Brief Report
Graft-versus-Host Disease in a Liver Transplant Recipient Robert H. Collins, Jr., MD; Barry Cooper, MD; Afzal Nikaein, PhD; Goran Klintmalm, MD, PhD; and Joseph W. Fay, MD Annals of Internal Medicine. 1992;116:391-392.
The classic requirements for graft-versus-host disease (GVHD) (1) exist in recipients of liver allografts: 1) The donor liver and recipient are histo-incompatible; 2) lymphocytes within the lymph nodes and lymphatics of the donor graft are capable of recognizing the recipient as foreign and reacting to the recipient (for example, hemolysis of ABO-incompatible erythrocytes by allograftderived antibodies has been well described [2]); and 3) the recipient is receiving post-transplant immunosuppressive therapy that could conceivably prevent recipient immune cells from eliminating anti-recipient donor cells. Despite the presence of immunosuppression, GVHD is believed to be a rare phenomenon in liver transplant patients; few well-documented cases have been reported (3-5). We report a case of GVHD in a liver transplant recipient and discuss diagnosis, treatment, and prevention of this possibly underdiagnosed syndrome. Case Report A 52-year-old white woman had an orthotopic liver transplant for massive cavernous hemangioma. She had no history, physical findings, or laboratory findings suggestive of immunodeficiency. A serologic test for human immunodeficiency virus was negative. The HLA type of the donor, a black man, was Aw74, ; Bw42, w70; Bw6; Cw2; DR2, w l 2 ; DQwl, w7; DRw52. The recipient's HLA type was A2,3; B7, w62; Bw6; Cw3; DR2,4; DQwl, w3; DRw53. Immunosuppressive therapy after the transplant consisted of cyclosporine, prednisolone, and azathioprine. The post-transplant course was unremarkable, and the patient was discharged 13 days after transplantation without experiencing any rejection. Thirty-five days after the transplant, however, she had a fever to 39.5 °C. Two days later she developed a maculopapular skin rash and pancytopenia. The rash involved the trunk, face, palms, and soles. The leukocyte count was 1.8 x 109/L, the hematocrit was 0.32, and the From Baylor University Medical Center, Dallas, Texas. For current author addresses, see end of text-
platelet count was 95 x 109/L. During the next 2 days, the leukocyte count decreased to 0.5 x 109/L. Over the next 10 days, she became dependent on erythrocyte and platelet transfusions. Liver function was not impaired. A bone marrow biopsy revealed severe panhypoplasia, and a skin biopsy revealed typical histologic findings of GVHD. HLA typing of circulating lymphocytes showed lymphocytes with the HLA phenotype of the donor: A w 7 4 , _ ; Bw42, w70; Bw6; Cw2. A diagnosis of GVHD was made, and the patient was treated with methylprednisolone, 3 mg/kg body weight per day. The pancytopenia persisted, however, and she developed diffuse erythroderma, diarrhea of 1 to 2 liters per day, and gastrointestinal bleeding. She died 20 days after the onset of the syndrome. Discussion Although the immunologic requirements for GVHD may exist in the setting of liver transplantation, only four other well-documented cases have been reported (3-5). (In another case, donor chimerism could not be shown [6]). In these cases and in ours, patients presented with fever, skin rashes (including involvement of the palms and soles), pancytopenia, and diarrhea. The syndrome began from 1.5 to 5 weeks after transplantation. Skin biopsies revealed histologic findings typical of acute GVHD, and donor chimerism was documented by HLA typing. The GVHD in these patients differs from GVHD seen in bone-marrow transplant recipients in two respects. In liver allograft recipients, 1) the liver is not involved because the alloreactive lymphocytes are derived from the liver and recognize the liver as self; and 2) pancytopenia is a prominent feature because hematopoietic cells of the recipient may serve as targets for alloreactive cells. If immunologic reactions occur in liver transplantation, the recipient immune cells usually prevail, and the liver is rejected. Why the donor immune system in rare cases can prevail is unclear. The donor immune system may become predominant under the following conditions: 1. The immune cells within the transplanted liver are particularly numerous or are particularly sensitized; for example, if the liver donor has been transfused previously with blood from a blood donor who shares HLA specificities with the liver transplant recipient. 2. The recipient's HLA phenotype is particularly immunogenic to the donor's immune cells. 3. The HLA type of the donor and recipient are such that the recipient does not recognize the donor immune cells as foreign. This may occur when the donor is homozygous for HLA determinants and shares a hap-
1 March 1992 • Annals of Internal Medicine Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
• Volume 116 • Number 5
391
lotype with a recipient heterozygous for HLA determinants (7). In this situation, the recipient does not recognize and eliminate the donor cells; however, the donor cells may recognize the unshared haplotype as foreign and react against the host. This histocompatibility situation is estimated to occur in 1 of 500 donorrecipient pairs (8). However, this was not the situation in our case or in the other reported cases. 4) The recipient is particularly immunosuppressed, allowing donor immune cells to gain an advantage. The patient may be immunosuppressed before transplantation, as may have been the case in the patients reported by Burdick and colleagues (3) and by Jamieson and associates (5). Our patient and the patient reported by Marubayashi and colleagues (4) had no obvious manifestations of immunosuppression before transplantation. Immunosuppressive therapy after the transplant could play a role, but it is unclear why this treatment would have a disproportionate effect on recipient cells. Thus, patients with one or more of these features might be expected to be more likely to develop GVHD. The syndrome clearly can occur, however, without the risk factor being obvious. Nevertheless, in patients deemed to be at high risk (for example, a patient with a known underlying immunosuppressive illness), preventive measures may be warranted. Such measures might include immunosuppression of the donor before organ harvest, physical removal of obvious nodal tissue from the graft, or perfusion of the graft with anti-T-cell drugs or antibodies. However, the efficacy of these measures is unknown. Treatment of established GVHD involves increased immunosuppression. In our patient, increased doses of corticosteroids were unsuccessful in altering the course of the syndrome. Antilymphocyte globulin or antithymocyte globulin have been used in patients treated successfully (3, 5) and unsuccessfully (4, 5). Ricin-linked anti-T-cell monoclonal antibody has resulted in improvement of corticosteroid-resistant GVHD in bone marrow transplant recipients (9); this antibody may be of value in liver transplant recipients who develop GVHD. Although development of GVHD after liver transplantation appears to be rare, pancytopenia and rash are fairly common in liver transplant recipients; these manifestations are often attributed to drug reactions or viral infections, although proof is usually lacking. It is conceivable, however, that pancytopenia and rash sometimes represent unrecognized GVHD. We reviewed over 500 charts of liver transplant recipients and found
several cases marked by severe pancytopenia, skin rashes, and diarrhea. Although we did not report these cases as examples of GVHD because there had been no test for chimerism, we suspect that the syndrome may be more common than has been thought. In view of the increasing frequency of orthotopic liver transplantation, careful prospective study to determine the incidence and spectrum of the syndrome is warranted. Addendum Another article describing GVHD in liver transplant recipients has recently been published (10). Acknowledgment: manuscript.
The authors thank Betty Webb for preparation of the
Grant Support: By the Delta Delta Delta Sorority Fund. Requests for Reprints: Robert H. Collins, Jr., MD, Bone Marrow Transplantation Research, Baylor University Medical Center, Dallas, TX 75246. Current Author Addresses: Drs. Collins and Fay: Bone Marrow Transplantation Research, Baylor University Medical Center, Dallas, TX 75246. Dr. Cooper: 3320 Live Oak, #600, Dallas, TX 75204. Dr. Nikaein: Transplant Immunology, Baylor University Medical Center, Dallas, TX 75246. Dr. Klintmalm: Transplant Surgery, Baylor University Medical Center, Dallas, TX 75246. References 1. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966;62:21-78. 2. Ramsey G, Nusbacher J, Starzl TE, Lindsay GD. Isohemagglutinins of graft origin after ABO-unmatched liver transplantation. N Engl J Med. 1984;311:1167-70. 3. Burdick J F , Vogelsang GB, Smith WJ, Farmer ER, Bias WB, Kaufman SH, et al. Severe graft-versus-host disease in a livertransplant recipient. N Engl J Med. 1988;318:689-91. 4. Marubayashi S, Matsuzaka C, Takeda A, Costa MM, Jamieson NV, Joysey V, et al. Fatal generalized acute graft-versus-host disease in a liver transplant recipient. Transplantation. 1990;50:709-11. 5. Jamieson NV, Joysey V, Friend PJ, et al. Graft-versus-host disease in solid organ transplantation. Transpl Int. 1991;4:67-71. 6. Bhaduri BR, Tan KC, Humphreys S, Williams R, Donaldson P, Vergani D, et al. Graft-versus-host disease after orthotopic liver transplantation in a child. Transplant Proc. 1990;22:2378-80. 7. Thaler M, Shamiss A, Orgad S, Huszar M, Nussinovitch N, Meissel S, et al. The role of blood from HLA-homozygous donors in fatal transfusion-associated graft-versus-host disease after open-heart surgery. N Engl J Med. 1989;321:25-8. 8. Kruskall MS, Alper CA, Awdeh Z, Yunis EJ. HLA-homozygous donors and transfusion-associated graft-versus-host disease [Letter]. N Engl J Med. 1990;322:1004-7. 9. Byers VS, Henslee AJ, Kernan NA, Blazer BR, Gingrich R, Phillips GL, et al. Use of an anti-pan T-lymphocyte ricin A chain immunotoxin in steroid-resistant acute graft-versus-host disease. Blood. 1990;75:1426-32. 10. Roberts J P , Ascher NL, Lake J, et al. Graft-versus-host disease after liver transplantation in humans: a report of four cases. Hepatology. 1991;14:274-81. © 1992 American College of Physicians
A chief event of life is the day in which we have encountered a mind that startled us. Ralph Waldo Emerson Essays: Second Series Character Emerson: Essays and Lectures The Library of America 1983, p. 493
392
1 March 1992 • Annals of Internal Medicine • Volume 116 • Number 5
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
Graft-versus-Host Disease in a Liver Transplant Recipient Robert H. Collins, Jr., MD; Barry Cooper, MD; Afzal Nikaein, PhD; Goran Klintmalm, MD, PhD; and Joseph W. Fay, MD Annals of Internal Medicine. 1992;116:391-392.
The classic requirements for graft-versus-host disease (GVHD) (1) exist in recipients of liver allografts: 1) The donor liver and recipient are histo-incompatible; 2) lymphocytes within the lymph nodes and lymphatics of the donor graft are capable of recognizing the recipient as foreign and reacting to the recipient (for example, hemolysis of ABO-incompatible erythrocytes by allograftderived antibodies has been well described [2]); and 3) the recipient is receiving post-transplant immunosuppressive therapy that could conceivably prevent recipient immune cells from eliminating anti-recipient donor cells. Despite the presence of immunosuppression, GVHD is believed to be a rare phenomenon in liver transplant patients; few well-documented cases have been reported (3-5). We report a case of GVHD in a liver transplant recipient and discuss diagnosis, treatment, and prevention of this possibly underdiagnosed syndrome. Case Report A 52-year-old white woman had an orthotopic liver transplant for massive cavernous hemangioma. She had no history, physical findings, or laboratory findings suggestive of immunodeficiency. A serologic test for human immunodeficiency virus was negative. The HLA type of the donor, a black man, was Aw74, ; Bw42, w70; Bw6; Cw2; DR2, w l 2 ; DQwl, w7; DRw52. The recipient's HLA type was A2,3; B7, w62; Bw6; Cw3; DR2,4; DQwl, w3; DRw53. Immunosuppressive therapy after the transplant consisted of cyclosporine, prednisolone, and azathioprine. The post-transplant course was unremarkable, and the patient was discharged 13 days after transplantation without experiencing any rejection. Thirty-five days after the transplant, however, she had a fever to 39.5 °C. Two days later she developed a maculopapular skin rash and pancytopenia. The rash involved the trunk, face, palms, and soles. The leukocyte count was 1.8 x 109/L, the hematocrit was 0.32, and the From Baylor University Medical Center, Dallas, Texas. For current author addresses, see end of text-
platelet count was 95 x 109/L. During the next 2 days, the leukocyte count decreased to 0.5 x 109/L. Over the next 10 days, she became dependent on erythrocyte and platelet transfusions. Liver function was not impaired. A bone marrow biopsy revealed severe panhypoplasia, and a skin biopsy revealed typical histologic findings of GVHD. HLA typing of circulating lymphocytes showed lymphocytes with the HLA phenotype of the donor: A w 7 4 , _ ; Bw42, w70; Bw6; Cw2. A diagnosis of GVHD was made, and the patient was treated with methylprednisolone, 3 mg/kg body weight per day. The pancytopenia persisted, however, and she developed diffuse erythroderma, diarrhea of 1 to 2 liters per day, and gastrointestinal bleeding. She died 20 days after the onset of the syndrome. Discussion Although the immunologic requirements for GVHD may exist in the setting of liver transplantation, only four other well-documented cases have been reported (3-5). (In another case, donor chimerism could not be shown [6]). In these cases and in ours, patients presented with fever, skin rashes (including involvement of the palms and soles), pancytopenia, and diarrhea. The syndrome began from 1.5 to 5 weeks after transplantation. Skin biopsies revealed histologic findings typical of acute GVHD, and donor chimerism was documented by HLA typing. The GVHD in these patients differs from GVHD seen in bone-marrow transplant recipients in two respects. In liver allograft recipients, 1) the liver is not involved because the alloreactive lymphocytes are derived from the liver and recognize the liver as self; and 2) pancytopenia is a prominent feature because hematopoietic cells of the recipient may serve as targets for alloreactive cells. If immunologic reactions occur in liver transplantation, the recipient immune cells usually prevail, and the liver is rejected. Why the donor immune system in rare cases can prevail is unclear. The donor immune system may become predominant under the following conditions: 1. The immune cells within the transplanted liver are particularly numerous or are particularly sensitized; for example, if the liver donor has been transfused previously with blood from a blood donor who shares HLA specificities with the liver transplant recipient. 2. The recipient's HLA phenotype is particularly immunogenic to the donor's immune cells. 3. The HLA type of the donor and recipient are such that the recipient does not recognize the donor immune cells as foreign. This may occur when the donor is homozygous for HLA determinants and shares a hap-
1 March 1992 • Annals of Internal Medicine Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
• Volume 116 • Number 5
391
lotype with a recipient heterozygous for HLA determinants (7). In this situation, the recipient does not recognize and eliminate the donor cells; however, the donor cells may recognize the unshared haplotype as foreign and react against the host. This histocompatibility situation is estimated to occur in 1 of 500 donorrecipient pairs (8). However, this was not the situation in our case or in the other reported cases. 4) The recipient is particularly immunosuppressed, allowing donor immune cells to gain an advantage. The patient may be immunosuppressed before transplantation, as may have been the case in the patients reported by Burdick and colleagues (3) and by Jamieson and associates (5). Our patient and the patient reported by Marubayashi and colleagues (4) had no obvious manifestations of immunosuppression before transplantation. Immunosuppressive therapy after the transplant could play a role, but it is unclear why this treatment would have a disproportionate effect on recipient cells. Thus, patients with one or more of these features might be expected to be more likely to develop GVHD. The syndrome clearly can occur, however, without the risk factor being obvious. Nevertheless, in patients deemed to be at high risk (for example, a patient with a known underlying immunosuppressive illness), preventive measures may be warranted. Such measures might include immunosuppression of the donor before organ harvest, physical removal of obvious nodal tissue from the graft, or perfusion of the graft with anti-T-cell drugs or antibodies. However, the efficacy of these measures is unknown. Treatment of established GVHD involves increased immunosuppression. In our patient, increased doses of corticosteroids were unsuccessful in altering the course of the syndrome. Antilymphocyte globulin or antithymocyte globulin have been used in patients treated successfully (3, 5) and unsuccessfully (4, 5). Ricin-linked anti-T-cell monoclonal antibody has resulted in improvement of corticosteroid-resistant GVHD in bone marrow transplant recipients (9); this antibody may be of value in liver transplant recipients who develop GVHD. Although development of GVHD after liver transplantation appears to be rare, pancytopenia and rash are fairly common in liver transplant recipients; these manifestations are often attributed to drug reactions or viral infections, although proof is usually lacking. It is conceivable, however, that pancytopenia and rash sometimes represent unrecognized GVHD. We reviewed over 500 charts of liver transplant recipients and found
several cases marked by severe pancytopenia, skin rashes, and diarrhea. Although we did not report these cases as examples of GVHD because there had been no test for chimerism, we suspect that the syndrome may be more common than has been thought. In view of the increasing frequency of orthotopic liver transplantation, careful prospective study to determine the incidence and spectrum of the syndrome is warranted. Addendum Another article describing GVHD in liver transplant recipients has recently been published (10). Acknowledgment: manuscript.
The authors thank Betty Webb for preparation of the
Grant Support: By the Delta Delta Delta Sorority Fund. Requests for Reprints: Robert H. Collins, Jr., MD, Bone Marrow Transplantation Research, Baylor University Medical Center, Dallas, TX 75246. Current Author Addresses: Drs. Collins and Fay: Bone Marrow Transplantation Research, Baylor University Medical Center, Dallas, TX 75246. Dr. Cooper: 3320 Live Oak, #600, Dallas, TX 75204. Dr. Nikaein: Transplant Immunology, Baylor University Medical Center, Dallas, TX 75246. Dr. Klintmalm: Transplant Surgery, Baylor University Medical Center, Dallas, TX 75246. References 1. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966;62:21-78. 2. Ramsey G, Nusbacher J, Starzl TE, Lindsay GD. Isohemagglutinins of graft origin after ABO-unmatched liver transplantation. N Engl J Med. 1984;311:1167-70. 3. Burdick J F , Vogelsang GB, Smith WJ, Farmer ER, Bias WB, Kaufman SH, et al. Severe graft-versus-host disease in a livertransplant recipient. N Engl J Med. 1988;318:689-91. 4. Marubayashi S, Matsuzaka C, Takeda A, Costa MM, Jamieson NV, Joysey V, et al. Fatal generalized acute graft-versus-host disease in a liver transplant recipient. Transplantation. 1990;50:709-11. 5. Jamieson NV, Joysey V, Friend PJ, et al. Graft-versus-host disease in solid organ transplantation. Transpl Int. 1991;4:67-71. 6. Bhaduri BR, Tan KC, Humphreys S, Williams R, Donaldson P, Vergani D, et al. Graft-versus-host disease after orthotopic liver transplantation in a child. Transplant Proc. 1990;22:2378-80. 7. Thaler M, Shamiss A, Orgad S, Huszar M, Nussinovitch N, Meissel S, et al. The role of blood from HLA-homozygous donors in fatal transfusion-associated graft-versus-host disease after open-heart surgery. N Engl J Med. 1989;321:25-8. 8. Kruskall MS, Alper CA, Awdeh Z, Yunis EJ. HLA-homozygous donors and transfusion-associated graft-versus-host disease [Letter]. N Engl J Med. 1990;322:1004-7. 9. Byers VS, Henslee AJ, Kernan NA, Blazer BR, Gingrich R, Phillips GL, et al. Use of an anti-pan T-lymphocyte ricin A chain immunotoxin in steroid-resistant acute graft-versus-host disease. Blood. 1990;75:1426-32. 10. Roberts J P , Ascher NL, Lake J, et al. Graft-versus-host disease after liver transplantation in humans: a report of four cases. Hepatology. 1991;14:274-81. © 1992 American College of Physicians
A chief event of life is the day in which we have encountered a mind that startled us. Ralph Waldo Emerson Essays: Second Series Character Emerson: Essays and Lectures The Library of America 1983, p. 493
392
1 March 1992 • Annals of Internal Medicine • Volume 116 • Number 5
Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019
