A.I.S.F. Monothematic Conference 2012 The Gut-Liver Axis: a bidirectional relation in health and disease Alcoholic steatohepatitis Gianluca Svegliati Baroni SOS “Epatopatie croniche e trapianto di fegato” Universita Politecnica Marche-Ospedali Riuniti Ancona Bologna, 5 ottobre 2012
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A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis
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Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d’interesse in relazione a questa presentazione
e
che la presentazione non contiene discussionedi farmaci in studio o ad uso off-label
LE CAUSE DELLE MALATTIE EPATICHE:
ALCOL
Consumo di bevande alcoliche
distinzione per classi di età
Abuso di alcol, come causa di patologie al fegato
che portano al decesso del paziente…l’ alcol ha un’ azione epatotossica diretta….agiscecome cofattore di danno accelerando la progressionedelle malattie epatiche croniche da altra causa…ilconsumo di alcol è la più importante determinantedella severità della malattia epatica, causando unincremento di mortalità di tre volte superiore nei forticonsumatori rispetto ai bassi consumatori.
Total number of first liver transplants = 1530
* Autoimmune 0.35%; liver rupture 0.15%
Re-OLTx N. = 100 (7.5%)
THE LIVER MATCH STUDYMain indications for liver transplantation
Angelico M. et al. Dig Liv Dis; 2011.
0
1,3
6,6
9,3
1,6
6,9 7,2 7,1
1,6
4,3
2,63,1
0
5
10
< 30 30 - 49 50 - 69 > 70
HCV/HBV
Alcol
NAFLD
Prevalenza età-specifica di alterazione degli indici di danno epatico nella popolazione generale di Cittanova (Ita lia
Meridionale) per eziologia, 2002-2003
Pendino et al. Hepatology 2005
%
Population Screened 4671
Excessive drinkers (>30g/day) 947 20.3 %
EtOH-Induced Liver Damage 305 6.5 %
Cirrhosis+HCC (10% symptom.) 33 0.7 %
Bellentani et al., Gut, 1997 and Add.Biol, 2002
“True” Clinical Prevalence of Ethanol induced Liver Diseases
PATOGENESI DELLA STEATOSI EPATICA:THE “MULTI-HIT“ THEORY
FIRST HIT SECOND HIT
?
Alterazioni potenziale redox
•Aumentato up-take e sintesi degli ac. grassi•Ridotta escrezione degli ac.grassi•Ridotta beta-ossidazione
Produzione di ROSDeplezione antiossidanti
•Lipoperossidazione •Induzione di citochine•Infiammazione•Apoptosi
THIRD HIT
•Cirrosi
?
Similarities and Differences in the Pathogenesis of Alc oholicand Nonalcoholic Steatohepatitis (Diehl et al., Sem Liv Dis 2009)
The natural history of ASH appears to be much more ‘‘aggressi ve’’ thanthat of NASH suggesting that ethanol and/or acetaldehyde ma y haveunique roles in steatohepatitis progression.
Acetaldehyde interacts with various molecules to form adducts that haveimmunogenic properties, and it has also been shown to direct ly activatecollagen gene expression in hepatic stellate cells (Svegliati-Baroni G et al.,1993, 1993, 1994, 1997, 2001, 2005, in press).
Ethanol itself disorders lipid membranes and its (nonoxida tive)metabolism also generates fatty acid ethyl esters that may be cytotoxic(Benedetti A et al., 1993, 1995).
Therefore, chronic exposure to ethanol and/or its metaboli tes may furtherchallenge livers that are concomitantly experiencing stre sses related tolipotoxicity, oxidative and ER stress, and exposure to cyto kines andPAMP recognition receptors, exacerbating hepatocyte inju ry and relatedinflammation and fibrogenesis.
Similarities and Differences in the Pathogenesis of Alc oholicand Nonalcoholic Steatohepatitis (Diehl et al., Sem Liv Dis 2009)
Prevalenza della malnutrizione in pazienti alcolisti
Mendenhall 1984
Mettere diapo colline marchigiane + salame + vino
16%
46%
76%
95%
0%
20%
40%
60%
80%
100%
Steatosis at US
C (n=67)
HD (n=69)
O (n=66)
O+HD (n=55)
Overall Prevalence
58.3%
Fatty Liver in the Dionysos study
(Too much food is worst than too much alcohol !)
Bellentani et al., Ann.Int.Med., 2000
EXPERIMENTALS MODELS OF ALCOHOLIC LIVER INJURY
Lieber-DeCarli liquid diet Intragastric infusion model
Synergistic steatohepatitis by moderate obesity and alc oholin mice despite increased adiponectin and p-AMPK
Toll-Like Receptor 4 Is Involved in the Mechanism of Early Alcohol-Induced Liver Injuryin Mice
TLR4-/-
Uesugi, Hepatology 2001
Toll-Like Receptor 4 Is Involved in the Mechanism of Early Alcohol-Induced Liver Injury in Mice
Uesugi, Hepatology 2001
Toll-like receptor 4 mediates alcohol-induced steatohepa titis through bonemarrow-derived and endogenous liver cells in mice
Inokuchi, Alcoholism Clin Exp Res 2011
TLR2: microbial lipopeptides;
TLR4: lipopolysaccharides (LPSs) from Gram-
TLR1/6: triacyl- and diacyllipopeptides;
TLR3: viral double-stranded RNA;
TLR5: bacterial flagellin.
TLR7 and TLR8: viral single-stranded RNA
Differential Liver Sensitization to Toll-like Receptor Pat hways in Mice With AlcoholicFatty Liver
Gustot et al., Hepatology 2006
1) The administration of broad-spectrumantibiotics reduced the severity of alcohol-induced fatty liver but did not modify alcohol-induced TLR gene expression;
2) ROS from NADPH oxidase increased the severity of alcohol-induced fatty liver and the expression of liver TLRs;
3) Severe steatosis is the visible part of a “first hit” on the liver, combined with anupregulation of TLRs;
4) The administration of microbial products toEtOH-exposed animals may induce the “second hit” on the liver with inflammatoryinfiltrate and satellitosis formation.
Differential Liver Sensitization to Toll-like Receptor Pat hways in Mice With AlcoholicFatty Liver
Ethanol Augments RANTES/CCL5 Expression in Rat Liver Sin usoidal EndothelialCells and Human Endothelial Cells via Activation of NF-B, HIF-1, and AP-1
Yeligar et al., J Immunol 2008
Tilg & Moschen, Hepatology 2010
The Multiple Parallel Hits Hypothesis
Acetaldehyde
Samuel & Shulman, Cell 2012
Synergistic steatohepatitis by moderate obesity and alc oholin mice despite increased adiponectin and p-AMPK
Xu et al., J Hepatol 2011
ER stress markers
Cell deathsignalingmolecules
Epigenetic Regulation of Hepatic Endoplasmic Reticulum St ress Pathways in the Ethanol-Fed Cystathionine Beta Synthase–Deficient Mous e
Esfandiari et al., AJP 2005; Hepatology 2010
Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog
Machida et al., PNAS 2009
Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog
Machida et al., PNAS 2009
A Randomized, Double-Blinded, Placebo-Controlled Mul ti-CenterTrial of Etanercept in the Treatment of Alcoholic Hepat itis
0
10
20
30
40
50
60
Etanercept Placebo
6-months mortality (%)
0
5
10
15
20
25
30
35
40
Etanercept Placebo
Infectious events (%)
Boetticher et al., Gastroenterology2008
Conclusions
• Alcohol consumption leads to increased intestinalpermeability and endotoxemia, which are involved inthe pathogenesis of ALD ;
• Intestinal microflora not only is the source ofcirculating endotoxins but also plays a role in thegeneration and accumulation of acetaldehyde in thecolonic lumen and has a subsequent influence onepithelial barrier dysfunction;
• Gut-liver axis stimuli represents a major second-hitin the pathogenesis of ASH ;
• It is therefore important to delineate the mechanismsinvolved in endotoxin-mediated liver cell injury todesign preventive and therapeutic strategies for thetreatment of ALD .
Ettore Svegliati BaroniCurriculum vitae
Nato: Ancona, 02/05/2012
Comitato Coordinatore AISF2052-2055 ?
Severity of liver injury in experimental alcoholic liver di sease.Correlation with plasma endotoxin, prostaglandin E2,leukotriene B4, and thromboxane B2.
Nanji et al, Am J Pathol 1993
Plasma levels of soluble tumor necrosis factor receptors p 55 and p75 in patients with alcoholic liver disease of increasin g severity
0
1000
2000
3000
4000
5000
6000
7000
Controls Steatosis Fibrosis Cirrhosis Cirrhosis with
AAH
Cirrhosis with
AAH +++
TNFsRp75 (pg/ml)
*
*
Naveau et al., J Hepatol 1998
* *
Synergistic steatohepatitis by moderate obesity and alc oholin mice despite increased adiponectin and p-AMPK
Xu et al., J Hepatol 2011
M1macrophages
M2macrophages
Overall Prevalence DionysosCohort
Liver Disease Prevalence 1992 (%)
Prevalence 2002 (%)
Persistent alteration of liver enzymes (LE)
27.6 27.2
Persistent alteration of LE with fatty liver (FL)
45 42
NAFLD (alcohol intake < 30 g/die)
25 32
AFLD (alcohol intake > 30 g/die)
20 10
Cirrhosis 1.1 1.0
L’acetaldeide stimola l’espressione del gene per il collagene (COL1A2).