Mycophenolate Mofetil–Related Gastrointestinal Mucosal Injury in Multivisceral Transplantation

doi:10.1016/j.transproceed.2009.12.027

Transplantation Proceedings

Volume 42, Issue 1, January–February 2010, Pages 82-84

https://doi.org/10.1016/j.transproceed.2009.12.027 Get rights and content

Abstract

Mycophenolate mofetil (MMF) has become an important and commonly used drug for maintenance immunosuppression therapy in recipients of all types of organ transplants. The drug is an antimetabolite that blocks the de novo pathway of purine synthesis. Although it selectively inhibits B- and T-lymphocyte proliferation, enterocytes are partially susceptible to MMF. One of the main limitations of this drug is gastrointestinal toxicity, with diarrhea the most frequently reported adverse effect. Most studies of MMF-associated gastrointestinal toxicity have been performed in patients with solid-organ transplants, although no data on changes related to MMF toxicity in bowel allografts have been published in the English literature. We evaluated mucosal intestinal biopsy tissue from patients with multivisceral transplants receiving MMF therapy. Our objective was to find morphologic changes that might be attributed to MMF toxicity, as well as changes that could differentiate MMF toxicity from acute rejection. Examination of the surface epithelium, lamina propria, and crypts in this small group of patients showed no specific changes that could be associated with MMF toxicity. Changes such as graft-vs-host disease or inflammatory bowel disease described in previous studies of solid-organ transplantation were not observed. Larger studies and the use of special stains and new markers might be necessary to characterize possible patterns of MMF toxicity and their differences from acute rejection.

Section snippets

Materials and Methods

The files of the Pathology Department of Jackson Memorial Hospital (Miami, Florida) were searched for all GI biopsies in patients who had received MTx transplants including stomach, small intestine, and colon from April 2008 to August 2009. Fifteen biopsies were studied from 4 patients who had received MTx transplants including stomach, small intestine, and colon. The biopsy tissue was assessed for changes in surface epithelium, lamina propria, and crypts. Graft-vs-host disease–, IBD-, and

Results

Fifteen biopsy specimens were studied from 4 patients who had received an MTx transplant including stomach, small intestine, and colon. All patients were receiving MMF therapy at the time of biopsy. Patient age ranged from 2 to 15 years. Patient sex, primary disease, and other demographic data are given in Table 1.

In 2 patients, biopsy was indicated because of diarrhea, and in 1 patient because of increased ostomy output (Table 2). Most biopsy specimens exhibited a normal endoscopic appearance,

Discussion

We explored biopsy tissue from GI grafts in patients with MTx receiving MMF therapy. Our objective was to find morphologic changes that might be attributed to MMF toxicity, as well as alterations that could differentiate MMF toxicity from acute rejection. Examination of the surface epithelium, lamina propria, or crypts in this small group of patients showed no specific changes that could be associated with MMF toxicity. Abnormalities described in previous studies such as GVHD or IBD were not

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Cited by (14)

Drugs that act on the immune system: Immunosuppressive and immunostimulatory drugs
2012, Side Effects of Drugs Annual
Citation Excerpt :
Gastrointestinal Gastrointestinal adverse events are among the main limitations of the use of mycophenolate mofetil. Examination of the surface epithelium, lamina propria, and crypts of mucosal intestinal biopsy tissue in 15 multivisceral transplant patients, including stomach, small intestine, and colon, showed neither specific changes that could be associated with mycophenolate mofetil toxicity nor changes that could differentiate mycophenolate mofetil-related toxicity from acute rejection [88c]. Immunologic In 69 renal transplant recipients, the use of mycophenolate mofetil (n = 32) was associated with a reduced serum antibody response and protection rate after inoculation with influenza vaccine compared with the antibody response in patients who took azathioprine (n = 37) [89c].
This review of the 2010 publications on immunosuppressive and immunostimulatory or immunoenhancing drugs covers ciclosporin, cyclophosphamide, everolimus, leflunomide, methotrexate, mizoribine, mycophenolate mofetil, sirolimus, tacrolimus, temsirolimus, the thiopurines, and the immunoenhancing drugs levamisole, picibanil, and thymosin α-1; there are also special reviews on fingolimod, glatiramer, gusperimus, imexon, and semapimod.
Nitric oxide and acute phase proteins are involved in pathogenesis of mycophenolate mofetilinduced gastrointestinal disorders in rats
2011, Transplantation Proceedings
Citation Excerpt :
To explain the anorexia and subsequent body weight loss, the most acceptable reasons may relate to direct effects of MMF on enterocytes that likely lead to malabsorption and maldigestion. In this regard the susceptibility of enerocytes to MMF has been reported in addition to effect on B and T lymphocytes.14 Moreover, because of the antibacterial-effects of MPA, there is the possibility of major changes in normal microbial populations in the GI tract with substitution by anaerobic bacteria, which in turn cause gas production and tissue damage.15
This study was designed to clarify the molecular mechanism(s) of mycophenolate mofetil (MMF)– induced gastrointestinal (GI) disorders. Forty-two adult Wistar rats were assigned to 7 groups including control and test hosts. The control animals received normal saline and the test animals various doses of MMF (10, 20, or 40 mg/kg) for 14 days, or MMF, aspirin, or lipopolysaccharide as single high doses (40, 200, and 1 mg/kg, respectively). To evaluate the GI disorders, are determined body weight gain, serum level of alkaline phosphatase (ALP), nitric oxide (NO), and acute phase proteins (APP). Additionally, we measured the duodenal NO content and myeloperoxidase activity. MMF administration resulted in a significant (P < .05) body weight loss and elevation of serum levels of ALP and NO. The duodenal NO content increased in the test groups with the highest levels among the aspirin-treated cohort. The myeloperoxidase activity and the serum level of APP were elevated among MMF- and aspirin-treated animals. Histopathologic examinations showed villous atrophy and inflammatory cells infiltration among MMF-treated animals. Our data suggested that the MMF-induced GI disorders were likely related to local inflammatory reactions, which may be attributed to elevated NO and myeloperoxidase activities that result in pathological injuries. Moreover, the biochemical alterations and histopathologic injuries due to MMF administration were similar to aspirin-induced local disorders rather than to lipopolysaccharide-induced systemic damage.
Mycophenolate monitoring in liver, thoracic, pancreas, and small bowel transplantation: A consensus report
2011, Transplantation Reviews
Citation Excerpt :
Diarrhea, vomiting, and nausea are frequent complications of MMF therapy, and changes in gastrointestinal (GI) histopathology are frequent in MMF-treated patients [56]. However, there was no evidence of specific damage attributable to MPA in a study of 4 patients with multivisceral transplants by Delacruz et al [57], who highlight the need for specific markers of MPA toxicity. The combination of MMF with SRL in thoracic transplant recipients has been particularly associated with adverse effects (affecting 30%–76%) and drug discontinuation (8%–75%), mostly secondary to SRL [30,50,58-61].
Assessing the value of mycophenolic acid (MPA) monitoring outside renal transplantation is hindered by the absence of any trial comparing fixed-dose and concentration-controlled therapy. However, in liver and thoracic transplantation particularly, clinical trials, observational studies with comparison groups, and case series have described MPA efficacy, exposure/efficacy relationships, pharmacokinetic variability, and clinical outcomes relating to plasma MPA concentrations. On the basis of this evidence, this report identifies MPA as an immunosuppressant for which the combination of variable disposition, efficacy, and adverse effects contributes to interindividual differences seemingly in excess of those optimal for a fixed-dosage mycophenolate regimen. Combined with experiences of MPA monitoring in other transplant indications, the data have been rationalized to define circumstances in which measurement of MPA concentrations can contribute to improved management of mycophenolate therapy in nonrenal transplant recipients.
Patterns of injury in mycophenolate mofetil-related colitis
2010, Transplantation Proceedings
Citation Excerpt :
The mechanism of epithelial damage in MMF-related diarrhea has not been determined.13 However, immune dysregulation caused by MMF could be involved through any of the mechanisms postulated for colonic damage in GVHD.2,11,14 Although direct MMF cytotoxicity cannot be ruled out, it is possible that the observed enterocyte injury may be indirectly mediated by the immunosuppressive effects of MMF.
Mycophenolate mofetil (MMF) was introduced as a new immune-suppression drug in the mid-1990s. It is widely utilized in solid-organ transplantation immune-suppression regimens. Side effects include gastrointestinal (GI) toxicity in the form of nausea, vomiting, and diarrhea. Physicians tend to reduce the dose of MMF or switch their patients to an enterio-coated formula to overcome the side effects. Because GI side effects are well linked to MMF, colonoscopy is not utilized in most of the cases to investigate the diarrhea. However, Crohn's disease-like changes in the colon, erosive enterocolitis, and graft versus host disease-like colonic changes associated with the use of MMF have been reported. Colonic findings in five patients whose symptoms resolved after substituting another agent for MMF are described in the present report. Repeat colonoscopy 4 months following discontinuation of MMF showed reparative changes in one of our patients. MMF is an important drug in organ transplantation immune-suppression regimens; however, with its widespread usage, additional side effects continue to be recognized.
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ComplicationMycophenolate Mofetil–Related Gastrointestinal Mucosal Injury in Multivisceral Transplantation

Abstract

Section snippets

Materials and Methods

Results

Discussion

Adverse gastrointestinal effects of mycophenolate mofetil

Drug Safety

Gastrointestinal complications in renal transplant recipients: MITOS study

Transplant Proc

Gastrointestinal complications in liver transplant recipients: MITOS study

Transplant Proc

Crohn's-like changes in the colon due to mycophenolate?

Colorectal Dis

Mycophenolate mofetil–induced colonic ulceration in renal transplant recipients

Transplant Proc

Complication
Mycophenolate Mofetil–Related Gastrointestinal Mucosal Injury in Multivisceral Transplantation