Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. Trends in Nonalcoholic Fatty Liver Disease–related Hospitalizations in US Children, Adolescents, and Young Adults à Corinna Koebnick, à Darios Getahun, à Kristi Reynolds, à Karen J. Coleman, y Amy H. Porter, à Jean M. Lawrence, z Mark Punyanitya, à Virginia P. Quinn, and à Steven J. Jacobsen à Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, { Baldwin Park Medical Center, Southern California Permanente Medical Group, Baldwin Park, CA, and { St. Luke’s-Roosevelt Hospital, Columbia University, NY, NY ABSTRACT Objective: To investigate temporal trends of nonalcoholic fatty liver disease (NAFLD) and obesity among hospitalized US children, adolescents, and young adults over the past 2 decades and to examine potential sex disparities in NAFLD hospitalizations. Methods: Hospitalization discharges with NAFLD or obesity were identified among children and young adults (6–25 years, weighted n ¼ 91,687,413) from the 1986 to 2006 National Hospital Discharge Survey data. Age- and sex-specific rates and trends in hospitalizations with NAFLD and obesity were estimated. Rates were standardized to age distribution of the 2000 US Census population. Sex disparities were examined for the most recent period 2004 to 2006 (weighted n ¼ 12,969,532). Results: Between 1986 to 1988 and 2004 to 2006, hospitalizations with NAFLD diagnosis increased from 0.9 to 4.3/100,000 population (P < 0.001). During the same time, hospitalizations with a diagnosis of obesity increased from 35.5 to 114.7/100,000 population (P < 0.001). During 2004 to 2006, hospitalization rates with a diagnosis of NAFLD were higher among females than among males (5.9 vs 2.7/ 100,000 population, P < 0.001), as were hospitalizations with a diagnosis of obesity (140.8 vs 61.5/100,000 population, P < 0.001). Obesity and diabetes were reported in 43.3% and 31.9%, respectively, of discharges with NAFLD. Conclusion: The prevalence of NAFLD among young hospitalized patients increased in the past 2 decades, paralleling obesity-related hospitalizations. This could be a consequence of the obesity epidemic or of increased screening for liver disease. JPGN 48:597–603, 2009. Key Words: Adults—Children—Hospitalizations—Nonalcoholic fatty liver disease—Obesity. # 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Nonalcoholic fatty liver disease (NAFLD) is charac- terized by an accumulation of fat in the liver (1,2) and is mainly attributed to obesity and insulin resistance (2,3). The pathological spectrum of NAFLD not only includes simple fatty liver (hepatic steatosis) but also hepatic fibrosis (steatohepatitis, NASH), and may progress to cirrhosis and hepatocellular carcinoma (4). More recent reports found an association between NAFLD and endo- thelial dysfunction and cardiovascular disease in adults (5,6) and carotid atherosclerosis in children (7). The prevalence estimates of NAFLD range from 0.7% in children ages 2 to 4 years to 17.3% in adolescents ages 15 to 19 years based on liver biopsies from autopsies (8). Results from the US National Health and Nutrition Examination Survey (NHANES 1999–2004) suggest a prevalence of NAFLD of 8% in adolescents ages 12 to 19 years based on elevated serum activity of the liver enzyme alanine aminotransferase (ALT) (9). Among obese children and adolescents, reports of NAFLD are significantly higher, with estimates ranging from about 10% (6) to 25% (10–12) based on elevated ALT com- pared with 42% to 77% based on ultrasound (10,11,13). Although obesity has become an increasingly import- ant public health problem, little is known about hospi- talization rates with a diagnosis of NAFLD among children, adolescents, and young adults. Therefore, the objectives of this study were to investigate temporal trends in hospitalizations with a diagnosis of NAFLD in US children, adolescents, and young adults during the last 2 decades and to examine whether NAFLD hospitalizations differ by sex in recent years. Further- more, we examined trends in hospitalizations with a Received August 29, 2008; accepted October 26, 2008. Address correspondence and reprint requests to Corinna Koebnick, PhD, Dept of Research and Evaluation, Kaiser Permanente Southern California, 100 Los Robles, 2nd Floor, Pasadena, CA 91101 (e-mail: Corinna.Koebnick@kp.org). This study was funded by Kaiser Permanente Direct Community Benefit Funds. The authors report no conflicts of interest. Journal of Pediatric Gastroenterology and Nutrition 48:597–603 # 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition 597 Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. diagnosis of obesity and other nonalcoholic chronic liver diseases. METHODS Study Design and Data Source We performed a temporal trend analysis using the National Hospital Discharge Survey (NHDS) data files for the years 1986 through 2006 inclusive. The study cohort consisted of children, adolescents, and young adults ages 6 to 25 years (weighted n ¼ 91,687,413). The NHDS 2004 to 2006 data were used to assess sex-specific differences in hospitalizations with mention of NAFLD (weighted n ¼ 12,969,532). The NHDS data files contain discharges from noninstitutional hospitals, excluding federal, military, and Veterans Affairs Medical Centers, located in 50 states and the District of Columbia. Only short-stay hospitals (hospitals with an average length of stay for all patients of less than 30 days) or those whose specialty is general (medical or surgical) or children’s general hospitals are included in the survey (14). The survey has been conducted annually by the National Center for Health Statistics since 1965. Starting with 1979 data, the NHDS has followed guidelines of the Uniform Hospital discharge dataset, which is a minimum dataset of items uniformly defined (15). NHDS data are weighted to reflect the US civilian, noninstitutionalized popu- lation. Estimates of the US civilian population are based on census figures provided by the US Bureau of the Census for each year (http://wonder.cdc.gov/population.html). In the NHDS dataset, people with multiple discharges during the year may be sampled more than once; therefore, all resulting estimates presented in this study are per discharge, not per person. Diagnosis Ascertainment Hospital discharges of children, adolescents, andyoung adults ages 6 to 25 years were extracted from the NHDS datasets. The NHDS dataset includes a maximum of 7 diagnoses. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes listed in the first through the seventh position were used to ascertain the following variables of interest: NAFLD (571.8); nonalcoholic chronic liver disease including NAFLD (571.8), chronic hepatitis (571.4), and nonalcoholic and biliary cirrhosis (571.5, 571.6), and other unspecified chronic liver dis- ease without mention of alcohol (571.9); and obesity (278.0). We also extracted diagnoses of hypertension (272.0–272.4), diabetes mellitus(250),disordersoflipidmetabolism(272.0,272.1,272.4), and cardiovascular disease (390–459). Alcohol-related disorders were defined as a listed diagnosis of any of the following ICD-9-CM codes: 291, 303,305, 980, V791, 944.6, 946.0– 946.3, 946.7–946.9, 571.0–571.3. For girls and young women, hospital discharges related to complications of pregnancy, child- birth, and normal delivery were defined as primary diagnosis of any of the following ICD-9-CM codes: 630–669, V27. Statistical Analysis The characteristics of all hospital discharges for the 3-year periods of 1986 to 1988 and 2004 to 2006 are presented to reflect changes over the observation period. Hospital discharges with diagnoses of NAFLD, nonalcoholic chronic liver diseases, and obesity were calculated per 100,000 population for each 3-year period to assess temporal trends. We combined years to improve stability of the annual estimates. Age-specific hospi- talization rates (per 100,000) were calculated using the 2000 US standard population. Sex disparities in hospitalizations with a diagnosis of NAFLD were analyzed for the most recent 3-year period (2004–2006). Estimates are provided for children and adolescents (6–18 years) and young adults (19–25 years). The distribution of NAFLD and nonalcoholic chronic liver disease between categories defined by sex or age group or both were compared using the x 2 test based on adjusted weights. The average length of hospital stay is given as mean and standard deviation (SD); hospital discharges with a length of less than 1 day were counted as 0.5 days. Student t test was used to compare length of stay between males and females. SPSS for Windows version 16.0 (SPSS Inc, Chicago, IL) was used for all analyses. We excluded those with a discharge diagnosis of NAFLD or other defined liver conditions that had an additional concurrent diagnosis suggesting alcohol abuse (excluded cases for NAFLD: 1986–2006 weighted n ¼ 813 and 2004–2006 weighted n ¼ 0, excluded cases for other nonalcoholic chronic liver disease: 1986–2006 weighted n ¼ 2490 and 2004–2006 weighted n ¼ 0). For secondary analysis on sex disparities, we excluded hospital discharges among females with a primary diagnosis related to complications of pregnancy, childbirth, and normal delivery (excluded discharges: 2004–2006 weighted n ¼ 5,749,465; 62.1% of all female discharges). RESULTS Discharge characteristics are similar between 1986 to 1988 and 2004 to 2006 with respect to sex, age group, and the number of pregnancy and delivery-related discharges (Table 1). The number of discharges with unknown race information, however, was higher in 2004 to 2006. Over the 2 decades of the study period, hospitalizations with a discharge diagnosis of NAFLD increased from 0.9 TABLE 1. Characteristics of hospital discharges 1986–1988 and 2004–2006 Variable 1986–1988 2004–2006 Weighted n 16,889,666 12,969,532 Male, % 30.4 28.6 Age group, % Children (6–11 y) 11.1 11.5 Adolescents (12–18 y) 27.8 27.9 Young adults (19–25 y) 61.1 60.7 Race, % White 66.4 55.0 Black 16.7 15.4 Other 5.2 5.1 Missing or unknown 11.7 24.5 Primary diagnosis of combined complications of pregnancy and childbirth, and deliveries (ICD-9-CM code 630–669, V27; %) 39.9 44.8 598 KOEBNICK ET AL. J Pediatr Gastroenterol Nutr, Vol. 48, No. 5, May 2009 Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. to 4.3/100,000 population among children, adolescents, and young adults combined (P ¼ 0.001, Fig. 1). During the same period, hospital discharges with a diagnosis of nonalcoholic chronic liver disease including NAFLD, chronic hepatitis, and nonalcoholic cirrhosis increased from 3.7 to 7.3/100,000 population. In the same 20-year period, hospital discharges with a diagnosis of obesity increased from 34.9 to 114.4/100,000 population (Fig. 1). In 1986 to 1988, 25.5% of hospitalizations with a discharge diagnosis of NAFLD also had a concurrent diagnosis of obesity compared with 43.3% in 2004 to 2006 (P < 0.001). A concurrent diagnosis of diabetes (including diabetes mellitus types 1 and 2) increased from 9.9% of NAFLD hospitalizations in 1986 to 1988 to 31.9% in 2004 to 2006 (P < 0.001). Although hospi- talizations with a NAFLD and a concurrent type 1 diabetes mellitus diagnosis remained relatively stable (9.9% vs 8.6%, respectively), NAFLD hospitalizations with a concurrent diagnosis of type 2 diabetes mellitus increased from 0% to 23.3% (P< 0.001). Hypertension as a concurrent discharge diagnosis was listed in 5.5% of NAFLD hospitalizations in 1986 to 1988 compared with 25.8% in 2004 to 2006 (P < 0.001). A concurrent diag- nosis of cardiovascular disease was reported in 13.2% of NAFLD hospitalizations in 1986 to 1988 compared with 29.1% in 2004 to 2006 (P < 0.001). No hospital dis- charges with a diagnosis of lipid metabolism disorders were reported in this specific population. We examined whether NAFLD and obesity hospital- ization rates differed by sex using the 2004 to 2006 dataset. Hospitalizations with a diagnosis of obesity were more frequent in females than in males (170.8 vs FIG. 1. Temporal trends in hospital discharges with mention of nonalcoholic fatty liver disease (NAFLD) and obesity in children, adolescents, and young adults (6–25 years) by 3-year period, 1986–2006. Age-specific rates are standardized to the 2000 US population. FIG. 2. Age-specific rates of hospital discharges with mention of nonalcoholic fatty liver disease (NAFLD), chronic hepatitis, or nonalcoholic cirrhosis by sex, 2004 to 2006. Age-specific rates are standardized to the 2000 US population. ÃÃà Rates are different with P < 0.001. NONALCOHOLIC FATTY LIVER DISEASE HOSPITALIZATIONS IN CHILDREN 599 J Pediatr Gastroenterol Nutr, Vol. 48, No. 5, May 2009 Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. 61.5/100,000 population, respectively, P < 0.001). NAFLD hospitalizations were also higher among females than among males (5.9 vs 2.7/100,000 population, P < 0.001). Because of the relative infrequency of NAFLD diagnosis, we were not able to differentiate between age groups by sex. Therefore, only data on nonalcoholic chronic liver disease including NAFLD, chronic hepatitis, and nonalcoholic cirrhosis are pre- sented. Hospital discharges with these diagnoses were also more common among females than among males (8.7 vs 6.0/100,000 population, P < 0.001, Fig. 2). Sex differences in hospitalizations with a discharge diagnosis of nonalcoholic chronic liver disease persisted among children and adolescents (7.2 vs 4.4/100,000 population, P ¼ 0.001) and young adults (11.5 vs 8.7/100,000 popu- lation, P ¼ 0.001). Estimates for children and adolescents may be unreliable due to the low number of NAFLD diagnoses (unweighted n for males was <60). In a secondary analysis, we excluded all discharges with a primary diagnosis related to complications of pregnancy, childbirth, and normal delivery (62.1% of all female discharges) for the most recent 3-year period (2004–2006). After exclusion of pregnancy and child- birth-related diagnosis, hospitalizations with a diagnosis of obesity were still more frequent in females than in males (125.0 vs 61.5/100,000 population, respectively, P < 0.001). Discharges with a diagnosis of NAFLD (5.5 vs 2.7/100,000 population, P < 0.001) and with a diag- nosis of nonalcoholic chronic liver disease including NAFLD, chronic hepatitis, and nonalcoholic cirrhosis (8.3 vs 6.0/100,000 population, P < 0.001) were also higher among females than among males after exclusion of pregnancy and childbirth-related diagnosis. Similarly, for discharges with a diagnosis of nonalcoholic chronic liver disease, the sex disparity persisted among children and adolescents (6.8 vs 4.4/100,000 population, P < 0.001) and young adults (11.0 vs 8.7/100,000 popu- lation, P < 0.001). For hospitalizations with mention of NAFLD in the years 2004 to 2006, the mean hospital length of stay was longer for males than for females (5.1 Æ 4.3 vs 3.1 Æ 1.9 days, P < 0.001). After exclusion of discharges with a primary diagnosis related to complications of pregnancy, childbirth, and normal delivery, the hospital length of stay for females remained essentially unaltered (3.1 Æ 2.0 days, P value for males vs females ¼ 0.001). For chronic liver disease, the hospital length of stay was 7.1 Æ 6.0 days for males and 4.5 Æ 4.3 days for females (P ¼ 0.003). The exclusion of discharges with a primary diagnosis related to complications of pregnancy, child- birth, and normal delivery resulted in a slight decrease in length of stay for females (3.5 Æ 2.8 days, P value for males vs females ¼ 0.005). Because the NHDS dataset includes a maximum of 7 diagnoses, we could underestimate hospital discharges with mention of NAFLD if NAFLD were coded in the eighth or higher position. Therefore, we further investi- gated the mean number of diagnoses and the frequency of discharges with 7 diagnoses. The mean number of given diagnoses increased from 2.3 Æ 1.4 in 1986 to 1988 to 3.7 Æ 1.9 in 2004 to 2006, with 2.0% and 13.8% of discharges containing the maximum of 7 diagnoses, respectively (P < 0.001). DISCUSSION Paralleling the obesity epidemic, hospital discharges with an associated diagnosis of NAFLD increased sig- nificantly during the last 2 decades. More than 40% of these discharges also had a concurrent diagnosis of obesity. Similar to obesity-related hospitalizations, hos- pitalizations with mention of NAFLD, nonalcoholic hepatitis, and cirrhosis were more frequent in female than in male children, adolescents, and young adults. During the past decade, the number of publications on NAFLD and NASH has increased dramatically, reflecting a growing interest in and awareness of these diseases (16). The revised 2007 Expert Committee recommen- dations on the assessment, prevention, and treatment of child and adolescent overweight and obesity now include screening the recommendations for NAFLD (17), a con- dition that was not included in the 1998 recommen- dations (18). The growing evidence that supported these recommendations may have contributed to the increasing number of hospitalizations with a diagnosis of NAFLD and other liver diseases associated with obesity. Although adult men and women in the United States have a similar prevalence of obesity (19), previous studies have shown that hospitalized women were more likely to have a diagnosis of obesity than hospitalized men (20). In a recent report based on data from the Healthcare Cost and Utilization Project (HCUP) Nation- wide Inpatient Sample (NIS), about 82% of patients with a principal diagnosis of obesity and 64% of patients with a secondary diagnosis of obesity were female (20). In that report, about 0.4% of patients with a principal diagnosis of obesity and 1.6% of patients with a secondary diag- nosis of obesity were younger than 18 years of age (20). However, the report included discharges with a primary diagnosis related to complications of pregnancy, child- birth, and normal delivery, which may make females more likely to be hospitalized with a diagnosis of obesity. Similar to adults, the prevalence of obesity (defined as above 95th percentile of body mass index for age) among children and adolescents in the United Staes is similar for boys and girls; about 16% of girls ages 6 to 11 years and 17% of girls ages 12 to 19 years were obese compared with 18% of boys in both age groups (21). The NHDS data for children, adolescents, and young adults show a similar trend as that observed in the HCUP data for all age groups combined (20), with more hospitalizations with a diagnosis of obesity in females than in males. 600 KOEBNICK ET AL. J Pediatr Gastroenterol Nutr, Vol. 48, No. 5, May 2009 Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. Comparable to hospitalizations with a diagnosis of obesity, our analyses of the NHDS data also demon- strated that female children, adolescents, and young adults are more likely to be hospitalized with an associ- ated discharge diagnosis of NAFLD, nonalcoholic chronic hepatitis, and cirrhosis than were males. This holds true even after exclusion of discharges with a primary diagnosis related to complications of pregnancy, childbirth, and normal delivery (more than 60% of female discharges). The prevalence of NAFLD has been shown to be higher in boys than in girls in many (9,11,22–36) but not all screening studies (10,13,37–39). Some studies used ALT as a surrogate marker for NAFLD (9,11, 23,25,27,29,31,34,36,37,39) and therefore may be sub- ject to misclassification due to the cutoff values for ALT used. It has been suggested that the normal range of some liver enzymes including ALT is higher in boys than in girls (40). Consequently, the cutoff value can lead to an overestimation of the NAFLD prevalence in boys or an underestimation in girls. However, a higher prevalence of NAFLD among boys compared with girls was also confirmed by other studies, which based the diagnosis of NAFLD on ultrasound (24,27–29,33,35), liver biopsy (22,26,30,32,39), and magnetic resonance imaging (23). The higher prevalence among boys is fairly consistent across most studies, regardless of study design. Sex hormones have been suggested to play a role in the development of NAFLD (31,41), but results from pub- lished studies are controversial and the potential mech- anisms are unclear. In mice, estrogen deficiency has been shown to promote progressive accumulation of fat in liver (42), and estrogen replacement reversed liver steatosis (43). However, estrogen supplementation did not yield any protective effect on diet-induced steatohepatitis (44). In the present study, hospitalizations with a diagnosis of NAFLD were more frequent in female than in male children, adolescents, and adults. These results may not contradict previous findings because findings based on hospitalization discharges may reflect more pro- nounced symptoms or more frequent screening or both in females. Our findings are comparable to the asso- ciation between the rates of obesity-related hospital discharges and the obesity prevalence across sexes (20). The high prevalence of autoimmune hepatitis among females, which is often diagnosed at ages 10 to 30 years, may partially explain a higher number of discharges with a diagnosis of chronic liver disease. However, auto- immune hepatitis is unlikely to explain the higher preva- lence of hospital discharges with a diagnosis of NAFLD among females. Strengths of the study are the large sample size of the NHDS dataset and the population-based study design enabling us to look at temporal trends of several decades. The NHDS is a nationally representative sample of inpatient discharges. The hospital response rate for this survey is around 90% in recent years, discharges are weighted and adjusted for nonresponse (14,45). We also addressed discharges with a primary diagnosis related to complications of pregnancy, childbirth, and normal deliv- ery, which may make females more likely to be hospi- talized and thus bias our results. However, our study has several limitations. First, our estimates may be unreliable for some subgroups, particu- larly among male subjects, due to the relative infrequency of hospital discharges with a diagnosis of NAFLD in this particular age group. Our findings are also based on hospital discharges and not individuals. Therefore, people with multiple discharges during 1 year were counted more than once. We were also not able to assess racial and ethnic differences in hospital-discharged patients with NAFLD. The NHDS includes a maximum of 7 ICD-9-CM codes per discharge; the first diagnosis corresponds to the primary diagnosis associated with the discharge. NAFLD or obesity may have been considered a minor diagnosis compared with other diagnoses and, therefore, may have been undercoded in this dataset. We can also not exclude the possibility that NAFLD was more likely to be coded among diagnoses 1 through 7 in recent years compared with earlier years due to increas- ing awareness of potential NAFLD in children, adoles- cents, and young adults. However, most discharges used for this analysis had fewer than the maximum of 7 diag- noses. Finally, underdiagnosis among males may be leading to our differential findings by sex. Obesity constitutes a serious and challenging health risk for children and adolescents. Childhood and adoles- cent obesity results in higher mortality (46), higher general morbidity (47), as well as higher risk for NAFLD (2,3), cardiovascular disease (48–50), and colorectal cancers (46,47). Insulin resistance, changes in adipose tissue hormones, such as leptin and adiponectin, earlier leptin activation of the hypothalamic–pituitary axis resulting in initiation and progress of puberty, and the presence of other features of the metabolic syndrome associated with increased adiposity may be held respon- sible for the increased mortality (51–53). Although NAFLD is associated with obesity, recent studies suggest that NAFLD is an independent risk factor for cardiovascular (5–7) and chronic kidney disease (54). NAFLD may progress to more severe disease states including end-stage liver disease and hepatocellular car- cinoma (4). The increasing number of hospitalizations with a diagnosis of NAFLD among children, adolescents, and young adults is alarming. Further studies are needed to gather more information on the progression of NAFLD to more severe diseases such as liver cirrhosis. The prevalence of NAFLD among hospitalized chil- dren, adolescents, and young adults increased in the past 2 decades, paralleling the trends in obesity-related hos- pitalizations. This could be a consequence of the obesity epidemic or of increased screening for liver disease. NONALCOHOLIC FATTY LIVER DISEASE HOSPITALIZATIONS IN CHILDREN 601 J Pediatr Gastroenterol Nutr, Vol. 48, No. 5, May 2009 Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. Detection and early treatment of NAFLD may prevent adverse health effects associated with NAFLD such as cardiovascular disease and end-stage liver disease. REFERENCES 1. Barshop NJ, Sirlin CB, Schwimmer JB, et al. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;28:13–24 . 2. Schreuder TC, Verwer BJ, van Nieuwkerk CM, et al. Nonalcoholic fatty liver disease: an overview of current insights in patho- genesis, diagnosis and treatment. World J Gastroenterol 2008; 14:2474–86 . 3. Adams LA, Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol 2007;17:863–9 . 4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221–31 . 5. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunc- tion and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005;42:473–80 . 6. Targher G, Arcaro G. Non-alcoholic fatty liver disease and in- creased risk of cardiovascular disease. Atherosclerosis 2007; 191:235–40 . 7. Pacifico L, Cantisani V, Ricci P, et al. Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Pediatr Res 2008;63:423–7 . 8. Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388–93 . 9. Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999–2004. Gastroenterology 2007;133:1814–20 . 10. Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diag- nosis and during follow-up in an Italian population. Dig Dis Sci 1997;42:1428–32 . 11. Guzzaloni G, Grugni G, Minocci A, et al. Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochem- ical parameters and glycemic and insulinemic responses to an oral glucose tolerance test. IntJObesRelatMetabDisord2000; 24:772–6 . 12. Tazawa Y, Noguchi H, Nishinomiya F, et al. Serum alanine aminotransferase activity in obese children. Acta Paediatr 1997;86:238–41 . 13. Chan DF, Li AM, Chu WC, et al. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord 2004;28:1257–63 . 14. Dennison CF, Pokras R. Design and operation of the National Hospital Discharge Survey: 1988 redesign. Available from: http:// www.cdc.gov/nchs/data/series/sr_01/sr01_039.pdf. National Cen- ter for Health Statistics; 2000. 15. Department of Health and Human Services. Health Information Policy council: 1984 Revision of the Uniform Hospital Discharge Data Set. Federal Register 1985;31:50. 16. Charlton M. Cirrhosis and liver failure in nonalcoholic fatty liver disease: molehill or mountain? Hepatology 2008;47:1431–3 . 17. Barlow SE. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 2007;120 (Suppl 4):S164–92 . 18. Barlow SE, Dietz WH. Obesity evaluation and treatment: Expert Committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics 1998; 102:E29 . 19. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006; 295:1549–55 . 20. Elixhauser A, Steiner C. Obese Patients in U.S. Hospitals, 2004. Rockville, MD: Agency for Healthcare Research and Quality; 2006. Report No.: http://www.hcup-us.ahrq.gov/reports/statbriefs/ sb20.pdf. 21. Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003–2006. JAMA 2008; 299:2401–5 . 22. Baldridge AD, Perez-Atayde AR, Graeme-Cook F, et al. Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr 1995;127:700–4 . 23. Burgert TS, Taksali SE, Dziura J, et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 2006;91:4287–94 . 24. Damaso AR, do Prado WL, de PA, et al. Relationship between nonalcoholic fatty liver disease prevalence and visceral fat in obese adolescents. Dig Liver Dis 2008;40:132–9 . 25. Imhof A, Kratzer W, Boehm B, et al. Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur J Epidemiol 2007;22:889–97 . 26. Kinugasa A, Tsunamoto K, Furukawa N, et al. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr 1984;3:408–14 . 27. Manton ND, Lipsett J, Moore DJ, et al. Non-alcoholic steatohe- patitis in children and adolescents. Med J Aust 2000;173:476–9 . 28. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000;30:48–53 . 29. Sartorio A, Del CA, Agosti F, et al. Predictors of non-alcoholic fatty liver disease in obese children. Eur J Clin Nutr 2007;61:877– 83 . 30. Schwimmer JB, Deutsch R, Rauch JB, et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr 2003;143:500–5 . 31. Schwimmer JB, McGreal N, Deutsch R, et al. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics 2005;115:e561–5 . 32. Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388– 93 . 33. Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995;40:2002–9 . 34. Yoo J, Lee S, Kim K, et al. Relationship between insulin resistance and serum alanine aminotransferase as a surrogate of NAFLD (nonalcoholic fatty liver disease) in obese Korean children. Dia- betes Res Clin Pract 2008;81:321–6 . 35. Zhou YJ, Li YY, Nie YQ, et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastro- enterol 2007;13:6419–24 . 36. Tsai PY, Yen CJ, Li YC, et al. Association between abnormal liver function and risk factors for metabolic syndrome among freshmen. J Adolesc Health 2007;41:132–7 . 37. Quiros-Tejeira RE, Rivera CA, Ziba TT, et al. Risk for nonalcoholic fatty liver disease in Hispanic youth with BMI > or ¼95th percentile. J Pediatr Gastroenterol Nutr 2007;44:228–36 . 38. Radetti G, Kleon W, Stuefer J, et al. Non-alcoholic fatty liver disease in obese children evaluated by magnetic resonance imaging. Acta Paediatr 2006;95:833–7 . 39. Zou CC, Liang L, Hong F, et al. Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr J 2005;52:519–24 . 40. Lockitch G, Halstead AC, Albersheim S, et al. Age- and sex-specific pediatric reference intervals for biochemistry analytes as measured with the Ektachem-700 analyzer. Clin Chem 1988; 34:1622–5 . 41. Patton HM, Sirlin C, Behling C, et al. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implica- tions for future research. J Pediatr Gastroenterol Nutr 2006;43:413– 27 . 602 KOEBNICK ET AL. J Pediatr Gastroenterol Nutr, Vol. 48, No. 5, May 2009 Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. 42. Paquette A, Shinoda M, Rabasa LR, et al. Time course of liver lipid infiltration in ovariectomized rats: impact of a high-fat diet. Maturitas 2007;58:182–90 . 43. Hewitt KN, Pratis K, Jones ME, et al. Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology 2004;145:1842–8 . 44. Kashireddy PR, Rao MS. Sex differences in choline-deficient diet- induced steatohepatitis in mice. Exp Biol Med (Maywood) 2004;229:158–62 . 45. DeFrances CJ, Hall MJ. 2005 National Hospital Discharge Survey. Adv Data 2007;12:1–19 . 46. Bjorge T, Engeland A, Tverdal A, et al. Body mass index in adolescence in relation to cause-specific mortality: a follow-up of 230,000 Norwegian adolescents. Am J Epidemiol 2008;168:30–7 . 47. Must A, Jacques PF, Dallal GE, et al. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992;327:1350–5 . 48. Baker JL, Olsen LW, Sorensen TI. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 2007;357:2329–37 . 49. Bibbins-Domingo K, Coxson P, Pletcher MJ, et al. Adolescent overweight and future adult coronary heart disease. N Engl J Med 2007;357:2371–9 . 50. Lawlor DA, Martin RM, Gunnell D, et al. Association of body mass index measured in childhood, adolescence, and young adulthood with risk of ischemic heart disease and stroke: findings from 3 historical cohort studies. Am J Clin Nutr 2006;83: 767–73 . 51. Guilherme A, Virbasius JV, Puri V, et al. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 2008;9:367–77 . 52. Jasik CB, Lustig RH. Adolescent obesity and puberty: the ‘‘perfect storm’’. Ann N Y Acad Sci 2008;1135:265–79 . 53. Vincent RP, Ashrafian H, le Roux CW. Mechanisms of disease: the role of gastrointestinal hormones in appetite and obesity. Nat Clin Pract Gastroenterol Hepatol 2008;5:268–77 . 54. Targher G, Bertolini L, Rodella S, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008;51:444–50 . NONALCOHOLIC FATTY LIVER DISEASE HOSPITALIZATIONS IN CHILDREN 603 J Pediatr Gastroenterol Nutr, Vol. 48, No. 5, May 2009 . nonalcoholic fatty liver disease (NAFLD) and obesity among hospitalized US children, adolescents, and young adults over the past 2 decades and to examine potential. adolescents, and young adults. During the past decade, the number of publications on NAFLD and NASH has increased dramatically, reflecting a growing interest in and