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From Binge Drinking to Alcoholic Liver Disease - Du Binge Drinking à l'Hépatite Alcoolique

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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.

Publicada em: Saúde e medicina
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From Binge Drinking to Alcoholic Liver Disease - Du Binge Drinking à l'Hépatite Alcoolique

  1. 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. 2. Alcohol-attributable deaths as a percentage of total deaths
  3. 3. Important variations iinn lliivveerr cciirrrrhhoossiiss mmoorrttaalliittyy aaccrroossss EEuurrooppee HHiigghheerr rraatteess iinn EEaasstteerrnn ccoouunnttrriieess tthhaann iinn WWeesstteerrnn EEuurrooppeeaann ccoouunnttrriieess
  4. 4. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD
  5. 5. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD
  6. 6. COUNTRIES WWIITTHH IIMMPPRROOVVEEMMEENNTTSS OOVVEERR PPAASSTT 1100--2200 YYEEAARRSS
  7. 7. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD
  8. 8. AAllccoohhooll ccoonnssuummppttiioonn iinn EEuurrooppee
  9. 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. 10. COUNTRIES WWIITTHH IINNCCRREEAASSIINNGG RRAATTEESS OOVVEERR PPAASSTT 1100--2200 YYEEAARRSS
  11. 11. Courtesy from D Leon. EASL 2010 Monothematic conference on ALD
  12. 12. Alcohol and mortality in Russia: prospective observational study of 151 000 adults David Zaridze, …. Peto R. Lancet 2014
  13. 13. Alcohol and mortality in Russia: prospective observational study of 151 000 adults David Zaridze, …. Peto R. Lancet 2014
  14. 14. TTHHEE EEMMEERRGGIINNGG IISSSSUUEESS:: BBiinnggee ddrriinnkkiinngg,, ““tthhee uunnsseettttlleedd ddaaiillyy ddoossee ooff aallccoohhooll iinnttaakkee”” iinn tthhee ccoonntteexxtt ooff oobbeessiittyy
  15. 15. Prevalence of NAFLD in EEuurroopp:: lleessssoonnss ffrroomm tthhee DDiioonnyyssooss ssttuuddyy PPrreevvaalleennccee ooff NNAAFFLLDD aasssseesssseedd bbyy uullttrraassoonnooggrraapphhyy == 2200%% Bedogni G, Hepatology 2005
  16. 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. 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. 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. 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. 20. Effect of binge drinking on the liver: An alarming public health issue? Leon DL, Lancet 2006
  21. 21. Alcohol a major ppuubblliicc hheeaalltthh iissssuuee TThhee bbiinnggee ddrriinnkkiinngg PPhheennoommeennoonn 11..22 bbiilllliioonnss 11..55 bbiilllliioonnss ↑ 25% Naimi TS, Jama 2003
  22. 22. How to reduce the burden of alchohol-attributable deaths: The most efficient public health policies
  23. 23. 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
  24. 24. 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
  25. 25. Disease progression non-iinnvvaassiivvee mmaarrkkeerrss iinn AALLDD Fibrotest < 0.32 0.32-0.58 >0.58 Naveau S, Hepatology 2009
  26. 26. Alcoholic liver disease aanndd bbiioollooggiiccaall mmaarrkkeerrss FFiibbrrootteesstt Naveau S et al., Clin Gastroenterol Hepatol. 2005
  27. 27. 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
  28. 28. 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
  29. 29. MMoovviinngg ttoowwaarrdd tthhee RReessppoonnssee GGuuiiddeedd tthheerraappyy
  30. 30. 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
  31. 31. 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]
  32. 32. • 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
  33. 33. 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
  34. 34. 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%
  35. 35. • 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
  36. 36. PPootteennttiiaall tthheerraappeeuuttiicc ttaarrggeettss iinn tthhee ffuuttuurree Unsuitable molecule ↓ RReeccoovveerryy ↑↑ LLiivveerr FFuunnccttiioonn DDiisseeaassee ↓↓ LLiivveerr FFuunnccttiioonn IInnffllaammmmaattiioonn NNeeccrroossiiss AAppooppttoossiiss ↓ ↑ Infection SSuurrvviivvaall PPrroobbaabbiilliittyy Survival Time
  37. 37. 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
  38. 38. 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
  39. 39. - RReeccoovveerryy ↑↑ LLiivveerr FFuunnccttiioonn DDiisseeaassee ↓↓ LLiivveerr FFuunnccttiioonn Ideal molecule IInnffllaammmmaattiioonn NNeeccrroossiiss AAppooppttoossiiss + - Infection SSuurrvviivvaall PPootteennttiiaall tthheerraappeeuuttiicc ttaarrggeettss iinn tthhee ffuuttuurree SSuurrvviivvaall PPrroobbaabbiilliittyy
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. • 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
  44. 44. 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
  45. 45. 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?
  46. 46. 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
  47. 47. 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.
  48. 48. 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
  49. 49. 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%]
  50. 50. 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
  51. 51. 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
  52. 52. EEaarrllyy LLTT iinn AAllccoohhoolliicc hheeppaattiittiiss
  53. 53. 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
  54. 54. Outcomes After Liver Transplantation for Alcoholic Hepatitis Are Similar to Alcoholic Cirrhosis Graft Survival Patient Survival Singal AK et al., Hepatology 2011
  55. 55. 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
  56. 56. 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
  57. 57. • 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
  58. 58. 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
  59. 59. 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
  60. 60. NIAAA Announces Request for Applications oonn AAllccoohhoolliicc HHeeppaattiittiiss “Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis”

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