Alcoholic liver disease

Academic base Harrisons 19th edition

1. Alcoholic Liver Disease By Dr K iran Bikkad

2. Introduction Chronic and excessive alcohol ingestion is one of the major causes of liver disease. Three major lesions, progressive injury : (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis.

3. Fatty liver is present in > 90 % of daily as well as binge drinkers. Only between 10 - 20 % of alcoholics will develop alcoholic hepatitis . No diagnostic tools that can predict individual susceptibility to alcoholic liver disease

4. Etiology

5. Pathology Fatty liver – initial & m/c histologic response to hepatotoxic stimuli , including excessive alcohol ingestion. A ccumulation of fat within hepatocytes bcoz of alcohol dehydrogenase. Despite extensive fatty change & distortion of the hepatocytes d/t fat, cessation of drinking results In normalization of hepatic architecture & fat content. S teatohepatitis & giant mitochondria, perivenular fibrosis , and macrovesicular fat causes progressive liver injury .

6. Pathology The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration spotty necrosis polymorphonuclear infiltrate fibrosis in the perivenular & perisinusoidal space of Disse . Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis.

7. CLINICAL FEATURES patients will present with Right upper quadrant discomfort N ausea J aundice Fever Spider nevi P ortal hypertension Ascites V ariceal bleeding

8. LABORATORY FEATURE Nonspecific M odest elevations of 2-7 fold. AST ALT γ- glutamyl transpeptidase (GGTP) Hypertriglyceridemia Hyperbilirubinemia A lkaline phosphatase

9. Derangement in hepatocyte synthetic function Hypoalbuminemia Coagulopathy Ultrasonography :- D etects fatty infiltration of the liver and determining liver size . Demonstration by ultrasound of portal vein flow reversal, ascites & intraabdominal venous collaterals

10. PROGNOSIS Critically ill patients with alcoholic hepatitis have short-term ( 30-day ) mortality rates >50%. Severe alcoholic hepatitis Coagulopathy ( PT increased > 5 sec) Anemia A lbumin concentrations <25 g/L ( 2.5 mg/ dL ) B ilirubin levels > 137 μ mol /L ( 8 mg/ dL ) R enal failure A scites .

11. D iscriminant function A discriminant function = 4.6 X (the prolongation of the prothrombin time above control [seconds]) + serum bilirubin (mg/ dL ) poor prognosis :- if discriminant function >32 Model for End-Stage Liver Disease (MELD) score ≥21

12. TREATMENT Complete abstinence from alcohol -- cornerstone in the treatment N utrition al suplimentation Pathogenic mechanisms in alcoholic hepatitis  cytokine release & injury by immunologic process S evere alcoholic hepatitis :  defined as a discriminant function >32 or MELD > 21 Rx :-- Prednisone 40 mg/d, or prednisolone 32 mg/d, for 4 weeks, followed by a steroid Taper

13. Exclusion criteria :- Active gastrointestinal bleeding R enal failure P ancreatitis . Women with encephalopathy from severe alcoholic hepatitis are good candidates for glucocorticoids .

14. Nonspecific TNF inhibitor Pentoxifylline U sed in severe alcoholic hepatitis B coz it decrease in hepatorenal syndrome.

15. Liver transplantation In patients with end-stage cirrhosis. Patients with alcoholic hepatitis largely excluded from transplant candidacy because of increased surgical mortality and high rates of recidivism following transplantation .

16. Cirrhosis D efined histopathologically In the past , thought that cirrhosis was never reversible Now a days when underlying insult that has caused the cirrhosis is removed , there can be reversal of fibrosis. E.g. : chronic hepatitis C Hemochromatosis alcoholic liver disease who discontinued alcohol use

17. Pathologic features C onsist Fibrosis Architectural distortion Regenerative nodules. Results in a Decrease in hepatocellular mass alteration of blood flow. activation of hepatic stellate cells increased collagen formation

18. Clinical features Advanced fibrosis includes bridging fibrosis nodularity Patients who have complications become decompensated should be considered for liver transplantation. Portal hypertension feature of decompensated cirrhosis responsible for the development of ascites bleeding from esophagogastric varices . Loss of hepatocellular function results in Jaundice coagulation disorders hypoalbuminemia contributes to portosystemic encephalopathy.

19. Chronic alcohol use produce fibrosis. Fibrosis can be centrilobular , pericellular , or periportal . T here is disruption of normal liver architecture and replacement of liver cells by regenerative nodules . In alcoholic cirrhosis, nodules are <3 mm in diameter; micronodular . With cessation of alcohol, larger nodules may form, mixed cirrhosis .

20. Pathogenesis Gastric alcohol dehydrogenase ( ADH) initiates alcohol metabolism. Three enzyme systems account for metabolism of alcohol in the liver :- C ytosolic ADH, M icrosomal ethanol oxidizing system ( MEOS) Peroxisomal catalase .

21. Intake of ethanol causes;- I ntracellular accumulation of triglycerides ( by increasing fatty acid uptake and by reducing fatty acid oxidation and lipoprotein secretion). Protein synthesis, glycosylation & secretion are impaired. Oxidative damage to hepatocyte membranes d/t reactive oxygen species.

22. Kupffer cell activation . Profibrogenic cytokines are produced stellate cell activation production of excess collagen and extracellular matrix.

23. Connective tissue appears in both periportal and pericentral zones and eventually connects portal triads with central veins forming regenerative nodules. Hepatocyte loss occurs, with increased collagen production and deposition, together with continuing hepatocyte destruction, the liver contracts and shrinks in size.

24. Clinical Features vague right upper quadrant abdominal pain Fever nausea and vomiting Diarrhea Anorexia malaise.

25. Specific Ascites Edema upper GI hemorrhage Jaundice encephalopathy

26. Examination liver and spleen enlarged, liver edge being firm and nodular. scleral icterus palmar erythema Spider angiomas parotid gland enlargement digital clubbing muscle wasting Edema Ascites decreased body hair gynecomastia testicular atrophy menstrual irregularities

27. Palmar erythema

28. Spider Angioma

29. Lab tests A nemic from chronic GI blood loss, nutritional deficiencies, or hypersplenism related to portal hypertension, or as a direct suppressive effect of alcohol on the bone marrow. Platelet counts are often reduced B ilirubin can be normal or elevated Prothrombin times prolonged ALT , AST elevated AST : ALT levels > 2:1 ratio

30. TREATMENT Abstinence good nutrition Complications such as the development of ascites and edema , variceal hemorrhage , or portosystemic encephalopathy all require specific management and treatment . Glucocorticoids are occasionally used discriminant function(DF ) value of >32 .

31. O ral pentoxifylline , decreases the production of TNF-α & other proinflammatory cytokines. I nhibitors of TNF-α such as infliximab or etanercept . Acamprosate Anabolic steroids, propylthiouracil , antioxidants, colchicine and penicillamine have all been used but do not show clear-cut benefits

32. HEPATIC ENCEPHALOPATHY a serious complication of CLD Broadly defined as an alteration in mental status & cognitive function in presence of liver failure More commonly seen in CLD. Gut-derived neurotoxins are not removed by liver because of vascular shunting. Ammonia levels- elevated Other compounds contribute :-- false neurotransmitters mercaptans

33. precipitating event Hypokalemia Infection increased dietary protein load electrolyte disturbances.

34. Clinical Features Brain edema with swelling of gray matter Cerebral herniation  complication T reatment is to decrease edema with mannitol and judicious use of intravenous fluids

35. Patients confused or change in personality. violent and difficult to manage; sleepy and difficult to rouse. If patients have ascites, this should be tapped to rule out infection. Evidence of GI bleeding should be sought A ppropriately hydrated . Electrolytes abnormalities corrected .

36. Diagnosis C linical Asterixis :- often present can be elicited by having patients extend their arms and bend their wrists back. Encephalopathic have a “liver flap”— i.e., a sudden forward movement of the wrist.

37. Treatment M anagement of precipitating factors. H ydration and correction of electrolyte imbalance are all that is necessary. R estriction of dietary protein ; however , negative impact on overall nutrition, thus discouraged. R eplacing animal-based protein with vegetable-based protein U se lactulose , a non absorbable disaccharide , which results in colonic acidification. Catharsis ensues , contributing to the elimination of nitrogenous products in gut

38. The goal of lactulose :-- to promote 2–3 soft stools per day. Poorly absorbed antibiotics used as adjunctive therapies. The alternating administration of neomycin & metronidazole to reduce the individual side effects of each: neomycin for renal insufficiency and ototoxicity metronidazole for peripheral neuropathy. R ifaximin at 550 mg twice daily Zinc supplementation