Il trapianto di fegato e di intestino

in pediatria

Lorenzo D’Antiga. Bergamo - Italy 29 Nov 2014

Il trapianto di fegato

11/28/2014

2

Outline

Indications to OLT in children

Early complications

Late complications

Long-term outcome and

perspective

0

8

17

25

33

42

50

Age at presentation (years)

Pe

rce

nta

ge

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Frequency of liver disease according to

age at presentation (3700 pts, KCH – London)

Most cases present early in life

As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly

diminished during the first two months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific.

(NEJM 2003;349:1157-1167)

Pediatric Liver Transplantation in Bergamo

(600 transplants). Age distribution

0

10

20

30

40

50

Num

ber

of

patients

0-1

1-2

2-3

3-4

4-5

5-6

6-7

7-8

8-9

9-10

10-1

1

11-1

2

12-1

3

13-1

4

14-1

5

15-1

6

16-1

7

17-1

8

18-1

9

19-2

0

20-2

1

Age at transplantation (years)

60%

Median age at OLT: 1.4 years

Indications to OLT in Bergamo

(600 pts)

EHBA

55% Inherited cholestatic

21%

Metabolic

9%

Fulminant

5%

Re-OLT

4%

Miscellaneous

6%

The split technique

Immunosuppressive drugs

Steroids

calcineurin inhibitors (CyA, Tacrolimus)

azathioprine

mycophenolate mofetil

mTOR inhibitors (sirolimus, everolimus)

anti IL2 receptor (basiliximab)

Outline

Indications to OLT in children

Early complications

Late complications

Long-term outcome and

perspective

Early complications

Bowel perforation

hepatic artery thrombosis

portal vein stenosis/thrombosis

biliary leak/strictures

outflow problems

acute cellular rejection

infection (CMV, EBV, bacterial)

renal impairment

Post transplant

lymphoproliferative disease

(PTLD)

surgical medical

Acute (cellular) rejection

2

3

1) Portal lymphocytic infiltrate

2) endothelitis

3) bile duct damage

1

Complications: hepatic-caval stenosis

5 year-old boy with Alagille Sdr. OLT

A few months after OLT large ascitis, graft dysfunction,

subcutaneous large vessels at lower abdomen

Caval stricture

Outline

Indications to OLT in children

Early complications

Late complications

Long-term outcome and

perspective

Complications related to immunosuppression

Late cellular rejection/chronic rejection

PTLD

infection (CMV, Varicella, influenza, Adenovirus, EBV, HPV,

bacterial)

Renal impairment/failure

de novo autoimmune hepatitis, chronic hepatitis

Bone disease

Dyslipidemia, diabetes, allergies

Hypertrophic cardiomyopathy

Hypertension

De novo malignancies

Post-transplant lymphoproliferative

disease (PTLD)

Affects 5-20% of all paediatric OLT

If EBV negative pre OLT => strict surveillance

Often preceded by sustained viral detection.

Non-specific symptoms : fever, malaise, mononucleosis-like, organ

enlargement gastrointestinal bleeding/anaemia,

High index of suspicion. Monitor EBV-DNA, pre-emptive approach.

imaging studies (USS, CT) are very important to detect the disease

mandatory to obtain tissue biopsies for final diagnosis

D’Antiga L et Al.: Liver Transplantation 2007;13:343-348

Hepatic osteodystrophy

short term long term

D’Antiga L et Al.: Transplantation 2002 D’Antiga L et Al.: Transplantation 2004

months

Skin cancer

Confirmed association with development of basal cell

and squamous cell carcinoma

Possible association with development of melanoma

Avoid exposure to sunlight, skin barriers not sufficient

to protect

Belloni-Fortina et Al. Arch Dermatol 2004; 140: 1079–1085.

Buell JF, Seminars in Pediatric Surgery, 2006;15:179

De novo tumours: incidence

Chronic kidney disease

Main cause: CNI

nephrotoxicity

Predisposing factors: older

age at OLT, reduced GFR at

OLT, underlying diagnosis

(Alagille, tyrosinemia,

polycistic kidney dis)

Arora-Gupta N, Pediatr Transplantation 2004

Outline

Indications to OLT in children

Early complications

Late complications

Long-term outcome and

perspective

Survival in ELTR database 01/1988 - 12/2010

Patient

ELTR registry

85%

Survival in Bergamo 01/1998 - 12/2013

92%

10-years survival (454 pts) 5-years survival (109 pts)

Chronic liver

disease in the

years 1970-1980:

60% mortality

Chronic liver

disease in the

years 2000-…:

90% survival

Il trapianto di intestino

Conditions leading to Intestinal Transplantation

(Pediatric)

Intestinal transplantation: different composite graft Definitions:

SBT intestine, but no liver or stomach

Liver/SBT intestine + liver, but no stomach

MVT intestine + stomach (± liver, ± spleen)

Fishbein T. N Engl J Med 2009;361:998-1008

David Sachs, Transplant Immunologist

“Transplanting the bowel? It’s

crazy: It is like transplanting a

huge lymph node enwrapped

in faeces”

Old (A and B) and new (C and D) views of transplantation recipients

Starzl T. E. PNAS 2004;101:14607-14614 Copyright © 2004, The National Academy of Sciences

Rejection

Consequences of transplanted donor lymphoid tissue

GVHD

Patient survival

32

What about graft function? 33

60% 50%

What is the best tolerated graft composition? 34

I risultati di Bergamo 35

Follow up medio: 1,7 anni

Sopravvivenza: 7/8 (87%)

Organi funzionanti: 6/9 (66%)

Nome

Data

Trapianto Tipo trapianto

Ultimo

f/up

Stato

Paziente Stato Organo

Data

Fallimento Durata f/up

GL 11/10/2006 FEGATO - INTESTINO 10/10/2007 Morto Funzionante 364

SC 14/06/2008 INTESTINO 02/05/2009 Vivo Funzionante 322

MMF 08/11/2008 INTESTINO 22/10/2011 Vivo Non Funzionante 13/01/2010 1078

FE 15/05/2009 MULTIVISCERALE 19/01/2012 Vivo Funzionante 979

VA 28/07/2009 MULTIVISCERALE 17/01/2012 Vivo Funzionante 903

TB 14/10/2009 FEGATO - INTESTINO 22/10/2011 Vivo Funzionante 738

FL 03/03/2010 MULTIVISCERALE MODIFICATO 07/11/2011 Vivo Funzionante 614

MMF 09/04/2010 INTESTINO 22/10/2011 Vivo Non Funzionante 10/10/2010 561

MG 21/08/2011 MULTIVISCERALE 19/01/2012 Vivo Funzionante 151

634

Complicanze gravi (PTLD, GVHD, PLE, rigetto cronico,

infezioni recidivanti): 7/9 (77%)

When to refer a child for ITx?

Intestinal failure itself is NOT an indication

Total AND definitive intestinal failure AND

complications of home PN

Indication is the impossibility to nourish the

patient by ant mean (NUTRITIONAL FAILURE)

D’Antiga & Goulet JPGN 2013

Survival: PN versus ITx

Pironi. Gut 2011;60:17-25

IT

X

Complicated

HPN

HPN

Complications that indicate ITx ?

Home PN impossible

Extensive vascular thrombosis. Loss of

venous access

Recurrent catheter infections

Severe liver disease

GRAZIE

Lorenzo D’Antiga Bergamo - Italy