NAFLD-Metabolic Syndrome- THE LINK
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The document discusses non-alcoholic fatty liver disease (NAFLD) and its relationship to metabolic syndrome. It begins by defining NAFLD and its subtypes, including simple steatosis and non-alcoholic steatohepatitis (NASH). It then discusses the risk factors and pathophysiology of NAFLD, noting its association with obesity, diabetes, and other components of metabolic syndrome. The document outlines current diagnostic and treatment approaches for NAFLD, including lifestyle modifications involving diet, exercise and weight loss. It also discusses potential drug therapies and newer treatment strategies being explored.
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NAFLD-Metabolic Syndrome- THE LINK
- 1. NAFLD ꝏ METABOLIC SYNDROME DR.S.VADIVEL KUMARAN MD(Gen.Med).,DM(Med.Gastro) Kauvery Hospital Alwarpet-Chennai
- 2. NAFLD It’s a clinico-histopathologic infirmity Hepatic pandemic of 21st century
- 3. Definitions Shutterstock ID: 286407365 Fat Deposition in Liver The macrovesicular steatosis that occupies at least 5% of the hepatocytes Simple Steatosis Presence of fat in the liver with or without the presence of lobular inflammation on histology Non-alcoholic Steatohepatitis or NASH Steatosis and inflammation are associated with the presence of one of the following 3 additional features on liver histology: Ballooning of hepatocytes Mallory hyaline bodies Fibrosis Duseja J, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
- 4. SYNONYMS Alcohol-like liver hepatitis Steatonecrosis Pseudo-alcoholic hepatitis Fatty liver hepatitis Diabetic hepatitis
- 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. MORBIDITY Globally- 25-30% India- 9-32%: Age group of 40-60yrs.
- 8. Risk Factors of NAFLD Calzadilla Bertot L, et al. Int J Mol Sci. 2016;17(5):774. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. Source: Patel V, 2016.
- 9. NASH Association Diabetes Metabolic syndrome Atherogenic dyslipidemia CAD CKD HCC “Two hit or Multiple hit”
- 10. OXIDATIVE STRESSORS Hepatic iron Antioxidant deficiency Leptin(↑) Altered gut microbes
- 11. NAFLD No longer a NASCENT finding
- 12. Prevalence in Asian Countries Prevalence (%) of NAFLD in different Asian countries are as follows1: Prevalence of NASH in patients with biopsy-proven NAFLD is 63.5%3 China 15%-40% India 30% Japan 25%-30% Korea 27% Affects around a quarter of the Asian adult population.1 NAFLD epidemic in Asia1,2 Obesity Metabolic syndrome Urbanisation Sedentary lifestyle Western diet 1. Fan JG, et al. J Hepatol. 2017;67(4):862-873. 2. Pati GK, et al. Euroasian J Hepatogastroenterol. 2016;6(2):154-162. 3. Younossi ZM, et al. Hepatology. 2016;64(1):73-84. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.
- 13. POPULAION 100% NAFL 30% NASH 7% NASH Cirrhosis 9-25% Liver failure 40-62% HCC 4-22%, Liver mortality 30-40% Improves- 15-25% Stable – 34-50% HCC- 0-0.5% Stable- 50-70% Progress- 25-37% HCC- 0-2.8%
- 15. NAFLD: 30-80% of obese individuals 30-50% of diabetics 90% of hyperlipidemics
- 18. International Diabetes Federation Definition: Abdominal obesity plus two other components: elevated BP, low HDL, elevated TG, or impaired fasting glucose
- 19. Definition Constellation of metabolic abnormalities that confer increased risk of cardiovascular disease(CVD) and diabetes mellitus.
- 20. Alternative names Metabolic syndrome Syndrome X Insulin resistance syndrome Deadly quartet Reaven’s syndrome
- 21. THE METABOLIC SYNDROME HYPERTENSION TYPE II DIABETES MELLITUS ATHEROSCLEROSIS INSULIN RESISTANCE DYSLIPIDEMIA Steatohepatitis..
- 22. IDF criteria 1. Waist circumference: ≥90 in males ≥80 in females 2. Plus two or more of the following a) Hypertriglyceridemia: ≥150 TG’s or specific medication b) Low HDL cholesterol: <40(M) and <50(F) or specific medication c) Hypertension: blood pressure ≥130 mm systolic or ≥85 mm diastolic or specific medication d) Fasting plasma glucose: ≥100 mg/dl or specific medication or previously diagnosed T2DM
- 23. 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 Metabolic syndrome today
- 24. 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 - 95%, and among alcoholics who are overweight - 76% Consequently, fatty liver is caused by obesity in a greater extent than by alcohol 1. Drapkina OM, Smirin VI, VT Ivashkin Nonalcoholic fatty liver disease - a modernapproach to the problem. Attending Doctor. 2010. Т. 5. # 5. pg. 57–61. 2. Drapkina OM, Smirin VI, VT Ivashkin Pathogenesis, treatment and epidemiology ofNAFLD - what's new? Epidemiology of NAFLD in Russia. RMJ. 2011; 28: 1717-1722
- 25. Increase in liver free fatty acids inflow (VLDL ) Glucose utilization in peripheral tissues … hyperinsulinemia SMC proliferation with phenotypic changes Fasting hypertriglyceridemia HDL, LDL Visceral obesity
- 26. Lipoprotein Structure Apolipoprotein Free cholesterol Cholesterol esters Triglycerides Phospholipids
- 27. Liver is a major target of injury in patients with MS Liver in metabolic syndrome American Journal of the Medical Sciences. 330(6):326-335, Dec 2005. Insulin resistance (≈ 30 % of adults) Fat accumulation into hepatocytes (gluconeogenesis, glycogenolysis) Nonalcoholic steatohepatitis Nonalcoholic fatty liver disease (up to 20 % of adults) cirrhosis and end-stage liver disease
- 31. Pathogenesis contd… Impaired insulin mediated glucose uptake Toxic injury to pancreatic islets Increased insulin resistance Hyperglycemia Type 2 DM Insulin resistance pp/fasting hyperinsulinemia Lipolysis by LPL Abundance of FFA’s
- 33. Gut microbiota :Pathogenesis of NAFLD (1)Increased production and absorption of gut short- chain fatty acids (2)Altered dietary choline metabolism by the microbiota (3)Altered bile acid pools by the microbiota (4)Increased delivery of microbiota derived ethanol to liver (5)Gut permeability alterations and release of endotoxin (6)Interaction between specific diet and microbiota March 33
- 34. LEAN NASH • The pathophysiology may be quite different. • Genetic predispositions, fructose- and cholesterol- rich diet, visceral adiposity and dyslipidaemia. • Risk for metabolic disturbances, cardiovascular morbidity or overall mortality. • Secondary causes to be ruled out • The effectiveness of exercise and pharmacotherapy-not known. • Weight loss is expected to help in visceral obesity • Further investigation is needed- mechanistic pathogenesis, risk assessment, natural history and therapeutic approach March 34
- 36. 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
- 37. Noninvasive Imaging of Steatosis Abdominal ultrasound1,2 First-line investigation for patients with suspected hepatic steatosis Qualitative assessment of fatty infiltration of liver Presence of >33% fat on liver biopsy, optimal for detection of steatosis by ultrasound Characteristic sonographic features3: Attenuation of image quickly within 4 to 5 cm of depth, making deeper structures, difficult to decipher • Echogenic diffusely but particularly important to note brightness within the first 2 to 3 cm of depth • Liver is uniformly heterogeneous • Thick subcutaneous depth (>2 cm) • Liver fills entire field with no edges visible (viewed as helpful but not necessary for diagnosis)
- 38. Simple noninvasive tests of fibrosis • NAFLD fibrosis score: age, hyperglycaemia, body mass index, platelet count, albumin, AST/ALT ratio • BARD score: body mass index, AST/ALT ratio, type 2 diabetes mellitus • FIB-4 score: age, AST, ALT
- 39. Serum Biomarkers • Biomarkers can be used in differentiating simple steatosis from NASH1 • But, biomarkers are still under evaluation1 • Potential biomarkers: cytokeratin-18 and terminal peptide of procollagen III1 NASH, non-alcoholic steatohepatitis. 1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218. 2. J Hepatol. 2016;64(6):1388-1402. Stock photo ID: 615791984 Serum biomarkers can be an acceptable alternative for diagnosis of steatosis when imaging modalities are not available.2
- 40. TREATMENT
- 41. Weight reduction- include a combination of caloric restriction, increased physical activity, and behavior modification. LIFESTYLE MODIFICATIONS
- 42. What to do..?
- 43. ~500 kcal restriction daily equates to weight reduction of 0.45Kg per week. Diets restricted in carbohydrate typically provide a rapid initial weight loss. Adherence to the diet is more important than which diet is chosen. A high-quality diet— i.e., enriched in fruits, vegetables, whole grains, lean poultry, and fish—should be encouraged to provide the maximum overall health benefit. DIET---
- 44. PHYSICAL ACTIVITY- 60–90 min of daily activity (At least 30 min.) Gradual increases in physical activity should be encouraged to enhance adherence and avoid injury. Some high-risk patients should undergo formal cardiovascular evaluation before initiating an exercise program. Physical activity could be formal exercise such as jogging, swimming, or tennis or routine activities, such as gardening, walking, and housecleaning.
- 45. Role of LSM in NAFLD LSM IS THE CORNERSTONE OF NAFLD MANAGEMENT EXERCISE AND CALORIC RESTRICTION INDUCING WEIGHT LOSS ARE NEEDED TO IMPROVE NAFLD
- 46. Appetite suppressants- phentermine and sibutramine. Absorption inhibitors- Orlistat Bariatric surgery is also an option for patients with BMI >40 kg/m2 or >35 kg/m2 with comorbidities. OBESITY
- 47. Statins and NAFLD Safety: ↑ AST / ALT in 1-3% of patients There are no convincing data on the relationship between ↑ AST / ALT and histologically verified 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
- 48. Statins for NAFLD: molecular mechanisms Argo C.K., Loria P., Statins in liver disease: a molehill, an iceberg, or neither? // Hepatology. 2008 Aug;48(2):662–9. • 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 Cirrhosis sonic hedgehog
- 49. A Fasting triglyceride value of <150 mg/dL is recommended. A weight reduction of >10% is necessary to lower fasting triglycerides. A fibrate (gemfibrozil or fenofibrate) is the drug of choice to lower fasting triglycerides and typically achieve a 35–50% reduction. Other drugs that lower triglycerides include statins, nicotinic acid, and high doses of omega-3 fatty acids. TRIGLYCERIDES
- 50. For rise in HDL cholesterol, weight reduction is an important strategy. Nicotinic acid is the only currently available drug with predictable HDL cholesterol-raising properties. Statins, fibrates, and bile acid sequestrants have modest effects (5–10%), and there is no effect on HDL cholesterol with ezetimibe or omega-3 fatty acids. HDL Cholesterol
- 51. • OCA • Lubiprostone • DMR- Procedure • DPP4 • Saroglitazar • Elafibrinor • Empagliflozin • Fecal Microbiota Transplantation • Current and Potential future drugs Newer approaches
- 52. New approaches in NAFLD drug therapy Journal of Hepatology 2018 vol. 68 j 362–375
- 53. New therapeutic strategies in nonalcoholic fatty liver disease: a focus on promising drugs for nonalcoholic steatohepatitis New therapeutic strategies in nonalcoholic fatty liver disease: a focus on promising drugs for nonalcoholic steatohepatitis Natalia Pydyn 2020
- 56. Effects of Interventions in NAFLD Weight Loss Insulin Resista nce Liver Enzymes Inflam matio n Fibrosis Lifestyle interventions Yes Yes Yes Yes Unproven Vitamin E No No Yes Yes No Pioglitazone Weight gain Yes Yes Yes Might be beneficial Ursodeoxychol ic acid No Yes Yes Yes Might be beneficial Metformin Yes Yes No No No Gitto S, et al. Gastroenterol Res Pract. 2015;2015:732870.