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- 1. Dr R V S N Sarma., M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist Visit: www.drsarma.in 1
- 2. Dr R V S N Sarma., M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist Visit: www.drsarma.in 2
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- 6. • Hepatocytes (PC) • Kuffer Cells (KC) • Stellate Cells (SC) • Endothelial Cells (LEC) • Other cells – epithelial cells of bile duct – endothelial cells of blood and lymphatic vessels – smooth muscle cells of arteries and veins – nerve cells, fibroblasts, inflammatory cells 6
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- 8. A clinico-pathologic syndrome encompassing a wide range of fatty liver disease in the absence of significant alcohol intake (2 drinks or fewer daily) and other common causes of Steatosis 8
- 9. • Non Alcoholic Fatty Liver Disease – NAFLD • Non Alcoholic Steato Hepatitis – NASH • Non Alcoholic Cirrhosis (> 60% of cryptogenic) These three are a consequence of Obesity & MS • Alcoholic Fatty Liver Disease – ALFD 9
- 10. • Fatty Liver • Alcoholic hepatitis • Alcoholic cirrhosis
- 11. • 1979 8 papers published • 1998 First NIH conference • 1999 First Clinical Trials • 2002 > 60 papers published • 2004 First book on NAFLD/NASH • 2005 > 354 papers published • Today > 1000 papers published 11
- 12. 1. Most common of all liver disorders & Abn. LFT. 2. Most frequent cause of chronic liver disease. 3. Affects about 10-24% of general population. 4. Up to 75% of individuals with Obesity, T2DM. 5. Children 3% and > 50% of obese children. 12
- 16. Lipid Accumulation Oxidative Stress Cytokine Activation 16 1st HIT 2nd HIT
- 17. 17 Fatty Liver 1st Hit Damaged Liver 2nd Hit Oxidative Stress Toxins Inflammatory Molecules Susceptibility Donnelly et al. J. Clin. Invest. 113: 1343, 2005 Day and James. Gastroenterol. 114: 842, 1998 Diet FFA Fats Burnt VLDL-TG Saturated > Unsaturated Apoptosis
- 19. Normal NAFLD NASH Cirrhosis 19 CV Risk FAT >5% Inflammation Scarring DCLD IR and MS 1st HIT 2nd HIT IR and MS
- 20. 20 Sum of Saturated FA (g/100g) 20 30 40 50 60 Alanine aminotransferase (U/L) 0 100 200 300 Amount of saturated lipids in liver Liver Injury N 35 SGPT
- 21. Severe NASH with fibrosis – 75% go in for cirrhosis 5 yr survival 67% 10 yr survival 45% NASH – Ballooning, Inflammation, Fibrosis Worse prognosis 30% develop cirrhosis Simple Steatosis or Fat Deposition of > 5% Benign course 3% develop cirrhosis 21
- 22. 22 Insulin Resistance Syndrome NIDDM TG HDL Hypertension Visceral Obesity Steatosis NASH
- 23. 23 Waist Circum 90 (M), 80 (F) Triglycerides >150 mg HDL <40 (M) < 50 (F) Dysglycemia FPG >100 or DM Hypertension >130 or 85 Rx. for any of the above conditions 2 of 5
- 24. NAFLD IR MS DM 24 NAFLD is the Hepatic component of MS
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- 27. 27 Insulin Resistance Inadequate Insulin prod Type 2 DM CKD, DPR, DPN, DAN Hyper Insulinaemia Metabolic Syndrome HT, Stroke, PCOS, NASH CAD
- 28. These are ONE If we find - look for NASH IR 98% MS 85% DM 70% 28
- 29. Nuclear Receptor Fam. • PPAR- • PPAR- • PPAR- Retinoid X Recp. RXR • PPAR- - Protective • Lipid metabolism • FFA -oxidation • Sensors for FFA levels • PPAR- IR – Imp. • PPAR- - Kuffer cells 29
- 30. SREBP Family • SREBP-1a • SREBP-1c • SREBP-2 Leptin –opposes SREBP • 30 Genes involved • Synthesis & uptake • Cholesterol, FFA • Phospholipids, TAG • Increase the above 30
- 31. 31 IR Adiponectin Obesity, PPAR- PC, KC, SC, LEC CC P450 A,E1 Glutathione PPAR- , SREBP1a,1c,2 NASH, CV Risk Free radicals Antioxidants Kuffer Cells NF-B O2 stress, Inflmma. Leptin, IL-6 FFA, PC1 Rad, TNF- NEFAs NO TNF- ATP in oxidative stress in oxidation in DAG & TAG
- 32. FFA oxidation Lipogenesis Lipid Export Hepatic Steatosis High Fat/CHO Diet Lack of Exercise Insulin Resistance IB and NFB activation IL6 &TNF-α Cellular FFA NAFLD
- 33. FFA oxidation Lipogenesis Lipid Export Hepatic Steatosis High Fat/CHO Diet Lack of Exercise Insulin Resistance Cellular FFA GLUT4 activity Reduced glucose entry into cells NAFLD
- 34. FFA oxidation Lipogenesis Lipid Export Hepatic Steatosis High Fat/CHO Diet Lack of Exercise Insulin Resistance White Adipose Tissue Adipokines- Adiponectin Cytokines - TNF-; IL-6 Oxidative Stress Endotoxin Cytokines ROS; Toxins NASH Peroxidation of hepatocyte membrane Cytokine release Stellate cell activation 2nd Hit NAFLD
- 35. FFA oxidation Lipogenesis Lipid Export Hepatic Steatosis High Fat/CHO Diet Lack of Exercise Insulin Resistance White Adipose Tissue Adipokines- Adiponectin Cytokines - TNF-; IL-6 Oxidative Stress Endotoxin Cytokines ROS; Toxins NASH Peroxidation of hepatocyte membrane Cytokine release Stellate cell activation 2nd Hit Diet &Exercise Orlistat Sibutramine Rimonabant Bariatric Surgery Statins Gemfibrozil Metformin Pioglitazone Rosiglitazone Diet & Exercise Probiotics, UDCA Antioxidants NAFLD
- 36. • 75% patients of NAFLD/NASH are women • All ages are affected – Risk of NASH with age • Caucasians > Hispanics > Africans > Asians • Indian Fatty Liver – BMI < 25, Non obese, WC • OSAS increases NASH; Its Rx. Reduces NASH 36
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- 39. 39 DM or Obesity No Yes Age < 45 0 4 < 1 SGOT/SGPT 0 50 > 1 > 45 12 47 < 1 13 66 > 1 Age Obesity T2DM SGOT/SGPT Number represents % of patients with NAFLD on USG who had significant fibrosis on biopsy Steatosis seen in 80% of obese patients NASH seen in 9-30% obese Hepatology 2003
- 40. • Alcohol • Obesity, WC • T2DM • Triglycerides • Medicines*, TPN • Wilsons’s Disease • -1 Anti-trypsin • AI Hepatitis • Hepatitis C • Inherited syndromes 40 * MTX, Valp, Acetaminophen, TC, Tamoxifen, Nefidepine, Amiodarone, CCl4
- 41. • Asymptomatic • Routine blood tests • Liver enzymes • Enlarged Liver (1/3) • RUQ periumb. Pain • Fatigue. Malaise • Anorexia, Nausea • > 90% are obese • USG e/o fatty liver • Acanthosis Nigricans • DM, HTN, Lipid abn. • OSAS, Snoring 41
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- 44. A. Mayo Clinic Score for NASH (Next slide) B. HAIR index (HTN; ALT > 40; Insulin Resistance) ≥ 2 are 80% Sensitive, 89% Specific of NASH C. BAAT index (BMI > 28; Age > 50; ALT > 2 times the normal; increased Triglycerides) ≤ 1 has 100% Negative Predictive Value for NASH 44
- 45. Six Parameters included A constant is used 1. Age (in years) 2. BMI (kg/m2) 3. IFG or DM 4. SGOT / SGPT 5. Platelet count (109/l) 6. Serum Albumin (g%) Calculation of the score [- 1.675 + (0.037 x Age) + (0.094 x BMI) + (1.13 x 0 or 1 for IFG/DM) + {(0.99 x (SGOT/SGPT)} – (0.013 x Platelet count) – (0.66 x Albumin)}] 45
- 46. - 1.455 or lower score No fibrosis / NASH - 1.456 to + 0.676 Probable NASH More than + 0.676 NASH Definite 46 Paul Angelo et al – Hepatology, Vol. 45, No. 4, 2007, p 846 - 854
- 47. • Ht, Wt, BMI, WC • Blood Pressure • OGTT – IR, DM • Fasting Lipid Profile • SB, SGPT, SGOT, AKP, GGT, Serum Proteins • Hemogram complete • USG Abdomen • HCV, HBsAg, ANA • Liver Biopsy, CT Abd • F and PP C-peptide • aPTT, PT, body fat 47
- 48. • 2 - 4 fold GPT & GOT • SGOT: SGPT Ratio < 1 • AKP slight in 1/3 • Dyslipidemia - TG • FBG and PPBG • BUN & Creatinine - N • Normal Albumin. PT • Low ANA + < 1 in 320 • Serum Ferritin • Iron saturation • SGOT: SGPT Ratio > 1 if Cirrhosis sets in 48
- 49. Biomarker Indicative of Utility as on date ROS Oxidative stress Conflicting Leptin Insulin Resistance Conflicting Adiponectin Insulin Sensitivity Lower in NASH hs-CRP Systemic Inflammation Higher in NASH Cytokeratin 18 Hepatic Apoptosis Higher in NASH 49
- 50. • Lipid Profile • Glucose • SGPT • SGOT • hs-CRP • 5 minutes time • Finger Prick 50
- 51. 51 RF/Metabolic Syndrome Fatty Liver on Imaging Elevated Transaminases R/O other Liver disease Image liver Measure GOT/GPT, Assess Alcohol use Image liver Excessive Alcohol Limited Alcohol AFLD NAFLD Biopsy Neg Pos Neg Reproduced from AGA Guidelines
- 52. • USG is enough; CT if USG is not informative • Imaging can detect > 33% fat on liver biopsy • Cannot differentiate Steatosis from steatohepatitis • Liver biopsy is usually not needed to diagnose fatty liver 52
- 53. • HBV – HBsAg, (HBV DNA) • HCV – anti-HCV, (HCV RNA) • Autoimmune hepatitis – ANA • Alfa-1 anti-trypsin deficiency • Wilson’s disease • Hepatic malignancy • Hepatic infection; Biliary disease 53
- 54. Black Pigmentation - Axilla Black Pigmentation - Neck 54
- 55. Black Pigmentation - Axilla Pigmentation - Knuckles 55
- 56. • Diffusely increased “bright” echogenicity • Liver echogenicity greater than kidney • Deep attenuation of Ultrasound signal • Vascular blurring • Unexplained SGPT • Other causes of liver disease, alcohol and medications have to be rigorously excluded 56
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- 58. Fibroscan
- 59. Fibroscan Scan: - AUROC 0.94 - Sens 0.94 - Spec 0.95
- 60. Fibrosis scores Score: - AUROC 0.85 - Sens 0.9 - Spec 0.97
- 61. CT Liver - Normal CT - NASH Liver 61
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- 64. 64 2020 g Mallory Bodies - Hyaline
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- 67. • Only accurate method of staging and diagnosis, • May convince patient of need for life-style change • NAFLD / NASH generally good prognosis • Key risk factors are addressed without a biopsy • Lack of effective therapy, cost and risk. • If cirrhosis is clinically suspected – biopsy needed 67
- 68. Steatosis • 0 : < 5% • 1 : 5 – 33% • 2 : 33 – 66% • 3 : > 66% Inflammation • 0 : No foci • 1 : < 2 / 200x • 2 : 2-4 / 200x • 3 : > 4 / 200x Ballooning • 0 : None • 1 : Few cells • 2 : Many cells prominent ballooning. 68
- 69. 69 NAS 5 NAS 3-4 NAS 2 • NASH • Probably NASH • No NASH
- 70. 70 NASH
- 71. • Similar to the recommendations for – T2DM and IR – HTN – Dyslipidemia – Obesity and Abdominal obesity 71
- 72. 1. Eat less fat, especially saturated fat 2. Keep blood sugars normal 3. Drink less or no alcohol 4. Exercise regularly 5. Match kilojoules to energy requirement 6. Don’t smoke 72
- 73. Control of risk factors • Decrease of 10% in BMI • Diet as already discussed • Aerobic exercise 30 min x 6 days /week • Statins where indicated 73
- 74. If no response after six months • Pt is at higher risk of fibrosis • Mayo Score or Liver biopsy to distinguish Steatosis versus steatohepatitis - prognosis • Add non-evidence based therapy 74
- 75. • Exercise is the cornerstone of therapy • Benefit of exercise even without weight • Biochemical improvement – liver enzymes • Variable histological improvement • Variable effect on progression to cirrhosis. 75
- 76. Insulin Sensitizing Agents • Glitazones; Metformin Lipid-Lowering Agents • Clofibrate; Gemfibrozil Future Potential Treatments • Anti-fibrotics; Probiotics • Silymarin; Selenium Membrane-Stabilizing • Urso deoxy cholic Acid • Betaine (SAM) Anti-Oxidants • Vitamin E; Vitamin C • Lecithin; -Carotene • Vitamin B Complex 76
- 77. Intervention Evidence Benefit Reference Weight Loss IR NASH Drenick 1970; Andersen 1991 Ueno 1997; Luyckx 1998 PPAR- Agonists IS, Fat Bioch, Histolog progression Caldwell 2001; Isley 2003, Promat 2004,Neuschwander 2003 Biguanides HIS, Cyclic AMPK activity Or prevent steatosis, inflm. Uygun 2004, Solomon 1997, Lin 2000, Uygun 2004 PPAR- Agonists PPAR- benefits In hepatic fat oxidation Laurin 1996, Basaranoglu 1999 UDCA, NAC, Betaine, Vit E Hepatic Injury Free radicals & Inflammation Laurin 1996, Abdelmalek 2001, Escudero 2002, Okan 2002,Santos 02 77
- 78. Author Study Drug No. Pts SGPT Enzyme Histology Laurin et al 1996 UDCA 24 Improved Improved Guma et al 1997 UDCA 24 Improved ND Ceriani et al 1998 UDCA 31 Improved ND Gulbahar et al 2000 NAC 11 Improved ND Lavine et al 2000 Vitamin E 11 Improved ND Caldwell et al 2001 Trioglitazone 10 Improved Improved Hasewaga et al 2001 Vitamin E 22 Improved Improved Marchesini et al 2001 Metformin 14 Improved ND Neuschwander-Tetri 2002 Rosiglitazone 30 Improved ND Nair et al 2002 Metformin 25 Improved ND 78
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- 80. • Evidence of efficacy in NASH/NAFLD is equivocal • 300 mg bid or 10 mg/kg in two divided doses PO • Can be given up to 12 to 24 mon.; depends on response • Cholestasis, PBC, PSC, Acute viral hepatitis, HBV, HCV • Chronic hepatitis, Alcoholic liver disease • Dissolution of cholesterol microliths / gallstones • Class E drug in pregnancy (not to be used in COP) 80
- 81. • NAFLD and NASH may resolve with weight loss • Liver fat content ; No effect on fibrosis & Inflam. • Diet and exercise improve insulin sensitivity, increase oxidative capacity and utilization of FFAs • Weight loss has clear benefits for CV risk & T2DM 81
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- 89. 1. There is general agreement that our modern sedentary lifestyles have much to answer for in the etiology of obesity. 2. There is an important role for exercise in the management of overweight combined with dietary control. 89
- 90. • After the initiation of exercise • Energy requirements increase immediately. • The resting metabolic rate increases. • Exercise must be maintained • Lest the metabolic rate will drop. 90
- 91. • Combined physical activity with proper diet Rx • Regular physical over a period of time results in Improvements in body fat content, visceral fat • HDL-cholesterol LDL cholesterol • Triglycerides and Blood sugar 91
- 92. • It is the main cause of liver enzymes; Isn’t that benign • Spectrum of disease – NAFLD – NASH – Cirrhosis - HCC • Insulin resistance, MS are the key pathogenic features • DM, TG, Non fatty abdominal obesity, increasing age • It is a marker of CV Risk. Rx. improve insulin sensitivity • Modify underlying metabolic risk factors – diet, exercise • Use Mayo scoring to predict NASH (fibrosis). No biopsy 92
- 93. THANK YOU ALL 93