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NAFLD

NAFLD. Dr Allister J Grant Consultant Hepatologist. How common is NAFLD?. The most common cause of abnormal liver function tests in the United States. Estimated 30.1 million with NAFLD and 8.6 million with NASH Affects 10-24% of the population 58-74% of the obese population

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NAFLD

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  1. NAFLD Dr Allister J Grant Consultant Hepatologist

  2. How common is NAFLD? • The most common cause of abnormal liver function tests in the United States. • Estimated 30.1 million with NAFLD and 8.6 million with NASH • Affects 10-24% of the population • 58-74% of the obese population • Affects 2.6% of children • 23-53% of obese children

  3. Age Adjusted Prevalence (%) of Overweight and Obese Americans Aged 20-74y

  4. Dallas Heart Study Results Healthy Fatty Liver fat < 5.5% Liver fat > 5.5% Steatosis = 31% Mean BMI =29 Liver enzymes NORMAL in most (79%) with steatosis

  5. LEICESTER

  6. Fatty Liver • Better detected by abdominal imaging than blood tests • Common in individuals who are • Overweight/obese • Type 2 diabetic • Dyslipidaemic • Regular alcohol consumers

  7. Hepatic SteatosisGender Disparities in Whites 45% 42% FLD 24% 24% M F M F F M Hispanics Whites Blacks

  8. Non Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology Steatohepatitis Steatosis Cirrhosis Hepatocellular carcinoma

  9. NAFLD Fatty Liver: Macrovescicular steatosis with nucleus positioning at cell periphery NASH: Mallory bodies, ballooning degeneration, lobular neutrophil inflammation and perisinusoidal fibrosis AGA Technical Review on Nonalcoholic Fatty Liver Disease Gastroenterology 2002;123:1705-1725

  10. NASH Steatosis Cirrhosis

  11. NASH- Peri-sinusiodal fibrosis

  12. Grading and Staging of NAFLD Brunt et al Am J Gastro 1999 Grading NAFLD 1.Macrovescicular steatosis Grade 0: None Grade 1: Up to 33% Grade 2: 33%-66% Grade 3: >66% 2. Necroinflammatory activity Mild, Mod, Severe

  13. NAFLD Diagnosis Role for Liver Biopsy?

  14. Role for Liver Biopsy? • Confirmatory test • Resolves diagnostic confusion • (e.g. AIH, HH) • Refines staging • Sensitive for “subclinical” fibrosis • Imperfect (sampling error) • Invasive procedure • Significant mortality.

  15. Diseases associated with Steatohepatitis 1.Alcoholism 2.Insulin resistance a.Metabolic Syndrome i.Obesity ii.Diabetes iii.Hypertriglyceridemia iv.Hypertension b.Lipoatrophy c.Mauriac Syndrome d.PCOS 3.Disorders of lipid metabolism a.Abetalipoproteinemia b.Hypobetalipoproteinemia c.Andersen’s disease d.Weber-Christian syndrome 4.Total parenteral nutrition 5. HCV 6.Severe weight loss a.Jejuno-ileal bypass b.Gastric bypass c.Severe starvation 7.Iatrogenic a.Amiodarone b.Diltiazem c.Tamoxifen d.Steroids e.HAART f. tetracycline g.glucosamine 8.Refeeding syndrome 9.Exposure to toxic agents a.Environment b.Workplace – Sb,Th,Ba

  16. NAFLD • NAFLD is a spectrum of disease which includes Fatty liver disease and NASH, but only NASH is known to progress to cirrhosis. 2nd hit Fatty Liver Obese BMI>28 Centipetal (apple) Bright liver on USS Insulin Resistance Normal ALT NASH Obese BMI>28 Bright liver on USS Abnormal ALT Features of metabolic syndrome Dyslipidaemia DM HBP Cirrhosis Bright/ small liver on USS + splenomegaly Abnormal ALT Thrombocytopenia Obesity Poorly controlled DM Poorly controlled lipids Hypertension

  17. High Fat/CHO Diet Lack of Exercise Pathogenesis of NASH Hepatic Steatosis White Adipose Tissue FFA oxidation Lipogenesis Lipid Export Adipokines- adiponectin Cytokines- TNF IL-6 Insulin Resistance Endotoxin Cytokines ROS Toxins Oxidative Stress 2nd Hit Peroxidation of hepatocyte membrane Cytokine release Stellate cell activation NASH

  18. High Fat/CHO Diet Lack of Exercise Pathogenesis of NASH Hepatic Steatosis FFA oxidation Lipogenesis Lipid Export CellularFFA IB and NFB activation IL6 &TNFα Insulin Resistance

  19. High Fat/CHO Diet Lack of Exercise Pathogenesis of NASH Hepatic Steatosis FFA oxidation Lipogenesis Lipid Export CellularFFA GLUT 4 activity Reduced glucose entry into cells Insulin Resistance

  20. High Fat/CHO Diet Lack of Exercise Probiotics Antioxidants Treatment Strategies In NASH Orlistat Sibutramine Rimonabant Bariatric Surgery Diet &Exercise Metformin Pioglitazone Rosiglitazone Statins Gemfibrozil Diet &Exercise Hepatic Steatosis White Adipose Tissue FFA oxidation Lipogenesis Lipid Export Adipokines- adiponectin Cytokines- TNF IL-6 Insulin Resistance Endotoxin Cytokines ROS Toxins Oxidative Stress 2nd Hit Peroxidation of hepatocyte membrane Cytokine release Stellate cell activation NASH

  21. Natural history • Simple steatosis: relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%. • NASH and fibrosis: risk of progress to cirrhosis between 0% at 5 years to 12% over 8 years. • Cirrhotic: high risk of developing hepatic decompensation and of dying from a liver-related cause including HCC.

  22. NASH Affects 3.5-5% of the population The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years. There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.

  23. Current Management of |NAFLD and NASH. APT. Younossi Z: 2008

  24. Initial Investigation • Look for risk factors • BMI, DM, HBP, Lipids,FHx, Drugs, Alcohol • Liver screen • Including Glc/GTT/HbA1c/Lipids/AST • Pl, Alb, INR • USS • Spleen size, fatty liver, collaterals

  25. Managemant of NASH • The patient should lose weight and exercise • Pharmacological treatment of Insulin-resistance • Treatment of Hyperlipidaemia • Hepatocyte-Protective treatment

  26. NASH Management 1) All patientsshould be encouraged to exercise, as there is good evidence that even in the absence of weight loss exercise improves NASH. Obese Patients Weight reducing diet (aim for 10%, 1-2lb per week) In patients with BMI>28 with risk factors, or >30 without risk factors, consider treatment with Orlistat. 2) Diabetic Patients Good diabetic control (HbA1c <6.5%) Metformin Thiazolidinediones (rosiglitazone and pioglitazone) Dietician for re-education. Diabetologist if glucose control is difficult. 

  27. NASH Management 3) Patients with Hyperlipidaemia and abnormal LFT’s Dyslipidaemia should be aggressively addressed Dietician Review Hypercholesterolaemia -Statins Hypertriglycerideaemia -Fibrate. Lipid Clinic Avoid Drugs amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic estrogens, tamoxifen Antioxidants?

  28. Thank you

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