Trends in Nonalcoholic Fatty Liver Disease–related Hospitalizations in US Children, Adolescents, and Young Adults Corinna Koebnick, Darios Getahun, Kristi Reynolds, Karen J.. Luke’s-Roos
Trang 1Trends in Nonalcoholic Fatty Liver Disease–related Hospitalizations in US Children, Adolescents, and Young Adults
Corinna Koebnick, Darios Getahun, Kristi Reynolds, Karen J Coleman, yAmy H Porter,
Jean M Lawrence, zMark Punyanitya, Virginia P Quinn, and Steven J Jacobsen
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 n¼ 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 n¼ 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.
Trang 2diagnosis 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
n¼ 91,687,413) The NHDS 2004 to 2006 data were used to
assess sex-specific differences in hospitalizations with mention
of NAFLD (weighted n¼ 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, and young 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),disorders oflipidmetabolism (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 x2test 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 n¼ 813 and 2004–2006 weighted n¼ 0, excluded cases for other nonalcoholic chronic liver disease: 1986–2006 weighted n¼ 2490 and 2004–2006 weighted n¼ 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
n¼ 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
Weighted n 16,889,666 12,969,532
Age group, %
Adolescents (12–18 y) 27.8 27.9 Young adults (19–25 y) 61.1 60.7 Race, %
Primary diagnosis of combined complications of pregnancy and childbirth, and deliveries (ICD-9-CM code 630–669, V27; %)
39.9 44.8
Trang 3to 4.3/100,000 population among children, adolescents,
and young adults combined (P¼ 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.Rates are different with P < 0.001.
Trang 461.5/100,000 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,
P¼ 0.001) and young adults (11.5 vs 8.7/100,000
popu-lation, P¼ 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 4.3 vs 3.1 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 2.0
days, P value for males vs females¼ 0.001) For chronic
liver disease, the hospital length of stay was 7.1 6.0
days for males and 4.5 4.3 days for females
(P¼ 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 2.8 days, P value for
males vs females¼ 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 1.4 in 1986 to 1988 to 3.7 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
Trang 5Comparable 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
Trang 6Detection and early treatment of NAFLD may prevent
adverse health effects associated with NAFLD such as
cardiovascular disease and end-stage liver disease
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