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  Table of Contents    
CASE REPORT  
Year : 2012  |  Volume : 55  |  Issue : 4  |  Page : 506-508
Mycophenolate mofetil-induced colitis with graft versus host disease-like features in a liver transplant recipient


1 Department of Pathology, Global Hospitals and Health City, Chennai, Tamilnadu, India
2 Department of Gastroenterology and Hepatology, Global Hospitals, Hyderabad, Andhra Pradesh, India

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Date of Web Publication4-Mar-2013
 

   Abstract 

Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug in the management of transplant recipients. Gastrointestinal (GI) toxicity (diarrhea) is the most frequently reported adverse event in MMF-treated transplant patients. MMF-induced Graft versus Host Disease has rarely been reported in literature. We report a case of MMF-induced colitis with Graft versus Host Disease-like features, to highlight the importance of high clinical suspicion for its diagnosis, and that appropriate management in such a setting can reduce morbidity and mortality. We also review the relevant literature.

Keywords: Gastrointestinal toxicity, liver transplant, mycophenolate mofetil, MMF-induced colitis, graft versus host disease-like features

How to cite this article:
Patra S, Vij M, Sukanya B, Kapoor D. Mycophenolate mofetil-induced colitis with graft versus host disease-like features in a liver transplant recipient. Indian J Pathol Microbiol 2012;55:506-8

How to cite this URL:
Patra S, Vij M, Sukanya B, Kapoor D. Mycophenolate mofetil-induced colitis with graft versus host disease-like features in a liver transplant recipient. Indian J Pathol Microbiol [serial online] 2012 [cited 2020 Dec 3];55:506-8. Available from: https://www.ijpmonline.org/text.asp?2012/55/4/506/107792



   Introduction Top


Mycophenolate mofetil (MMF) was introduced as a new immune-suppression drug in the mid 1990s. It is widely utilized in bone marrow and solid-organ transplantation immune-suppression regimens. [1] The side effects include marrow suppression and gastrointestinal (GI) toxicity, in the form of dyspepsia, nausea, vomiting, and diarrhea. Physicians tend to reduce the dose of MMF or switch their patients to an enteric-coated formula to overcome the side effects. The histological changes associated with the use of MMF have been reported as Crohn's disease-like changes in the colon, erosive or ischemic enterocolitis, and graft versus host disease-like colonic changes. [2],[3],[4],[5],[6] The colonic findings in a patient whose symptoms resolved after withdrawing MMF, are described in the present case report.


   Case Report Top


The present case concerns a 50-year-old male, who underwent living donor liver transplant (LDLT) at our center for nonalcoholic-related fatty liver disease (NAFLD), related end-stage liver disease in 2008. The patient was on triple immuno-suppression with steroids, MMF, and tacrolimus. Approximately eight months after the transplant, he presented to the Gastroenterology and Hepatology Department, with complaints of significant weight loss, sitophobia for five months, and a recent onset of bleeding per rectum. The general physical examination revealed pallor, evidence of recent weight loss, and a laparotomy scar. Liver Function Tests revealed good graft function with all parameters within normal limits. A complete hematological profile revealed anemia, leucopenia, and thrombocytopenia. Ultrasound of the abdomen showed thickened terminal ileum, with a normal graft. Colonoscopy was done and demonstrated ileal and cecal ulcers [Figure 1]a. Biopsies were taken. Histopathology revealed crypt dropout, with focal disarray of the crypt architecture, along with apoptosis of the crypt epithelial cells. The crypt epithelial apoptotic rate was greater than 5 / 100 crypts. The lamina propria was edematous and showed focal collection of mild lymphomononuclear inflammatory cell infiltrate [Figure 1]b and c, giving an empty appearance to the lamina propria. Adjoining crypt epithelium showed evidence of regeneration with hyperchromatic nuclei and mitosis. The report was communicated as MMF-induced colitis with graft versus host disease-like features. With this report, no alteration was made in the immunosuppression except for withdrawing MMF. This resulted in the resolution of symptoms within a week and healing of the ileal and cecal ulcers, which was confirmed on repeat colonoscopy after one month [Figure 1]d. Pancytopenia was also corrected. Thus, suggesting a causal association between MMF and apoptosis-induced crypt loss.
Figure 1: (a) Colonoscopy showing ulcer in the ileocecal region. (b) Mucosal biopsies crypt cell apoptosis with focal crypt distortion and dropout. (c) Prominent apoptosis in the crypt epithelium. (d) Repeat colonoscopy showing healing of ulcers

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   Discussion Top


Liver transplantation provides a means for patients with advanced liver disease to attain long-term survival, with a good quality of life. A growing number of agents are available to achieve immunosuppression in liver transplant recipients, including calcineurin inhibitors (CNIs), corticosteroids, MMF, and sirolimus. MMF is a pro-drug of mycophenolic acid (MPA), an antibiotic substance derived from Penicillium stoloniferum. MMF was approved by the Food and Drug Administration (FDA) in 2000, to prevent liver transplant rejection. [1]

This drug has led to a significant decrease in the incidence of acute allograft rejection in solid organ transplant patients. [7] The major clinical limitations of MMF are related to hematopoietic suppression and gastrointestinal toxicity. Although gastrointestinal (GI) toxicity is a known complication of MMF, literature characterizing the pathological features of MMF in the GI tract is sparse. [2],[3] Few earlier studies have described histological abnormalities in the colon associated with MMF, with graft versus host disease (GVHD)-like, inflammatory bowel disease (IBD), or Crohn-like changes, as well as, erosive or ischemic enterocolitis. [2],[3],[4],[5],[6] The case report by Kim and Park described a 49-year-old woman with diarrhea following renal transplantation, who was found to have mucosal ulcers, hyperemia, and edema during colonoscopy. The findings on biopsy were consistent with ischemic colitis. [6]

Mycophenolate mofetil is subject to near complete metabolic conversion to its active component, mycophenolic acid (MPA), within the liver. MPA is a potent inhibitor of inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis. By inhibiting inosine monophosphate dehydrogenase, MPA prevents the proliferation of T and B lymphocytes and the formation of antibodies from B cells. It may also inhibit the recruitment of leukocytes to the inflammatory sites. Although it selectively inhibits B and T lymphocyte proliferation, enterocytes are partially susceptible to MMF, and one of the main limitations of this drug is gastrointestinal (GI) toxicity. [8]

Morphologically, MMF colitis may demonstrate GVHD-like features, including a mild crypt architectural disturbance, edematous lamina propria, and increased apoptosis of crypt epithelial cells, with no increase in inflammation. An ischemia-like pattern shows crypt loss and atrophy along with mucin depletion. The lamina propria is devoid of significant inflammation. A self-limiting pattern shows preserved crypt architecture and the lamina propria shows an increased number of inflammatory cells containing many neutrophils. Neutrophilic infiltration of the crypts is seen. [3] The inflammatory bowel disease-like pattern shows dilated damaged crypts with moderate mucin depletion. A mild inflammatory infiltrate is present in the lamina propria. Dilated damaged crypts are characterized by cystically dilated crypts with flat or atrophic epithelial lining, sometimes showing regenerative atypia, and lumens that are either empty or contain sparse neutrophils or debris. The dilated damaged crypts, together with increased crypt epithelial apoptosis, suggest an acute or subacute phase of antimetabolite drug-induced epithelial injury, whereas, the crypt architectural disarray, with occasional crypt loss, suggests chronicity or previous episodes of injury with partial healing. [2],[3]

The histopathological features in colonic biopsies of patients on MMF were studied by Dalle et al. [3] They reported discontinuous crypt architectural changes, increased epithelial mucin secretion, mild active inflammation, focal dilated and inflammed crypts, but no increase in apoptosis. These changes were interpreted as being Crohn-like. Papadimitriou et al. found that apoptosis and enterocyte atypia, increased neuroendocrine cells, and architectural distortion was more prominent among MMF patients compared to the controls. [5] They also compared the findings in MMF patients with GVHD patients and IBD patients and concluded that MMF-related colitis was more similar to GHVD than IBD, but apoptosis was milder than in GVHD patients. Other isolated cases of pseudomembranous colitis and ischemic colitis attributed to MMF have also been reported in literature .[6],[9] Studies have shown that MMF may reduce the crypt proliferative index and may result in impaired healing of colonic anastomoses. [10]

The distinction between MMF-associated graft versus host disease-like changes and true graft versus host disease is of great clinical significance. Although graft versus host disease in solid organ transplant patients is uncommon, it can occur in patients within 12 weeks following transplantation. Solid organs contain immunologically competent cells from the donor that are transplanted into the recipient, which can then initiate an immune response against the recipient. Among these, the incidence of graft versus host disease is highest following small bowel transplant (about 5%), possibly due to a large number of donor lymphocytes in the transplanted organ. The treatment for MMF toxicity is to decrease the dosage of mycophenolate mofetil, and subsequently evaluate whether the patient's symptoms resolve. In contrast, the treatment for graft versus host disease is to increase immunosuppression with corticosteroids, and depending on the severity of the symptoms, add other immunosuppressive agents. [2],[3]

In conclusion, transplant hepatologists and pathologists should be aware of the potential manifestations of MMF-induced GI toxicity, including graft versus host disease like features. One should have a high index of suspicion for its diagnosis in the appropriate setting, to avoid management errors. Increased awareness among the pathologists about the morphological spectrum of MMF-induced GI toxicity is required, to avoid diagnostic errors.

 
   References Top

1.Ziriakus M. Hoffman-La Roche receives FDA approval to market CellCept for preventing liver transplant rejection. Transplant News. advance online publication August 28, 2000 (ISSN: 1090-4964).  Back to cited text no. 1
    
2.Selbst MK, AhrensWA, Robert ME, Friedman A, Proctor DD, Jain D.Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil.Mod Pathol 2009;22:737-43.  Back to cited text no. 2
    
3.Parfitt JR, Jayakumar S, Driman DK.Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes.Am J Surg Pathol 2008;32:1367-72.  Back to cited text no. 3
[PUBMED]    
4.Dalle IJ, Maes BD, Geboes KP, Lemahieu W, Geboes K. Crohn's-like changes in the colon due to mycophenolate? Colorectal Dis 2005;7:27-34.  Back to cited text no. 4
[PUBMED]    
5.Papadimitriou JC, Cangro CB, Lustberg A, Khaled A, Nogueira J, Wiland A, et al.Histologic features of mycophenolate mofetil-related colitis: A graft-versus-host disease-like pattern. Int J Surg Pathol 2003;11:295-302.  Back to cited text no. 5
[PUBMED]    
6.Kim HC, Park SB. Mycophenolate mofetil-inducedischemic colitis. Transplant Proc 2000;32:1896-7.  Back to cited text no. 6
[PUBMED]    
7.European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321-5.  Back to cited text no. 7
[PUBMED]    
8.Behrend M.Adverse gastrointestinal effects of mycophenolate mofetil: Aetiology, incidence and management. Drug Saf 2001;24:645-63.  Back to cited text no. 8
[PUBMED]    
9.Josefiak K, Arns W, Merkel F, Weber M. Pseudomembranous colitis under therapy with mycophenolate mofetil following pancreas - 8kidney double transplantation. Nephrol Dial Transplant 2001;16:1959-60.  Back to cited text no. 9
[PUBMED]    
10.Zeeh J, Inglin R, Baumann G, Dirsch O, Riley NE, Gerken G, et al. Mycophenolate mofetil impairs healing of left-sided colon anastomoses. Transplantation 2001;71:1429-35.  Back to cited text no. 10
[PUBMED]    

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Correspondence Address:
Sushma Patra
Department of Pathology, Global Hospitals and Health City, Chennai-600 100, Tamilnadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.107792

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