Case 42

Published on 18/02/2015 by admin

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Last modified 18/02/2015

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CASE 42

Elizabeth is a 19-year-old girl with severe Crohn’s disease. In the course of this disease characterized by diarrhea, pain, loss of appetite, and weight loss, the associated inflammatory processes led to bowel obstruction that necessitated resection of a large portion of the intestine. Unfortunately, so much of the small intestine was removed that the remaining segment could no longer absorb the required nutrients. Consequently, Elizabeth began receiving total parenteral nutrition, which is intravenous feeding. As such, she was an ideal candidate for a pilot intestinal transplant program and had received a small intestinal transplant 1 month earlier. In this procedure, the surgeon transplants a segment of a cadaver’s small intestine into the patient. The patient was also prescribed a regimen of immunosuppressive drugs to overcome the rejection, but this also increases the risk of infection.

After 27 days, Elizabeth returned to the hospital showing evidence of weight gain, but with a diffuse “weeping” rash covering her body, abdominal cramps, and a fever of 5 days’ duration. As you begin to consider this problem, think of issues related to transplantation in general, of the side effects of transplantation, and of small intestinal transplantation in particular.

QUESTIONS FOR GROUP DISCUSSION

1. What is Crohn’s disease? Families of patients with Crohn’s disease have shown a strong association with mutations in the NOD2 gene. What is NOD2?

2. Ex vivo studies have repeatedly shown that macrophages isolated from diseased intestinal segments of Crohn’s disease patients produce more interleukin (IL)-12 compared with macrophages isolated from control patients. Explain how IL-12 production would lead to an increase in interferon gamma (IFNγ), tumor necrosis factor (TNF), and IL-2 but a decrease in IL-4.

3. IFNγ, TNF, and IL-2 play a significant role in various aspects of the immune system. Discuss these and how each might play a role in destruction of the intestine.

4. T cells isolated from Crohn’s disease patients also produce more IFNγ and decreased amounts of IL-4. Both IL-12 and IFNγ play an important role in inflammation, and this is supported by studies in which Crohn’s disease patients treated with antibodies that block the IL-12 receptor showed a significant decrease in inflammation.

5. Acute graft rejection by the host’s immune system is the most frequent early complication of transplantation. What is acute graft rejection, and what is the primary underlying cause? How do we try to avoid this problem clinically?

6. Evidence for acute rejection would be nonspecific (e.g., fever) as well as physiologic “failure” of the graft. Explain the role of cytokines in nonspecific graft rejection and how cytokines play a role in the induction of fever.

7. Rejection of an intestinal graft would manifest as a loss of weight with cramping. Explain what is causing the cramping.

8. Acute rejection episodes are best treated by increasing nonspecific immunosuppression. However, the side effects of immunosuppression itself are often the cause of the patient’s main complaints. CD4+ T cells are usually the target for immunosuppression. Review the role of CD4+ T cells in immune responses and in acute rejection.

9. What organs and tissues are particularly susceptible to drug (cyclosporine and tacrolimus) toxicity? In addition to the drug toxicity, to what malignancies and types of infections are immunosuppressed patients particularly prone?

10. A peculiarity to intestinal transplantation is that we generally transplant donor lymphoid tissue here (as well as the intestinal graft itself). In fact, the intestine is a source of some 50% of the total body lymphoid pool and can lead to graft versus host disease (GvHD). Discuss how a diagnosis of GvHD would explain the cramps, fever, and weeping rash.

RECOMMENDED APPROACH

Implications/Analysis of Family History

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