Trapianto di Fegato nell'ottica della Medicina di Genere: Problematiche Mediche e di Equita'
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Patologia epatica in una prospettiva di genere
Modena 18 Giugno 2020
Trapianto di Fegato nell’ottica della
Medicina di Genere: Problematiche
Mediche e di Equita’
Patrizia Burra
Multivisceral Transplant Unit, Gastroenterology
Department of Surgery, Oncology and Gastroenterology
Padua University Hospital
Padua
Influence of gender in liver transplantation Access to the waiting list Waiting list mortality Transplant rates Complications Quality of life Patient and graft survival Sexual dysfunction
Influence of gender in liver transplantation Access to the waiting list Waiting list mortality Transplant rates Complications Quality of life Patient and graft survival Sexual dysfunction
In an era of organ shortage, who get the
liver and who die in the waiting list ?
?
In an era of organ shortage, who get the
liver and who die in the waiting list ?
Mean annual waiting list mortality = 10.2%
Fink JGH 2007
In an era of organ shortage, who get the
liver and who die in the waiting list ?
Female = 18%
Male = 9%
(Relative risk 1.9;
p=0.0026)
Mean annual waiting list mortality = 10.2%
Fink JGH 2007
Females have lower transplant rates before and after
MELD (creatinine, INR, bilirubin) era
UNOS LT waiting list
N= 78.998
Mathur, Am J Transpl 2011
Why Gender Disparity with MELD
(creatinine, bilirubin, INR)?
Compared with Men, Women had:
1) lower creatinine (lower MELD)
(2) lower eGFR (worse renal function)
(3) higher bilirubin and INR (worse liver function)
Myers J Hep 2011
Padua Liver Transplant Center
-2017-
Listed Transplanted
Female Female
51 24/110
(35%) (22%)
Male Male
95 86/110
(65%) (78%)
Burra, Germani, Ferrarese - Resoconto Trapianto di Fegato, Padova 2017
Number of liver transplants overtime
according to recipient gender in Alcohol-
related Liver Disease (ALD) patients
Male Female
1200
1000
800
600
400
200
0
2001
2002
2004
2000
2005
2007
2008
2010
2011
2003
2012
2006
2009
1989
1994
1998
1988
1990
1991
1995
1997
1992
1996
1999
1993
Germani G, Villa E, Burra P et Al. Liver Int 2020Donor graft quality and gender
Donor quality differs significantly between female and
male donor, since female donors are:
- older
- shorter
- die more frequently of stroke
Probably gender differences in donor quality, rather than
gender mismatch are predictive of graft loss.
Lai, Am J Transpl 2011Donor/recipient gender mismatch
Graft survival according to donor-recipient sex combination
Marino, Hepatol 1995Changes in donor/recipient gender matching
overtime in ALD patients
M/M F/M F/F M/F Lineare (F/M)
60,2
57,2
53,2 51,9
50
31,6
29,5
27
24,5
% 21,5
11,4 10,29,6 10,2 10,6
6,9 8,3 10 8,3 7,8
1988-1992 1993-1997 1998-2002 2003-2007 2008-2012
ELTR - Burra AISF Monothematic on Alcoholic Liver Disease Rome 2017Graft survival according to donor/recipient
gender matching in ALD patients
pIndications to liver transplantation
according to recipient gender
Male Female
29
20
18
15 16
13 13 14 13
%
9
7
4 5 5 4 5 4 5
1 1
ALF AIH PBC PSC ALD HBV HCV HCC Metab. Other
Germani G, Villa E, Burra P et Al. Liver Int 2020Indications to liver transplantation
according to recipient gender
Male Female
29
All pIndications to liver transplantation
according to recipient gender
Male Female
29
all pInfluence of gender in liver transplantation Access to the waiting list Waiting list mortality Transplant rates Complications Quality of life Patient and graft survival Sexual dysfunction
Liver transplantation for alcohol-related liver
disease: Padua experience (1991-2019)
ALD
Average in 28 years = 20.8%
110
102
101
91
75 82 87 81
72
76 73 79
72 73 71
58 64
57
54
34 31 38 33 36
20 19 20 27 27
17 22 24 19 18 21 21 21 22 19
16 13 14 16 14 13 15
6 8 10 7 5 8
4 2 4 2 4 3
Burra and Germani, Resoconto Trapianti 2020Alcohol relapse after transplantation Relapse rate of harmful alcohol consumption=10% Univariate analysis: pretransplant abstinence
Causes of death/graft loss according to
recipient gender in ALD patients
Male Female
ELTR - Burra AISF Monothematic on Alcoholic Liver Disease Rome 2017Better graft survival in female vs male after
transplantation for alcoholic liver disease
pIncreased liver transplantation rate
for HCC overtime in males in Padua in 10 years
Whole cohort Males Females
Lineare (Whole cohort) Lineare (Males) Lineare (Females)
18
16
14
12
10
8
6
4
2
0
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Ferrarese WJG 2018Long-Term Patient Survival in patients transplanted
for HBV-related cirrhosis according to gender
- Padua University Hospital -
p = 0.96, log-rank test
Ferrarese & Russo ESOT 2019Changing scenario on waiting list registrations
before and after new antivirals for HCV (DAAs)
Padua University Hospital Experience
*
24,2
21,3
-8% * * p=0.007 vs pre DAA
19,1 18,6
16,7 15,9
Decompensated
%
HCC
10,8
9,5
8,6
7,1 7,4 7,2 6,8
5,9
5 5,4
4,1
2,5 2,2
0,13 0,4 0,7
0 0
HCV ALD HBV NASH AI/Chol Other HCV ALD HBV NASH AI/Chol Other
Pre-DAAs (2006-2013) Post-DAAs (2014-2017)
Ferrarese & Burra WJG 2018Liver Transplantation
before and after DAAs introduction
Padua University Hospital Experience
23,4
22,9
20,8
18,3
-5% 16,5 Decompensated
14,7 HCC
%
11
8,9 8,9
8 8,2
7 6,8
4,9 4,6 4,6
3,6
2,3 1,8
1,3
0,2 0,2 0 0
HCV ALD HBV NASH AI/Chol Other HCV ALD HBV NASH AI/Chol Other
Pre-DAAs (2006-2013) Post-DAAs (2014-2017)
Ferrarese & Burra WJG 2018Worse graft survival in HCV positive female vs
male liver transplant recipients
1 year 3 years 5 years 10 years
Male 72% 65% 59% 47%
pThe natural history of non-alcoholic fatty liver disease
HCCPRE-TRANSPLANT
NASH
NAFLD
POST-TRANSPLANT
Recurrence
De novo
Burra Transplantation 2019De novo metabolic syndrome in 98 HCV+
and 61 HCV- recipients according to
recipient gender
Male Female
77
70
pPrevalence of the components of metabolic syndrome
before and after liver transplantation: Padua experience
Pre-LT 6-months P value* 12-months P 24-months P value*
post-LT post-LT value* post-LT
Obesity 18 (27%) 15 (26%) 1.00 24 (38%) 0.267 23 (36%) 0.26
IFG 17 (27%) 18 (29%) 1.00 18 (29%) 1.00 21 (33%) 0.557
DMII 10 (16%) 21 (33%) 0.003 21 (33%) 0.003 21 (33%) 0.003
Hypertension 8 (13%) 24 (38%) < 0.001 23 (37%) 0.001 19 (30%) 0.013
Hypertriglicerydemia 9 (14%) 20 (31%) 0.035 24 (38%) 0.006 15 (24%) 0.263
Becchetti, Burra, Germani et al. AISF 2019Menopause and metabolic syndrome
In a long term observational study metabolic
syndrome was a significantly risk
of mortality, in a period of 12 years, for
postmenopausal women, compared to
men and premenopausal women.
Lin J Clin Endocrinol Metab. 2010Cardiovascular diseases
Coronary artery disease in women increases at the onset of
menopause due to the loss of female sex hormones.
Trapani, Current Gerontology and Geriatrics Research 2010
Yanes, American Journal of Hypertension 2011Osteoporosis and bone fractures
After liver transplantation, bone turnover is increased.
Immunosuppressive drugs are responsible for bone loss.
Bone fractures rates range from 24%-65% after liver transplantation.
Women with PBC and severe preexisting bone disease appear
to be at greatest risk of osteoporosis and bone fractures after
liver transplantation.
Ebeling, J Clin Endocrinol Metabol 2009Causes of
death/graft loss
according to
recipient gender
Germani G et Al. Liver Int 2020Influence of donor and recipient gender on liver
transplantation outcomes in Europe: factors
associated with lower survival
FEMALE MALE
Donor BMI >30 (p=0.005) Donor/recipient gender
mismatch (p=0.003)
Donor age >60 years (p=0.027) Donor age >60 years (p=0.027)
Recipient age (p=0.0001) Recipient age (p=0.0001)
Germani G, Villa E, Burra P et Al. Liver Int 2020Patient survival after liver transplantation according
to recipient gender (Log-Rank P < .0001)
Germani et al, Liver International, 2020Influence of gender in liver transplantation Access to the waiting list Waiting list mortality Transplant rates Complications Quality of life Patient and graft survival Sexual dysfunction
Quality of life Effects of gender on quality of life, conflicting data. (Tome Journal of Hepatology 2008) Men lower quality of life than female recipients. (Kober Psychother Psychosom 1990) The largest study to date reported that female gender lowers quality of life scores after liver transplant. (Cowling Ann Surg 2004) No significance differences. (Bravata Liver Transplantation 2001, Moore Liver Transplantation 2000)
Sexual dysfunction in 129 men with liver cirrhosis
and 123 men after liver transplantation
Burra Transplantation 2010Sexual dysfunction in 45 women with liver cirrhosis
and 54 women after liver transplantation
Burra Transplantation 2010Mean International Index Erectile Function (IIEF)
score in 123 male patients transplanted for alcohol- and non
alcohol-related liver disease
Wellbeing
Satisfaction
Libido p=ns
Orgasm
Erection
0 5 10 15 20 25
Mean IIEF score
Non alcohol-related Alcohol-related
Burra Transplantation 2010Mean International Index Erectile Function (IIEF)
score in 123 male patients transplanted for alcohol- and non
alcohol-related liver disease
Wellbeing IIEF correlation:
Age
Satisfaction Depression
Libido p=ns
Orgasm
Erection
0 5 10 15 20 25
Mean IIEF score
Non alcohol-related Alcohol-related
Burra Transplantation 2010Mean Female Sexual Function Index (FSFI)
score in 54 liver transplanted female patients
Distress
Pain
Satisfaction
Orgasm p=0.04
Lubrification
Arousal p=0.04
Desire
FSFI tot
0 5 10 15 20 25 30
Mean FSFI score
Other aetiologies Viral-related Alcohol-related
Burra Liver Transplantation 2009Mean Female Sexual Function Index (FSFI)
score in 54 liver transplanted female patients
Distress
FSFI correlation:
Pain
Age
Satisfaction Depression
Orgasm p=0.04
Lubrification
Arousal p=0.04
Desire
FSFI tot
0 5 10 15 20 25 30
Mean FSFI score
Other aetiologies Viral-related Alcohol-related
Burra Liver Transplantation 2009Burra & Villa AISF Position Paper Liver transplantation and pregnancy Digestive and Liver Disease 2016
A = no risk in human studies
B = no evidence of risk in humans
has been found
C = human risk cannot be ruled out
D = evidence of human risk
X = contraindicated
McKay NEJM 2006mTORi and fertility in men •Sirolimus and Everolimus treatment results in a decrease in testosterone level and increase in LH and FSH. •Spermatogenesis seems to be disrupted. •They have deleterious actions on the testis and impairs gonadal function after transplantation. Deutsch AJT 2007; Huyghe E, Transpl Int 2007; Rovira Transplantation 2012
Successful pregnancy in a liver transplant recipient treated with cyclosporine and azathioprine Loreno M & Burra P, Transpl Int 2005;17:730-734 • 33-year-old woman, liver transplantation for Caroli’s disease, on cyclosporine and azathioprine. • 2 years later de novo HBV hepatitis, on lamivudine. • 4 years later the patient became pregnant (lamivudine, cyclosporine and azathioprine were not discontinued). • The course of gestation was uneventful, caesarean section after 36 weeks, the newborn infant was a healthy male weighing 3.080 g and measuring 50 cm.
Risk of pregnancy complications in
the recipient
•Hypertension (20-40%)
•Pre-eclampsia (10-30%)
•Diabetes (10%)
McKAy NEJM 2006Pregnancy outcome in liver recipients on neoral vs. tacrolimus
Sifontis NM, Am J Transpl 2007;S2:1264A
Neoral Tacrolimus
Recipients 22 42
Pregnancy outcomes 36 59
Livebirths 30 42
Spontaneous abortions 6 16
Stillbirths 0 1
Gestational age, mean±SD (wk) 37.4±2.8 36.4±3.4
Birth weight, mean±SD (g) 2750±750 2684±782
Maternal comorbid pregnancy (%)
Hypertension* 44 21
Diabetes* 0 12
Preeclampsia 27 17
Rejection 3 7
Post-partum rejection 3 15
*pBreastfeeding and Immunosuppressive Drugs • The exposure to immunosuppressants via breast milk is smaller than during the pregnancy. • Only 0.1% of a Steroid dose passes to breast milk. • In some studies, no detrimental effects of Azathioprine on the newborns have been proven. • Mofetil Mycophenolate due to its confirmed teratogenic there are no studies describing its activity during breastfeeding in humans. Studies on rats have shown that it passes to the mother’s milk. Greenberger Clin Pharmacol Ther 1993;53:324-328. Ito Am J Obstet Gynecol 1993;168:1393-1399. Saarikoski Am J Obstet Gynecol 1973;115:1100-1106. Mycophenolate REMS. Safety information. https://www.mycophe- nolaterems.com/SafetyInformation.aspx. Accessed May 26, 2016.
Contraceptive methods available after liver transplantation
Effectiveness Drug interactions Reversibility
IUD (Intrauterine ++ - ++
contraceptive devices)
COCs (Combined oral or ++ + ++
transdermal
contraceptives)
Progestin-only pill ++ (-) ++
DMPA (Depot ++ (-) ++
medroxy-
progesterone acetate
(every 3 months
injection)
Barrier method + - ++
Surgical sterilization ++ - -
Heneghan MA, J Hep 2008;49:507-519Pregnancy after liver transplantation:
Padua Experience 1990-2020
2 Budd Chiari
Syndrome 10 healthy
8 women 1 CSP newborns
1 Caroli
Syndrome
3 Acute Liver
Failure
Lymphoma after
1 Biliary atresia
delivery in one case
followed by death
Courtesy of Sciarrone unplublished data 2020Non-adherence to medical prescriptions before and
after liver transplantation (LT)
No difference according to gender
Terapia
Therapy Visits
Visita Exams
Esami
% 70
60 60
50 50
44 50
40
30
20 18
13,4 17,8
10 12,7 12
0
Pre-trapianto
Pre-LT A6-month
6 mesi after LT
post-LT
6-month after LT 12-month after LT
A 12 mesi post-LT
Burra P. & Germani G. Liver Transplantation 2011Adherence in 218 solid organ transplant recipients
• Anonymous 15-item questionnaire, assessing adherence to
immunosuppression, lifestyle, and general prescriptions.
• The percentage of nonadherent kidney transplant recipients
was significantly lower compared with other organ
% transplanted patients.
• Among patients nonadherent to the correct lifestyle, the
rates of men and of patients with disability pension were
significantly higher compared to adherent patients.
Germani G, Lazzaro S, Burra P. Transpl Proc. 2011Conclusion
«In the liver transplant setting, the notion of gender as a
binary female/male factor is now giving way to the awareness
of more complex processes within the female gender that
follow also hormonal patterns and need to be addressed
directly and specifically.»
P.Burra, E.De Martin, S.Gitto, E.Villa
on behalf of WIH
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