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Table of Contents
CASE REPORT
Year : 2018  |  Volume : 12  |  Issue : 3  |  Page : 213-215

Graft versus host disease occurring in living donor liver transplant


1 Department of Histopathology, SRL Ltd, Fortis Escorts Okhla, New Delhi, India
2 Department of Hepatology, Fortis Escorts Okhla, New Delhi, India
3 Department of Liver Transplant Surgery, Fortis Escorts Okhla, New Delhi, India

Date of Web Publication28-Sep-2018

Correspondence Address:
Dr. Nalini Bansal
C6/18 Iind Floor, Ardee City, Sector 52, Gurgaon - 122 003, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_17_18

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  Abstract 


Graft versus host disease (GVHD) is a serious disease occurring posttransplant. Most cases are seen after hematopoietic bone marrow/stem cell transplantation where the donor cells recognize host antigens and start reacting against them. The initial organs to be involved are skin, gut, and liver. Patients can present with maculopapular rashes, diarrhea, or jaundice. Early diagnosis and timely institution of therapy may salvage these patients. GVHD is rarely also identified in solid organ transplantation seen frequently with small bowel transplantation. Cases of GVHD after liver transplantation are very rare. We herein describe a case of GVHD following a deceased donor liver transplant with a review of pathophysiology of GVHD in liver transplant.

Keywords: GVHD, liver, graft versus host disease, liver transplant


How to cite this article:
Bansal N, Wadhawan M, Vij V. Graft versus host disease occurring in living donor liver transplant. Indian J Transplant 2018;12:213-5

How to cite this URL:
Bansal N, Wadhawan M, Vij V. Graft versus host disease occurring in living donor liver transplant. Indian J Transplant [serial online] 2018 [cited 2018 Dec 11];12:213-5. Available from: http://www.ijtonline.in/text.asp?2018/12/3/213/242423




  Introduction Top


Graft versus host disease (GVHD) occurring after liver transplant is very rare accounting for only 0.1%–2% cases. Liver being a rich organ in lymphocyte population can rarely lead to GVHD. It occurs if there is presence of antigens in host cells which are not seen in donor. After transplantation, the donor lymphocytes residing within the grafted organ can recognize antigens in the recipient body and can elicit a GVHD. As the hepatocytes remain largely unaffected, the patients present with pancytopenia with relatively normal liver function tests.


  Case Report Top


We report a case of a 60-year-old male who was a follow up case of liver transplant (cadaveric) done on June 2016 at an outside hospital for cryptogenic cirrhosis with hepatocellular carcinoma (HCC). He had received valganciclovir for 2 weeks previously for Cytomegalovirus infection. He presented with complaints of bleeding per rectum, two episodes on July 2016. His blood investigation showed hemoglobin of 6.8 mg%, total leukocyte count 100/mm3, and low platelet count. The patient was resuscitated and taken up for endoscopy. Side viewing endoscopy done the next day showed fresh blood coming from ampulla. Ultrasonography Doppler done showed a pseudoaneurysm arising from hepatic artery and was taken up for digital subtraction angiography with a plan of arterial stenting. During the procedure, pseudoaneurysm was seen arising from hepatic artery anastomotic site and he underwent hepatic artery reconstruction with inflow achieved from gastroduodenal artery with extension arterial graft and Roux-en-Y hepaticojejunostomy. The patient was extubated on the next postoperative day (POD). Vitals remained stable, and his nasogastric tube was removed on POD 3 and was allowed orally. Postoperatively, the patient had persistently low white blood cell (WBC) and platelet counts. Granulocyte-monocyte colony-stimulating factor (GM-CSF) was given and showed a rise in WBC count (maximum 3100/cumm) only and decline once it was discontinued. His platelet count remained low [Table 1]. Hematology consultation was taken and advice followed. He had evidence of paralytic ileus which was managed by restricting oral diet. Contrast-enhanced computed tomography done showed dilated small bowel loops suggestive of paralytic ileus. The hepatic arterial flow was normal and minimal bilateral pleural effusion.
Table 1: Laboratory investigation of the patient

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On POD 14th, the patient had an episode of breathlessness and fall in blood pressure. He was started on ionotropic support and noninvasive ventilation. In view of sepsis, antibiotics were upgraded (meropenem and colistin) and antifungals added. His immunosuppression was withheld and continued on intravenous (IV) steroids. He also developed rash over his body along with palmar rashes [Figure 1]. Dermatology consultation was taken and skin biopsy was done. His skin biopsy tissue revealed features of GVHD with presence of apoptotic keratinocytes, leukocytic extravasation, and basal cell vacuolization [Figure 2]a and [Figure 2]b. There were areas of papillary dermal fibrosis which was highlighted on Masson's trichrome stain [Figure 2]c.
Figure 1: (a and b) Maculopapular rashes over the body and palm

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Figure 2: (a and b) Skin biopsy showing apoptotic keratinocytes (H and E, ×10, ×40), (c) papillary dermal fibrosis (MT, ×20)

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Skin biopsy features were those of likely GVHD with both features of acute and chronic feature. Because of his worsening clinical condition (POD 16th), he was intubated and electively ventilated and extubated after 3 days. In view of GVHD, he received two doses of IV immunoglobulin. GM-CSF was also given, but his WBC count remained low. Despite all supportive measures, patient's general condition kept on deteriorating, requiring high inotropic and ventilator support. Next day, the patient developed asystole, and despite all available resuscitative measures, he succumbed to his illness.


  Discussion Top


GVHD is a grave complication occurring posttransplant carrying high morbidity and mortality. Occurrence of GVHD is universal in recipient of allogeneic bone marrow transplantation in the absence of conditioning or prophylaxis given before transplant. The reason is that the transplantation of lymphocytes/stem cells will identify antigens on the host tissue and cause donor T-cell activation, release of cytokines, leading to a cytokine storm. The released cytokines than attack various organs of the host commonly being skin, gut, and liver. Human leukocyte antigen (HLA) mismatching is the main cause of GVHD. Presence of extra antigen on recipient cells is the major cause of GVHD. National Institute of Health 2014 has recently given recommendations for GVHD grading and staging.[1]

Diagnostic categories for histopathology reporting have been defined as no GVHD, possible GVHD, and likely GVHD. No GVHD means no evidence of GVHD on biopsy tissue. Possible GVHD is diagnosed in the presence of confounding factors and likely GVHD with clinical and histological features is concordant with the diagnosis.

Different histological grading systems have been utilized for grading of skin and gut GVHD. However, hepatic GVHD are not graded histologically. Skin and gut GVHD are graded from 0 to 4.[1]

Graft versus host disease in liver transplantation

Occurrence of GVHD is very rare after liver transplantation (LT) with about 163 cases being reported in the literature. The incidence varies from 0.1% to 2%.[2],[3]

The pathogenesis of GVHD in LT occurs in three continuous phases. First is a pro-inflammatory state where host macrophages release tumor necrosis factor α and interleukin (IL)-1, resulting in increased host antigen-presenting cell activity. In the second phase, donor-derived T-lymphocytes present in the donor liver activate, stimulated by 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-γ. In the third phase, anti-host T-cells, especially CD8 T-cells, release granzyme and perforin, leading to further inflammation and promotion of GVHD.

Murali et al. reviewed the data for 156 patients with GVHD after LT.[4] The alloreactive donor lymphocytes engraft and proliferate in the recipient bone marrow and start an immune-mediated attack on hematopoietic stem cells, resulting in pancytopenia with relative sparing of liver function tests.

Median time to GVHD onset from LT was 28 days (interquartile range 21–38 days). Our case presented 8 weeks posttransplant. The higher the load of unmatched donor lymphocytes in the grafted organ the higher are the chances of GVHD. Major risk factors noted for the development of GVHD include older age, donor-recipient age difference >20 years, presence of HCC, younger donor age, any HLA Class I mis match, and glucose.

Diagnosis relies on combination of clinical, histological, and serological findings. Histology of GVHD in liver transplant is similar to that seen due to hematopoietic transplants.

Patients with GVHD usually show donor lymphocyte macrochimerism, i.e., presence of both donor and recipient lymphocytes in recipient blood (>1% donor lymphocyte chimerism) in the recipient tissues (skin, gastrointestinal mucosa, peripheral blood), ranging from 1% to 80%.[5]

High ferritin in GVHD patients was noted in a case series by Murali et al. in five patients. Our case also had high ferritin levels.

Prognosis of GVHD postliver transplant remains dismal with a mortality of about 85%.[6]

The management of GVHD after LT is mostly derived from treatment of GVHD following hematopoietic stem cell transplantation.[7]

The most frequently reported treatment regimen for GVHD after LT was high-dose steroids (ranging from 2 mg/kg/day to 20 mg/kg/day).[4]

Extracorporeal photopheresis is effective in post hematopoietic stem cell GVHD but has only rarely been used for solid organ transplant-associated GVHD, with only one reported survivor thus far.[8]

GVHD after liver transplant is thus a rare phenomenon. The resident lymphocytes in the donor organ are central to the pathogenesis of GVHD. The prognosis remains dismal despite therapy.

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Salomao M, Dorritie K, Mapara MY, Sepulveda A. Histopathology of graft-vs. Host disease of gastrointestinal tract and liver: An update. Am J Clin Pathol 2016;145:591-603.  Back to cited text no. 1
    
2.
Chan EY, Larson AM, Gernsheimer TB, Kowdley KV, Carithers RL Jr., Reyes JD, et al. Recipient and donor factors influence the incidence of graft-vs.-Host disease in liver transplant patients. Liver Transpl 2007;13:516-22.  Back to cited text no. 2
    
3.
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. 3
    
4.
Murali AR, Chandra S, Stewart Z, Blazar BR, Farooq U, Ince MN, et al. Graft versus host disease after liver transplantation in adults: A Case series, review of literature, and an approach to management. Transplantation 2016;100:2661-70.  Back to cited text no. 4
    
5.
Domiati-Saad R, Klintmalm GB, Netto G, Agura ED, Chinnakotla S, Smith DM, et al. Acute graft versus host disease after liver transplantation: Patterns of lymphocyte chimerism. Am J Transplant 2005;5:2968-73.  Back to cited text no. 5
    
6.
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. 6
    
7.
Collins RH Jr., Cooper B, Nikaein A, Klintmalm G, Fay JW. Graft-versus-host disease in a liver transplant recipient. Ann Intern Med 1992;116:391-2.  Back to cited text no. 7
    
8.
Brown TJ, Gentry C, Hammer ST, Hwang CS, Vusirikala M, Patel PA, et al. Novel application of extracorporeal photopheresis as treatment of graft-versus-host disease following liver transplantation. ACG Case Rep J 2017;4:e48.  Back to cited text no. 8
    


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