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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)