The document discusses non-alcoholic fatty liver disease (NAFLD), which includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is strongly associated with obesity and metabolic syndrome. The prevalence of NAFLD is increasing globally and varies from 5-30% in different regions. Diagnosis requires imaging and liver biopsy. Treatment focuses on lifestyle modifications and medications to improve insulin resistance.

1. DR. Shatdal Chaudhary MD NAFLD

2. N on- A lcoholic F atty L iver D isease (NAFLD) An epidemic of new millenium . A new consequence of the obesity epidemic . Represents a spectrum of conditions characterized by macrovesicular hepatic steatosis in the absence of significant alcohol intake. Includes histological pattern : Simple steatosis( without inflammation) Steatohepatitis(NASH) with inflammation fibrosis & cirrhosis

3. N on- A lcoholic F atty L iver D isease (NAFLD) Fatty liver (Steatosis) Steatohepatitis - inflammation - fibrosis Cirrhosis Normal liver

4. The Brief History of NAFLD Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005 1979 ~8 papers published 1998 First NIH conference 1999 First Clinical Trials 2002 ~60 papers published Release of first book on NAFLD/NASH 2005 ~354 papers published

5. Prevalence of fatty liver “ Estimated” prevalence is 2.8 - 25 % of population 20 to 30 % adults in western countries have NAFLD of which 2 to 3 % are NASH ( Imaging & autopsy study) Steatosis seen in 80 % obese patients NASH seen in 9 - 30 % obese Hepatology 2003

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. Prevalence of NAFLD In General Population In Asian Pacific Region Name of the Percentage NAFLD in Country Adults Japan 9 – 30% China 5 – 18% Korea 18 % India 5 – 28% Indonesia 30% Malaysia 17 % Singapore 5%

8. Prevalence of NAFLD In High Risk Population In Asian Pacific Region Name of the Diabetes Obesity Dyslipidemia country Japan 40-50% 50-80% 42-58% China 35% 70-80% 57% Korea 35% 10-50% 26-35% India 30-90% 15-20% NA Indonesia 52% 47% 56%

9. Aetiological Classification Primary NAFLD : associated with metabolic syndrome. Secondary NAFLD : includes fatty liver diseases with a proximate causes.

10. Types of NAFLD Primary Secondary 1 Insulin resistance 1 severe weight loss Obesity jejunoileal bypass Diabetes gastric bypass Hypertriglyceridemia severe starvation Hypertension 2 total parenteral nutrition 3 Iatrogenic Amiodarone Diltiazem Tamoxifen Steroids HAART 3 Refeeding syndrome 4 Toxic exposure Hydrocarbon , yellow phosphorus 5 Disorders of lipid metabolism Abetalipoproteinemia Hypobetalipoproteinemia Andersen’s disease Weber –christian syndrome

11. Morbid Obesity Four studies evaluating > 600 morbidly obese patients undergoing gastric bypass All patients underwent intraoperative liver biopsies Prevalence of NAFL ranged from 30-90% and NASH was documented in 33-42%. > 2/3 of morbidly obese patients undergoing gastric bypass surgery have NAFL/NASH 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. Type 2 Diabetes Mellitus Recent study surveyed 100 patients with type 2 DM and used U/S to screen for NAFLD Detected fatty liver in 50% of patients Performed subsequent liver biopsy in those with NAFLD: NAFL: 13% NASH: 86% Fibrosis: 22% Gupte, et al. J Gastro Hepatol 2004;19:854-858.

13. Dyslipidemia Canadian study used U/S to screen 95 adults with dyslipidemia Detected fatty liver in 50% Steatosis was particularly common in individuals with moderate to severe hypertriglyceridemia or mixed dyslipidemia Hypertriglyceridemia and mixed dyslipidemia increased the risk for hepatic steatosis by ~5-fold Assy N, et al. Dig Dis Sci 2000;45:1929-1934.

14. Pathophysiology Salgado W, et al. Acta Cir. Bras. 2006; 21.

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. Liver Damage 2 nd Hit Liver Damage Sat FA 2 nd Hit Apoptosis Hepatocyte Mass Fatty Liver

17. Pathophysiology Other factors involved in NASH pathogenesis Bacterial overgrowth Increased hepatic oxidative stress Production of ethanol and TNF- α Direct activation of inflammatory cytokines and liver macrophages via release of lipopolysaccarides Leptin Obesity gene Regulates food intake and body composition Leads to hepatic steotosis by promoting insulin resistance or by modulating insulin signalling in hepatocytes

18. Pathophysiology: others Serum and liver iron Mitochondrial β oxidation leads to generation of hydrogen peroxide In presence of increased iron hydrogen peroxide converted to hydroxyl free radicles This leads to oxidative stress and hepatocellular injury

19. Pathophysiology: others TNF- α Corelates with obesity Derives from adipose tissue Decrease phosphorylation of insulin receptor Reduce expression of GLUT-4 Contributes toward insulin resistence Also causes chemotaxis, activation of stellate cells, Mallory hyaline formation, collagen synthesis

20. Clinical Presentation Variable clinical presentation Typically asymptomatic, but may have hepatomegaly and abdominal discomfort Liver enzymes may be normal in >75% of cases, making them insensitive in detecting NAFLD When increased, usually only modestly and limited to aminotransferases ALT upper limits of normal: <30 in M, <20 in F

21. Natural history and clinical outcomes of NASH 20% 30—40% NASH CIRRHOSIS Liver related Death Sub acute HCC Post-OLTX Failure recurrance

22. Diagnosis Cf h/o Disturbed liver enzymes Radioimaging Biopsy

23. Lab Studies No laboratory studies can help definitively establish a diagnosis of fatty liver or NASH. Aminotransferases Elevated AST or ALT As much as 10-fold 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. Alkaline phosphatase Can be elevated Usually less than 2 to 3 times normal

24. Diagnosis Diagnosis of NAFLD can often be made by imaging studies, including U/S, CT or MRI – detects presence of fat

25. Diagnosis (cont.) MR spectroscopy accurately measures hepatic triglyceride content Has advantage over U/S, CT and MRI as it is quantitative rather than qualitative

26. Diagnosis (cont.) No imaging studies can differentiate between the histological subtypes of benign steatosis or aggressive NASH, or stage the degree of fibrosis Need tissue for staging and to make diagnosis of NASH

27. Liver biopsy A liver biopsy and histopathological examination are required to establish the diagnosis. 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).

28. Doing liver biopsy is controversial Arguments favoring Exclusion of other cause To distinguish steatosis from NASH Estimation of prognosis Determination of progression Arguments against biopsy Good prognosis Lack of effective therapy Risk & cost associated with biopsy

29. Histology Histologic diagnosis of NAFL requires presence of ≥ 5% steatosis Indistinguishable from alcoholic fatty liver

30. Histology NASH involves presence of steatosis with evidence of inflammation and hepatocyte injury: Ballooning Mallory bodies

31. Histology Histologic evidence of steatohepatitis may disappear with progression to cirrhosis Thus, significant proportion of cryptogenic cirrhosis is likely related to unrecognized NASH

32. COMPLICATION Cirrosis Risk- 8 to 15% Hepatocellular carcinoma Risk: 1-2%

33. NASH Criteria (AGA guidelines) Characteristic liver biopsy that shows fatty change with inflammation Indistinguishable from alcoholic hepatitis Convincing evidence of negligible alcohol consumption (less than 20g alcohol per day) Detailed history obtained independently by 3 physicians, interrogation of family members Absence of serologic evidence of Hep B or Hep C infection Should not exclude those with evidence of past Hep B infection, but should exclude patients with positive HBs Ag or HCV Ab

34. Clues for severe NASH Old age(>50 yrs) Presence of diabetes Pesence of obesity AST/ALT > 1 ALT >2 times of normal TG >1.7m mol/L

35. Prognosis Patients with bland steatosis (NAFL) have a benign liver-related prognosis 1.5% develop cirrhosis 1% die from liver-related causes over 10-20 years Almost 30% of patients with NASH and fibrosis become cirrhotic within 5-10 years Those with biopsy-proven NASH have a liver-related death rate of ~10% NASH cirrhosis may develop into HCC ~13% of cases of all HCC are related to NASH cirrhosis Endstage NAFLD accounts for ~5-10% of liver transplants Matteoni C, et al. Gastroenterology 1999;116:1413-1419.

36. Treatment Aim to improve insulin sensitivity and modify underlying metabolic risk factors Diet and exercise Insulin Sensitizing Agents (metformin, TZD) Lipid lowering medications (statins, fibrates) L-Carnitine supplementation

37. McCullough AJ. N Engl J Med 2006; 355: 2361-3.

38. Treatment Lifestyle modification Diet and exercise Weight reduction Insulin sensitizers Metformin Troglitazone Rosiglitazone Pioglitazone Lipid Lowering agents Antioxidants Vitamin E Vitamin C Hepatoprotective agents Betaine Ursodeoxycholic acid Pentoxyfylline Angiotensin-converting enzyme inhibitors Probucol

39. Treatment (cont.) Beneficial according to preliminary studies: Insulin sensitizers: TZD > metformin Benefit unproven by preliminary studies Lipid lowering agents Antioxidants Probiotics (animal models only) Not beneficial Ursodiol

40. Betaine Metabolite of Choline increases S-adenosylmethionine levels (SAM) protect against steatosis and decrease oxidative stress.

41. Pentoxifylline Production of tumour necrosis factor-alpha is one of the primary events in many types of liver injury Patients with NASH have been shown to have higher levels of TNF-alpha. Biochemical improvement was demonstrated in certain study

42. Probucol Probucol is a lipid-lowering drug with potent antioxidant properties that tends to accumulate in fatty tissues Significant improvement in ALT levels with normalization of aminotranferases