Perspectives in clinical gastroenterology and hepatologyManagement of Dyslipidemia as a Cardiovascular Risk Factor in Individuals With Nonalcoholic Fatty Liver Disease
Section snippets
Dyslipidemia in Nonalcoholic Fatty Liver Disease
Dyslipidemia is frequent in individuals with NAFLD. A substudy from the Multi-Ethnic Study of Atherosclerosis assessed the relationship between radiographically diagnosed NAFLD and dyslipidemia.6 NAFLD was associated independently with increased triglyceride levels, increased low-density lipoprotein (LDL) particle concentration, decreased LDL particle size, and decreased high-density lipoprotein (HDL) levels after controlling for insulin resistance. These findings have been replicated in
Cardiovascular Disease and Nonalcoholic Fatty Liver Disease
CVD events are a frequent cause of morbidity and mortality in individuals with NAFLD (Table 1). Three community-based studies have shown that individuals with radiographically diagnosed NAFLD have an increased risk of CVD events and mortality compared with individuals without NAFLD.13, 14, 15 Hamaguchi et al16 assessed 1637 subjects in a community-based cohort from Japan for NAFLD by ultrasonography. Nineteen percent of the cohort was found to have NAFLD. Cardiovascular (CV) events occurred in
Cardiovascular Risk Stratification in Nonalcoholic Fatty Liver Disease
Several different methods are used in the general population to estimate CVD risk including the Framingham Risk Score (FRS). The FRS is a validated measure of CV risk in the general population. Incorporating age, sex, cholesterol, HDL, smoking status, and hypertension, the FRS predicts an individual's 10-year risk of myocardial infarction or CVD death. Furthermore, the FRS has been validated as a predictor of CVD in NAFLD and should be used to risk-stratify individuals and guide treatment of
Management of Dyslipidemia and Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease
Lifestyle modification, encompassing weight loss and increased physical activity, is the cornerstone of dyslipidemia management in NAFLD. However, for groups with increased CVD risk, lifestyle modification should be accompanied by lipid-lowering therapy. Guidelines set forth by the NCEP Adult Treatment Panel III provide guidance on which groups should be targeted for lipid-lowering therapy and outline treatment goals (Figure 1).12 These guidelines were not designed specifically to address
Diabetes Mellitus
DM is associated with an increased risk of CVD. Because DM is highly prevalent among individuals with NAFLD, comprehensive management is essential for CVD risk reduction. A detailed discussion of the management of DM in individuals with NAFLD is beyond the scope of this review. However, primary and secondary prevention of CVD events in individuals with DM should focus on multifactorial risk reduction, including treatment of hypertension and dyslipidemia.51 In addition, specific treatments of DM
Fatty Liver and Newly Approved Lipid-Lowering Agents
Statins are effective LDL-lowering agents; however, in an important subset of individuals, statins cannot lower LDL to goal treatment levels. Therefore, the search for medications to improve LDL lowering is ongoing. Two new lipid-lowering agents recently were approved. Mipomersen, an anti-sense oligonucleotide, binds to and degrades hepatic apolipoprotein B messenger RNA, decreasing circulating LDL levels. Mipomersen is effective at LDL lowering in individuals with hyperlipidemia, homozygous
Future Directions
NAFLD is an increasing epidemic in the United States and is associated with CV mortality. Many individuals with NAFLD will die of CVD before the development of end-stage liver disease. Thus, the careful management of CVD risk factors including dyslipidemia in individuals with NAFLD is essential to reduce CVD-related mortality. Gastroenterologists and hepatologists should play an active role in comprehensive CVD risk assessment including screening for dyslipidemia, DM, the MetS, cigarette
References (84)
- et al.
Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study
Gastroenterology
(2011) - et al.
Nonalcoholic fatty liver disease and serum lipoproteins: the Multi-Ethnic Study of Atherosclerosis
Atherosclerosis
(2013) - et al.
Non-high-density lipoprotein cholesterol as a biomarker for nonalcoholic steatohepatitis
Clin Gastroenterol Hepatol
(2012) - et al.
Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk
J Am Coll Cardiol
(2009) - et al.
Beyond low-density lipoprotein cholesterol: respective contributions of non-high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women
J Am Coll Cardiol
(2009) - et al.
The natural history of nonalcoholic fatty liver disease: a population-based cohort study
Gastroenterology
(2005) - et al.
Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome
Hepatology
(2003) - et al.
The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis
J Am Coll Cardiol
(2010) - et al.
Carotid artery intima-media thickness in nonalcoholic fatty liver disease
Am J Med
(2008) - et al.
Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction
Gastroenterology
(2009)
The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease
J Hepatol
Fructose consumption as a risk factor for non-alcoholic fatty liver disease
J Hepatol
Increased exercise level and plasma lipoprotein concentrations: a one-year, randomized, controlled study in sedentary, middle-aged men
Metabolism
Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD)
J Hepatol
Obstructive sleep apnea as a risk factor for type 2 diabetes
Am J Med
Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome
Chest
Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese
J Hepatol
Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study: a post-hoc analysis
Lancet
Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study
J Hepatol
Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-alpha-lowering property
Dig Liver Dis
Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes
Gastroenterology
Statins for hyperlipidemia in patients with chronic liver disease: are they safe?
Clin Gastroenterol Hepatol
Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity
Gastroenterology
n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review
Am J Clin Nutr
n-3 fatty acids and serum lipoproteins: human studies
Am J Clin Nutr
Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease
Dig Liver Dis
Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia
Am J Cardiol
A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease
Dig Liver Dis
Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study
Hepatology
Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin
J Am Coll Cardiol
Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia
Am J Cardiol
Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study
Lancet
Long-term follow-up of patients with nonalcoholic fatty liver
Clin Gastroenterol Hepatol
Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity
Hepatology
Cirrhosis and liver failure in nonalcoholic fatty liver disease: molehill or mountain?
Hepatology
Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity
Ann Med
Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study
Am J Gastroenterol
Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes
Diabetes Care
Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study
Hepatology
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
Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients
Diabetes Care
The metabolic syndrome as a predictor of nonalcoholic fatty liver disease
Ann Intern Med
Cited by (33)
IFN-α-2b treatment protects against diet-induced obesity and alleviates non-alcoholic fatty liver disease in mice
2019, Toxicology and Applied PharmacologyCitation Excerpt :In humans, NAFLD arises when excess fat accumulates in hepatocytes in people who consume little or no alcohol. Due to the obesity epidemic across the world, NAFLD is increasingly becoming one of the most prevalent chronic liver disorders, and it is strongly associated with an increased risk of developing cardiovascular disease (Corey and Chalasani, 2014), which is the topmost cause of mortality amongst individuals with NAFLD (Targher et al., 2010). It is important to remark that NAFLD-associated dyslipidemia is amongst the most important cardiovascular disease risk factors, and at the same time it is one of the most easily modifiable.
Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis
2016, Mechanisms of Ageing and DevelopmentCitation Excerpt :Therefore, further studies are required to determine whether LDLR up- or down-regulation is related to NASH/NAFLD pathogenesis (Arguello et al., 2015). On the other hand, atherogenic dyslipidemia, which is characterized by high concentrations of plasma triglycerides, LDL and decreased high-density lipoprotein (HDL) levels (Cohen and Fisher, 2013; Corey and Chalasani, 2014), increases insulin-induced hepatic lipid synthesis and is associated with disease severity in NAFLD patients (Siddiqui et al., 2015). It has been shown that liver CD36 expression is also upregulated like LDLR, and linked to the severity of steatosis in animal and human NASH (Van Rooyen et al., 2011; Miquilena-Colina et al., 2011).
Recent insights on the role of cholesterol in non-alcoholic fatty liver disease
2015, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :This is indeed a low rate considering the cardiovascular risk of this patient population and is likely related to a fear to liver toxicity, which is a rather rare event [240]. Thus, dyslipidemia management with statins should not be withheld in individuals with NAFLD as this drug class significantly reduces cardiovascular events in these patients [142] and might be of benefit for liver disease. With regard to ezetimibe, an agent that reduces intrahepatic cholesterol by inhibiting cholesterol absorption from the intestine through inhibition of the NPC1L1 sterol transporter channel and modestly lowers serum cholesterol levels [246], both preclinical studies [106,247] and clinical data [248,249] suggest that ezetimibe may be beneficial for NAFLD.
Chronic liver disease is not associated with statin prescription in a primary care cohort
2023, Journal of Investigative Medicine
This article has an accompanying continuing medical education activity on page e60. Learning Objectives—At the end of this activity, the successful learner will be able to evaluate patients with NAFLD for cardiovascular disease risk and formulate a comprehensive treatment plan to address cardiovascular disease risk factors.
Conflicts of interest This author discloses the following: Dr Chalasani has served as a consultant in the past 12 months to Lilly, Salix, Aegerion, Merck, Abbott, and Mochida in the area of drug hepatotoxicity. He has also received research grant support from Gilead, Genfit, Takeda, Cumberland Pharmaceuticals, Intercept pharmaceuticals, and Enterome. The remaining author discloses no conflicts.
Funding Supported in part by a National Institutes of Health grant (K24 DK069290A to N.C.) and an AASLD Clinical and Translational Research Award (K.E.C.).