Nonalcoholic fatty liver disease and the heart in children and adolescents

Table 1 Studies of the association between nonalcoholic fatty liver disease and markers of atherosclerosis in children and adolescents

Ref.	Study population and sample size	Diagnosis	Outcome	Main results
Schwimmer et al[21]	Children (n = 817) who died of external causes from 1993 to 2003; 15% with NAFLD	Autoptic liver biopsy	Atherosclerosis was assessed as absent, mild (aorta only), moderate (coronary artery streaks/plaques), or severe (coronary artery narrowing)	For the entire cohort, mild atherosclerosis was present in 21% and moderate to severe in 2%. Atherosclerosis was significantly more common in children with fatty liver than those without (30% vs 19%, P < 0.001)
Schwimmer et al[9]	Overweight children with (n = 150), and without (n = 150) NAFLD, matched for gender, age, and severity of obesity	Liver biopsy	Prevalence of cardiovascular risk factors (abdominal obesity, dyslipidemia, hypertension, IR, and glucose abnormalities)	NAFLD was strongly associated with multiple cardiovascular risk factors independently of both BMI and hyperinsulinemia
Pacifico et al[22]	Obese children with (n = 29), and without NAFLD (n = 33); healthy lean controls (n = 30)	Liver ultrasound	cIMT, mean (95%CI)	NAFLD vs no NAFLD and controls: 0.58 (0.54-0.62) mm vs 0.49 (0.46-0.52) mm and 0.40 (0.36-0.43) mm; P < 0.01 and P < 0.0005, respectively Log cIMT was associated with NAFLD severity in a multiple linear regression analysis adjusted for age, gender, Tanner stage, and cardiovascular risk factors Coefficient b, 0.08; P < 0.0005
Demircioğlu et al[23]	Obese children with mild (n = 32), moderate-severe NAFLD (n = 22), and without NAFLD (n = 26); healthy lean controls (n = 30) matched for age and gender	Liver ultrasound	cIMT, mean ± SD	All obese vs controls:
				Left CCA, 0.414 ± 0.071 mm vs 0.352 ± 0.054 mm, P < 0.0001
				Left CB, 0.412 ± 0.067 mm vs 0.350 ± 0.058 mm, P < 0.0001
				Left ICA, 0.324 ± 0.068 mm vs 0.266 ± 0.056 mm, P < 0.0001
				NAFLD was significantly associated with left CCA, CB, ICA in multiple regression linear analyses adjusted for age, gender, weight, mean ALT level, TC, obesity, and grade of hepatosteatosis
				CCA = standardized β, 0.451; P = 0.01
				CB = standardized β, 0.627; P < 0.0001
				ICA = standardized β, 0.501; P = 0.020
Kelishadi et al[24]	Obese adolescents with (n = 25), and without (n = 25) components of MetS; normal weight adolescents with (n = 25) and without (n = 25) components of MetS	Liver ultrasound and elevated ALT	cIMT, mean ± SD	NWMN vs NWMA vs POMN vs POMA: 0.29 ± 0.02 mm vs 0.37 ± 0.04 mm vs 0.41 ± 0.05 mm; the differences were significant between groups with the exception of NWMA vs POMN
				cIMT was significantly associated with NAFLD in a logistic regression analysis after adjustment for age, gender and pubertal status
				Odds ratio, 1.2 (95%CI: 1.03-2.1)
Manco et al[25]	Overweight and obese children with (n = 31), and without (n = 49) NAFLD, matched for age, gender, and BMI	Liver biopsy	cIMT, median (IQR)	NAFLD vs no NAFLD:
				Right cIMT, 0.47 (0.07) mm vs 0.48 (0.05) mm, P = 0.659
				Left cIMT, 0.49 (0.12) mm vs 0.47 (0.05) mm, P = 0.039
				NAFLD was not associated with cIMT in a multivariate analysis
Caserta et al[26]	Randomly selected adolescents (n = 642) of whom 30.5% and 13.5% were, respectively, overweight and obese. Overall prevalence of NAFLD, 12.5%	Liver ultrasound	cIMT, mean (95%CI)	NAFLD vs no NAFLD: 0.417 (0.409-0.425) mm vs 0.395 (0.392-0.397) mm, P < 0.001
				NAFLD was significantly associated with cIMT in a multivariate analysis after adjustment for age, BP, BMI, TG, c-HDL, TC, IR, MetS, grade of steatosis
				Standardized β, 0.0147 (95%CI: 0.0054-0.0240); P = 0.002
Pacifico et al[14]	Obese children with (n = 100), and without (n = 150) NAFLD; healthy lean controls (n = 150)	Liver ultrasound and elevated ALT	cIMT and FMD, mean (95%CI)	Controls and no NAFLD vs NAFLD: cIMT, 0.47 (0.46-0.48) mm and 0.52 (0.50-0.54) mm vs 0.55 (0.53-0.54) mm, P < 0.0001 and P < 0.01, respectively
				FMD, 15.0 (13.9-17.3) and 11.8 (10.1-13.7) vs 6.7 (5.0-8.6) %, P < 0.01 and P < 0.001 respectively
				NAFLD was associated with low FMD and increased cIMT in a multiple logistic regression analysis after adjustment for age, gender, Tanner stage, and MetS
				Odds ratio, 2.31 (95%CI: 1.35-3.97); P = 0.002 and 1.99 (95%CI: 1.18-3.38); P = 0.010, respectively
Nobili et al[27]	Children with NAFLD (n = 118)	Liver biopsy	Atherogenic lipid profile (TG/HDL-c, TC/HDL-c and LDL-c/HDL-c ratios)	The severity of liver injury was strongly associated with a more atherogenic profile, independently of BMI, insulin resistance, and the presence of MetS
Weghuber et al[28]	Obese children with (n = 14), and without (n = 14) NAFLD	Proton MR spectroscopy	FMD, mean ± SD	NAFLD vs no NAFLD: 108.6% ± 11.8% vs 110.7% ± 9.0%; P = 0.41
El-Koofy et al[29]	Overweight/obese children (n = 33)	Liver biopsy	Atherogenic lipid profile (TC, LDL-c, HDL-c, TG)	Children with NAFLD had significantly higher TC, LDL-c, TG and lower HDL-c compared to patients with normal liver histology (P < 0.05)
Sert et al[30]	Obese children with (n = 44), and without (n = 36) NAFLD; lean subjects (n = 37)	Liver ultrasound and elevated ALT	cIMT, mean ± SD	Lean and no NAFLD vs NAFLD: 0.0359 ± 0.012 mm vs 0.378 ± 0.017 mm vs 0.440 ± 0.026 mm, P < 0.05 and P < 0.05, respectively
Akın et al[31]	Obese children with (n = 56), and without (n = 101) NAFLD	Liver ultrasound	cIMT, mean (95%CI)	NAFLD vs no NAFLD: 0.48 (0.47-0.49) mm vs 0.45 (0.44-0.45) mm, P < 0.001
				NAFLD was the only variable associated with increased cIMT in a multiple regression adjusted for age and gender
				β, 0.031 [SE (β) = 0.008]; P < 0.001
Gökçe et al[32]	Obese children with (n = 50), and without (n = 30) NAFLD; healthy lean controls (n = 30)	Liver ultrasound	cIMT, mean ± SD	NAFLD vs no NAFLD vs control group:
				Right cIMT, 0.46 ± 0.21 mm vs 0.35 ± 0.09 mm vs 0.30 ± 0.13 mm, P < 0.01
				Left cIMT, 0.44 ± 0.09 mm vs 0.35 ± 0.08 mm vs 0.27 ± 0.04 mm, P < 0.01
				NAFLD was the only variable associated with increased cIMT in a multiple regression adjusted for age, gender, BMI, BP, TG, HDL-c, IR and MetS
				Right cIMT = β, 0.241; P < 0.05
				Left cIMT = β, 0.425; P < 0.01
Sert et al[33]	Obese children with (n = 97), and without (n = 83) NAFLD; lean subjects (n = 68)	Liver ultrasound and elevated ALT	cIMT, mean ± SD	Lean and no NAFLD vs NAFLD: 0.354 ± 0.009 mm vs 0.383 ± 0.019 mm vs 0.437 ± 0.028 mm; P < 0.05 and P < 0.05, respectively
Alp et al[34]	Obese children with (n = 93), and without (n = 307) NAFLD; healthy lean controls (n = 150)	Liver ultrasound	cIMT, mean ± SD	Severe NAFLD vs mild NAFLD vs no NAFLD vs controls: 0.09 ± 0.01 cm vs 0.10 ± 0.01 cm vs 0.09 ± 0.01 cm vs 0.06 ± 0.01 cm, P < 0.001
Huang et al[35]	Adolescents (n = 964)	Liver ultrasound	PWV, mean ± SD	No NAFLD, low metabolic risk vs NAFLD, low metabolic risk vs no NAFLD, high metabolic risk vs NAFLD, high metabolic risk: males, 6.6 ± 0.7 m/s vs 6.7 ± 0.6 m/s vs 6.9 ± 1.0 m/s; females, 6.2 ± 0.7 m/s vs 6.3 ± 0.7 m/s vs 6.5 ± 0.7 m/s vs 6.4 ± 0.6 m/s
				Males and females who had NAFLD in the presence of the metabolic cluster had greater PWV
				b, 0.20 (95%CI: 0.01-0.38); P = 0.037
Jin et al[36]	Obese children (n = 71), and healthy controls (n = 47)	Liver ultrasound	PWV, mean ± SD	Obese vs controls: 4.54 ± 0.66 m/s vs 3.70 ± 0.66 m/s, P < 0.001
				Fatty liver was positively correlated with PWV (P < 0.01)

NAFLD: Nonalcoholic fatty liver disease; IR: Insulin resistance; BMI: Body mass index; cIMT: Carotid intima media thickness; CCA: Common carotid artery; CB: Carotid bulbus; ICA: Internal carotid artery; ALT: Alanine aminotransferase; TC: Total cholesterol; MetS: Metabolic syndrome; NWMN: Normal weight metabolically normal; NWMA: Normal weight metabolically abnormal; POMN: Phenotipically obese metabolically normal; POMA: Phenotipically obese metabolically abnormal; IQR: Interquartile range; BP: Blood pressure; TG: Triglycerides; FMD: Flow-mediated dilation; HDL-c: High-density lipoprotein cholesterol; LDL-c: Low-density lipoprotein cholesterol; MR: Magnetic resonance; PWV: Pulse wave velocity.