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Table of Contents
Year : 2019  |  Volume : 13  |  Issue : 2  |  Page : 130-133

Graft-versus-host disease: Rare complication postliver transplant

1 Department of Gastroenterology and Hepatology, Max Super Specialty Hospital, New Delhi, India
2 Department of Pathology, Max Super Specialty Hospital, New Delhi, India
3 Department of Hepatology, School of Digestive and Liver Disease, Institute of Postgraduate Medical Education and Research, SSKM Hospital, Kolkata, West Bengal, India
4 Center for Liver and Biliary Sciences, Max Super Specialty Hospital, New Delhi, India

Date of Submission29-Oct-2018
Date of Acceptance02-Dec-2018
Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Nivedita Pandey
Department of Gastroenterology and Hepatology, Max Super Specialty Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_71_18

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Graft-versus-host disease (GVHD) following liver transplantation (LT) is an uncommon complication but has high mortality and represents a major diagnostic challenge. A 63-year-old male with nonalcoholic steatohepatitis-related decompensated cirrhosis underwent deceased donor LT. His postoperative course was complicated by fever, diarrhea, skin rashes, and pancytopenia. He developed a diffuse erythematous rash, which progressed to erythroderma. Biopsies of the duodenum and skin were consistent with acute GVHD. This was confirmed by chimerism study performed on the bone marrow. The patient was treated with basiliximab, corticosteroids, tacrolimus, and mycophenolate; however, he had minimal response to intensive immunosuppressive therapy. The patient died due to multiorgan failure.

Keywords: Graft-versus-host disease, liver transplant, skin rash

How to cite this article:
Pandey N, Bansal B, Jaiswal A, Gupta S. Graft-versus-host disease: Rare complication postliver transplant. Indian J Transplant 2019;13:130-3

How to cite this URL:
Pandey N, Bansal B, Jaiswal A, Gupta S. Graft-versus-host disease: Rare complication postliver transplant. Indian J Transplant [serial online] 2019 [cited 2020 Aug 6];13:130-3. Available from: http://www.ijtonline.in/text.asp?2019/13/2/130/261847

  Introduction Top

Acute graft-versus-host disease (GVHD), a reaction of donor immune cells against host tissues, is a frequent complication (35%–50%) after allogeneic hematopoietic stem cell transplantation (HSCT).[1] In 1988, Burdick et al. first described acute GVHD after orthotopic liver transplantation (OLT).[2] Acute GVHD after liver transplantation (LT) is rare, occurring in 0.1%–2% of patients; however, it is a severe complication with an 85% mortality rate in adult recipients.[3],[4],[5],[6] Acute GVHD typically occurs 1–8 weeks after LT with symptoms of fever, diarrhea, and skin rashes in the early clinical course, followed by pancytopenia, sepsis, and even death.[7] At present, the correct diagnosis and management of GVHD following LT remain a major challenge. Herein, we report a patient with acute GVHD after LT confirmed with chimerism study; the patient was treated aggressively but succumbed to his diagnosis.

  Case Report Top

A 63-year-old male with a history of nonalcoholic steatohepatitis-related decompensated chronic liver disease underwent ABO-compatible deceased donor-related LT in September 2017. Induction immunosuppression was given with methylprednisolone followed by tacrolimus, mycophenolate mofetil, and prednisone. Early postoperative course was uneventful. Four weeks after transplant, the patient was admitted with fever, diarrhea, and an erythematous, targetoid, macular desquamating rash with oral ulcers. He was pancytopenic, white cell count was 300/uL, hemoglobin was 7.3 g/dL, and platelets were 40,000/uL. The rash progressed to involve the entire integument and was most pronounced on the palms and soles. An infectious workup was negative. Liver function tests were normal.

Skin biopsy findings were: epidermis was thinned out/atrophic with vacuolar degeneration of basal cell layer, mild spongiosis, and lymphocytic exocytosis. A large number of necrotic/apoptotic keratinocytes were seen in the basal layer and at all the levels of the epidermis. Lymphocyte satellitosis was seen around few necrotic keratinocytes. Focally melanin pigment was seen in the corneum. Focal mild epidermal clefting was seen. Superficial debris showed minimal perivascular lymphocytic infiltrate. Dermis showed loss of pilosebaceous structures and thickened collagen bundles in the papillary and reticular dermis [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Figure 1: Atrophic epidermis with thick collagen bundles in dermis

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Figure 2: Basal layer vacuolization and lymphocyte exocytosis

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Figure 3: Necrotic/Apoptotic keratinocytes involving all layers of epidermis

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Figure 4: High power view of necrotic keratinocytes

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Bone marrow aspiration smears were particulate and showed markedly hypocellular particles. Erythroid and myeloid precursors were markedly reduced in number and only scattered forms were seen exhibiting normal morphology. Megakaryocytes appeared to be adequate. Background population of lymphocytes and macrophages was seen [Figure 5] and [Figure 6].
Figure 5: Marked hypocellular bone marrow (Aspirate)

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Figure 6: Hypocellular marrow spaces with few erythroid cells (biopsy)

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Chimerism study on the bone marrow specimen showed that 49% cells show XX pattern (female donor) and 51% cells show XY pattern (patient).

Based on the clinical picture, histology, and bone marrow findings, a diagnosis of acute GVHD with dermal sclerodermoid features was made. The patient was treated with methylprednisolone and intravenous basiliximab. Immunosuppression was continued. Despite aggressive treatment, the patient continued to deteriorate and died within a week of presentation due to multiorgan failure.

  Discussion Top

GVHD in OLT is rare but has a mortality rate of 85%.[1],[4],[7] In OLT, immunocompetent donor-derived lymphocytes undergo activation following exposure to recipient-derived antigens. Activated donor T-lymphocytes mediate an immune response against recipient tissue.[7] The target tissues in GVHD following OLT are the bone marrow, skin, and the gut, with notable sparing of the liver.[7]

The pathogenesis of GVHD in OLT occurs in three continuous phases. In the first phase, surgery induces a pro-inflammatory state where host macrophages release tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1), resulting in increased host antigen-presenting cell activity. In the second phase, donor-derived T-lymphocytes residing in the donor's liver activate, stimulated by the HLA/peptide complex interactions, resulting in IL-2 receptor expression and clonal expansion, ultimately leading to the release of pro-inflammatory cytokines IL-2 and interferon gamma.[3],[7] In the third phase, anti-host T-cells release granzyme and perforin, leading to further inflammation and promotion of GVHD.[7],[8]

In OLT, GVHD presents 1–8 weeks after transplant.[1],[7] In 15% of cases, the patient presents with only dermatologic symptoms of rash involving the palms and soles, with eventual bullous transformation and desquamation.[6],[7] GVHD resulting in multisystem organ failure has an 85% mortality rate. The natural history of post-OLT GVHD is a relapsing-remitting pattern of diarrhea, rash, fever, and neutropenia, culminating in sepsis and death.[7] A diagnosis of GVHD after OLT is confirmed by biopsy of the affected tissues, which will demonstrate donor-derived lymphocytic infiltration in the appropriate clinicopathological setting.[5],[7]

GVHD should be suspected in symptomatic patients if chimerism is demonstrated by polymerase chain reaction or HLA typing of lymphocytes in the peripheral blood.[1],[5],[6] Early recognition requires thoughtful synthesis of the pathological, laboratory, and clinical data, and prompt treatment is essential.[5] There are no guidelines for the treatment of post-OLT GVHD. Current therapy is borrowed from GVHD treatment following HSCT and consists of immunosuppression with high doses of corticosteroids or calcineurin inhibitors.[5],[7],[8] However, this is frequently complicated by toxicity and infections.[5],[6],[7],[8],[9] Salvage therapies in steroid-refractory GVHD after OLT are mostly ineffective. Administration of OKT3 or anti-thymocyte globulin (ATG) produces a profound immunosuppression but is not associated with remission and frequently results in fatal infections.[5],[7] Targeting T-lymphocytes with daclizumab and basiliximab are associated with remission of skin GVHD but are usually inadequate in suppressing gut GVHD.[5],[7] Anti-TNFα agents are also not effective in treating GVHD and are associated with fungal infections.[4],[9]

Decreasing immunosuppression following LT allows host lymphocytes to regain activity against donor lymphocytes with the risk of graft rejection.[4],[6],[9] Finally, T-lymphocyte elimination with ATG or irradiation has not proven to be worthwhile due to the unknown risk of impairing engraftment.[1],[7],[10] Extracorporeal photopheresis has been effective in GVHD following HSCT and is regarded as a second-line treatment, resulting in response rates as high as 80% and up to 50% long-term survival, but its role in post-LT GVHD is not clear.[9],[11],[12]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Faraci M, Caviglia I, Biral E, Morreale G, Giardino S, Garbarino L, et al. Acute graft-versus-host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single-center experience during 10 yr. Pediatr Transplant 2012;16:887-93.  Back to cited text no. 1
Burdick JF, Vogelsang GB, Smith WJ, Farmer ER, Bias WB, Kaufmann SH, et al. Severe graft-versus-host disease in a liver-transplant recipient. N Engl J Med 1988;318:689-91.  Back to cited text no. 2
Chen XB, Yang J, Xu MQ, Wen TF, Yan LN. Unsuccessful treatment of four patients with acute graft vs. host disease after liver transplantation. World J Gastroenterol 2012;18:84-9.  Back to cited text no. 3
Rogulj IM, Deeg J, Lee SJ. Acute graft versus host disease after orthotopic liver transplantation. J Hematol Oncol 2012;5:50.  Back to cited text no. 4
Perri R, Assi M, Talwalkar J, Heimbach J, Hogan W, Moore SB, et al. Graft vs. host disease after liver transplantation: A new approach is needed. Liver Transpl 2007;13:1092-9.  Back to cited text no. 5
Taylor AL, Gibbs P, Sudhindran S, Key T, Goodman RS, Morgan CH, et al. Monitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation. Transplantation 2004;77:441-6.  Back to cited text no. 6
Post GR, Black JS, Cortes GY, Pollack RB, Wolff DJ, Lazarchick J, et al. The utility of fluorescence in situ hybridization (FISH) analysis in diagnosing graft versus host disease following orthotopic liver transplant. Ann Clin Lab Sci 2011;41:188-92.  Back to cited text no. 7
Kitko CL, Levine JE. Extracorporeal photopheresis in prevention and treatment of acute GVHD. Transfus Apher Sci 2015;52:151-6.  Back to cited text no. 8
Perotti C, Sniecinski I. A concise review on extracorporeal photochemotherapy: Where we began and where we are now and where are we going! Transfus Apher Sci 2015;52:360-8.  Back to cited text no. 9
Korngold R, Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Med 1978;148:1687-98.  Back to cited text no. 10
Richter HI, Stege H, Ruzicka T, Soehngen D, Heyll A, Krutmann J. Extracorporeal photopheresis in the treatment of acute graft-versus-host disease. J Am Acad Dermatol 1997;36:787-9.  Back to cited text no. 11
Malagola M, Cancelli V, Skert C, Leali PF, Ferrari E, Tiburzi A, et al. Extracorporeal photopheresis for treatment of acute and chronic graft versus host disease: An Italian multicentric retrospective analysis on 94 patients on behalf of the Gruppo Italiano Trapianto di Midollo Osseo. Transplantation 2016;100:e147-55.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]


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