Clinical Case Clinical Case ConferenceConference

Ranjeeta BahirwaniRanjeeta Bahirwani

July 28, 2010July 28, 2010

Blame it on the Sauce….Blame it on the Sauce….Cc- “I feel like crap and am yellow”Cc- “I feel like crap and am yellow”

50 M with no PMH admitted with 1 week h/o50 M with no PMH admitted with 1 week h/o

jaundice, abdominal pain and distention; alsojaundice, abdominal pain and distention; also

with increasing fatigue.with increasing fatigue. + h/o chronic alcohol abuse, attempted AA without + h/o chronic alcohol abuse, attempted AA without

successsuccess Recent alcohol binging over the past 2 months Recent alcohol binging over the past 2 months

especially on weekends-drinks a fifth of whiskey/dayespecially on weekends-drinks a fifth of whiskey/day

Clinical CaseClinical Case

PMH/PSH:PMH/PSH: NoneNone

Allergies:Allergies: NKDANKDA

FH:FH: No FH of liver No FH of liver

diseasedisease

Medications:Medications: NoneNone

Social History:Social History:Single businessmanSingle businessman + ETOH-multiple attempts + ETOH-multiple attempts

at rehabat rehab No IVDUNo IVDU No tobaccoNo tobacco

Physical ExaminationPhysical Examination

Vitals: 98 F, 98, 90/45, 18, 98% RA Vitals: 98 F, 98, 90/45, 18, 98% RA GEN: + jaundice, NADGEN: + jaundice, NAD HEENT: + scleral icterusHEENT: + scleral icterus CV: RRR, no murmurs/rubsCV: RRR, no murmurs/rubs Lungs: CTABLungs: CTAB Abdomen: no caput medusae, distended with Abdomen: no caput medusae, distended with

shifting dullness, + mild TTP diffusely, no HSMshifting dullness, + mild TTP diffusely, no HSM Ext: 1+ LE edema bilaterallyExt: 1+ LE edema bilaterally Skin: no spider angiomataSkin: no spider angiomata Neuro: A + O x 3; no asterixisNeuro: A + O x 3; no asterixis

LabsLabs

133

3.8

110

10

43100

2.320.2

N-87%

11.1

MCV 105 198

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

QuestionsQuestions

What is your clinical assessment of What is your clinical assessment of this patient?this patient?

How would you manage him next?How would you manage him next? What is his prognosis?What is his prognosis?

Clinical Case Clinical Case ConferenceConference

Ranjeeta BahirwaniRanjeeta Bahirwani

July 28, 2010July 28, 2010

Alcoholic Liver DiseaseAlcoholic Liver Disease

Affects 1% of the US PopulationAffects 1% of the US Population Ranges from simple steatosis, Ranges from simple steatosis,

alcoholic hepatitis, to cirrhosis alcoholic hepatitis, to cirrhosis Accounts for >12000 deaths/yr Accounts for >12000 deaths/yr 22ndnd most frequent indication for OLT most frequent indication for OLT

Alcoholic Liver Disease-Alcoholic Liver Disease-SpectrumSpectrum

Alcoholic HepatitisAlcoholic Hepatitis

Clinical syndrome of jaundice and liver failure, Clinical syndrome of jaundice and liver failure, generally with chronic alcohol use (mean ~100 generally with chronic alcohol use (mean ~100 gm/day)gm/day)

Common symptoms apart from jaundice include Common symptoms apart from jaundice include fever, ascites, cachexia, RUQ pain and HEfever, ascites, cachexia, RUQ pain and HE

Risk factors include amount of alcohol ingested Risk factors include amount of alcohol ingested (not a linear relationship); increased risk with (not a linear relationship); increased risk with female sex female sex

Genetic factors (increased risk in children of Genetic factors (increased risk in children of alcoholics)alcoholics)

Protein calorie malnutritionProtein calorie malnutrition Concomitant viral hepatitis (HCV)Concomitant viral hepatitis (HCV)

PathogenesisPathogenesis Oxidative metabolism to acetaldehyde Oxidative metabolism to acetaldehyde

generates reactive oxygen species, generates reactive oxygen species, which induce lipid peroxidation, causing which induce lipid peroxidation, causing hepatocellular death via hepatocellular death via necrosis/apoptosisnecrosis/apoptosis

Increased endotoxin levels due to Increased endotoxin levels due to intestinal permeability leading to intestinal permeability leading to increased pro-inflammatory cytokines by increased pro-inflammatory cytokines by activating Kupffer cells (TNF activating Kupffer cells (TNF αα levels levels are higher in pts with AH than in pts are higher in pts with AH than in pts with inactive cirrhosis)with inactive cirrhosis)

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

DiagnosisDiagnosis

Elevated AST and ALT ( rarely > 300 IU/ml)Elevated AST and ALT ( rarely > 300 IU/ml) AST/ALT > 2:1 (> 80% pts)AST/ALT > 2:1 (> 80% pts) Increased GGT (70-90% pts) -independent of Increased GGT (70-90% pts) -independent of

liver diseaseliver disease Leukocytosis with neutrophiliaLeukocytosis with neutrophilia Increased MCV (80-100% pts) –due to Increased MCV (80-100% pts) –due to

ETOH induced marrow toxicity, B12/folate ETOH induced marrow toxicity, B12/folate deficiency deficiency

Elevated creatinine-ominous sign (HRS)Elevated creatinine-ominous sign (HRS) Carbohydrate deficient transferrinCarbohydrate deficient transferrin Elevated IgA levelsElevated IgA levels Hyperbilirubinemia, coagulopathy, TCPHyperbilirubinemia, coagulopathy, TCP

HistologyHistology

Assessing Illness Assessing Illness SeveritySeverity

Maddrey’s Discriminant FunctionMaddrey’s Discriminant Function MELDMELD Glasgow Alcoholic Hepatitis ScoreGlasgow Alcoholic Hepatitis Score ECBLECBL Lille modelLille model

Maddrey’s Discriminant Maddrey’s Discriminant FunctionFunction

Most commonly used predictive model; Most commonly used predictive model; developed to facilitate assessment of response developed to facilitate assessment of response to steroids in 1978; modified in 1989to steroids in 1978; modified in 1989

A DF ≥ 32 in the presence of HE predicts > A DF ≥ 32 in the presence of HE predicts > 50% mortality at 28 days (in the absence of 50% mortality at 28 days (in the absence of therapy); one month survival > 90% if DF < therapy); one month survival > 90% if DF < 3232

Ramond MJ et al. N Engl J Med 1992; 326: 507–512.

 Discriminant function = (4.6 x [PT -control PT]) + (serum bilirubin)

MELDMELD MELD score has been shown in multiple studies MELD score has been shown in multiple studies

to predict short term mortality in pts with AHto predict short term mortality in pts with AH MELD >11 is roughly equivalent to DF >32; MELD >11 is roughly equivalent to DF >32;

although studies have suggested MELD cutoffs although studies have suggested MELD cutoffs of 18, 19 and 21 for predicting prognosisof 18, 19 and 21 for predicting prognosis

MELD score on admission ≥ 18, MELD at 1 MELD score on admission ≥ 18, MELD at 1 week week 20 or rise in MELD 20 or rise in MELD 2 have been 2 have been shown in a retrospective study to be more shown in a retrospective study to be more sensitive (91%) and specific (85%) than DF or sensitive (91%) and specific (85%) than DF or CTP score in predicting mortalityCTP score in predicting mortality

Dunn W et al. Hepatology 2005; 41: 353-8Dunn W et al. Hepatology 2005; 41: 353-8

Srikureja W et al. J Hepatol 2005; 42:700-6Srikureja W et al. J Hepatol 2005; 42:700-6

Glasgow Alcoholic Hepatitis Glasgow Alcoholic Hepatitis ScoreScore

Derived in 2005 to identify variables related to 28 Derived in 2005 to identify variables related to 28 and 84 day survival after admission in pts with AH and 84 day survival after admission in pts with AH

In patients with DF ≥ 32 and GAHS < 9, no In patients with DF ≥ 32 and GAHS < 9, no difference in survival noted with steroids difference in survival noted with steroids

With DF ≥ 32 and GAHS ≥ 9, 24 day (78 vs 52%) With DF ≥ 32 and GAHS ≥ 9, 24 day (78 vs 52%) and 84 day (59 vs 38%) survival better with and 84 day (59 vs 38%) survival better with steroidssteroids

Forrest EH et al. Gut 2005; 54: 1174-9Forrest EH et al. Gut 2005; 54: 1174-9Forrest EH et al. Gut 2007; 56: 1743-6Forrest EH et al. Gut 2007; 56: 1743-6

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

ECBLECBL Derived to determine which patients 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 ModelLille Model Model generated using 6 variables to Model generated using 6 variables to identify patients with

severe AH (DF ≥≥ 32) not responding to steroidsLille 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 ModelLille Model

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

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

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

Therapy-CorticosteroidsTherapy-Corticosteroids Most intensely studied yet most hotly debatedMost intensely studied yet most hotly debated Block cytotoxic as well as inflammatory pathways (inhibit NF-KB, decrease TNF Block cytotoxic as well as inflammatory pathways (inhibit NF-KB, decrease TNF αα levels) levels) Decrease intracellular adhesion molecule 1 in sinusoidal cells-inhibit leukocyte activationDecrease intracellular adhesion molecule 1 in sinusoidal cells-inhibit leukocyte activation

Prednisolone 40mg daily recommended in pts with DF ≥ 32 orPrednisolone 40mg daily recommended in pts with DF ≥ 32 or

HE for 28 day course +/- taper (provided ECBL or Lille scoreHE for 28 day course +/- taper (provided ECBL or Lille score

< 0.45)< 0.45)

CONTRAINDICATIONS:CONTRAINDICATIONS:

-Infection/sepsis-Infection/sepsis

-GI bleed-GI bleed

-Renal insufficiency-Renal insufficiency

Steroids for AHSteroids for AH Data from the 3 largest trials of Prednisolone vs placebo analyzed patients with DF ≥ 32Data from the 3 largest trials of Prednisolone vs placebo analyzed patients with DF ≥ 32 28 day survival was 85% vs 65%; NNT 528 day survival was 85% vs 65%; NNT 5 The 5 largest trials were re-analyzed in Cochrane review which confirmed the survival The 5 largest trials were re-analyzed in Cochrane review which confirmed the survival

benefit in patients with DF benefit in patients with DF ≥≥ 32 or HE

*** ~40% pts with AH are UNRESPONSIVE to steroids

Mathurin P, Hepatology 2008; 48: 635AMathurin P, Hepatology 2008; 48: 635A

Rambaldi A APT 2008; 27:1167-78Rambaldi A APT 2008; 27:1167-78

Steroids-Role of Steroids-Role of InfectionInfection

Study of 246 pts with severe AH revealed Study of 246 pts with severe AH revealed no difference in infection rates before or no difference in infection rates before or after initiation of steroids (25.6 versus after initiation of steroids (25.6 versus 23.7%)23.7%)

Infection occurred more frequently in Infection occurred more frequently in steroid non-responders (42.5%) versus steroid non-responders (42.5%) versus responders (11.1%)responders (11.1%)

Lille model and MELD were associated Lille model and MELD were associated with survival, not presence of infectionwith survival, not presence of infection

Louvet A et al. Gastroenterology 2009; 137: 541-8Louvet A et al. Gastroenterology 2009; 137: 541-8

Infection in Patients With Severe Alcoholic Infection in Patients With Severe Alcoholic Hepatitis Treated With Steroids: Early Response Hepatitis Treated With Steroids: Early Response

to Therapy Is the Key Factorto Therapy Is the Key Factor

Louvet A et al. Gastroenterology 2009; 137: 541-8Louvet A et al. Gastroenterology 2009; 137: 541-8

PentoxifyllinePentoxifylline

Non-selective phosphodiesterase inhibitor Non-selective phosphodiesterase inhibitor and TNF and TNF αα suppressor suppressor

RCT of 101 patients with severe AH (DF RCT of 101 patients with severe AH (DF ≥ 32) ≥ 32) receiving 4 weeks of PTX 400mg TID versus receiving 4 weeks of PTX 400mg TID versus placebo revealed lower hospital mortality in placebo revealed lower hospital mortality in PTX group (24.5%) versus placebo group PTX group (24.5%) versus placebo group (46.1%)-(46.1%)-HRS was the cause of death in 50% HRS was the cause of death in 50% PTX pts and 92% of placebo ptsPTX pts and 92% of placebo pts

***TNF ***TNF αα levels were not predictive of survival levels were not predictive of survival but increased markedly in non-survivors vs but increased markedly in non-survivors vs survivorssurvivors

Akriviadis E et al. Gastroenterology 2000; 119:1637-48Akriviadis E et al. Gastroenterology 2000; 119:1637-48

Pentoxifylline vs Pentoxifylline vs PrednisolonePrednisolone

RCT of 68 pts with severe AH (DF RCT of 68 pts with severe AH (DF ≥ 32) receiving ≥ 32) receiving Prednisolone vs PTX Prednisolone vs PTX

3 month mortality was 35% in steroid group vs 14.7% in 3 month mortality was 35% in steroid group vs 14.7% in PTX; more pts in steroid group developed HRSPTX; more pts in steroid group developed HRS

Krishna De et al. World J Gastroenterol 2009; 15:1613-19 Krishna De et al. World J Gastroenterol 2009; 15:1613-19

PTX in Steroid Non-PTX in Steroid Non-RespondersResponders

121 pts with severe AH were treated with 121 pts with severe AH were treated with steroids; of 87 non-responders (using ECBL), 29 steroids; of 87 non-responders (using ECBL), 29 were switched to PTX and 58 kept on steroidswere switched to PTX and 58 kept on steroids

There was no survival benefit at 2 months in pts There was no survival benefit at 2 months in pts switched to PTX (35.5 versus 31%)switched to PTX (35.5 versus 31%)

Louvet A et al. J Hepatol 2008; 48: 465-70Louvet A et al. J Hepatol 2008; 48: 465-70

PTX in Advanced PTX in Advanced CirrhosisCirrhosis 335 patients with cirrhosis (CTP C) were given PTX or placebo for 6 months-mortality was no 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 different at 2 or 6 months in either group (6 month mortality 30% in PTX group and 31.5% in placebo group)placebo group)

The proportions of patients without complications (infection, renal insufficiency, HE, or GI bleed) 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 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%). months (66.8% vs 49.7%).

133 pts had AH, 55 had DF 133 pts had AH, 55 had DF 32 and got steroids along with PTX vs placebo-there was no 32 and got steroids along with PTX vs placebo-there was no difference in 2 and 6 month mortality between these groupsdifference in 2 and 6 month mortality between these groups

Lebrec D et al. Gastroenterology 2010; 138: 1755-62Lebrec D et al. Gastroenterology 2010; 138: 1755-62

Lebrec D et al. Gastroenterology 2010; 138: 1755-62Lebrec D et al. Gastroenterology 2010; 138: 1755-62

PTX in Advanced PTX in Advanced CirrhosisCirrhosis

TNF TNF αα antagonists antagonists Infliximab and Etanercept have been studied for Infliximab and Etanercept have been studied for

severe AHsevere AH Infliximab showed a positive effect in small Infliximab showed a positive effect in small

studies; RCT comparing Infliximab and studies; RCT comparing Infliximab and Prednisolone was stopped early due to increase Prednisolone was stopped early due to increase rates of infections and deathrates of infections and death

Etanercept was studied in 48 patients with Etanercept was studied in 48 patients with MELD MELD 15 15

versus placebo x 3 weeks; 6 month mortality versus placebo x 3 weeks; 6 month mortality was higher in Etanercept group (58 versus 23%); was higher in Etanercept group (58 versus 23%); infection rates were also higher (35 versus 9%)infection rates were also higher (35 versus 9%)

Naveau S et al. Hepatology 2004; 39: 1390-7Naveau S et al. Hepatology 2004; 39: 1390-7Boetticher NC et al. Gastroenterology 2008; 135: 1953-60Boetticher NC et al. Gastroenterology 2008; 135: 1953-60

Other agentsOther agents

PTU- (? mitigates hepatic ischemia from PTU- (? mitigates hepatic ischemia from ETOH induced hypermetabolic state)-no ETOH induced hypermetabolic state)-no benefitbenefit

Anabolic androgenic steroids-increase Anabolic androgenic steroids-increase muscle mass but do not improve survivalmuscle mass but do not improve survival

Vitamin EVitamin E SilymarinSilymarin ColchicineColchicine S-AdenosylmethionineS-Adenosylmethionine

NutritionNutrition

Risk of death in AH is closely Risk of death in AH is closely correlated with degree of malnutritioncorrelated with degree of malnutrition

RCT comparing enteral tube feeding RCT comparing enteral tube feeding (2000 kcal/day) vs Prednisolone in 71 (2000 kcal/day) vs Prednisolone in 71 pts with severe AH revealed similar 1 pts with severe AH revealed similar 1 month and 1 yr survival in both groups month and 1 yr survival in both groups highlighting the effects of nutritional highlighting the effects of nutritional supportsupport

Cabre E et al. Hepatology 2000; 32: 36-42Cabre E et al. Hepatology 2000; 32: 36-42

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

AASLD AlgorithmAASLD Algorithm

Liver TransplantationLiver Transplantation

AH is considered a contraindication AH is considered a contraindication to transplantation and 6 months of to transplantation and 6 months of abstinence is recommended as abstinence is recommended as minimal listing criterion although minimal listing criterion although small studies have shown no worse small studies have shown no worse outcomes in pts with AHoutcomes in pts with AH

Recidivism rates range from 11-50% Recidivism rates range from 11-50% at 3-5 years post-transplantationat 3-5 years post-transplantation

Mathurin P. Liver Transplantation 2005; 11: S21-24Mathurin P. Liver Transplantation 2005; 11: S21-24