Mini Review ARTICLE
Is There an Association of Vascular Disease and Atherosclerosis in Children and Adolescents With Obesity and Non-alcoholic Fatty Liver Disease?
- Department of Pediatrics, Johns Hopkins Medicine, All Children's Hospital, St. Petersburg, FL, United States
Carotid intima media thickness (cIMT) and brachial flow-mediated dilation (FMD) evaluated by ultrasound are non-invasive markers of atherosclerosis. Increased cIMT in adults has been correlated to early vascular damage. Several studies show similar correlations of elevated cIMT in children with obesity, hyperlipidemia, and metabolic syndrome. Additionally, several articles have correlated non-alcoholic fatty liver disease (NAFLD) with elevated cIMT, indicating early atherosclerosis. It is alarming that these vascular changes may be seen in children as young as 10 years of age. Children with NAFLD may also have an increased pulse wave velocity that correlates to increased arterial stiffness and increased left ventricular dimension, mass, and diastolic dysfunction. These articles are persuasive, indicating a correlation of Pediatric NAFLD and early vascular disease. However, study limitations include the use of elevated alanine aminotransferase (ALT) and echogenic changes on ultrasound that may have low accuracy to identify NAFLD. Ultrasound has low sensitivities and specificities for detection of NAFLD and therefore is not recommended for diagnosis. In comparison, studies that used liver biopsy or proton magnetic resonance spectroscopy to identify NAFLD did not find a correlation with elevated cIMT or reduction in FMD. Due to these conflicting findings, more studies looking at cIMT and FMD changes in children with NAFLD are needed with more accurate diagnostic methods for steatosis to identify if there truly is a correlation of increased liver steatosis to early atherosclerosis.
The prevalence of obesity in the United States has increased in the past 4 years to 1 in 5 children (1). There has also been a considerable increase in the prevalence of obesity from 2015 to 2016 in children ages 2–5 years (1). Recent data shows increased rates of obesity in children of Hispanic and African American heritage as compared to other races (1). Obesity is a disease that effects the whole body. Non-alcoholic fatty liver disease (NAFLD) is just one finding in patients with obesity. As the rates of obesity increase, so does the prevalence of NAFLD (2). NAFLD is truly a histological diagnosis defined as steatosis >5% (3), and often is clinically asymptomatic. It occurs in higher frequency in individuals of Hispanic origin (especially from South America) and of Middle Eastern origin (4, 5). It also occurs with intermediate frequency in Whites, and less commonly in Blacks (4, 5). Those individuals of Hispanic heritage with fatty liver may have a higher rate of progression to fibrosis (5). In addition, it now well-known that children with the rs738409 C>G adiponutrin/patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism gene mutation have a higher risk of severe steatosis and progression to fibrosis (6). NAFLD can progress over time to a condition called nonalcoholic steatohepatitis (NASH), which has features of ballooning steatosis, fibrosis, and inflammation (4). There are concerns that NASH in young adults will become the leading cause of liver transplants in the future (7). In addition to liver damage, could the finding of NAFLD be correlated to early cardiac disease?
Historically, Berenson et al. published their post mortem autopsy findings of individuals ages 2–39 years, showing that aortic or coronary artery fatty streaks and fibrous plaques were strongly correlated to elevated body mass index (BMI), elevated blood pressure, and mixed hyperlipidemia (8). One non-invasive method to assess vascular changes is evaluation of carotid intima media thickness (cIMT) via carotid ultrasound. Increased cIMT in adults has been correlated to early vascular damage (9, 10). In addition, there are findings of coronary artery disease and altered ventricular function in adults with NAFLD (11–13). Adults with NAFLD were found to have coronary artery stenosis, higher coronary artery calcium, and all types of plaque (calcified and non-calcified) as compared to controls (14). Similarly, the authors of a systematic review and meta-analysis study showed increased left ventricular mass in adult patients with NAFLD as compared to controls (15). Clearly, there are many well-described associations of atherosclerosis and structural heart disease in adults who have NAFLD.
As discussed previously, there are racial difference with the prevalence of NAFLD. Similarly, there may be different prevalence and onset of cardiac disease in certain racial groups. In one recent adult study, the authors found that NAFLD was highest in patients who were of Hispanic heritage and lowest in Blacks and Chinese (16). Overall, the total prevalence of abdominal aortic calcification was highest in Whites, followed by Chinese, Blacks, and Hispanics (16). However, when evaluating the participants with NAFLD, the abdominal aortic calcification was highest in Hispanics, followed by Chinese, then Blacks, and finally Whites (16). The authors concluded that NAFLD did have an increased association with abdominal aortic calcification, and may affect different racial groups differently (16).
Such studies looking at the association of NAFLD and atherosclerosis with different racial groups has not been evaluated in children. This may be a possible topic for future Pediatric NAFLD research, looking at the differences and the onset of cardiac disease in various racial groups.
However, several pediatric articles have been published demonstrating the association of cIMT or brachial flow-mediated dilation (FMD) changes in children with NAFLD (17–34). In comparison, fewer and more recent articles have been published that do not show this association (35–37). The pediatric data currently published may have limitations and may not be generalizable to all children with NAFLD, due to the different onset and progression of heart disease in different racial groups. Overall, there likely is an association when taking into account the significant amount of published studies showing a link between NAFLD and vascular disease. However, better well-designed studies are needed with more accurate methods to identify NAFLD while taking into account racial onset and prevalence of hepatic steatosis. The articles published regarding the association of NAFLD with cIMT and FMD changes are reviewed in this article.
The articles were identified with the help of an unbiased medical librarian at Johns Hopkins All Children's Hospital. Two independent searches 6 months apart was conducted. Embase and PubMed were used to identify articles that fit the criteria. The search was limited to ages 0–18 years, and key words of NAFLD, cIMT, FMD, hyperlipidemia, obesity, and atherosclerosis. Each term was used in combination to limit articles and each item was also searched independently. Articles that were relevant to this review were used. Articles were excluded if they did not have research subjects with NAFLD.
Studies Supporting Association of NAFLD With Elevated cIMT and Low FMD
Overall, there have been more articles in the literature in support of early vascular changes like elevated cIMT and low FMD in children with NAFLD and obesity (17–34). What is interesting is that these articles used either abdominal ultrasound alone or abdominal ultrasound and elevated liver enzymes (alanine aminotransferase in most studies >40 U/L) to identify steatosis and NAFLD (17–34, 38). One study also used magnetic resonance imaging (MRI) findings as well to identify patients with steatosis (19). In some papers, a grading system was used to identify the level of steatosis or changes on liver ultrasound (18, 21–23, 26, 28, 29, 33). Many of the papers either used BMI percentile (14, 17–19, 21–23, 25, 26, 28, 32, 38, 39) or a fixed BMI >28–30 kg/m2 to define obesity (27, 29–31, 33). Echocardiography and carotid ultrasound were used to identify cIMT. FMD was evaluated via Doppler ultrasound imaging before and after an ischemic event caused by reduced blood flow from an inflated sphygmomanometer (19, 21, 37). All the papers excluded patients if they had systemic diseases or significant alcohol use.
There has been a series of articles by Pacifico et al. that have dominated the research in this area. In one of their studies, the authors found reduced FMD in obese children with NAFLD when exposed to ischemia (30). Children with NAFLD and obesity had elevated cIMT which was even higher if they had metabolic syndrome (30). In another study by the same group, the patients who had hepatic steatosis had higher mean and maximum cIMT measurements (23). They also found elevated cIMT was associated with elevated blood pressure, insulin resistance, NAFLD, and high triglyceride to high density lipoprotein cholesterol (TG/ HDL-c) ratio (12). The authors also demonstrated that after 12 month intervention of diet and exercise in children with NAFLD and obesity, the FMD improved but elevated cIMT did not regress (19). Failure of improvement of cIMT with lifestyle intervention is concerning, and further studies need to be done to see if this is a reproducible finding in children.
Other authors have also found similar correlations of elevated cIMT with NAFLD (18, 20–22, 25–28, 31, 33, 34), and have linked increased severity of steatosis to even higher cIMT values (18, 25), and lower FMD values (21). The inclusion of hepatic steatosis on ultrasound may improve the cIMT predictability of cardiac disease as compared to metabolic syndrome alone (28). A correlation of higher cIMT measurements was found with elevated aspartate aminotransferase to platelet ratio index (APRI), which is a marker for hepatic fibrosis (33).
Structural heart changes have also been reported such as increased thickening of the left ventricle, higher interventricular septal thickness in systole, increased left ventricular posterior wall thickness in diastole, increased left atrial and aortic diameters, higher left ventricular mass, and higher left ventricular mass index in children with NAFLD and obesity (22, 30, 31). The authors of one study looked at applanation tonometry to measure arterial stiffness via pulse wave velocity (29). They found that those patients who had NAFLD with other high risk metabolic abnormalities had greater pulse wave velocity as compared to those without metabolic complications (29).
In summary, there are many articles showing an association of early signs of structural heart disease and atherosclerosis in children with NAFLD. Perhaps practitioners need to be more concerned with the finding of NAFLD, as this may be a sign of early heart disease in children.
Studies Lacking Association of NAFLD With Elevated cIMT and Low FMD
What is interesting is that some newer articles do not support the association of elevated cIMT and low FMD in children who have NAFLD. What is unique about these articles is the use of either magnetic resonance spectroscopy or liver biopsy to define steatosis (35–37). When comparing degree of steatosis, inflammation, and fibrosis, there was no correlation with elevated right or left cIMT values (36). Steatosis and serum ALT was not correlated to elevated cIMT or arterial wall stiffness (35) either. The only predictor was BMI for abnormalities on cIMT (36). In addition, there was no association of hepatic fat fraction and FMD changes (37).
Diagnosis of Liver Steatosis, Fibrosis, and NAFLD
At this time, the North American Society of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) clinical practice guideline for NAFLD in children recommends the use of serum ALT at the age of 10 years (40) for screening. Ultrasound has fallen out of favor for the screening and diagnosis of NAFLD due to the low sensitivities and specificities (40, 41). There are new radiologic techniques like magnetic resonance elastography with better sensitivities and specificities that are validated for the evaluation of hepatic steatosis and fibrosis (40, 42) in children. Magnetic resonance elastography also has ~88% sensitivity and 85% specificity for detecting fibrosis (43). Ultimately, the gold standard for the evaluation of liver steatosis and fibrosis is histology of liver biopsy samples (3, 38, 44). Liver biopsy or magnetic resonance imaging are more accurate but also more expensive techniques for diagnosis (43). Liver biopsy is also invasive and can have complications of bleeding and damage to the gallbladder. There is also an added cost of anesthesia and 12–24 h hospital admission for observation post liver biopsy. To reduce the cost of diagnosis, non-invasive fibrosis scores, or serum biomarkers are under evaluation. In children, thus far, fibrosis scores that are typically used in adults are not accurate in predicting liver fibrosis (43). Equally, serum fibrosis biomarkers like caspase-cleaved cytokeratin 18 (CK18) show promise in recent research studies, but need further validation before it is recommended as part of clinical practice (43).
Overall, there are many studies correlating elevated BMI, hepatic steatosis, and metabolic syndrome with increased cIMT, lower FMD, possible increased arterial stiffness, and ventricular dysfunction in children. These articles predominantly used liver ultrasound with or without serum ALT to identify NAFLD. Some authors also used ultrasound grading of the echogenicity to correlate with severity of hepatic steatosis. Recently, ultrasound has fallen out of favor for screening for NAFLD due to the sensitivities and specificities of the test, and may not be an accurate way to identify hepatic steatosis. In comparison, the articles that define NAFLD with liver biopsy or proton magnetic resonance spectroscopy did not find this correlation to structural heart or vascular changes.
There is also a different prevalence of NAFLD in different racial groups. Perhaps the onset of cardiac disease, therefore, is different in different ethnic groups as well. One limitation of these studies is generalizability of the findings to all races and populations. Robust studies are needed which use more accurate diagnostic techniques for NAFLD, and take into consideration the differences of the disease frequency in different ethnic groups.
With the global health and economic impact of increased rates of obesity and therefore NAFLD in children, it is important for future research to identify if there is a correlation of hepatic steatosis to early atherosclerosis and at what age this occurs. The information from the future research would help create clinical programs for early diagnosis and intervention before significant vascular disease begins.
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Want to give thanks to Pamela Williams, MS, MLS, AHIP, medical librarian at Johns Hopkins. All Children's Hospital for her help with the search for the articles.
2. 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) 162:496–500e1. doi: 10.1016/j.jpeds.2012.08.043
3. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Nonalcoholic steatohepatitis clinical research network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology (2005) 41:1313–21. doi: 10.1002/hep.20701
4. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the american association for the study of liver diseases. Hepatology (2018) 67:328–57. doi: 10.1002/hep.29367
5. Rich NE, Oji S, Mufti AR, Browning JD, Parikh ND, Odewole M, et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. (2018) 16:198–210. doi: 10.1016/j.cgh.2017.09.041
6. Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, et al. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology (2010) 52:1274–80. doi: 10.1002/hep.23823
7. Doycheva I, Issa D, Watt KD, Lopez R, Rifai G, Alkhouri N. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in young adults in the United States. J Clin Gastroenterol. (2018) 52:339–46. doi: 10.1097/MCG.0000000000000925
8. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults, The Bogalusa Heart Study. N Engl J Med. (1998) 338:1650–6. doi: 10.1056/NEJM199806043382302
9. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the atherosclerosis risk in communities (ARIC) study 1987–1999. Am J Epidemiol. (1997) 146:483–94. doi: 10.1093/oxfordjournals.aje.a009302
10. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: cardiovascular health study collaborative research group. N Engl J Med. (1999) 340:14–22.
11. Fotbolcu H, Yakar T, Duman D, Karaahmet T, Tigen K, Cevik C, et al. Impairment of the left ventricular systolic and diastolic function in patients with non-alcoholic fatty liver disease. Cardiol J. (2010) 17:457–63.
12. Bonapace S, Perseghin G, Molon G, Canali G, Bertolini L, Zoppini G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care (2012) 35:389–95. doi: 10.2337/dc11-1820
13. Goland S, Shimoni S, Zornitzki T, Knobler H, Azoulai O, Lutaty G, et al. Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic and tissue Doppler imaging assessment. J Clin Gastroenterol. (2006) 40:949–55. doi: 10.1097/01.mcg.0000225668.53673.e6
14. Lee SB, Park GM, Lee JY, Lee BU, Park JH, Kim BG, et al. Association between non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: an observational cohort study. J Hepatol. (2018) 68:1018–24. doi: 10.1016/j.jhep.2017.12.012
15. Bonci E, Chiesa C, Versacci P, Anania C, Silvestri L, Pacifico L. Association of nonalcoholic fatty liver disease with subclinical cardiovascular changes: a systematic review and meta-analysis. Biomed Res Int. (2015) 2015:213737. doi: 10.1155/2015/213737
16. Remigio-Baker RA, Allison MA, Forbang NI, Loomba R, Anderson CAM, Budoff M, et al. Race/ethnic and sex disparities in the non-alcoholic fatty liver disease-abdominal aortic calcification association: the multi-ethnic study of atherosclerosis.Atherosclerosis (2017) 258:89–96. doi: 10.1016/j.atherosclerosis.2016.11.021
17. Pacifico L, Anania C, Martino F, Cantisani V, Pascone R, Marcantonio A, et al. Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease. Hepatology (2010) 52:1643–51. doi: 10.1002/hep.23890
18. Demircioglu F, Koçyigit A, Arslan N, Cakmakçi H, Hizli S, Sedat AT. Intima-media thickness of carotid artery and susceptibility to atherosclerosis in obese children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. (2008) 47:68–75. doi: 10.1097/MPG.0b013e31816232c9
19. Pacifico L, Arca M, Anania C, Cantisani V, Di Martino M, Chiesa C. Arterial function and structure after a 1-year lifestyle intervention in children with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. (2013) 23:1010–6. doi: 10.1016/j.numecd.2012.08.003
20. Madan SA, John F, Pyrsopoulos N, Pitchumoni CS. Nonalcoholic fatty liver disease and carotid artery atherosclerosis in children and adults: a meta-analysis. Eur J Gastroenterol Hepatol. (2015) 27:1237–48. doi: 10.1097/MEG.0000000000000429
21. Torun E, Aydin S, Gökçe S, Özgen IT, Donmez T, Cesur Y. Carotid intima-media thickness and flow-mediated dilation in obese children with non-alcoholic fatty liver disease. Turk J Gastroenterol. (2014) 25(Suppl. 1):92–8. doi: 10.5152/tjg.2014.5552
22. Alp H, Karaarslan S, Selver Eklioglu B, Atabek ME, Altin H, Baysal T. Association between nonalcoholic fatty liver disease and cardiovascular risk in obese children and adolescents. Can J Cardiol. (2013) 29:1118–25. doi: 10.1016/j.cjca.2012.07.846
23. Pacifico L, Cantisani V, Ricci P, Osborn JF, Schiavo E, Anania C, et al. Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Pediatr Res. (2008) 63:423–7. doi: 10.1203/PDR.0b013e318165b8e7
24. Pacifico L, Chiesa C, Anania C, De Merulis A, Osborn JF, Romaggioli S, et al. Nonalcoholic fatty liver disease and the heart in children and adolescents. World J Gastroenterol. (2014) 20:9055–71. doi: 10.3748/wjg.v20.i27.9055
25. Hacihamdioglu B, Okutan V, Yozgat Y, Yildirim D, Kocaoglu M, Lenk MK, et al. Abdominal obesity is an independent risk factor for increased carotid intima- media thickness in obese children. Turk J Pediatr. (2011) 53:48–54.
26. Akin L, Kurtoglu S, Yikilmaz A, Kendirci M, Elmali F, Mazicioglu M. Fatty liver is a good indicator of subclinical atherosclerosis risk in obese children and adolescents regardless of liver enzyme elevation. Acta Paediatr. (2013) 102:e107–13. doi: 10.1111/apa.12099
27. Kelishadi R, Cook SR, Amra B, Adibi A. Factors associated with insulin resistance and non-alcoholic fatty liver disease among youths. Atherosclerosis (2009) 204:538–43. doi: 10.1016/j.atherosclerosis.2008.09.034
28. Rutigliano I, Vinci R, De Filippo G, Mancini M, Stoppino L, d'Apolito M, et al. Metabolic syndrome, hepatic steatosis, and cardiovascular risk in children. Nutrition (2017) 36:1–7. doi: 10.1016/j.nut.2016.10.017
29. Huang RC, Beilin LJ, Ayonrinde O, Mori TA, Olynyk JK, Burrows S, et al. Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents. Hepatology (2013) 58:1306–14. doi: 10.1002/hep.26495
30. Sert A, Aypar E, Pirgon O, Yilmaz H, Odabas D, Tolu I. Left ventricular function by echocardiography, tissue Doppler imaging, and carotid intima-media thickness in obese adolescents with nonalcoholic fatty liver disease. Am J Cardiol. (2013) 112:436–43. doi: 10.1016/j.amjcard.2013.03.056
31. Sert A, Pirgon O, Aypar E, Yilmaz H, Odabas D. Relationship between left ventricular mass and carotid intima media thickness in obese adolescents with non-alcoholic fatty liver disease. J Pediatr Endocrinol Metab. (2012) 25:927–34. doi: 10.1515/jpem-2012-0187
32. Pacifico L, Bonci E, Andreoli G, Romaggioli S, Di Miscio R, Lombardo CV, et al. Association of serum triglyceride-to-HDL cholesterol ratio with carotid artery intima-media thickness, insulin resistance and nonalcoholic fatty liver disease in children and adolescents. Nutr Metab Cardiovasc Dis. (2014) 24:737–43. doi: 10.1016/j.numecd.2014.01.010
33. Sert A, Pirgon O, Aypar E, Yilmaz H, Dündar B. Relationship between aspartate aminotransferase-to-platelet ratio index and carotid intima-media thickness in obese adolescents with non-alcoholic fatty liver disease. J Clin Res Pediatr Endocrinol. (2013) 5:182–8. doi: 10.4274/Jcrpe.891
34. Caserta CA, Pendino GM, Amante A, Vacalebre C, Fiorillo MT, Surace P, et al. Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy. Am J Epidemiol. (2010) 171:1195–202. doi: 10.1093/aje/kwq073
35. Koot BG, de Groot E, van der Baan-Slootweg OH, Bohte AE, Nederveen AJ, Jansen PL, et al. Nonalcoholic fatty liver disease and cardiovascular risk in children with obesity. Obesity. (2015) 23:1239–43. doi: 10.1002/oby.21076
36. Manco M, Bedogni G, Monti L, Morino G, Natali G, Nobili V. Intima-media thickness and liver histology in obese children and adolescents with non-alcoholic fatty liver disease. Atherosclerosis (2010) 209:463–8. doi: 10.1016/j.atherosclerosis.2009.10.014
37. Weghuber D, Roden M, Franz C, Chmelik M, Torabia S, Nowotny P, et al. Vascular function in obese children with non-alcoholic fatty liver disease. Int J Pediatr Obes. (2011) 6:120–7. doi: 10.3109/17477161003792580
38. Fang J, Zhang JP, Luo CX, Yu XM, Lv LQ. Carotid Intima-media thickness in childhood and adolescent obesity relations to abdominal obesity, high triglyceride level and insulin resistance. Int J Med Sci. (2010) 18:278–83. doi: 10.7150/ijms.7.278
39. Caserta CA, Pendino GM, Alicante S, Amante A, Amato F, Fiorillo M, et al. MAREA Study Group: body mass index, cardiovascular risk factors, and carotid intima-media thickness in a pediatric population in southern Italy. J Pediatr Gastroenterol Nutr. (2010) 51:216–20. doi: 10.1097/MPG.0b013e3181d4c21d
40. Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al. NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children: recommendations from the expert committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. (2017) 64:319–34. doi: 10.1097/MPG.0000000000001482
41. Awai HI, Newton KP, Sirlin CB, Behling C, Schwimmer JB. Evidence and recommendations for imaging liver fat in children, based on systematic review. Clin Gastroenterol Hepatol. (2014) 12:765–73. doi: 10.1016/j.cgh.2013.09.050
42. Schwimmer JB, Middleton MS, Behling C, Newton KP, Awai HI, Paiz MN, et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology (2015) 61:1887–95. doi: 10.1002/hep.27666
Keywords: pediatrics, non-alcoholic fatty liver disease, carotid intima media thickness, atherosclerosis, brachial flow mediated dilation
Citation: Karjoo S (2018) Is There an Association of Vascular Disease and Atherosclerosis in Children and Adolescents With Obesity and Non-alcoholic Fatty Liver Disease? Front. Pediatr. 6:345. doi: 10.3389/fped.2018.00345
Received: 28 August 2018; Accepted: 25 October 2018;
Published: 16 November 2018.
Edited by:Fatima Cody Stanford, Massachusetts General Hospital, Harvard Medical School, United States
Reviewed by:Dexter Canoy, University of Oxford, United Kingdom
Tudor Lucian Pop, Iuliu Haţieganu University of Medicine and Pharmacy, Romania
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*Correspondence: Sara Karjoo, firstname.lastname@example.org