Felix Stickel

Department of Clinical Research - Hepatology, University of Berne

&

Hepatology Unit, Klinik Beau-Site, Hirslanden Berne;

Switzerland

Therapy of Severe Alcoholic Hepatitis

VII Workshop Internacional de Atulização em Hepatologia, Curitiba 2014

Case report

• 46-year old male Arab patient, owner of construction company,

married, 3 sons, 1 daughter

• 19.11.2013 presentation with declining physical strength since 3 weeks,

jaundice, bilateral leg edema, weight gain (+11kg/2 weeks), abdominal

distension; temperature 37.9°C, pulse 106/min, RR 109/76 mmHg

• Spider angiomata, palmar erythema, no flap, no hepatic fetor,

significant ascites, BMI 31.3 kg/m2 (doubtful – ascites!)

• Loss of appetite since 12 months, poor food intake, alcohol ¾ bottle of

Scotch Whisky/day, nicotine 1 ½ packs/day (30 pys)

• Sigmoid resection 2004 for perforated diverticulitis;

arterial hypertension, amlodipine 5mg od since 2 years

Case report Laboratory

AST (U/L), ULN 35 167

ALT (U/L), ULN 35 66

gGT (U/L), ULN 40 242

Bilirubine (mmol/l), ULN 20 76

Albumine (g/L), NR 35-50 22.4

INR (NR 0.9-1.2) 2.28

Hemoglobin, g/L, NR 120-154 110

Leucocytes, 4-9 17.0

MCV, 81-99 96 fL

Sodium (mmol/L), NR 136-144 126

What else do you want to know?

Case report Laboratory

Creatinine (mmol/L), NR 44-83 507

CRP (mg/L), ULN 5 34.7

Ceruloplasmin, g/L, NR 0.2-0-6 0.42

Ferritin (mg/L), NR 11-310 442

Transferrin saturation, ULN 35% 43

Glucose (mmol/L), NR 4.1-6.6 6

Potassium (mmol/L), NR 3.6-5.1 4.9

Negative findings for Hepatitis A/B/C/E, HIV,

Autoantibodies, normal levels of Ig‘s, CDT

What‘s next?

Case report - Ultrasound

4.5cm

10.9cm

What‘s the likely diagnosis?

A Decompensated alcoholic cirrhosis with hepatorenal failure

Why not: Spleen normal, rapid evolution of symptoms and signs

B Chronic alcoholic liver damage with acute-on-chronic drug-induced liver

injury

Why not: amlodipine longer than 6 mo (and rare anyway)

C Alcoholic liver disease complicated by acute severe alcoholic hepatitis and

subsequent hepatorenal failure

Why not: no reason why not…

D Acute-on-chronic alcoholic liver disease precipitated by occult GI bleeding

and/or infection

Why not: no reason why not…

Screening for GI-bleeding and infections

Varices grade I Rectal polyp

inapparent No UTI

Alcoholic hepatitis

• Alcoholic steatohepatitis (ASH) present in

~20% of patients with ALD undergoing

biopsy

• Severe ASH less frequent

• Clinical picture: sudden onset of jaundice in

a drinker with fever, signs of impaired liver

function, right upper quadrant pain

• Mortality high in severe cases (40%) and

even higher in those unresponsive to

therapy (>80%)

Can we establish the working diagnosis of severe alcoholic

hepatitis based on information already available?

Yes, we even should, because of

Clinical presentation highly suspicious

Emergency situation (renal failure)

Non-invasive severity scores available

EASL Clinical Practice Guidelines J Hepatol 2012;57:399-20

MELD 33

Transjugular liver biopsy

Steatosis

Cholestasis

Ballooning

Neutrophilic infiltrate

Lymphocytic infiltrate

Alcoholic hepatitis – medical treatments

• Glucocorticosteroids + (DF≥32)

• Total enteral nutrition +

• Anti-TNFa biologicals -

• Pentoxifylline -/+ (HRS)

• N-acetylcysteine -/+ (28 days)

Corticosteroids in (severe) ASH

Cabré et al, Hepatology 32, 36, 2000

intention to treat

Alcoholic hepatitis – role of total enteral nutrition (TEN)

Pentoxifylline in severe ASH

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

N=164

N=171

Prednisolone and Pentoxifylline in severe ASH

Mathurin et al. JAMA 2013;310:1033-41

N=137

N=133

Prednisolone + N-acetylcysteine in severe ASH

Prednisolone + NAC N=85

N=89 Prednisolone + NAC N=89

P=0.006

P=0.06

P=0.07 (log rank)

Nguyen-Khac et al. N Engl J Med 2011;365:1781-9

Mortality of severe ASH

Louvet et al Hepatology 2007

Responders

Non-responders

The Lille Model – predicting survival according to therapy response

Louvet et al. Hepatology 2007

Age

Albumin (day 0)

Bilirubin (day 0 vs 7)

Renal function

Coagulation (day 0)

http://www.lillemodel.com/score.asp

What can we offer to non-responders?

Aims

• To determine whether early liver transplantation in non-responders to medical therapy improves 6-month survival

• To evaluate alcohol relapse

Patients (n=26)

• Subjects with first episode of ASH

• Non responsive to steroid (40mg

prednisolone) as defined by a Lille score ≥0.45

or worsening of liver function by day 7

• Strict selection criteria:

- absolute consensus of paramedical and medical staff

- no co-morbidities

- social integration

- supportive family members

- psychiatric evaluation and addictive profile

Background

• Patients with severe ASH non-responsive to steroid treatment have a mortality >80%

• The 6-months rule precludes such patients from OLT listing

Male no. [%] 15 [57.7%]

Age (y) median [95%CI] 47.4 [42.7-52.4]

Corticosteroids treatment (d) Median [95%CI] 11.5 [7-18]

Hepatorenal syndrome, no. [%] 15 [57.7%]

Hemofiltration/MARS® [%] 10 [38.5 %]

Infection before transplantation no [%] 18 [69.2%]

Mathurin P, N Engl J Med 2011;365:1790-1800

Results

• No alcohol relapse within the 6 month period

• 3 patients resumed alcohol consumption during

data collection at 720, 740 and 1140 days

• Despite counseling, 2 patients remained daily

consumers (30 g/day and > 50 g/, respectively)

whereas 1 had occasional consumption

(approximately 10g/week)

Mathurin P, N Engl J Med 2011;365:1790-1800

Outcomes of OLT in Alcoholic Cirrhotics and ASH are similar

Graft survival

Patient survival

Graft survival

Singal AK, Hepatology 2012;55:1398-1405

NS

NS

I‘ve stopped drinking, but only while I‘m asleep

George Best, Manchester United

Outcome of patient I.A.

• Hepatorenal syndrome: Terlipressin + Albumin, later to switch to

Noradrenalin + Albumin (hemodynamic monitoring); gradual recovery

of renal function

• Start with Prednisolone 40mg + Pentoxifyllin 3x400mg

• Referral to transplant unit for assessment of eligibility for living donor

transplantation (son at age of 22 years)

• Assessment of Lille model at day 7 of corticosteroids: 0.072 – complete

responder, continuation of steroids for 28 days, and subsequent taper

for 14 days until stop

• One episode of spontaneous bacterial peritonitis, one urinary tract

infection (both treated with antibiotics)

• Full recovery with near-normal liver function (June 2014), non-drinking

Conclusion

• Severe alcoholic steatohepatitis is a relatively infrequent complication

in alcoholics but has a grave prognosis

• Early diagnosis and assessment of eligibility for corticosteroide therapy

is pivotal and well-evaluated scores are available

• Liver biopsy can be usefuly, but is not imperative

• Exclusion of severe (and occult hepatitis B) infections is mandatory

• Response to corticosteroid therapy can be assessed by the Lille model

which should be used for detecting responders, and particularly non-

responders

• Non-responders may be candidates for liver transplantation