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ALCOHOLIC LIVER DISEASE Dr. Rakesh Kumar . Adi (D.M.) Gastroenterology Osmania General Hospital
PARADOX <ul><li>Why does cirrhosis develop in only a  </li></ul><ul><li>small fraction  of  alcoholics ?  </li></ul><ul><l...
<ul><li>Background </li></ul><ul><li>Spectrum of ALD </li></ul><ul><li>Alcoholic hepatitis </li></ul><ul><li>Presentations...
India : alcohol   <ul><li>The prevalence of  use of alcohol ranges from a low of  7%  in Gujarat , to  75%  in  Arunachal ...
BEVERAGES <ul><li>Beverage  Alcohol (%)  </li></ul><ul><li>Beer (12 oz)  5 %  </li></ul><ul><li>Wine (4 oz)  12 %  </li></...
Standard drink  (  12 gms   abs.alcohol  ) 4 4 One beer  wine  hard liqour   1 ounce = 30 ml
Simple conversion <ul><li>BEER  :  ml / 25 </li></ul><ul><li>WINE  :  ml / 10 </li></ul><ul><li>HARD LIQOUR :  ml/ 3 </li>...
Risk for the development of ALD.   <ul><li>Time to develop ALD = to amount of  </li></ul><ul><li>alcohol consumed </li></u...
Risk of liver disease <ul><li>Amount of alcohol consumed,  </li></ul><ul><li>Genetic factors </li></ul><ul><li>Female sex ...
Alcohol Abuse vs. Alcohol Dependence <ul><li>Alcohol abusers  as those who drink despite  </li></ul><ul><li>recurrent soci...
DETECTION OF ALCOHOL ABUSE <ul><li>CAGE  ( C ut down,  A nnoyed by criticism,  G uilty about drinking , E ye-opener in the...
Laboratory markers <ul><li>GGT  </li></ul><ul><li>MCV </li></ul><ul><li>CDT : Elevated levels of  carbohydrate-deficient t...
Spectrum of disease <ul><li>ALD comprises an overlapping spectrum of pathological processes </li></ul><ul><li>Steatosis (a...
SPECTRUM
Spectrum
ALCOHOLIC HEPATITIS <ul><li>It is a form of hepatic injury that  </li></ul><ul><li>carries a significant morbidity and  </...
Ethanol Metabolism <ul><li>Ethanol is metabolized by three major systems in the liver:  </li></ul><ul><li>Alcohol dehydrog...
Pathways
Pathogenesis   <ul><li>Genetic factors (  ADH2 ,ALDH2  ) </li></ul><ul><li>Toxic metabolites of ALDH ( adducts ) </li></ul...
ALCOHOL ENDOTOXEMIA ACETALDEHYDE OXIDATIVE STRESS MALNUTRITION KUFFER CELL ACTIVATION INFLAMMATION HEPATOCYTE INJURY STELL...
PATHOLOGY   <ul><li>Steatosis </li></ul><ul><li>Ballooning necrosis </li></ul><ul><li>Mallory’s hyaline bodies  </li></ul>...
HPE <ul><li>Low power field </li></ul><ul><li>Steatosis </li></ul><ul><li>Inflammation </li></ul><ul><li>Fibrosis </li></ul>
HPE Ballooning Degeneration of hepatocyte  Mallory bodies
Presentations   <ul><li>Asymptomatic  (majority of cases) </li></ul><ul><li>Hepatomegaly </li></ul><ul><li>Biochemistry mi...
Clincal Features <ul><li>Symptoms </li></ul><ul><li>Jaundice </li></ul><ul><li>Fatigue </li></ul><ul><li>Anorexia  </li></...
Lab   <ul><li>Both AST and ALT are INC. ,  < 300  IU/mL  </li></ul><ul><ul><li>AST>ALT of  2   ( 80% ) </li></ul></ul><ul>...
Others….. <ul><li>High CDT </li></ul><ul><li>High gamma globulin (IgA) </li></ul><ul><li>High uric acid </li></ul><ul><li>...
Prognosis of AH: Why Score it? <ul><li>To identify patients at greatest risk of </li></ul><ul><li>death </li></ul><ul><li>...
Prognostic Scores for AH <ul><li>Discriminant function (Modified DF) </li></ul><ul><li>Glasgow Alcoholic Hepatitis Score <...
Maddrey Discriminant Function <ul><li>4.6 x (prolongation of PT) + Bilrubin </li></ul><ul><li>If < 32 1 month mortality  1...
Glasgow Alcoholic Hepatitis Score (GAHS ) <ul><li>Variable  1  2  3 </li></ul><ul><li>Age  (years)  <50  >50  – </li></ul>...
A prognostic model (the  ‘‘Lille’’   model )   <ul><li>At  day 0  : Presence  of  encephalopathy </li></ul><ul><li>mDF ,  ...
MANAGEMENT <ul><li>Life style Modification </li></ul><ul><li>Nutrition Therapy </li></ul><ul><li>Drugs  </li></ul>
Life style Modification <ul><li>EtOH intake  :  80% survival rate in those  </li></ul><ul><li>who abstain  </li></ul><ul><...
Nutrition Therapy <ul><li>Nutritional supplement  improves  </li></ul><ul><li>hepatic function, and outcome in AH . </li><...
DRUGS
 
Corticosteroids   <ul><li>Decrease the immune response </li></ul><ul><li>Anti inflammatory </li></ul><ul><li>Antifibrotic ...
<ul><li>Prednisolone  : 32 mg PO for  4 weeks followed by taper </li></ul><ul><li>Active form prednisolone, rather than th...
<ul><li>The  ASG  recommends use of steroids for sev. AH </li></ul><ul><li>Ideal patient has  </li></ul><ul><li>1) MDF > 3...
Pentoxifylline <ul><li>It attenuates TNF-a release and action </li></ul><ul><li>Exerts an antifibrinogenic action  </li></...
<ul><li>Side-effects : Epigastric pain, vomiting, and dyspepsia  </li></ul><ul><li>Dose  :  400  mg TID </li></ul><ul><li>...
Specific Anti–TNF Therapy   <ul><li>Infliximab  (anti-TNF antibody  </li></ul><ul><li>Etanercept , a TNF receptor antagoni...
Antioxidants <ul><li>S-adenosylmethionine  : Benefits of SAM in ALD include roles as an  </li></ul><ul><li>Antioxidant  </...
<ul><li>Propylthiouracil  : </li></ul><ul><li>No significant effects of PTU vs placebo on mortality, complications of live...
Newer Approaches <ul><li>Polyenylphosphatidylcholine </li></ul><ul><li>N-acetyl cysteine </li></ul><ul><li>Combination the...
 
Thank q
Women : alcohol   <ul><li>Women alcoholics begin drinking later,  </li></ul><ul><li>and drink less alcohol per day than me...
<ul><li>More pronounced fatty liver </li></ul><ul><li>Less induction of fatty acid binding protein (higher FFA) </li></ul>...
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ALCOHOLIC LIVER DISEASE

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ALCOHOLIC LIVER DISEASE

  1. 1. ALCOHOLIC LIVER DISEASE Dr. Rakesh Kumar . Adi (D.M.) Gastroenterology Osmania General Hospital
  2. 2. PARADOX <ul><li>Why does cirrhosis develop in only a </li></ul><ul><li>small fraction of alcoholics ? </li></ul><ul><li>What is the pathogenesis of sev. ALD ? </li></ul><ul><li>What are the most effective treatments </li></ul><ul><li>for patients with adv. disease ? </li></ul>
  3. 3. <ul><li>Background </li></ul><ul><li>Spectrum of ALD </li></ul><ul><li>Alcoholic hepatitis </li></ul><ul><li>Presentations </li></ul><ul><li>Management </li></ul><ul><li>Prognosis </li></ul>
  4. 4. India : alcohol <ul><li>The prevalence of use of alcohol ranges from a low of 7% in Gujarat , to 75% in Arunachal Pradesh. </li></ul><ul><li>The per capita consumption is </li></ul><ul><li>4 lit/adult /year </li></ul><ul><li>It accounts for 50% of CLD </li></ul><ul><li>ALD cause of mortality M: 11/100000 </li></ul><ul><li>F: 6/100000 </li></ul>
  5. 5. BEVERAGES <ul><li>Beverage Alcohol (%) </li></ul><ul><li>Beer (12 oz) 5 % </li></ul><ul><li>Wine (4 oz) 12 % </li></ul><ul><li>Hard liquor (1.5 oz) 40 % </li></ul><ul><li>( Brandy, Whisky, Rum) </li></ul><ul><li>Local brew </li></ul><ul><li>Arrack 40 -50 </li></ul><ul><li>Toddy 5- 10 </li></ul>
  6. 6. Standard drink ( 12 gms abs.alcohol ) 4 4 One beer wine hard liqour 1 ounce = 30 ml
  7. 7. Simple conversion <ul><li>BEER : ml / 25 </li></ul><ul><li>WINE : ml / 10 </li></ul><ul><li>HARD LIQOUR : ml/ 3 </li></ul><ul><li>} Gms of alcohol </li></ul>
  8. 8. Risk for the development of ALD. <ul><li>Time to develop ALD = to amount of </li></ul><ul><li>alcohol consumed </li></ul><ul><li>Men : 60-80 gm/day for 10 years </li></ul><ul><li>Women : 20-40 gm/day for 10 years </li></ul><ul><li>Alcoholic cirrhosis , develops ONLY in 10 to 20% of those who are chronically heavy drinkers. </li></ul>
  9. 9. Risk of liver disease <ul><li>Amount of alcohol consumed, </li></ul><ul><li>Genetic factors </li></ul><ul><li>Female sex </li></ul><ul><li>Obesity </li></ul><ul><li>Chronic viral hepatitis </li></ul><ul><li>Nutritional impairment and </li></ul><ul><li>Drugs </li></ul>
  10. 10. Alcohol Abuse vs. Alcohol Dependence <ul><li>Alcohol abusers as those who drink despite </li></ul><ul><li>recurrent social, interpersonal, and legal </li></ul><ul><li>problems </li></ul><ul><li>Dependence - presence of 3 or more symptoms </li></ul><ul><li>a) tolerance </li></ul><ul><li>b) withdrawal symptoms </li></ul><ul><li>c) loss of control over drinking </li></ul><ul><li>d) strong desire to drink </li></ul><ul><li>e) drinking despite harm </li></ul>
  11. 11. DETECTION OF ALCOHOL ABUSE <ul><li>CAGE ( C ut down, A nnoyed by criticism, G uilty about drinking , E ye-opener in the morning) </li></ul><ul><li>AUDIT ( A lcohol U se D isorders I dentification T est) 10-item questionnaire </li></ul>
  12. 12. Laboratory markers <ul><li>GGT </li></ul><ul><li>MCV </li></ul><ul><li>CDT : Elevated levels of carbohydrate-deficient transferrin </li></ul><ul><li>Combined MCV and GGT detects 70% of the alcohol-dependent population. </li></ul><ul><li>CDT may be more sensitive in evaluating drinking </li></ul>
  13. 13. Spectrum of disease <ul><li>ALD comprises an overlapping spectrum of pathological processes </li></ul><ul><li>Steatosis (alcoholic fatty liver) </li></ul><ul><li>Alcoholic hepatitis </li></ul><ul><li>Alcoholic cirrhosis. </li></ul>
  14. 14. SPECTRUM
  15. 15. Spectrum
  16. 16. ALCOHOLIC HEPATITIS <ul><li>It is a form of hepatic injury that </li></ul><ul><li>carries a significant morbidity and </li></ul><ul><li>exceptional high short term mortality . </li></ul>
  17. 17. Ethanol Metabolism <ul><li>Ethanol is metabolized by three major systems in the liver: </li></ul><ul><li>Alcohol dehydrogenases (ADHs), </li></ul><ul><li>Cytochrome P450 2E1 (CYP2E1), </li></ul><ul><li>Catalase </li></ul>
  18. 18. Pathways
  19. 19. Pathogenesis <ul><li>Genetic factors ( ADH2 ,ALDH2 ) </li></ul><ul><li>Toxic metabolites of ALDH ( adducts ) </li></ul><ul><li>Free radicals and oxidative stress ( ROS ) </li></ul><ul><li>Role of immune system </li></ul><ul><li>Hypermetabolic state of hepatocyte </li></ul><ul><li>Cytokines ( TNF ,TGF ) </li></ul><ul><li>Malnutrition </li></ul>
  20. 20. ALCOHOL ENDOTOXEMIA ACETALDEHYDE OXIDATIVE STRESS MALNUTRITION KUFFER CELL ACTIVATION INFLAMMATION HEPATOCYTE INJURY STELLATE CELL ACTIVATION FIBROSIS IMPAIRED REGENERATION ALCOHOLIC HEPATITIS Gut permeability ADH CYP2E1 TNF ADDUCTS TGF
  21. 21. PATHOLOGY <ul><li>Steatosis </li></ul><ul><li>Ballooning necrosis </li></ul><ul><li>Mallory’s hyaline bodies </li></ul><ul><li>Neutrofilic cellular infiltration </li></ul><ul><li>Fibrosis </li></ul>
  22. 22. HPE <ul><li>Low power field </li></ul><ul><li>Steatosis </li></ul><ul><li>Inflammation </li></ul><ul><li>Fibrosis </li></ul>
  23. 23. HPE Ballooning Degeneration of hepatocyte Mallory bodies
  24. 24. Presentations <ul><li>Asymptomatic (majority of cases) </li></ul><ul><li>Hepatomegaly </li></ul><ul><li>Biochemistry mildly abnormal </li></ul><ul><li>Needs histology for confirmation </li></ul><ul><li>Symptomatic (minority of cases) </li></ul><ul><li>Liver failure </li></ul>
  25. 25. Clincal Features <ul><li>Symptoms </li></ul><ul><li>Jaundice </li></ul><ul><li>Fatigue </li></ul><ul><li>Anorexia </li></ul><ul><li>Weight loss </li></ul><ul><li>Fever </li></ul><ul><li>Pain in RHC </li></ul><ul><li>Physical examination </li></ul><ul><li>Stigma of CLD </li></ul><ul><li>Tender hepatomegaly </li></ul><ul><li>Hepatic decompensation- </li></ul><ul><li>Ascites, </li></ul><ul><li>Eso. varies </li></ul><ul><li>Encephalopathy. </li></ul>
  26. 26. Lab <ul><li>Both AST and ALT are INC. , < 300 IU/mL </li></ul><ul><ul><li>AST>ALT of 2 ( 80% ) </li></ul></ul><ul><ul><li>Inc in GGT </li></ul></ul><ul><ul><li>Macocytosis with anemia </li></ul></ul><ul><ul><li>Thrombocytopenia </li></ul></ul><ul><ul><li>Leukocytosis- correlates with degree of injury. </li></ul></ul><ul><ul><li>Increasing Bilrubin And PT correlate with severity of liver disease </li></ul></ul>
  27. 27. Others….. <ul><li>High CDT </li></ul><ul><li>High gamma globulin (IgA) </li></ul><ul><li>High uric acid </li></ul><ul><li>High serum lactate </li></ul><ul><li>Low albumin </li></ul><ul><li>High triglycerides </li></ul>
  28. 28. Prognosis of AH: Why Score it? <ul><li>To identify patients at greatest risk of </li></ul><ul><li>death </li></ul><ul><li>To decide when to offer second line </li></ul><ul><li>treatment (Steroids/ pentoxifylline) </li></ul><ul><li>Design of clinical studies for Rx of AH </li></ul>
  29. 29. Prognostic Scores for AH <ul><li>Discriminant function (Modified DF) </li></ul><ul><li>Glasgow Alcoholic Hepatitis Score </li></ul><ul><li>MELD </li></ul><ul><li>CTP </li></ul>
  30. 30. Maddrey Discriminant Function <ul><li>4.6 x (prolongation of PT) + Bilrubin </li></ul><ul><li>If < 32 1 month mortality 10 % </li></ul><ul><li>If > 32, 1 month mortality is 35% ; </li></ul><ul><li>45 % + encephalopathy. </li></ul><ul><li>75 % + HRS </li></ul>
  31. 31. Glasgow Alcoholic Hepatitis Score (GAHS ) <ul><li>Variable 1 2 3 </li></ul><ul><li>Age (years) <50 >50 – </li></ul><ul><li>WBC (109/L) <15 >15 – </li></ul><ul><li>Urea (mmol/L) <5 >5 – </li></ul><ul><li>PT ratio(INR) <1.5 1.5–2.0 >2.0 </li></ul><ul><li>Bil. (mg/dL) <7.4 7.4–14.8 >14.8 </li></ul><ul><li>score > 9 ass. With poor prognosis </li></ul>
  32. 32. A prognostic model (the ‘‘Lille’’ model ) <ul><li>At day 0 : Presence of encephalopathy </li></ul><ul><li>mDF , </li></ul><ul><li>creatinine </li></ul><ul><li>and an early change in bil.( DAY 7) </li></ul><ul><li>Score >> 0.5 predicted nearly 80% of </li></ul><ul><li>the deaths at 6 months </li></ul>
  33. 33. MANAGEMENT <ul><li>Life style Modification </li></ul><ul><li>Nutrition Therapy </li></ul><ul><li>Drugs </li></ul>
  34. 34. Life style Modification <ul><li>EtOH intake : 80% survival rate in those </li></ul><ul><li>who abstain </li></ul><ul><li>Smoking : Cigarette smoking is an </li></ul><ul><li>independent risk factor for </li></ul><ul><li>cirrhosis in ALD </li></ul><ul><li>Am J Epi. 1994 </li></ul><ul><li>Obesity </li></ul>
  35. 35. Nutrition Therapy <ul><li>Nutritional supplement improves </li></ul><ul><li>hepatic function, and outcome in AH . </li></ul><ul><li>Patients consuming > 3000 kcal/d had virtually no mortality, </li></ul><ul><li>whereas those consuming < 1000 kcal/d had > 80% 6-month mortality </li></ul><ul><li>Alcohol Clin Exp 1995 </li></ul>
  36. 36. DRUGS
  37. 38. Corticosteroids <ul><li>Decrease the immune response </li></ul><ul><li>Anti inflammatory </li></ul><ul><li>Antifibrotic </li></ul><ul><li>Increase production of albumin </li></ul><ul><li>Improve ascites. </li></ul><ul><li>Improve caloric intake by improving appetite </li></ul>
  38. 39. <ul><li>Prednisolone : 32 mg PO for 4 weeks followed by taper </li></ul><ul><li>Active form prednisolone, rather than the inactive precursor prednisone, is preferred </li></ul><ul><li>NO long term survival benefits </li></ul>
  39. 40. <ul><li>The ASG recommends use of steroids for sev. AH </li></ul><ul><li>Ideal patient has </li></ul><ul><li>1) MDF > 32 with </li></ul><ul><li>2)Spontaneous encephalopathy </li></ul><ul><li>4)No contraindications such as active </li></ul><ul><li>GI bleeding, HRS ,sepsis, AVH </li></ul>Carithers, Ann Int Med, 1989 Mendenhall, NEJM, 1984
  40. 41. Pentoxifylline <ul><li>It attenuates TNF-a release and action </li></ul><ul><li>Exerts an antifibrinogenic action </li></ul><ul><li>lower portal hypertension </li></ul><ul><li>Decreases blood viscosity </li></ul><ul><li>Improve organ microcirculation </li></ul><ul><li>Tissue oxygenation </li></ul>
  41. 42. <ul><li>Side-effects : Epigastric pain, vomiting, and dyspepsia </li></ul><ul><li>Dose : 400 mg TID </li></ul><ul><li>Improvement in short-term (4-week) survival </li></ul><ul><li>Decrease in the rate of development of hepatorenal syndrome </li></ul>Akriviadis, Gastroenterology, 2000
  42. 43. Specific Anti–TNF Therapy <ul><li>Infliximab (anti-TNF antibody </li></ul><ul><li>Etanercept , a TNF receptor antagonist, </li></ul><ul><li>Until more data are available, specific anti-TNF therapy should be used only in the context of a clinical trial. </li></ul>
  43. 44. Antioxidants <ul><li>S-adenosylmethionine : Benefits of SAM in ALD include roles as an </li></ul><ul><li>Antioxidant </li></ul><ul><li>Critical methyl donor </li></ul><ul><li>Decreasing TNF levels, and </li></ul><ul><li>Glutathionine </li></ul>
  44. 45. <ul><li>Propylthiouracil : </li></ul><ul><li>No significant effects of PTU vs placebo on mortality, complications of liver disease . </li></ul><ul><li>Cochrane review of 6RCT </li></ul><ul><li>Colchicine : </li></ul><ul><li>NO beneficial effect on overall mortality . </li></ul><ul><li>Morgan, Gastroenterology, 2002 </li></ul>
  45. 46. Newer Approaches <ul><li>Polyenylphosphatidylcholine </li></ul><ul><li>N-acetyl cysteine </li></ul><ul><li>Combination therapy </li></ul><ul><li>Liver transplantation : </li></ul><ul><li>OLT for alcoholic hepatitis is not currently recommended . </li></ul><ul><li>LAG Guidelines 2006 </li></ul>
  46. 48. Thank q
  47. 49. Women : alcohol <ul><li>Women alcoholics begin drinking later, </li></ul><ul><li>and drink less alcohol per day than men </li></ul><ul><li>Women drink for fewer years than men . </li></ul><ul><li>Yet , Women die of ALD at a 10 year earlier age than men. </li></ul>
  48. 50. <ul><li>More pronounced fatty liver </li></ul><ul><li>Less induction of fatty acid binding protein (higher FFA) </li></ul><ul><li>Increased plasma endotoxin levels </li></ul><ul><li>Increased CD 13 </li></ul><ul><li>More severe pericentral hypoxia </li></ul><ul><li>More marked activation of NfkB </li></ul>Women’s Risk of ALD

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