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O R I G I N A L A R T I C L E

Increasing Burden of Chronic Liver Disease Among Adolescents and Young Adults in the USA: A Silent Epidemic

Iliana Doycheva1 • Kymberly D. Watt2 • Ghassoub Rifai3 • Rachel Abou Mrad3 •

Rocio Lopez4 • Nizar N. Zein3 • William D. Carey3 • Naim Alkhouri3,5

Received: 18 November 2016 / Accepted: 6 February 2017 / Published online: 13 February 2017

� Springer Science+Business Media New York 2017

Abstract

Background and Aims Chronic liver disease (CLD) starts

or becomes established in the adolescent and young adult

(AYA) age group. This study aimed to estimate trends in

CLD prevalence among US AYAs and to assess factors

associated with CLD.

Methods Cross-sectional data from 14,547 AYAs (popu-

lation-weighted N = 68,274,386) aged 15–39 years enrol-

led in the National Health and Nutrition Examination

Survey from 1988 to 2012 were used. Nonalcoholic fatty

liver disease (NAFLD) was defined as elevated alanine

aminotransferase ([19 U/L for females and [30 U/L for males) in subjects with BMI C 25 kg/m

2 ; alcoholic liver

disease (ALD) as excessive alcohol use (C3 drinks/day for

men and C2 drinks/day for women) and elevated amino-

transferases after excluding alternative etiologies.

Participants were considered hepatitis C virus (HCV)

positive if antibody to HCV and HCV-RNA was positive.

Results There was a sharp increase in the prevalence of

CLD from 12.9% in 1988–1994 to 28.5% in 1999–2004

that remained stable after that (27.7%). NAFLD was the

most common etiology accounting for 22% of all CLD in

the later period. The prevalence of ALD has been steadily

increasing throughout the years, while HCV has been

decreasing. On multivariate analysis, being overweight/

obese, Mexican–American ethnicity, later study period,

older age, and male gender, were associated with higher

odds of having CLD.

Conclusion More than one quarter of US AYAs might be

affected by CLD. CLD prevalence in this age group has

more than doubled over the past three decades mainly due

to rise in NAFLD prevalence.

Keywords Young population � Nonalcoholic fatty liver disease � Obesity � Alcoholic liver disease � Hepatitis CElectronic supplementary material The online version of this

article (doi:10.1007/s10620-017-4492-3) contains supplementary material, which is available to authorized users.

& Naim Alkhouri [email protected]

Iliana Doycheva

[email protected]

Kymberly D. Watt

[email protected]

Ghassoub Rifai

[email protected]

Rachel Abou Mrad

[email protected]

Rocio Lopez

[email protected]

Nizar N. Zein

[email protected]

William D. Carey

[email protected]

1 Division of Gastroenterology and Hepatology, Medical

University, Sofia, Bulgaria

2 Gastroenterology and Hepatology Department, Mayo Clinic,

Rochester, MN, USA

3 Digestive Disease Institute, Cleveland Clinic, Cleveland, OH,

USA

4 Department of Quantitative Health Sciences, Lerner Research

Institute, Cleveland Clinic, Cleveland, OH, USA

5 Department of Pediatric Gastroenterology and Hepatology,

Cleveland Clinic Children’s Hospital, 9500 Euclid Avenue,

A-111, Cleveland, OH 44195, USA

123

Dig Dis Sci (2017) 62:1373–1380

DOI 10.1007/s10620-017-4492-3

Abbreviations

ALD Alcoholic liver disease

ALT Alanine aminotransferase

AST Aspartate aminotransferase

AYA Adolescent and young adult

BMI Body mass index

CI Confidence interval

CLD Chronic liver disease

HCV Hepatitis C virus

IDU Injection drug user

NAFLD Nonalcoholic fatty liver disease

NHANES National Health and Nutrition Examination

Survey

OR Odds ratio

Introduction

Adolescents and young adults (AYAs) aged 15–39 years

constitute approximately one-third of the American popu-

lation equating over 103 million people [1]. Risk factors

arising during these years of age have a great impact for

development of chronic liver disease (CLD) and its pro-

gression later in life. Among the most important ones is

obesity that remains high (34% of young adults aged

20–39 years) [2] mainly due to unhealthy diet and

decreased physical activity and plays a pivotal role for

development of nonalcoholic fatty liver disease (NAFLD).

High prevalence of binge and heavy drinking in youth and

college students [3] can eventually lead to development of

alcoholic liver disease (ALD) and accelerates progression

of CLD with alternative etiologies. Despite noted decline

in the prevalence of hepatitis C virus (HCV) infection

among injection drug users (IDUs) aged \39 years between 1998 and 2008 [4], more recent data for the period

2006–2012 indicate an alarming overall increase in acute

HCV infection in young IDUs (B30 years age), especially

among white residents of nonurban areas [5, 6].

Acquisition and progression of CLD in AYAs is largely

underestimated and often remains unrecognized. Young

persons are less likely to seek medical care, often lack

health insurance, and are unaware of risks of CLD and

available preventive programs. This leads to delayed

diagnosis and lack of timely management and predisposes

AYAs to silent progression, eventually resulting in

advanced liver disease in middle and late-middle age. This

could be one of the reasons for the highest mortality rate

from CLD and cirrhosis in 55- to 64-year-old persons over

the last decade [7]. Therefore, the purpose of this study was

to estimate changes in overall CLD prevalence among US

AYAs over the past three decades and trends in the

prevalence of its major etiologies: NAFLD, ALD, and

HCV. We also aimed to determine risk factors associated

with CLD in AYAs.

Methods

Study Design and Study Cohort

This is a cross-sectional analysis of nationally representa-

tive data for subjects who were 15–39 years old at the time

of enrollment in the National Health and Nutrition Exam-

ination Survey (NHANES) III 1988–1994 and continuous

NHANES 1999–2012. The NHANES is an ongoing, pop-

ulation-based health and nutrition survey of the civilian,

noninstitutionalized US population. The methods and study

design of NHANES have been previously described [8].

For analyses purposes, cycles were grouped into three

periods: 1988–1994, 1999–2004, and 2007–2012. Partici-

pants were excluded if there was missing information on

alcohol use, hepatitis B or hepatitis C status, body mass

index (BMI), alanine aminotransferase (ALT), aspartate

aminotransferase (AST), or lack of information on hepa-

totoxic medications use (Supplementary Table 1).

Definitions

NAFLD was defined as elevated ALT ([19 U/L for females and [30 U/L for males) in subjects with BMI C 25 kg/m

2 in the absence of chronic viral hepatitis

(B or C) and lack of excessive alcohol use and hepatotoxic

medications (steroids, lipid-lowering or antituberculous

drugs used for prevention or treatment). ALD was defined

as excessive alcohol use (C3 drinks/day for men and C2

drinks/day for women in the past year) and elevated ALT

or AST ([31 U/L for females and [37 U/L for males) in the absence of viral hepatitis (B or C) and no hepatotoxic

medications. Average daily alcohol consumption was cal-

culated using the formula: average number of drinks on

drinking days 9 average number of drinking days over the

past year/365. Diagnosis of hepatitis B virus (HBV) was

accepted if the participant had positive hepatitis B surface

antigen (HBsAg). If hepatitis C antibody (anti-HCV Ab)

was indeterminate or positive, then HCV-RNA was

checked and if positive, participant was considered to have

HCV infection.

Statistical Analysis

Data are presented as mean or percentage ± standard error.

Regression analysis was used to assess trends across the

different time periods. Linear and polynomial regression

1374 Dig Dis Sci (2017) 62:1373–1380

123

was assessed, and the most appropriate functional form for

the trend was assessed by examination of regression

diagnostic plots. In addition, logistic regression analysis

was used to determine factors associated with CLD and to

evaluate risk over time. All analyses were performed using

SAS survey procedures (version 9.4, The SAS Institute,

Cary, NC), which account for the complex sampling design

of NHANES and appropriately weight participants in sta-

tistical models. Since we combined different NHANES

cycles, combined weights were calculated following the

instructions provided in the NHANES analytic guidelines

[9].

Results

Participant Characteristics

A total of 14,547 participants (population-weighted

N = 68,274,386) for all three periods were included in the

study. Table 1 summarizes demographic and clinical

characteristics of the included subjects (Table 1).

There was no significant difference in age, gender, and

excessive alcohol use between the study periods, but pos-

itive trend in increasing BMI and higher proportion of

overweight, obese, and severely obese subjects were noted

over the course of three periods. For example, the mean

BMI in the first period from 1988 to 1994 was

25.5 ± 0.15 kg/m 2

compared to 27.8 ± 0.16 kg/m 2

(P \ 0.001) for the last period from 2007 to 2012. Simi- larly, the prevalence of obesity in the first period was at

17% compared to 29.8% in the last period.

Prevalence of Chronic Liver Disease in AYAs

There was a steep rise in the overall prevalence of CLD in

AYAs from 1988–1994 to 1999–2004 [12.9%; 95% con-

fidence interval (CI), 10.5–15.2 to 28.5%; 95% CI

26.6–30.4%] that subsequently leveled off in the

2007–2012 period (27.7%; 95% CI 25.7–29.6%) (Fig. 1).

NAFLD was by far the most common etiology of CLD

accounting for 22.2% (95% CI 20.3–24.1%) of all CLD in

the last period and showing the same pattern of increase as

total CLD. In comparison, ALD has been slowly and

steadily increasing throughout the years, affecting 5.1% of

AYAs in 2007–2012 period, while HCV has significantly

decreased from 1.8 to 0.36% between the first and last

periods. The overall prevalence of HBV was very low

(0.1%) among AYAs, and this was the reason we did not

include in further analyses.

On stratified analyses, similar trends of increase for

overall CLD, NAFLD, and ALD and decrease in HCV

were observed among both sexes, all ethnic groups, and in

overweight and obese subjects, except stable ALD in non-

Hispanic Black participants and not statistically significant

decrease in HCV in non-Hispanic Whites (Table 2).

Additionally, there was no change in CLD, NAFLD, and

ALD prevalence among severely obese subjects.

The prevalence of CLD among young Mexican–Amer-

icans was 41.1% in the latest period. Similar to the entire

cohort, NAFLD and ALD increased and HCV decreased in

this cohort (Supplementary Table 2). The prevalence of

NAFLD has more than doubled over the studied periods

(from 15.4% in 1988–1994 to 33.5% in 2007–2012,

P \ 0.001) and paralleled the increased rate of overweight/ obesity in this subgroup. There was no association between

age, gender, and being overweight/obese and CLD across

periods (P [ 0.15 for all).

Risk Factors for Chronic Liver Disease in AYAs

On multivariate logistic regression analysis, being over-

weight or obese was the strongest predictor of CLD diag-

nosis [odds ratio (OR) 13.6; 95% CI 11.2–16.5].

Participants in later study periods (1999–2004 and

2007–2012) had a twofold increase in the risk of having

CLD compared to participants in the earlier study period

(1988–1994). In terms of ethnicity and compared to Cau-

casians, being Mexican–American was associated with an

increased risk of CLD (OR 1.6; 95% CI 1.3–1.8,

P \ 0.001) while being non-Hispanic Black seemed pro- tective (OR 0.64; 95% CI 0.56–0.73), P \ 0.001). Other risk factors for CLD in AYAs were male gender and older

age (Table 3).

Subgroup analyses by gender, weight, and ethnicity

demonstrated the same risk factors for CLD with the

exception of subjects with normal weight where older age

was the only risk factor and male gender seemed protective

(Supplementary Table 3). Among White participants, older

age and male gender were not risk factors.

Discussion

In this study, we have used the nationally representative

data of NHANES to estimate the prevalence and analyze

trends of overall CLD and its major etiologies in US AYAs

over the last three decades. We found that more than one

quarter of AYAs might be affected by CLD and the

prevalence has more than doubled over the past three

decades. This increase is mainly due and mirrors a steep

rise of NAFLD in this age group.

Over the last decades, the surge in obesity and metabolic

syndrome in all age groups played a key role for NAFLD

development and expectedly was the leading etiology of

CLD in our study. Potential major contributors for this

Dig Dis Sci (2017) 62:1373–1380 1375

123

finding were the significant increase in overweight and

obese subjects over the three studied NHANES periods and

twice as high proportion of Mexican–American partici-

pants (that also included all persons of Hispanic ethnicity

for the 2007–2010 study period) [9] in the last compared to

first period. Similarly, a 2.5-fold increase in NAFLD

prevalence among subjects 18–35 years old (9.6% in

1988–1994 to 24% in 2005–2010) was demonstrated in a

recent analysis using the same definition of NAFLD [10].

Notably, cirrhosis due to nonalcoholic steatohepatitis has

progressively risen from 2001 to 2012 as an indication for

liver transplantation in young adults \40 years [11] and has become the second most common indication for liver

transplantation in all US adults [12]. In addition to liver-

related complications, NAFLD in young people has been

associated with a variety of metabolic and cardiovascular

abnormalities that could potentially increase their risk of

cardiovascular morbidity and mortality later in life [13].

We have observed a stable CLD prevalence over the

latter two time periods, which likely reflects the steady

NAFLD prevalence during these years. A possible expla-

nation is the raised concern of growing obesity epidemic in

the USA at the beginning of the twenty-first century [14]

and ensuing development of several health initiatives:

labeling of food products, decreased portion sizes, addi-

tional taxation of sugar-sweetened beverages, and price

incentive on healthy food [15]. Given the greatest weight

gain among AYAs was observed at the age of early to mid-

twenties [16], the Early Adult Reduction of weight through

LifestYle intervention (EARLY) Trials for AYAs 18–35 of

age was funded in 2009 [17]. Additionally, between 2000

and 2010, a greater than 40% increase was noted in adults

that had been advised by their physician to exercise or do

other physical activity as part of the Healthy People 2020

goals [18].

Table 1 Demographic and clinical characteristics of study participants by NHANES period

Characteristics 1988–1994 1999–2004 2007–2012 P value trend

n = 23,884,136 n = 22,071,277 n = 22,318,973

Age (years) 28.9 ± 0.18 29.7 ± 0.17 28.9 ± 0.18 0.77

Male 12,366,883 (51.8) 11,105,983 (50.3) 11,509,320 (51.6) 0.82

Race

White (non-Hispanic) 18,071,915 (75.7) 14,582,811 (66.1) 13,435,450 (60.2) \0.001 Black (non-Hispanic) 2,604,988 (10.9) 2,566,016 (11.6) 2,693,674 (12.1) 0.39

Mexican–American 1,534,358 (6.4) 2,439,629 (11.1) 2,747,971 (12.3) \0.001 Other race 1,672,874 (7.0) 2,482,821 (11.2) 3,441,878 (15.4) \0.001 BMI (kg/m

2 ) 25.5 ± 0.15 27.3 ± 0.14 27.8 ± 0.16 \0.001

Overweight a

10,743,585 (45.0) 12,649,334 (57.3) 13,514,767 (60.6) \0.001 Obese

a 4,053,499 (17.0) 5,937,754 (26.9) 6,642,869 (29.8) \0.001

Severely obese a

491,571 (2.1) 1,059,136 (4.8) 1,242,429 (5.6) \0.001 Avg. daily alcohol consumption 0.68 ± 0.03 0.50 ± 0.03 0.52 ± 0.02 \0.001 Excessive alcohol use 3,902,364 (16.3) 2,394,244 (10.8) 3,136,496 (14.1) 0.063

ALT (U/L) 18.5 ± 0.46 26.5 ± 0.72 25.5 ± 0.32 \0.001 AST (U/L) 21.2 ± 0.21 23.9 ± 0.31 24.6 ± 0.20 \0.001

Values presented as mean ± standard error or weighted frequency (%)

ALT alanine aminotransferase, AST aspartate aminotransferase, BMI body mass index a

Overweight was defined as BMI of 25–29.9 kg/m 2 ; obese—BMI of 30–39.9 kg/m

2 ; severely obese—BMI C 40 kg/m

2

Fig. 1 Trends in overall CLD prevalence and its major etiologies among US AYAs, NHANES III 1988–1994 to NHANES 1999–2004,

and NHANES 2007–2012. The estimated prevalence in % is

presented above each bar. Error bars indicate the 95% confidence

intervals

1376 Dig Dis Sci (2017) 62:1373–1380

123

Binge drinking is the most common pattern of alcohol

use among US adolescents and young adults 18–25 years

[3], which puts them at risk of becoming heavy drinkers

later in life and subsequently to develop ALD [19].

Although a linear decrease in current alcohol use in youth

has been noted from 1991 to 2015 [3], we observed a

steady, continuous rise of ALD prevalence in AYAs over

the last two decades, which might be reflecting the con-

sequences of previous higher use. Likewise, in the general

population, a 45% increase in ALD as an indication for LT

Table 2 CLD prevalence among AYAs in the three

studied NHANES periods

Characteristics 1988–1994 1999–2004 2007–2012 P value trend

CLD (HCV, ALD and NAFLD)

All AYAs 12.9 (10.5–15.2) 28.5 (26.6–30.4) 27.7 (25.7–29.6) \0.001 Male 15.2 (11.9–18.4) 30.9 (28.2–33.6) 30.2 (27.8–32.7) \0.001 Female 10.4 (8.2–12.6) 26.1 (23.9–28.2) 24.9 (22.5–27.3) \0.001 White (non-Hispanic) 12.0 (9.1–14.8) 28.1 (25.4–30.7) 26.6 (23.9–29.4) \0.001 Black (non-Hispanic) 13.8 (12.1–15.5) 22.8 (19.8–25.8) 20.0 (17.3–22.6) \0.001 Mexican–American 21.6 (18.3–24.9) 39.4 (35.7–43.1) 41.1 (37.4–44.9) \0.001 Overweight 24.2 (20.7–27.7) 46.4 (43.9–49.0) 42.8 (40.5–45.1) \0.001 Obese 31.7 (27.0–36.5) 52.6 (49.3–55.9) 52.1 (48.5–55.7) \0.001 Severely obese 49.6 (35.7–63.5) 57.1 (48.8–65.4) 57.3 (48.8–65.7) 0.4

NAFLD

All AYAs 8.8 (7.2–10.3) 23.5 (22.0–25.0) 22.2 (20.3–24.1) \0.001 Male 10.6 (8.5–12.7) 26.6 (24.3–28.9) 26.0 (23.8–28.3) \0.001 Female 6.8 (5.2–8.4) 20.3 (18.4–22.2) 18.1 (15.7–20.6) \0.001 White (non-Hispanic) 8.4 (6.4–10.4) 22.3 (20.3–24.4) 20.7 (18.2–23.2) \0.001 Black (non-Hispanic) 7.9 (6.5–9.2) 19.4 (16.8–21.9) 17.3 (14.7–19.9) \0.001 Mexican–American 15.4 (12.8–17.9) 34.9 (31.8–38.0) 33.5 (30.3–36.8) \0.001 Overweight 19.5 (16.6–22.4) 41.0 (38.7–43.2) 36.7 (34.5–38.9) \0.001 Obese 25.9 (21.6–30.3) 46.8 (43.6–50.1) 45.5 (41.8–49.2) \0.001 Severely obese 40.2 (27.1–53.3) 52.9 (44.1–61.7) 50.3 (42.3–58.2) 0.31

ALD

All AYAs 2.30 (1.50–3.10) 4.40 (3.50–5.40) 5.10 (4.20–5.90) \0.001 Male 2.00 (1.03–2.90) 3.50 (2.40–4.50) 3.80 (2.90–4.70) 0.006

Female 2.70 (1.60–3.80) 5.40 (3.80–7.00) 6.50 (5.20–7.70) \0.001 White (non-Hispanic) 2.20 (1.30–3.10) 5.10 (3.80–6.50) 5.40 (4.20–6.70) \0.001 Black (non-Hispanic) 2.40 (1.60–3.20) 2.30 (1.10–3.40) 2.50 (1.50–3.40) 0.94

Mexican–American 4.10 (2.90–5.30) 3.80 (2.50–5.10) 7.50 (6.10–8.90) \0.001 Overweight 3.40 (2.20–4.60) 4.90 (3.80–6.00) 5.90 (4.80–6.90) 0.004

Obese 3.90 (2.20–5.60) 5.20 (3.30–7.00) 6.40 (5.10–7.70) 0.02

Severely obese 9.40 (1.90–17.0) 4.20 (0.60–7.80) 7.00 (4.10–9.90) 0.8

HCV

All adolescents 1.80 (1.04–2.50) 0.62 (0.40–0.84) 0.36 (0.12–0.60) \0.001 Male 2.60 (1.40–3.80) 0.86 (0.44–1.30) 0.42 (0.10–0.75) 0.001

Female 0.89 (0.45–1.30) 0.38 (0.07–0.70) 0.29 (0.05–0.53) 0.019

White (non-Hispanic) 1.40 (0.56–2.30) 0.59 (0.34–0.84) 0.50 (0.09–0.91) 0.061

Black (non-Hispanic) 3.50 (2.40–4.60) 1.20 (0.14–2.20) 0.18 (0.00–0.43) \0.001 Mexican–American 2.10 (1.30–2.90) 0.67 (0.00–1.40) 0.11 (0.00–0.32) \0.001 Overweight 1.30 (0.86–1.70) 0.57 (0.21–0.93) 0.26 (0.08–0.43) \0.001 Obese 1.90 (0.83–3.00) 0.59 (0.05–1.10) 0.23 (0.06–0.40) 0.002

Severely obese 0.00 0.00 0.00 –

Prevalence presented as % (95% confidence interval)

ALD alcoholic liver disease, CLD chronic liver disease, HCV hepatitis C virus, NAFLD nonalcoholic fatty

liver disease

Dig Dis Sci (2017) 62:1373–1380 1377

123

was noted over the last decade [12]. Similarly to NAFLD,

ALD has been also associated with increased liver-related

mortality, but does not affect overall and cardiovascular

mortality [20].

In concordance with decreasing prevalence of anti-HCV

in the general US population [21], our study also found a

significant decline of HCV in AYAs (1.8% in 1988–1994

to 0.36% in 2007–2010). Given that injection drug use is

the most important risk factor for acquisition of HCV, our

result could be explained with the observed trend of

reduced HCV prevalence and incidence among IDUs in the

period spanning from 1998 to 2008 [4]. The introduction of

widely available syringe and needle exchange programs

and opiate substitution treatment likely contributed for that.

However, these results should not ease our concern

regarding HCV burden in AYAs as more recent data have

demonstrated an alarming rising incidence of HCV infec-

tion in young IDUs B30 years in 2006–2012 period [5].

The same trend of steep rise of acute HCV in AYAs was

noted between 2010 and 2014 [6, 22]. Additionally, a

recent analysis demonstrated a 22% increase in HCV

detection in women of childbearing age [23]. The change

in demographic composition of young IDUs, sharing drug

preparation equipment as main factor for transmission,

increasing prescription opioid misuse with subsequent

transitioning to heroin use, and difficulties to engage young

people in preventive programs and behavioral interventions

are now the most important problems [24]. These data in

conjunction with low awareness of HCV status among

young IDUs [25] predict an upsurge of HCV prevalence in

the future.

The risk factors for CLD identified in our study mirror

those associated with increased NAFLD risk in adolescents

[26] and AYAs [10] and again emphasize the predomi-

nance of NAFLD in this age group. Our results

demonstrated almost 14-fold higher odds of CLD in sub-

jects with increased BMI. This finding is of utmost

importance in light of growing evidence on the role of BMI

for overall and liver-related mortality later in life. In a large

cohort of over 2 million Israeli adolescents, higher BMI

during teenage years, even within reference range was

associated with increased all-cause and cardiovascular

mortality in mid-adulthood [27]. Furthermore, adolescents

with BMI C 25 kg/m 2

and weight gain during early

adulthood (18–35 years) carried the highest mortality risk

when compared to those who gain weight later in life [28].

Recent longitudinal study also highlighted the key role of

BMI in young subjects and showed that being overweight

in late adolescence predisposes to development of severe

liver disease later in life even after adjustment for alcohol

use [29]. Notably, obesity in early adulthood (mid-20 s to

mid-40 s) was associated with more than twofold increased

risk of hepatocellular carcinoma (OR 2.6; 95% CI 1.4–4.4)

at an earlier age than commonly seen, regardless of well-

established risk factors [30].

Of great importance is also the increased risk of CLD

among AYAs with Mexican–American ethnicity as young

people represent a high proportion of the Hispanic popu-

lation that is projected to double in number by 2060 [31].

In accordance with previous studies in middle-aged adults

[32, 33], we also found the highest NAFLD prevalence in

this subgroup.

The main strength of our study is that it analyzes CLD in

US AYAs based on a large, nation-representative, popu-

lation-based sample and adds to our knowledge of the

estimated prevalence of CLD and its major etiologies in

this age group. However, some limitations should be

acknowledged. First, the cross-sectional design of

NHANES precludes causal inferences. Second, NAFLD

and ALD are likely underdiagnosed as ALT is an imprecise

marker for diagnosis of NAFLD that cannot differentiate

between NAFLD and NASH [34] and young population

tends to underreport heavy alcohol intake [35]. It is also

important to recognize that our definition of NAFLD could

have missed lean NAFLD subjects, especially as it has

been shown they are younger than those with overweight/

obese NAFLD [36]. Lastly, although NAFLD is the most

common explanation for elevated ALT in overweight/

obese AYAs, we might have captured individuals with

alternative etiologies. In support of this, a pediatric study

that used elevated ALT for detection of suspected NAFLD

in overweight/obese children encountered that 18% of

those referred for further evaluation and 24% of those who

were biopsied had liver disease other than NAFLD [37].

Currently, CLD and cirrhosis are the seventh cause of

death in the age group 25–44 years and rank fifth in the

population 45–64 years [7]. CLD has also shown the

highest inpatient mortality [38]. Importantly, it has been

Table 3 Multivariate analysis of risk factors for CLD among AYAs

Variable OR (95% CI) P value

Age (per 5 year) 1.10 (1.05–1.20) \0.001 Male versus female 1.20 (1.07–1.30) \0.001 Overweight or obese 13.60 (11.20–16.50) \0.001 Race

White

Black (non-Hispanic) 0.64 (0.56–0.73) \0.001 Mexican–American 1.60 (1.30–1.80) \0.001 Other race 0.98 (0.81–1.20) 0.87

Study year

1988–1994

1999–2004 2.40 (1.90–3.10) \0.001 2007–2012 2.10 (1.70–2.70) \0.001

OR odds ratio, CI confidence interval

1378 Dig Dis Sci (2017) 62:1373–1380

123

associated with impaired quality of life and incurs a con-

siderable economic burden [39]. These facts in conjunction

with the results of our study prompt immediate measures

toward increased awareness of rising CLD among AYAs

and require collaborative efforts for implementation of

effective prevention programs. Future research should

focus on distinctive features of CLD in AYAs that would

help us stratify young people at highest risk of CLD and

introduce timely management strategies.

Author’s contributions ID involved in interpretation of data. RL performed statistical analysis. NA involved in study concept and

design, data analysis and interpretation. ID, NA drafting of the

manuscript. KW, GR, RAM, NNZ, WC, RL, NA performed critical

revision of the manuscript. ID, KW, GR, RAM, NNZ, WC, RL, NA

approved final submission.

Compliance with ethical standards

Conflict of interest The authors declare no conflicts of interest.

References

1. United States Census Bureau. Estimates of U.S. Population by

Age and Sex: April 1, 2010, to July 1, 2015. Available at: http://

factfinder.census.gov/faces/tableservices/jsf/pages/productview.

xhtml?src=bkmk. Accessed October 31, 2016.

2. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden

CL. Trends in obesity among adults in the United States, 2005 to

2014. JAMA. 2016;315:2284–2291.

3. Kann L, McManus T, Harris WA, et al. Youth risk behavior

surveillance—United States, 2015. MMWR Surveill Summ.

2016;65:1–174.

4. Mehta SH, Astemborski J, Kirk GD, et al. Changes in blood-

borne infection risk among injection drug users. J Infect Dis.

2011;203:587–594.

5. Suryaprasad AG, White JZ, Xu F, et al. Emerging epidemic of

hepatitis C virus infections among young nonurban persons who

inject drugs in the United States, 2006–2012. Clin Infect Dis.

2014;59:1411–1419.

6. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus

infection related to injection drug use among persons aged \/ =30 years—Kentucky, Tennessee, Virginia, and West Virginia,

2006–2012. MMWR Morb Mortal Wkly Rep. 2015;64:453–458.

7. Heron M. Deaths: leading causes for 2013. Natl Vital Stat Rep.

2016;65:1–95.

8. CDC. NCHS. Key concepts about NHANES survey design.

Available at: http://www.cdc.gov/nchs/tutorials/Nhanes/Survey

Design/SampleDesign/Info1.htm. Accessed October 31, 2016.

9. Johnson CL, Paulose-Ram R, Ogden CL, et al. National health and

nutrition examination survey: analytic guidelines, 1999–2010.

Vital Health Stat.. 2013;2:1–24.

10. Mrad RA, Merjaneh N, Mubarak G, Lopez R, Zein NN, Alkhouri

N. The increasing burden of nonalcoholic fatty liver disease

among young adults in the United States: a growing epidemic

[Letter to the Editor]. Hepatology. 2016;64:1386–1387.

11. Alkhouri N, Hanouneh IA, Zein NN, et al. Liver transplantation

for nonalcoholic steatohepatitis in young patients. Transpl Int.

2016;29:418–424.

12. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohep-

atitis is the second leading etiology of liver disease among adults

awaiting liver transplantation in the United States. Gastroen-

terology. 2015;148:547–555.

13. Singh GK, Vitola BE, Holland MR, et al. Alterations in ven-

tricular structure and function in obese adolescents with nonal-

coholic fatty liver disease. J Pediatr. 2013;162:1160–1168, 1168

e1161.

14. Office of the Surgeon General (US), Office of Disease Prevention

and Health Promotion (US), Centers for Disease Control and

Prevention (US), National Institutes of Health (US). The surgeon

general’s call to action to prevent and decrease overweight and

obesity. Rockville (MD): Office of the Surgeon General (US);

2001. Available from: https://www.ncbi.nlm.nih.gov/books/

NBK44206/.

15. Hurt RT, Kulisek C, Buchanan LA, McClave SA. The obesity

epidemic: challenges, health initiatives, and implications for

gastroenterologists. Gastroenterol Hepatol (N Y). 2010;6:

780–792.

16. Lewis CE, Jacobs DR Jr, McCreath H, et al. Weight gain con-

tinues in the 1990s: 10-year trends in weight and overweight from

the CARDIA study. Coronary artery risk development in young

adults. Am J Epidemiol. 2000;151:1172–1181.

17. Lytle LA, Svetkey LP, Patrick K, et al. The EARLY trials: a

consortium of studies targeting weight control in young adults.

Transl Behav Med. 2014;4:304–313.

18. Barnes PM, Schoenborn CA. Trends in adults receiving a rec-

ommendation for exercise or other physical activity from a

physician or other health professional. NCHS Data Brief. 2012;

1–8.

19. Mathurin P, Deltenre P. Effect of binge drinking on the liver: an

alarming public health issue? Gut. 2009;58:613–617.

20. Trimble G, Zheng L, Mishra A, Kalwaney S, Mir HM, Younossi

ZM. Mortality associated with alcohol-related liver disease. Ali- ment Pharmacol Ther. 2013;38:596–602.

21. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C

virus infection in the United States, National Health and Nutrition

Examination Survey 2003 to 2010. Ann Intern Med. 2014;160:

293–300.

22. CDC. Surveillance for Viral Hepatitis—United States, 2014.

Available at: http://www.cdc.gov/hepatitis/statistics/2014surveil

lance/index.htm. Page last updated: June 22, 2016. Accessed

October 31, 2016.

23. Koneru A, Nelson N, Hariri S, et al. Increased hepatitis C virus

(HCV) detection in women of childbearing age and potential risk

for vertical transmission—United States and Kentucky, 2011–2014.

Morb Mortal Wkly Rep. 2016;65:705–710.

24. Hepatitis C virus infection in young persons who inject drugs.

Consultation Report. February 26–27, 2013. https://www.aids.

gov/pdf/hcv-and-young-pwid-consultation-report.pdf. Accessed

January 3, 2017.

25. Hagan H, Campbell J, Thiede H, et al. Self-reported hepatitis C

virus antibody status and risk behavior in young injectors. Public

Health Rep. 2006;121:710–719.

26. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonal-

coholic fatty liver disease among United States adolescents,

1988–1994 to 2007–2010. J Pediatr. 2013;162(496–500):e491.

27. Twig G, Yaniv G, Levine H, et al. Body-Mass Index in 2.3

million adolescents and cardiovascular death in adulthood. N

Engl J Med. 2016;374:2430–2440.

28. Adams KF, Leitzmann MF, Ballard-Barbash R, et al. Body mass

and weight change in adults in relation to mortality risk. Am J

Epidemiol. 2014;179:135–144.

29. Hagstrom H, Stal P, Hultcrantz R, Hemmingsson T, Andreasson

A. Overweight in late adolescence predicts development of

Dig Dis Sci (2017) 62:1373–1380 1379

123

severe liver disease later in life: A 39 years follow-up study. J

Hepatol. 2016;65:363–368.

30. Hassan MM, Abdel-Wahab R, Kaseb A, et al. Obesity early in

adulthood increases risk but does not affect outcomes of hepa-

tocellular carcinoma. Gastroenterology. 2015;149:119–129.

31. Colby SL, Ortman JM. Projections of the size and composition of

the U.S. Population: 2014 to 2060. Current Population Reports,

P25-1143, U.S. Census Bureau, Washington, DC, 2014.

32. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of

hepatic steatosis in an urban population in the United States:

impact of ethnicity. Hepatology. 2004;40:1387–1395.

33. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonal-

coholic fatty liver disease and nonalcoholic steatohepatitis among

a largely middle-aged population utilizing ultrasound and liver

biopsy: a prospective study. Gastroenterology. 2011;140:

124–131.

34. Neuschwander-Tetri BA, Clark JM, Bass NM, et al. Clinical,

laboratory and histological associations in adults with nonalco-

holic fatty liver disease. Hepatology. 2010;52:913–924.

35. Northcote J, Livingston M. Accuracy of self-reported drinking:

observational verification of ‘last occasion’ drink estimates of

young adults. Alcohol Alcohol. 2011;46:709–713.

36. Younossi ZM, Stepanova M, Negro F, et al. Nonalcoholic fatty

liver disease in lean individuals in the United States. Medicine

(Baltimore). 2012;91:319–327.

37. Schwimmer JB, Newton KP, Awai HI, et al. Paediatric gas-

troenterology evaluation of overweight and obese children

referred from primary care for suspected non-alcoholic fatty liver

disease. Aliment Pharmacol Ther. 2013;38:1267–1277.

38. Peery AF, Crockett SD, Barritt AS, et al. Burden of gastroin-

testinal, liver, and pancreatic diseases in the United States.

Gastroenterology. 2015;149(1731–1741):e1733.

39. Stepanova M, De Avila L, Afendy M, et al. Direct and indirect

economic burden of chronic liver disease in the United States.

Clin Gastroenterol Hepatol. 2016. doi:10.1016/j.cgh.2016.07.

020.

1380 Dig Dis Sci (2017) 62:1373–1380

123