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Relapse of sclerosing cholangitis after liver transplant in patients with hyper-IG M syndrome
ELSEVIER
Relapse of Sclerosing Cholangitis After Liver Transplant with Hyper-k M Syndrome V. Martinez
Ibanez, T. Espanol,
N. Matamoros,
J. Iglesias, H. Allende,
H
YPER-Ig M syndrome (HIgM) is a primary immunodeficiency’ characterized by recurrent infections due to very low Ig G, Ig A, and Ig E serum levels with normal or, more frequently, increased levels of Ig M.’ Clinical features of HIgM include recurrent bacterial infections of the respiratory and gastrointestinal tracts. Stomatitis and mouth ulcers, with or without neutropenia, and sclerosing cholangitis are frequent autoimmune manifestations in these patients. Pneumocistis carinii pneumonia and other opportunistic infections are common presenting features and are more frequently seen in those with an X-linked inheritance pattern (X-HIgM). The molecular defect for X-HIgM3 has recently been identified after it was demonstrated that T-cell membrane molecules such as CD40 ligand (CD40L) play a crucial role in B-cell differentiation4 and in the switch from IgM to other Ig isotype production. The absence of CD40L on the surface of activated peripheral blood T lymphocytes has been shown to be directly responsible for this immunodeficiency. The gene for CD40L was placed at band q26 of the X chromosome and mutations of the gene have been identified in these patients.5 We describe five patients diagnosed with X-HIgM with CD40 deficiency who presented sclerosing cholangitis (SC), 4 to 7 years after diagnosis of hypogammaglobulinaemia. Three of the five underwent liver transplantation (LTx) and suffered relapse of SC 10, 18, and 25 months post-LTx.
PATIENTS
AND
METHODS
We studied five patients from three families: patients 1 and 2 were two males, first cousins, diagnosed of HIgM syndrome at 6 and 3 months of age, respectively. Patient 2 underwent liver transplantation (LTx) at 10 years of age. A maternal uncle and a brother of the second patient died of infection in the first year of life. Patients 3 and 4, from the second family, were male twins diagnosed with HIgM at 2 years of age. Patient 3 was diagnosed with SC earlier than his brother and underwent LTx. Patient 5, from a third family, was a boy diagnosed with HIgM at 9 months of age. He underwent LTx at 14 years of age. Main clinical and immunologic data are shown in Table 1. Immunoglobulin levels were determined by nephelometry. Peripheral blood lymphocytes were labeled with monoclonal antibody (MoAb) (anti-CD3, CD4, CD8, CD20, CD56) and counted in a flow cytometer (Becton-Dickinson). CD40L expression was mea-
0041-1315/97/$17.00 PII SO041 -1345(96)00172-8
in Patients
T. Lucaya, and C. Margarit
Table 1. Clinical and Immunologic Data Patients Age at diagnosis
1
of HIgM:
lg G (mg %) lg M (mg %) lg A (mg %) B cells % Age of diagnosis of SC Age at Ltx
2
6m 3m 125 138 112 103 15 15 12 18 8~ -
6~ 1OY
3
4
2y 320 870 <8 9
2y 410 1130 18 8
6~ 6%~
llY -
5
9m 360 540 <5 10 5Y 14Y
Abbreviations: HIgM, hyper lg M syndrome; SC, sclerosing cholangitis; Ltx: liver transplantation.
sured in PBL-stimulated cells (with PMA and ionomicyne 6-hour RPM1 1640/37”/5% CO* cell culture) with MoAb.
in a
RESULTS
Patients 1, 2, and 5 were treated with intramuscular gammaglobulin (GG) at 6, 3, and 9 months, respectively until intravenous GG was established at the ages of 3,31/2, and 13 years, respectively. Patient 5 presented repeated respiratory bacterial infections, and bronchiectasias was diagnosed at 13 years of age. Criptosporidium infection was detected in patients 1 and 2 at 4 and 5 years of age, respectively. Leishmania donovani was diagnosed in the diseased native liver of patient 2. LTx was performed in patients 2, 3, and 5. The postoperative course was uncomplicated with the usual immunosuppressive therapy (cyclosporine and 6-month steroids). Liver dysfunction was observed at 25, 18, and 10 months post-LTx, respectively. Transcutaneous liver puncture and transhepatic cholangiography were performed in all three cases and pathology studies and imaging (Fig 1) were consistent with relapse of SC. Follow-up
of The Patients
Patient 1 died of liver failure at 14 years of age. Patients 2 and 3 died 35 and 21 months post-LTx at the ages of 13 and 8 years, respectively, with relapsed SC. Patients 4 and 5 are currently in liver failure at 17 and 15 years of age, (2 years after LTx), respectively. Address reprint requests to V. Martinez Ibanez, Manuel Girona 86, 7-2 D, 08034 Barcelona, Spain.
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
432
Transplantation
Proceedings,
29, 432-433
(1997)
SCLEROSING
CHOIANGITIS
AND HYPER-IGM
SYNDROME
433
our three X-HIgM transplanted patients had this kind of infection, and the outcome has been similar in all of them. Furthermore, relapse of SC has not been observed in a group of SC patients without immunodeficiencies who underwent LTx.” Most probably a similar T-cell deficiency in both diseases, a primary defect in X-HIgM and a secondary defect in patients with HIV, gives a predisposition to develop this autoimmune phenomenon. Infections would be only the triggering mechanism in a susceptible host. Beside opportunistic infections, other causes of SC after LTx included arterial thrombosis, prolonged graft ischemia, and ABO-incompatible allografts,‘” which were not present in these patients. Histologically, distinguishing between SC and chronic rejection may therefore be the most difficult. Diagnosis of SC is based on liver biopsy and postmorten histologic findings, which included periductal fibrosis and features of large and medium-size bile duct obstruction without evidence of foam-cell arteriopathy and on cholangiographic demonstration of diffusely multifocal strictures (Fig 1). As a consequence, LTx must be very cautiously indicated in patients with primary immunodeficiencies, mainly those with HIgM and therefore, correction of the genetic defect may be a bone marrow transplant from a compatible donor” and consequently, autoimmune complication such as the SC in these patients could be avoided. Fig 1. Percutaneous transhepatic cholangiography showing multifocal strictures associated with irregularity of the extrahepatic bile ducts in patient 4.
DISCUSSION
X-HIgM syndrome is a primary hypogammaglobulinaemia caused by a T-cell defect frequently associated with autoimmune manifestations of which sclerosing cholangitis is the most severe. Although intravenous globulin substitution therapy” has dramatically decreased the incidence of bacterial infections, the persistence of the T-cell defect could account for the presence of autoimmune manifestations such as SC and opportunistic infections in the transplanted liver in these patients. As a consequence, relapse of SC in the graft can be due to the same mechanism that provokes SC in the native liver.’ Cryptosporidium infection has been considered responsible of SC in patients with HIV infection,’ but only one of
REFERENCES 1. Report of a WHO scientific (supp):2, 1995
group: Clin Exp Immunol 99
2. Notarangelo LD, Duse M, Ugazio AG: Immunodef Rev 3:101, 1992 3. Korthauer U, Graf D, Mages HW, et al: Nature 361:539,1993 4. Noelle RJ, Leadbetter JA, Arufo A: Immunol Today 13:431, 1992 5. Kraakman MEM, de Weers M, Espariol T, et al: Clin Genet 48:46, 1995 6. Haeney M: Clin Exp Immunol 97 (suppl l):ll, 1994 7. Mieli-Vergani G, Lobo-Yeo A, McFarlane BM, et al: Hepatology 9:198, 1989 8. Pol S, Romana CA, Richard S, et al: N Engl J Med 328:95, 1993 9. Debray D, Pariente D, Urvoas E, et al: J Pediatr 124:49, 1994 10. Sebagh M, Farges 0, Kalil A, et al: Am J Surg Path01 19:81, 1995 11. Thomas C, de Saint Basile G, Le Deist F, et al: N Engl J Med 3331426, 1995
Relapse of Sclerosing Cholangitis After Liver Transplant with Hyper-k M Syndrome V. Martinez
Ibanez, T. Espanol,
N. Matamoros,
J. Iglesias, H. Allende,
H
YPER-Ig M syndrome (HIgM) is a primary immunodeficiency’ characterized by recurrent infections due to very low Ig G, Ig A, and Ig E serum levels with normal or, more frequently, increased levels of Ig M.’ Clinical features of HIgM include recurrent bacterial infections of the respiratory and gastrointestinal tracts. Stomatitis and mouth ulcers, with or without neutropenia, and sclerosing cholangitis are frequent autoimmune manifestations in these patients. Pneumocistis carinii pneumonia and other opportunistic infections are common presenting features and are more frequently seen in those with an X-linked inheritance pattern (X-HIgM). The molecular defect for X-HIgM3 has recently been identified after it was demonstrated that T-cell membrane molecules such as CD40 ligand (CD40L) play a crucial role in B-cell differentiation4 and in the switch from IgM to other Ig isotype production. The absence of CD40L on the surface of activated peripheral blood T lymphocytes has been shown to be directly responsible for this immunodeficiency. The gene for CD40L was placed at band q26 of the X chromosome and mutations of the gene have been identified in these patients.5 We describe five patients diagnosed with X-HIgM with CD40 deficiency who presented sclerosing cholangitis (SC), 4 to 7 years after diagnosis of hypogammaglobulinaemia. Three of the five underwent liver transplantation (LTx) and suffered relapse of SC 10, 18, and 25 months post-LTx.
PATIENTS
AND
METHODS
We studied five patients from three families: patients 1 and 2 were two males, first cousins, diagnosed of HIgM syndrome at 6 and 3 months of age, respectively. Patient 2 underwent liver transplantation (LTx) at 10 years of age. A maternal uncle and a brother of the second patient died of infection in the first year of life. Patients 3 and 4, from the second family, were male twins diagnosed with HIgM at 2 years of age. Patient 3 was diagnosed with SC earlier than his brother and underwent LTx. Patient 5, from a third family, was a boy diagnosed with HIgM at 9 months of age. He underwent LTx at 14 years of age. Main clinical and immunologic data are shown in Table 1. Immunoglobulin levels were determined by nephelometry. Peripheral blood lymphocytes were labeled with monoclonal antibody (MoAb) (anti-CD3, CD4, CD8, CD20, CD56) and counted in a flow cytometer (Becton-Dickinson). CD40L expression was mea-
0041-1315/97/$17.00 PII SO041 -1345(96)00172-8
in Patients
T. Lucaya, and C. Margarit
Table 1. Clinical and Immunologic Data Patients Age at diagnosis
1
of HIgM:
lg G (mg %) lg M (mg %) lg A (mg %) B cells % Age of diagnosis of SC Age at Ltx
2
6m 3m 125 138 112 103 15 15 12 18 8~ -
6~ 1OY
3
4
2y 320 870 <8 9
2y 410 1130 18 8
6~ 6%~
llY -
5
9m 360 540 <5 10 5Y 14Y
Abbreviations: HIgM, hyper lg M syndrome; SC, sclerosing cholangitis; Ltx: liver transplantation.
sured in PBL-stimulated cells (with PMA and ionomicyne 6-hour RPM1 1640/37”/5% CO* cell culture) with MoAb.
in a
RESULTS
Patients 1, 2, and 5 were treated with intramuscular gammaglobulin (GG) at 6, 3, and 9 months, respectively until intravenous GG was established at the ages of 3,31/2, and 13 years, respectively. Patient 5 presented repeated respiratory bacterial infections, and bronchiectasias was diagnosed at 13 years of age. Criptosporidium infection was detected in patients 1 and 2 at 4 and 5 years of age, respectively. Leishmania donovani was diagnosed in the diseased native liver of patient 2. LTx was performed in patients 2, 3, and 5. The postoperative course was uncomplicated with the usual immunosuppressive therapy (cyclosporine and 6-month steroids). Liver dysfunction was observed at 25, 18, and 10 months post-LTx, respectively. Transcutaneous liver puncture and transhepatic cholangiography were performed in all three cases and pathology studies and imaging (Fig 1) were consistent with relapse of SC. Follow-up
of The Patients
Patient 1 died of liver failure at 14 years of age. Patients 2 and 3 died 35 and 21 months post-LTx at the ages of 13 and 8 years, respectively, with relapsed SC. Patients 4 and 5 are currently in liver failure at 17 and 15 years of age, (2 years after LTx), respectively. Address reprint requests to V. Martinez Ibanez, Manuel Girona 86, 7-2 D, 08034 Barcelona, Spain.
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
432
Transplantation
Proceedings,
29, 432-433
(1997)
SCLEROSING
CHOIANGITIS
AND HYPER-IGM
SYNDROME
433
our three X-HIgM transplanted patients had this kind of infection, and the outcome has been similar in all of them. Furthermore, relapse of SC has not been observed in a group of SC patients without immunodeficiencies who underwent LTx.” Most probably a similar T-cell deficiency in both diseases, a primary defect in X-HIgM and a secondary defect in patients with HIV, gives a predisposition to develop this autoimmune phenomenon. Infections would be only the triggering mechanism in a susceptible host. Beside opportunistic infections, other causes of SC after LTx included arterial thrombosis, prolonged graft ischemia, and ABO-incompatible allografts,‘” which were not present in these patients. Histologically, distinguishing between SC and chronic rejection may therefore be the most difficult. Diagnosis of SC is based on liver biopsy and postmorten histologic findings, which included periductal fibrosis and features of large and medium-size bile duct obstruction without evidence of foam-cell arteriopathy and on cholangiographic demonstration of diffusely multifocal strictures (Fig 1). As a consequence, LTx must be very cautiously indicated in patients with primary immunodeficiencies, mainly those with HIgM and therefore, correction of the genetic defect may be a bone marrow transplant from a compatible donor” and consequently, autoimmune complication such as the SC in these patients could be avoided. Fig 1. Percutaneous transhepatic cholangiography showing multifocal strictures associated with irregularity of the extrahepatic bile ducts in patient 4.
DISCUSSION
X-HIgM syndrome is a primary hypogammaglobulinaemia caused by a T-cell defect frequently associated with autoimmune manifestations of which sclerosing cholangitis is the most severe. Although intravenous globulin substitution therapy” has dramatically decreased the incidence of bacterial infections, the persistence of the T-cell defect could account for the presence of autoimmune manifestations such as SC and opportunistic infections in the transplanted liver in these patients. As a consequence, relapse of SC in the graft can be due to the same mechanism that provokes SC in the native liver.’ Cryptosporidium infection has been considered responsible of SC in patients with HIV infection,’ but only one of
REFERENCES 1. Report of a WHO scientific (supp):2, 1995
group: Clin Exp Immunol 99
2. Notarangelo LD, Duse M, Ugazio AG: Immunodef Rev 3:101, 1992 3. Korthauer U, Graf D, Mages HW, et al: Nature 361:539,1993 4. Noelle RJ, Leadbetter JA, Arufo A: Immunol Today 13:431, 1992 5. Kraakman MEM, de Weers M, Espariol T, et al: Clin Genet 48:46, 1995 6. Haeney M: Clin Exp Immunol 97 (suppl l):ll, 1994 7. Mieli-Vergani G, Lobo-Yeo A, McFarlane BM, et al: Hepatology 9:198, 1989 8. Pol S, Romana CA, Richard S, et al: N Engl J Med 328:95, 1993 9. Debray D, Pariente D, Urvoas E, et al: J Pediatr 124:49, 1994 10. Sebagh M, Farges 0, Kalil A, et al: Am J Surg Path01 19:81, 1995 11. Thomas C, de Saint Basile G, Le Deist F, et al: N Engl J Med 3331426, 1995