A Cause of Late Graft Dysfunction After Liver Transplantation in

Children: De-Novo Autoimmune Hepatitis

M. Spada, A. Bertani, A. Sonzogni, W. Petz, S. Riva, G. Torre, M.L. Melzi, D. Alberti, M. Colledan,
A. Segalin, A. Lucianetti, and B. Gridelli

L ATE graft dysfunction (LGD) after liver transplanta-

tion (LTx) is commonly associated with rejection,
vascular complications, biliary complications, viral and bac-
terial infectious disease, and recurrence of primitive disease
or post transplantation lymphoproliferative disease
(PTLD). De-novo autoimmune hepatitis (AH) has recently
been described as a possible cause of late graft dysfunction
after pediatric and adult LTx not suffering from AH before
LTx, once any of the previously mentioned causes of LGD
can not be established.1,2 This peculiar form of LGD
appears to be associated to clinical, biochemical and histo-
logical features of an autoimmune disorder and can be
effectively treated with the therapy protocols currently
adopted for AH.1 In this study, we retrospectively reviewed
our pediatric LTx series to investigate the occurrence of late
graft dysfunction and de-novo AH and to analyze the
circumstances of diagnosis, the clinical course and the
results of therapeutic management of these patients.
PATIENTS AND METHODS
The study population comprises 95 children who underwent LTx at
our center from October 1997 to July 2000 and 21 patients who are
currently on follow-up at our center, and transplanted by us at the
Policlinico of Milano between 1991 and 1997. Median age at the
time of transplantation was 1.6 years and median weight was 10 kg.
The main indication to LTx was biliary atresia (68%). The clinical
criteria adopted for the diagnosis of de-novo AH were the presence
of (1) abnormal liver function tests (LFTs), (2) high serum
concentrations of immunoglobulin (IgG), (3) presence of autoan-
tibodies, and (4) histological evidence of chronic hepatitis.1 A
semi-quantitative score was adopted for the evaluation of liver
biopsies performed at the onset of LGD and during follow up,
assigning 1 to 4 points to the following parameters: portal infiltrate,
interface hepatitis, lobular necrosis and parenchymal fibrosis.3 All
patients were ruled out for the presence of biliary and vascular
complications and viral infection. When a diagnosis of de novo AH
was made, patients were treated with Azathioprine (AZA) at the
dose of 1.5–2 mg 䡠 kg⫺1 䡠 day⫺1 and Prednisone at the dose of 2 mg 䡠
kg⫺1 䡠 day⫺1. Steroids were tapered within 6 – 8 weeks down to 5
mg 䡠 kg⫺1 in responder patients.
RESULTS
Five (4.3%) out of these 116 patients developed LGD,
without evidence of vascular or biliary complication and of
viral infection, after a median time from LTx of 29 months
(range 17 to 111). Two children were females and three
were males. Patient median age at the time of transplanta-
tion was 1.2 years (range 0.6 to 18). The indication for LTx
was in 4 cases biliary atresia and in one case ␣-1 antitripsin
deficiency. All but one child received an ABO-concordant
graft. Baseline immunosuppression was with Cyclosporin
and Prednisone in 3 cases and with Tacrolimus and Pred-
nisone in 2 cases. All patients showed abnormal LFTs
From the Liver Transplantation Center and the Department of
Pathology (A.So.), Ospedali Riuniti di Bergamo, Italy.
Address reprint requests to Marco Spada, MD, PhD, Chirurgia
3, Ospedali Riuniti, Largo Barozzi 1, 24128 Begamo, Italy.

Table 1. Patients’ Biochemistry and Immunological Status Assessed at the Time of Late Graft Dysfunction (LGD)
and After Treatment
Patient Time ALT (UI/L) AST (UI/L) IgG (mg/dL) Autoantibodies

1 Onset of LGD 122 305 1300 LKM (1:500)

After Therapy 31 23 1070 LKM (1:80)
2 Onset of LGD 466 381 1603 ANA (1:80), ASMA (1:40)
After Therapy 25 27 1078 Negative
3 Onset of LGD 47 322 3010 ASMA
After Therapy 46 47 1280 Negative
4 Onset of LGD 131 140 1925 LKM (1:320)
After Therapy 42 67 1326 Negative
5 Onset of LGD 689 1011 1800 ASMA (1:80)
After Therapy 54 59 1480 Negative
LKM: Liver/kidney anti-microsome; ANA: Anti-nuclear; ASMA: Anti-smooth muscle.

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1747

Transplantation Proceedings, 33, 1747–1748 (2001)

1748 SPADA, BERTANI, SONZOGNI ET AL

Table 2. Histological Score of the Five Patients Assessed at the Time of Late Graft Dysfunction (LGD) and After Treatment
Patient Time of liver biopsy Portal Infiltrate Interface Hepatitis Lobular Necrosis Fibrosis Total

1 Onset of LGD 2 1 1 1 5
After Therapy 1 0 0 0 1
2 Onset of LGD 2 2 2 1 7
After Therapy 1 1 1 1 4
3 Onset of LGD 3 3 3 3 12
After Therapy 1 0 1 0 2
4 Onset of LGD 2 2 2 2 8
After Therapy 1 0 0 1 2
5 Onset of LGD 3 2 3 2 10
After Therapy 0 0 0 1 1

(median AST: 131 UI/L), raised IgG titers (median IgG steroids reduced, and he eventually recovered. He is now
concentration: 1800 mg/dL) and the presence of autoanti- well, with normal LFTs, under low dose of Tacrolimus and
bodies (Table 1). steroids.
Two patients had a clear clinical history of de-novo AH.
In both, more than one episode of acute cellular rejection CONCLUSIONS
developed early after transplantation, successfully treated
De novo autoimmune hepatitis has been recognized as a
with steroid boluses. Both showed abnormal LFTs, raised
possible cause of late graft dysfunction in patients with no
immunoglobulin titers and autoantibodies (Table 1). The
other evident cause of liver dysfunction and with evidence
liver biopsies showed pictures of chronic hepatitis (Table 2).
of chronic hepatitis at liver biopsy.1,2 Our experience con-
They were treated with the AH protocol with persistent
firms that de novo AH should be suspected in those liver
remission in one child (patient 1) and with relapse of graft
transplant recipients presenting late graft dysfunction with
dysfunction in the other (patient 2), occurring during
high titers of IgG and of autoantibodies once ischemical,
steroids tapering, and requiring a further increase in the
mechanical and infective causes are excluded. Histological
steroids therapy to achieve stable remission. In the other 3
evidence of chronic hepatitis should always be obtained.3,4
cases the diagnosis of de novo AH was more complex. In
Although some of the histological lesions can mimic or
one patient (patient 3) moderate acute cellular rejection
overlap the pattern of early chronic rejection,5 we believe
was associated to a picture of moderate hepatitis in the liver
that AH should be still considered and treated as a specific
biopsy performed 42 months after transplantation (Table
post-LTx complication. The proposed treatment protocol
2). The child was first treated for acute rejection with
for de novo AH allowed indeed achieved remission in all
steroid boluses, with only incomplete remission. Two
the cases, but 3 patients experienced recurrence during
months later, when LFTs worsened and a more character-
steroids tapering. New immunosuppressive protocols
istic picture of chronic hepatitis was evident at liver biopsy,
should be proposed and tested to treat this complication
he was successfully treated with the AH protocol (Table 1).
and to reduce adverse events. Recent experimental data
In one child (patient 4) LGD was concomitant to lym-
suggest that autoimmune response may play a critical role
phoadenopathy and positive anti-EBV IgM titers. The
in the rejection process6 and may contribute to the initia-
suspect of EBV-related disease was raised and an excisional
tion or to the progression of chronic rejection,7 pointing out
biopsy of the lymph nodes was performed. Histopathology
the need of further investigation of the relationships be-
was negative for PTLD. At this time an elevated IgG titer
tween de-novo AH and acute and chronic rejection and
and the presence of autoantibodies were demonstrated and
viral infections.
the patient was treated with the AH protocol. Remission of
LGD was achieved, but during steroids tapering 3 episodes
of relapse developed, requiring therapy adjustment. The REFERENCES
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