Send letter to journal:
Re: Crohn’s ileitis after liver transplantation from a living-related donor with Crohn’s disease

Dear Editor

We read with interest the case described recently by Sonwalkar et al, of a patient who developed fulminant Crohn’s colitis after allogeneic stem cell transplantation (ASCT).[1] Although the donor had no known Crohn’s disease (CD) and did not carry the IBD3 or IBD5 haplotypes associated with CD, HLA class III mismatches at IBD3 and a CD-associated polymorphism of the 5'UTR of NOD2/CARD15 were present in the donor and in the reconstituted immune cell population of the recipient post ASCT. The authors hypothesized that adoptive transfer of CD susceptibility may have occurred between ACST donor and recipient.[1]

Herein, we report a case of a patient who developed CD after receiving a living-related liver transplant from a donor with known CD. A 24 year old female received a liver transplant from a living-related donor for decompensated cirrhosis secondary to vertically transmitted chronic hepatitis C infection. The family history was significant for a maternal aunt diagnosed with CD who served as the liver donor and a maternal uncle and grandfather with colon cancer. Following liver transplantation the patient was maintained on an immunosuppressive regimen consisting of tacrolimus 3mg twice daily, sirolimus 5 mg daily, as well as TMP-SMZ prophylaxis. Her initial post-transplant course was uneventful, but later developed recurrent hepatitis C infection, treated with pegylated interferon and ribavirin. She presented with symptoms consistent with intermittent small bowel obstruction 11 months post-transplant. She was also receiving prednisone 15 mg daily at that time. A CT scan of the abdomen and pelvis (Figure 1A) and an upper GI with small bowel follow through study(Figure 1B) demonstrated marked fold thickening of the distal ileum. An enteroscopy demonstrated patchy ulcerations in the jejunum and Roux-en-Y limb of the small bowel. Biopsies showed focal ulceration and mild active inflammation without evidence of granuloma or viral inclusions. Wireless capsule endoscopy (WCE) demonstrated multiple erosive and ulcerative changes in the distal small intestine (Figure 1C and D). Because of persistent symptoms and concern for possible lymphoproliferative disorder, the patient underwent an open laparoscopy, which revealed nodularity of the terminal ileum. Intraoperative colonoscopy demonstrated nodularity and 3 ulcers in the distal ileum. Histopathologic examination of the resected ileal specimen demonstrated focal villous blunting, expansion of the lamina propria with acute and chronic inflammatory cells, reactive crypt changes and occasional crypt abscesses and focal gastric metaplasia (Figure 1E, arrow and insert). Mucosal ulcerations were underlined by inflamed granulation tissue containing occasional histiocytes and multinucleated giant cells. The submucosa (SM) also showed intense fibrosis and hyperplasia of the nerve bundles.

Few cases of de novo IBD developing after liver transplantation for chronic liver disease other than PSC have been described.[2-5] We present a case of CD developing in the recipient of a liver transplant from a living-related donor with known history of CD. The recipient tested negative for any of the three common CD-associated NOD2/CARD15 variants (R702W, G908R, 1007fsinsC) but unfortunately we were not able to screen the liver donor for these polymorphisms. Our case, similar to the one described by Sonwalkar et al, raises the intriguing possibility that CD susceptibility may have been transferred to the recipient with liver transplantation as well. Collins et al, have reported complete and stable replacement of recipient hematopoiesis and B lymphopoiesis with donor- derived cells approximately 6 weeks following orthotopic liver transplantation for hemochromatosis.[6] T lineage reconstitution also occurred and derived almost exclusively from expansion of mature, memory/effector T cells from the transplanted liver. One possibility is that the expanded immune cells have become tolerant to the graft but not to the intestinal luminal antigens leading to the development of CD.[5] Whether liver donor selection should exclude those with a known diagnosis of CD is unclear and is still premature to answer.

Figure 1A-E

References

1. Sonwalkar SA, James RM, Ahmad T, et al. Fulminant crohn's colitis after allogeneic stem cell transplantation. Gut 2003; 52:1518-1521.

2. Passfall J, Distler A, Riecken EO, Zeitz M. Development of ulcerative colitis under the immunosuppressive effect of cyclosporine. Clin Invest 1992; 70:611-613.

3. Riley TR, Schoen RE, Lee RG, Rakela J. A case series of transplant recipients who despite immunosuppression developed inflammatory bowel disease. Am J Gastroenterol 1997; 92:279-282.

4. Cuoco L, Tursi A, Cammarota G, Papa A, Fedeli G, Gasbarrini G. Onset of ulcerative colitis during immunosuppressive therapy for liver transplantation. Am J Gastroenterol 1997; 92:2134-2135.

5. Ramji A, Owen DA, Erb SR, Scudamore CH, Yoshida EM. Post-liver transplant Crohn's disease: graft tolerance but not self-tolerance? Digestive Diseases & Sciences 2002; 47:522-7.

6. Collins RH, Jr., Sackler M, Pitcher CJ, et al. Immune reconstitution with donor-derived memory/effector T cells after orthotopic liver transplantation. Experimental Hematology 1997; 25:147-59.

Send letter to journal:
Re: Adoptive transfer of genetic susceptibility to Crohn's disease?

Dear Editor

We read with great interest the stimulating case report about fulminant Crohn’s colitis following allogenic stem cell transplantation by Sonwalkar and colleagues [1] and the respective editorial.[2] The authors and the editorialists hypothesize whether the colitis might be ascribed to the adoptive transfer of stem cells displaying genetic alterations which are associated with Crohn’s disease. However, the ileal sparing disease localization and the course of the colitis which finally necessitated urgent colectomy is rather unusual for Crohn’s colitis. In addition, the genetic mismatch between donor and recipient is hardly compatible with the outlined hypothesis.

According to the cited manuscript by Lesage and coworkers[3] the allele difference at position –33 of the 5’UTR polymorphism of the NOD2 gene is not regarded as "a disease causing mutation". In line with this concept is the fact that the donor and his first-degree relatives did not suffer from Crohn’s disease. Besides this observation, the authors did not describe in detail which particular genetic mutations or polymorphisms differed between donor and recipient. However, some of the described genes are simply not associated with inflammatory bowel disease. As shown by some of the authors [4] and ourselves,[5] polymorphisms in the MICB gene (which is not situated within the HLA class III but the HLA class I region) are not associated with Crohn’s disease. The same holds true for polymorphisms of the HSP70 gene which were weakly associated with a more severe course of Crohn’s disease in Japanese but not with the disease itself.[6] To the best of our knowledge, data about possible associations between mutations of the LMP2, LMP7 and the NOTCH4 gene and Crohn’s disease are completely lacking. In conclusion, at best only an extremely weak genetic predisposition can be extracted from the extensive genotyping and, thus, the postulated transfer of genetic susceptibility remains highly speculative.

The increased incidence of inflammatory bowel disease in patients with congenital immune defects and the recently described increased adherence of bacteria at the intestinal mucosa, which might particularly be facilitated in the presence of mutated NOD2 protein, suggest that the initial event in the complex pathophysiologic process in Crohn’s disease is compatible with an impaired mucosal clearing function which precedes an excessive largely T-cell driven immunologic activity. This hypothesis is further sustained by various genetically engineered animal models which are protected from the development of enterocolitis under germ free conditions and therapeutic approaches, such as the use of immunostimulatory substances or antibiotic therapy (For overview: [7]). Thus, a complementary explanation for the described phenomenon might be the persistent immunosuppressive therapy the donor had received.

References

(1) Sonwalkar SA, James RM, Ahmad T, Zhang L, Verbeke CS, Barnard DL, Jewell DP, Hull MA. Fulminant Crohn’s colitis after allogeneic stem cell transplantation. Gut 2003;52:1518-1521.

(2) Holtmann MH, Neurath MF. Transplanting the genetic susceptibility to Crohn’s disease. Gut 2003;52:1394-1396.

(3) Lesage S, Zouali H, Cezard JP, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002;70:845-57.

(4) Ahmad T, Marshall SE, Mulcahy-Hawes K, et al. High resolution MIC genotyping: design and application to the investigation of inflammatory bowel disease susceptibility. Tissue Antigens 2002;60:164-79.

(5) Glas J, Martin K, Brunnler G, et al. MICA, MICB and C1_4_1 polymorphism in Crohn's disease and ulcerative colitis. Tissue Antigens 2001;58:243-9.

(6) Esaki M, Furuse M, Matsumoto T, et al. Polymorphism of heat-shock protein gene HSP70-2 in Crohn disease: possible genetic marker for two forms of Crohn disease. Scand J Gastroenterol 1999;34:703-7.

(7) Folwaczny C, Glas J, Torok HP. Crohn's disease: an immunodeficiency? Eur J Gastroenterol Hepatol 2003;15:621-6.