ALKOHOL – INDUZIERTE HEPATITIS: PATHOPHYSIOLOGIE UND BEHANDLUNG

Helmut K. SeitzZentrum für Alkoholforschung, Lebererkrankungen und Ernährung,

Krankenhaus Salem und Universität Heidelberg

Falk Symposium 157 : Chronische Hepatitis: metabolisch, cholestatisch, viral und autoimmun

10.-11. Oktober 2006, Freiburg

Alcohol

Normal Liver

Alcoholic Fatty Liver (90-100 %)

Alcoholic Steato Hepatitis (ASH) (10-35 %)

Alcoholic Cirrhosis (8-20 %)

Hepatocellular Cancer (1-2 % p.a.)

Diet, Genetics, Female gender

NATURAL COURSE OF ALCOHOLIC LIVER DISEASE

AFL ASH

PATHOGENESIS OF ALCOHOLIC FATTY LIVER AND INFLAMMATION

VLDLTGFFA

ß -OXIDATION

GUT

FATTY TISSUE

Chylomicrones

FFA

Microtubules

ω-OxidationAcetyl-CoA

Cell-InjuryInflammation

ER-STRESS

ROS

IKK-β/NFκB Activation

Cathepsin BRelease

TNF-α InterleukinesOsteopontin

CYP2E1

Homocysteine

CholindeficiencyMTTP-Defect

Endotoxins

NAD+

Ethanol

AMP-K

Acetaldehyde

PPAR-α SREBP-1c

ETHANOL

AA

NADH β-Oxidation

HSF

ENDOTOXIN AND ALCOHOLIC LIVER DISEASE

EndotoxinsAcetaldehyde

Fibrosis

HypoxiaTLR4/CD14

KC

TNF α

GUT BACTERIA+ ETHANOL

LPS

ChemokinesCytokines

Apoptosis

TGF ß

?

IL-1, 4, 6, 8, 10

TNF α-R

Necrosis NF-KB

ESTROGENS

POLYMORPHISM

THERAPY

ANTIBIOTICS PROBIOTICS

CYP2E1

Aceton

Ethanol

FFA

Ethanol Acetaldehyde

ROS Fibrogenesis

PUFA (Fishoil) Lipids Lipidperoxidation Cell-Injury

LPP (4-Hydroxy Nonenal)

Carcinogenesis

CYP2E1 ABChlormethiazole

ROLE OF CYP2E1 IN ALCOHOLIC LIVER DISEASE

DYNAMICS OF CYP2E1 INDUCTION AND DISAPEARANCE

Oneta C, Lieber CS, Ji JJ, Rüttiman S, Rosman J, Seitz HK. J-Hepatol 2002;36:47-52

Glassen B, Seitz HK 2006

PROGRESSION ON FATTY LIVER

FATTY TISSUE FATTY LIVER

CYP2E1

FFA

IRON

FIBROSIS

CIRRHOSISHEPATITIS

SURVIVAL FACTORNECROSIS

CANCER

PROLIFERATIONAPOPTOSIS

ENDOTOXINS KC

IR

ROS

ETHANOL

ETHANOL

ETHANOL

TNFα

GENETIC RISK FACTORS FOR ALD

Gene Disease Effect References

ADH1B Ethanol consumption multiple studiesADH 1C HCC Homann et al. 2006ALDH2 Cirrhosis Enomoto et al.1991

TNFα ASH Grove et al.1997Bathgate et al. 2000Ladero et al. 2002

IL-10 ALD Grove et al. 2000Ladero et al. 2002

CD 14 ASH/Cirrhosis Järvelainen et al. 2001

MnSOD Steatosis, ASH Degoul et al. 2001Steward et al. 2002

+++

+--+-+

+-

ObesityFat

EFFECT OF GENDER ON THE DEVELOPMENT OF ADVANCED ALD

62334 - 8Marbet et al. 1987500

Stop drinking58141 - 3Pares et al. 1986

78140.5 - 8Krassner et al. 1977

female (%)male (%)

Progression from ASH to cirrhosis

Time of observation (years)

Author

PROGNOSIS

Discriminant function (DF) 1)

4,6 x (PTT patient – PTT control ) + bilirubin (mg%)

≥ 32 = 1 month mortality 50 %

MELD 2)

9,57 x loge (crea mg%) + 3,78 x loge (bili mg%) + 11,2 x loge (INR) + 6,43

≥ 21 = 3 month mortality 20 %

1) Maddrey et al. Gastroenterology 75,193:19782) Wiesner et al. Gastroenterology 124,91:2003

GLASGOW ALCOHOLIC HEPATITIS SCORE

> 14.57.25-14.5< 7.25Bilirubin (mg%)

> 2.01.5-2.0< 1.5PT ratio

-> 5< 5Urea (mmol/l)

-> 15< 15WCC (109/l)

-> 50< 50AGE321

SCORE

OVERALL ACCURACYOUTCOME ON DAY 84

57 %vs.78 %day 6-953 %vs.75 %day 1 GAHS vs. DF

(Forrest et al.GUT 2005;54:1174-79)

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

NUTRITIONAL THERAPY IN ASH (oral/enteral)Cabré et al., Hepatology 32 (2000) 36-42

1-year follow up mortality : TEN 8 %PRED 37 % (p = 0.04)

8 drop outs in TEN

RCT (n = 71) severe ASH: standard diet (1g prot./d)+ 40 g prednisolone

vs.NGT 2000 kcal/d72 g prot./d

PARENTERAL NUTRITION

7 RCTs ; n = 244

21-30 days outcome:

Improvement in albumine and nitrogen balance. No survival benefit.

NUTRITIONAL THERAPY NUTRITIONAL THERAPY

EstablishedEstablished–– Oral/Oral/enteralenteral nutrition:nutrition: improves malnutrition and improves malnutrition and

complication rate (A), influence on ASH complication rate (A), influence on ASH mortality questionable (B)mortality questionable (B)

–– EnteralEnteral nutrition through NGnutrition through NG--tubetube: : effective, effective, complications not elevated, poor compliancecomplications not elevated, poor compliance(B)(B)

–– ParenteralParenteral nutrition:nutrition: insufficient datainsufficient data

Stickel F., Stickel F., HoehnHoehn B., B., SchuppanSchuppan D., Seitz HK., Aliment D., Seitz HK., Aliment Pharm Ther Pharm Ther 2003;18:3572003;18:357

No advantage on survival by

• parenteral nutrition

• branched-chain amino acids

• anabolic steroids

• vitamin supplementation

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

. DRUGS- ANTIOXIDANTS

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

. DRUGS- ANTIOXIDANTS- STEROIDS

humoralhumoral immun immun responseresponse((acetaldehyde adductsacetaldehyde adducts))

proinflammatory cytokinesproinflammatory cytokines((TNFTNFαα, , TGFTGFββ, IL, IL--1, IL1, IL--8)8)

GlucocorticosteroidsGlucocorticosteroidsGlucocorticosteroids

Kupffer cellsKupffer cells neutrophilicneutrophilicgranulocytsgranulocyts

THERAPY OF ASH WITH GLUCOCORTICOSTEROIDSTHERAPY OF ASH WITH GLUCOCORTICOSTEROIDS

Metaanalysis: therapeutic benefit (Imperiale & McCullough, Ann Int Med 1990;113:299)Metaanalysis: Metaanalysis: therapeutic benefittherapeutic benefit (Imperiale & McCullough, Ann (Imperiale & McCullough, Ann Int MedInt Med 1990;113:299)1990;113:299)

Metaanalysis: no therapeutic benefit (Christensen & Gluud, Gut 1995;37:113)Metaanalysis: noMetaanalysis: no therapeutictherapeutic benefitbenefit ((ChristensenChristensen & & GluudGluud, Gut 1995;37:113), Gut 1995;37:113)

Metaanalysis: therapeutic benefit (Mathurin et al., J Hepatol 2002;36:480)Metaanalysis: Metaanalysis: therapeutictherapeutic benefitbenefit ((MathurinMathurin et al., J et al., J HepatolHepatol 2002;36:480)2002;36:480)

EFFECTIVENESS OF GLUCOCORTICOSTEROIDS IN ASHEFFECTIVENESS OF GLUCOCORTICOSTEROIDS IN ASH

CORTICOSTEROIDS IN ASH

• Corticosteroids seem to be effective in a subgroup of patients with ASH

• No G.I. bleeding. No infection• Severe ASH with DF > 32• Early change in bilirubin predicts response to

treatment• Major complication sepsis

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

. DRUGS- ANTIOXIDANTS- STEROIDS- PENTOXIFYLLINE

• Design: Pat. with ASH (DF > 32)• double-blind, placebo-controlled TX 3 x 400 mg/ d

for 28 days• Primary endpoint:• short-time survival, HRS

•• Design:Design: Pat. Pat. with with ASH (DF > 32)ASH (DF > 32)•• doubledouble--blind, placeboblind, placebo--controlledcontrolled TX 3 x 400 mg/ d TX 3 x 400 mg/ d

forfor 28 28 daysdays•• Primary endpointPrimary endpoint::•• shortshort--time time survivalsurvival, HRS, HRS

PENTOXIFYLLINE IN ASH: CLINICAL STUDYPENTOXIFYLLINE IN ASH:PENTOXIFYLLINE IN ASH: CLINICAL STUDYCLINICAL STUDY

AkriviadisAkriviadis et al., Gastroenterology2000;119:1637et al., Gastroenterology2000;119:1637

0102030405060708090

100

PTX CTR

28-days mortality

p = 0,037p = 0,037

%%

Results:•improved survival by PTX, mainlydue to reduction of HRS•Suppression of TNFa •Effect exceeds expected benefit by glucocorticosteroids

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

. DRUGS- ANTIOXIDANTS- STEROIDS- PENTOXIFYLLINE- TNF-α ANTIBODY

TNF-α ANTIBODYTHERAPY IN ASH

Tilg et al. J Hep 38, 415:2003

Patients 12 (DF > 32, biopsy proven)Therapy Infliximab 5 mg/kg b.wt

Norfloxacin (Ascites)Results Survival (15 months) 10/12 (83 %)

2 deaths due to septicemia

Spahr et al. J Hep 37,448:2002

Patients 20 (DF > 32, biopsy proven)Therapy Infliximab 5 mg/kg b. wt. + 40 mg prednisoneResults no survival difference

decrease in IL6, IL8 and DF

TNF-α ANTIBODYTHERAPY IN ASH

Patients 36 (DF > 32)Therapy 40 mg prednisolone (28 days)

+ 3x (week 0,2,4) 10 mg/kg infliximabvs

40 mg prednisolone (28 days)+ placebo

Results Mortality 39 % vs. 18 % (NS)Mortality due to infections

22 % vs. 11 %Severe infections 83 % vs. 28 % (pc 0.002)no difference in DF at any time

Naveau et al., Hepatology 39, 1390:2004

PROBLEMS

1. Dosis 5 mg/kg b.wt. vs. 3 x 10 mg/kg b.wt.

2. Combined therapy with steroids

3. Different degrees of severity of ASHDF: 70 ± 15 (severe infections)

37 ± 18 (remaining patients)Tilg-study: DF: 54Spahr-study: DF: 39

ETANERCEPT THERAPY IN ASH

. Etanercept: soluble TNF-receptor: FC Fusion protein

. 13 patients with ASH (DF > 15 and/or HE)

. 2 weeks treatment

. 32 mg/kg b.wt. as loadine dosefollowed by 25 mg s.c. a day 4, 8 and 12

RESULTS:30 day survival = 92 %90 day suvival = 83 %Adverse Effects = 23 %

Menon et al. Am J Gastroenterol 99,255,2004

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

. DRUGS- ANTIOXIDANTS- STEROIDS-PENTOXIFYLLINE- TNF-α ANTIBODY

. EXTRACORPOREAL DETOXIFICATION (MARS)

MARS AND ASH

8 Patients (all HE, 5 HRS 1, 2 HRS 2)

5 HRS1

2 † (<30 Tage)1 † (<90 Tage)1 OLT (21 Tage)1 alive (90 Tage)

2HRS2 1 †alive (90 Tage)

No HRS alive (90 Tage)

Predicted mortality 90 days (MELD) 76 %

Jalan et al. J Hep 38,24-31:2003

mortality 50%/63%

THERAPY OF ASH

. ABSTINENCE

. NUTRITIONAL THERAPY

. DRUGS- ANTIOXIDANTS- STEROIDS- PENTOXIFYLLINE- TNF-α ANTIBODY

. EXTRACORPOREAL DETOXIFICATION (MARS)

. LIVER TRANSPLANTATION

LIVER TRANSPLANTATION IN ALCOHOLIC LlVER DISEASE

Tome et al. J Hep 36,793,2002

1. Antiinflammatory compoundsIL10 , thalidomid (Kupffer cell sensibilization)

2. Misoprostol (down regulation of TNF-a production)

3. Adiponectin (AMP activated kinase)4. CYP2E1 inhibitors (chlomethiazole!)5. PPAR α stimulation (Wy 14,643)6. IKK-β inhibitors (aspirin)

FUTURE PERSPECTIVES

CONCLUSION I

1. Major pathophysiological factors in ASH are the production of fatty liver due to various ethanol associated mechanisms, oxidative stress predominantly generated by CYP2E1 and TNF-a mainly from Kupffer cells.

2. Diets (polyunsaturated vs. saturated fat) may modulate pathogenesis. Obesity and female gender are risk factors.

CONCLUSION II

3. Therapy of ASH includes abstinence, nutritional therapy as well as drug therapy.

• A subgroup of patients with severe ASH (DF>32) jaundice and encephalopathy may respond to steroids with an increased survival. Early change inbilirubin levels may be predictor for response.Pentoxifylline has also improved survival by reducing hepatorenal syndrome, however, this needs further confirmation. Data on the effect of TNF alpha antibodies are controversial and need reconsideration.

Ethanol Acetaldehyde

NAD+ NADH

ADH

Polymorphism

Acetate

ALDH Glutathion

Methyl-Transfer

Phospholipids(Membrane Alteration)

Mitochondrial Damage

Fatty Liver

Apoptosis

NF-KB

Carcinogenesis

Proteinbinding

CYP2E1O2

Hypoxia

ROS

DNA-Damage

Lipidperoxidation

Oxidized proteinsloss of functionneoantigens

Carcinogenesis

Drugs, Retinoids, Carcinogen

Toxicity Proliferation

Arachidonic Acid

Prostaglandins

COX2

Metabolite

Blood flow

ETHANOL METABOLISM AND ALCOHOLIC LIVER DISEASE

MnSOD

COMPARISON OF EXPERIMENTAL NASH WITH ASH PATHOGENESIS

CYP2E1

TNF αIL-1β

AMPK

PPARβPTEN

Lipolytic factorsPPARα

Lipogenic factorsPPARγ, LXRα, SREBP1c

NAFLDETHANOL (35%)

Tsukamoto et al., ACER 30 (Suppl)89A:2006

ENCEPHALOPATHY AND ASCITES 90 DAYS MORTALITY

Dunn et al. Hepatology 41, 353: 2005

78++

21+-

25-+

000

90 days mortalityAE

ANTIOXIDANTS

1. Mezey et al., J. Hepatol. 40 (2004) 40-46Vitamin E (1000 IU) per day has no beneficial effect on hepatic function or mortality in patients with mild to moderate AH (DF ca. 19)

2. Phillips et al., J. Hepatol. 44 (2006) 784-790AntioxidantVit. C / Vit. E / Se / methionine / allopurinol / desferrioxamine/N-acetylcystein / β-carotin

In 101 patients with severe AH (DF ca. 60) for 1 month mortality AO vs CS 46 % vs. 30 % (p = 0.05)

vs30 mg predisolone

PENTOXIFYLLINE

• non-selective phosphodiesterase inhibitor• improves rheology and therefore used for

peripheral arterial occlusive disease• inhibits synthesis and liberation of TNF α• decreases granolocyte activation and

lymphocyte proliferation• antifibrotic effect in animal experiments

(Raetsch et al., Gut 2002, 50: 241)