Fatty liver and Cardiovascular Disease

1. Fatty liver and Cardiovascular Disease Seyed Moayed Alavian M.D. Professor of Gastroenterology and Hepatology Editor-in-chief of Hepatitis Monthly E mail: editor@hepatmon.com 3rd International Congress of Preventive Cardiology- Shiraz Grand Hotel, October 3-5, 2014.

2. Importance • NAFLD is frequently associated with obesity, diabetes mellitus and the metabolic syndrome. However, nowadays, its prevalence has grown to 30% in the general population with growing pattern in developing countries. • There are emerging evidence regarding contribution of diabetes, obesity, intake of high fat foods and metabolic syndrome to higher incidence of HCC in the world. NAFLD is a consequence : Obesity low activity Kelishadi et all 2011, Khedmat et all 2011

3. Obesity is associated with hypertension, insulin resistance, diabetes type 2, hyperlipidemia and ischemic heart disease. The epidemic of obesity in Iran and the world is a major public health issue and more than fourth of adult patients are obese and more than 3% are morbid obese in Iran . Kelishadi et all 2008

4. Fatty liver disease can be found in patients with diabetes mellitus and obesity or can be diagnosed in individuals without these diseases. • This raises questions regarding the influence of fatty liver disease on mortality and the risk of diabetes in the future. Alavian SM. Diabetes mellitus and fatty liver disease: Which comes first? Int J Endocrinol Metab. 2010

5. The most important are insulin resistance, type 2 diabetes mellitus, abnormality in lipid profiles, high blood pressure, cardiovascular disease, stroke, and fatty liver disease . • NASH is a component of metabolic syndrome and its consequences, and it is not surprising that elevations in ALT activity are frequently present in people with diabetes mellitus and cardiovascular disease and are associated with increased mortality. • Doctors should alert their patients that fatty liver puts them at high risk of acquiring diabetes mellitus and cardiovascular disease in the future. Alavian SM. Diabetes mellitus and fatty liver disease: Which comes first? Int J Endocrinol Metab. 2010

6. Differentiation NAFL: NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH: NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. The prevalence of NASH ranging from 3 to 5%.

7. Steatohepatitis Simple Fatty liver Steatohepatitis + Fibrosis NASH-Cirrhosis

8. Non-invasive assessment of steatohepatitis and advanced fibrosis in NAFLD • NAFLD fibrosis score. • Transient elastography (Fibroscan)

9. Non-invasive assessment of steatohepatitis and advanced fibrosis in NAFLD NAFLD fibrosis score: Based on six readily available variables (age, BMI, BS, Plat, albumin, AST/ALT ratio) and it is calculated using the published formula (http://nafldscore.com). Meta-analysis of 13 studies consisting of 3,064 patients, NAFLD Fibrosis Score 1.455 had 90% sensitivity and 60% specificity to exclude advanced fibrosis whereas a score 0.676 had 67% sensitivity and 97% specificity to identify the presence of advanced fibrosis.

10. Non-invasive assessment of steatohepatitis and advanced fibrosis in NAFLD • Transient elastography: • Fibroscan: Although a recent meta-analysis showed high sensitivity and specificity for identifying fibrosis in NAFLD, has a high failure rate in individuals with a higher BMI. • MR elastography: is rarely used in clinical practice.

11. Invasive assessment of steatohepatitis and advanced fibrosis in NAFLD • When to obtain a LBx in NAFLD? • At increased risk to have steatohepatitis and advanced fibrosis. • The presence of metabolic syndrome and the NAFLD fibrosis score may be used for identifying patients who are at risk for steatohepatitis and advanced fibrosis. • Patients with suspected NAFLD in whom competing etiologies for hepatic steatosis, co-existing chronic liver diseases cannot be excluded without a liver biopsy. • Current evidence does not support routinely repeating a liver biopsy in patients with NAFL or NASH.

12. NASH is reversible? In NASH cases, about 20% of patients lead to cirrhosis during their lifetime. Edmison J et all. 2007 In a cohort of 39 cases with NAFLD, liver fibrosis improved in 31%, progressed in 28% and unchanged in 41% during 2.4 years. Tight glycemic control, rather than weight reduction,ameliorates liver fibrosis. Hamaguchi E, et al. 2010 Prospective study of 52 NAFLD cases with 36 months f/u, 27% had fibrosis progression, 48% had static disease and 25% had fibrosis regression. Wong VW, et al. 2010

13. Non-alcoholic fatty liver disease: Natural history Steatosis have very slow, if any, histological progression, while patients with NASH can exhibit histological progression to ESLD. Patients with NAFLD have increased overall mortality compared to matched control populations. The most common cause of death in NAFLD is CVD. Patient with NASH (but no NAFLD) have an increased liver related mortality rate. Ten year survival of NAFLD with fibrosis and cirrhosis in recent study was 81.5% that was not different from match patient with HCV cirrhosis.

14. NAFLD in Iran In a large scale study on 10,368 subjects in Tehran, the prevalence of the metabolic syndrome was 30.1% . Azizi et al. 2003 NAFLD is associated with male gender, old age, obesity, and MS. It’s prevalence was 21.5%. Lankarani et al.2013 An autopsy of 895 deaths from non-hepatic causes: Steatosis; 31.6% Steatohepatitis; 2.1% Sotoudehmanesh et al.2006

15. NAFLD in Iran Prevalence of NAFLD in Iranian children was 7.1%. Alavian etal.2009 Prevalence of NASH in Iran was 2.9 %. Sohrabpour et al. 2011 Prevalence of NASH in Iran adults was 3.3%. Rogha et al.2011 Prevalence of NAFLD in T2DM in Iran was 55.8%. Merat et al.2011

16. Fatty Liver and Cardiovascular Diseases Patients with nonalcoholic fatty liver disease, both adults and children, typically meet the diagnostic criteria for the metabolic syndrome (i.e., abdominal obesity, hypertension, atherogenic dyslipidemia, and dysglycemia) and therefore have multiple risk factors for cardiovascular disease.

17. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. • A systematic review and meta-analysis of seven cross-sectional studies (involving a total of 3497 subjects) confirmed that nonalcoholic fatty liver disease diagnosed on ultrasonography is strongly associated with increased carotid-artery intimal medial thickness and an increased prevalence of carotid atherosclerotic plaques. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol. 2008

18. Liver: an alarm for the heart? 317 adult patients who underwent elective coronary angiography classified into either of normal and clinically relevant. The groups were significantly different in terms of gender, fasting blood glucose, low-density lipoproteins, diabetes, hypertension and FL. In binary logistic regression, FL was the strongest independent predictor of CAD (OR) = 8.48%, followed by DM (P = 0.002, OR= 2.94) and male gender (P = 0.014, OR= 2.31). This pattern of associations did not change after clinically significant variables (waist-to-hip ratio, body mass index, triglycerides and high density lipoproteins) were added to analysis. Mirbagheri SA, et al. Liver: an alarm for the heart? Liver Int. 2007 Alavian SM. 'Liver: an alarm for the heart?'. Liver Int. 2008

19. Liver: an alarm for the heart? • Conclusion: Fatty liver seems to be a strong independent alarm for the presence of significant CAD. • This association is independent of the shared risk factors for both diseases, such as age, male gender, hyperglycaemia, diabetes and abnormal lipid profile. Mirbagheri SA, et al. Liver: an alarm for the heart? Liver Int. 2007 Alavian SM. 'Liver: an alarm for the heart?'. Liver Int. 2008

20. Sonographic fatty liver, overweight and ischemic heart disease Lin YC, et al. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol. 2005

21. Sonographic fatty liver, overweight and ischemic heart disease • In conclusion • Sonographic FL is an independent correlate of CAD electrocardiographic abnormalities. • The presence of fatty liver and its severity should be carefully considered as independent risk factors for IHD. Synergistic effect between fatty liver and overweight for developing IHD. Abdominal sonographic examination may provide valuable information for IHD risk assessment in addition to limited report about liver status, especially for overweight males Lin YC, et al. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol. 2005

22. Carotid artery wall thickness and nonalcoholic fatty liver disease. Targher G, et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care. 2006

23. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. • In patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function Lautamaki R, et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. American journal of physiology Endocrinology and metabolism. 2006

24. Insulin resistance • liver steatosis links, via myocardial insulin resistance as part of a generalized state of insulin resistance, to the risk of coronary syndromes.

25. Causes of Death in NAFLD/NASH Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003–1.76; P .03). Adams LA, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005

26. Causes of Death in NAFLD/NASH Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. IHD is more common than liver related-death in NAFLD patients. Adams LA, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005

27. Management of NAFLD/NASH

28. Changing the life style and modification of obesity can help us for the best achievement . Unfortunately changing the life style is not possible every time and the most of drugs are ineffective for control of obesity and fatty live , however weight loss is mandatory for stopping the natural history of NAFLDs. Khosravi S, Alavian SM et all 2011

29. Weight loss is mandatory • Weight loss generally reduces hepatic steatosis. • Loss of 3–5% of body weight improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necro-inflammation. • Exercise alone in adults with NAFLD may reduce hepatic steatosis but its ability to improve other aspects of liver histology remains unknown.

30. Medical therapy • All medical treatment of obesity fail to achieve the mean weight loss of more than 10% of body weight and unfortunately weight regain following these forms of treatment is almost universal.