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Clinical Case Conference

Clinical Case Conference. Ranjeeta Bahirwani July 28, 2010. Blame it on the Sauce…. Cc- “I feel like crap and am yellow”. 50 M with no PMH admitted with 1 week h/o jaundice, abdominal pain and distention; also with increasing fatigue.

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Clinical Case Conference

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  1. Clinical Case Conference Ranjeeta Bahirwani July 28, 2010

  2. Blame it on the Sauce…. Cc- “I feel like crap and am yellow” • 50 M with no PMH admitted with 1 week h/o jaundice, abdominal pain and distention; also with increasing fatigue. • + h/o chronic alcohol abuse, attempted AA without success • Recent alcohol binging over the past 2 months especially on weekends-drinks a fifth of whiskey/day

  3. Clinical Case PMH/PSH: None Allergies: NKDA FH: No FH of liver disease Medications: None Social History: Single businessman + ETOH-multiple attempts at rehab No IVDU No tobacco

  4. Physical Examination Vitals: 98 F, 98, 90/45, 18, 98% RA GEN: + jaundice, NAD HEENT: + scleral icterus CV: RRR, no murmurs/rubs Lungs: CTAB Abdomen: no caput medusae, distended with shifting dullness, + mild TTP diffusely, no HSM Ext: 1+ LE edema bilaterally Skin: no spider angiomata Neuro: A + O x 3; no asterixis

  5. Labs 133 110 43 11.1 MCV 105 100 20.2 N-87% 198 3.8 10 2.3 TB 25.3, DB 17.3; albumin 2.5 AST 185, ALT 50, Alk phos 90; amylase 150, lipase 230 INR 2.2, PT 22.1, PTT 49 Ascites: albumin <1, 150 WBC (10% segs) RUQ U/S: large ascites, nodular liver, mild splenomegaly

  6. Questions • What is your clinical assessment of this patient? • How would you manage him next? • What is his prognosis?

  7. Clinical Case Conference Ranjeeta Bahirwani July 28, 2010

  8. Alcoholic Liver Disease • Affects 1% of the US Population • Ranges from simple steatosis, alcoholic hepatitis, to cirrhosis • Accounts for >12000 deaths/yr • 2nd most frequent indication for OLT

  9. Alcoholic Liver Disease-Spectrum

  10. Alcoholic Hepatitis • Clinical syndrome of jaundice and liver failure, generally with chronic alcohol use (mean ~100 gm/day) • Common symptoms apart from jaundice include fever, ascites, cachexia, RUQ pain and HE • Risk factors include amount of alcohol ingested (not a linear relationship); increased risk with female sex • Genetic factors (increased risk in children of alcoholics) • Protein calorie malnutrition • Concomitant viral hepatitis (HCV)

  11. Pathogenesis • Oxidative metabolism to acetaldehyde generates reactive oxygen species, which induce lipid peroxidation, causing hepatocellular death via necrosis/apoptosis • Increased endotoxin levels due to intestinal permeability leading to increased pro-inflammatory cytokines by activating Kupffer cells (TNF α levels are higher in pts with AH than in pts with inactive cirrhosis)

  12. Lucey M et al. N Engl J Med 2009;360:2758-2769

  13. Diagnosis • Elevated AST and ALT ( rarely > 300 IU/ml) • AST/ALT > 2:1 (> 80% pts) • Increased GGT (70-90% pts) -independent of liver disease • Leukocytosis with neutrophilia • Increased MCV (80-100% pts) –due to ETOH induced marrow toxicity, B12/folate deficiency • Elevated creatinine-ominous sign (HRS) • Carbohydrate deficient transferrin • Elevated IgA levels • Hyperbilirubinemia, coagulopathy, TCP

  14. Histology

  15. Assessing Illness Severity • Maddrey’s Discriminant Function • MELD • Glasgow Alcoholic Hepatitis Score • ECBL • Lille model

  16. Maddrey’s Discriminant Function • Most commonly used predictive model; developed to facilitate assessment of response to steroids in 1978; modified in 1989 • A DF ≥ 32 in the presence of HE predicts > 50% mortality at 28 days (in the absence of therapy); one month survival > 90% if DF < 32 Ramond MJ et al. N Engl J Med 1992; 326: 507–512. Discriminant function = (4.6 x [PT -control PT]) + (serum bilirubin)

  17. MELD • MELD score has been shown in multiple studies to predict short term mortality in pts with AH • MELD >11 is roughly equivalent to DF >32; although studies have suggested MELD cutoffs of 18, 19 and 21 for predicting prognosis • MELD score on admission ≥ 18, MELD at 1 week  20 or rise in MELD  2 have been shown in a retrospective study to be more sensitive (91%) and specific (85%) than DF or CTP score in predicting mortality Dunn W et al. Hepatology 2005; 41: 353-8 Srikureja W et al. J Hepatol 2005; 42:700-6

  18. Glasgow Alcoholic Hepatitis Score • Derived in 2005 to identify variables related to 28 and 84 day survival after admission in pts with AH • In patients with DF ≥ 32 and GAHS < 9, no difference in survival noted with steroids • With DF ≥ 32 and GAHS ≥ 9, 24 day (78 vs 52%) and 84 day (59 vs 38%) survival better with steroids Forrest EH et al. Gut 2005; 54: 1174-9 Forrest EH et al. Gut 2007; 56: 1743-6 Score 1 2 3 Age <50 ≥ 50 WCC(109/l) <15 ≥15 Urea (mmol/l) <5 ≥5 PT ratio <1.5 1.5-2.0 >2.0 Bili (mol/l) <125 125-250 >250

  19. ECBL • Derived to determine which patients with severe (DF ≥ 32) and biopsy-proven AH do not respond to corticosteroids • An early change in bilirubin levels (ECBL), defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment identified 95% of pts with continued improvement in liver function on steroids • At 6 months, patients with ECBL had 83% survival compared to 23% without drop in bilirubin at day 7 Mathurin P et al. Hepatology 2003;38:1363-1369

  20. Lille Model • Model generated using 6 variables to identify patients with severe AH (DF ≥ 32) not responding to steroids Lille score: 3.19–0.101×Age (years) +0.147×Albumin on day 0 (g/L) +0.0165×Evolution in bilirubin level (μmol/L) −0.206× Renal insufficiency −0.0065× Bilirubin on day 0 (μmol/L) −0.0096×PT (seconds) • Pts with score ≥ 0.45 had marked decrease in 6 month survival (25% vs 85%), predicted 75% of observed deaths • Better than CTP, DF, GAHS, and MELD at predicting prognosis Louvet A et al. Hepatology 2007; 45: 1348-54

  21. Lille Model Louvet A et al. Hepatology 2007; 45: 1348-54

  22. Lucey M et al. N Engl J Med 2009; 360: 2758-2769 Lucey M et al. N Engl J Med 2009;360:2758-2769

  23. Therapy-Corticosteroids • Most intensely studied yet most hotly debated • Block cytotoxic as well as inflammatory pathways (inhibit NF-KB, decrease TNF α levels) • Decrease intracellular adhesion molecule 1 in sinusoidal cells-inhibit leukocyte activation Prednisolone 40mg daily recommended in pts with DF ≥ 32 or HE for 28 day course +/- taper (provided ECBL or Lille score < 0.45) CONTRAINDICATIONS: -Infection/sepsis -GI bleed -Renal insufficiency

  24. Steroids for AH • Data from the 3 largest trials of Prednisolonevs placebo analyzed patients with DF ≥ 32 • 28 day survival was 85% vs 65%; NNT 5 • The 5 largest trials were re-analyzed in Cochrane review which confirmed the survival benefit in patients with DF ≥ 32 or HE *** ~40% pts with AH are UNRESPONSIVE to steroids Mathurin P, Hepatology 2008; 48: 635A Rambaldi A APT 2008; 27:1167-78

  25. Steroids-Role of Infection • Study of 246 pts with severe AH revealed no difference in infection rates before or after initiation of steroids (25.6 versus 23.7%) • Infection occurred more frequently in steroid non-responders (42.5%) versus responders (11.1%) • Lille model and MELD were associated with survival, not presence of infection Louvet A et al. Gastroenterology 2009; 137: 541-8

  26. Infection in Patients With Severe Alcoholic Hepatitis Treated With Steroids: Early Response to Therapy Is the Key Factor Louvet A et al. Gastroenterology 2009; 137: 541-8

  27. Pentoxifylline • Non-selective phosphodiesterase inhibitor and TNF α suppressor • RCT of 101 patients with severe AH (DF ≥ 32) receiving 4 weeks of PTX 400mg TID versus placebo revealed lower hospital mortality in PTX group (24.5%) versus placebo group (46.1%)-HRS was the cause of death in 50% PTX pts and 92% of placebo pts ***TNF α levels were not predictive of survival but increased markedly in non-survivors vs survivors Akriviadis E et al. Gastroenterology 2000; 119:1637-48

  28. Pentoxifylline vs Prednisolone RCT of 68 pts with severe AH (DF ≥ 32) receiving Prednisolone vs PTX 3 month mortality was 35% in steroid group vs 14.7% in PTX; more pts in steroid group developed HRS Krishna De et al. World J Gastroenterol 2009; 15:1613-19

  29. PTX in Steroid Non-Responders • 121 pts with severe AH were treated with steroids; of 87 non-responders (using ECBL), 29 were switched to PTX and 58 kept on steroids • There was no survival benefit at 2 months in pts switched to PTX (35.5 versus 31%) Louvet A et al. J Hepatol 2008; 48: 465-70

  30. PTX in Advanced Cirrhosis • 335 patients with cirrhosis (CTP C) were given PTX or placebo for 6 months-mortality was no different at 2 or 6 months in either group (6 month mortality 30% in PTX group and 31.5% in placebo group) • The proportions of patients without complications (infection, renal insufficiency, HE, or GI bleed) were higher in the PTX group than in the placebo group at 2 months (78.6% vs 63.4%) and 6 months (66.8% vs 49.7%). • 133 pts had AH, 55 had DF  32 and got steroids along with PTX vs placebo-there was no difference in 2 and 6 month mortality between these groups Lebrec D et al. Gastroenterology 2010; 138: 1755-62

  31. PTX in Advanced Cirrhosis Lebrec D et al. Gastroenterology 2010; 138: 1755-62

  32. TNF α antagonists • Infliximab and Etanercept have been studied for severe AH • Infliximab showed a positive effect in small studies; RCT comparing Infliximab and Prednisolone was stopped early due to increase rates of infections and death • Etanercept was studied in 48 patients with MELD  15 versus placebo x 3 weeks; 6 month mortality was higher in Etanercept group (58 versus 23%); infection rates were also higher (35 versus 9%) Naveau S et al. Hepatology 2004; 39: 1390-7 Boetticher NC et al. Gastroenterology 2008; 135: 1953-60

  33. Other agents • PTU- (? mitigates hepatic ischemia from ETOH induced hypermetabolic state)-no benefit • Anabolic androgenic steroids-increase muscle mass but do not improve survival • Vitamin E • Silymarin • Colchicine • S-Adenosylmethionine

  34. Nutrition • Risk of death in AH is closely correlated with degree of malnutrition • RCT comparing enteral tube feeding (2000 kcal/day) vs Prednisolone in 71 pts with severe AH revealed similar 1 month and 1 yr survival in both groups highlighting the effects of nutritional support Cabre E et al. Hepatology 2000; 32: 36-42

  35. Lucey M et al. N Engl J Med 2009; 360: 2758-2769

  36. AASLD Algorithm

  37. Liver Transplantation • AH is considered a contraindication to transplantation and 6 months of abstinence is recommended as minimal listing criterion although small studies have shown no worse outcomes in pts with AH • Recidivism rates range from 11-50% at 3-5 years post-transplantation Mathurin P. Liver Transplantation 2005; 11: S21-24

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