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

• 31 disorders

• 362,000 infants screened

• 57 cases diagnosed

• 15.7 per 100,000 screened

0.0157%

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

Am J Clin Nutr 2010

Genes + Diet NAFLD PNPLA3 GG + Sugar intake

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

JCI 2009

Clin OB Gyn 2013

Cell 2010 Cell Metab 2011

Altered CpG Methylation

of PPARa enhancer

In Offsprings’ Livers

Stewart Clin OB Gyn 2013

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

CDC Growth Curves

Age 0-36 months Age 2-20 years

JKMA 2009

High velocity periods of growth: ? Primed for NAFLD

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)

JAMA 4.4.2016piceh.org

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