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  1. 1. DR. Shatdal Chaudhary MD <ul><li>NAFLD </li></ul>
  2. 2. N on- A lcoholic F atty L iver D isease (NAFLD) <ul><li>An epidemic of new millenium . </li></ul><ul><li>A new consequence of the obesity epidemic . </li></ul><ul><li>Represents a spectrum of conditions characterized by macrovesicular hepatic steatosis in the absence of significant alcohol intake. </li></ul><ul><li>Includes histological pattern : </li></ul><ul><ul><li>Simple steatosis( without inflammation) </li></ul></ul><ul><ul><li>Steatohepatitis(NASH) with inflammation fibrosis & cirrhosis </li></ul></ul>
  3. 3. N on- A lcoholic F atty L iver D isease (NAFLD) Fatty liver (Steatosis) Steatohepatitis - inflammation - fibrosis Cirrhosis Normal liver
  4. 4. The Brief History of NAFLD Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005 <ul><li>1979 ~8 papers published </li></ul><ul><li>1998 First NIH conference </li></ul><ul><li>1999 First Clinical Trials </li></ul><ul><li>2002 ~60 papers published </li></ul><ul><li>Release of first book on NAFLD/NASH </li></ul><ul><li>2005 ~354 papers published </li></ul>
  5. 5. Prevalence of fatty liver <ul><li>“ Estimated” prevalence is 2.8 - 25 % of population </li></ul><ul><li>20 to 30 % adults in western countries have NAFLD of which 2 to 3 % are NASH </li></ul><ul><li>( Imaging & autopsy study) </li></ul><ul><li>Steatosis seen in 80 % obese patients </li></ul><ul><li>NASH seen in 9 - 30 % obese </li></ul><ul><li>Hepatology 2003 </li></ul>
  6. 6. NAFLD 1. Most common of all liver disorders. 2. Frequent cause of chronic liver disease. 3. Present in 3% of children and >50% of obese children. Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005
  7. 7. Prevalence of NAFLD In General Population In Asian Pacific Region <ul><li>Name of the Percentage NAFLD in Country Adults </li></ul><ul><li>Japan 9 – 30% </li></ul><ul><li>China 5 – 18% </li></ul><ul><li>Korea 18 % </li></ul><ul><li>India 5 – 28% </li></ul><ul><li>Indonesia 30% </li></ul><ul><li>Malaysia 17 % </li></ul><ul><li>Singapore 5% </li></ul>
  8. 8. Prevalence of NAFLD In High Risk Population In Asian Pacific Region <ul><li>Name of the Diabetes Obesity Dyslipidemia </li></ul><ul><li>country </li></ul><ul><li>Japan 40-50% 50-80% 42-58% </li></ul><ul><li>China 35% 70-80% 57% </li></ul><ul><li>Korea 35% 10-50% 26-35% </li></ul><ul><li>India 30-90% 15-20% NA </li></ul><ul><li>Indonesia 52% 47% 56% </li></ul>
  9. 9. Aetiological Classification <ul><li>Primary NAFLD : associated with metabolic syndrome. </li></ul><ul><li>Secondary NAFLD : includes fatty liver diseases with a proximate causes. </li></ul>
  10. 10. Types of NAFLD <ul><li>Primary Secondary </li></ul><ul><li>1 Insulin resistance 1 severe weight loss </li></ul><ul><li>Obesity jejunoileal bypass </li></ul><ul><li>Diabetes gastric bypass </li></ul><ul><li>Hypertriglyceridemia severe starvation </li></ul><ul><li>Hypertension 2 total parenteral nutrition </li></ul><ul><li>3 Iatrogenic </li></ul><ul><li>Amiodarone </li></ul><ul><li>Diltiazem </li></ul><ul><li>Tamoxifen </li></ul><ul><li>Steroids </li></ul><ul><li>HAART </li></ul><ul><li>3 Refeeding syndrome </li></ul><ul><li>4 Toxic exposure </li></ul><ul><li>Hydrocarbon , yellow phosphorus </li></ul><ul><li>5 Disorders of lipid metabolism </li></ul><ul><li>Abetalipoproteinemia </li></ul><ul><li>Hypobetalipoproteinemia </li></ul><ul><li>Andersen’s disease </li></ul><ul><li>Weber –christian syndrome </li></ul>
  11. 11. Morbid Obesity <ul><li>Four studies evaluating > 600 morbidly obese patients undergoing gastric bypass </li></ul><ul><ul><li>All patients underwent intraoperative liver biopsies </li></ul></ul><ul><ul><li>Prevalence of NAFL ranged from 30-90% and NASH was documented in 33-42%.  </li></ul></ul><ul><ul><li>> 2/3 of morbidly obese patients undergoing gastric bypass surgery have NAFL/NASH </li></ul></ul>Abrams GA, et al.  Hepatology 2004;40:475-483; Frantzides CT, et al.  J Gastrointest Surg 2004;8:849-855; Dallal RM, et al. Obes Surg 2004;14:47-53; Beymer C, et al.  Arch Surg 2003;138:1240-1244.
  12. 12. Type 2 Diabetes Mellitus <ul><li>Recent study surveyed 100 patients with type 2 DM and used U/S to screen for NAFLD </li></ul><ul><ul><li>Detected fatty liver in 50% of patients </li></ul></ul><ul><ul><li>Performed subsequent liver biopsy in those with NAFLD: </li></ul></ul><ul><ul><ul><li>NAFL: 13% </li></ul></ul></ul><ul><ul><ul><li>NASH: 86% </li></ul></ul></ul><ul><ul><ul><li>Fibrosis: 22% </li></ul></ul></ul>Gupte, et al.  J Gastro Hepatol 2004;19:854-858.
  13. 13. Dyslipidemia <ul><li>Canadian study used U/S to screen 95 adults with dyslipidemia </li></ul><ul><ul><li>Detected fatty liver in 50% </li></ul></ul><ul><ul><li>Steatosis was particularly common in individuals with moderate to severe hypertriglyceridemia or mixed dyslipidemia </li></ul></ul><ul><ul><li>Hypertriglyceridemia and mixed dyslipidemia increased the risk for hepatic steatosis by ~5-fold </li></ul></ul>Assy N, et al. Dig Dis Sci 2000;45:1929-1934.
  14. 14. Pathophysiology Salgado W, et al. Acta Cir. Bras. 2006; 21.  
  15. 15. Two-hit Hypothesis Fatty Liver 1 st Hit Damaged Liver 2 nd 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 Burned VLDL-TG
  16. 16. Liver Damage 2 nd Hit Liver Damage Sat FA 2 nd Hit Apoptosis Hepatocyte Mass Fatty Liver
  17. 17. Pathophysiology <ul><li>Other factors involved in NASH pathogenesis </li></ul><ul><ul><li>Bacterial overgrowth </li></ul></ul><ul><ul><ul><li>Increased hepatic oxidative stress </li></ul></ul></ul><ul><ul><ul><li>Production of ethanol and TNF- α </li></ul></ul></ul><ul><ul><ul><li>Direct activation of inflammatory cytokines and liver macrophages via release of lipopolysaccarides </li></ul></ul></ul><ul><ul><li>Leptin </li></ul></ul><ul><ul><li>Obesity gene </li></ul></ul><ul><ul><ul><li>Regulates food intake and body composition </li></ul></ul></ul><ul><ul><ul><li>Leads to hepatic steotosis by promoting insulin resistance or by modulating insulin signalling in hepatocytes </li></ul></ul></ul>
  18. 18. Pathophysiology: others <ul><li>Serum and liver iron </li></ul><ul><ul><li>Mitochondrial β oxidation leads to generation of hydrogen peroxide </li></ul></ul><ul><ul><li>In presence of increased iron hydrogen peroxide converted to hydroxyl free radicles </li></ul></ul><ul><ul><li>This leads to oxidative stress and hepatocellular injury </li></ul></ul>
  19. 19. Pathophysiology: others <ul><li>TNF- α </li></ul><ul><ul><li>Corelates with obesity </li></ul></ul><ul><ul><li>Derives from adipose tissue </li></ul></ul><ul><ul><li>Decrease phosphorylation of insulin receptor </li></ul></ul><ul><ul><li>Reduce expression of GLUT-4 </li></ul></ul><ul><ul><li>Contributes toward insulin resistence </li></ul></ul><ul><ul><li>Also causes chemotaxis, activation of stellate cells, Mallory hyaline formation, collagen synthesis </li></ul></ul>
  20. 20. Clinical Presentation <ul><li>Variable clinical presentation </li></ul><ul><li>Typically asymptomatic, but may have hepatomegaly and abdominal discomfort </li></ul><ul><li>Liver enzymes may be normal in >75% of cases, making them insensitive in detecting NAFLD </li></ul><ul><ul><li>When increased, usually only modestly and limited to aminotransferases </li></ul></ul><ul><ul><li>ALT upper limits of normal: <30 in M, <20 in F </li></ul></ul>
  21. 21. Natural history and clinical outcomes of NASH <ul><li>20% 30—40% </li></ul><ul><li>NASH CIRRHOSIS Liver related Death </li></ul><ul><li>Sub acute HCC Post-OLTX </li></ul><ul><li>Failure recurrance </li></ul>
  22. 22. Diagnosis <ul><li>Cf </li></ul><ul><li>h/o </li></ul><ul><li>Disturbed liver enzymes </li></ul><ul><li>Radioimaging </li></ul><ul><li>Biopsy </li></ul>
  23. 23. Lab Studies <ul><li>No laboratory studies can help definitively establish a diagnosis of fatty liver or NASH. </li></ul><ul><li>Aminotransferases </li></ul><ul><ul><li>Elevated AST or ALT </li></ul></ul><ul><ul><li>As much as 10-fold </li></ul></ul><ul><ul><li>In the absence of cirrhosis, an AST-to-ALT ratio of greater than 2 suggests alcohol use, whereas a ratio of less than 1 may occur in patients with NASH. </li></ul></ul><ul><li>Alkaline phosphatase </li></ul><ul><ul><li>Can be elevated </li></ul></ul><ul><ul><li>Usually less than 2 to 3 times normal </li></ul></ul>
  24. 24. Diagnosis <ul><li>Diagnosis of NAFLD can often be made by imaging studies, including U/S, CT or MRI – detects presence of fat </li></ul>
  25. 25. Diagnosis (cont.) <ul><li>MR spectroscopy accurately measures hepatic triglyceride content </li></ul><ul><ul><li>Has advantage over U/S, CT and MRI as it is quantitative rather than qualitative </li></ul></ul>
  26. 26. Diagnosis (cont.) <ul><li>No imaging studies can differentiate between the histological subtypes of benign steatosis or aggressive NASH, or stage the degree of fibrosis </li></ul><ul><ul><li>Need tissue for staging and to make diagnosis of NASH </li></ul></ul>
  27. 27. <ul><li>Liver biopsy </li></ul><ul><ul><li>A liver biopsy and histopathological examination are required to establish the diagnosis. </li></ul></ul><ul><ul><li>The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use). </li></ul></ul>
  28. 28. <ul><li>Doing liver biopsy is controversial </li></ul><ul><ul><li>Arguments favoring </li></ul></ul><ul><ul><ul><li>Exclusion of other cause </li></ul></ul></ul><ul><ul><ul><li>To distinguish steatosis from NASH </li></ul></ul></ul><ul><ul><ul><li>Estimation of prognosis </li></ul></ul></ul><ul><ul><ul><li>Determination of progression </li></ul></ul></ul><ul><ul><li>Arguments against biopsy </li></ul></ul><ul><ul><ul><li>Good prognosis </li></ul></ul></ul><ul><ul><ul><li>Lack of effective therapy </li></ul></ul></ul><ul><ul><ul><li>Risk & cost associated with biopsy </li></ul></ul></ul>
  29. 29. Histology <ul><li>Histologic diagnosis of NAFL requires presence of ≥ 5% steatosis </li></ul><ul><ul><li>Indistinguishable from alcoholic fatty liver </li></ul></ul>
  30. 30. Histology <ul><li>NASH involves presence of steatosis with evidence of inflammation and hepatocyte injury: </li></ul><ul><ul><li>Ballooning </li></ul></ul><ul><ul><li>Mallory bodies </li></ul></ul>
  31. 31. Histology <ul><li>Histologic evidence of steatohepatitis may disappear with progression to cirrhosis </li></ul><ul><ul><li>Thus, significant proportion of cryptogenic cirrhosis is likely related to unrecognized NASH </li></ul></ul>
  32. 32. COMPLICATION <ul><li>Cirrosis </li></ul><ul><ul><li>Risk- 8 to 15% </li></ul></ul><ul><li>Hepatocellular carcinoma </li></ul><ul><ul><li>Risk: 1-2% </li></ul></ul>
  33. 33. NASH Criteria (AGA guidelines) <ul><li>Characteristic liver biopsy that shows fatty change with inflammation </li></ul><ul><ul><li>Indistinguishable from alcoholic hepatitis </li></ul></ul><ul><li>Convincing evidence of negligible alcohol consumption (less than 20g alcohol per day) </li></ul><ul><ul><li>Detailed history obtained independently by 3 physicians, interrogation of family members </li></ul></ul><ul><li>Absence of serologic evidence of Hep B or Hep C infection </li></ul><ul><ul><li>Should not exclude those with evidence of past Hep B infection, but should exclude patients with positive HBs Ag or HCV Ab </li></ul></ul>
  34. 34. <ul><li>Clues for severe NASH </li></ul><ul><ul><li>Old age(>50 yrs) </li></ul></ul><ul><ul><li>Presence of diabetes </li></ul></ul><ul><ul><li>Pesence of obesity </li></ul></ul><ul><ul><li>AST/ALT > 1 </li></ul></ul><ul><ul><li>ALT >2 times of normal </li></ul></ul><ul><ul><li>TG >1.7m mol/L </li></ul></ul>
  35. 35. Prognosis <ul><li>Patients with bland steatosis (NAFL) have a benign liver-related prognosis </li></ul><ul><ul><li>1.5% develop cirrhosis </li></ul></ul><ul><ul><li>1% die from liver-related causes over 10-20 years </li></ul></ul><ul><li>Almost 30% of patients with NASH and fibrosis become cirrhotic within 5-10 years </li></ul><ul><ul><li>Those with biopsy-proven NASH have a liver-related death rate of ~10% </li></ul></ul><ul><li>NASH cirrhosis may develop into HCC </li></ul><ul><ul><li>~13% of cases of all HCC are related to NASH cirrhosis </li></ul></ul><ul><ul><li>Endstage NAFLD accounts for ~5-10% of liver transplants </li></ul></ul>Matteoni C, et al. Gastroenterology 1999;116:1413-1419.
  36. 36. Treatment <ul><li>Aim to improve insulin sensitivity and modify underlying metabolic risk factors </li></ul><ul><ul><li>Diet and exercise </li></ul></ul><ul><ul><li>Insulin Sensitizing Agents (metformin, TZD) </li></ul></ul><ul><ul><li>Lipid lowering medications (statins, fibrates) </li></ul></ul><ul><li>L-Carnitine supplementation </li></ul>
  37. 37. McCullough AJ. N Engl J Med 2006; 355: 2361-3.
  38. 38. Treatment <ul><li>Lifestyle modification </li></ul><ul><ul><li>Diet and exercise </li></ul></ul><ul><li>Weight reduction </li></ul><ul><li>Insulin sensitizers </li></ul><ul><ul><li>Metformin </li></ul></ul><ul><ul><li>Troglitazone </li></ul></ul><ul><ul><li>Rosiglitazone </li></ul></ul><ul><ul><li>Pioglitazone </li></ul></ul><ul><li>Lipid Lowering agents </li></ul><ul><li>Antioxidants </li></ul><ul><ul><li>Vitamin E </li></ul></ul><ul><ul><li>Vitamin C </li></ul></ul><ul><li>Hepatoprotective agents </li></ul><ul><ul><li>Betaine </li></ul></ul><ul><ul><li>Ursodeoxycholic acid </li></ul></ul><ul><ul><li>Pentoxyfylline </li></ul></ul><ul><li>Angiotensin-converting enzyme inhibitors </li></ul><ul><li>Probucol </li></ul>
  39. 39. Treatment (cont.) <ul><li>Beneficial according to preliminary studies: </li></ul><ul><ul><li>Insulin sensitizers: TZD > metformin </li></ul></ul><ul><li>Benefit unproven by preliminary studies </li></ul><ul><ul><li>Lipid lowering agents </li></ul></ul><ul><ul><li>Antioxidants </li></ul></ul><ul><ul><li>Probiotics (animal models only) </li></ul></ul><ul><li>Not beneficial </li></ul><ul><ul><li>Ursodiol </li></ul></ul>
  40. 40. Betaine <ul><li>Metabolite of Choline </li></ul><ul><li>increases S-adenosylmethionine levels (SAM) </li></ul><ul><li>protect against steatosis and decrease oxidative stress. </li></ul>
  41. 41. Pentoxifylline <ul><li>Production of tumour necrosis factor-alpha is one of the primary events in many types of liver injury </li></ul><ul><li>Patients with NASH have been shown to have higher levels of TNF-alpha. </li></ul><ul><li>Biochemical improvement was demonstrated in certain study </li></ul>
  42. 42. Probucol <ul><li>Probucol is a lipid-lowering drug with potent antioxidant properties that tends to accumulate in fatty tissues </li></ul><ul><li>Significant improvement in ALT levels with normalization of aminotranferases </li></ul>