Gastrointestinal Pathology

MMF-Associated Colitis

David Driman
London Health Sciences Centre
London, Ontario, Canada


Clinical History
This 31 year old male presented with a one month history of profuse watery diarrhea and vomiting. He had had a heart transplant 2 years previously for familial dilated cardiomyopathy. Routine blood work was normal and his stools contained no ova or parasites. He was taking the following medication: tacrolimus, mycophenolate mofetil, aspirin, lansoprazole, atorvastatin and buproprion. Colonoscopy showed patchy erythema but there were no ulcers or other striking abnormalities. Several biopsies were taken.


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Figure 1
Patchy crypt architectural distortion, variable inflammation and scattered dilated crypts
Figure 2
Dilated crypts containing neutrophils and cell debris; some crypts lined by hypereosinophilic epithelium with a regenerative apparance
Figure 3
Increased lamina propria eosinophils, damaged crypt filled with neutrophils; other crypts showing reactive changes with hypermucinous epithelium
Figure 4
Crypt epithelial apoptosis

Figure 5
IBD type appearance with lamina propria edema and crypt architectural abnormalities
Figure 6
Crypt distortion and branching
Figure 7
Crypt distortion and loss in association with small dilated damaged crypts
Figure 8
Small damaged crypts; one lined by hypereosinophilic regenerative type epithelium, the other dilated and lined by atrophic thinned epithelium

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The submitted images show colorectal mucosa with patchy abnormalities. There are scattered architectural abnormalities with crypt distortion and occasional branched crypts. Focal erosive changes are present and some biopsies have lamina propria edema. There is an increased number of eosinophils in the lamina propria. Crypts are abnormal; scattered crypt abscesses are present and isolated abnormal crypts appear dilated and lined by cells with variably attenuated and hypereosinophilic cells, some of which have prominent nucleoli. There is increased crypt apoptosis.

Differential Diagnoses:
  • MMF-associated colitis

  • Graft-vs-host disease

  • Idiopathic inflammatory bowel disease

  • Infectious colitis

Final Diagnosis:
MMF-associated colitis

Case Discussion:

What is MMF and how does it injure the GI tract?
Mycophenolate mofetil (MMF) is an anti-metabolite drug used in the maintenance immunosuppressive therapy for organ transplant recipients.It is approved by the FDA for use in the setting of allogeneic kidney, heart and liver transplantation, and has led to a significant decrease in the incidence of acute rejection in solid organ transplant recipients. [1]

MMF is converted to its active component, mycophenolic acid (MPA) in the liver. [2] MPA inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis. [2] Lymphocyte proliferation, which is 90% dependent on this pathway of purine synthesis, is selectively inhibited by MPA, accounting for the role of MMF as an immunosuppressant. [2] However, enterocytes are also dependent on this pathway of purine synthesis, which accounts for their selective vulnerability to MMF's anti-metabolite effects. [2]In addition, MMF may reduce the crypt proliferative index, resulting in impaired healing of injured colonic mucosa. [3, 4] In clinical practice, this GI toxicity is one of the main limitations of the drug's use, [2] with diarrhea the most frequently reported adverse effect, occurring in up to half of patients. [5, 6, 7]

What are the pathological effects of MMF on the colon and rectum?
In post-transplant patients with lower GI symptoms, the clinical differential diagnosis typically includes infections, graft-vs-host disease (GVHD) and other disorders such as chronic idiopathic inflammatory bowel disease (IBD). Because of differences in treatment for these conditions, accurate diagnosis is essential, and biopsies are often used to establish the correct diagnosis.

MMF injury can mimic a variety of other conditions such as GVHD, IBD, ischemia, acute self-limited colitis, and ulcerative enterocolitis . [3, 8, 9, 10, 11, 12, 13, 14] Of these, differentiation from GHVD is probably the most difficult and the most important, especially in the setting of allogeneic bone marrow /peripheral blood stem cell transplantation when GVHD is typically in the clinical differential diagnosis as a cause of diarrhea.Accurate diagnosis is important because the treatment for MMF colitis is to reduce immunosuppression by reducing MMF dosage while the treatment for GVHD is to increase immunosuppression with corticosteroids and other agents.

MMF colitisis characterized primarily by features that mimic advanced GVHD; these include mild crypt architectural disarray, foci of crypt loss and prominent lamina propria edema which give biopsies an "empty" appearance. Degenerate appearing, irregularly dilated crypts are characteristic and have flat or atrophic epithelial lining, sometimes showing regenerative or bizarre atypia; crypt lumens are either empty or contain neutrophils or debris. There is increased crypt epithelial apoptosis. Patchy collections of neutrophils may also be seen. While most of these features are relatively nonspecific on their own, the crypt abnormalities seem to be a feature of anti-metabolite drug induced colitis. These abnormalities, together with increased crypt epithelial apoptosis, suggest an acute or subacute phase of anti-metabolite drug induced epithelial injury, while the crypt architectural disarray, with occasional crypt loss, suggests chronicity or previous episodes of injury with partial healing. Of interest, despite the striking abnormalities that can be present in MMF colitis, most cases show remarkably few endoscopic abnormalities. [7]

Differentiation from GVHD: In practice, most cases of GVHD occur in patients who have bone marrow or stem cell transplants, but it can occur in the setting of solid organtransplantation, especially liver transplantation. There are no definitive ways of differentiating these conditions, but apoptosis tends to be more prominent in GVHD than with MMF injury, [12]and the peculiar crypt abnormalities described above are commoner with MMF injury.

Differentiation from infectious colitis: Biopsies with MMF-like changes but in which neutrophils are particularly prominent may represent a primary bacterial infection as the cause of the patient's symptoms. In such cases, it is reasonable to diagnose MMF injury but to make a statement to the effect that concurrent infectious colitis cannot be excluded (and should be excluded clinically).

Differentiation from IBD: The clinical manifestations of MMF colitis may mimic IBD and IBD-like changes can be seen with MMF injury, with features such as increased chronic inflammation in the lamina propria, crypt distortion, focal cryptitis, and mucin depletion. [3, 11, 14, 15] MMF injury is typically associated with less lamina propria inflammation, and atypical dilated crypts lined by bizarre regenerative epithelium are not a feature of IBD.

Differentiation from other causes of increased colorectal mucosal apoptosis: Apart from GVHD, increased crypt epithelial apoptosis can also be seen as an effect of drugs such as nonsteroidal anti-inflammatory agents (NSAIDs) [16] and bowel preparation agents, especially phosphosoda. [17] In such settings, the other epithelial abnormalities associated with MMF are absent.

What are the pathological effects of MMF on the upper GI tract?
Approximately 40% of patients on MMF complain of dyspeptic symptoms [18] but the effects on the upper GI tract are minor compared with the lower GI tract. Abnormalities reflect local mucosal irritation similar to that induced by NSAIDs. [18] MMF may be associated with ulcerative esophagitis, reactive gastropathy type changes and duodenal ulcers; [7] celiac disease type changes have also been reported. [19] Increased apoptosis is the most useful finding in MMF injury and a recent paper [20] has provided apoptotic count guidelines for attributing injury to MMF, as follows: duodenum: ≥2 apoptotic bodies per 100 crypts, stomach: ≥3 apoptotic bodies per 100 glands, esophagus: ≥2 apoptotic bodies per 10 HPFs.

What are the other causes of diarrhea in the post-transplant patient?
There are numerous causes of diarrhea in transplant recipients; these can be divided into infective and non-infective etiologies.

CMV and C. difficile are the commonest infectious causes of post-transplant diarrhea. [21] CMV should be carefully searched for in biopsies, regardless of whether any other cause of diarrhea (e.g. MMF colitis) has been identified. Whether or not to routinely use immunohistochemistry for CMV in cases in which inclusions are not identified in routine sections is a matter of debate, and will ultimately come down to the index of suspicion. Other viruses such as herpes simplex virus, Epstein–Barr virus and adenovirus are more rarely implicated. Parasitic infections, such as Cryptosporidiumand Entamoeba histolytica, and mycobacterial infections, particularly those due to atypical mycobacteria, should be excluded.

Non-infective causes of diarrhea include the effects of drugs (M MF, cyclosporine, tacrolimus, sirolimus) , diverticulitis, which may be more liable to complications post transplant, ischemic colitis and de novo IBD, which may develop in the post-transplant setting.

Conclusion:
MMF has the potential to injury both the upper and lower GI tract. Upper GI tract effects include NSAID-like injury as well as increased apoptosis. In the lower GI tract, MMF effects are related to its anti-metabolite effects, producing GVHD-like changes, including mild architectural distortion with dilated crypts lined by atypical appearing regenerative epithelium, lamina propria edema, increased crypt epithelial apoptosis and patchy neutrophilic inflammation. In the post-transplant setting, this constellation of findings should allow the correct diagnosis of MMF-induced colitis to be made with the appropriate management of reducing MMF dosage, and should help obviate erroneous diagnoses such as GVHD or IBD.

References:
  1. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321–1325.

  2. Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil. Drug Safety 2001;24:645-663.

  3. Dalle IJ, Maes BD, Geboes KP, Lemahieu W, Geboes K. Crohn's-like changes in the colon due to mycophenolate? Colorectal Disease 2005;7:27-34.

  4. Zeeh J, Inglin R, Baumann G, et al. Mycophenolate mofetil impairs healing of left-sided colon anastomoses. Transplantation 2001;71:1429-1435.

  5. Gil-Vernet S, Amado A, Ortega F, et al. Gastrointestinal complications in renal transplant recipients: MITOS study. Transplant Proc. 2007;39:2190-2193.

  6. Herrero JI, Benlloch S, Bernardos A. Gastrointestinal complications in liver transplant recipients: MITOS study. Transplant Proc. 2007;39:2311-2313.

  7. Parfitt JR, Jayakumar S, Driman DK. Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-vs-host disease-like changes. Am J Surg Pathol 2008;32:1367-1372.

  8. Golconda MS, Valente JF, Bejarano P, Gilinsky N, First MR. Mycophenolate mofetil-induced colonic ulceration in renal transplant recipients. Transplantation Proc. 1999;31-272-273.

  9. Halim MA, Said T, Nair P, et al. De novo Crohn's disease in a renal transplant patient. Transplantation Proc. 2007;39:1278-1279.

  10. Kim HC, Park SB. Mycophenolate mofetil-induced ischemic colitis. Transplantation Proc. 2000;32:1896-1897.

  11. Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea. Transplantation 2003;75:665-672.

  12. Papadimitriou JC, Cangro CB, Lustberg 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.

  13. Papadimitriou JC, Drachenberg CB, Beskow CO, et al. Graft-versus-host disease-like features in mycophenolate mofetil-related colitis. Transplantation Proc. 2001;33:2237-2238.

  14. Selbst M, Ahrens W, Robert M, et al. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Mod Pathol 2009;22:737-743.

  15. Phatak U, Seo-Mayer P, Jain D et al. Mycophenolate mofetil-induced colitis in children. J Clin Gastroenterol 2009;43: 967-969.

  16. Lee FD. Importance of apoptosis in the histopathology of drug related lesions in the large intestine. J Clin Pathol 1993;46:118–122.

  17. Driman DK, Preiksaitis HG. Colorectal inflammation and increased cell proliferation associated with oral sodium phosphate bowel preparation solution. Hum Pathol 1998;29:972-978.

  18. Behrend M, Braun F. Enteric-coated mycophenolate sodium. Tolerability profile compared with mycophenolate mofetil. Drugs 2005;65:1037-1050.

  19. Ducloux D, Ottignon Y, Semhoun-Ducloux S, et al. Mycophenolate mofetil-induced villous atrophy. Transplantation 1998;66:1115-1116.

  20. Nguyen T, Park JY, Scudiere JR, Montgomery E. Mycophenolic acid (Cellcept and Myofortic) induced injury of the upper GI tract. Am J Surg Pathol 2009;33:1355-63.

  21. Ginsburg PM, Thuluvath PJ. Diarrhea in liver transplant recipients: Etiology and management. Liver Transplantation 2005;11: 881–890.