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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

Clinical Case Conference

Ranjeeta Bahirwani

July 28, 2010


Blame it on the sauce
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
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


Physical examination
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


Clinical case conference
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


Questions
Questions

  • What is your clinical assessment of this patient?

  • How would you manage him next?

  • What is his prognosis?


Clinical case conference1

Clinical Case Conference

Ranjeeta Bahirwani

July 28, 2010


Alcoholic liver disease
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 hepatitis
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
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)



Diagnosis
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



Assessing illness severity
Assessing Illness Severity

  • Maddrey’s Discriminant Function

  • MELD

  • Glasgow Alcoholic Hepatitis Score

  • ECBL

  • Lille model


Maddrey s discriminant function
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)


Clinical case conference
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
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


Clinical case conference
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
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 model1
Lille Model

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


Clinical case conference

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 corticosteroids
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
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


Steroids role of infection
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


Clinical case conference
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
Pentoxifylline Treated With Steroids: Early Response to Therapy Is the Key Factor

  • 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
Pentoxifylline vs Prednisolone Treated With Steroids: Early Response to Therapy Is the Key Factor

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
PTX in Steroid Non-Responders Treated With Steroids: Early Response to Therapy Is the Key Factor

  • 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
PTX in Advanced Cirrhosis Treated With Steroids: Early Response to Therapy Is the Key Factor

  • 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


Clinical case conference

PTX in Advanced Cirrhosis Treated With Steroids: Early Response to Therapy Is the Key Factor

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


Tnf antagonists
TNF Treated With Steroids: Early Response to Therapy Is the Key Factorα 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
Other agents Treated With Steroids: Early Response to Therapy Is the Key Factor

  • 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
Nutrition Treated With Steroids: Early Response to Therapy Is the Key Factor

  • 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


Clinical case conference

Lucey M et al. N Engl J Med 2009; 360: 2758-2769 Treated With Steroids: Early Response to Therapy Is the Key Factor


Clinical case conference

AASLD Algorithm Treated With Steroids: Early Response to Therapy Is the Key Factor


Liver transplantation
Liver Transplantation Treated With Steroids: Early Response to Therapy Is the Key Factor

  • 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