Nonalcoholic Fatty Liver Disease and Carotid

Atherosclerosis in ChildrenLucia Pacifico, Vito Cantisani, Paolo Ricci, John F.

Osborn, Elisa Schiavo, Caterina Anania, Eva Ferrara, Giuliano Dvisic, and Claudio Chiesa

Departments of Pediatrics, Radiology, and Public Health Sciences, La Sapienza University of Rome;

National Research Council, Rome, Italy

Pacifico L, et al. Pediatr Res 2008; vol. 63, April issue. Epud ahead of print January 24, 2008

Background

Nonalcoholic fatty liver disease (NAFLD) is closely associated with several features of

the metabolic syndrome, a highly atherogenic condition.

Its presence could signify a substantial cardiovascular risk above and beyond that

conferred by individual risk factors

Although an association between hepatic steatosis and atherosclerotic risk factors has been described

in adult patients, possible relationships between NAFLD and atherosclerosis in

children remain to be investigated

OBJECTIVE

The aims of our study were to determine the presence of subclinical atherosclerosis (measured as carotid intima-media thickness,IMT) in obese children with and without NAFLD, and to evaluate correlates of carotid IMT

SUBJECTSPeriod: 12-month

CASES:

Children with primary obesity

CONTROLS:

Healthy children

INCLUSION CRITERIA •BMI > 95th percentile for age and sex •evaluation for fatty liver upon detection of hepatomegaly and/or elevated liver chemistry

EXCLUSION CRITERIA•causes of chronic hepatitis other than obesity (ex. hepatitis B, C, Wilson’s disease, α-1-antitrypsin deficiency)•alcohol intake or smoking (where appropriate) •type 1 or 2 diabetes•any condition known to influence body composition

INCLUSION CRITERIA•BMI appropriate for age and sex

EXCLUSION CRITERIA•no history of alcohol consumption or smoking (where appropriate) •normal aminotransferase levels •normal liver ultrasound •negative serology for hepatitis B and C

MATERIALS AND METHODS All patients underwent:

a complete physical examination (including weight, height, BMI and determination of the stage of puberty). The degree of obesity (SD score) was quantified by Cole’s least mean square method.

measurements of systolic blood pressure (BP) and diastolic BP

laboratory tests including glucose, insulin, aminotransferases, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, leptin and adiponectin

measurements of body composition

MATERIALS AND METHODS

liver ultrasound scanning - The severity of hepatic steatosis was graded as

mild, moderate, or severe carotid ultrasound - The measurement was performed at the common

carotid artery near the bifurcation during end diastole. We measured 4 values on each side, and maximum and mean IMT were calculated separately for each side

RESULTS

Obesechildren:62

Healthycontrols: 30

Obese children

Controls P

Age - years 10.0 (9.4-10.7) 10.1 (8.8-11.3) 0.89

Gender – Male (%) 34 (54.8) 14 (46.6) 0.50

Prepubertal stage:

17 (27.4) 10 (33.3) 0.16

BMI- kg/m2 24.7 (23.8-25.7) 17.5 (16.6-18.4) <0.0001

SD score-BMI 1.92 (1.78-2.07) -0.04 (-0.39-0.29) <0.0001

Systolic BP mmHg

115 (109-120) 106 (104-108) <0.0001

Diastolic BP mmHg

73 (72-74) 69 ( 68-70) <0.0001Values are means (95% confidence intervals)

RESULTS

Obesechildren: 62

Healthycontrols: 30

Obese children

Controls P

ALT 35 (28-42) 17 (15-19) <0.01

Triglycerides mg/dL 105 (90-123) 75 (65-87) <0.01

Total cholesterol mg/dL

146 (123-162) 144 (131-157) 0.67

HDL mg/dL 38 (36-40) 42 (40-45) <0.05

Adiponectin ng/mL 11 (9.6-12.8) 12.2 (10.0-14.9) 0.51

Leptin ng/dL 17 (14.6-20) 6 (4.8-7.5) <0.0001

Insulin μU/mL 13.7 (11.2-16.7) 8.2 (7.0-9.6) <0.01

HOMA-IR 3 (2.4-3.7) 1.8 (1.5-2.1) <0.01

Maximum IMT mm 0.53 (0.50-0.56) 0.40 (0.36-0.43) <0.0001

Mean IMT mm 0.49 (0.46-0.52) 0.39 (0.35-0.43) <0.0001

Values are geometric means (95% confidence intervals)

RESULTS

NAFLD:29

no NAFLD:33

Obese children

46,7%

NAFLD no NAFLD P

Age - years 10.4 (9.5-11.4) 10 (9.0-11.0)) 0.59

Gender – Male (%)

15 (51.7) 19 (57.5) 0.56

Prepubertal stage

7 (24.1) 10 (30.3) 0.90

BMI- kg/m2 25.4 (24.2-26.5)

24.3 (23.0-25.6)

0.24

SD score-BMI 1.95 (1.82-2.07)

1.91 (1.67-2.15)

0.81

Systolic BP mmHg

115 (112-118) 110 (108-113) <0.01

Diastolic BP mmHg

74 (72-76) 72 (71-74) 0.09

Values are means (95% confidence intervals)

The diagnosis of NAFLD was based on ultrasoun scan

RESULTS

NAFLD: 29

no NAFLD: 33

Obese children

46,7%

NAFLD no NAFLD P

ALT 52 (39-65) 22 (18-27) <0.0001

Triglycerides mg/dL 108 (91-134) 99 (75-130) 0.48

Total cholesterol mg/dL

152 (132–174) 125 (93-167) 0.28

HDL mg/dL 37 (34-40) 39 (37-42) 0.31

Insulin μU/mL 17.3 (12.6-23.7) 11 (8.8–14.7) <0.05

HOMA-IR 4 (2.8–5.5) 2.5 (1.9–3.3) <0.05

Leptin ng/mL 18.3 (14.4–23.4) 16.1 (12.9–20.2)

0.43

Adiponectin ng/mL 9.3 (7.4–11.7) 12.7 (10.6–15.1)

<0.05

Mean IMT m. 0.54 (0.50–0.58) 0.45 (0.42–0.48)

<0.01

Maximum IMT m. 0.58 (0.54–0.62) 0.49 (0.46-0.52)

<0.01Values are geometric means (95% confidence intervals)

RESULTS

Stepwise regression analysis*

Independent variable Coefficient, b

eb 95% CI for eb

P

Fatty liver severity score 0.080 1.083 1.041-1.119 <0.0001

Tanner stage 0.053 1.053 1.022-1.084 <0.01

Variables independently associated with carotid IMT in obese children: * Results of a stepwise linear regression analysis started with the following independent variables: age, gender, pubertal

stage, BMI, fat mass, systolic and diastolic BP, total and HDL cholesterol, triglycerides, HOMA-IR values, adiponectin and leptin

levels.

CONCLUSIONSOur study indicate, for the first time, that: 1)obese patients with NAFLD have a marked

increase in carotid IMT in comparison with control healthy children ;

2) carotid IMT is higher for obese children with NAFLD than obese children without liver involvement but with similar BMI;

3) the presence of NAFLD independently predicts carotid IMT after adjustment for a broad spectrum of potential confounders, including insulin resistance, a major atherogenic risk factor that is strongly correlated to NAFLD.