein level less than 40 mg/dl for men and less than 50 mg/dl for women. Metabolic syndrome, as defined by the National Cholesterol Education Program Adult Treatment Panel III criteria, 14 includes at least 3 of the following criteria: waist circumference greater than 102 cm in men or greater than 88 cm in women, fasting plasma glucose level greater than 110 mg/dl, blood pressure greater than 130/85 mm Hg, increased triglyceride level greater than 150 mg/dl, and high-density lipoprotein level less than 40 mg/dl in men or less than 50 in women. Increased serum aminotransferase levels were defined as alanine transaminase level greater than 40 U/L or aspartate aminotransferase level greater than 37 U/L in men and alanine transaminase or aspartate aminotransferase level greater than 31 U/L in women. Increased transferrin saturation was diagnosed at a level of 50% or higher. Insulin resistance (IR) was determined by the homeostasis of model assessment score. 15 A homeostasis of model assessment score of 3.0 or greater was defined as IR. Four major race or ethnic groups included non-hispanic whites, non-hispanic blacks, Hispanics, and other, which included Aleut, Eskimo, American Indian, Asian, or Pacific Islander. A positive smoking history was defined as ongoing smoking or more than 100 cigarettes in the past 5 years. For the NHANES cycle, relevant history was collected from the adult data file; in the other cycles, the Smoking and Tobacco Use questionnaires were used. Alcohol consumption was defined as greater than 20 g/d for men and greater than 10 g/d for women within a year before the completion of data collection. Alcohol intake was calculated according to self-reported data on the amount and frequency of alcohol consumption collected as a part of the NHANES III examination questionnaire and Alcohol Use questionnaires in later NHANES cycles. Injection drug use history was collected from the Drug Use questionnaires for and study cycles. For the same cycles, blood transfusion history (including the year of the first blood transfusion) was collected from Medical Conditions questionnaires. Obesity was defined as a body mass index of 30 or greater and visceral obesity was defined using the thresholds for waist circumference used for the National Cholesterol Education Program Adult Treatment Panel III definition of metabolic syndrome. 14 Etiology of Chronic Liver Disease For the purpose of this study, CH-B was defined as a positive test for hepatitis B surface antigen. Similarly, individuals with positive HCV antibody were defined as hepatitis C positive (HCV ). Of those HCV patients with available HCV RNA data, 73.8% in , 75.1% in , and 75.6% in cycles were HCV RNA positive by polymerase chain reaction and were considered to have CH-C. Iron overload was defined as transferrin saturation 50%. ALD was presumed in subjects who reported excessive alcohol use and had increased serum aminotransferase levels (according to the earlier-described definitions) without other causes of liver disease. Finally, subjects were presumed to have NAFLD, if they had increased serum aminotransferase levels (defined previously) in the absence of any other evidence of CLD, such as excessive alcohol use, increased transferrin saturation, or a positive hepatitis B or hepatitis C test. From this NAFLD cohort, a subgroup of nonalcoholic steatohepatitis (NASH) was considered as individuals who had NAFLD together with DM or IR as defined previously. This definition of NASH was considered reasonable because of the tremendously high prevalence

3 526 YOUNOSSI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 6 of NASH in patients with type II diabetes or IR Therefore, in this study, we assumed that NAFLD patients who had DM or IR, will most likely have NASH. Together, individuals with CH-B, CH-C, iron overload, ALD, and NAFLD were included in the cohort for CLD. Subjects without evidence of liver disease according to the inclusion criteria described here were considered to have no CLD and were used as the control cohort. Statistical Analyses Sample weights were used to account for nonresponse and unequal selection probabilities for certain categories of the population, and stratum and sampling units accounted for the survey design effects using Taylor series linearization. When merging NHANES study cycles, appropriate selection of sampling weights and adjustment coefficients were applied according to the NHANES Analytic and Reporting Guidelines. 13 In addition, where recommended by the US National Center for Health Statistics, laboratory parameters measured with different laboratory techniques were made comparable between the cycles by conversion with a linear transformation. 13 The prevalence of various clinical parameters, including CLD subtypes and metabolic syndrome components, was compared among the 3 study cycles by using the stratum-specific chi-square test for independence. Finally, logistic regression was used to identify independent predictors of NAFLD, CLD, and CH-C in each of the study cycles. P values of.05 or less were considered significant. Additionally, independent predictors of ALD and HBV are only provided in the Supplementary Tables. All analyses were run with SAS 9.1 and SUDAAN 10.0 (SAS Institute, Inc, Cary, NC). This study was approved by the Institutional Review Board of Inova Health System. Results Study Population This study included a cohort of 39,500 adults from 3 NHANES cycles (N 15,855 from NHANES , 13,970 from NHANES , and 9670 from ) with complete clinical, demographic, and laboratory data (Table 1). Prevalence of Chronic Liver Diseases and Subtypes Our analyses suggest that prevalence rates for CLDs are steadily increasing: 11.78% 0.48% ( ), 15.66% 0.41% ( ), and 14.78% 0.58% ( ) (P.0001). The rates for different types of CLDs during the same time period indicate that the prevalence of CH-B has remained stable (0.36% 0.08%, 0.33% 0.06%, and 0.34% 0.08%, in the 3 study cycles, respectively; P.05). Similarly, no significant differences were observed in the prevalence of HCV antibody-positivity (1.95% 0.22% to 1.97% 0.20%, 1.68% 0.15%; P.05) or CH-C (1.44% 0.21% in to 1.27% 0.15% in ; P.05). Furthermore, although there was an initial increase, the prevalence of ALD has remained stable over the past decade (1.38% 0.16% to 2.21% 0.18% to 2.05% 0.21% in the 3 study cycles, respectively; P.0143) (Table 1). During the same period, the prevalence of NAFLD has increased steadily: 5.51% 0.31% ( ), 9.84% 0.33% Table 1. Prevalence of CLDs and Clinicodemographic Characteristics of the US Population Between 1988 and 2008 Parameter/cycle P value N 15,866 13, Age, y Male sex, % Ethnicity Caucasian, % African American, % Excessive alcohol use, % History of smoking, % History of injection drug use, % NA History of blood transfusion before 1991, % NA History of blood transfusion after 1992, % NA Obesity, % Visceral obesity, % Insulin resistance, % Type II diabetes, % Hypercholesterolemia, % Hypertension, % CLD, % ALD, % CH-B, % Iron overload, % HCV antibody( ), % CH-C, % NAFLD, % NASH, % Portion of NAFLD in CLD, % NA, not available.

4 June 2011 PREVALENCE OF CHRONIC LIVER DISEASES 527 Table 2. Independent Predictors of CLD Between 1988 and 2008 Age 0.99 ( ) 0.99 ( ) 1.00 ( ) Male sex 1.41 ( ) 1.34 ( ) 1.63 ( ) Caucasian 0.67 ( ) 0.70 ( ) 0.60 ( ) African American 0.64 ( ) 0.90 ( ) 0.55 ( ) Visceral obesity 1.18 ( ) 1.43 ( ) 1.26 ( ) Obesity 1.27 ( ) 1.13 ( ) 1.74 ( ) Type II diabetes 1.76 ( ) 1.05 ( ) 1.12 ( ) Hypercholesterolemia 0.93 ( ) 1.17 ( ) 1.55 ( ) Hypertension 1.36 ( ) 0.89 ( ) 1.12 ( ) Excessive alcohol use 2.37 ( ) 1.89 ( ) 1.64 ( ) Smoking 1.15 ( ) 1.18 ( ) 1.03 ( ) Injection drug use NA 8.00 ( ) 3.65 ( ) Blood transfusion before 1991 NA 1.26 ( ) 1.43 ( ) Blood transfusion after 1992 NA 0.70 ( ) 1.11 ( ) NA, not available. ( ), and 11.01% 0.51% ( ) (P.0001). By restricting the analysis to individuals with a presumed diagnosis of NASH, the prevalence of NASH increased from 0.65% 0.07% ( ) to 0.82% 0.10% ( ), and 1.10% 0.14% ( ) (P.0055). To assess the underlying causes for this increase in the prevalence of NAFLD, we studied changes in the prevalence rates of metabolic syndrome components that are known to be major risk factors for NAFLD and NASH. Our analysis showed that all components of metabolic syndrome, except for hypercholesterolemia, increased over the past 2 decades. In fact, the prevalence rates for obesity (21.74% 0.65% in , 30.02% 0.67% in , and 33.22% 1.08% in ; P.0001), visceral obesity (35.18% 0.73%, 48.16% 0.84%, and 51.43% 1.25%; P.0001), type II diabetes (5.55% 0.29%, 7.88% 0.33%, and 9.11% 0.47%; P.0001), IR (23.29% 0.80%, 32.50% 0.94%, and 35.00% 1.41%; P.0001), and hypertension (22.68% 0.80%, 33.11% 0.73%, and 34.08% 1.05%; P.0001) all increased significantly over time (Table 1). Independent Predictors of Chronic Liver Diseases All chronic liver diseases. The proportion of the change in the prevalence rates of CLDs that can be attributed to NAFLD was determined by analyzing the proportion of individuals with CLD who were diagnosed with NAFLD during the 3 NHANES cycles. This analysis showed steady increases in the proportion of CLD patients who were diagnosed with NAFLD over this period. Between 1988 and 1994, NAFLD accounted for 46.8% 1.9% of all CLDs, between 1999 and 2004 its share increased to 62.8% 1.5%, and between 2005 and 2008 it accounted for as much as 75.1% 1.6% (P.0001). On the other hand, HCV accounted for 13.3% 1.6% of CLDs between 1988 and 1994, 12.5% 1.2% between 1999 and 2004, and 11.4% 1.0% between 2005 and 2008 (P.05). To determine factors independently associated with CLD, we performed a number of multivariate analyses. Multivariate analysis of the period between 1988 and 1994 showed that male sex, non-caucasian non-african American ethnicity, obesity, type II diabetes, hypertension, and excessive alcohol intake all were associated independently with CLD. Similar results were obtained for the 2 subsequent NHANES cycles. Components of metabolic syndrome (eg, obesity) and a history of intravenous drug abuse were also independent predictors of CLD during this time period (Table 2). Nonalcoholic fatty liver disease. A multivariate analysis assessing independent predictors of NAFLD showed that obesity (defined by body mass index or waist circumference), type II diabetes, hyperlipidemia, older age, non-cauca- Table 3. Independent Predictors of NAFLD Between 1988 and 2008 Age 0.98 ( ) 0.99 ( ) 0.99 ( ) Male sex 1.40 ( ) 1.55 ( ) 1.63 ( ) Caucasian 0.59 ( ) 0.65 ( ) 0.68 ( ) African American 0.45 ( ) 0.42 ( ) 0.49 ( ) Visceral obesity 1.46 ( ) 1.85 ( ) 1.32 ( ) Obesity 1.64 ( ) 1.21 ( ) 1.84 ( ) Type II diabetes 1.98 ( ) 0.95 ( ) 0.93 ( ) Hypercholesterolemia 1.33 ( ) 1.41 ( ) 1.85 ( ) Hypertension 1.59 ( ) 1.35 ( ) 1.10 ( ) Smoking 0.62 ( ) 0.62 ( ) 0.63 ( )

5 528 YOUNOSSI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 6 Figure 1. Prevalence rates for CLD over time. sian non-african American ethnicity, and being a nonsmoker were associated independently with NAFLD (Table 3). Other causes of chronic liver disease. Additional multivariate analyses were performed to assess the independent predictors of CH-B, CH-C, and ALD. As expected, all the previously reported risk factors for HCV remained independently associated with CH-C, including a history of intravenous drug abuse, male sex, black ethnicity, and excessive alcohol use (Supplementary Table 1). In addition, our results show that Caucasian ethnicity (odds ratio, 0.31; 95% confidence interval [CI], ) was associated independently with a lower risk for CH-B in data. On the other hand, for data, history of intravenous drug use (odds ratio, 5.82; 95% CI, ) and receiving a blood transfusion before 1991 (odds ratio, 5.51; 95% CI, ) were found to be independent risk factors for chronic hepatitis B (Supplementary Table 2). Finally, male sex, history of smoking, and hypertension all were associated with alcohol-related liver disease (Supplementary Table 3) across all 3 study cycles. Discussion This is a population-based study assessing changes in the prevalence of common causes of CLD in the United States over the past 2 decades (Figure 1). A major finding of this study is that the prevalence of CLD, in general, is steadily increasing. This increase in the prevalence of CLD suggests that liver disease will remain among one of the major causes of mortality and morbidity in the United States and will be responsible for substantial medical resource use. This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases as well as the expected shortage of individuals trained in hepatology who are available to care for these patients. 16,17 Finally, the shortage of organs for liver transplantation for patients with end-stage liver diseases will prevent some individuals from receiving this life-saving, standard treatment for advanced cirrhosis and its complications. 16 A second major finding of our study indicates that the face of CLD in the United States is also changing. Although chronic viral hepatitis remains an important cause of CLD, the contribution of NAFLD to the total burden of CLD is increasing by the rapidly increasing prevalence of obesity. Nevertheless, it is important to emphasize that the complications of chronic viral hepatitis, such as HCC, will continue to cause a significant stress to health care resource use for the next few decades. 6 As described previously, within the spectrum of NAFLD, only patients with NASH have the potential to progress to cirrhosis and liver-related mortality In fact, liver biopsy data from diabetic patients show that a large number of diabetic patients have histologic NASH and, furthermore, type II diabetes is an independent predictor of advanced fibrosis. 8,10,18,21 24 In addition, it has been shown that patients with a combination of NAFLD and DM have higher rates of cirrhosis, liver-related mortality, and overall mortality. 21 Together, these studies support the validity of the clinical definition of NASH that we used in our study. Nevertheless, it is important to acknowledge that these definitions almost certainly underestimate the true prevalence of NAFLD and NASH because some patients with NAFLD and NASH may not have increased aminotransferase levels as required by our criteria. Nonetheless, this study shows that the prevalence of NAFLD and NASH is increasing parallel to the steady increases seen in the prevalence of obesity and type II diabetes in the United States. The independent predictors of CLD and etiologic categories of CLD confirm some of the known factors associated with HCV, HBV, alcohol-related liver disease, and NAFLD. However, in addition to risk factors associated with HCV, components of metabolic syndrome, such as obesity, account for many cases of CLD in the United States. Finally, although older age is an independent predictor of NAFLD and NASH, the increasing prevalence of obesity and NAFLD among US children and adolescents makes future projections even more dire. 25,26 As this young population ages, they are expected to become more obese and more likely to develop type II diabetes, both of which can lead to even higher rates of NAFLD and NASH. This cohort will certainly contribute to the future burden of CLD related to NASH, which potentially could become overwhelming. Several important limitations of this study must be considered. First, we had a relatively low threshold for the definition

6 June 2011 PREVALENCE OF CHRONIC LIVER DISEASES 529 of excessive alcohol consumption, potentially leading to a misclassification of individuals with ALD. Nevertheless, we believe that individuals who drink excessively and have increased aminotransferase levels, as defined here, are at risk for the damaging effects of alcohol either as the primary culprit, or as a secondary factor that accentuates the negative impact of other liver diseases, such as obesity-related fatty liver disease. Another limitation was that our clinical definition for NAFLD and NASH lacks histologic confirmation. As noted previously, this definition may underestimate the true prevalence of NAFLD and NASH. On the other hand, we observed a high prevalence of metabolic conditions, such as obesity and type II diabetes, which are strongly associated with NAFLD and NASH, indirectly supporting the validity of the study definitions. Finally, our analysis was limited to adults, but given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the United States. Despite these limitations, this study presents a large cohort of the US general population for whom in-depth liver-specific data are available. It reveals the changing face of CLDs and its major etiologic subtypes in the United States over a relatively long period. In conclusion, this study provides strong evidence for the steadily increasing prevalence of CLD in the United States. In addition, we show that all causes of CLD, other than NAFLD, are generally stable. These data suggest that NAFLD is poised to become the most important cause of CLD in the near future. The increase in the prevalence of NAFLD is driven by age and components of metabolic syndrome. As the US population ages and becomes more obese, the prevalence of NAFLD and the subtype of NASH will certainly increase. We postulate that by treating components of metabolic syndrome in patients with CLD, we may be able to ameliorate the anticipated wave of liver disease complications in the United States. 27 This approach requires recognition of NAFLD as an important cause of CLD, and implementing a health care policy that dedicates substantial resources to the care of patients with CLD. These resources must expand patients access to care and the availability of insurance coverage, 28 encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients. We acknowledge that the problems with NAFLD or NASHrelated liver disease will not be resolved with medication alone. Rather, we believe that a true multidimensional public health program should addresses dietary, lifestyle, and environmental factors responsible for the epidemic of obesity and metabolic conditions. This approach is especially important because the rates of obesity and NAFLD are increasing rapidly in our children. As this young cohort ages, they will have a substantial impact on our overall and liver-specific health, and on associated resource use for decades to come. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at doi: / j.cgh References 1. Xu J, Kochanek KD, Murphy SL, et al. Deaths: final data for Natl Vital Stat Rep 2010;58: El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132: Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, , featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116: Younossi Z, Boparai N, Kiwi M, et al. Health-related quality of life assessment in chronic liver disease: impact of type and severity of disease. Am J Gastroenterol 2001;96: Afendy A, Kallman J, Stepanova M, et al. Predictors of healthrelated quality of life (HRQL) in patients with chronic liver disease. Aliment Pharmacol Ther 2009;30: Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple co-hort model of HCV prevalence and disease progression. Gastroenterology 2010;138: Ong JP, Pitts A, Younossi ZM. Increased mortality and liverrelated mortality in patients with nonalcoholic fatty liver disease. J Hepatol 2008;49: Hossain N, Afendy A, Stepanova M, et al. Independent predictors of fibrosis in patients with non-alcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7: Rafiq N, Younossi ZM. Non-alcoholic fatty liver disease. A practical approach to evaluation and management. Clin Liver Dis 2009;13: Neuschwander-Tetri BA, Clark JM, Bass NM, et al. Clinical, laboratory and histological associations in adults with non-alcoholic fatty liver disease. Hepatology 2010;52: Marrero JA, Fontana RJ, Su GL, et al. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002;36: Yalamanchili K, Saadeh S, Klintmalm GB, et al. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transplant 2010;16: Anonymous. Analytic and reporting guidelines: the Third National Health and Nutrition Examination Survey, NHANES III ( ). Hyattsville, MD: CDC/NCHS, Cleeman JI. Executive 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: Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000;23: Merion RM. Current status and future of liver transplantation. Semin Liver Dis 2010;30: Bacon BR. Workforce issues in hepatology: what is needed? Hepatology 2008;47: Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with liver disease: a population-based study. Gut 2010;59: Matteoni CA, Younossi ZM, Gramlich T, et al. Non-alcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116: Musso G, Gambino R, Cassader M, et al. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2010 Nov 2. [Epub ahead of print]. 21. Younossi ZM, Gramlich T, Matteoni C, et al. Non-alcoholic fatty liver disease in patients with type II diabetes. Clin Gastroenterol Hepatol 2004;2: Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:

7 530 YOUNOSSI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No Marchesini G, Brizi M, Blanchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30: Lang IA, Kipping RR, Jago R, et al. Variation in childhood and adolescent obesity prevalence defined by international and country-specific criteria in England and the United States. Eur J Clin Nutr 2011;65: Dunn W, Schwimmer JB. The obesity epidemic and nonalcoholic fatty liver disease in children. Curr Gastroenterol Rep 2008;10: Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome as independent predictors of mortality in chronic liver disease: a population-based study. Gut 2010;59: Stepanova M, Kanwal F, El-Serag HB, et al. Insurance status and treatment candidacy of hepatitis C patients: analysis of population-based data from the United States. Hepatology 2011;53: Reprint requests Address requests for reprints to: Zobair M. Younossi, MD, MPH, Betty and Guy Beatty Center for Integrated Research, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, Virginia zobair.younossi@inova.org; fax: (703) Conflicts of interest The authors disclose no conflicts. Funding This study was supported in part by the Liver Disease Outcomes Fund of the Center for Liver Diseases at Inova Fairfax Hospital, Inova Health System (Falls Church, VA).

8 530.e1 YOUNOSSI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 6 Supplementary Table 1. Independent Predictors of Hepatitis C Between 1988 and 2008 Age 1.00 ( ) 1.00 ( ) 1.03 ( ) Male sex 1.60 ( ) 0.89 ( ) 1.12 ( ) African American 1.97 ( ) 3.77 ( ) 2.98 ( ) Type II diabetes 1.90 ( ) 1.31 ( ) 2.11 ( ) Excessive alcohol use 2.47 ( ) 1.29 ( ) 3.47 ( ) Smoking 2.99 ( ) 4.36 ( ) 4.79 ( ) Injection drug use NA ( ) ( ) NA, not available. Supplementary Table 2. Independent Predictors of Hepatitis B Between 1988 and 2008 Age 1.02 ( ) 1.02 ( ) 1.02 ( ) Male sex 1.88 ( ) 2.87 ( ) 2.56 ( ) Caucasian 0.31 ( ) 0.36 ( ) 0.35 ( ) African American 1.56 ( ) 3.38 ( ) 1.39 ( ) Visceral obesity 0.39 ( ) 1.72 ( ) 0.21 ( ) Obesity 0.73 ( ) 0.77 ( ) 0.63 ( ) Type II diabetes 1.67 ( ) 1.72 ( ) 1.59 ( ) Hypercholesterolemia 0.78 ( ) 0.69 ( ) 1.47 ( ) Hypertension 0.31 ( ) 0.38 ( ) 1.53 ( ) Excessive alcohol use 0.55 ( ) No cases 1.33 ( ) Smoking 0.67 ( ) 1.94 ( ) 2.38 ( ) Injection drug use NA 1.48 ( ) 5.82 ( ) Blood transfusion before 1991 NA No cases 5.51 ( ) Blood transfusion after 1992 NA No cases 2.04 ( ) NA, not available. Supplementary Table 3. Independent Predictors of Alcohol-Related Liver Disease Between 1988 and 2008 Male sex 1.59 ( ) 2.41 ( ) 2.70 ( ) Hypertension 2.19 ( ) 1.18 ( ) 2.05 ( ) Smoking 2.40 ( ) 3.67 ( ) 5.84 ( )