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Intestinal Transplant and Gut Motility

Samuel Kocoshis, MD Medical Director, Nutrition and Small Intestinal Transplantation Cincinnati Children's Hospital Medical Center

Does Small Intestinal Transplantation Result in a Motility Disorder?

Yes and No

Abnormal Motility Post Transplant?

· Yes

­ Animal data show that rejection is associated with abnormal motility ­ Human data show that rejection is associated with abnormal motility

· No

­ Animal data show that in the absence of rejection, motility is nearly normal ­ There are some human transplant recipients who have normal manometric tracings


What Must We Conclude?

Motility Abnormalities Among Intestinal Transplant Recipients Are Closely Associated With Rejection

Contractile Force in Response to Bethanecol

Sugitani et al: Transplantation 1997;63:186-194

Myoelectric Changes Seen With Rejection

Sugitani et al: Transplantation 1997;63:186-194


Morphologic Changes of Rejecting Bowel


acute rejection

chronic rejection

Sugitani et al: Transplantation 1997;63:186-194

Microscopic Picture of Chronic Rejection

obliterative vasculopathy and thickened muscularis propria

lymphocytic infiltrate

Sugitani et al: Transplantation 1997;63:186-194

Fibronectin Staining of Myocytes in Chronic Rejection

control: small, homogeneously sized cells

chronic rejection: variably enlarged cells

Sugitani et al: Transplantation 1997;63:186-194


Morphometric Analysis of Muscle Hyperplasia in Rejecting Bowel

Sugitani et al: Transplantation 1997;63:186-194

Morphometric Analysis of Muscle Thickness in Rejecting Bowel

Sugitani et al: Transplantation 1997;63:186-194

How Is the Transplanted Bowel Innervated?

· Methods

­ Intrinsic and Extrinsic Innervation of Dogs Undergoing Intestinal Autotransplantation Was Evaluated at Various Intervals:

· · · · · 1 month, n=7 3 months, n=6 6 months, n=6 12 months, n=6 24 months, n=2

­ Staining for CCA, peptide Y, substance P, CGRP, and TH

Sugitani et al. Surgery 1998: 123; 25-35.


How Is the Transplanted Bowel Innervated?

· Results

­ No reinnervation until 12 months ­ Subsequently, TH fibers were evident

· None crossed the intestinal anastomosis · All crossed from mesentery to allograft along the vascular anastomosis

· Conclusion

­ Reinnervation occurs, but it is a slow process and highly selective for TH fibers

Sugitani et al. Surgery 1998: 123; 25-35.

Given These Findings, How Does the Transplanted Bowel Differ Manometrically From the Normal Native Bowel?

Normal Antroduodenal Motility

Fasting Condition

· Phase I Period of silence. Defined as less than 3 pressure wawes/10 min. Follows a phase III. · Phase II Period of uncoordinated contractions. Defined by amplitude, duration, propagation distance and · velocity of single contractions, and cumulative motility index · Phase III Period of coordinated contractions. Defined as regular rhythmic contractions at high frequency, lasting from 2-15 min and migrating aborally. Propagation velocity and maximal frequency decrease while duration increases aborally

Postprandial Condition

· Loss of cycling activity

Hanson: Physiol. Res. 51: 541-556, 2002


Fasting, Normal Phases II, III, & I

Normal Postprandial Tracing

Manometric Findings Described Pediatric Intestinal Transplant Patients

· 8 patients were studied · Manometry was performed 3-23 mo. Post transplant · Findings

­ ­ ­ ­ ­

· Conclusions

Dissociation of MMCs across duodenojejunal anastomosis Spontaneous MMCs seen in only 5 of the 8 MMCs were seen during the postprandial period in 4 of 5 MMCs only following octreatide in 2 of 3 without spontaneous MMCs No MMCs in one patient despite octreatide (recovered from exfoliative rejection) ­ Giant waves propagated from native bowel to allograft ­ Only patient with totally normal fed pattern had undergone multivisceral transplant including stomach and duodenum ­ Extrinsic innervation is unnecessary for generation of an MMC ­ Rejection adversely affects motility Mousa et al. Trans Proc 1998: 30;2535-2536.


Giant Contractions In Transplant Patients Having Experienced Rejection

Bjornsson & Abrahamsson Am J Gastroenterol 1999;94:54­64.

Feeding Normally Disrupts an MMC

Fenton et al. Gut 1983;24:897-903

Persistent MMC During Feeding Typical In Transplant Patients With Dyspepsia

Fenton et al. Gut 1983;24:897-903


Typical Findings Following Exfoliative Rejection: Abortive Response to Ocreatide

Typical Histology of Exfoliative Rejection

Recovering Exfoliative Rejection Early Phase


Exfoliative Rejection, Recovery Complete

Exfoliative Rejection: Recovery With Metaplastic Changes

Reverse Peristalsis with Obstruction (Chronic Rejection)

Jadcherla et al. JPGHN 2005:41; 247-250


Spectrum of Chronic Rejection

· Classical

­ This process results in patchy intimal fibrosis of submucosal arteries ­ Ischemic changes result in focal stricturing and patchy villous atrophy ­ Obstruction tends not to improve with steroids and progressively worsens ­ Limited resection is generally not very successful

· Sclerosing Peritonitis

­ Vascular changes occur in this too, but there is generally a thick peal constricting bowel and resulting in a frozen bowel ­ Inflammation involves serosal surface of bowel and peritoneum ­ Obstruction may transiently improve with steroids, but recurrence is the rule ­ Limited resection is just as unsuccessful as it is in classic chronic rejection

Chronic Rejection: Marked Intimal Fibrosis of Submucosal Artery

Chronic Rejection: Gross Explant


Chronic Rejection: Villous Effacement

Sclerosing Peritonitis: Thickened Mesentery & Narrow Allograft Ileal Lumen

What to Do

· An ounce of prevention is worth a pound of cure!....Prevention and early treatment of rejection

­ Follow serum citrulline levels ­ Follow fecal calprotectin

David et al Transpl 2007:84;1077

· Levels >13 rule of moderate or severe rejection w/negative predictive value of 96 & 99%, respectively

Sudan et al Ann. Surg 2007:246;311

· ROC suggests that a level of >92mg/kg detects rejection with sensitivity of 83% and specificity of 77%


Are Nonspecific Therapies of Value?

· For hypersecretion

­ ­ ­ ­ Loperamide--probably not effective Clonidine--not effective according to Rovera Octreatide--not studied, possibly effective Marine clay--probably not effective

· For pseudo-obstruction picture

­ Erythromycin--probably not effective ­ Metaclopramide--probably not effective ­ May require antibiotics if complications of bacterial overgrowth occur

· Generally, should treat with antibiotics having an anaerobic spectrum if you wish to improve physiology

What To Do After Recovery from Exfoliation or During Chronic Rejection

· · · · Limp along as long as possible Utilize continuous enteral feedings Consider elemental feedings When TPN dependence overtakes the patient, list for retransplant if patient and family concur


· Motility disorders are common, but not universal after small intestinal transplantation · There appears to be a close correlation between rejection and abnormal motility · Severe rejection can result in a permanent pseudo-obstruction picture · Transit time through the allograft is often too rapid · In animal studies, extrinsic innervation has been documented.



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