The Inflamed Liver and Atherosclerosis: A Link Between Histologic Severity of Nonalcoholic Fatty Liver Disease and Increased Cardiovascular Risk (original) (raw)

Abstract

Background

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It encompasses a spectrum of disease ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Growing evidence links NAFLD to cardiovascular (CV) disease; however, the association between the histologic severity of NAFLD and CV risk remains poorly understood.

Aim

To assess the relationship between severity of liver injury and CV risk markers in a large, well-characterized group of patients with biopsy-proven NAFLD.

Methods

Our cohort consisted of 83 consecutive patients undergoing liver biopsy for clinical suspicion of NAFLD. Patients were subsequently divided into three groups: normal biopsy (n = 11) simple steatosis (n = 36), and NASH (n = 36). CV risk markers included: triglyceride/high-density lipoprotein (HDL), total cholesterol/HDL, and low-density lipoprotein/HDL ratios.

Results

All lipid ratios were found to be significantly associated with NAFLD (p < 0.05) after adjusting for age and gender. More importantly, there was a stepwise, statistically significant increase in lipid ratios from patients with normal biopsies to patients with simple steatosis to those with NASH (p < 0.05). A positive correlation was found between the lipid ratios and NAFLD activity score (NAS) as well as the individual histological features of the NAS (steatosis, inflammation, and ballooning) with the strongest correlation being with NAS (rho (95% CI) 0.41 (0.21, 0.62), p < 0.001).

Conclusion

In patients with NAFLD, the histologic severity of liver injury and inflammation is strongly associated with an increased CV risk and an atherogenic lipid profile.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

MS:

Metabolic syndrome

BMI:

Body mass index

IR:

Insulin resistance

CV:

Cardiovascular

TG:

Triglyceride

TC:

Total cholesterol

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

HOMA:

Homeostatic model assessment

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

BP:

Blood pressure

NAS:

NAFLD activity score

WC:

Waist circumference

References

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231.
    Article CAS PubMed Google Scholar
  2. Brunt EM, Tiniakos DG. Pathological features of NASH. Front Biosci. 2005;10:1475–1484.
    CAS PubMed Google Scholar
  3. Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis. 2008;28:386–395.
    Article CAS PubMed Google Scholar
  4. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415–1428.
    Article CAS PubMed Google Scholar
  5. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683–689.
    Article CAS PubMed Google Scholar
  6. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–184.
    Article CAS PubMed Google Scholar
  7. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–2180.
    Article CAS PubMed Google Scholar
  8. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808.
    CAS PubMed Google Scholar
  9. Cali AM, Zern TL, Taksali SE, et al. Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state. Diabetes Care. 2007;30:3093–3098.
    Article CAS PubMed Google Scholar
  10. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008;103:1372–1379.
    Article CAS PubMed Google Scholar
  11. Biddinger SB, Hernandez-Ono A, Rask-Madsen C, et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 2008;7:125–134.
    Article CAS PubMed Google Scholar
  12. Guillen N, Acin S, Navarro MA, et al. Squalene in a sex-dependent manner modulates atherosclerotic lesion which correlates with hepatic fat content in apoE-knockout male mice. Atherosclerosis. 2008;197:72–83.
    Article CAS PubMed Google Scholar
  13. Ioannou GN, Weiss NS, Boyko EJ, Mozaffarian D, Lee SP. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology. 2006;43:1145–1151.
    Article CAS PubMed Google Scholar
  14. Ruttmann E, Brant LJ, Concin H, Diem G, Rapp K, Ulmer H. Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation. 2005;112:2130–2137.
    Article CAS PubMed Google Scholar
  15. Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991;325:373–381.
    Article CAS PubMed Google Scholar
  16. McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol. 2005;96:399–404.
    Article CAS PubMed Google Scholar
  17. Quijada Z, Paoli M, Zerpa Y, et al. The triglyceride/HDL-cholesterol ratio as a marker of cardiovascular risk in obese children; association with traditional and emergent risk factors. Pediatr Diabetes. 2008;9:464–471.
    Article CAS PubMed Google Scholar
  18. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.
    Article PubMed Google Scholar
  19. Targher G. Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens. Diabet Med. 2007;24:1–6.
    Article CAS PubMed Google Scholar
  20. Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005;25:1045–1050.
    Article CAS PubMed Google Scholar
  21. Targher G, Bertolini L, Rodella S, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30:2119–2121.
    Article CAS PubMed Google Scholar
  22. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42:473–480.
    Article PubMed Google Scholar
  23. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419.
    Article CAS PubMed Google Scholar
  24. Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–689.
    Article PubMed Google Scholar
  25. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1497–1502.
    Article CAS PubMed Google Scholar
  26. Musso G, Gambino R, Biroli G, et al. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2005;100:2438–2446.
    Article CAS PubMed Google Scholar
  27. Pagano C, Soardo G, Esposito W, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol. 2005;152:113–118.
    Article CAS PubMed Google Scholar
  28. Targher G. Relationship between high-sensitivity C-reactive protein levels and liver histology in subjects with non-alcoholic fatty liver disease. J Hepatol. 2006;45:879–881. (author reply 881–872).
    Article CAS PubMed Google Scholar
  29. Targher G, Bertolini L, Scala L, et al. Plasma PAI-1 levels are increased in patients with nonalcoholic steatohepatitis. Diabetes Care. 2007;30:e31–32.
    Article PubMed Google Scholar
  30. Arbones-Mainar JM, Navarro MA, Carnicer R, et al. Accelerated atherosclerosis in apolipoprotein E-deficient mice fed Western diets containing palm oil compared with extra virgin olive oils: a role for small, dense high-density lipoproteins. Atherosclerosis. 2007;194:372–382.
    Article CAS PubMed Google Scholar

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Acknowledgments

This work was supported by NIH DK076852 to AEF.

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Authors and Affiliations

  1. Department of Pediatric Gastroenterology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
    Naim Alkhouri & Ariel E. Feldstein
  2. Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
    Tarek Abu-Rajab Tamimi, Lisa Yerian & Nizar N. Zein
  3. Quantitative Health Sciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
    Rocio Lopez
  4. Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
    Ariel E. Feldstein

Authors

  1. Naim Alkhouri
  2. Tarek Abu-Rajab Tamimi
  3. Lisa Yerian
  4. Rocio Lopez
  5. Nizar N. Zein
  6. Ariel E. Feldstein

Corresponding author

Correspondence toNaim Alkhouri.

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Alkhouri, N., Tamimi, T.AR., Yerian, L. et al. The Inflamed Liver and Atherosclerosis: A Link Between Histologic Severity of Nonalcoholic Fatty Liver Disease and Increased Cardiovascular Risk.Dig Dis Sci 55, 2644–2650 (2010). https://doi.org/10.1007/s10620-009-1075-y

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