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A cause of late graft dysfunction after liver transplantation in children: de-novo autoimmune hepatitis
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 transplantation (LTx) is commonly associated with rejection, vascular complications, biliary complications, viral and bacterial 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 histological 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 transplantation 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 Prednisone 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 After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy
122 31 466 25 47 46 131 42 689 54
305 23 381 27 322 47 140 67 1011 59
1300 1070 1603 1078 3010 1280 1925 1326 1800 1480
LKM (1:500) LKM (1:80) ANA (1:80), ASMA (1:40) Negative ASMA Negative LKM (1:320) Negative ASMA (1:80) Negative
2 3 4 5
LKM: Liver/kidney anti-microsome; ANA: Anti-nuclear; ASMA: Anti-smooth muscle.
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/01/$–see front matter PII S0041-1345(00)02826-8 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
1 2 3 4 5
Time of liver biopsy
Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy
Portal Infiltrate
Interface Hepatitis
Lobular Necrosis
Fibrosis
Total
2 1 2 1 3 1 2 1 3 0
1 0 2 1 3 0 2 0 2 0
1 0 2 1 3 1 2 0 3 0
1 0 1 1 3 0 2 1 2 1
5 1 7 4 12 2 8 2 10 1
(median AST: 131 UI/L), raised IgG titers (median IgG concentration: 1800 mg/dL) and the presence of autoantibodies (Table 1). Two patients had a clear clinical history of de-novo AH. In both, more than one episode of acute cellular rejection developed early after transplantation, successfully treated with steroid boluses. Both showed abnormal LFTs, raised immunoglobulin titers and autoantibodies (Table 1). The liver biopsies showed pictures of chronic hepatitis (Table 2). They were treated with the AH protocol with persistent remission in one child (patient 1) and with relapse of graft dysfunction in the other (patient 2), occurring during steroids tapering, and requiring a further increase in the steroids therapy to achieve stable remission. In the other 3 cases the diagnosis of de novo AH was more complex. In one patient (patient 3) moderate acute cellular rejection was associated to a picture of moderate hepatitis in the liver biopsy performed 42 months after transplantation (Table 2). The child was first treated for acute rejection with steroid boluses, with only incomplete remission. Two months later, when LFTs worsened and a more characteristic picture of chronic hepatitis was evident at liver biopsy, he was successfully treated with the AH protocol (Table 1). In one child (patient 4) LGD was concomitant to lymphoadenopathy and positive anti-EBV IgM titers. The suspect of EBV-related disease was raised and an excisional biopsy of the lymph nodes was performed. Histopathology was negative for PTLD. At this time an elevated IgG titer and the presence of autoantibodies were demonstrated and 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 last case (patient 5) was a 1-year old boy who underwent urgent retransplantation on day 1 for primary non-function from an ABO-incompatible donor. He developed LGD 10 months after LTx, first interpreted as chronic rejection: liver histology showed the presence of vanishing bile duct syndrome and moderate chronic hepatitis (Table 2). Rejection treatment was unsuccessful, with worsening of LFTs and of liver histology, showing severe chronic hepatitis. Treatment for de novo AH was established with LFTs normalization. During treatment he developed bacterial sepsis, requiring ICU admission. AZA was withdrawn and
steroids reduced, and he eventually recovered. He is now well, with normal LFTs, under low dose of Tacrolimus and steroids. CONCLUSIONS
De novo autoimmune hepatitis has been recognized as a possible cause of late graft dysfunction in patients with no other evident cause of liver dysfunction and with evidence of chronic hepatitis at liver biopsy.1,2 Our experience confirms that de novo AH should be suspected in those liver transplant recipients presenting late graft dysfunction with high titers of IgG and of autoantibodies once ischemical, mechanical and infective causes are excluded. Histological evidence of chronic hepatitis should always be obtained.3,4 Although some of the histological lesions can mimic or overlap the pattern of early chronic rejection,5 we believe that AH should be still considered and treated as a specific post-LTx complication. The proposed treatment protocol for de novo AH allowed indeed achieved remission in all the cases, but 3 patients experienced recurrence during steroids tapering. New immunosuppressive protocols should be proposed and tested to treat this complication and to reduce adverse events. Recent experimental data suggest that autoimmune response may play a critical role in the rejection process6 and may contribute to the initiation or to the progression of chronic rejection,7 pointing out the need of further investigation of the relationships between de-novo AH and acute and chronic rejection and viral infections. REFERENCES 1. Kerkar N, Hadzic N, Davies ET, et al: The Lancet 351:409, 1988 2. Jones DEJ, James OFW, Portmann B, et al: Hepatology 30:53, 1999 3. Scheuer PJ: J Hepatol 13:372, 1991 4. Johnson PJ, McFarlane IG: Hepatology 18:998, 1993 5. Blakolmer K, Jain A, Ruppert K, et al: Transplantation 69:2330, 2000 6. Fedoseyava EV, Kishimoto K, Rolls H, et al: Transplantation 69(Suppl):S111, 2000 7. Fedoseyava EV, Kishimoto K, Rolls H, et al: Transplantation 69(Suppl):S112, 2000
L
ATE graft dysfunction (LGD) after liver transplantation (LTx) is commonly associated with rejection, vascular complications, biliary complications, viral and bacterial 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 histological 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 transplantation 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 Prednisone 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 After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy
122 31 466 25 47 46 131 42 689 54
305 23 381 27 322 47 140 67 1011 59
1300 1070 1603 1078 3010 1280 1925 1326 1800 1480
LKM (1:500) LKM (1:80) ANA (1:80), ASMA (1:40) Negative ASMA Negative LKM (1:320) Negative ASMA (1:80) Negative
2 3 4 5
LKM: Liver/kidney anti-microsome; ANA: Anti-nuclear; ASMA: Anti-smooth muscle.
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/01/$–see front matter PII S0041-1345(00)02826-8 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
1 2 3 4 5
Time of liver biopsy
Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy Onset of LGD After Therapy
Portal Infiltrate
Interface Hepatitis
Lobular Necrosis
Fibrosis
Total
2 1 2 1 3 1 2 1 3 0
1 0 2 1 3 0 2 0 2 0
1 0 2 1 3 1 2 0 3 0
1 0 1 1 3 0 2 1 2 1
5 1 7 4 12 2 8 2 10 1
(median AST: 131 UI/L), raised IgG titers (median IgG concentration: 1800 mg/dL) and the presence of autoantibodies (Table 1). Two patients had a clear clinical history of de-novo AH. In both, more than one episode of acute cellular rejection developed early after transplantation, successfully treated with steroid boluses. Both showed abnormal LFTs, raised immunoglobulin titers and autoantibodies (Table 1). The liver biopsies showed pictures of chronic hepatitis (Table 2). They were treated with the AH protocol with persistent remission in one child (patient 1) and with relapse of graft dysfunction in the other (patient 2), occurring during steroids tapering, and requiring a further increase in the steroids therapy to achieve stable remission. In the other 3 cases the diagnosis of de novo AH was more complex. In one patient (patient 3) moderate acute cellular rejection was associated to a picture of moderate hepatitis in the liver biopsy performed 42 months after transplantation (Table 2). The child was first treated for acute rejection with steroid boluses, with only incomplete remission. Two months later, when LFTs worsened and a more characteristic picture of chronic hepatitis was evident at liver biopsy, he was successfully treated with the AH protocol (Table 1). In one child (patient 4) LGD was concomitant to lymphoadenopathy and positive anti-EBV IgM titers. The suspect of EBV-related disease was raised and an excisional biopsy of the lymph nodes was performed. Histopathology was negative for PTLD. At this time an elevated IgG titer and the presence of autoantibodies were demonstrated and 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 last case (patient 5) was a 1-year old boy who underwent urgent retransplantation on day 1 for primary non-function from an ABO-incompatible donor. He developed LGD 10 months after LTx, first interpreted as chronic rejection: liver histology showed the presence of vanishing bile duct syndrome and moderate chronic hepatitis (Table 2). Rejection treatment was unsuccessful, with worsening of LFTs and of liver histology, showing severe chronic hepatitis. Treatment for de novo AH was established with LFTs normalization. During treatment he developed bacterial sepsis, requiring ICU admission. AZA was withdrawn and
steroids reduced, and he eventually recovered. He is now well, with normal LFTs, under low dose of Tacrolimus and steroids. CONCLUSIONS
De novo autoimmune hepatitis has been recognized as a possible cause of late graft dysfunction in patients with no other evident cause of liver dysfunction and with evidence of chronic hepatitis at liver biopsy.1,2 Our experience confirms that de novo AH should be suspected in those liver transplant recipients presenting late graft dysfunction with high titers of IgG and of autoantibodies once ischemical, mechanical and infective causes are excluded. Histological evidence of chronic hepatitis should always be obtained.3,4 Although some of the histological lesions can mimic or overlap the pattern of early chronic rejection,5 we believe that AH should be still considered and treated as a specific post-LTx complication. The proposed treatment protocol for de novo AH allowed indeed achieved remission in all the cases, but 3 patients experienced recurrence during steroids tapering. New immunosuppressive protocols should be proposed and tested to treat this complication and to reduce adverse events. Recent experimental data suggest that autoimmune response may play a critical role in the rejection process6 and may contribute to the initiation or to the progression of chronic rejection,7 pointing out the need of further investigation of the relationships between de-novo AH and acute and chronic rejection and viral infections. REFERENCES 1. Kerkar N, Hadzic N, Davies ET, et al: The Lancet 351:409, 1988 2. Jones DEJ, James OFW, Portmann B, et al: Hepatology 30:53, 1999 3. Scheuer PJ: J Hepatol 13:372, 1991 4. Johnson PJ, McFarlane IG: Hepatology 18:998, 1993 5. Blakolmer K, Jain A, Ruppert K, et al: Transplantation 69:2330, 2000 6. Fedoseyava EV, Kishimoto K, Rolls H, et al: Transplantation 69(Suppl):S111, 2000 7. Fedoseyava EV, Kishimoto K, Rolls H, et al: Transplantation 69(Suppl):S112, 2000