Alcoholic Liver Disease as First Indication

Alcoholic Liver Disease as First Indication Patrizia Burra Multivisceral Transplant Unit Gastroenterology Department of Surgery, Oncology and Gastroenterology Padua University Hospital, Padua, Italy

Patrizia Burra, MD, PhD UOSD Trapianto Multiviscerale, Azienda Ospedaliera Universita Padova Il sottoscritto dichiara di non aver avuto/di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene/contiene discussione di farmaci in studio o ad uso off-label

Percentage of liver transplants in the US by etiology of liver disease, 2002 2015. Blue=Virus Yellow=Alcohol Red= Goldeberg D, et al. Gastroenterology 2017

Percentage of liver transplants for HCC in the US by etiology of liver disease, 2002 2015 Blue=Virus Yellow=Alcohol Red= Goldeberg D, et al. Gastroenterology 2017

Liver Transplantation for : Padua experience (1991-2017) TOT Average in 15 years = 22.3% 91 58 72 76 73 73 71 64 72 75 82 87 81 79 78 20 19 20 27 4 2 6 4 34 31 8 10 54 38 33 36 27 2 4 7 5 3 57 8 16 13 17 14 16 14 13 22 24 19 18 21 15 21 19 *Jan-Sept 2017

Number of liver transplants performed in Europe according to Countries ELTR data on 5.723 liver transplantation for alcoholic liver disease France UK Spain Germany Italy Neuberger J Hepatol 2002;36:130-137 from European Liver Transplant Registry www.eltr.com

Alcoholic cirrhosis as indication to liver transplantation in Spain Legaz et al. Alcohol Clin Exp Res. 2016

Trends on main indications for liver transplantation In Spain Legaz et al. Alcohol Clin Exp Res. 2016

Survival curves according to main indications for liver transplant in Spain in the short and long term Legaz et al. Alcohol Clin Exp Res. 2016

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Number of liver transplants for alcoholic liver disease overtime according to recipient gender in Europe 1200 Male Female 1000 800 600 400 200 0 Burra WIH 2017

Changes in indications to liver transplantation overtime in male patients 100% ALF AIH PBC PSC HCC Metabolic Other 90% 80% 70% 60% 50% 40% 30% 20% HCC 10% 0% 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Changes in indications to liver transplantation overtime in female patients 100% ALF AIH PBC PSC HCC Metabolic Other 90% 80% 70% 60% 50% 40% 30% HCC 20% 10% 0% 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Indications to liver transplantation in Europe Male Female 29 % 13 15 13 16 14 18 13 20 4 5 1 1 5 4 9 5 7 4 5 ALF AIH PBC PSC HCC Metab. Other Germani, EASL 2016

Indications to liver transplantation in Europe Male Female 29 % 13 All p<0.001 15 13 16 14 18 13 20 4 5 1 1 5 4 9 5 7 4 5 ALF AIH PBC PSC HCC Metab. Other Germani, EASL 2016

Indications to liver transplantation in Europe Male Female 29 % 13 15 13 all p<0.001 16 14 18 13 20 4 5 1 1 5 4 9 5 7 4 5 ALF AIH PBC PSC HCC Metab. Other Germani, EASL 2016

RECIPIENT AGE Changes over time in recipients transplanted for alcoholic liver disease in Europe <30 30-39 40-49 50-59 >60 <30 30-39 40-49 50-59 >60 % 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 Germani, EASL 2016

DONOR AGE Changes overtime of donor age in recipients transplanted for alcoholic liver disease in Europe <40 40-59 >60 <40 40-59 >60 % 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 Germani, EASL 2016

Effect of donor/recipient matching on the outcome of liver transplantation Marino Hepatology 1995

Changes in donor/recipient gender matching overtime in patients transplanted for alcoholic liver disease in Europe M/M F/M F/F M/F Linear (F/M) 60.2 57.2 53.2 51.9 50 % 21.5 24.5 27 29.5 31.6 11.4 10.2 10.2 10.6 6.9 8.3 10 9.6 8.3 7.8 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012

2003 2005 2007 2009 2011 2013 2015 2003 2005 2007 2009 2011 2013 2015 2003 2005 2007 2009 2011 2013 2015 LT WL rate per 100,000 US population Waiting list for liver transplant in the era of DAAs 47.591 patients, UNOS database 2003 2015. The rate for decompensated cirrhosis has decreased by 32%, for has increased by 41%, for HCC has increased in both and. Annual Standardized Incidence Rates (ASIR) of LT Wait-Listing per 100,000 US Population Overall Decompensated cirrhosis HCC 10 IFN PI DAA 6 IFN PI DAA 5 IFN PI DAA 9 8 5 4 7 6 5 4 3 3 4 3 2 2 2 1 1 1 0 0 0 Year of wait-list registration Flemming JA, et al. Hepatology 2017;65:804 12

AD AD AD % 50 40 30 Trajectories in Waiting List Registration over time Padua University Hospital p=0.01 Decompensated Cirrhosis 20 p=0.0003 10 0 2006-2009 2010-2013 2014-2016 *Delisting after DAAs: 0% to 5,6% Ferrarese, Transplantation submitted

% AD AD AD % 50 40 30 Trajectories in Waiting List Registration over time Padua University Hospital p=0.01 Decompensated Cirrhosis 20 p=0.0003 10 700 60 50 40 30 20 10 0 *Delisting after DAAs: 0% to 5,6% 2006-2009 2010-2013 2014-2016 HCC p=0.02 2006-2009 2010-2013 2014-2016 Ferrarese, Transplantation submitted

AD AD AD % 70 60 50 40 30 20 10 0 Trajectories in Liver Transplantation over time Padua University Hospital p=0.02 Decompensated Cirrhosis 2006-2009 2010-2013 2014-2016 Ferrarese, Transplantation submitted

% AD AD AD % 70 60 50 40 30 20 10 0 70 60 50 40 30 20 10 0 Trajectories in Liver Transplantation over time Padua University Hospital p=0.02 2006-2009 2010-2013 2014-2016 HCC 2006-2009 2010-2013 2014-2016 Ferrarese, Transplantation submitted Decompensated Cirrhosis

Alcoholic Liver Disease as First Indication: does it really matter? Ethical issues (Germani) Abstinence before transplant (Pageaux) Neoplastic risk HCC development Metabolic alterations Neurological abnormalities Prevention of relapse (Addolorato) Outcome (Toniutto) Early transplant for severe acute alcoholic hepatitis (Germani)

Evaluation of the candidate with alcoholic liver disease for liver transplantation Medical Severity of liver disease (CPT, MELD, other ) Co-morbidities

Evaluation of the candidate with alcoholic liver disease for liver transplantation Medical Severity of liver disease (CPT, MELD, other ) Co-morbidities Psychological/Psychiatric/Toxicologic/Social Alcohol abuse or dependence Polydrug abuse Amount and duration of alcohol consumption Alcohol abstinence Previous alcohol rehabilitation Social stability and family relationship Admission of alcoholism

Alcohol Abuse and Risk of Upper Aero Digestive Tract Cancer Jiménez-Romero et al. WJG. 2015 Ursic-Bedoya J et al. WJG. 2015

Multivariate analysis of the risk factors for solid organ malignancy Risk Factors for Solid Organ Malignancy: Multivariate Analysis Risk factor HR (95%CI) P value Age by decade 1.33 (1.05-1.66) 0.014 Smoking history 1.72 (1.06-2.79) 0.029 2.14 (1.22-3.73) 0.007 PSC 2.62 (1.50-4.56) 0.001 Watt K. Gastroenterology 2009

Evaluation of smoking habits in candidates to liver transplantation with alcoholic liver disease Alcohol and tobacco use commonly co-occur, with at least 90% of those with an alcohol problem also using tobacco. More than 40% are smoking across all time periods after transplant. Alcoholic liver disease recipients resume smoking early post-transplant, increase their consumption over time. DiMartini LT 2005

Alcoholic liver disease () and solid tumors after liver transplantation 2.770 italian liver transplant recipients 186 cancers 32 head and neck cancers 9 esophageal cancer 10-year cumulative risk for head, neck and esophageal cancer was 2.53% Piselli, Burra & Serraino TI 2015

Alcoholic liver disease () and solid tumors after liver transplantation Head and neck cancers SIR 11.8 in liver transplant for (tongue 23, laryns 13.7) SIR 1.8 in liver transplant for non Esophageal cancer SIR 23.7 in liver transplant for SIR 2.9 in liver transplant for non SIR Standardized Incidence Ratios Piselli, Burra & Serraino TI 2015

Natural history of chronic liver disease Pellicoro A Nature Reviews Immunology 2014

Genetic risk markers in alcoholrelated development of HCC Ethanol metabolism Oxidative stress Inflammation process Iron or lipid metabolism Nahon P & Nault JC Liv Int 2017

Cumulative incidence of HCC according to Geography and Etiology of Cirrhosis Alcohol 1.7 x 100 person-years Fattovich G Gastroenterology 2004

HCC and alcohol consumption With viral hepatitis in sharpe decline in EU, excessive alcohol consumption will become the main cause of HCC. Alcohol and Digestive Cancers Across Europe: Time fo Change UEG EU Affairs 2017

Common and unique features of and NAFLD in HCC Goossens & Yoshida, Gastroenterology 2016 Courtesy of Svegliati Baroni

Predictors of Metabolic syndrome after liver transplantation Predictors of MetS OR 95% CI Shorter time from LT 1.03 1.01-1.03 Older age 1.08 1.04-1.13 Alcoholic liver disease 3.88 1.43-10.51 BMI >25 before LT 6.17 2.56-14.89 Reduction of physical activity as cause of weight gain after LT 7.10 1.71-29.5 Reduced calcium intake 7.73 1.75-34.23 Anastacio LR, Nutrition 2011

SPECT to evaluate cerebral blood flow alterations in patients with alcoholic liver disease Burra, EJGH 2004

Regional brain activity after liver transplantation by etiology of liver disease Senzolo & Burra Transplant International 2009

Senzolo & Burra, Transplantation 2002

Adherence to medical regimen in patients with alcohol-related liver disease Germani G, AASLD 2009 To medical treatment No Yes To outpatient clinics No Yes To blood tests No Yes Alcohol Non Alcohol (n=67) (n=67) (%) (%) p 43.1 54.7 45.3 56.9 52.9 47.1 49.6 50.4 44.4 55.6 50.8 49.2 n.s. n.s. n.s.

Patient survival after liver transplantation according to liver disease in Europe (ELTR-ELITA data) Burra P. Am J Transpl 2010

Take home messages Alcohol-related liver disease represents up to one third of indications to liver transplantation. Stringent evaluation of co-morbidities and risk of tumors should be performed in candidates to liver transplant. Overall, alcohol-related liver disease represents a favourable indication to liver transplantation.

Consensus Conference Venice 15 February 2018 ILTS Annual Congress Lisbon 23-26 May 2018 www.ilts.org burra@unipd.it