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Non-alcoholic Fatty Liver Disease and Its Links with Inflammation and Atherosclerosis

Abstract

Purpose of Review

We summarize best data of the association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD).

Recent Findings

NAFLD has been linked with insulin resistance, obesity, and metabolic syndrome, conditions known to be associated with CVD and subclinical atherosclerosis. The rising evidence of the association between NAFLD and subclinical CVD may suggest that NAFLD is not only a marker but also may be actively involved in pathogenesis of CVD.

Summary

It is an overview of previous studies assessing relationships between NAFLD and markers of cardiovascular disease, as the presence of coronary artery calcification, increased arterial stiffness, and elevated carotid media thickness, in order to better understand the interplay between these conditions.

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Fig. 1

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

MS:

Metabolic syndrome

BMD:

Bone mineral density

NASH:

Non-alcoholic steatohepatitis

c-IMT:

Carotid wall intimal medial thickness

IL:

Interleukin

TNF-α:

Tumor necrosis factor α

CAD:

Coronary artery heart disease

APOB:

Apoprotein B

FFA:

Free fatty acid

CRP:

C-reactive protein

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CVD:

Cardiovascular disease

LDL:

Low density lipoprotein

VLDL:

Very low density lipoprotein

HDL:

High density lipoprotein

FMD:

Flow mediated dilation

OR:

Odds ratio

CI:

Confidence interval

P:

P value

CAC:

Coronary artery calcification

cf-PWV:

Carotid-femoral pulse wave velocity

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095–128.

  2. 2.

    Khot U, Khotm M, Bajzer C, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898–904.

  3. 3.

    Lazo M. Clark Jm. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28(4):339–50.

  4. 4.

    D’Adamo E. Cali Am, Weiss R, et al. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care. 2010;33(8):1817–22.

  5. 5.

    Kotronen A, YkiJarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(1):27–38.

  6. 6.

    Kotronen A, Velagapudi VR, Yetukuri L, et al. Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations. Diabetologia. 2009;52(4):684–90.

  7. 7.

    Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341–50.

  8. 8.

    Pacifico L. Nobiliv, Anania C, et al. Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk. World J Gastroenterol. 2011;17(26):3082–91.

  9. 9.

    Schwimmer JB, Pardee PE, Lavine JE, et al. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008;118(3):277–83.

  10. 10.

    Sorrentino P, Terracciano L, D’Angelo S, et al. Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMAIR, and hypertension. Am J Gastroenterol. 2010;105(2):336–44.

  11. 11.

    Youssoni ZM, Blissett D, Blissett T, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64(5):1577–86.

  12. 12.

    Lonardo A, Nascimbeni F, Mantovani A, et al. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68(2):335–52.

  13. 13.

    •• Targher G, Byrne C, Lonardo A, et al. Nonalcoholic fatty liver disease and risk of incident cardiovascular disease: a metaanalysis. J Hepatol. 2016;65(3):589–600 Excelent metaanalysis that quantify themagnitude of the association between NAFLD (and its severity) and risk of CVD events.

  14. 14.

    Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol. 2005;11(31):4838–42.

  15. 15.

    Bugianesi E, Gastaldelli A. Hepatic and cardiac steatosis: Are they coupled? Heart Fail Clin. 2012;8(4):663–70.

  16. 16.

    Gaggini M, Morelli M, Buzzigoli E, et al. Nonalcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients. 2013;5(5):1544–60.

  17. 17.

    Hamagushi M, Kojima T, Takeda N. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13(10):1579–84.

  18. 18.

    Choi DH, Lee SJ, Kang CD, et al. Nonalcoholic fatty liver disease is associated with coronary artery disease in Koreans. World J Gastroenterol. 2013;19(38):6453–7.

  19. 19.

    Perera N, Indrakumar J, Abeysinghe WV, et al. Nonalcoholic fatty liver disease increases the mortality from acute coronary syndrome: an observational study from Sri Lanka. BMC Cardiovasc Disord. 2016;16:37.

  20. 20.

    Gastaldelli A, Kozakova M, Højlund K, et al. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009;49(5):1537–44.

  21. 21.

    Kozakova M, Palombo C, Eng MP, et al. Fatty liver index, gammaglutamyltransferase, and early carotid plaques. Hepatology. 2012;55(5):1406–15.

  22. 22.

    ZelberSagi S, Salomone F, Yeshua H, et al. Nonhighdensity lipoprotein cholesterol independently predicts new onset of nonalcoholic fatty liver disease. Liver Int. 2014;34(6):e128–35.

  23. 23.

    Wu S, Wu F, Ding Y, et al. Association of nonalcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and metaanalysis. Sci Rep. 2016;6:33386.

  24. 24.

    Bonci E, Chiesa C, Versacci P, et al. Association of nonalcoholic fatty liver disease with subclinical cardiovascular changes: a systematic review and metaanalysis. Biomed Res Int. 2015;213737:2015.

  25. 25.

    Ridker PM, Hennekens CH, Buring JE, et al. Creactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12):836–43.

  26. 26.

    Assy N, Bekirov I, Mejritsky Y, et al. Association between thrombotic risk factors and extent of fibrosis in patients with nonalcoholic fatty liver diseases. World J Gastroenterol. 2005;11(37):5834–9.

  27. 27.

    Takaki A, Kawai D, Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in nonalcoholic steatohepatitis (NASH). Int J Mol Sci. 2013;14(10):20704–28.

  28. 28.

    Targher G, Bertolini L, Scala L, et al. Associations between serum 25hydroxyvitamin D3 concentrations and liver histology in patients with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007;17(7):517–24.

  29. 29.

    Li XL, Sui JQ, Lu LL, et al. Gene polymorphisms associated with nonalcoholic fatty liver disease and coronary artery disease: a concise review. Lipids Health Dis. 2016;15:53.

  30. 30.

    Lee YJ, Shim JY, Moon BS, et al. The relationship between arterial stiffness and nonalcoholic fatty liver disease. Dig Dis Sci. 2012;57(1):196–203.

  31. 31.

    Targher G, Bertolini L, Padovani R, et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care. 2006;29(6):1325–30.

  32. 32.

    Madan SA, John F, Pyrsopoulos N, et al. Nonalcoholic fatty liver disease and carotid artery atherosclerosis in children and adults: a metaanalysis. Eur J Gastroenterol Hepatol. 2015;27(11):1237–48.

  33. 33.

    Pacifico L, Anania C, Martino F, et al. Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease. Hepatology. 2010;52(5):1643–165.

  34. 34.

    Weghuber D, Rodenm M, Franz C, et al. Vascular function in obese children with nonalcoholic fatty liver disease. Int J Pediatr Obes. 2011;6(2):120–7.

  35. 35.

    Torun E, Aydin S, Gökçe S, et al. Carotid intima media thickness and flowmediated dilation in obese children with nonalcoholic fatty liver disease. Turk J Gastroenterol. 2014;25(Suppl. 1):92–8.

  36. 36.

    Pacifico L, Perla FM, Roggini M, et al. A systematic review of NAFLDassociated extrahepatic disorders in youths. J Clin Med. 8(6). https://doi.org/10.3390/jcm8060868.

  37. 37.

    Zieman S, Melenovsky V, Kass D. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932–43.

  38. 38.

    Johnson C, Baugh R, Wilson C, et al. Age related changes in the tunica media of the vertebral artery: implications for the assessment of vessels injured by trauma. J Clin Pathol. 2001;54(2):139–45.

  39. 39.

    VilellaNogueira C, Leite N, Cardoso C, et al. NAFLD and increased aortic stiffness: parallel or common physiopathological mechanisms? Int J Mol Sci. 2016;17(4):460.

  40. 40.

    Harisson S. Nonalcoholic fatty liver disease and fibrosis progression:the good, the bad, and the unknown. Clin Gastroenterol Hepatol. 2015;13(4):655–7.

  41. 41.

    Shiotani A, Motoyama M, Matsuda T, et al. Brachialankle pulse wave velocity in Japanese university students. Intern Med. 2005;44(7):696–701.

  42. 42.

    Vlachopoulos C, Manesis E, Baou K, et al. Increased arterial stiffness and impaired endothelial function in nonalcoholic fatty liver disease: a pilot study. Am J Hypertens. 2010;23:1183–9.

  43. 43.

    Kim B, Kim N, Kim BS, et al. The association between nonalcoholic fatty liver disease,metabolic syndrome and arterial stiffness in nondiabetic, nonhypertensive individuals. Cardiology. 2012;123:54–61.

  44. 44.

    Huang Y, Bi Y, Xu M, et al. Nonalcoholic fatty liver disease is associated with atherosclerosis in middleaged and elderly Chinese. Arterioscler Thromb Vasc Biol. 2012;32:2321–6.

  45. 45.

    Huang C, Beilin J, Ayonrinde O, et al. Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents. Hepatology. 2013;58(4):1306–14.

  46. 46.

    Bilgin B, Sunbul M, Kani H, et al. Arterial stiffness is associated independently with liver stiffness in biopsyproven nonalcoholic fatty liver disease: a transient elastography study. Eur J Gastroenterol Hepatol. 2019. https://doi.org/10.1097/MEG.0000000000001471.

  47. 47.

    Sunbulm A. Durmus E, et al. Arterial stiffness in patients with nonalcoholic fatty liver disease is related to fibrosis stage and epicardial adipose tissue thickness. Atherosclerosis. 2014;237(2):490–3.

  48. 48.

    • Haradap BI, Drager F. Nonalcoholic fatty liver disease presence and severity is associated with aortic stiffness beyond abdominal obesity: the ELSABrasil. Atherosclerosis. 2019;284:59–65 This crosssectional study demonstrates the association of NAFLD with aortic stiffness in a racially/ethnically diverse population free of CVD.

  49. 49.

    Jaruvongvanich V, Wirunsawanya K, Saranguankeo A, et al. Increased arterial stiffness in nonalcoholic fatty liver disease: a systematic review and metaanalysis. Eur J Gastroenterol Hepatol. 2017;29(9):e28–35. https://doi.org/10.1097/MEG.0000000000000909.

  50. 50.

    Lin Z. G, Zhang J, et al. Nonalcoholic fatty liver disease is associated with progression of arterial stiffness. Nutr Metab Cardiovasc Dis. 2015;25(2):218–23.

  51. 51.

    Silverman M, Blaha M, Krumholz H, et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the multiethnic study of atherosclerosis. Eur Heart J. 2014;35(33):2232–41.

  52. 52.

    Al Rifai M, Silverman M, Nasir K. The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the multiethnic study of atherosclerosis (MESA). Atherosclerosis. 2015;239(2):629–33.

  53. 53.

    Song D, Chang U, Kang S. Noninvasive serum fibrosis markers are associated with coronary artery calcification in patients with nonalcoholic fatty liver disease. Gut Liver. 2019. https://doi.org/10.5009/gnl18439.

  54. 54.

    Kim D, Choi S, Park E, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology. 2012;56(2):605–13.

  55. 55.

    Gummesson A, Strömberg U, Schmidt C. Nonalcoholicfatty liver disease is a strong predictor of coronary artery calcification in metabolically healthy subjects: a crosssectional, populationbased study in middleaged subjects. PLoS One. 2018;13(8):e0202666. https://doi.org/10.1371/journal.pone.0202666eCollection 2018.

  56. 56.

    • Cho Y, Kang Y, Yoo J. The impact of nonalcoholic fatty liver disease and metabolic syndrome on the progression of coronary artery calcification. Sci Rep. 2018;8:12004 First study to demonstratethat NAFLD is an independent contributor to CAC progression, irrespective of the presence of metabolic syndrome.

  57. 57.

    • Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis. 2019;282:110–20 Critical review of the association of NAFLD and CVD.

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Author information

Priscila Pollo-Flores supervised the study. Débora Vieira-Soares did critical review of the manuscript. Gabriela Muller-Machado drafted and did critical revision of manuscript. Luan Abdallah, Ricardo Cardoso de Matos and Yves Pacheco Dias March e Souza drafted and wrote the manuscript.

Correspondence to Priscila Pollo-Flores.

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Abdallah, L.R., de Matos, R.C., e Souza, Y.P.D.M. et al. Non-alcoholic Fatty Liver Disease and Its Links with Inflammation and Atherosclerosis. Curr Atheroscler Rep 22, 7 (2020). https://doi.org/10.1007/s11883-020-0820-8

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Keywords

  • Non-alcoholic fatty liver disease
  • Steatohepatitis
  • Inflammation
  • Cardiovascular risks
  • Atherosclerosis
  • Aortic stiffness
  • Carotid media thickness
  • Coronary artery calcification