Atherosclerosis is the liver disease

1. First Moscow Medical University Chair of cardiology department of the clinic of the Internal Medicine Atherosclerosis is the liver disease Prof. O. Drapkina PACE Moscow 17.10.14

2. Mr. Lipoprotein • Professor Emeritus of MedicineFormer Director of Cardiovascular Research InstituteUniversity of California, San Francisco Richard J. Havel

3. Lipoprotein Structure Free cholesterol Phospholipids Apolipoprotein Triglycerides Cholesterol esters

5. Non-alcoholic fatty liver disease • NAFLD is probably the most common liver disease in many countries affecting 10% to 24% of the general population. • There is a direct correlation between body mass index (BMI) and prevalence and severity of NAFLD. Annals of hepatology 2002; 1(1): January-March: 12-19

6. Nonalcoholic steatohepatitis: morphology CMAJ 2005;172(7):899-905

7. Prevalence of NAFLD in Europe Total population (people with normal weight) • 15 – 20 % children • 20 – 24 % adults – on average 22% • Increases with age • Found more frequently in men • More frequently found among Europeans than Latin Americans Fan, 2009, EASL Congress

8. NAFLD in Russia • 27% of patients seeking help from general practitioners (DIREG, 2007) 30787 primary care patients were enrolled into open multicenter national-wide prospective study • Drapkina O, Ivashkin V, EASL, 2010 • Drapkina O, Ivashkin V., London, 2009

9. 27% of primary care patientsin Russia (DIREG, 2007)* NAFLD in Russia • NAFLD was found in 100% of MS patients. • Simple liver steatosis in 58 % , NASH in 42 % (n=25) of MS patients** *Ivashkin V, Drapkina O, EASL, 2010, Drapkina O, Congress on Prediabetes and the Metabolic Syndrome, 2011

10. Obesity - a major ethiologic factor in NAFLD • The prevalence of fatty liver in the general population is about 23% • The prevalence among alcoholics reaches 46%, among the obese - 76%, and among alcoholics  who are overweight - 95% • Consequently, fatty liver  is caused by  obesity in a greater extent than by alcohol • Drapkina OM, Smirin VI, VT Ivashkin Nonalcoholic fatty liver disease - a modernapproach to the problem. Attending Doctor. 2010. Т. 5. # 5. pg. 57–61. • Drapkina OM, Smirin VI, VT Ivashkin Pathogenesis, treatment and epidemiology ofNAFLD - what's new?Epidemiology of NAFLD in Russia. RMJ. 2011; 28: 1717-1722

11. Metabolic syndrome today • 20 – 30 % of population in economically advanced countries, but… • Only 5 % in those with normal BMI; • 22 % of overweighted patients • 60 % of patients with obesity

12. THE METABOLIC SYNDROME Steatohepatitis.. TYPE II DIABETES MELLITUS INSULIN RESISTANCE HYPERTENSION DYSLIPIDEMIA ATHEROSCLEROSIS

13. Visceral obesity • Increase in liverfree fatty acids inflow (VLDL) • Glucose utilization in peripheral tissues  … hyperinsulinemia • SMC proliferation with phenotypic changes Fasting hypertriglyceridemia HDL,LDL

14. Liver in metabolic syndrome • Liver is a major target of injury in patients with MS Insulin resistance (≈ 30 % of adults) Fat accumulation into hepatocytes (gluconeogenesis, glycogenolysis) Nonalcoholic fatty liver disease (up to 20 % of adults) Nonalcoholic steatohepatitis cirrhosis and end-stage liver disease American Journal of the Medical Sciences. 330(6):326-335, Dec 2005.

15. Cardiovascular diseases and NAFLD:disease and mortality rates. Results of prospective studies • Adams LA et al. Gastroenterology 2005;129:113–12 • Ekstedt M et al. Hepatology 2006;44:865–873.873 • Dunn W et al. Am J Gastroenterol 2008;103:2263–2271 • Ong JP et al. J Hepatol 2008;49:608–612 . . . . Cardiovascular diseases are the main cause of mortality among patients with NAFLD!

16. NAFLD and the risk of cardiovascular disorders • Драпкина О.М., Смирин В.И., Ивашкин В.Т. Патогенез, лечение и эпидемиология НАЖБП – что нового? Эпидемиология НАЖБП в России. РМЖ. 2011; 28: 1717-1722 • Ghouri N., Preiss D., Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 2010; 52:1156–1161.

17. Acetyl CoA Сholic acid (500-700 mg) synthesis in the liver (1g) Exogenously (300-500 mg) Pool of cholesterol (~140 g) Bile cholesterol (600 mg) Cell membranes (85 mg) Steroids (40 mg) Cholesterol synthesis

18. Cholesterol synthesis in NASH Acetyl CoA HMGCR (srebp-2) Free cholesterol LDLR LAL LDL-C Min et al, Cell Metabol, 2012

19. NAFLD • The thickness of the epicardial fat  and DCHF • Endothelial dysfunction • Systemic inflammation • Traditional  atherosclerosis markers • Drapkina O 2011 • Targer G., Day P.D., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363:1341–50.

20. Epicardial fat – fat shell of the heart EF and the myocardium share the same microcirculation, so the epicardial fat should be considered the true visceral fat depot of the heart. Epicardial fat and … steatosis of the heart

21. MEASUREMENT OF EPICARDIAL FAT USINGECHOCARDIOGRAPHY • EF is measured from 2D parasternal longaxis • at the point on the free wall of the right perpendicular to the aortic valve

22. POTENTIAL USES OF ECHOCARDIOGRAPHIC EPICARDIALFAT THICKNESS FOR DIAGNOSIS • 14 NASH (biopsy) vs 14 controls • EF was associated with intrahepatic fat accumulation (7.9±2.1 vs 4.1±1.8 mm) • EF was associated with visceral fat, BMI, Waist circumferences, HOMA-IR and ALT (p<0.01) CapristoE, 2010 • >7,5-9,5 mm - MS • 7.9±1.6 (MS)vs. 5.1±1.9 mm(no MS) • >9,5 mm - IR • > 7 mm - atherosclerosis and CAD (only in woman) • >4,5 мм - low coronary flow reserve in women. • >3 мм - independent risk factor of CAD

23. Epicardial fat: marker of metabolic syndrome, early vascular damage and diastolic dysfunction • Patients with MS had significantly higher epicardial fat thickness than controls (4.95±2.6 and 2.69±1.8 mm, p=0.01). • Age, BMI, waist circumference, fasting glucose, HOMA-IR, intima-media thickness were significantly higher in subjects with MS and increased epicardial fat than without, while theechocardiographic diastolic function index early/atrial peak flow (E/A) was significantly lower. • At multivariate analysis HOMA-IR remained the independent variable associated with epicardial fat (p=0.04, OR1.8, 95% CI1.037-3.58). Heart Failure 2012 Congress, Belgrad, 20 May 2012 Drapkina O,KorneevaO

24. NAFLD • The thickness of the epicardial fat  and DCHF • Endothelial dysfunction • Systemic inflammation • Traditional  atherosclerosis markers • Drapkina O 2011 • Targer G., Day P.D., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363:1341–50.

25. NAFLD and endothelial dysfunction vasodilatation % Villanova N, et al. Hepatology,2005

26. Arterial stiffness and : the Cardio-GOOSE study • The study population consisted of 220 participants (123 women), aged between 30 and 70 years, who participated in the GOOSE study. Arterial stiffness was determined by measuring the carotid-femoral pulse wave velocity (PWV) by means of the PulsePen device. Preclinical atherosclerosis was detected by carotid intima-media thickness (IMT) measurement. NAFLD+MS NAFLD PWW Norma Salvi P., Ruffini R., Agnoletti D.et al. Increased arterial stiffness in nonalcoholic fatty liver disease: the Cardio-GOOSE study. J Hypertens. 2010; 28(8): 1699-707.

27. Arterial stiffness SI 9,8 м/с RI 25,6% AIx31,6% AIx75 21,1% Spa, мм.рт.ст. 120

28. NAFLD • The thickness of the epicardial fat  and DCHF • Endothelial dysfunction • Systemic inflammation • Traditional  atherosclerosis markers • Drapkina O 2011 • Targer G., Day P.D., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363:1341–50.

29. NAFLD - a chronic inflammatory process • In non-smoking patients with hepatic steatosis observed elevated levels of CRP, fibrinogen, v-WF, PAI-1,when compared with patients without evidence of steatosis • Excluding the impact of other factors such as age, BMI, BP, insulin resistance, triglyceride levels Targher G et al. Diabet Med 2005;22:999–1004

30. NAFLD - a chronic inflammatory process • There is a correlation between levels of CRP and IL-6 and the degree of inflammation and fibrosis in NAFLD  Wieckowska A et al. Am J Gastroenterol 2008;103:1372–1379

31. Statins and NAFLD • Safety: ↑ AST / ALT in 1-3% of patients • There are no convincing data on the relationship between ↑ AST / ALT and histologicallyverified liver damage against statins • Atorvastatin (80 mg) reduced the AST / ALT, and possibly reduced steatosis[Gomez-Dominguez, 2006; Kiyici, 2003] • Pravastatin (80 mg) reduced ALT [Lewis et al. 2007] • Possible mechanisms - Reduction of TNF-alpha, IL-6, CRP, - Reduced delivery of FFA to the liver, the effect on insulin through adiponectin  

32. Statins are safe to use (GREACE study) N= 1600 0 18 36 Time (months) Athyros et al, Lancet. 2010 Dec 4;376(9756):1916-22.

33. Statins for NAFLD: molecular mechanisms • Effect on the metabolism of the gene sonic hedgehog (sHh) - progression of fibrosis and reparative mechanisms • Inhibition of sHh reduces weight gain from dietary habits • sHh: effects on stellate cells and possible involvement in the pathogenesis of C sonic hedgehog Argo C.K., Loria P., Statins in liver disease: a molehill, an iceberg, or neither? // Hepatology. 2008 Aug;48(2):662–9.

34. The Liver-Heart Connection