Case 2 -
London Health Sciences Centre
London, Ontario, Canada
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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.
Case 2 - Slide 1
Case 2 - Figure 1
Patchy crypt architectural distortion, variable inflammation and scattered dilated crypts
Case 2 - Figure 2
Dilated crypts containing neutrophils and cell debris; some crypts lined by hypereosinophilic epithelium with a regenerative apparance
Case 2 - Figure 3
Increased lamina propria eosinophils, damaged crypt filled with neutrophils; other crypts showing reactive changes with hypermucinous epithelium
Case 2 - Figure 4
Crypt epithelial apoptosis
Case 2 - Figure 5
IBD type appearance with lamina propria edema and crypt architectural abnormalities
Case 2 - Figure 6
Crypt distortion and branching
Case 2 - Figure 7
Crypt distortion and loss in association with small dilated damaged crypts
Case 2 - 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.
- MMF-associated colitis
- Graft-vs-host disease
- Idiopathic inflammatory bowel disease
- Infectious colitis
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. 
MMF is converted to its active component, mycophenolic acid (MPA)
in the liver.  MPA inhibits
inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis. 
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.  However, enterocytes are
also dependent on this pathway of purine synthesis, which accounts for their selective vulnerability to
MMF's anti-metabolite effects. In addition, MMF may reduce the crypt proliferative index, resulting in
impaired healing of injured colonic mucosa.
In clinical practice, this GI toxicity is one of the
main limitations of the drug's use,  with diarrhea the most frequently reported adverse effect,
occurring in up to half of patients.
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
MMF injury can mimic a variety of other conditions such as GVHD, IBD, ischemia, acute self-limited
colitis, and ulcerative enterocolitis .
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. 
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, 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
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.
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)
 and bowel preparation agents, especially phosphosoda.
 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  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.  MMF may be associated with ulcerative esophagitis, reactive gastropathy
type changes and duodenal ulcers;  celiac disease type changes have also been reported.
apoptosis is the most useful finding in MMF injury and a recent paper  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
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.  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.
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.
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