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Abbreviations
DNL

de novo lipogenesis

FFAs

free fatty acids

FGF-21

fibroblast growth factor 21

IR

insulin resistance

MR

magnetic resonance

NAFLD

nonalcoholic fatty liver disease

NASH

non-alcoholic steatohepatitis

TG

triglyceride

VLDL

very-low-density lipoprotein.

Concurrent with the rising prevalence of childhood obesity in the last 30 years, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common liver disease in pediatrics.[1] The liver is one of the main ectopic sites where lipids may accumulate in obese subjects. Ectopic fat disposition occurs particularly when the energy storage capacity of adipose tissue is exceeded, leading to an increase net lipid flux to nonadipose organs, thereby causing lipotoxicity and insulin resistance (IR).[2] As described in adults, adolescents with fatty liver display IR, glucose intolerance, and dyslipidemia.[3-6] Thus, fatty liver has emerged as the hepatic component of the metabolic syndrome and a strong cardiovascular risk factor even at very early age.[7, 8]

Although the associations between NAFLD and cardiac dysfunction have been well studied in adults, in the pediatric population information is sparse. In this regard, the study by Perseghin et al. is noteworthy.[9] Using cardiac imaging (magnetic resonance [MR] imaging) and 31P-MR spectroscopy, they measured intra- and extrapericardial fat along with myocardial energy metabolism in young, overweight nondiabetic subjects and found that increased epicardial fat was associated with abnormal cardiac metabolism, in the absence of morphologic and functional cardiac abnormalities.[9] Thus, in young men with fatty liver, independent of known traditional cardiac risk factors, cardiac remodeling appears to be an early event.

How early in life can these associations be detected? The answer can be found in the excellent report by Pacifico et al. in this issue of HEPATOLOGY.[10] They show that obese children with NAFLD have a higher interventricular septal thickness as well as a higher isovolumetric relaxation time, compared to obese youths without NALFD and lean controls. Notably, when the group of obese subjects was divided according to the presence of nonalcoholic steatohepatitis (NASH), it was evident that some functional cardiac differences were more pronounced in the group with NASH; this observation is intriguing and needs to be further investigated. It is important to understand, for example, whether hepatic inflammation or fibrosis per se might have a stronger association with the cardiac phenotype than any other hepatic alterations, because it is remarkable that such changes occur long before the onset of cirrhosis and portal hypertension, suggesting that the cardiac alterations may not be the consequence of the changes of intrahepatic hemodynamic conditions.

Although these observations clearly describe the relationships between NAFLD/NASH and cardiac dysfunction early in life, the underlying mechanisms explaining their development remains to be determined. In an attempt to understand the independence of the nature of the associations between NAFLD and cardiac variables, the researchers used multiple stepwise regression analysis, which indicated that the echocardiographic features of early diastolic and systolic dysfunction were associated with NAFLD, independently from anthropometric and metabolic variables.

Potential mechanisms linking NAFLD to cardiac dysfunction are shown in Fig. 1.

image

Figure 1. Proposed pathophysiological mechanisms linking NAFLD to cardiac dysfunction in obese adolescents. NAFLD is the result of genetics (PNPLA3 and GCKR) and environmental factors (dietary habits, IR, increased de novo lipogenesis, and adipose tissue lipolysis). Although the pathogenic link between cardiac hypertrophy and fatty liver is currently unknown, several data suggest that IR and FGF-21 resistance may be responsible for the cardiac dysfunctions observed in subjects with NAFLD.

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Driven mainly by a strong genetic susceptibility[11-13] and by a high intake of dietary simple sugar,[14] increased fat deposition in the liver occurs secondary to an increased activation of genes (sterol-regulatory element-binding protein 1) regulating de novo lipogenesis (DNL), together with a high flux of free fatty acids (FFAs) derived from excessive lipolysis from the dysfunctional adipocytes.[15] The increased FFA flux also contributes to an increased triglyceride (TG) production and very-low-density lipoprotein (VLDL) secretion. Excessive FFA availability in the liver promotes the formation of a variety of fat-derived, potentially toxic, lipid metabolites, such as diacylglycerol, that activate the IkappaB kinase/nuclear factor kappa B pathway, causing IR.[15] In the heart, the increased supply of FFAs may ultimately exceed their oxidative disposal, leading to oxidative stress lipotoxicity and impairment of energy homeostasis and, ultimately, cardiac dysfunction.[9]

Although many hypotheses have been proposed to explain the link between NAFLD and cardiac dysfunction, recent new studies suggest that fibroblast growth factor 21 (FGF-21) might be playing a role.[16] FGF-21 is a protein, mainly secreted by the liver, that exerts modulatory effects on glucose and insulin sensitivity.[16] FGF-21 has a hepatoprotective action, but subjects with NAFLD show a condition of “FGF-21 resistance,” which worsens in subjects with steatoheptatitis.[17] A recent study[18] has shown that FGF-21 knockout mice exhibit enhanced induction of cardiac hypertrophy, and that in vitro the treatment of cardiomyocytes with FGF-21 reverses these cardiac alterations.[18] Others have also reported a reduced FGF-21 in subjects with NASH.[19] Therefore, one could speculate that the FGF-21 resistance or reduced levels observed in subjects with NAFLD/NASH, may lead them to develop anatomic and functional cardiac alterations.

Although several events may underlie the development of cardiac alterations in subjects with NAFLD, the study by Pacifico et al.[10] robustly indicates that functional cardiac abnormalities are well established across the spectrum of NAFLD in obese youths. Given the presence of multiple serious complications in these very young subjects with NAFLD, and that children may have longer exposure to factors contributing to NAFLD progression, accumulation of fat in the liver should no longer be considered as a “simple disease.” The failure to prevent or reverse the development of NAFLD-related IR makes it more urgent to design strategies to contain what could be a more devastating wave of cardiovascular complications in these youngsters. This might be possible only if we gain a better understanding of the mechanisms by which NAFLD and its associated comorbidities develop.

  • Nicola Santoro, M.D., Ph.D.

  • Sonia Caprio, M.D.

  • Department of Pediatrics

  • Yale University School of Medicine

  • New Haven, CT

References

  1. Top of page
  2. References
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    Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr 2013;162:496-500.
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    Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unraveling the mechanism. Lancet 2010;375:2267-2277.
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    Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 2006;91:4287-4294.
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    Cali AM, De Oliveira AM, Kim H, Chen S, Reyes-Mugica M, Escalera S, et al. Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? Hepatology 2009;49:1896-1903.
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    D'Adamo E, Northrup V, Weiss R, Santoro N, Pierpont B, Savoye M, et al. Ethnic differences in lipoprotein subclasses in obese adolescents: importance of liver and intraabdominal fat accretion. Am J Clin Nutr 2010;92:500-508.
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    D'Adamo E, Cali AM, Weiss R, Santoro N, Pierpont B, Northrup V, et al Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care 2010;33:1817-1822.
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    Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation 2008;118:277-283.
  • 9
    Perseghin G, Natali G, De Cobelli F, Lattuada G, Esposito A, Belloni E, et al. Abnormal left ventricular energy metabolism in obese men with preserved systolic and diastolic functions is associated with insulin resistance. Diabetes Care 2007;30:1520-1526.
  • 10
    Pacifico L, Di Martino M, De Merulis A, Bezzi M, Osborn JF, Catalano C, et al. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology 2014;59:461-470.
  • 11
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
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    Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, et al. A variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2011;55:781-789.
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    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007;5:426-437.
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    Giannini C, Feldstein A, Santoro N, Kim G, Kursawe R, Pierpont B, Caprio S. Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab 2013;98:2993-3000.
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    Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013;4:2019.
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    Alisi A, Ceccarelli S, Panera N, Prono F, Petrini S, De Stefanis C, et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS One 2013;8:e67160.