Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide, affecting up to 25% of the general population. It is strongly associated with obesity, type 2 diabetes, and metabolic syndrome. The pathogenesis involves insulin resistance leading to fatty infiltration of the liver followed by oxidative stress causing inflammation and fibrosis. Clinical features are often asymptomatic, though elevated liver enzymes and hepatomegaly may be seen. Diagnosis relies on excluding other causes of liver disease and imaging or biopsy. Potential therapies focus on lifestyle changes like diet, exercise and weight loss as well as treatments targeting underlying conditions and antioxidants.

1. NONALCOHOLIC FATTY LIVER DISEASE Moderator: Dr. Tung Vir Singh Arya (DM) Speaker: Ajay Kumar

2. contents Introduction Epidemiology Causes Pathogenesis Clinical features and investigations Potential therapies conclusion

3. NASH Ludwig 1980 Macrovesicular Fatty Liver Changes Focal Hepatic Cell Necrosis Acute & Chronic Inflammatry Cell Infiltration Mallory Hyaline Fibrosis & Cirrhosis No H/O Alcohol Abuse

4. EPIDEMIOLOGY NAFLD is probably most common liver disorder in world incidence of 10–24% in the general population and probably similar figures in Europe and Japan Mostly in 4th to 6th decade of life More common in female Very common in type II DM and Metabolic syndrome 75 % of type II diabetics have some form of NAFLD

5. As far as obesity is regarded, steatosis has been reported in 70% of obese and 35% of lean patients and NASH in 18.5% of obese and 2.7% of lean patients in a consecutive study, although some authors have reported even higher figures (up to 95% in some studies . The prevalence of simple steatosis in obese patients is ∼60%, whereas 20–25% present NASH and 2–3% present cirrhosis .

6. IN INDIA Epidemiological studies suggest prevalence of NAFLD in around 9% to 32% of general population in India with higher prevalence in those with overweight or obesity and those with diabetes or prediabetes Clinicopathological studies show that NAFLD is an important cause of unexplained rise in hepatic transaminases, cryptogenic cirrhosis and cryptogenic hepatocellular carcinoma in Indian patients There is high prevalence of insulin resistance and nearly half of Indian patients with NAFLD have evidence of full-blown metabolic syndrome.

7. CAUSES OF NAFLD Acquired metabolic disorder(DM,obesity ,hyperlipidemia,starvation) Cytotoxic & cytostatic drugs Metals(Sb,P,U) Inborn error ofmetabolism(Abetalipoproteinemia, galactocemia) Surgical procedure( gastric bypass,jejunoileal bypass) Miscellaneous(IBD,severeanemia,TPN)

8. Acquired metabolic disorder DM obesity hyperlipidemia starvation

9. Cytotoxic & cytostatic drugs Azathioprine Methotrexate L-Asparginase Tamoxifen Amiodarrone Steroids Nucleoside analogues Calcium Channel blockers

10. Metals Sb P U

11. Inborn error ofmetabolism Abetalipoproteinemia galactocemia Glycogen storage disorder Refsum’s disease Hereditary fructose intolerance Limb lipodystrophy tyrosinemia

12. Surgical procedure ( gastric bypass,jejunoileal bypass) Miscellaneous (IBD,severeanemia,TPN)

14. PATHOGENESIS Proposed by DAY and JAMES in 1998 Described by “two hit hypothesis” FIRST HIT : disregulation of fatty acid metabolism leads to steatosis SECOND HIT: “oxidative stress” -may be environmental or genetic factors

16. macrovesicular steatosis

17. oxidative stress

18. Role of Diet Evidence exists demonstrating that the diet of NASH patients is rich in unsaturated fat and cholesterol but poor in polyunsaturated fat, fiber, and vitamins E and C compared with that of healthy subjects. These levels of unsaturated fat in the diet correlate with a lower sensitivity to insulin, with high postprandial triglyceride levels in these patients, and with other aspects of the metabolic syndrome

19. Role of intestinal bacterial overgrowth in the pathogenesis of NASH A clear link between intestinal bacterial overgrowth and liver damage during NASH has recently been established. Bacterial overgrowth has been detected in NASH patients with breath tests with lactulose and D-xylose , as well as in some forms of secondary NASH, such as that associated with obesity-related intestinal surgery Intestinal bacteria may increase hepatic oxidative stress by at least two mechanisms 1) increased endogenous ethanol production 2) release of LPS.

21. Gross section of fatty liver

22. HISTOPATHOGENESIS Features Present in all or most cases : Macrovesicularsteatosis Parenchymal inflammation Hepatocyte necrosis Bollooning degeneration

23. Biopsy showing inflammation and fatty infiltration

24. Features Observed with varying frequency : Perivenularperisinusoidal or periportal fibrosis Cirrhosis Mallory bodies Glycogenated nuclei Lipogranulomas and stainable hepatic iron

25. CLINICAL FEATURES COMMON UNCOMMON SYMPTOMS: -none (48 to 100%) SIGNS: -Hepatomegaly SYMPTONS: - RUQ vague pain - Fatigue - Malaise SIGNES: - Splenomegaly - Spider angiomata - Palmarerythema & ascites

26. LABORATORY FEATURES COMMON: - 2 to 4 fold elevation serum ALT and AST AST/ALT < 1 in most patients - Serum alkphosphatase level slightly elevated in one third pt. - Normal serum bil and serum albumin & PT - Elevated serum ferritin

27. UNCOMMON: - Low titer ANA - Elevated transferrin saturation - HFE gene mutation

28. ultrasonographic fatty liver grades. Grade 0 Normal parenchymal liver ecogenicity Grade 1 Increased liver echogenicity without haziness of vessel walls Grade 2 Increased liver echogenicity with haziness of vessel walls Grade 3 Increased liver echogenicity leading to loss of normal contrast between liver and diaphragm

29. USG Comparison with normal

31. DIAGNOSTIC APPROACH Elevated lever enzyme or Heptomegaly Exclude excessive alcohol and other form of liver disease by history & lab tests Image liver by US , CT or MRI Normal Fatty Liver present Liver Biopsy Consider Liver biopsy to stage dis& define risk of progression

33. histological evaluation of morphological changes in a liver biopsy is required, in particular, to differentiate between simple steatosis and steatohepatitis.

34. The presence of obesity or type 2 diabetes, high levels of alanineaminotransferase (ALT) and triglycerides, hypertension, and an aspartateaminotransferase/ALT ratio greater than unity may justify performing a biopsy

36. POTENTIAL THERAPIES AVOIDANCE OF TOXINS: - Discontinue offending medication/toxins - Minimize alcohol intake EXERCISE AND DIET: -Moderate sustained exercise and weight loss in overweight patients BARIATRIC SURGERY FOR MORBID OBESITY

37. Diet Modification advised to reduce saturated/trans fat and increase polyunsaturated fat, with special emphasize on omega-3 fatty acids. reduce added sugar to its minimum, try to avoid soft drinks containing sugar, including fruit juices that contain a lot of fructose, and increase their fiber intake. For the heavy meat eaters, especially those of red and processed meats, less meat and increased fish intake should be recommended. Minimizing fast food intake will also help maintain a healthy diet.

38. exercise An 8-week resistance exercise programme brought about an approximately 13% reduction in liver fat. This was accompanied by an approximately 12% increase in insulin sensitivity, and increased fat oxidation during submaximal exercise in the absence of any change in body weight. Resistance exercise provides an alternative to aerobic exercise; it improves muscular strength, muscle mass and metabolic control, safely and effectively, in vulnerable populations independent of weight loss. It places less of a demand on the cardiorespiratory system and may therefore be accessible to more patients

40. Correction of obesity with hypocaloric diets and physical exercise Rapid weight loss and long-lasting fasting periods should be avoided, since they lead to an increase in the flow of FFAs to the liver. A gradual weight reduction has been associated with an improvement of hepatic lesions, including fibrosis

42. Control of hyperglycemia with diet, insulin, or oral antidiabetic agents. Simultaneous treatment of overweight in these patients is of paramount importance.

43. Withdrawal from treatment with amiodarone, perhexilinemaleate, tamoxifen, or other drugs to which NASH development has been attributed. Likewise, exposure to hepatotoxic environmental agents, including alcohol, should be avoided, particularly where fibrosis is histologically detected in a biopsy

44. Control of hyperlipemia with diet, or, when indicated, with hypolipemic drugs. Gemfibrozil (600 mg/day) or bezafibrate showed more favorable results in terms of biochemical parameters and development of steatosis. Orlistat, an inhibitor of lipoprotein lipase, has been recently proven to be beneficial for NASH patients, inducing normalization of transaminases and reduction in liver steatosis and inflammatory activity

45. Change in IV Nutrition In parenteral nutrition-associated NASH, modifying the composition of the infusion, replacing glucose with lipids. Glucose stimulates insulin secretion, thus inhibiting FFA oxidation and leading to their accumulation and synthesis in the liver. Supplementation with choline is indicated to increase the synthesis of lecitin, necessary for VLDL formation

46. For those undergoing bariatric surgery In patients undergoing surgery to treat obesity, reconstructing intestinal transit to help improve hepatic lesions. Metronidazol may prevent the development of NASH by preventing the absorption of bacterial overgrowth-derived endotoxin in excluded loops

47. Antibiotics Because bacterial overgrowth–derived lipoproteins may be involved in the development of NASH, oral metronidazol (0.75–2 g/day for 3 months, followed by a similar period without treatment) may be efficacious in reverting steatosis and, in some cases, inflammation and fibrosis. Oral polymixin B may improve parenteral nutrition–associated NASH by reducing liver exposure to intestinal flora-derived endotoxin.

48. Metadoxine has proved efficacious in the treatment of alcoholic liver steatosis, as shown by biochemical data and echographical signs. This drug restores hepatic glutathione concentrations and acts as an antifibrogenic agent. These therapeutic effects, along with the proven efficacy in steatosis, may justify its indication for the treatment of NASH.

49. Silymarin also possesses antioxidant and antifibrogenic properties, with beneficial effects in alcoholic liver disease , supporting its indication for the treatment of NASH. Betaine treatment has shown beneficial biochemical and histological effects in a pilot study of NASH patients . Additional drugs currently in assessment include ghrelin and pentoxyphylline . Other promising, potentially useful antioxidant agents include vitamin E and N-acetylcysteine.

50. Reduction of peripheral resistance to insulin rosiglitazone have also shown some efficacy in improving liver enzyme levels and histology . Similarly, pioglitazone has also been tested in a pilot study with 18 nondiabetic NASH patients . Administration of a daily dose of 30 mg for 48 weeks resulted in normalization of ALT levels in 72% of patients. Hepatic fat content and size, as well as glucose and FFA sensitivity to insulin, were consistently improved, as well as histological signs of steatosis.

51. Metformin In addition to improving hyperinsulinemia and insulin sensitivity in animals and humans , metformin inhibits hepatic TNF-α and several TNF-inducible responses, which, as stated above, are likely to promote hepatic steatosis and necrosis. Metformin statistically significantly improved serum alanine/aspartateaminotransferase levels as well as insulin resistance, whereas it decreased insulin and C-peptide levels. metformin could be a promising agent for the treatment of NASH patients

52. Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholicsteatohepatitis (43% vs. 19%, P=0.001),

53. LIVER TRANSPLANTATION Patients with NAFLD in whom end stage liver disease developed should be evaluated Outcome of liver transplantation in these patient is good NAFLD can recur after liver transplantation Risk factors for recurrent NAFLD after liver transplantation are hypertriglyceridemia, DM, obesity & glucocorticoids therapy

54. Take Home Message NAFLD is more common than alcoholic fatty liver disease Insulin resistance and free radical oxidative damage is the culprit for pathogenesis Diagnosis of exclusion Diet Control and exercise is the hope for future Supplement therapies have got some role

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