Nonalcoholic fatty liver disease

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Nonalcoholic fatty liver disease

  1. 1. NONALCOHOLIC FATTY LIVER DISEASE<br />Moderator: <br />Dr. Tung Vir Singh Arya (DM)<br />Speaker: Ajay Kumar<br />
  2. 2. contents<br />Introduction<br />Epidemiology<br />Causes<br />Pathogenesis<br />Clinical features and investigations<br />Potential therapies<br />conclusion<br />
  3. 3. NASH<br />Ludwig 1980<br />Macrovesicular Fatty Liver Changes<br />Focal Hepatic Cell Necrosis Acute & Chronic Inflammatry Cell Infiltration Mallory Hyaline<br />Fibrosis & Cirrhosis<br />No H/O Alcohol Abuse<br />
  4. 4. EPIDEMIOLOGY<br />NAFLD is probably most common liver disorder in world<br />incidence of 10–24% in the general population and probably similar figures in Europe and Japan <br />Mostly in 4th to 6th decade of life<br />More common in female<br />Very common in type II DM and Metabolic syndrome<br />75 % of type II diabetics have some form of NAFLD<br />
  5. 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 .<br />
  6. 6. IN INDIA<br /> Epidemiological studies suggest prevalence of NAFLD in around 9% to 32% of general population in India with <br />higher prevalence in those with overweight or obesity and those with diabetes or prediabetes<br /> Clinicopathological studies show that NAFLD is an important cause of unexplained rise in hepatic transaminases, cryptogenic cirrhosis and cryptogenic hepatocellular carcinoma in Indian patients<br />There is high prevalence of insulin resistance and nearly half of Indian patients with NAFLD have evidence of full-blown metabolic syndrome.<br />
  7. 7. CAUSES OF NAFLD<br />Acquired metabolic disorder(DM,obesity ,hyperlipidemia,starvation)<br />Cytotoxic & cytostatic drugs<br />Metals(Sb,P,U)<br />Inborn error ofmetabolism(Abetalipoproteinemia, galactocemia)<br />Surgical procedure( gastric bypass,jejunoileal bypass)<br />Miscellaneous(IBD,severeanemia,TPN)<br />
  8. 8. Acquired metabolic disorder<br />DM<br />obesity <br />hyperlipidemia<br />starvation<br />
  9. 9. Cytotoxic & cytostatic drugs<br />Azathioprine<br />Methotrexate<br />L-Asparginase<br />Tamoxifen<br />Amiodarrone<br />Steroids<br />Nucleoside analogues<br />Calcium Channel blockers<br />
  10. 10. Metals<br />Sb<br />P<br />U<br />
  11. 11. Inborn error ofmetabolism<br />Abetalipoproteinemia<br />galactocemia<br />Glycogen storage disorder<br />Refsum’s disease<br />Hereditary fructose intolerance<br />Limb lipodystrophy<br />tyrosinemia<br />
  12. 12. Surgical procedure<br />( gastric bypass,jejunoileal bypass)<br />Miscellaneous<br />(IBD,severeanemia,TPN)<br />
  13. 13.
  14. 14. PATHOGENESIS<br />Proposed by DAY and JAMES in 1998<br />Described by “two hit hypothesis”<br />FIRST HIT : disregulation of fatty acid metabolism leads to steatosis<br />SECOND HIT: “oxidative stress” <br /> -may be environmental or genetic factors <br />
  15. 15.
  16. 16. macrovesicular steatosis<br />
  17. 17. oxidative stress<br />
  18. 18. Role of Diet<br />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. <br />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 <br />
  19. 19. Role of intestinal bacterial overgrowth in the pathogenesis of NASH<br />A clear link between intestinal bacterial overgrowth and liver damage during NASH has recently been established. <br />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<br /> Intestinal bacteria may increase hepatic oxidative stress by at least two mechanisms<br />  1) increased endogenous ethanol production<br />2) release of LPS.<br />
  20. 20.
  21. 21. Gross section of fatty liver<br />
  22. 22. HISTOPATHOGENESIS<br />Features Present in all or most cases : <br />Macrovesicularsteatosis<br />Parenchymal inflammation <br />Hepatocyte necrosis <br />Bollooning degeneration<br />
  23. 23. Biopsy showing inflammation and fatty infiltration<br />
  24. 24. Features Observed with varying frequency :<br />Perivenularperisinusoidal or periportal fibrosis<br />Cirrhosis<br />Mallory bodies<br />Glycogenated nuclei<br />Lipogranulomas and stainable hepatic iron<br />
  25. 25. CLINICAL FEATURES<br />COMMON<br />UNCOMMON<br />SYMPTOMS: -none (48 to 100%)<br />SIGNS: <br /> -Hepatomegaly<br />SYMPTONS:<br /> - RUQ vague pain<br /> - Fatigue<br /> - Malaise <br />SIGNES: <br /> - Splenomegaly<br /> - Spider angiomata<br /> - Palmarerythema & ascites<br />
  26. 26. LABORATORY FEATURES<br />COMMON:<br /> - 2 to 4 fold elevation serum ALT and AST<br /> AST/ALT < 1 in most patients<br /> - Serum alkphosphatase level slightly <br /> elevated in one third pt.<br /> - Normal serum bil and serum albumin & <br /> PT<br /> - Elevated serum ferritin<br />
  27. 27. UNCOMMON: <br /> - Low titer ANA<br /> - Elevated transferrin saturation<br /> - HFE gene mutation<br />
  28. 28. ultrasonographic fatty liver grades.<br />Grade 0 Normal parenchymal liver ecogenicity<br />Grade 1 Increased liver echogenicity without haziness of vessel walls<br />Grade 2 Increased liver echogenicity with haziness of <br /> vessel walls<br />Grade 3 Increased liver echogenicity leading to loss of <br /> normal contrast between liver and diaphragm<br />
  29. 29. USG Comparison with normal<br />
  30. 30.
  31. 31. DIAGNOSTIC APPROACH<br />Elevated lever enzyme or Heptomegaly<br />Exclude excessive alcohol and other form of liver disease by history & lab tests <br />Image liver by US , CT or MRI<br />Normal<br />Fatty Liver present<br />Liver Biopsy<br />Consider Liver biopsy to stage dis& define risk of progression<br />
  32. 32. <ul><li>clinical signs and liver test values have a poor predictive value for making a specific diagnosis,
  33. 33. histological evaluation of morphological changes in a liver biopsy is required, in particular, to differentiate between simple steatosis and steatohepatitis.
  34. 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
  35. 35. A standardized staging system for nonalcoholic fatty liver disease has been published</li></li></ul><li>
  36. 36. POTENTIAL THERAPIES <br />AVOIDANCE OF TOXINS: <br /> - Discontinue offending medication/toxins<br /> - Minimize alcohol intake<br /> EXERCISE AND DIET: <br /> -Moderate sustained exercise and weight <br /> loss in overweight patients<br />BARIATRIC SURGERY FOR MORBID OBESITY<br />
  37. 37. Diet Modification<br /> advised to reduce saturated/trans fat and increase polyunsaturated fat, with special emphasize on omega-3 fatty acids. <br />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.<br /> For the heavy meat eaters, especially those of red and processed meats, less meat and increased fish intake should be recommended.<br /> Minimizing fast food intake will also help maintain a healthy diet.<br />
  38. 38. exercise<br /> An 8-week resistance exercise programme brought about an approximately 13% reduction in liver fat.<br /> 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.<br />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.<br />It places less of a demand on the cardiorespiratory system and may therefore be accessible to more patients<br />
  39. 39.
  40. 40. Correction of obesity with hypocaloric diets and physical exercise<br />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.<br /> A gradual weight reduction has been associated with an improvement of hepatic lesions, including fibrosis <br />
  41. 41.
  42. 42. Control of hyperglycemia<br />with diet, insulin, or oral antidiabetic agents. Simultaneous treatment of overweight in these patients is of paramount importance.<br />
  43. 43. Withdrawal<br />from treatment with amiodarone, perhexilinemaleate, tamoxifen, or other drugs to which NASH development has been attributed.<br /> Likewise, exposure to hepatotoxic environmental agents, including alcohol, should be avoided, particularly where fibrosis is histologically detected in a biopsy<br />
  44. 44. Control of hyperlipemia<br />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.<br />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<br />
  45. 45. Change in IV Nutrition<br />In parenteral nutrition-associated NASH, modifying the composition of the infusion, replacing glucose with lipids. <br />Glucose stimulates insulin secretion, thus inhibiting FFA oxidation and leading to their accumulation and synthesis in the liver.<br /> Supplementation with choline is indicated to increase the synthesis of lecitin, necessary for VLDL formation<br />
  46. 46. For those undergoing bariatric surgery<br />In patients undergoing surgery to treat obesity, reconstructing intestinal transit to help improve hepatic lesions.<br />Metronidazol may prevent the development of NASH by preventing the absorption of bacterial overgrowth-derived endotoxin in excluded loops<br />
  47. 47. Antibiotics<br />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. <br />Oral polymixin B may improve parenteral nutrition–associated NASH by reducing liver exposure to intestinal flora-derived endotoxin.<br />
  48. 48. Metadoxine<br />has proved efficacious in the treatment of alcoholic liver steatosis, as shown by biochemical data and echographical signs. <br />This drug restores hepatic glutathione concentrations and acts as an antifibrogenic agent. <br />These therapeutic effects, along with the proven efficacy in steatosis, may justify its indication for the treatment of NASH.<br />
  49. 49. Silymarin<br />also possesses antioxidant and antifibrogenic properties, with beneficial effects in alcoholic liver disease , supporting its indication for the treatment of NASH.<br />Betaine treatment has shown beneficial biochemical and histological effects in a pilot study of NASH patients .<br /> Additional drugs currently in assessment include ghrelin and pentoxyphylline . Other promising, potentially useful antioxidant agents include vitamin E and N-acetylcysteine.<br />
  50. 50. Reduction of peripheral resistance to insulin<br />rosiglitazone have also shown some efficacy in improving liver enzyme levels and histology .<br /> 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.<br />
  51. 51. Metformin<br />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. <br />Metformin statistically significantly improved serum alanine/aspartateaminotransferase levels as well as insulin resistance, whereas it decreased insulin and C-peptide levels.<br />metformin could be a promising agent for the treatment of NASH patients<br />
  52. 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),<br />
  53. 53. LIVER TRANSPLANTATION<br />Patients with NAFLD in whom end stage liver disease developed should be evaluated<br />Outcome of liver transplantation in these patient is good<br />NAFLD can recur after liver transplantation<br />Risk factors for recurrent NAFLD after liver transplantation are hypertriglyceridemia, DM, obesity & glucocorticoids therapy<br />
  54. 54. Take Home Message<br />NAFLD is more common than alcoholic fatty liver disease<br />Insulin resistance and free radical oxidative damage is the culprit for pathogenesis<br />Diagnosis of exclusion<br />Diet Control and exercise is the hope for future<br />Supplement therapies have got some role<br />
  55. 55. THANK YOU<br />

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