ALD(ALCOHOLIC LIVER DISEASE) pethology .pptx

ALD(ALCOHOLIC LIVER DISEASE)

1. ALD(ALCOHOLIC LIVER DISEASE)

2. Chronic and excessive alcohol (ethanol) consumption is one of the major causes of liver disease, Three major, distinctive, but overlapping lesions, 1. hepatic steatosis (fatty liver), 2.alcoholic hepatitis, 3.alcoholic cirrhosis.

3. METABOLISM OF ETHANOL LIVER is the main organ , FORMATION OF ACETALDEHYDE , alcohol dehydrogenases,(ADH), cytochrome p450 2E1(CYP2E1) Catalase(least important)

4. 1. ADH ----Present in the cytoplasm of liver and the main enzyme system involved in alcohol metabolism at low concentrations 2.Cytochrome P450 ---- Blood alcohol high, microsomal ethanol- oxidizing system participates in its metabolism, generate reactive oxygen species, 3. catalase– present in peroxisomes and its of minor importance,

5. FORMATION OF ACETIC ACID Acetaldehyde ---- Acetic acid by ALDH in the mitochondria, acetic acid utilized in mitochondrial respiratory chain.

6. ETIOLOGY RISK FACTORS 1. Amount and duration of alcohol intake, - time required to develop ALD is directly related, - short- term ingestion of about 80 g of alcohol over one to several days -- - produces mild, reversible hepatic steatosis , - daily intake of 80 g or more—severe injury, --daily consumption of 160g or more for 10-20 years—very severe injury,

7. 2. gender—female are more susceptible to ALD, Develop advanced liver disease with less alcohol intake, estrogen increases gut permeability to endotoxins (gut derived)---production of pro-inflammatory cytokines and chemokines from macrophages and kupffer cells---injury to liver cells,

8. 3. Ethnicity- ethnic difference is noticed in liver injury, 4. Genetic factors- polymorphism in detoxifying enzymes have been identified, 5.Associated conditions---iron overload and chronic infections with HCV, HBV increase the severity of ALD

9. PATHOGENESIS Alcohol is a direct hepatotoxic and its metabolic product acetaldehyde plays an etiologic role in ALD About 10—15% develop cirrhosis,

10. OXIDATIVE STRESS /REACTIVE OXYGEN SPECIES Metabolism of alcohol by CYP2E1 IN Microsomes produces reactive oxygen species----lipid peroxidation of cell membranes---liver injury, IMMUNE AND INFLAMMATORY MECHANISM BY FORMING CHEMICAL ADDUCTS Acetaldehyde---chemical adducts ---initiate immune response—liver cell injury

11. , INCREASED REDOX(NADH: NAD+) RATIO decreased NAD in cytoplasm and mitochondria, In cytoplasm inhibits oxidation of fatty acid—accumulation fat in liver cell In mitochondria generate , reactive oxygen species –damage liver cell,

12. INCREASED PRODUCTION OF PROINFLAMMATORY CYTOKINES In the intestinal flora, alcohol causes release of endotoxin (LPS), from gram negative bacteria ---enter the portal circulation--stimulate production of TNF ,IL-6,TGF –liver cell injury, Impaired proteasome function ---death of hepatocytes—release cytokines IL-8 , IL-18 –liver cell injury.

13. DIRECT TOXICITY BY FORMING PROTEIN ADDUCTS acetaldehyde with reactive residues on protein—form toxic molecules– direct damage the hepatocyte, HYPOXIC DAMAGE alcohol increases oxygen demand by liver—hypoxia of the centrilobular region,

14. REDUCED LEVELS OF ADH AND ALDH ISOENZYMES Efficiency of alcohol metabolism depends on the enzymes, Low level can not oxidize acetaldehyde, ABNORMAL METABOLISM OF METHIONINE Causes decreased level of glutathione --liver cell injury,

15. MALNUTRITION AND DEFECIENCY OF VITAMINS alcohol becomes major source of calories in the diet—causes INDUCTION OF ENZYMES alcohol competes with other compounds metabolized with same enzyme system—increases conversion of drugs to toxic metabolites,

16. MECHANISMS OF STEATOSIS IN ALCOHOLISM - increases the catabolism of fat in the peripheral tissues—delivery of free fatty acids to the liver, - increases the synthesis of fatty acid in the liver, -decreases the oxidation of fatty acids by mitochondria, -increases the production of triglycerides, -impairs the assembly and release of lipoproteins,

17. MECHANISMS OF CIRRHOSIS/FIBROSIS Stellate cells present in the space of Disse , are quiescent and store vitamin A Alcohol activates hepatic stellate cell---transformed into highly fibrogenic cells with myofibroblast -like contractile property---produce collagen-fibrosis

18. MORPHOLOGY HEPATIC STEATOSIS GROSS Liver is enlarged about 4-6 kg soft ,yellow ,greasy MICROSCOPY 1. microvesicular steatosis —accumulation of small, clear vacuoles of lipid with in cytoplasm of hepatocytes, initial and most common histologic response, nuclei of affected hepatocytes are centrally located and cytoplasm looks foamy,

19. 2. macrovesicular steatosis - develops with continuing alcohol ingestion, - clear large lipid vacuole/s which compress and displace the hepatocytes nucleus to the periphery of the cell, - completely reversible 3.Absence of inflammation or fibrosis, but continued intake, leads to fibrosis

20. ALCOHOLIC HEPATITIS May be a precursor to development of cirrhosis, GROSS Enlarged liver, yellow due to steatosis , firm due to fibrosis, MICROSCOPY -1. Ballooning degeneration of hepatocytes---swollen liver cells, having pale stained, finely granular or clumped cytoplasm, -2.Mallory bodies(Mallory- Denk bodies/Mallory hyaline)---consist of tangled skeins of cytokeratin intermediate filaments,

21. cytokeratin 8 and 18 - appear as dense, eosinophilic ropey cytoplasmic inclusions/ clumps, situated in perinuclear location, in degenerating hepatocytes, MB-characteristic but not specific, 3.NEUTROPHILIC INFILTRATION—seen around ballooned hepatocytes, portal tracts infiltrated by lymphocytes and macrophages, 4.ALCOHOLIC STEATOFIBROSIS fibrosis initially starts as sclerosis of central veins followed by perisinusoidal fibrosis,

22. fibrosis spreads further outward to the periphery of lobule, enclosing single or small groups of hepatocytes in a CHICKEN WIRE FENCE PATTERN,

23. ALCOHOLIC CIRRHOSIS chronic, irreversible and end stage of alcoholic liver disease, known as LAENNEC CIRRHOSIS GROSS EARLY STAGE—yellow tan, fatty, and enlarged LATE STAGE- brown, nonfatty , diffusely nodular, firm, size becomes smaller and shrunken, nodularity more prominent less than 3mm – micronodular . more than 3mm- macronodular

24. MICROSCOPY 1. Loss of architecture, hepatocyte injury and consequent fibrosis leads, 2. Regenerating nodules initially nodule are small - micronodular larger one - macronodular , . 3. Fibrosis 4. Vascular reorganization, new vascular channels formed in the fibrotic septa,

25. CLINICAL FEATURES Symptoms may be nonspecific, such as malaise, anorexia, weight loss, upper abdominal discomfort and tender hepatomegaly, Alcohol withdrawal and an adequate diet liver can return to normal, Repeated bouts of alcoholic hepatitis may lead to cirrhosis .

26. LABORATORY DIAGNOSIS Elevated AST which is more than ALT Raised gamma glutamyl transpeptidase , Hyperbilirubinemia , Hypoproteinemia with reversal of albumin- globulin ratio, prolonged PT and APTT Anemia , neutrophilic leukocytosis

27. NONALCOHOLIC FATTY LIVER DISEASE(NAFLD)

28. Presence of hepatic steatosis who do not consume alcohol or do so in very small quantities, The most common cause of chronic liver disease,

29. Histologic hallmarks of NAFLD associated with metabolic syndrome, Increased incidence along with obesity, HCV AND HBV infection, hepatocellular carcinoma, Prevalence varies among ethnic groups,

30. PATHOGENESIS 2 HIT MODEL Insulin resistance gives rise to hepatic steatosis , Hepatocellular oxidative injury resulting in liver cell necrosis and inflammatory reactions to it,

31. NASH– Clinical features of liver injury and histological features of hepatitis, Associated abnormalities 1.type 2 diabetes 2.obeisity 3. dyslipidemia 4. hypertension Insulin resistance AND metabolic syndrome,

32. Initiating events are obesity and insulin resistance, I I Increase the mobilization of ffa from adipose tissue and taken up by hepatocytes I I 50% Of lipid in hepatocytes derived from adipose tissue, remaining de novo synthesis in liver cells

33. CLINICAL FEATURES MC cause of incidental elevation of serum transaminases, asymptomatic, fatigue, malaise, right upper quadrant discomfort, liver biopsy needed to detect NASH,

34. THANK YOU