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Saul J. Karpen, M.D., Ph.D.
Pediatric NAFLD:Biomarkers in a Special Population
Raymond F. Schinazi Distinguished Biomedical Chair
Professor of Pediatrics
NASH BioMarkers April 29, 2016
No Financial Disclosures
Member, NASH CRN
Topics• Pediatric NAFLD: State of the Problem
• Pediatricians: Screening mentality
• Genes + Diet : PNPLA3, Fructose, …
• Mothers & Fathers: +/- assigning fault
• Hormones & Growth Factors:
Windows into establishing NAFLD
• Current Biomarker Options: ALT, DBMI
Generation XXL
1995 2000
Obese Adolescents:
5% in 1980 21% in 2012CDC.gov
In press 4.27.2016
“ … steatosis at baseline predicted carotid plaque occurrence”
Pediatric NAFLD is “steatosis at baseline”
NAFLD: Prevalence by Age
0
5
10
15
20
2-4 years 5-9 years 10-14 years 15-19 years
%
Schwimmer, J. B. et al. Pediatrics2005;115:e561-e565Source: Dr. Miriam Vos
Topics• Pediatric NAFLD: State of the Problem
• Pediatricians: Screening mentality
• Genes + Diet : PNPLA3, Fructose
• Mothers & Fathers: +/- assigning fault
• Hormones & Growth Factors: Windows into establishing NAFLD
• Current Biomarker Options: ALT, DBMI
Newborn screening & disease prevention is central to the Pediatric “Culture”
http://genes-r-us.uthscsa.edu/resources/consumer/statemap.htm
AAP Screening Recommendations for NAFLD
Pediatrics 2007
PE BMI Labs (Biannual)
85-94th %ile(+ other risk factors)
>95th %ile• Lipid Panel
• Glucose
• ALT & AST
or
Screening: “Normal” ALT
SAFETY Study
Cutoff levels at 43 children’s hospitals
– mean 53 U/L (range 30-90)
95th %ile in normal weight, healthy
26 U/L for boys
23 U/L for girls
Schwimmer et al, Gastro 2010
Source: Dr. Miriam Vos
Increasing Prevalence of NAFLD among U.S.
Adolescents, 1988 to 2010
0
2
4
6
8
10
12
1988-94 1999-02 2003-06 2007-10
% S
usp
ecte
d N
AFLD
ALT >25.8 U/L for boys; >22.1 U/L for girls ALT> 30 U/L
***
***
***
Welsh, Karpen, Vos,
J Ped 2013Source: Dr. Miriam Vos
Suspected NAFLD (%) 1988-94 1999-02 2003-06 2007-10
Overweight (BMI 85-95%) 10.1 20.5 17.8 17.2Obese (>95%) 20.7 32.4 37.9 38.2Superobese (>99%) 27.2 52.1 58.8 51.6
J Pediatr. 2013 Mar;162(3):496–500.e1. 12
Topics• Pediatric NAFLD: State of the Problem
• Pediatricians: Screening mentality
• Genes + Diet : PNPLA3, Fructose, …
• Mothers & Fathers: +/- assigning fault
• Hormones & Growth Factors:
Windows into establishing NAFLD
• Current Biomarker Options: ALT, DBMI
Nature Genetics 2008
•Dallas Heart Study
•Hepatic Fat content
(1H-MRS)
•1032 African
•696 European
•383 Hispanic
•GWAS
PNPLA3p=5.9 x 10-10
Diabetes 2010
Hepatology 2010
% with NASH
PNPLA3 I148M (GG) SNP:
• prevalence in Hispanic Children (30+ %)
• risk of:
• NASH
• Cirrhosis
• HCC
Topics• Pediatric NAFLD: State of the Problem
• Pediatricians: Screening mentality
• Genes + Diet : PNPLA3, Fructose
• Mothers & Fathers: +/- assigning fault
• Hormones & Growth Factors: Windows into establishing NAFLD
• Current Biomarker Options: ALT, DBMI
Topics• Pediatric NAFLD: State of the Problem
• Pediatricians: Screening mentality
• Genes + Diet : PNPLA3, Fructose
• Mothers & Fathers: +/- assigning fault
• Hormones & Growth Factors: Windows into establishing NAFLD
• Current Biomarker Options: ALT, DBMI
Topics• Pediatric NAFLD: State of the Problem
• Pediatricians: Screening mentality
• Genes + Diet : PNPLA3, Fructose, …
• Mothers & Fathers: +/- assigning fault
• Hormones & Growth Factors:
Windows into establishing NAFLD
• Current Biomarker Options: ALT, DBMI
Brunt EM. Histological assessment of nonalcoholic fatty liver disease in adults and children. Clinical Liver Disease. 2012;1:107–110.
Adults: Pericentral Steatosis
Pediatrics: Periportal Steatosis
Obese (& Normal) Adolescents Adults with CV
DiseaseNEJM
4.13.2016
• Israeli Army Recruits
• 1967-2010
• Mean Age: 17 yo
• 60% Male
BMI %ile CV Mortality
Hazard Ratio
• 50th-74th 1.32 (1.2-1.5)
• 75th-84th 1.76 (1.5-2.0)
• 85th-94th 2.25 (2.0-2.6)
• > 95th 3.46 (2.9-4.1)
Summary: Pediatric NAFLD
• Starts early & utilizes/usurps normal growth
– Mother & Father (your patients…)
– Fetal Imprinting related to maternal diet during pregnancy
– Relationship to times of rapid growth?
• Screening of children: BMI + ALT, Glucose,…
– Pediatric culture of screening should be co-opted
– Obesity + Genetics (PNPLA3) + Diet – Child-specific issues
– BMI: +/- Concern at the 50th %ile, Certainly at the 85th%ile
– Opportunity for an Intervention for a Lifetime
• “Special” population Nothis is the population
• Noninvasive measures: ?– Need large serial, multi-cultural pediatric longitudinal studies
– The “experiment” is ongoing & expected to shorten life expectancy