Non alcoholic fatty liver disease and atherosclerosis Raul Santos, MD Sao Paulo Medical School Hospital Sao Paulo, Brazil
Disclosure Honoraria received for consult and/or speaker : Astra Zeneca, Amgen, Genzyme/ISIS, BMS, Pfizer, Eli Lilly, Biolab, Jansen, Boehringer- Ingelheim, Unilever, Sanofi/Regeneron, Novartis. 2
Sudden death is more frequent in those naturally fat in comparison with the thin ones Hipocrates, V Century B.C.
Metabolic Syndrome and Risk of Incident Cardiovascular Events and Death : A Systematic Review and Meta-Analysis of Longitudinal Studies RR and 95% CI for Metabolic Syndrome and Incident Cardiovascular Events and Death Studies are listed in chronological order by year that their cohorts were created (except for the last study listed, which includes multiple cohorts). Gami AS et al. JACC 2007; 49: 403-414 4
NAFLD and atherosclerosis Definitions Prevalence Epidemiological evidence so far Mechanisms associated Dyslipidemia Dysglycemia Inflammation Blood pressure? Treatment
Hepatic Steatosis/NAFLD Bhatia L S et al. Eur Heart J 2012;eurheartj.ehr453
The Super Size of The Problem: Excess Body Weight and NAFLD Steatosis BMI < 30 kg/m 2 : 25% have steatosis 1 BMI>30 kg/m 2: > 65 75% steatosis and 15-20% NASH BMI>35 kg/m 2 : 85 90% steatosis NASH: 40 to 95% are obese > 50% DM2 80% dyslipidemia 1-Argo CK & Caldwell SH. Clin Liver Dis2009;13:511-31 Preiss D & Satar N. Clinical Science (2008) 115, 141 150
NAFLD According to The Liver Specialist Preiss D & Satar N Clinical Science (2008) 115, 141 150
Mechanisms of Hepatic Steatosis Development Postic & Girard J Clin Invest. 2008; 118(3):829 838 9
Fructose consumption and NAFLD: a new/old kid in the block? Dekker M J et al. Am J Physiol Endocrinol Metab 2010;299:E685-E694
Gut microbiota and liver disease Journal of Gastroenterology and Hepatology Volume 29, Issue 6, pages 1139-1148, 15 MAY 2014 DOI: 10.1111/jgh.12556 http://onlinelibrary.wiley.com/doi/10.1111/jgh.12556/full#jgh12556-fig-0001
NAFLD as Seen by The Cardiologist?
Hepatic Steatosis is Independently Associated with Coronary Artery Calcification N=505 Steatosis 40%. HS (-) HS (+) P value Model 1 1 (reference) 1.49 (1.00-2.21) Model 2 1 (reference) 1.68 (1.00-2.82) Model 3 1 (reference) 1.73 (1.02-2.95) 0.05 0.05 0.04 Model 1: Adjusting for age Model 2: Adjusting for age, pulse pressure (systolic-diastolic blood pressure), body mass index, smoking status, alcohol consumption, METS, LDL cholesterol, TG/HDL ratio, fasting glucose, blood pressure medication and lipid lowering medication. Model 3: Additional adjustment for ALT/AST ratio and GGT Santos RD et al Atherosclerosis 2007;194:517-9
Carotid-Artery Intimal Medial Thickness in Patients with Nonalcoholic Fatty Liver Disease. Targher G et al. N Engl J Med 2010;363:1341-1350.
27 studies NAFLD associated with: CAC IMT Aortic Stiffness Altered FMD Independently of risk factors or the metabolic syndrome Oni et al. Atherosclerosis 2013; 230: 258-267
NAFLD NASH Steatosis Ekstedt et al. HEPATOLOGY 2006;44:865-873
Limitations of the epidemiological studies associating NAFLD with CVD Influence of confounders ex- DM, risk factors of the MS Different methods to diagnose NAFLD exenzymes, ultra-sound Small studies with biopsy proven subjects Steatosis vs. NASH? However no doubt NAFLD is a marker of increased CVD
Pathophysiology associating NAFLD with CVD
N=821 The area under the ROC curve for steatosis was 0.80 (95% CI 0.77 0.83), 0.80 in men (95% CI 0.77 0.83) and 0.83 (95% CI 0.73 0.93) in women. Carvalho JAM et al. Ann Med. 2011;43:487-94
N=6,333 HS= 2,288 Model 1: unadjusted. Model 2: adjusted for age, gender, alcohol use, and physical activity. Model 3: adjusted for model 2 plus BMI, waist circumference, hypertension or antihypertensive medications, diabetes or use of diabetes medications, hyperglycemia, log hs-crp, smoking, and use of lipid-lowering medications. Makadia et al. Am J Cardiol 2013;112:1599-1604
Liver Fat and VLDL 1 production Adiels et al. Diabetologia 2006;49:755-65
Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with Increased systemic inflammation Chiadi E. Ndumele, Khurram Nasir, Raquel D. Conceiçao, Jose A.M. Carvalho, Roger S. Blumenthal, Raul D. Santos N=2,338; steatosis 32% Ndumele CE, et al. Arterioscler Thromb Vasc Biol. 2011;31:1927-32.
Percentage of hs-crp > 3 mg/l Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with Increased systemic inflammation Chiadi E. Ndumele, Khurram Nasir, Raquel D. Conceiçao, Jose A.M. Carvalho, Roger S. Blumenthal, Raul D. Santos N=2,338; steatosis 32% 50 40 41 48 Associations of Combined Presence of Hepatic Steatosis, Metabolic Syndrome, and Obesity With High hs-crp ( 3 mg/l) in Multivariate Logistic Regression Analyses No. of Conditions Present Model 1* OR (95% CI) Model 2 OR (95% CI) None Reference group Reference group 30 20 10 27 17 None 1 2 3 Number of Factors 1 1.80 (1.42 to 2.29) 1.92 (1.49 to 2.48) 2 3.29 (2.50 to 4.34) 3.38 (2.50 to 4.57) 3 4.44 (3.27 to 6.01) 4.53 (3.23 to 6.35) *Model 1: unadjusted. Model 2: adjusted for age, gender, diabetes mellitus, LDL-C, smoking status (current smoker or nonsmoker), use of lipid-lowering medication, and physical activity (assessed by the International Physical Activity Questionnaire as low, moderate, or high physical activity). Reference group: No hepatic steatosis, metabolic syndrome, or obesity. Ndumele CE, et al. Arterioscler Thromb Vasc Biol. 2011;31:1927-32. 23
Possible Mechanisms Leading to Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease. Targher G et al. N Engl J Med 2010;363:1341-1350.
Hepatic Steatosis Is Independently Associated With Hyperreactive Blood Pressure Response on The Exercise Stress Test N= 13,410 subjects (mean age: 42.4 years, 26.6% female). HS 29.5% (n=3,956). Laurinavicius AG, Santos RD et al. Submitted
Hepatic Steatosis Is Independently Associated With Hyperreactive Blood Pressure Response on The Exercise Stress Test N= 13,410 subjects (mean age: 42.4 years, 26.6% female). HS 29.5% (n=3,956). Laurinavicius AG, Santos RD et al. Submitted
Additive effects of Hepatic Steatosis on Waist Circumference as a Predictor of Hyperreactive Blood Pressure Response on The Exercise Stress Test Laurinavicius AG, Santos RD et al. Submitted
Relation between baseline muscle sympathetic nervous activity and visceral abdominal fat Visceral abdominal fat Subcutaneous abdominal fat Total fat mass Alvarez G E et al. Circulation 2002;106:2533-2536
Treatment
NAFLD Treatment Weight Loss Exercise Control of Dyslipidemia NAFLD treatment per se Lipid Lowering Drugs Statins Ezetimibe TZD and Vitamin E GLP-1
Routine Physical Activity and Hepatic Steatosis in Obese Subjects N=5,743 Oni et al. Am J Cardiol in press doi 10.1016/j.amjcard.2014.09.044
Evolution of Liver Enzymes in Subjects Receiving or Not Statins : Liver Enzymes Elevated at Baseline GREACE With Statins N=227 Wo Statins N=210 Athyros et al. Lancet 2010;376:1916-1922
Ezetimibe Reduces Hepatic Fat measured by MRI in Insulin-Resistant Obese Subjects on a Weight Loss Diet Chan et al. Diabetes Care. 2010;33:1134-9
Pioglitazone and Vitamin E Improve Steatosis and Liver Inflammation Before After Sanyal AJ et al. N Engl J Med 2010;362: online supplement.
Glucagon-like Peptide-1 Receptor (GLP-1R) is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway Gupta NA et al. Hepatology. 2010; 51: 1584 1592.
Conclusions NAFLD is not simply a fat deposit in the liver NAFLD is highly prevalent The liver plays an important role in dyslipidemia, insulin resitance and inflammation and posssibly sympathetic activation. There is clear association between NAFLD and atherosclerosis (Causality?) Lifestyle changes and some medications might be useful in treating NAFLD and preventing both its complications and CVD