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Table of Contents
Year : 2019  |  Volume : 37  |  Issue : 4  |  Page : 213-216

Graft-versus-host disease after orthotopic liver transplantation: A case report and review of the literature

1 Department of Dermatology, Chang Gung Memorial Hospital, Keelung; College of Medicine, Chang Gung University, Taoyuan, Taiwan
2 Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan

Date of Submission11-Sep-2018
Date of Decision19-Dec-2018
Date of Acceptance12-Feb-2019
Date of Web Publication16-Dec-2019

Correspondence Address:
Dr. Ching-Sheng Yang
Department of Dermatology, Chang Gung Memorial Hospital, No. 5 Fusing St., Taoyuan 333
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_2_19

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Graft-versus-host disease (GVHD) after liver transplantation (LT) is a rare complication with high mortality and is clinically characterized by fever, skin rash, and diarrhea. The clinical manifestations of GVHD after LT are nonspecific and may resemble viral infection or adverse drug reaction, posing a diagnostic and therapeutic challenge. We report a 60-year-old male who presented with generalized erythematous to violaceous macules and papules accompanied by fever and diarrhea after orthotopic LT. A skin biopsy and human leukocyte antigen typing of peripheral blood confirmed a Grade 2 GVHD. Clinical manifestations and diagnosis of GVHD following LT are discussed. While potentially under-recognized, clinicians should be aware of this rare but potentially fatal complication, as prompt intervention may improve outcomes in LT.

Keywords: Chimerism, graft-versus-host disease, liver transplantation

How to cite this article:
Chen WT, Kuo TT, Kuo KL, Yang CS. Graft-versus-host disease after orthotopic liver transplantation: A case report and review of the literature. Dermatol Sin 2019;37:213-6

How to cite this URL:
Chen WT, Kuo TT, Kuo KL, Yang CS. Graft-versus-host disease after orthotopic liver transplantation: A case report and review of the literature. Dermatol Sin [serial online] 2019 [cited 2022 Dec 5];37:213-6. Available from: https://www.dermsinica.org/text.asp?2019/37/4/213/273097

  Introduction Top

Unlike graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), GVHD after liver transplantation (LT) is a rare complication.[-3] GVHD develops when donor T-cells recognize cells from the recipient tissue as foreign antigens and initiate an immune attack on multiple organ systems. Solid organ transplants, such as small intestine or liver, contain more immunocompetent donor lymphocytes and are associated with a higher incidence of GVHD (5%–6% and 1%–2%, respectively).[4] The mortality rate for GVHD of LT has been reported to be up to 85%.[1] Prompt diagnosis for early intervention of GVHD after LT is difficult and challenging because the cutaneous manifestations are nonspecific and may mimic viral exanthem or adverse drug eruption.[5] We report a case of a 60-year-old man with acute GVHD after orthotopic LT.

  Case Report Top

A 60-year-old man visited the emergency department for generalized malaise, pruritic rashes, and fever for 1 week. He had a history of chronic hepatitis B with cirrhosis and stage three chronic kidney disease and received orthotopic LT for end-stage liver failure 1 month ago. The patient began receiving posttransplantation oral tacrolimus and prophylactic entecavir use since 1 month ago. On examination, he had a fever of 38.9°C and hyperpigmented oval-to-round macules and papules diffusely scattered on four limbs, especially on hands and feet [Figure 1]a, [Figure 1], [Figure 1]c. The initial impression was acute GVHD, but viral exanthem and drug reaction with eosinophilia and systemic symptoms were also considered. While the patient had a history of tacrolimus and entecavir drug use, both medications had low notoriety for cutaneous adverse reactions[6],[7] and had been used for over 1 month, and thus, drug reaction was less favored.
Figure 1: Cutaneous manifestation and histopathologic findings of graft-versus-host disease after liver transplantation. Hyperpigmented oval-to-round macules and papules diffusely scattered on four limbs, especially hands and feet (a-c). Biopsy showed mild acanthosis with dyskeratotic cells, exocytosis, vacuolar degeneration of basal cells, melanin incontinence, and lymphocytes at interface and around dermal vessels (d)

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Laboratory data were remarkable for leukopenia (1100 cells/mm3 with 79% neutrophils and 1% eosinophils), decreased platelet count (121,000 cells/mm3), and anemia (8.3 g/dL). Elevated serum creatinine level was noted, consistent with his baseline chronic kidney disease, while liver enzyme was within normal limit. Blood, stool, and urine cultures were negative. Serology and polymerase chain reaction (PCR) for cytomegalovirus (CMV), Epstein–Barr virus (EBV), and herpes simplex virus was negative. To confirm the diagnosis of GVHD, skin biopsy and human leukocyte antigen (HLA) typing of peripheral blood lymphocyte were performed. The biopsy specimen showed mild acanthosis with dyskeratotic cells, exocytosis, vacuolar degeneration of basal cells, melanin incontinence, and lymphocytes at the interface and around dermal vessels [Figure 1]d, which were consistent with Grade 2 GVHD. The HLA typing of peripheral blood lymphocytes also identified chimerism. Based on these findings, a diagnosis of GVHD was established.

Pulse steroid therapy combined with increased immunosuppressants with titrated dose of tacrolimus and newly added everolimus were given. Valganciclovir and entecavir were also used for prophylaxis of CMV infection and prevention of hepatitis B virus reactivation, respectively. Patient's GVHD was temporarily controlled, and he was discharged from our hospital. However, the patient subsequently was diagnosed with Pneumocystis jiroveci pneumonia with sepsis 1 month later and eventually expired due to multiple organ failure.

  Discussion Top

GVHD is a multisystem disease that can occur after blood, bone marrow, or solid organ transplantation. GVHD after solid organ transplantation is rare but has a potentially lethal complication, especially in LT.[4] GVHD occurs between 2 and 8 weeks after LT and often involves multiple organs, including the skin, gastrointestinal tract, and hematopoietic tissue.[1],[2] Skin rashes are usually the first manifestation, developing on an average of 48.3 days.[8] A systematic review by Kim et al. described the dermatologic manifestations of GVHD as highly variable.[9] Patients may present with pruritic erythematous to violaceous macules and papules with desquamation. The most common gastrointestinal symptom of GVHD is diarrhea caused by the destruction of the intestinal mucosa but can also be secondary to infectious causes or medications such as mycophenolate mofetil.[10],[11] Because the transplanted liver is the source of the donor T-lymphocytes, impaired liver function is not common.[12] However, pancytopenia is regularly seen in patients with GVHD after LT.[11] Normal liver function and presence of pancytopenia differentiate GVHD after LT from GVHD after HSCT.[11],[13] Differences between acute GVHD after LT and HSCT are described in [Table 1]. It is worth noting that pancytopenia and diarrhea have also been shown to be poor prognostic factors for GVHD after LT.[11]
Table 1: Differences between acute graft-versus-host disease after liver transplantation and hematopoietic stem cell transplantation

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There are two risk factors that have been identified for GVHD after LT, including HLA matching between donor and recipient and an immunocompromised state in the recipient. Recipients receiving a well-matched graft have an increased risk of developing GVHD, especially in cases with one-way donor-recipient HLA-matching.[1],[14],[15] The plausible mechanism is because alloreactive donor lymphocytes from a well-matched graft are less likely to be rapidly destroyed in the recipient.[16] An immunocompromised state in the recipient, including old age, previous immunosuppression, and diabetes mellitus, has been shown to be another risk factor.[17] Previous studies showed that patients >65 years at the time of LT were nine times more likely to develop GVHD than those aged <65 years.[1]

Viral exanthem and drug eruption should be considered in the differential diagnoses because clinical and histopathologic features resemble the cutaneous manifestations of acute GVHD after LT. Opportunistic viral infections after transplantation, including CMV, EBV, and human herpes virus, can be detected by serology and PCR. Specific histopathologic findings of skin biopsy, such as intranuclear inclusions in CMV infection, may be useful for distinguishing viral diseases from GVHD.[18] However, it is difficult to differentiate viral exanthem from GVHD if no serologic and histopathologic evidence of viral infections are detected. Therefore, prophylaxis with antiviral agents should be given in consideration of potential viral infection.[18] To evaluate potential adverse drug eruption, comprehensive review of drug history needs to be taken for the assessment of drug causalities, such as ALDEN algorithm of drug causality assessment and the Naranjo algorithm.[19],[20]

Skin biopsy and HLA typing of peripheral blood is helpful in making the diagnosis of GVHD after LT. Skin biopsy showing epidermal dyskeratosis with vacuolar degeneration of basal cells, exocytosis of lymphocytes, and melanin incontinence is highly suggestive of GVHD. Vacuolar interface changes can also be present around the hair follicle.[21] However, the histopathologic features in skin are not pathognomonic for GVHD and are also present in drug eruptions. The identification of chimerism, which is defined as the presence of cells expressing donor antigens, in the peripheral blood is a useful early diagnostic aid.[22] In addition, serial detection of the chimerism can predict evolving GHVD.[23] In addition, fluorescence in situ hybridization with specific probes for the sex chromosomes to monitor the recipient to donor ratio is an alternative method for confirming the diagnosis of GVHD.[24]

Till date, there is no standardized treatment for GVHD after LT. High-dose or pulse steroid therapy is used as the first-line treatment of acute GVHD after LT.[25] Unfortunately, GVHD after LT is less responsive to corticosteroids than GVHD after HSCT. The combination with nonsteroid immunosuppression has also been used, including anti-thymocyte globulin or other immunosuppressants. Therapy with monoclonal antibodies, interleukin-2 and interleukin-12 antagonists and tumor necrosis factor-alpha inhibitors, may also play potential roles in future management.[17],[26],[27] Despite these interventions, the mortality rate of GVHD after LT still remains high.

In summary, we report a case of GVHD occurring 1 month after orthotopic LT. The diagnosis of GVHD after LT was based on the clinical manifestation, histopathological evidence, and demonstration of chimerism. Taiwan has a large number of LTs, with approximately 3000 cases between 2003 and 2012.[28] Given the estimated incidence of GVHD and the volume of LTs in Taiwan, this entity is likely under-diagnosed and under-reported. Therefore, clinicians should be aware of this rare but potentially fatal complication, as prompt detection and management of GVHD can contribute to better outcomes in LT.

Ethical approval

The study was approved by the Institutional Review Board of Chang Gung Medical Foundation, in compliance with Taiwanese law (IRB no. 201901670B0).

Declaration of patient consent

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

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Conflicts of interest

There are no conflicts of interest

  References Top

Smith DM, Agura E, Netto G, Collins R, Levy M, Goldstein R, et al. Liver transplant-associated graft-versus-host disease. Transplantation 2003;75:118-26.  Back to cited text no. 1
Taylor AL, Gibbs P, Bradley JA. Acute graft versus host disease following liver transplantation: The enemy within. Am J Transplant 2004;4:466-74.  Back to cited text no. 2
Ball LM, Egeler RM; EBMT Paediatric Working Party. Acute GvHD: Pathogenesis and classification. Bone Marrow Transplant 2008;41 Suppl 2:S58-64.  Back to cited text no. 3
Sharma A, Armstrong AE, Posner MP, Kimball PM, Cotterell AH, King AL, et al. Graft-versus-host disease after solid organ transplantation: A single center experience and review of literature. Ann Transplant 2012;17:133-9.  Back to cited text no. 4
Zhang Y, Ruiz P. Solid organ transplant-associated acute graft-versus-host disease. Arch Pathol Lab Med 2010;134:1220-4.  Back to cited text no. 5
Mockenhaupt M. Drug Notoriety; 2017. Available from: http://www.regiscar.org/pdf/DrugNotoriety2015.xls. [Last accessed on 2018 Dec 19].  Back to cited text no. 6
Kim JT, Jeong HW, Choi KH, Yoon TY, Sung N, Choi YK, et al. Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B. World J Gastroenterol 2014;20:15931-6.  Back to cited text no. 7
Pollack MS, Speeg KV, Callander NS, Freytes CO, Espinoza AA, Esterl RM, et al. Severe, late-onset graft-versus-host disease in a liver transplant recipient documented by chimerism analysis. Hum Immunol 2005;66:28-31.  Back to cited text no. 8
Kim GY, Schmelkin LA, Davis MD, El-Azhary RA, Farrell AM, Meves A, et al. Dermatologic manifestations of solid organ transplantation-associated graft-versus-host disease: A systematic review. J Am Acad Dermatol 2018;78:1097-101.  Back to cited text no. 9
Calmet FH, Yarur AJ, Pukazhendhi G, Ahmad J, Bhamidimarri KR. Endoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation. Ann Gastroenterol 2015;28:366-73.  Back to cited text no. 10
Akbulut S, Yilmaz M, Yilmaz S. Graft-versus-host disease after liver transplantation: A comprehensive literature review. World J Gastroenterol 2012;18:5240-8.  Back to cited text no. 11
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Lee SE, Cho BS, Kim JH, Yoon JH, Shin SH, Yahng SA, et al. Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant 2013;48:587-92.  Back to cited text no. 13
Kiuchi T, Harada H, Matsukawa H, Kasahara M, Inomata Y, Uemoto S, et al. One-way donor-recipient HLA-matching as a risk factor for graft-versus-host disease in living-related liver transplantation. Transpl Int 1998;11 Suppl 1:S383-4.  Back to cited text no. 14
Whitington PF, Rubin CM, Alonso EM, McKeithan TW, Anastasi J, Hart J, et al. Complete lymphoid chimerism and chronic graft-versus-host disease in an infant recipient of a hepatic allograft from an HLA-homozygous parental living donor. Transplantation 1996;62:1516-9.  Back to cited text no. 15
Parham P, McQueen KL. Alloreactive killer cells: Hindrance and help for haematopoietic transplants. Nat Rev Immunol 2003;3:108-22.  Back to cited text no. 16
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Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: Comparison with case-control analysis. Clin Pharmacol Ther 2010;88:60-8.  Back to cited text no. 20
Kim GY, Schmelkin LA, Davis MD, El-Azhary RA, Wieland CN, Leise MD, et al. Clinical and histopathologic manifestations of solid organ transplantation-associated graft-versus-host disease involving the skin: A single-center retrospective study. J Cutan Pathol 2018;45:817-23.  Back to cited text no. 21
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. 22
Garcia J, Beduschi T, Ruiz P, Tekin A, Fan J, Nishida S, et al. Chimerism for Early Detection of Graft Versus Host Disease in Intestinal Transplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/chimerism-for-early-detection-of-graft-versus-host-disease-in-intestinal-transplantation/. [Last accessed on 2019 Oct 28].  Back to cited text no. 23
Kanehira K, Riegert-Johnson DL, Chen D, Gibson LE, Grinnell SD, Velgaleti GV, et al. FISH diagnosis of acute graft-versus-host disease following living-related liver transplant. J Mol Diagn 2009;11:355-8.  Back to cited text no. 24
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  [Figure 1]

  [Table 1]


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