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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

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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

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Morphologic Changes of Rejecting Bowel

autotransplant

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

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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.

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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

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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.

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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

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Typical Findings Following Exfoliative Rejection: Abortive Response to Ocreatide

Typical Histology of Exfoliative Rejection

Recovering Exfoliative Rejection Early Phase

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Exfoliative Rejection, Recovery Complete

Exfoliative Rejection: Recovery With Metaplastic Changes

Reverse Peristalsis with Obstruction (Chronic Rejection)

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

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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

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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%

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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

Summary

· 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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