Conférence du Professeur Philippe Mathurin (Hôpital Universitaire Claure Huriez, Lille, France), Juin 2014. Le "Binge Drinking" est un des enjeux de santé publique majeur dans tous les pays occidentaux. Une augmentation de la mortalité par cirrhose alcoolique est constatée dans les pays où l'alcoolisme chronique et le Binge Drinking sont les plus répandus.

1. Journée d’Hépatologie du Centre Hépato-Biliaire – 13 juin 2014 - Paris
DDuu « bbiinnggee ddrriinnkkiinngg »
àà ll’’hhééppaattiittee aallccoooolliiqquuee
Pr. Philippe Mathurin
Hôpital Universitaire Claude Huriez
Lille, France

2. Alcohol-attributable deaths as a percentage of total
deaths

3. Important variations iinn lliivveerr cciirrrrhhoossiiss
mmoorrttaalliittyy aaccrroossss EEuurrooppee
HHiigghheerr rraatteess iinn EEaasstteerrnn ccoouunnttrriieess tthhaann iinn WWeesstteerrnn
EEuurrooppeeaann ccoouunnttrriieess

4. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD

5. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD

6. COUNTRIES WWIITTHH IIMMPPRROOVVEEMMEENNTTSS
OOVVEERR PPAASSTT
1100--2200 YYEEAARRSS

7. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD

8. AAllccoohhooll ccoonnssuummppttiioonn iinn EEuurrooppee

9. Cirrhosis in Europe: AA ppuubblliicc hheeaalltthh iissssuuee
Age-adjusted (world population) mortality rates from cirrhosis per
100,000 men
Bosetti C, J Hepat 2007

10. COUNTRIES WWIITTHH IINNCCRREEAASSIINNGG
RRAATTEESS OOVVEERR PPAASSTT 1100--2200
YYEEAARRSS

11. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD

12. Alcohol and mortality in Russia: prospective
observational study of 151 000 adults
David Zaridze, …. Peto R. Lancet 2014

13. Alcohol and mortality in Russia: prospective
observational study of 151 000 adults
David Zaridze, …. Peto R. Lancet 2014

14. TTHHEE EEMMEERRGGIINNGG IISSSSUUEESS::
BBiinnggee ddrriinnkkiinngg,, ““tthhee uunnsseettttlleedd
ddaaiillyy ddoossee ooff aallccoohhooll iinnttaakkee”” iinn
tthhee ccoonntteexxtt ooff oobbeessiittyy

15. Prevalence of NAFLD in EEuurroopp:: lleessssoonnss ffrroomm tthhee
DDiioonnyyssooss ssttuuddyy
PPrreevvaalleennccee ooff NNAAFFLLDD aasssseesssseedd bbyy
uullttrraassoonnooggrraapphhyy == 2200%%
Bedogni G, Hepatology 2005

16. PPrrooggrreessssiioonn ooff oobbeessiittyy oovveerr tthhee ttiimmee
11999977 :: 88..22 %%
22000000 :: 99..66 %%
22000033 :: 1111..33 %%
22000066 :: 1122..44 %%
+ 17%
+ 17,7 %
+ 9,7%
Data from Obepi Survey 2009

17. Excess weight risk factor for
Alcoholic Liver Disease
60%
Overweight Patients
Non-Overweight Patients
35%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Alcoholic Cirrhosis
Naveau S, Hepatology 1997

18. Effect of binge drinking on the liver:
An alarming public health issue?
• 3 questions on the potential impact of binge drinking in terms of liver disease:
1. Do experimental data suggest a deleterious impact of binge drinking on liver tissue?
→ Answer: YES
2. Do behavioral studies suggest that adolescent binge drinkers are at higher risk of being
heavy drinkers in adulthood, with the consequent risk of alcoholic liver disease?
→ Answer : YES
Probability of becoming a chronic drinker at an adult age was higher in male and female
adolescent binge drinkers than in non-bingers: 6.7 % vs 2.3% and 9.6 vs 4.8 %
3. Do epidemiological data support a future increase in the risk of cirrhosis related to binge
drinking?
→ Answer Likely
Drastic increase in liver cirrhosis and mortality rates in the UK is particularly alarming
Mathurin Gut 2009; McCarty CA Pediatrics 2004

19. Effect of binge drinking on the liver:
An alarming public health issue?
Binge drinking is a major public heath issue that
can no longer be considered simply a
momentary risk factor of behavioral concerns,
but must now be viewed in light of long-term
consequences, such as alcohol-induced liver
disease
Mathurin Gut 2009
McCarty CA Pediatrics 2004

20. Effect of binge drinking on the liver:
An alarming public health issue?
Leon DL, Lancet 2006

21. Alcohol a major ppuubblliicc hheeaalltthh iissssuuee
TThhee bbiinnggee ddrriinnkkiinngg PPhheennoommeennoonn
11..22 bbiilllliioonnss
11..55 bbiilllliioonnss
↑ 25%
Naimi TS, Jama 2003

22. How to reduce the burden of
alchohol-attributable deaths:
The most efficient public
health policies

29. EASL call for EU action – on liver
disease
• Recognise alcohol consumption as one of the cross-cutting
risk factors for non-communicable diseases, including liver
disease
• Acknowledge liver disease as a public health priority in
the EU’s public health and research policies and funding
programmes
• Ensure liver disease is addressed in future policy
developments in the field of non-communicable diseases

30. Public health policy need to use the
same concept than type II diabetes
 Primary prevention:
● For type II diabetes:
- reduction of overweight in general population
- modification of lifestyle at population level
→ Physical activity
→ behavior changes in terms of alimentation
● For alcoholic liver disease
- Decrease of alcohol consumption per inhabitant per year
 Like type II diabetes there is a need to promote resarch program on
● better understanding of how cirrhosis develops in people at risk
● how to prevent or delay the development of cirrhosis and its complications

31. Disease progression non-iinnvvaassiivvee mmaarrkkeerrss iinn AALLDD
Fibrotest
< 0.32
0.32-0.58
>0.58
Naveau S, Hepatology 2009

32. Alcoholic liver disease aanndd bbiioollooggiiccaall mmaarrkkeerrss
FFiibbrrootteesstt
Naveau S et al., Clin Gastroenterol Hepatol. 2005

33. Le Dépistage améliore la survie
CHC sur VHC % des patients à
un stade précoce
Taux d’accès au
dépistage
Accès aux traitements
curatifs (%)
Pas de dépisgge 19% 0% 14,5%
Dépistage actuel
42% 57% 25,0%
[Observatoire ANGH Chang]
97 % Taux dépistage 42% 97% 32,5%
Efficacité CHC 2000 87% 57% 40,5%
CHC 2000 + 97% Accès
87% 97% 58,5%
dépistage
Mourad A, Hepatology 2014

34. O’Shea RS, Hepatology 2010
Journal of Hepatology 2012
• First-line therapy in patients with severe ASH includes
corticosteroids or pentoxifylline especially if there are
contraindications to steroid therapy

35. MMoovviinngg ttoowwaarrdd tthhee RReessppoonnssee
GGuuiiddeedd tthheerraappyy

36. LLiillllee mmooddeell:: aa ttooooll ffoorr nneeww ssttrraatteeggiieess
EEvvaalluuaattiioonn ooff LLiillllee mmooddeell oonn oovveerraallll ppaattiieennttss ((nn==443388))
100 %
75 %
50 %
25 %
hhttttpp::////wwwwww..lliilllleemmooddeell..ccoomm
Lille score < 0.45 85±2.5%
p<0.00001
Lille score ≥ 0.45 25±3.8%
50 days 100 days 150 days 180 days
Louvet A et al, Hepatology 2007

37. Complete responders
Lille score ≤0.16 [≤35th percentile]
Partial responders
Lille score 0.16-0.56 [35-70th percentile]
P Mathurin, Gut 2011
Null responders
Lille score ≥0.56 [≥ 70th percentile]

38. • Current management
• Near Future
• Distant Future : Arbitrary selection of novel molecules
already tested in human beings
• Transplantation for non-responders to medical
therapy
• Future Requirements

39. N-acetylcysteine aanndd ccoorrttiiccoosstteerrooiiddss ::
TThhee nneeaarr ffuuttuurree ??
NNAACC aalloonnee iiss iinneeffffiicciieenntt
Stewart S, J Hepatol 2007; Moreno C, J Hepatol 2010
Nguyen-Khac E,New Engl J Med 2011

40. Prednisolone With vvss WWiitthhoouutt PPeennttooxxiiffyylllliinnee
15.3%
Steroids + pentoxifylline
n=133
Steroids + Placebo
n=137
EEnndd ppooiinntt == 66 mmoonntthh--ssuurrvviivvaall
227700 ppaattiieennttss iinncclluuddeedd
AH biopsy proven
Madddrey ≥ 32
Jaundice < 3 months
n=270
Mathurin P et al, JAMA 2013
p=0.07
8.4%
11.7%
p=0.007
3.1%

41. • Current management
• Near Future
• Distant Future : Arbitrary selection of novel
molecules already tested in human beings
• Transplantation for non-responders to medical
therapy
• Future Requirements

42. PPootteennttiiaall tthheerraappeeuuttiicc ttaarrggeettss iinn tthhee ffuuttuurree
Unsuitable molecule
↓
RReeccoovveerryy
↑↑ LLiivveerr FFuunnccttiioonn
DDiisseeaassee
↓↓ LLiivveerr FFuunnccttiioonn
IInnffllaammmmaattiioonn
NNeeccrroossiiss
AAppooppttoossiiss
↓
↑
Infection
SSuurrvviivvaall PPrroobbaabbiilliittyy
Survival Time

43. What can we learn from anti-TNF-a story
TNF-a and ALD
McClain CJ, Hepatology 1989
Kamimura Hepatology 1995
Yin M, Gastroenterology 1999
Chang J, Hepatology 2004
Yamada Y et al, PNAS 1997
TNF alpha
TTNNFF--a aanndd LLiivveerr RReeggeenneerraattiioonn

44. What can we learn from anti-TNF-a story?
Tilg H , J Hepatol 2003
Spahr L J hepatol 2002*
SSttuuddyy DDeessiiggnn
Mookerjee Gut 2003
SSiinnggllee DDoossee
Sharma P, J Hepatol 2009
Inclusion criterion : Meld ≥15 Inclusion criterion : Maddrey
SSttuuddyy DDeessiiggnn OOff RRCCTTSS
MMuullttiippllee DDoosseess
NC Boetticher, Gastroenterology 2008
≥32
Naveau S Hepatology 2004
↑risk of Infections

45. -
RReeccoovveerryy
↑↑ LLiivveerr FFuunnccttiioonn
DDiisseeaassee
↓↓ LLiivveerr FFuunnccttiioonn
Ideal molecule
IInnffllaammmmaattiioonn
NNeeccrroossiiss
AAppooppttoossiiss
+
-
Infection
SSuurrvviivvaall
PPootteennttiiaall tthheerraappeeuuttiicc ttaarrggeettss iinn tthhee ffuuttuurree
SSuurrvviivvaall PPrroobbaabbiilliittyy

46. Potential therapeutic ttaarrggeettss iinn tthhee ffuuttuurree
IL-1 receptor antagonist (IL-1Ra)
human IL-1ra [Anakinra®]
↓↓ AAllccoohhooll lliivveerr iinnjjuurryy
Petrasek J, J Clin Invest 2012
BBRRDDUU IInnccoorrppoorraattiioonn
human IL-1ra [Anakinra®]
↑↑ LLiivveerr rreeggeenneerraattiioonn
Sgroi A, PlosOne 2011 Boulton Ra, Hepatology 1997

47. Potential therapeutic ttaarrggeettss iinn tthhee ffuuttuurree
Interleukin 22 [F-652]
in phase I study
↓↓ AAllccoohhooll lliivveerr iinnjjuurryy
Ki SH, Hepatology 2010
↑↑ LLiivveerr rreeggeenneerraattiioonn
Feng D, Gastroenterology 2012 Park O, Hepatology 2010

48. Potential therapeutic ttaarrggeettss iinn tthhee ffuuttuurree
Eculizumab [Soliris®]
Antibody against C5
↓↓ AAllccoohhooll lliivveerr iinnjjuurryy
Pritchard MT, Gastroenterology 2007
Cohen JI, Gastroenterology 2010
BBlloocckkiinngg CC55 iimmpprroovveess oouuttccoommee iinn SSeeppssiiss
Woehrl B, J Clin Invest 2011

49. • Current management
• Near Future
• Distant Future : Arbitrary selection of novel
molecules already tested in human beings
• Transplantation for non-responders to medical
therapy
• Future Requirements

50. SSeevveerree AAllccoohhoolliicc HHeeppaattiittiiss
LLiivveerr TTrraannssppllaannttaattiioonn:: aa lloonngg wwaayy ttoo ggoo
WWhheerree DDoo WWee AAllll CCoommee FFrroomm ??
• RReecceenntt ffoorrmmaall rreeccooggnniittiioonn tthhaatt AAHH iiss aann aabbssoolluuttee ccoonnttrraaiinnddiiccaattiioonn bbyy UUKK ttrraannssppllaanntt
cceennttrreess ((BBaatthhggaattee AAJJ,, LLaanncceett 2000066))
• AAbbssttiinneennccee pprree--ttrraannssppllaanntt iiss nneecceessssaarryy ttoo eexxcclluuddee tthhoossee wwhhoo wwiillll iimmpprroovvee aanndd nnoott
nneeeedd ttrraannssppllaannttaattiioonn
• AAbbssttiinneennccee iiss uusseeffuull ttoo aallllooww ttiimmee ffoorr aasssseessssiinngg aanndd vveerriiffyyiinngg aallccoohhooll aaddddiiccttiivvee
bbeehhaavviioouurr bbuutt « 6-month rule » is not a robust criterion
Foster PF, Hepatology 1997
Liver transplantation for alcoholic liver disease: bias, beliefs, 6-month rule,
and relapse- but where are the data.
Beresford TP, Everson GT Liver Transpl 2000

51. Where Do We Come From ?
SSEEVVEERREE AALLCCOOHHOOLLIICC HHEEPPAATTIITTIISS
LLIIVVEERR TTRRAANNSSPPLLAANNTTAATTIIOONN
Where Do I Come From ?
• Atterbury CE. The alcoholic in the lifeboat. Should drinkers be candidates for liver
transplantation? J Clin Gastroenterol 1986
The Jury stated:
- wait-and-watch strategy using the 6-month criterion
may be unfair for some non-responders with 70- 80%
probability of dying during this period
- recommended pilot studies evaluating early liver
transplantation in non-responders
• Lucey MR J Hepatol 2002; Is liver transplantation an appropriate treatment for acute
alcoholic hepatitis?

52. Early liver transplantation:
The French and Belgium Experience
Philippe Mathurin1, Christophe Moreno2, Didier Samuel3, Jérôme
Dumortier4, Julia Salleron5, François Durand6, Hélène Castel1,
Alain Duhamel5, Georges-Philippe Pageaux7, Vincent Leroy8,
Sébastien Dharancy1, Alexandre Louvet1, Emmanuel Boleslawski1,
Valerio Lucidi2, Thierry Gustot2, Claire Francoz6, Christian
Letoublon8, Denis Castaing3, Jacques Belghiti6, Vincent Donckier2,
François-René Pruvot1, Jean-Charles Duclos-Vallée3
Brussels, Grenoble, Lille, Lyon, Montpellier, Beaujon,
Villejuif
New EnglJ Med 2011

53. EEaarrllyy LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss
• Early liver transplantation in non-responders undergoing
their ffiirrsstt event of liver disease
• Non responders were identified using Lille score ≥0.45 or
worsening of liver function by day 7.

54. Early LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss
SSeelleeccttiioonn pprroocceessss== 44 TTeeaamm cciirrcclleess
Family structure
Patient
Time toward complete consensus
= nurses, i.e. one resident and one fellow
specialist in addiction
= senior hepatologists
senior anesthetist and surgeons

55. EEaarrllyy LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss
Transplanted non responders N=26
Male gender no. [%] 15 [57.7%]
Age (years) median [95%CI] 47.4 [42.7-52.4]
Duration of corticosteroids treatment (days)
Median [95%CI]
11.5 [7-18]
Hepatorenal syndrome, no. [%] 15 [57.7%]
Hemodiafiltration or MARS® system no. [%] 10 [38.5 %]
Infection before transplantation no [%] 18 [69.2%]
Mechanical ventilation no [%] 4 [15.4%]

56. Median [95%CI]
Lille score 0.88 [0.76 – 0.95]
MELD on first day of therapy 30.1 [27.7 - 33.4]
MELD day 7 28.5 [26.2 – 33.7]
MELD at listing 34.2 [29 – 37]
MELD day 0 - MELD Listing - 5.44 [-7.3 – 2]
MELD day 7 - MELD Listing - 1.9[-6 – 0]
Time (days) from end of therapy to
13 [6 – 17]
listing
Time (days) from listing to LT 8.5 [3 – 11]
* MMaaxxiimmuumm ooff LLiillllee ssccoorree iiss 11
**
EEaarrllyy LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss

57. Early Transplantation sshhiifftt ssuurrvviivvaall ooff
uunnrreessppoonnssiivvee ttoo rreessppoonnddeerrss
• Final combined database included a total of 651 patients. Matching was
performed using the global optimal algorithm
• For matching criteria, we used the following pre-established ranges: age (+/- 10
years), gender, Maddrey function (<60; 60-90 and >90) and Lille score (+/-0.15)
• The overall optimal algorithm was able to select 3 unresponsive matched controls
for 20 transplanted patients, 2 unresponsive matched controls for 3 transplanted
patients and only 1 unresponsive matched control for 3 transplanted patients.
• The overall optimal algorithm was able to select 4 responsive matched controls for
21 transplanted patients, 2 responsive matched controls for 3 transplanted
patients and only 1 responsive matched control for 2 transplanted patients

58. EEaarrllyy LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss

59. EEaarrllyy LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss
• No alcohol relapse within the 6 month period
• 3 patients resumed alcohol consumption during data collection
- at 720, 740 and 1140 days
[2 daily consumers and 1 had occasional consumption (approximately
10g/week)]
• 2 centers have prospective data base of severe alcoholic hepatitis only 4
(1.83%) were directly selected by the 2 centers from their own recruitment
• Proportions of eLT among the total number of procedures, and number
of procedures for alcoholic liver disease, were 26/891 [2.92%]) and 26/315,
[8.25%], respectively

60. Outcomes After Liver Transplantation for Alcoholic
Hepatitis Are Similar to Alcoholic Cirrhosis
Graft Survival Patient Survival
Singal AK et al., Hepatology 2011

61. 1. In patients with severe ASH not responding to medical therapy,
early LT need to be further evaluated in carefully-selected
patients
Journal of Hepatology 2012

62. PPHHRRCC QQuuiicckkTTrraannss--HHAAAA
AAHH nnoott rreessppoonnddiinngg ttoo mmeeddiiccaall tthheerraappyy
AAllggoorriitthhmm bbaasseedd oonn oobbjjeeccttiivvee ccrriitteerriiaa
RRaannggee ooff SSccoorree ffrroomm 00 ttoo 225500 GO
AAllggoorriitthhmm ssccoorree ≥≥ 222200 GO
AAllggoorriitthhmm ssccoorree << 222200GO
Not selected
SSeelleecctteedd
CCoonnttrrooll ggrroouupp
AAllccoohhoolliicc ccaannddiiddaatteess ffoorr
lliivveerr ttrraannssppllaannttaattiioonn
Classical selection
6-month criteria
Primary objective
Non inferiority in terms of alcohol relapse
Secondary endpoint survival benefit
Non responders
Not Transplanted

63. • Current management
• Near Future
• Distant Future : Arbitrary selection of novel
molecules already tested in human beings
• Transplantation for non-responders to medical
therapy
• Future Requirements

64. Better KKnnoowwlleeddggee ooff tthhee NNaattuurraall HHiissttoorryy
66 mmoonntthhss Deaths due to liver injury in > 90 % of cases
No impact of alcoholism behavior
66--MMOONNTTHH PPEERRIIOODD
SSUURRVVIIVVIINNGG TTHHEE 66 MMOONNTTHH PPEERRIIOODD
OOPPTTIIMMAALL PPEERRIIOODD FFOORR SSTTUUDDIIEESS TTEESSTTIINNGG DDRRUUGG
PPRREEVVEENNTTIINNGG LLIIVVEERR IINNJJUURRYY
AAlliivvee RReessppoonnddeerrss ttoo mmeeddiiccaall tthheerraappyy
GGoooodd LLiivveerr FFuunnccttiioonn
Abstainers during 5 years
Risk of Liver-Related death ≈ 15%
Relapsers during 5 years
Risk of Liver-Related death ≈ 50%
AAFFTTEERR 66 MMOONNTTHHSS
AAVVOOIIDD SSTTUUDDIIEESS TTEESSTTIINNGG DDRRUUGG PPRREEVVEENNTTIINNGG LLIIVVEERR IINNJJUURRYY
AAlliivvee NNoonn--RReessppoonnddeerrss ttoo mmeeddiiccaall
tthheerraappyy
IInntteerrmmeeddiiaattee LLiivveerr ddyyssffuunnccttiioonn
Abstainers during 5 years
Risk of Liver-Related death ≈ 50%
Relapsers during 5 years
Risk of Liver-Related death ≈ 90%
Louvet A, AASLD 2010

65. UUnnmmeett nneeeeddss
• Animal models mimicking better liver Injury in human beings (liver
dysfunction and regeneration)
• Better network between basic and clinician researchers
• Official recommendations from experts of scientific societies on the
criteria that need to be fulfilled for an optimal study design
• Development and validation of surrogate markers of survival (like the
RECIST criteria in cancers) for testing of new molecules in phase I
and/or II
• Bring pharmaceutical companies to test and develop molecules

66. NIAAA Announces Request for Applications oonn AAllccoohhoolliicc HHeeppaattiittiiss
“Integrated Approaches for Identifying
Molecular Targets in Alcoholic Hepatitis”