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. + 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

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

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 4

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 5

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

Clinical Case Conference Ranjeeta Bahirwani July 28, 2010

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

Alcoholic Liver Disease-Spectrum

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)

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)

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

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

Histology

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

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)

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

Glasgow Alcoholic Hepatitis Score 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 Score 1 2 3 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

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

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

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

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

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

Steroids for AH Data from the 3 largest trials of Prednisolone vs 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

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

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

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

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

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

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

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

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

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

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

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

AASLD Algorithm

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