Nonalcoholic Fatty Liver Disease and Cardiovascular Disease Risk

Abstract

The metabolic syndrome (MetSyn) is a constellation of cardiovascular risk factors that occur simultaneously in many individuals. The National Cholesterol Education Program Adult Treatment Panel III defines MetSyn as the presence of any 3 of the following 5 criteria: abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and hyperglycemia.1National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report.Circulation. 2002; 106: 3143-3421Crossref PubMed Scopus (11132) Google Scholar MetSyn is highly prevalent in the United States and is associated with increased cardiovascular risk.2Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5712) Google Scholar, 3Gami A.S. Witt B.J. Howard D.E. et al.Metabolic syndrome and risk of incident cardiovascular events and death.J Am Coll Cardiol. 2007; 49: 403-414Crossref PubMed Scopus (1419) Google Scholar Although the presence of nonalcoholic fatty liver disease (NAFLD) is not traditionally considered a criterion for MetSyn, it is highly prevalent in individuals with MetSyn.4Hamaguchi M. Kojima T. Takeda N. et al.The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Scopus (834) Google Scholar, 5Hanley A.J. Williams K. Festa A. et al.Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study.Diabetes. 2005; 54: 3140-3147Crossref PubMed Scopus (339) Google ScholarBecause of its strong association with MetSyn, it is not surprising that NAFLD has been reported to be associated with an increased risk for cardiovascular disease events.6Targher G. Bertolini L. Poli F. et al.Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients.Diabetes. 2005; 54: 3541-3546Crossref PubMed Scopus (473) Google Scholar, 7Targher G. Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens.Diabet Med. 2007; 24: 1-6Crossref PubMed Scopus (194) Google Scholar In this issue of Clinical Gastroenterology and Hepatology, Stepanova and Younossi8Stepanova M. Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol. 2012; 10: 646-650Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar further explore the association between NAFLD and prevalent cardiovascular disease and cardiovascular disease–related mortality by using data from the National Health and Nutrition Examination Survey. In their analysis, a larger proportion of individuals with ultrasound-proven NAFLD had a history of congestive heart failure, stroke, angina, or myocardial infarction than those without NAFLD. In analyses that adjusted for the presence of obesity and diabetes but not hypertension or dyslipidemia, the presence of NAFLD was independently associated with the presence of any 1 of these 4 manifestations of cardiovascular disease (odds ratio, 1.23; 95% confidence interval, 1.04–1.44).During a mean follow-up of just over 14 years, individuals with NAFLD had higher rates of all-cause (16%) and cardiovascular disease–related (6%) mortality than those without NAFLD (11% and 3%, respectively; P < .0001 for both comparisons). Among those with NAFLD, cardiovascular disease was the most common cause of death, accounting for 38% of all deaths. Despite higher rates of cardiovascular disease mortality among those with NAFLD compared with those without, NAFLD was not independently associated with cardiovascular disease–related mortality in analyses that adjusted for the presence of obesity and diabetes but not hypertension or dyslipidemia (hazard ratio, 0.92; 95% confidence interval, 0.70–1.19). The authors concluded that longer follow-up time might eventually confirm the independent association of NAFLD with cardiovascular disease–related mortality.There is not much debate that NAFLD is closely associated to the presence of MetSyn. However, to what degree NAFLD directly contributes to the increased cardiovascular risk observed in individuals with MetSyn is less clear. These data from Stepanova and Younossi8Stepanova M. Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol. 2012; 10: 646-650Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar demonstrate that the strength of the associations between NAFLD and prevalent cardiovascular disease and future cardiovascular disease–related mortality is significantly attenuated by the presence of traditional MetSyn components such as obesity and diabetes. At first glance, this would suggest that NAFLD is not associated with cardiovascular disease independent of these other known cardiovascular risk factors. However, these risk factors might be in the epidemiologic causal pathway between NAFLD and cardiovascular events, ie, NAFLD contributes to the pathophysiology of these factors such as diabetes and their resultant adverse cardiovascular effects.The importance of this distinction cannot be understated. As Stepanova and Younossi8Stepanova M. Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol. 2012; 10: 646-650Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar describe, the lipotoxicity and proinflammatory milieu that accompany NAFLD might in fact contribute to the pathophysiology of MetSyn and subsequently contribute to the increased risk for adverse cardiovascular events observed in individuals with MetSyn. The greater the degree to which fatty infiltration in the liver serves as a source of the characteristic high triglyceride/low HDL-C dyslipidemia, elevated blood pressures, and insulin resistance observed in MetSyn, the more important it will be to develop treatment strategies aimed at reducing the amount of fatty infiltration in the liver or its adverse metabolic effects. Therapies directed toward NAFLD or its adverse metabolic effects might prove to be important in modifying the cardiovascular risk associated with MetSyn.Regardless, individuals with NAFLD are very likely to meet current criteria for MetSyn and, by definition, possess multiple cardiovascular risk factors. These individuals have significantly higher rates of both all-cause and cardiovascular disease–related mortality. As a result, the identification of NAFLD should prompt clinicians to screen these individuals for cardiovascular risk factors and aggressively manage them in an attempt to reduce overall cardiovascular risk. To what degree NAFLD directly contributes to the underlying pathophysiology of MetSyn rather than simply being an end-organ manifestation of the syndrome is less clear. Further research investigating to what extent fatty infiltration in the liver directly contributes to the pathophysiology of MetSyn will be invaluable in determining to what degree therapies aimed at NAFLD might reduce the cardiovascular risk associated with MetSyn. The metabolic syndrome (MetSyn) is a constellation of cardiovascular risk factors that occur simultaneously in many individuals. The National Cholesterol Education Program Adult Treatment Panel III defines MetSyn as the presence of any 3 of the following 5 criteria: abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and hyperglycemia.1National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report.Circulation. 2002; 106: 3143-3421Crossref PubMed Scopus (11132) Google Scholar MetSyn is highly prevalent in the United States and is associated with increased cardiovascular risk.2Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5712) Google Scholar, 3Gami A.S. Witt B.J. Howard D.E. et al.Metabolic syndrome and risk of incident cardiovascular events and death.J Am Coll Cardiol. 2007; 49: 403-414Crossref PubMed Scopus (1419) Google Scholar Although the presence of nonalcoholic fatty liver disease (NAFLD) is not traditionally considered a criterion for MetSyn, it is highly prevalent in individuals with MetSyn.4Hamaguchi M. Kojima T. Takeda N. et al.The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.Ann Intern Med. 2005; 143: 722-728Crossref PubMed Scopus (834) Google Scholar, 5Hanley A.J. Williams K. Festa A. et al.Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study.Diabetes. 2005; 54: 3140-3147Crossref PubMed Scopus (339) Google Scholar Because of its strong association with MetSyn, it is not surprising that NAFLD has been reported to be associated with an increased risk for cardiovascular disease events.6Targher G. Bertolini L. Poli F. et al.Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients.Diabetes. 2005; 54: 3541-3546Crossref PubMed Scopus (473) Google Scholar, 7Targher G. Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens.Diabet Med. 2007; 24: 1-6Crossref PubMed Scopus (194) Google Scholar In this issue of Clinical Gastroenterology and Hepatology, Stepanova and Younossi8Stepanova M. Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol. 2012; 10: 646-650Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar further explore the association between NAFLD and prevalent cardiovascular disease and cardiovascular disease–related mortality by using data from the National Health and Nutrition Examination Survey. In their analysis, a larger proportion of individuals with ultrasound-proven NAFLD had a history of congestive heart failure, stroke, angina, or myocardial infarction than those without NAFLD. In analyses that adjusted for the presence of obesity and diabetes but not hypertension or dyslipidemia, the presence of NAFLD was independently associated with the presence of any 1 of these 4 manifestations of cardiovascular disease (odds ratio, 1.23; 95% confidence interval, 1.04–1.44). During a mean follow-up of just over 14 years, individuals with NAFLD had higher rates of all-cause (16%) and cardiovascular disease–related (6%) mortality than those without NAFLD (11% and 3%, respectively; P < .0001 for both comparisons). Among those with NAFLD, cardiovascular disease was the most common cause of death, accounting for 38% of all deaths. Despite higher rates of cardiovascular disease mortality among those with NAFLD compared with those without, NAFLD was not independently associated with cardiovascular disease–related mortality in analyses that adjusted for the presence of obesity and diabetes but not hypertension or dyslipidemia (hazard ratio, 0.92; 95% confidence interval, 0.70–1.19). The authors concluded that longer follow-up time might eventually confirm the independent association of NAFLD with cardiovascular disease–related mortality. There is not much debate that NAFLD is closely associated to the presence of MetSyn. However, to what degree NAFLD directly contributes to the increased cardiovascular risk observed in individuals with MetSyn is less clear. These data from Stepanova and Younossi8Stepanova M. Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol. 2012; 10: 646-650Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar demonstrate that the strength of the associations between NAFLD and prevalent cardiovascular disease and future cardiovascular disease–related mortality is significantly attenuated by the presence of traditional MetSyn components such as obesity and diabetes. At first glance, this would suggest that NAFLD is not associated with cardiovascular disease independent of these other known cardiovascular risk factors. However, these risk factors might be in the epidemiologic causal pathway between NAFLD and cardiovascular events, ie, NAFLD contributes to the pathophysiology of these factors such as diabetes and their resultant adverse cardiovascular effects. The importance of this distinction cannot be understated. As Stepanova and Younossi8Stepanova M. Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population.Clin Gastroenterol Hepatol. 2012; 10: 646-650Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar describe, the lipotoxicity and proinflammatory milieu that accompany NAFLD might in fact contribute to the pathophysiology of MetSyn and subsequently contribute to the increased risk for adverse cardiovascular events observed in individuals with MetSyn. The greater the degree to which fatty infiltration in the liver serves as a source of the characteristic high triglyceride/low HDL-C dyslipidemia, elevated blood pressures, and insulin resistance observed in MetSyn, the more important it will be to develop treatment strategies aimed at reducing the amount of fatty infiltration in the liver or its adverse metabolic effects. Therapies directed toward NAFLD or its adverse metabolic effects might prove to be important in modifying the cardiovascular risk associated with MetSyn. Regardless, individuals with NAFLD are very likely to meet current criteria for MetSyn and, by definition, possess multiple cardiovascular risk factors. These individuals have significantly higher rates of both all-cause and cardiovascular disease–related mortality. As a result, the identification of NAFLD should prompt clinicians to screen these individuals for cardiovascular risk factors and aggressively manage them in an attempt to reduce overall cardiovascular risk. To what degree NAFLD directly contributes to the underlying pathophysiology of MetSyn rather than simply being an end-organ manifestation of the syndrome is less clear. Further research investigating to what extent fatty infiltration in the liver directly contributes to the pathophysiology of MetSyn will be invaluable in determining to what degree therapies aimed at NAFLD might reduce the cardiovascular risk associated with MetSyn. Independent Association Between Nonalcoholic Fatty Liver Disease and Cardiovascular Disease in the US PopulationClinical Gastroenterology and HepatologyVol. 10Issue 6PreviewNonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs) have common metabolic risk factors. Despite reports from clinical studies, the association between NAFLD, cardiovascular disease, and cardiovascular mortality are not clear at the population level. Full-Text PDF