Gastrolearning XV lezione Management del paziente in lista d'attesa per trapianto di fegato - Prof. P. Toniutto (Università di Udine)

1. Pierluigi Toniutto
Medical Liver Transplant Section
University of Udine
CLINICAL MANAGEMENT OF PATIENTS
AWAITING LIVER TRANSPLANTATION

2. AIM OF THE CARE DURING THE
WAITING PERIOD
• Waiting time for transplantation varies between 3 and 18 months
• The aims of the pre-transplant management are:
– Avoid deterioration of liver function
– Maintain the nutritional status of the patient
– Avoid the appearance of contraindications to transplantation
- Active infections
- Tumour extension (for those listed for HCC)
– Confirm the need for transplantation
– Survey the appearance of contraindication to transplantation
– Improve the results of transplantation

3. CARE OF PATIENT DURING WAITING TIME
• Required a regular follow-up
• Every 2 to 4 weeks depending on the severity of liver disease
• Routine US doppler, surveillance of oesophageal varices,
management of ascites
• This follow-up can be done:
– Directly by the transplant center
– By the referring general physician or specialist
– All therapeutic decisions should be made in accordance with the
transplant physicians

4. SUMMARY OF CARE DURING THE WAITING
LIST PERIOD
LISTED
GENERAL CARE LIVER SPECIFIC
COMPLICATIONS
NUTRITIONAL/
PSYCHOSOCIAL
MELD update
Immunization
PPD
HCC screening
BMD screen
Treatment of primary etiology
Portal hypertension
Ascites
HE
Pruritus
Renal complications (HRS)
Pulmonary complications
Prevention of HCC extension
Support depression
Drug screen
Nutrition

5. SUMMARY OF CARE DURING THE WAITING
LIST PERIOD
LISTED
GENERAL CARE LIVER SPECIFIC
COMPLICATIONS
NUTRITIONAL/
PSYCHOSOCIAL
MELD update
Immunization
PPD
HCC screening
BMD screen
Treatment of primary etiology
Portal hypertension
Ascites
HE
Pruritus
Renal complications (HRS)
Pulmonary complications
Prevention of HCC extension
Support depression
Drug screen
Nutrition

6. FREQUENCY OF VISITS BASED ON MELD SCORE VALUE
*Every six months update for NITp certification

7. AIMS OF THE PERIODICAL VISITS
PERFORMED DURING THE FOLLOW-UP
• Update the parameters used for MELD scoring
• Assessment of electrolytes, complete blood count, coagulation
profile
• Assessment of HE, ascites, edema
• Blood pressure and pulse measurement
• Screening for HCC by ultrasound and CT or MRI
- Viral hepatitis B and C, HH and alcoholic cirrhosis are at
elevated risk of HCC development

8. HCC SCREENING TOOLS DURING THE WAITING TIME
AISF HCC Guidelines; Dig Liv Dis,2013

9. Hayashi et al. Liver Transplantation; 2004
HCC PRE-TRANSPLANT DIAGNOSIS AND
OUTCOMES IN 172 ADULTS
172 adult liver Tx
129 pre-MELD 43 post-MELD
15 pre Tx HCC diagnosis 15 pre Tx HCC diagnosis
3 no HCC in explant 5 no HCC in explant
8/30 (26.6%) false positive diagnosis

10. TREATMENT OF PRIMARY ETIOLOGY
•Management of HBV infection
•Management of HCV infection

11. TREATMENT OF PRIMARY ETIOLOGY
•Management of HBV infection
•Management of HCV infection

12. KEY ISSUES OF THERAPY IN PATIENTS WITH HBV
RELATED CIRRHOSIS WAITING FOR LT/1
• Oral antiviral treatment when applied as early as possible helps
to improve prognosis in decompensated HBV-induced liver
cirrhosis, and may even delay or prevent the need for LT.
• Monotherapy with nucleos(t)ide analogs (NUCs) with high
barriers to resistance like ETV or TFV are recommended as first
line treatment options according to current guidelines.
• The overall safety and tolerability of NUCs is high in
decompensated cirrhosis, but adaptation of the dosage according
to renal function and renal monitoring is required.

13. KEY ISSUES OF THERAPY IN PATIENTS WITH HBV
RELATED CIRRHOSIS WAITING FOR LT/2
• Lactic acidosis has been described in rare instances especially in
patients with a high MELD score treated with ETV.
• Liver function determined by Child-Pugh and MELD score is the
best predictor to differentiate patients who may stabilize and
individuals who will require liver transplantation despite initiation
of antiviral therapy.
• The risk of HCC development remains significant even in those
patients with successful antiviral therapy and complete
suppression of HBV DNA. Thus, thorough HCC surveillance
remains mandatory.

14. 86% Improved
14% Not Improved
50% Improved/Stabilized
14% Not Improved
30% Death*
2% No F/U
N = 176 (226)
CPT A = 40%, B = 38%, C = 22%
43%
Transplanted
21%
Removed from
Wait List
36%
Still Wait Listed
*All deaths occurred prior to 24 weeks
Schiff et al. Liver Transpl; 2007
OUTCOME OF WAIT-LISTED LAM RESISTANT HBV
CIRRHOSIS TREATED WITH ADEFOVIR

15. EFFECT OF ENTECAVIR ON HBV-RELATED ACUTE-ON-
CHRONIC LIVER FAILURE
• Hepatitis B related acute-on-chronic liver failure (HBV-ACLF) has poor prognosis
• Efficacy and safety of ETV in patients with HBV-ACLF evaluated in retrospective study
(N=248)
– 124 patients ETV vs. 124 patients control (no nucleos(t)ide analog)
By multivariate logistic regression, high INR, ≥2 complications and high total bilirubin,
but not HBV DNA, were independent predictors of liver-related mortality in HBV-ACLF
By multivariate logistic regression, high INR, ≥2 complications and high total bilirubin,
but not HBV DNA, were independent predictors of liver-related mortality in HBV-ACLF
Multivariate Logistic Regression Analysis of Independent Risk Factors
for Mortality in Patients with HBV-ACLF
Odds Ratio
95% CI
Lower Upper
High Total Bilirubin (µmol/L) 1.003 1.001 1.005
High INR 2.589 1.501 4.465
≥2 Complications 9.568 4.319 21.197
HBV DNA (log copies/mL) 1.120 0.869 1.445
Ma K, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 742.

16. ENTECAVIR TREATMENT DECREASES
DISEASE PROGRESSION IN HBV-RELATED ACUTE-ON-
CHRONIC LIVER FAILURE
• ETV group achieved improvement of MELD score compared to controls
• 1- and 3-month survival rates of ETV group (72.58% and 61.29%), significantly
higher than that in control group (53.23% and 45.97%)
Ma K, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 742.

17. EFFICACY AT WEEK 48
TDFTDF
(N = 45)(N = 45)
TVDTVD
(N = 45)(N = 45)
ETVETV
(N = 22)(N = 22)
% with HBV DNA < 400 copies/mL 71% 88% 73%
MELD score Median change
Absolute MELD Week 48 (median)
-2.0-2.0
8
-2.0-2.0
8
-2.0-2.0
8
CTP score Mean change
Absolute CTP Week 48 (median)
-1-1
6
-1-1
6
-1-1
5
Median ALT (U/L) 29 33 31
• An ITT noncompleter/switch = failure analysis was used
• Patients who switched from blinded medication to open-label TVD were considered noncompleters in all 3 arms of the study
• Patients who underwent orthotopic liver transplant (OLT) (6 total; 2 TDF, 4 FTC/TDF) are censored from the HBV
DNA, serology, biochemical, MELD and CPT analyses
Liaw Y-F, et al., AASLD 2009; Oral #322.
Study 108: TDF vs FTC + TDF vs ETV

18. ADATTAMENTO POSOLOGICO NUC
INTERVALLI TRA I DOSAGGI /RIDUZIONE DOSE E GFR
Farmaco TelbivudinaTelbivudina EntecavirEntecavir AdefovirAdefovir TenofovirTenofovir
GFRmL/minGFRmL/min
/ 1.73 m/ 1.73 m22
SCSC
Dose 600 mg
Naïve a
Lamivudina
dose 0,5 mg
“Experienced”
a Lamivudina
Dose 10 mg Dose 245 mg
> 50> 50 24h ogni 24 hr
1 mg ogni 24 hr
24 h 24 h
30-4930-49 48 h ogni 48 h
0,5 mg ogni 24
hr
48 h 48 h
10-3010-30 72 h ogni 72 hr
0,5 mg ogni 48
hr
72 h 72-96h
ESRDESRD 96 h ogni 5-7 gg
0,5 mg ogni 72
hr
7 giorni 7 giorni

19. 0
100
200
300
400
500
600
700
800
HBV
HCV
Kim WR, Gastroenterology 2009
year
DECLINE OF LIVER TRANSPLANTATION FOR HBV
CIRRHOSIS IN US
The pattern of liver transplantation waiting list registration among patients
with hepatitis B suggests that the widespread application of oral antiviral
therapy for HBV contributed to the decreased incidence of decompensated
liver disease.

20. Status
Pre-LT
Anhepatic
First week
Weeks 2-12
>Week 12
HBsAg+
DNA-
HBsAg+
DNA+
Start NUC pre-Op NUC > 4 weeks
DNA- DNA+
20.000 UI HBIG IV
10.000 UI HBIG IV 20.000 UI HBIG IV x 2
10000 UI/day
10.000 UI HBIG IV to keep
HBsAb >200 IU/L
Reduce HBIG dose
HBsAb >100 IU/L
HBV PROPHYLAXIS RECOMMENDATIONS
Dikcson et al. Liver Transpl, mod.; 2006

21. ETV MONOTHERAPY IS EFFECTIVE
IN SUPPRESSING HBV AFTER LT
Fung et al. Gastroenterology; 2011.
• 80 HBsAg+ recipients (47 LDLT)
• Only 21 (26%) had HBV-DNA- at LT
• All free of HBIG
• ETV 0.5 mg in all except 9 (1 mg)
• Median follow-up of 26 months
Study design Summary of pre LT antiviral therapy

22. ETV MONOTHERAPY IS EFFECTIVE
IN SUPPRESSING HBV AFTER LT
Fung et al. Gastroenterology; 2011.
• Total number of HBsAg positive patients at the end of follow-up: 18 (22.5%)
• (8 patients had persistent HBsAg and 10 had HBsAg reappearance)
• Only 1 patient had HBV-DNA positivity in the serum (37 IU/ml)
Cumulative rate of HBsAg
seroclearance
Cumulative rate of HBsAg
relapse

23. Fung et al. Gastroenterology; 2011.
CUMULATIVE RATE OF HBsAg SEROCLEARANCE AFTER LT IN
RELATIONSHIP TO HBsAg AND HBV-DNA SERUM LEVELS AT LT

24. TREATMENT OF PRIMARY ETIOLOGY
•Management of HBV infection
•Management of HCV infection

25. PREVENTION OF GRAFT HCV RECURRENCE BY
ANTIVIRAL THERAPY IN CIRRHOTICS
AWAITING LIVER TRANSPLANT
Everson GT. Clin Gastro Hepatol. 2005.
Patients(%)
HCV Free
Posttransplant*
EVR
0
20
40
60
80
100
10
30
50
70
90
SVR Transplant
Everson
Forns
Thomas
Crippin
*Regardless of achieving SVR pretransplant

26. Forns et al. J Hepatol 2003; Carrion et al. J Hepatol 2009; Everson et al. Hepatology 2013.
EFFICACY AND SAFETY OF PEG-IFN PLUS RBV IN HCV
POSITIVE RECIPIENTS IN THE WAITING LIST

27. Verna et al. AASLD 2012.
PRELIMINARY DATA OF TRIPLE THERAPY IN HCV
POSITIVE RECIPIENTS IN THE WAITING LIST

28. CUPIC FRENCH COHORT: SVR 12 RESULTS
Fontaine et al. EASL 2013
- SAES in 57% (TVR) and 40.4% (BOC)
- Death 2,8% (TVR) and 0.9% (BOC)
- Infections in 6.5% (TVR) and 4.4% (BOC)
- Hepatic decompensation 0.9% (TVR) and 1.8% (BOC)

29. www.clinicaltrial.gov:
DAA AND PREVENTION OF HCV RECURRENCE
W k 0 + 1 2
Sofosbuvir 400 mg QD+ RBVSofosbuvir 400 mg QD+ RBV S V R 1 2
C O N T A I N M E N T : S o f o s b u v i r + R B V P r io r t o L i v e r T r a n s p la n t
♦ 40-60 HCVPatients on LT list due to HCC
– Expected transplant within 3-12 months
♦ Primary efficacy endpoint : SVR12 post-LT
L T
T r e a t u p t o t i m e o f L T o r m a x i m u m o f 2 4 w e e k s
ClinicalTrials.gov. NCT01559844
D A A a n d p r e v e n t i o n o f h e p a t i t is C r e c u r r e n c e
W k 0 + 1 2
Sofosbuvir 400 mg QD + RBVSofosbuvir 400 mg QD + RBV S V R 1 2
O N T A IN M E N T : S o f o s b u v ir + R B V P r io r t o L iv e r T r a n s p la n t
♦ 40-60 HCV Patients on LT list due to HCC
– Expected transplant within 3-12 months
♦ Primary efficacy endpoint : SVR12 post-LT
L T
T r e a t u p t o t im e o f L T o r m a x im u m o f 2 4 w e e k s
ClinicalTrials.gov. NCT01559844
a n d p r e v e n t io n o f h e p a t it is C r e c u r r e n c e

30. Crespo et al. Gastroenterology; 2012.
PREVENTION OF HCV RECURRENCE

31. SUMMARY OF CARE DURING THE WAITING
LIST PERIOD
LISTED
GENERAL CARE LIVER SPECIFIC
COMPLICATIONS
NUTRITIONAL/
PSYCHOSOCIAL
MELD update
Immunization
PPD
HCC screening
BMD screen
Treatment of primary etiology
Portal hypertension
Ascites
HE
Pruritus
Renal complications (HRS)
Pulmonary complications
Prevention of HCC extension
Support depression
Drug screen
Nutrition

32. LIVER SPECIFIC COMPLICATIONS
• Gastrointestinal bleeding should be prevented via routine endoscopy
(variceal band ligation) with or without beta blockers.
• Routine paracentesis with albumin supplementation is the best way to
control refractory ascites and prevent malnutrition.
• Patients with hepatorenal syndrome (HRS) type 1 can be transplanted
after control of HRS with pharmacological agents such as terlipressin.
• In some cases of refractory ascites and HRS type 2, TIPS can be
attempted.
• Treatment and prevention of recurrent spontaneous bacterial peritonitis
is essential.
• Patients with portal thrombosis should be treated with anticoagulation
to avoid portal thrombus extension.

33. PULMONARY COMPLICATIONS INDUCED BY
ADVANCED LIVER DISEASES
Hoeper et al. Lancet; 2004; Palma et al. J Hepatol; 2006.Houlihan et al. Aliment. Pharmacol Ther, 2013

34. HEPATOPULMONARY SYNDROME
•HPS occurs in 4% to 25% of candidates to liver transplantation
•Characterized by
− Cirrhosis and or portal hypertension
− Hypoxia (alveolar-arterial oxygen gradient >20 mmHg)
− Intrapulmonary vascular dilatation
•Pulmonary features include
− Digital clubbing
− Cyanosis
− Dyspnea
− Platypnea
− Orthodeoxia
Hoeper et al. Lancet; 2004; Palma et al. J Hepatol; 2006.

35. WORK UP FOR HEPATOPOLMONARY SYNDROME
Sharma et al. Liver Transpl; 2005, mod.
Arterial hypoxemia
PaO2 <70 mmHg
A-a gradient > 20 mmHg
No evidence of pulmonary disease
Echocardiography with saline solution
(presence of microbubbles in the left cardiac chamber after 5 heart beats
after the visualization in the right chambers)
99
TC macroaggregated albumin (shunt index >7%)
Negative Positive
HPS

36. HEPATOPULMONARY SYNDROME AND LT
Hoeper et al. Lancet; 2004; Palma et al. J Hepatol; 2006.
• Liver transplantation is the only known effective therapy for
HPS and most patients have an improvement in oxygenation
at 1 year
• A number of centers have described worse outcome in
patients with severe HPS (PaO2 ≤50 mmHg)
• Mortality rates of 16% and 30% at 3 months as a whole and
in severe HPS
• More recently mortality rates 7% and 14% as a whole and for
severe HPS
• No contraindications for LT independently from PaO2 values
in the absence of other comorbidities (MELD exception)
- List priority for PaO2 <60 mmHg
Houlihan et al. Aliment. Pharmacol Ther, 2013; AISF-CCTF-SITO Proposed Consensus Conference; 2013

37. PORTO-PULMONARY HYPERTENSION (PoPH)
•PoPH occurs in 2% to 6% of candidates to liver transplantation
•More frequent in severe portal hypertension and refractory
ascites, HIV+ recipients, female gender, autoimmune disease
(S100A4 SNPs and genetic variation in oestrogen signalling)
•Characterized by:
- Portal hypertension with or without liver disease
- Resting mean pulmonary artery pressure (mPAP) >25
mmHg
- Pulmonary vascular resistance (PVR) >240 dynes/s/cm-5
- Pulmonary capillary wedge pressure ≤15 mmHg
- Exclusion of secondary causes of pulmonary arterial
hypertension
Arguedas et al. Hepatology; 2003; Houlihan et al. Aliment. Pharmacol Ther, 2013

38. CLINICAL MANIFESTATIONS OF PoPH
•Initially mild and non specific (fatigue, edema)
•Physical signs of PoPH (right ventricular heave, loud pulmonary
second heart sound and elevated jugular venous pressure)
•In more advanced disease: dyspnea on exertion, syncope, chest
pain, hemoptysis and orthopnea
•Using doppler echocardiography the estimated upper 95% limit
for PASP among low risk normal individuals is 37.2 mmHg
- 6% of normal subjects over 50 years of age and in 5% of obese
PASP >40 mmHg
•In cirrhotics a threshold estimated PASP of 30 mmHg
demonstrated PPV of 59% and NPV of 100% in identifying
patients with PoPH
Houlihan et al. Aliment. Pharmacol Ther, 2013

39. ASSESSMENT AND MANAGEMENT
ALGORITHM OF PoPH
Houlihan et al. Aliment. Pharmacol Ther, 2013

40. PHARMACOLOGICAL INTERVENTION IN PoPH
Houlihan et al. Aliment. Pharmacol Ther, 2013
• Bosentan (dual endothelin-A and endothelin-B receptor
antagonist)
- Can be associated with hepatotoxicity – careful
monitoring required
- Contraindicated in decompensated cirrhosis
• Sildenafil (phosphodiesterase inhibitor)
• No large controlled trials

41. PoPH AND LT
• Patients with PoPH and decompensated cirrhosis must be
evaluated for listing independently from MELD score if
responders to vasoactive therapy
• Listing priority for those with MPAP >35 mmHg pre
vasoactive treatment
• Check of therapy response every 3 months by right heart
catheterization
• Criteria for response: MPAP <35 mmHg and PVR <400
dynes/s/cm-5
or normal PVR (<240 dynes.s.cm-5
) and normal
right heart function
• MPAP >50 mmHg despite vasoactive therapy must be
considered as absolute contraindication to LT
Houlihan et al. Aliment. Pharmacol Ther, 2013; AISF-CCTF-SITO Proposed Consensus Conference; 2013

42. SUMMARY OF CARE DURING THE WAITING
LIST PERIOD
LISTED
GENERAL CARE LIVER SPECIFIC
COMPLICATIONS
NUTRITIONAL/
PSYCHOSOCIAL
MELD update
Immunization
PPD
HCC screening
BMD screen
Treatment of primary etiology
Portal hypertension
Ascites
HE
Pruritus
Renal complications (HRS)
Pulmonary complications
Prevention of HCC extension
Support depression
Drug screen
Nutrition

43. ALCOHOL DEPENDENCE IN THE CANDIDATE TO LT
• In order to ration organs, most programmes require a 6-month period of
abstinence prior to evaluation of alcoholic patients.
• The 6-month period of abstinence is presumed:
- to permit some patients to recover from their liver disease and obviate
the need for LT
- to identify subsets of patients likely to maintain abstinence after LT
• Data concerning the utility of the 6-month rule as a predictor of long-term
sobriety are controversial
• Drinking habits of transplanted patients need to be routinely screened with
tools of proven reliability
• Severe acute alcoholic hepatitis failing to respond medical therapy (Lille
score ≥0.45 at day 7) – controversial indication to LT

44. DECISIONAL ALGHORITM IN PATIENTS
WITH HISTORY OF ALCOHOL CONSUMPTION
History of alcoholism
Non compliance-
Social problems?
Success of previous treatments?
No Yes
Yes
No
Therapy and re-evaluateYes
Not candidate
No
Active psychosis?
YesNo
Psychiatric therapy terminated? No
Not candidate
Yes
Familiar support?
NoYes
Social support available?
Reasonable candidate
Yes
Questionable candidate
No
Yowsey S. and Schneekloth T. In: Transplantation of the liver, 2nd edition. Elsevier and Saunders Ed. 2005.

45. SURVIVAL OF PATIENTS IN RELATIONSHIP TO PRIMARY
INDICATION FOR LT IN EUROPE (01/1988-06/2007)
years
survival(%)
(N. = 14149)
(N. = 11843)
(N. = 3969)
(N. = 2914)
(N. = 1601)
European Liver Transplant Registry; 2008
%

46. SURVIVAL IN PATIENTS TRANSPLANTED FOR ALCOHOLIC
DISEASE IN RELATIONSHIP TO MAINTAINANCE OF ABSTINENCE
Pfitzmann et al. Liver Transpl; 2007.
0 2 64 108
0
20
40
60
80
Survival(%)
years after LT
100
abstinent after LT
resumed drinking after LT
slip drinkers
abusive drinkers

47. RISK FACTORS AND CAUSES OF DEATH FOR
RECURRENT ALCOHOL CONSUMPTION AFTER LT
Pfitzmann et al. Liver Transpl; 2007.
Jauhar et al. Liver Transpl; 2004. Pfitzmann et al. Liver Transpl; 2007.

48. ALCOHOL ADDICTION AND LT
• Alcohol abuse is a frequent cause of acute and chronic liver
disease in the general population.
• The social and financial costs of alcoholic liver disease
treatment are growing
• Long term prognosis after LT for alcoholic liver disease
depends on alcohol relapse
• The predictors of relapse must be checked accurately before LT
• Survival is significantly reduced for patients who relapse due to
the development of liver cirrhosis and de novo malignancies

49. CONCLUSIONS
• In liver centers, a detailed evaluation of the recipient is performed
to ensure that transplantation is indicated and feasible.
• Regular follow-up of patients on the waiting list is crucial for the
success of transplantation and the reduction of mortality among
these patients.
• The aggressive care of candidates to LT has permitted to maintain
in the waiting list patients with very advanced liver disease. This
should be carefully accompanied by a clear policy of selection of
patients who will be transplanted