Graft versus host disease after liver transplantation: A case report.

Graft Versus Host Disease (GVHD) is a severe immunological-clinicopathological condition mediated by healthy T-lymphocytes in donor tissue against the immunosuppressed host tissue and rarely seen after solid organ transplantation (SOT). A 72-year old male patient underwent cadaveric liver transplantation. On day 34 of the postoperative follow-up, the patient developed fever, generalized skin rash and hemorrhagic lesions in the oropharynx. Skin biopsy was consistent with GVHD. Despite high-dose corticosteroid treatment, he died on postoperative day 51. Although it is seen rarely after liver transplantation, GVHD is an important clinical entity for which early diagnosis is critical due to its high rates of mortality. © Copyright 2022 by Hepatology Forum - Available online at www.hepatologyforum.org.

Introduction

Graft versus Host Disease (GVHD) is a rare complication of hematopoietic stem cell transplantation. It is a clinical syndrome mediated by healthy T-lymphocytes in the donor tissue, which indicates severe immunological reaction against host tissues and consequent organ dysfunction. This rare condition may develop much less frequently after liver transplantation (LT). The incidence is 0.06-2% with a mortality rate over 75%. It usually develops 2 and 6 weeks after LT.[ It gives clinical symptoms with fever, rash, diarrhea and cytopenia. Generally, liver function tests are not affected. Currently, high-dose corticosteroids are usually administered, although there is no effective treatment. The report herein presents a patient with GVHD who developed following deceased donor LT (DDLT).

Case Report

A 72-year old male patient underwent cadaveric liver transplantation in March 2018 due to cryptogenic liver cirrhosis and hepatocellular carcinoma (HCC). The donor was a 56-year old AB Rh (+) female with a history of surgery due to a lesion in the posterior fossa (pathology consistent with epidermal cyst). Brain death had occurred due to sudden-onset increased intracranial pressure and her liver had been transplanted. The recipient’s explant pathology revealed moderately differentiated nodular-infiltrative HCC of 2 cm and autoimmune hepatitis in the non-tumor areas of the liver.

On day 34 of the recipient’s postoperative follow-up under ongoing tacrolimus and steroid treatment, the fever, generalized skin rash and hemorrhagic lesions in the oropharynx developed (Fig. 1). Pancytopenia developed and gradually deepened. He was not receiving mycophenolate mofetil therapy. Also, CMV DNA was negative. Skin biopsy revealed parakeratosis in focal epidermis regions, mild acanthosis, abundant dyskeratotic cells, occasional apoptotic cells in the basal layer, hydropic degeneration, vascular proliferation in the upper dermis, pigment-loaded macrophages and few lymphocytes around some of the vessels. PAS-AB staining was insignificant. The available findings and clinical presentation of the patient, along with hematology and dermatology consultations, led to a GVHD-Grade II result.

Figure 1.

Generalized skin rash and haemorrhagic lesions in oropharynx.

Pulse steroid treatment and plasmapheresis were administered due to the presence of GVHD. Tacrolimus treatment was discontinued. Diarrhea developed in the follow-up of the patient and no significant findings were noted in the stool analysis. PRA Class I and II antigens were found to be negative in the patient. The patient’s blood test results after LT are shown in Table 1. Despite the high-dose steroid treatment and supportive treatments (G-CSF, erythrocyte or platelet replacement), the patient died on the postoperative day 51.

Table 1.

The patient’s post-LT blood test results

Post-LT	AST	ALT	LDH	CRP	HB	PLT	WBC	NEUT	LYMP
Day 0Day 7Day 14Day 21Day 28Day 34Day 35Day 36Day 37Day 38Day 39Day 40Day 41Day 42Day 43Day 44Day 45Day 46Day 47Day 48Day 49Day 50Day 51	43881171074563670156482013108998966621	2062419991917153193624431191287663242	58816514513213589211219819141091806629483423377392498512461337289310371	33.930.427.28.211.9116.4115.254.253.670.9240.1139.9126.51187040.163.3101.75025.621.848.1337.9	1011.411.4111110.48.17.27.47.77.59.28.78.17.17.79.59.28.97.16.68.18.2	5910731326113953342325272223171474322113314241110	302011110133001152092204320278015801040250110504030307070502030702030	1790874010720967079303000125071047050100100000000000	610900112011204007809008305202001004040404000000000

LT: Liver transplantation; AST: Aspartat aminotransferase; ALT: Alanin aminotransferase; LDH: Lactate dehydrogenase; CRP: C-reactive protein; Hb: Hemoglobin; PLT: Platelet; WBC: White blood cell; Neut: Neutrophil; LYMP: Lymphocyte.

Discussion

Graft Versus Host Disease (GVHD) is a severe immunological-clinicopathological condition mediated by the healthy T-lymphocytes in donor tissue against the immunosuppressed host tissue. GVHD was first described by Billingham in 1966. Immunocompetent cells of the donor are defined as cells that react against the recipient antigen. There are 3 conditions required for GVHD to develop; in order for the graft to generate an antigenic stimulus in the recipient. It must contain immunoblot cells, contain foreign tissue compatibility antigens, the recipient must be immunosuppressed and unable to respond to foreign lymphoid cells.[

In the pathogenesis of GVHD after solid organ transplantation, donor suppressive and cytotoxic T cells as well as lymphocyte-secreting helper T lymphocytes are involved in response to receptor cells. The possibility of GVHD development after SOT varies depending on the amount of lymphoid tissue present in the organs. Accordingly, GVHD is more common in the pancreas-spleen and small intestine after more lymphoid tissue.[

Tissue compatibility antigens are glycoprotein structures on the surface of nucleated cells. These antigens are encoded by various genes on different chromosomes. The major tissue compatibility antigens, the most important ones, are encoded in the HLA region on the short arm of chromosome 6. It’s stated that graft versus host disease can develop even in transplants performed between individuals with fully compatible HLA antigens. This suggests that minor tissue antigens also play a role in graft versus host reaction.[

The probability of GVHD development in solid organ transplantation varies depending on the amount of lymphoid tissue present in the organs. According to this, GVHD is more common in the pancreas-spleen and small bowel transplantation where lymphoid tissue is abundant.[

The risk of GVHD increases as the recipient age increases. Thymus tissue is more deficient in elderly patients than in younger patients, allowing the formation of GVHD-inducing T cell clones. The risk of GVHD is higher in male patients who receive bone marrow, especially from a female donor. The role of the mechanism of the Y antigen in male patients.[

In acute GVHD, on immunofluorescent examination, 39% of cases had IgM deposition in the dermo-epidermal region, as well as Ig and C3 deposition in the perivascular region. Biopsy specimens of patients with acute GVHD showed significant CD4 and CD8 T lymphocytes as well as CD 56 NK cells.[

Although studies in the literature are mostly on post-bone marrow transplantation and it is stated that CMV seropositivity in both donor and the recipient increases the risk of GVHD development.[

In a review of 61 studies covering 87 patients, pancytopenia showed that the age difference between donor and recipient, the diagnosis of initial symptoms, or the time to start of treatment was statistically significant.[

Glucocorticoids reduce the number and function of lymphocytes. In the treatment of acute GVHD, it is generally recommended to initiate high-dose pulse therapy or at a dose of 2 mg /kg /day in moderate to advanced patients. Approximately 50% of patients with Grade II and IV respond to systemic corticosteroid therapy and 25% of patients had a complete recovery. Cyclosporine and ATG can be added to the treatment in patients without steroid response.

Conclusion

Although seen rarely after liver transplantation, GVHD is an important clinical entity for which early diagnosis is critical due to the high rates of mortality. Our case is presented to raise awareness because of the development of GVHD after SOT, its confusion with other rare post-transplant conditions, and the need for early treatment. Studies to continue to reduce the mortality rate with the effectiveness of the new generation of drugs.