nonalcoholic fatty liver diseases Alcoholic liver diseases Acute liver failure

1. nonalcoholicfattyliverdiseasesAlcoholicliverdiseasesAcuteliverfailurenonalcoholicfattyliverdiseasesAlcoholicliverdiseasesAcuteliverfailure Yasar Kucukardali MD Professor / InternalMedicine

3. Non-Alcoholic Steatohepatitis • Represents only a part of wide spectrum of non alcoholic fatty liver • Prevalence – 2 to 3 % • NASH – 3rd most common cause of CLD in North America after alcoholic liver disease & Hepatitis C • The most common cause of raised transaminases more than 6 months.

4. NASH was coined by Ludwig et al while describing a series of patients of non-alcoholic, diabetic patients, mostly females, in whom liver histology was consistent with alcoholic liver disease but did not have a history of alcohol consumption.

5. Prevalence • Steatosis is the most common cause of raised transaminases & affects 10-24 % of gen.population while only 2-3 % of gen.population have steatohepatitis. • In pts undergoing liver biopsy, the prevalence of NAFLD & steatohepatitis ranges from 15-39% &1.2-4.8% respectively.

6. Risk Factors for NAFLD • Obesity • Diabetes • Hyperlipidemia • Female sex

9. etiology • Drugs / Toxins • Metals – Antimony Barium salts Carbon disulfide Thallium compounds • Cytotoxic/cytostatic drugs • Antibiotics – Bleomycin Tetracycline • Others – Amiodarone Estrogen Glucocorticoids

10. etiology • Inborn errors of metabolism – • Abetalipoproteinemia • Galactosemia • Glycogen storage disease • Weber-Christian syndrome • Wilson’s Disease • Nutritional – • Obesity • Rapid weight loss • Kwashiorkor

11. etiology • Surgical – • Jejuno colic bypass • Jejunoileal bypass • Gastroplasty • Extensive bowel resection

12. Pathogenesis • Increased delivery of fatty acids to liver Obesity Starvation • Increased synthesis of fatty acids in liver excess carbohydrate ( TPN ) • Decreased mitochondrial beta oxidation of fatty acids Carnitine deficiency Mitochondrial dysfunction • Decreased incorporation of triglycerides into functional VLDL Impaired apolipoprotein synthesis

13. Pathogenesis • Impaired cholesterol esterification Choline deficiency Protein malnutrition • Impaired export of VLDL from hepatocyte • Insulin resistance increased lipolysis hyperinsulinemia

14. Pathology • Diagnosis of NASH depends on histopathological features & exclusion of alcohol as the cause of disease. • Liver biopsy features : steatosispolymorphonuclear and / mononuclear hepatocyte ballooning and necrosi, malloryhyaline,glycogenatednuclei,metamitochondria and fibrosis indistinguishable from alcoholic liver disease

15. Pathology • Steatosis in NASH – macrovesicular • Inflammation of steatohepatitis is predominantly lobular, whereas intense portal inflammation with interface activity is seen in chronic viral, autoimmune & drug indued hepatitis • But in children , NASH may have portal infiltrate. • Neutrophilic cells in lobular inflammatory infiltrate • Balloon degeneration – recognized form & characteristic finding in NASH. • Mallory hyaline may be +/- . It is characteristic of alcoholic hepatitis

16. Pathology • Pattern of fibrosis is initial collagen deposition in perivenular & peri sinusoidal spaces of Zone 3 . • Chicken wire fibrosis • Fibrosis – in 66% pts • While 25% have severe fibrosis • And 14% have well established cirrhosis

19. Histological Differential Diagnosis • Hepatitis C • Primary Biliary Cirrhosis • Autoimmune hepatitis • Alpha 1 anti trypsin deficiency • Hemochromatosis

20. Clinical features Symptoms & Signs • Most of the patients are asymptomatic • 1/3rd present with nonspecific constitutional symptoms like weakness, fatigue & malaise. • Rapid onset of Fulminant hepatic failure – NASH d//t drugs like nucleoside analogues, tetracyclines • Hepatomegaly , splenomegaly • Presence of ascites, spider angiomata – indicate development of cirrhosis

21. Clinical featuresLaboratory findings • Mild – moderate elevations of S.Transaminases, typically less than 4 times the upper normal limit. • ALT level greater than AST in absence of cirrhosis. • Liver biopsy

22. Diagnosis • Clinical history • Exclusion of significant alcohol intake • Pursue dietary history, medication, occupational exposure to organic solvents • Family history of liver disease • Other causes of CLD – infections, metabolic heriditary & autoimmune causes to be ruled out • Liver biopsy – confirm diagnosis & for prognostic information

23. Natural course • Steatosis • Steatohepatitis • Cirrhosis • Steatosis – good prognosis • Steatohepatitis , cirrhosis – bad prognosis

27. Treatment • Treatment options are limited • Weight Reduction: • wt loss – normalization of s.aminotransferases. • Means of wt loss is important not the amount of wt loss • Recommended wt loss – 230 g/day or 1.6 kg/week • Diet : 45 -100 g high quality animal protein less than 100g carbohydrates less than 10 g fat per day providing 600 -800 kcal

28. Treatment • Ursodeoxycholic acid : • Has membrane stabilizing / cytoprotective / immunological effect • 10-15 mg/kg/day for 6-12 months – significant improvement in transaminases levels and degree of steatohepatitis

29. Treatment • Liver Transplantation : • NASH – A relative contraindication • Many of pts with NASH with CLD who underwent Liver Transplant – redeveloped NASH in the new donor liver ( 2/3 cases ) & • 1/3rd cases – liver transplantation is unsuccessful.

30. Newer treatment modalities • Inhibition of macrophage activation: • Anti oxidant ( Vit E ) glutathione prodrugs • Antibiotics, preprobiotics • Anti cytokines ( anti TNF alpha antibodies, pentoxiphylline )

31. Protect hepatocyte ATP stores • PARP inhibitors • Minimize CYP2F activity • Dietary modification ( avoid fats ) • Insulin sensitizers : pioglitazone • Antiobesity drugs : sibutramine, orlistat • Antilipid drugs : Simvastatin, Procusol

38. Alcoholic liver diseases

39. INTRODUCTION  • There is a spectrum of clinicalandlaboratoryfindings in patientswithalcoholicliverdisease, rangingfromasymptomaticfattylivertoalcoholichepatitistoend-stageliverfailurewithjaundice, coagulopathy, andencephalopathy • Unfortunately, manyalcoholicsfirstbecomesymptomaticonlywhen severe, life threateningliverdisease is alreadypresent. • Even at thisstage, abstinence can result in significantreversal in somepatients.

40. Patientswithalcoholicliverdiseaseoftenhavecoexistingdysfunction in otherorgans. cardiomyopathy, skeletalmusclewasting, neuropathies, pancreaticdysfunction. • The presence of feverandabdominalpainshouldnot be takenlightly in a patientwithalcoholichepatitiswithcirrhosisandascites, and can mimicthepresentation of spontaneousbacterialperitonitis. • Thedistinctionbetweenthesedisordersshould be madebyasciticfluidanalysis. A polymorphonuclearleukocytecountthat is ≥250/mm3 is presumptiveevidence of spontaneousbacterialperitonitis since it does not occurwithalcoholichepatitisalone.

41. Excessive alcohol consumption is the leading cause of liver disease. • Alcoholic liver disease comprises of three main stages • Hepatic steatosis • Alcoholic hepatitis • Cirrhosis

42. Hepatic steatosis • Pathogenesis : • Fatty change is an acute, reversible manifestation of ethanol ingestion. • Ethanol causes • Increased fatty acid synthesis by causing catabolism of fat in the peripheral tissues • Acetaldehyde which is metabolite of ethanol converts NAD+ to NADH. An excess NADH stimulates lipid biosynthesis. • Oxidation of fatty acid by mitochondria is decreased • Acetaldehyde impairs the function of microtubules, resulting in decreased transport of lipoproteins from liver • Collectively these metabolic consequences produce fatty liver.

43. Pathology: • Gross: • The liver becomes yellow, greasy and is enlarged (up to 4 to 6 kg) • The increase in weight is because of accumulation of fat, protein and water

44. Microscopy: • Following even moderate intake of alcohol, small (microvesicular) lipid droplets accumulates in the liver • With chronic intake of alcohol, more lipid accumulates, creating a large macrovesicular globules, compressing the nucleus the periphery.

45. Steatosis in Alcoholism

46. Clinical features of alcoholic steatosis • Hepatomegaly • Mild elevation of serum bilirubin, alkaline phasphatase and gamma GT

47. Alcoholic hepatitis • Is characterized by • Hepatocyte swelling and necrosis • Mallory bodies • Neutrophilic inflammatory response • Perivenular fibrosis

48. Hepatocyte swelling and necrosis: • Single or scattered foci of cells undergo swelling (ballooning degeneration) and necrosis

49. Mallory bodies: • Scattered hepatocytes accumulate cytokeratin intermediate filaments and other proteins • Visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes

50. Neutrophilic reaction: • Neutrophils accumulate around the degenerating hepatocytes, particularly those having Mallory bodies. • Lymphocytes and macrophages also enter portal tracts and spill into parenchyma