New Onset New Onset “Autoimmune Hepatitis“ “Autoimmune Hepatitis“

in Liver Pediatric in Liver Pediatric RecipientsRecipients

A. SONZOGNI , M. SPADA , S. RIVA,A. SONZOGNI , M. SPADA , S. RIVA,M. COLLEDAN , A. LUCIANETTI, M. COLLEDAN , A. LUCIANETTI,

A. SEGALIN, A. BERTANI, M. L. MELZI , A. SEGALIN, A. BERTANI, M. L. MELZI , B. GRIDELLIB. GRIDELLI

LIVER TRANSPLANTATION CENTER, LIVER TRANSPLANTATION CENTER, OSPEDALI RIUNITI , BERGAMO , ITALYOSPEDALI RIUNITI , BERGAMO , ITALY

A. J. DEMETRISA. J. DEMETRISTRANSPLANTATION PATHOLOGY UPMC,TRANSPLANTATION PATHOLOGY UPMC,

PITTSBURGH PA , USAPITTSBURGH PA , USA

M. MINERVINIM. MINERVINIISMETT , PALERMO , ITALYISMETT , PALERMO , ITALY

INTRODUCTIONINTRODUCTION- de novo “autoimmune” hepatitis is

a major problem in pediatric liver transplantation

- appearance of autoantibodies is associated with a wide spectrum of clinical / histological

features

AIM OF THE AIM OF THE STUDYSTUDY

To investigate the impact of “autoimmune hepatitis” as long-

term complication of pediatric OLT and links with other post-operative

diseases

MATERIALSMATERIALS

• median age at tx 1.8 yrs. (0.2-17 yrs.)

• median follow-up 1.5 yrs. (0.2 - 10 yrs.)

113 liver tx in 102 pts

7%

58%

4%2%5%

24%

alagille

biliary atresia

pfic

fulminant hepatitis

hepatoblastoma

others

NATIVE DISEASES

IMMUNOSUPPRESSIONIMMUNOSUPPRESSION

CYCLOSPORIN 58

TACROLIMUS 29

SWITCH CYCLO - TACRO 15

OLT & AUTOANTIBODIESOLT & AUTOANTIBODIES16 / 102 pts ( 15 % )

• median age at tx 3.7 yrs ( 0.7 -15 yrs.)• median follow-up 1.5 yrs. ( 0.4 - 10 yrs.)• median time from OLT 3.6 yrs (0.2-9.9yrs.)

6%6%

88%

biliary atresiaalagillealfa- 1-deficiency

TYPE OF GRAFTTYPE OF GRAFT

WHOLE LIVER 7

REDUCED LIVER II-III SEG. 4

IN SITU SPLIT II-III SEGM. 5

IMMUNOSUPPRESSION IN IMMUNOSUPPRESSION IN PTS. W/AUTOANTIBODIESPTS. W/AUTOANTIBODIES

CYCLOSPORIN 8

TACROLIMUS 3

SWITCH CYCLO-TACROLIMUS 5

TYPE OFTYPE OF AUTOANTIBODIESAUTOANTIBODIES

3 ANA + ASMA 5 ANA 4 ASMA 1 ASMA+ ANA + ENA 1 ASMA + cANCA 2 LKM

CLINICAL PRESENTATIONCLINICAL PRESENTATION

median ALT 145 U./l. (n.v. up to 45 U./l. ) range 45 - 350

median IgG 1400 mg. / dl. ( n.v. 310 - 160 mg./ dl. ) range 600 - 2170

AUTOIMMUNE AUTOIMMUNE HEPATITIS HEPATITIS

SCORE *SCORE *

1 72 13 14 55 116 97 108 79 510 611 -212 413 414 1015 1016 4

1 72 13 14 55 116 97 108 79 510 611 -212 413 414 1015 1016 4

* J. Hepatology 31: 929-938, 1999

CLINICAL CLINICAL PRESENTATIONPRESENTATION

IN 7 / 16 PATIENTS LIVER FUNCTION TEST ALTERATIONS PRECEEDED APPEARANCE OF

AUTOANTIBODIES

MEDIUM LAG TIME 5.5 MONTHS

( 3-10 MONTHS)

PREVIOUS POST-OLT PREVIOUS POST-OLT COMPLICATIONSCOMPLICATIONS

ACR ( 4 ) biliary strictures ( 1 ) ACR & polisierositis ( 1 ) ACR & biliary strictures ( 2 ) ACR & colic stricture ( 1 ) ACR and portal thrombosis ( 1 ) chronic varicella virus infection

(1)

1 chronic hepatitis HAI 4/18 bridging fibrosis

2 chronic hepatitis HAI 3/18 indeterminate for ACR

3 chronic hepatitis HAI 3/18 fibr. stage 3;ACR RAI 5/9

4 chronic hepatitis HAI 5/18 marked steatosis

5 chronic hepatitis HAI 4/18

6 chronic hepatitis HAI 4/18 ACR RAI 5/9

7 chronic hepatitis HAI 3/18

8 chronic hepatitis HAI 9/18 bridging fibr.;ACR RAI 4/9

9 chronic hepatitis HAI 4/18 central necrosis,ACR indet.

10 biopsy not performed

11 ACR RAI 3/9; marginal bx

12 chronic hepatitis HAI 3/18

13 ACR RAI 4/9 + centr. venulitis coesistent chr. hepatitis?

14 chronic hepatitis HAI 4/18 ACR RAI 3/9

15 chronic hepatitis HAI 5/1816 chronic hepatitis HAI 5/18

CLINICAL FOLLOW - CLINICAL FOLLOW - UPUP

NO THERAPY 10

PERSISTENCE OF AUTOAB’S 7 DISAPPAEARANCE OF AUTOAB’S 3

STEROIDS THERAPY 2

PERSISTENCE OF AUTOAB’S 2

STEROIDS & AZOTHIOPRINE 4

PERSISTENCE OF AUTOAB’S 4

HISTOLOGICAL FOLLOW-UPHISTOLOGICAL FOLLOW-UP

NO THERAPY 1 1 UNCHANGED

STEROIDS & AZOTHIOPRINE 4 2 UNCHANGED * 2 IMPROVED 1 ( 4 TO 2 HAI ) 1 ( 5 TO 2 HAI ) * 1 pt. w/autoab’s disapparearance

NO THERAPY 1 1 UNCHANGED

STEROIDS & AZOTHIOPRINE 4 2 UNCHANGED * 2 IMPROVED 1 ( 4 TO 2 HAI ) 1 ( 5 TO 2 HAI ) * 1 pt. w/autoab’s disapparearance

EBV - STATUS

•unknown EBV status 9 •follow-up <1 month 9•medium follow-up 1.5 yrs•known EBV status 68 EBNA-Ig +ve 32 (47 %)

EBNA-Ig -ve 36 (53 %)

•unknown EBV status 9 •follow-up <1 month 9•medium follow-up 1.5 yrs•known EBV status 68 EBNA-Ig +ve 32 (47 %)

EBNA-Ig -ve 36 (53 %)

PTS W/OUT AUTOAB

PTS W/AUTOAB

•unknown EBV status 3 •medium follow-up 3 yrs•known EBV status 13 EBNA-Ig +ve 3 (23 %)

EBNA-Ig -ve 10 (77 %)

•unknown EBV status 3 •medium follow-up 3 yrs•known EBV status 13 EBNA-Ig +ve 3 (23 %)

EBNA-Ig -ve 10 (77 %)

EBV INFECTION POST - OLTEBV INFECTION POST - OLT

59%

9%32%

38%

31%

31%

no symptoms EBV-DNA -ve

no symptoms EBV-NA +ve

symptomaticEBV-DNA +ve

NO NO AUTOABAUTOAB

AUTOAAUTOABB

ITEMS TO BE FURTHER ITEMS TO BE FURTHER INVESTIGATEDINVESTIGATED

What is incidence of the disease ? What is its outcome ? Which is its treatment ?

ITEMS TO BE FURTHER ITEMS TO BE FURTHER INVESTIGATED INVESTIGATED

• Are there any links with post-OLT infectious diseases ?

• Are there any links with native pathology ?