- Email: [email protected]
Gastrointestinal Transplantation: An Update
SPECIAL REPORT
Gastrointestinal Transplantation: An Update Nagappan Kumar* and David Grant† Gastrointestinal transplantation is a life-saving option for patients who have chronic intestinal failure and cannot tolerate total parenteral nutrition (TPN). Early referral is important because of the scarcity of donors and the increased risk of complications in debilitated recipients. One-year patient survival rates range from 50% to 70%. Despite the use of intense immune suppression, most patients experience at least 1 episode of graft rejection. More than 80% of the survivors are able to stop TPN and resume an unrestricted oral diet. Patients with functioning grafts have a good quality of life. (Liver Transpl 2000;6:515-519.)
P
arenteral nutrition (PN) remains the standard of care for patients with intestinal failure. Because most patients on PN do well,1 transplantation is usually reserved for the patients with intestinal failure who cannot tolerate PN. Some of the indications for gastrointestinal transplantation (GIT) in children and adults are listed in Table 1. The need for GIT is estimated to be 2 to 3 cases per million per year, with equal numbers of pediatric and adult recipients.2
Patient Evaluation Early referral is important because of the scarcity of donors and the increased risk of complications in debilitated recipients. An expert panel, convened by Dr. A. Lagnas and Dr. S. Kaufman at the VI International Small Bowel Transplant Symposium, Omaha, NE, October 6-9, 1999, identified the following groups as having high failure rates on PN: (1) infants with less than 25 cm of small intestine, total intestinal aganglionosis, or microvillus inclusion disease; and (2) adults with a total small bowel resection resulting in a duodenal-to-colon anastomosis. In studies by Bueno et al3 and Beath et al,4 the presence of a bilirubin level of greater than 100 mmol/L, splenomegaly, or cirrhosis was associated with a high risk of death in infants on PN. Potential candidates for GIT require a careful assessment, including a detailed history to confirm PN dependency; radiographs to define the GI anatomy; a Doppler ultrasound survey to document vascular access; and motility studies. The diagnosis of Munchausen’s disease or Munchausen-by-proxy should be considered when symptoms seem exaggerated or improbable, when there are discrepancies between the claimed and
documented illnesses, or when there seems to be a temporal association between the presence of a parent and a deterioration in their child’s health.
Choice of Surgical Procedure An isolated small bowel transplant is the preferred surgical option. Transplantation should be considered when patients have had 1 or more episodes of lifethreatening intravenous catheter sepsis, when venous access becomes limited to less than half of the standard sites, or when there is progressive PN-induced liver dysfunction. Mild to moderate liver dysfunction with serum bilirubin levels of up to 100 mmol/L or more can be corrected with an isolated small bowel transplant. A combined liver and small bowel transplant is indicated for patients with bridging hepatic fibrosis or cirrhosis, portal hypertension, and/or severely impaired liver synthetic function. Multivisceral grafts with or without the liver, pancreas, and stomach are offered to (1) patients with diffuse motility disorders; (2) patients with unreconstructable GI tracts secondary to severe abdominal trauma, vascular events, or surgical misadventures; or (3) patients who require an evisceration to remove large desmoid tumors. The choice of surgery for patients with pseudoobstruction is controversial. When conventional treatment has been exhausted, one option is to remove the native jejunum, the ileum, and the distal stomach and then reconstruct the GI tract with the small bowel allograft, using the Roux-en-Y technique. Another option is to replace the native GI tract with a multivisceral graft. If a normal native liver is removed to facilitate multivisceral transplantation, the recipiFrom the *Department of Surgery, University of Western Ontario, London, Ontario, Canada; and †Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Address reprint requests to David Grant, MD, The Toronto General Hospital, 621 University Ave, Room NU-10-114, Toronto, Ontario, Canada M5G 2C4. Telephone: 416-340-5230; FAX: 416-595-1905; E-mail: [email protected] Copyright r 2000 by the American Association for the Study of Liver Diseases 1527-6465/00/0604-0027$3.00/0 doi:10.1053/jlts.2000.9126
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Table 1. Indications for Intestinal Transplantation Indications in Children Gastroschisis Hirschsprung’s disease Intestinal atresia Intractable diarrhea of infancy Microvillus inclusion and tufting disease Necrotizing enterocolitis Omphalocele Pseudo-obstruction Volvulus Indications in Adults Crohn’s disease Desmoid tumor Gardner’s syndrome Ischemia Pseudo-obstruction Trauma Volvulus
ent’s liver may be offered to another patient as a domino graft.
Organ Procurement Until recently, the criteria for intestinal donation have included the following: (1) negative cytomegalovirus (CMV) serology; (2) a donor weight of 20%-30% less than the recipient (to avoid space problems created by loss of the peritoneal domain when the native small bowel has been removed); and (3) an identical blood group with the recipient (to avoid the postoperative hemolysis caused by antibodies from B cells within the graft). Because of the high death rates on the waiting lists, these criteria are being reassessed.5,6 At the Omaha Symposium, J. de Ville de Goyet (Birmingham, UK) described techniques to transplant blood-group– compatible, reduced-size grafts with an up to 5-to-1 donor-to-recipient weight discrepancy. His approach included reducing the liver with an extra-hilar technique, resecting a portion of the mid-small bowel, debulking fatty tissues in the small bowel mesentery, and closing the abdominal wall with prosthetic materials. Most cadaveric liver donors are suitable candidates for intestinal donation. The intestinal graft can be dissected in situ or on the bench after removal. When the liver and small bowel are transplanted together, the duodenum and the head of the pancreas are kept intact to avoid the need for biliary reconstruction.7 Intestinal grafts can be stored in the University of
Wisconsin (UW) solution for 8 to 16 hours. The safe upper limit for storage is poorly defined. Histological studies of human small bowel stored in UW solution at 47C have shown no changes caused by preservation for up to 6 hours. By 9 hours of preservation, however, epithelial detachment started from the tips of villi and extended down into the crypts, and by 11 hours these changes were diffuse.8 Fewer than 20 cases of living donation have been performed. A detailed description of the techniques for removing a terminal ileal graft measuring up to 150 cm has been published by Gruessner and Sharp.9 It is not known if intestinal graft rejection rates will be reduced by HLA matching. It is worth noting, however, that the longest survivor after GIT in the precyclosporine era received an HLA-matched graft from her sibling.10 The potential advantages of living donation must be weighed against the risks, which include anastomotic leak, adhesion formation leading to intestinal obstruction, impaired absorption of vitamin B12, and impaired absorption of bile salts. To date, no donor deaths have been reported. Recipient Operation When performing isolated intestinal grafts, the donor superior mesenteric artery (SMA) is anastomosed to the recipient’s SMA or to the infrarenal abdominal aorta. For liver/small bowel and multivisceral grafts, a conduit of donor aorta containing the donor celiac and superior mesenteric arteries is anastomosed to the recipient’s supra-celiac or infra-renal aorta. Interestingly, it does not seem to matter whether the portal venous drainage of the graft is directed into the inferior vena cava (IVC) or into the portal system of the recipient.11 The proximal donor bowel is anastomosed to the native bowel. A stoma is created to provide endoscopic access for biopsies to monitor for, and to diagnose, graft rejection. The distal donor bowel is exteriorized as an end ileostomy or anastomosed end-to-end to the recipient’s colon, with creation of a proximal, diverting loop ileostomy. The ileostomy can be closed 3 months or more after the transplant once the recipient has fully recovered from the transplant surgery. Inclusion of colon in the graft is controversial and avoided by most centers. Experimental studies have shown that adding a colon segment slows intestinal transit time and improves absorption.12 However, clinical studies have suggested that adding the colon segment increases the rate of sepsis.13
Gastrointestinal Transplantation: An Update
Immune Suppression Most centers currently use tacrolimus, mycophenolate mofetil, and tapering doses of steroids for immune suppression after GIT. Tacrolimus is administered orally, aiming for trough levels of 20 to 30 ng/mL for the first month, 10 to 15 ng/mL by 3 months, and 7.5 to 10 ng/mL by 1 year. Patients must be monitored closely for evidence of nephrotoxicity and cardiac toxicity.14 More data are needed on the pharmacokinetics of mycophenolate mofetil in intestinal recipients and it must be kept in mind that this drug can be toxic to the small bowel.15 Other immune suppressive agents that are currently being evaluated include: anti– interleukin-2 antibodies, rapamycin, and antibodies against tumor necrosis factor. Eighty percent of intestinal recipients have 1 or more episodes of graft rejection.16 Whether a simultaneous liver graft reduces the risks of intestinal rejection, as initially predicted,17 is still controversial: some centers have reported a difference, while other centers have not (data presented at the Omaha Symposium by A. Lagnas, Omaha, NE; J. Reyes, Pittsburgh, PA; and O. Goulet, Paris, France). Early intestinal graft rejection is usually asymptomatic. Patients with advanced rejection present with fever, abdominal pain, increased stoma output, and an ileus. The most specific method to detect rejection is surveillance endoscopy (through the stoma) performed twice weekly during the first month, weekly for 3 months, and monthly for 1 year. The endoscopic features of graft rejection include edema, friability, erosions, granularity, hypomotility, and ulcers.18 Video magnification may enhance the sensitivity of endoscopy for the detection of rejection.19 One third of patients with graft rejection have a normal-appearing bowel18 and graft rejection can be patchy. Thus, multiple, random biopsy specimens must be obtained to avoid detection errors. The histological features of acute rejection range from an increased lymphocytic infiltrate in lamina propria, cryptitis, crypt apoptosis, and blunting of the villi, to severe exfoliation of the epithelium or a diffuse pseudomembranous enterocolitis.20,21 The ileum is most often affected, but the jejunum may be involved in the absence of ileal rejection. Viral enteritis and posttransplant lymphoproliferative disorders (PTLD) can be mistaken for graft rejection, and these conditions must be ruled out before giving extra immune suppression. Acute graft rejection is treated with corticosteroid boluses. Steroid-resistant rejection is treated with an antilymphocyte preparation. When treating severe re-
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jection, one must balance patient safety against the prospects for salvaging the graft. Severe rejection with mucosal denudation can resolve with additional immune suppression, but it is often a safer choice in this situation to stop immune suppression, remove the graft, resume PN, and list the patient for another transplant. Villous atrophy, subintimal vascular thickening, and muscular fibrosis characterize chronic rejection. A superior mesenteric angiogram may show segmental narrowing of jejunal and ileal arteries. A full-thickness biopsy may be required to confirm the diagnosis. As with other forms of chronic graft rejection, no effective treatment has been identified. Infections Risk factors for infections include the use of intense immune suppression, impaired gut barrier function due to preservation injury or graft rejection, and the requirement for central venous catheters to provide postoperative PN. Patients are started on enteral feedings soon after transplantation to optimize gut barrier function and reduce the risk of bacterial translocation. Glutamine supplementation of the PN and enteral feeds may enhance gut barrier function by (1) having a direct trophic effect on the intestinal mucosa, (2) increasing the level of secretory IgA, and (3) altering the composition of the intestinal flora, favoring bacterial species that lack the characteristics necessary for translocation.22 Intestinal recipients are given broad-spectrum antibacterial, antiviral, and antifungal prophylaxis to reduce the risk of sepsis. Specific strategies to prevent cytomegalovirus (CMV) infections include the use of CMV negative donor organs in CMV-negative recipients, the use of CMV-negative or leukocyte-depleted blood products, and the administration of hyperimmune globulin (which may also provide some protection against Epstein-Barr virus [EBV] infections). PTLD At the Omaha Symposium, the rate of PTLD in the patients in the Intestinal Transplant Registry was reported to range from 8% for small bowel recipients to 15% for multivisceral recipients; half of these cases had resolved with treatment. PTLD rates have been higher in children than in adults. The frequency of this complication has decreased since the introduction of routine screening of intestinal biopsy specimens and peripheral blood samples for EBV-early RNA (EBER).23 Increasing EBER titers and early PTLD are treated
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with high-dose gancyclovir and a reduction in immune suppression. Intestinal recipients with PTLD who do not improve on the latter therapies may respond to chemotherapy.24 Disease Recurrence There is one report of recurrent Crohn’s disease after small bowel transplantation.25
Graft and Patient Survival A preliminary analysis of latest data from the Intestinal Transplant Registry was presented at the Omaha Symposium. The database included information on 474 transplants in 446 patients who received transplants at 46 centers between January 1985 and May 1999. The types of transplants included the small bowel alone (46%), the intestine plus the liver (40%), and multivisceral transplants (14%). The 1-year graft and patient survival rates for transplants performed since 1995 were 57%/65% for intestinal grafts; 62%/ 66% for small bowel and liver grafts; and 52%/52% for multivisceral grafts. Graft and patient survival rates decreased by another 10% to 15% by 3 years, but these actuarial calculations may be misleading because most of the patients have been followed for a brief time. Patient and graft survival rates are 10% to 15% higher at centers that have performed more than 10 transplants, suggesting that there is a significant learning curve for GIT. The main causes of graft failure and death after GIT were graft rejection, sepsis, multiorgan failure, and PTLD. Graft Function Intestinal recipients are able to resume full enteral nutrition by 2 to 6 weeks. The delay in achieving full graft function is caused by multiple factors including denervation of the graft, lymphatic disruption, and the effects of reperfusion injury after preservation. The protocol for the introduction of enteral feeds varies from program to program. Janes et al26 recommend starting enteral feeding through a nasoduodenal tube within days of transplantation. They begin with an elemental formula, which is advanced to a peptidebased formula supplemented with medium chain triglyceride oil, and then to an intact protein with fiber diet. An oral diet is started simultaneously with clear fluids and switched to a regular diet as tolerated.26 Stoma output is initially high after GIT, but stool volumes gradually decrease to the normal range over time. Supplemental zinc and magnesium are often required during the early postoperative period. Fat
malabsorption is common because of lymphatic disruption; pancreatic enzyme supplementation may improve fat uptake. High ileostomy output is treated with bicarbonate, intravenous fluids, constipating agents such as loperamide or codeine, or octreotide and clonidine, which increase fluid and electrolyte absorption. GIT can provide independence from PN for many years. O. Goulet (Paris, France) reviewed the case of the longest survivor after GIT at the Omaha Symposium. This child lost her native small bowel because of a volvulus. She did not tolerate PN and underwent an isolated intestinal transplant at less than 1 year of age. Eleven years later, she is on an unrestricted oral diet. She does not require PN or supplemental fluids. She has grown and developed normally. Quality of Life Successful GIT provides a good quality of life. A retrospective study at the University of Pittsburgh reported significant improvement in psychological, physical, and social function following GIT as compared with the period of total PN dependence.27 An analysis of the Registry Database presented at the Omaha Symposium reported that more than 80% of the patients who had survived for more than 6 months after transplantation were independent of PN and had normal Karnofsky performance scores.
Future Directions The results of GIT are slowly improving. To become the standard treatment for intestinal failure, GIT will have to offer fewer risks, lower costs, and a better quality of life than PN.28 Safer and more effective immune suppressive protocols must be developed to achieve these goals.
References 1. Howard L, Heaphey L, Fleming CR, Lininger L, Steiger E. Four years of North American registry home parenteral nutrition: Outcome data and their implications for patient management. J Parenteral Enteral Nutr 1991;15:384-393. 2. Beath SV, Brook GA, Kelly DA, Buckels JA, Mayer AD. Demand for pediatric small bowel transplantation in the United Kingdom. Transplant Proc 1998;30:2531-2532. 3. Bueno J, Ohwada S, Kocoshis S, Mazariegos GV, Dvorchik I, Sigurdsson L, et al. Factors impacting the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999;34:27-32. 4. Beath SV, Needham SJ, Kelly DA, Booth IW, Raafat F, Buick RG, et al. Clinical features and prognosis of children assessed for
Gastrointestinal Transplantation: An Update
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
isolated small bowel or combined small bowel and liver transplantation. J Pediatr Surg 1997;32:459-461. Reyes J, Fishbein T, Bueno J, Mazariegos G, Abu-Elmagd K. Reduced-size orthotopic composite liver-intestinal allograft. Transplantation 1998;66:489-492. Sindhi R, Landmark J, Byers WS, Fox IJ, Heffron TG, Vanderhoof J, et al. Combined liver/small bowel transplantation using a blood group compatible but non-identical donor. Transplantation 1996;61:1782-1783. Langnas AN, Shaw BW Jr, Antonson DL, Kaufman SS, Mack DR, Heffron TG, et al. Preliminary experience with intestinal transplantation in infants and children. Pediatrics 1996;97:443448. Tesi RJ, Jaffe BM, McBride V, Haque S. Histopathologic changes in the human small intestine during storage in Viaspan organ preservation solution. Arch Pathol Lab Med 1997;121:714718. Gruessner RW, Sharp HL. Living-related intestinal transplantation: First report of a standardized surgical technique. Transplantation 1997;64:1605-1607. Fortner JG, Sichuk G, Litwin SD, Beattie EJ. Immunological responses to an intestinal allograft with HLA identical donorrecipient. Transplantation 1972;14:531-536. Grant D. Intestinal transplantation: 1997 report of the international registry. Intestinal Transplant Registry. Transplantation 1999;67:1061-1064. Black RT, Hashimoto T, Zhong RZ, Behme RJ, Garcia BM, Duff JH, et al. Transplantation of segmental rat intestinal grafts including the ileocecal value and the ascending colon. Transplantation 1994;57:997-1002. Abu-Elmagd K, Todo S, Tzakis A, Reyes J, Nour B, Furukawa H, et al. Three years clinical experience with intestinal transplantation. J Am Coll Surg 1995;179:385-400. Atkison P, Joubert G, Barron A, Grant D, Paradis K, Seidman E, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients [see comments]. Lancet 1995; 345:894-896. Ducloux D, Ottignon Y, Semhoun-Ducloux S, Labbe S, Saint-Hillier Y, Miguet JP, et al. Mycophenolate mofetil-induced villous atrophy. Transplantation 1998;66:1115-1116. Reyes J, Mazariegos GV. Pediatric transplantation. Surg Clin North Am 1999;79:163-189.
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17. Grant D, Wall W, Mimeault R, Zhong R, Garcia B, Stiller C, et al. Successful small-bowel/liver transplantation. Lancet 1990;335: 181-184. 18. Sigurdsson L, Reyes J, Putnam PE, del Rosario JF, Di Lorenzo C, Orenstein SR, et al. Endoscopies in pediatric small intestinal transplant recipients: Five years experience. Am J Gastroenterol 1998;93:207-211. 19. Kato T, O’Brien CB, Nishida S, Hoppe H, Gasser M, Berho M, et al. The first case report of the use of a zoom videoendoscope for the evaluation of small bowel graft mucosa in a human after intestinal transplantation. Gastrointest Endosc 1999;50:257261. 20. Lee RG, Nakamura K, Athanassios CT, Abu-Elmagd K, Furukawa H, Hutson W, et al. Pathology of human intestinal transplantation. Gastroenterology 1996;110:1820-1834. 21. Tsamandas AC, Furukawa H, Abu-Elmagd K, Todo S, Demetris AJ, Lee RG. Liver allograft pathology in liver/small bowel or multivisceral recipients. Mod Pathol 1996;9:767-773. 22. Li YS, Li JS, Jiang JW, Liu FN, Li N, Qin WS, Zhu H. Glycyl-glutamine enriched long term total parenteral nutrition attenduates bacterial translocation following small bowel transplantation in the pig. J Surg Res 1999;82:106-111. 23. Finn L, Reyes J, Bueno J, Yunis E. Epstein-Barr virus infections in children after transplantation of the small intestine. Am J Surg Pathol 1998;22:299-309. 24. Gross TG, Hinrichs SH, Winner J, Greiner TC, Kaufman SS, Sammut PH, et al. Treatment of post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation with low-dose chemotherapy [letter]. Ann Oncol 1998;9:339-340. 25. Sustento RN, Ruiz P, Rogers A, Viciana AL, Conn HO, Tzakis AG. Recurrent Crohn’s disease in transplanted bowel. Lancet 1997;349:688-691. 26. Janes S, Beath SV, Jones R, MacDonald A, Kelly DA. Enteral feeding after intestinal transplantation: The Birmingham experience. Transplant Proc 1997;29:1855-1856. 27. DiMartini A, Rovera GM, Graham TO, Furukawa H, Todo S, Funovits M, et al. Quality of life after small intestinal transplantation and among home parenteral nutrition patients. J Parenteral Enteral Nutr 1998;22:357-362. 28. Brook G. Quality of life issues: Parenteral nutrition to small bowel transplantation—A review. Nutrition 1998;14:813-816.
Gastrointestinal Transplantation: An Update Nagappan Kumar* and David Grant† Gastrointestinal transplantation is a life-saving option for patients who have chronic intestinal failure and cannot tolerate total parenteral nutrition (TPN). Early referral is important because of the scarcity of donors and the increased risk of complications in debilitated recipients. One-year patient survival rates range from 50% to 70%. Despite the use of intense immune suppression, most patients experience at least 1 episode of graft rejection. More than 80% of the survivors are able to stop TPN and resume an unrestricted oral diet. Patients with functioning grafts have a good quality of life. (Liver Transpl 2000;6:515-519.)
P
arenteral nutrition (PN) remains the standard of care for patients with intestinal failure. Because most patients on PN do well,1 transplantation is usually reserved for the patients with intestinal failure who cannot tolerate PN. Some of the indications for gastrointestinal transplantation (GIT) in children and adults are listed in Table 1. The need for GIT is estimated to be 2 to 3 cases per million per year, with equal numbers of pediatric and adult recipients.2
Patient Evaluation Early referral is important because of the scarcity of donors and the increased risk of complications in debilitated recipients. An expert panel, convened by Dr. A. Lagnas and Dr. S. Kaufman at the VI International Small Bowel Transplant Symposium, Omaha, NE, October 6-9, 1999, identified the following groups as having high failure rates on PN: (1) infants with less than 25 cm of small intestine, total intestinal aganglionosis, or microvillus inclusion disease; and (2) adults with a total small bowel resection resulting in a duodenal-to-colon anastomosis. In studies by Bueno et al3 and Beath et al,4 the presence of a bilirubin level of greater than 100 mmol/L, splenomegaly, or cirrhosis was associated with a high risk of death in infants on PN. Potential candidates for GIT require a careful assessment, including a detailed history to confirm PN dependency; radiographs to define the GI anatomy; a Doppler ultrasound survey to document vascular access; and motility studies. The diagnosis of Munchausen’s disease or Munchausen-by-proxy should be considered when symptoms seem exaggerated or improbable, when there are discrepancies between the claimed and
documented illnesses, or when there seems to be a temporal association between the presence of a parent and a deterioration in their child’s health.
Choice of Surgical Procedure An isolated small bowel transplant is the preferred surgical option. Transplantation should be considered when patients have had 1 or more episodes of lifethreatening intravenous catheter sepsis, when venous access becomes limited to less than half of the standard sites, or when there is progressive PN-induced liver dysfunction. Mild to moderate liver dysfunction with serum bilirubin levels of up to 100 mmol/L or more can be corrected with an isolated small bowel transplant. A combined liver and small bowel transplant is indicated for patients with bridging hepatic fibrosis or cirrhosis, portal hypertension, and/or severely impaired liver synthetic function. Multivisceral grafts with or without the liver, pancreas, and stomach are offered to (1) patients with diffuse motility disorders; (2) patients with unreconstructable GI tracts secondary to severe abdominal trauma, vascular events, or surgical misadventures; or (3) patients who require an evisceration to remove large desmoid tumors. The choice of surgery for patients with pseudoobstruction is controversial. When conventional treatment has been exhausted, one option is to remove the native jejunum, the ileum, and the distal stomach and then reconstruct the GI tract with the small bowel allograft, using the Roux-en-Y technique. Another option is to replace the native GI tract with a multivisceral graft. If a normal native liver is removed to facilitate multivisceral transplantation, the recipiFrom the *Department of Surgery, University of Western Ontario, London, Ontario, Canada; and †Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Address reprint requests to David Grant, MD, The Toronto General Hospital, 621 University Ave, Room NU-10-114, Toronto, Ontario, Canada M5G 2C4. Telephone: 416-340-5230; FAX: 416-595-1905; E-mail: [email protected] Copyright r 2000 by the American Association for the Study of Liver Diseases 1527-6465/00/0604-0027$3.00/0 doi:10.1053/jlts.2000.9126
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Table 1. Indications for Intestinal Transplantation Indications in Children Gastroschisis Hirschsprung’s disease Intestinal atresia Intractable diarrhea of infancy Microvillus inclusion and tufting disease Necrotizing enterocolitis Omphalocele Pseudo-obstruction Volvulus Indications in Adults Crohn’s disease Desmoid tumor Gardner’s syndrome Ischemia Pseudo-obstruction Trauma Volvulus
ent’s liver may be offered to another patient as a domino graft.
Organ Procurement Until recently, the criteria for intestinal donation have included the following: (1) negative cytomegalovirus (CMV) serology; (2) a donor weight of 20%-30% less than the recipient (to avoid space problems created by loss of the peritoneal domain when the native small bowel has been removed); and (3) an identical blood group with the recipient (to avoid the postoperative hemolysis caused by antibodies from B cells within the graft). Because of the high death rates on the waiting lists, these criteria are being reassessed.5,6 At the Omaha Symposium, J. de Ville de Goyet (Birmingham, UK) described techniques to transplant blood-group– compatible, reduced-size grafts with an up to 5-to-1 donor-to-recipient weight discrepancy. His approach included reducing the liver with an extra-hilar technique, resecting a portion of the mid-small bowel, debulking fatty tissues in the small bowel mesentery, and closing the abdominal wall with prosthetic materials. Most cadaveric liver donors are suitable candidates for intestinal donation. The intestinal graft can be dissected in situ or on the bench after removal. When the liver and small bowel are transplanted together, the duodenum and the head of the pancreas are kept intact to avoid the need for biliary reconstruction.7 Intestinal grafts can be stored in the University of
Wisconsin (UW) solution for 8 to 16 hours. The safe upper limit for storage is poorly defined. Histological studies of human small bowel stored in UW solution at 47C have shown no changes caused by preservation for up to 6 hours. By 9 hours of preservation, however, epithelial detachment started from the tips of villi and extended down into the crypts, and by 11 hours these changes were diffuse.8 Fewer than 20 cases of living donation have been performed. A detailed description of the techniques for removing a terminal ileal graft measuring up to 150 cm has been published by Gruessner and Sharp.9 It is not known if intestinal graft rejection rates will be reduced by HLA matching. It is worth noting, however, that the longest survivor after GIT in the precyclosporine era received an HLA-matched graft from her sibling.10 The potential advantages of living donation must be weighed against the risks, which include anastomotic leak, adhesion formation leading to intestinal obstruction, impaired absorption of vitamin B12, and impaired absorption of bile salts. To date, no donor deaths have been reported. Recipient Operation When performing isolated intestinal grafts, the donor superior mesenteric artery (SMA) is anastomosed to the recipient’s SMA or to the infrarenal abdominal aorta. For liver/small bowel and multivisceral grafts, a conduit of donor aorta containing the donor celiac and superior mesenteric arteries is anastomosed to the recipient’s supra-celiac or infra-renal aorta. Interestingly, it does not seem to matter whether the portal venous drainage of the graft is directed into the inferior vena cava (IVC) or into the portal system of the recipient.11 The proximal donor bowel is anastomosed to the native bowel. A stoma is created to provide endoscopic access for biopsies to monitor for, and to diagnose, graft rejection. The distal donor bowel is exteriorized as an end ileostomy or anastomosed end-to-end to the recipient’s colon, with creation of a proximal, diverting loop ileostomy. The ileostomy can be closed 3 months or more after the transplant once the recipient has fully recovered from the transplant surgery. Inclusion of colon in the graft is controversial and avoided by most centers. Experimental studies have shown that adding a colon segment slows intestinal transit time and improves absorption.12 However, clinical studies have suggested that adding the colon segment increases the rate of sepsis.13
Gastrointestinal Transplantation: An Update
Immune Suppression Most centers currently use tacrolimus, mycophenolate mofetil, and tapering doses of steroids for immune suppression after GIT. Tacrolimus is administered orally, aiming for trough levels of 20 to 30 ng/mL for the first month, 10 to 15 ng/mL by 3 months, and 7.5 to 10 ng/mL by 1 year. Patients must be monitored closely for evidence of nephrotoxicity and cardiac toxicity.14 More data are needed on the pharmacokinetics of mycophenolate mofetil in intestinal recipients and it must be kept in mind that this drug can be toxic to the small bowel.15 Other immune suppressive agents that are currently being evaluated include: anti– interleukin-2 antibodies, rapamycin, and antibodies against tumor necrosis factor. Eighty percent of intestinal recipients have 1 or more episodes of graft rejection.16 Whether a simultaneous liver graft reduces the risks of intestinal rejection, as initially predicted,17 is still controversial: some centers have reported a difference, while other centers have not (data presented at the Omaha Symposium by A. Lagnas, Omaha, NE; J. Reyes, Pittsburgh, PA; and O. Goulet, Paris, France). Early intestinal graft rejection is usually asymptomatic. Patients with advanced rejection present with fever, abdominal pain, increased stoma output, and an ileus. The most specific method to detect rejection is surveillance endoscopy (through the stoma) performed twice weekly during the first month, weekly for 3 months, and monthly for 1 year. The endoscopic features of graft rejection include edema, friability, erosions, granularity, hypomotility, and ulcers.18 Video magnification may enhance the sensitivity of endoscopy for the detection of rejection.19 One third of patients with graft rejection have a normal-appearing bowel18 and graft rejection can be patchy. Thus, multiple, random biopsy specimens must be obtained to avoid detection errors. The histological features of acute rejection range from an increased lymphocytic infiltrate in lamina propria, cryptitis, crypt apoptosis, and blunting of the villi, to severe exfoliation of the epithelium or a diffuse pseudomembranous enterocolitis.20,21 The ileum is most often affected, but the jejunum may be involved in the absence of ileal rejection. Viral enteritis and posttransplant lymphoproliferative disorders (PTLD) can be mistaken for graft rejection, and these conditions must be ruled out before giving extra immune suppression. Acute graft rejection is treated with corticosteroid boluses. Steroid-resistant rejection is treated with an antilymphocyte preparation. When treating severe re-
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jection, one must balance patient safety against the prospects for salvaging the graft. Severe rejection with mucosal denudation can resolve with additional immune suppression, but it is often a safer choice in this situation to stop immune suppression, remove the graft, resume PN, and list the patient for another transplant. Villous atrophy, subintimal vascular thickening, and muscular fibrosis characterize chronic rejection. A superior mesenteric angiogram may show segmental narrowing of jejunal and ileal arteries. A full-thickness biopsy may be required to confirm the diagnosis. As with other forms of chronic graft rejection, no effective treatment has been identified. Infections Risk factors for infections include the use of intense immune suppression, impaired gut barrier function due to preservation injury or graft rejection, and the requirement for central venous catheters to provide postoperative PN. Patients are started on enteral feedings soon after transplantation to optimize gut barrier function and reduce the risk of bacterial translocation. Glutamine supplementation of the PN and enteral feeds may enhance gut barrier function by (1) having a direct trophic effect on the intestinal mucosa, (2) increasing the level of secretory IgA, and (3) altering the composition of the intestinal flora, favoring bacterial species that lack the characteristics necessary for translocation.22 Intestinal recipients are given broad-spectrum antibacterial, antiviral, and antifungal prophylaxis to reduce the risk of sepsis. Specific strategies to prevent cytomegalovirus (CMV) infections include the use of CMV negative donor organs in CMV-negative recipients, the use of CMV-negative or leukocyte-depleted blood products, and the administration of hyperimmune globulin (which may also provide some protection against Epstein-Barr virus [EBV] infections). PTLD At the Omaha Symposium, the rate of PTLD in the patients in the Intestinal Transplant Registry was reported to range from 8% for small bowel recipients to 15% for multivisceral recipients; half of these cases had resolved with treatment. PTLD rates have been higher in children than in adults. The frequency of this complication has decreased since the introduction of routine screening of intestinal biopsy specimens and peripheral blood samples for EBV-early RNA (EBER).23 Increasing EBER titers and early PTLD are treated
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with high-dose gancyclovir and a reduction in immune suppression. Intestinal recipients with PTLD who do not improve on the latter therapies may respond to chemotherapy.24 Disease Recurrence There is one report of recurrent Crohn’s disease after small bowel transplantation.25
Graft and Patient Survival A preliminary analysis of latest data from the Intestinal Transplant Registry was presented at the Omaha Symposium. The database included information on 474 transplants in 446 patients who received transplants at 46 centers between January 1985 and May 1999. The types of transplants included the small bowel alone (46%), the intestine plus the liver (40%), and multivisceral transplants (14%). The 1-year graft and patient survival rates for transplants performed since 1995 were 57%/65% for intestinal grafts; 62%/ 66% for small bowel and liver grafts; and 52%/52% for multivisceral grafts. Graft and patient survival rates decreased by another 10% to 15% by 3 years, but these actuarial calculations may be misleading because most of the patients have been followed for a brief time. Patient and graft survival rates are 10% to 15% higher at centers that have performed more than 10 transplants, suggesting that there is a significant learning curve for GIT. The main causes of graft failure and death after GIT were graft rejection, sepsis, multiorgan failure, and PTLD. Graft Function Intestinal recipients are able to resume full enteral nutrition by 2 to 6 weeks. The delay in achieving full graft function is caused by multiple factors including denervation of the graft, lymphatic disruption, and the effects of reperfusion injury after preservation. The protocol for the introduction of enteral feeds varies from program to program. Janes et al26 recommend starting enteral feeding through a nasoduodenal tube within days of transplantation. They begin with an elemental formula, which is advanced to a peptidebased formula supplemented with medium chain triglyceride oil, and then to an intact protein with fiber diet. An oral diet is started simultaneously with clear fluids and switched to a regular diet as tolerated.26 Stoma output is initially high after GIT, but stool volumes gradually decrease to the normal range over time. Supplemental zinc and magnesium are often required during the early postoperative period. Fat
malabsorption is common because of lymphatic disruption; pancreatic enzyme supplementation may improve fat uptake. High ileostomy output is treated with bicarbonate, intravenous fluids, constipating agents such as loperamide or codeine, or octreotide and clonidine, which increase fluid and electrolyte absorption. GIT can provide independence from PN for many years. O. Goulet (Paris, France) reviewed the case of the longest survivor after GIT at the Omaha Symposium. This child lost her native small bowel because of a volvulus. She did not tolerate PN and underwent an isolated intestinal transplant at less than 1 year of age. Eleven years later, she is on an unrestricted oral diet. She does not require PN or supplemental fluids. She has grown and developed normally. Quality of Life Successful GIT provides a good quality of life. A retrospective study at the University of Pittsburgh reported significant improvement in psychological, physical, and social function following GIT as compared with the period of total PN dependence.27 An analysis of the Registry Database presented at the Omaha Symposium reported that more than 80% of the patients who had survived for more than 6 months after transplantation were independent of PN and had normal Karnofsky performance scores.
Future Directions The results of GIT are slowly improving. To become the standard treatment for intestinal failure, GIT will have to offer fewer risks, lower costs, and a better quality of life than PN.28 Safer and more effective immune suppressive protocols must be developed to achieve these goals.
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