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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 ?