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.

Table 2 Studies of the association between nonalcoholic fatty liver disease and alterations in cardiac structure and function in the adult population

Ref.	Study population and sample size	Diagnosis	Outcomes	Main results
Lautamäki et al[15]	T2DM and coronary artery disease patients with (n = 27), and without (n = 28) fatty liver. The 2 groups were matched for age, BMI, and fasting plasma glucose	Hepatic MRS	Myocardial insulin resistance and perfusion (PET)	In patients with T2DM and coronary artery disease, liver fat is an indicator of myocardial insulin resistance and reduced coronary functional capacity
Goland et al[17]	Nondiabetic, normotensive patients with NAFLD (n = 38), and age and gender-matched controls (n = 25)	Liver ultrasound and liver biopsy in a subgroup of 11 NAFLD patients	LV structure and function (M-mode echocardiography; and pulsed Doppler echocardiography)	Patients with NAFLD had mild changes in cardiac geometry (thickening of the interventricular septum and posterior wall, and increased LV mass) as well as significant differences in parameters of diastolic function compared with the control group
Perseghin et al[16]	Young nondiabetic men matched for anthropometric features with (n = 21) or without (n = 21) fatty liver	MRS	LV morphology and function; Intrapericardial and extrapericardial fat content; and resting LV energy metabolism (Cardiac MRI and cardiac 31P-MRS)	Newly found young individuals with fatty liver had excessive fat accumulation in the epicardial area and abnormal LV energy metabolism despite normal LV morphological features and systolic and diastolic functions
Fallo et al[45]	Never-treated essential hypertensive patients with (n = 48) or without (n = 38) fatty liver. The 2 groups were similar as to gender, age and blood pressure levels	Liver ultrasound	LV structure and function (M-mode echocardiography; and pulsed Doppler echocardiography)	NAFLD patients had similar prevalence of LV hypertrophy compared to subjects without NAFLD, but a higher prevalence of LV diastolic dysfunction
Rijzewijk et al[46]	T2DM patients with (n = 32) and without (n = 29) fatty liver	MRS	Cardiac perfusion and substrate metabolism; LV morphology and function (PET, cardiac MRI and cardiac 31P-MRS)	T2DM patients with fatty liver showed decreased myocardial perfusion, glucose uptake, high-energy phosphate metabolism compared with similar patients without hepatic steatosis
Fotbolcu et al[18]	Nondiabetic, normotensive patients with NAFLD (n = 35) and control subjects (n = 30). The 2 groups were similar as to gender and age	Liver ultrasound	LV structure and function (M-mode echocardiography; Pulsed and Tissue Doppler echocardiography)	Patients with NAFLD had changes in cardiac geometry (thickening of the interventricular septum and posterior wall, and increased LV mass) as well as significant differences in parameters of systolic and diastolic function compared with the control group
Bonapace et al[47]	T2DM patients with (n = 32) and without (n = 18) fatty liver. The 2 groups were similar as to gender, age, BMI, waist circumference, and diabetes duration	Liver ultrasound	LV structure and function (M-mode echocardiography; Pulsed and Tissue Doppler echocardiography)	T2DM patients with fatty liver showed LV diastolic dysfunction, even if the LV morphology and systolic function were preserved
Mantovani et al[48]	Hypertensive T2DM patients with (n = 59) and without (n = 57) fatty liver	Liver ultrasound	LV structure (M-mode echocardiography)	Hypertensive T2DM patients with NAFLD have a remarkably higher frequency of LV hypertrophy than hypertensive diabetic patients without NAFLD
Hallsworth et al[49]	Adult subjects matched for anthropometric features with (n = 19) or without (n = 19) fatty liver	MRS	Cardiac structure, function, and metabolism (cardiac MRI, cardiac tagging, and cardiac 31P-MRS)	The major findings in NAFLD patients compared to controls were: thickening of the cardiac wall, independent of changes in LV mass; altered myocardial strains; concentric remodeling; evidence of diastolic dysfunction; but no significant difference in cardiac energetics
Karabay et al[50]	NAFLD patients (n = 55) and healthy controls (n = 21; normal laboratory values and liver ultrasound)	Liver biopsy	LV structure and function (M-mode echocardiography; Pulsed and Tissue Doppler echocardiography; and speckle tracking echocardiography)	Patients with NAFLD had changes in cardiac geometry (thickening of the interventricular septum and posterior wall, and increased LV mass) as well as significant differences in parameters of diastolic function compared with the control group
				LV global longitudinal strain and strain rate in systole were lower in NAFLD group as compared to controls; however no significant differences were found among NAFLD groups (i.e., simple steatosis, borderline NASH, and definite NASH)

T2DM: Type 2 diabetes mellitus; BMI: Body mass index; MRS: Magnetic resonance spectroscopy; PET: Positron emission tomography; NAFLD: Nonalcoholic fatty liver disease; LV: Left ventricular; NASH: Nonalcoholic steatohepatitis.

Table 3 Studies of the association between nonalcoholic fatty liver disease and alterations in cardiac structure and function in children and adolescents

Ref.	Study population and sample size	Diagnosis	Outcomes	Main results
Sert et al[30]	Obese adolescents with (n = 44), and without (n = 36) NAFLD; and control subjects (n = 37)	Liver ultrasound and elevated serum alanine aminotransferase	LV structure (M-mode echocardiography)	Increased LV mass was found in NAFLD group compared to both lean controls and obese subjects without NAFLD
Alp et al[34]	Obese children and adolescents with (n = 93), and without (n = 307) NAFLD matched for gender and age; and control subjects (n = 150)	Liver ultrasound	LV structure and function; Epicardial fat (M-mode echocardiography; Pulsed and Tissue Doppler echocardiography)	Increased end-systolic thickness of the interventricular septum, and larger LV mass, as well as LV systolic and diastolic dysfunction were found in NAFLD group. In addition, obese children with NAFLD had increased epicardial fat thickness
Singh et al[51]	Obese children and adolescents with (n = 15), and without (n = 15) NAFLD matched for age, gender, Tanner stage, and BMI z score; and control subjects (n = 15) matched for gender, age, and Tanner stage	Hepatic MRS	LV structure and function; Intracardiac triglyceride content (Integrated backscatter ultrasonography and speckle tracking echocardiography; cardiac MRS)	LV global longitudinal strain and early diastolic strain rates were significantly decreased in obese children with NAFLD compared to both lean controls and obese subjects without NAFLD. Intracardiac triglyceride content was not different among the 3 groups
Sert et al[33]	Obese adolescents with (n = 97), and without (n = 83) NAFLD; and control subjects (n = 68)	Liver ultrasound and elevated serum alanine aminotransferase	LV structure and function (M-mode echocardiography; Pulsed and Tissue Doppler echocardiography)	Obese adolescents with NAFLD exhibited increased LV dimensions and mass, as well as LV diastolic dysfunction
Pacifico et al[52]	Obese children and adolescents with (n = 54), and without (n = 54) NAFLD matched for age, gender, pubertal status, and BMI-SD score; and healthy control subjects (n = 18) matched for gender, age, and pubertal status	Hepatic magnetic resonance imaging; and liver biopsy in a subgroup of 41 NAFLD patients	LV structure and function; Epicardial fat (M-mode echocardiography; Pulsed and Tissue Doppler echocardiography)	Increased interventricular septum thickness at end-diastole and at end-systole, as well as LV systolic and diastolic dysfunction were found in NAFLD group. Children with more severe liver histology had worse LV dysfunction than those with more mild liver changes. NAFLD group had also increased epicardial fat thickness
Fintini et al[53]	Children with biopsy-proven NAFLD (n = 50). No patients without NAFLD, and no healthy control children were included	Liver biopsy	LV structure and function (M-mode echocardiography; and pulsed Doppler echocardiography)	About 35% (n = 18) of the 50 children with NAFLD had LV hypertrophy. Children with NASH showed, almost invariably, the presence of clear cut LV hypertrophy

NAFLD: Nonalcoholic fatty liver disease; LV: Left ventricular; BMI: Body mass index; MRS: Magnetic resonance spectroscopy; NASH: Nonalcoholic steatohepatitis.