Intestinal transplantation for gut failure

Abstract

In recent years, we have witnessed increasing clinical experience with intestinal transplantation at selected centers. Although early results with this therapy were poor, several important advances have led to improved outcomes. These improvements prompted the Centers for Medicare and Medicaid Services to issue a memorandum on October 4, 2000, according federal reimbursement for intestinal transplantation at selected centers and for selected indications.1Health Care Financing Administration (HCFA), Program Memorandum Intermediaries/Carriers.Intestinal Transplantation. 2000; (December)Google Scholar The Centers for Medicare and Medicaid Services stipulated that, to qualify for transplantation, patients must meet a specific definition of intestinal failure and have experienced failure of parenteral nutrition (Table 1). In addition, the Centers for Medicare and Medicaid Services set forth center-specific criteria for reimbursement, including 1-year patient survival rates of at least 65% and minimum center volume of at least 10 transplants performed per year. Only 4 centers in the United States currently meet these criteria (Mount Sinai Medical Center, University of Pittsburgh Medical Center, University of Miami, and University of Nebraska Medical Center). Thus, intestinal transplantation is currently at a crossroads, transitioning from its historical status as an experimental therapy to standard care for patients with appropriate indications.Table 1Medicare-Approved Criteria for Failure of Parenteral NutritionImpending or overt liver failure due to TPN-induced liver injuryThrombosis of 2 or more central veinsThe development of 2 or more episodes of systemic sepsis secondary to line infection per year that requires hospitalization indicates failure of TPN therapyA single episode of line-related fungemia, septic shock, and/or acute respiratory distress syndrome is considered an indicator of TPN failureFrequent episodes of severe dehydration despite intravenous fluid supplementation in addition to TPN Open table in a new tab Presently, appropriate indications, timing of referral, and outcomes of intestinal transplantation are not well recognized among physicians caring for patients who may be candidates for this therapy. Definitions of terms such as “intestinal failure” and “failure of parenteral nutrition” are not standard, and there is no accepted algorithm for integrating parenteral nutrition, intestinal rehabilitation, and transplantation for patients with intestinal failure. Herein we review (1) the applicability of intestinal transplantation for patients with intestinal failure, (2) the current state of medical practice in intestinal transplantation with an emphasis on recent improvements, and (3) current results of this therapy. We also offer for the general gastroenterologist or gastrointestinal surgeon a rational approach to managing intestinal failure and integrating intestinal rehabilitation, parenteral nutrition, and transplantation.2Fishbein T.M. Schiano T. LeLeiko N. Facciuto M. Ben-Haim M. Emre S. Sheiner P.A. Schwartz M.E. Miller C.M. An integrated approach to intestinal failure results of a new program with TPN, bowel rehabilitation and transplantation.J Gastrointest Surg. 2002; 6: 554-562Crossref PubMed Scopus (48) Google Scholar Intestinal transplantation techniques were developed in animals and first attempted in humans in 1964 and 1967, when immunosuppression was relatively primitive and no allograft survived long-term.3Lillehei R.C. Goott B. Miller F.A. The physiological response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival.Ann Surg. 1959; 150: 543-560Crossref PubMed Scopus (213) Google Scholar, 4Starzl T.E. Kaupp Jr, H.A. Brock D.R. et al.Homotransplantation of multiple visceral organs.Am J Surg. 1962; 103: 219-229Abstract Full Text PDF PubMed Scopus (86) Google Scholar, 5Deterling R. Intestinal transplantation laboratory experience and a report of a clinical case.Am J Surg. 1971; 121 (Discussion of paper by Alican F, Hardy JD, Cayirili M, et al.): 150Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 6Lillehei R.C. Idezuki Y. Feemster J.A. Dietzman R.H. Kelly W.D. Merkel F.K. Goetz F.C. Lyons G.W. Manax W.G. Transplantation of stomach, intestine, and pancreas experimental and clinical observations.Surgery. 1967; 62: 721-741PubMed Google Scholar Parenteral nutrition did not yet exist, and patients with devastating intestinal catastrophes were treated with only supportive measures until their intestine compensated or they died of starvation. Patients with massive intestinal necrosis were often treated with only palliative measures. In the 1970s, as cyclosporine was introduced and the modern era of transplantation began, total parenteral nutrition (TPN) evolved to allow salvage and ultimately long-term survival of patients with devastating losses of gastrointestinal function or what we might now term intestinal failure.7Dudrick S.J. Wilmore D.W. Vars H.M. Rhoads J.E. Long-term parenteral nutrition with growth, development and positive nitrogen balance.Surgery. 1968; 64: 134-142PubMed Google Scholar Parenteral nutrition was far more successful than early attempts at transplantation.8Asfar S. Zhong R. Grant D. Small bowel transplantation.Surg Clin North Am. 1994; 74: 1197-1211PubMed Google Scholar, 9Howard L. Ament M. Fleming C.R. Shike M. Steiger E. Current use and clinical outcome of home parenteral nutrition therapies in the United States.Gastroenterology. 1995; 109: 355-365Abstract Full Text PDF PubMed Scopus (449) Google Scholar Eventually, increasing numbers of TPN-supported patients survived long enough to develop cholestatic liver failure, complete loss of access sites, or recurrent line-related episodes of sepsis.10Vanhuynegen L. Parmentier P. Portuliege C.A. In place bacteriologic diagnosis of total parenteral nutrition catheter infection.Surgery. 1988; 103: 174-177PubMed Google Scholar, 11Colomb V. Goult O. Ronbaud C. De Potter S. Long term parenteral nutrition in children liver and gallbladder disease.Transplant Proc. 1992; 24: 1054-1055PubMed Google Scholar, 12Fleming C.R. Hepatobiliary complications in adults receiving nutrition support.Dig Dis. 1994; 12: 191-198Crossref PubMed Scopus (42) Google Scholar In these patients with inadequate intestinal function and end-stage complications of parenteral nutrition, attempts at intestinal transplantation were renewed. Transplantation was offered as a late lifesaving salvage procedure rather than as primary therapy. Such patients were considered to have failed parenteral nutrition and were referred for transplantation with severe synthetic liver dysfunction, portal hypertension, and recurrent episodes of sepsis. In most cases, the intestine was transplanted in combination with a liver graft or as part of a multivisceral allograft (comprising the liver, pancreas, small bowel, and stomach, with or without additional organs in selected instances).13Grant D. Wall W. Mimeault R. Zhong R. Ghent C. Garcia B. Stiller C. Duff J. Successful small-bowel/liver transplantation.Lancet. 1990; 335: 181-184Abstract PubMed Scopus (403) Google Scholar, 14Starzl T.E. Rowe M.I. Todo S. Jaffe R. Tzakis A. Hoffman A.L. Esquivel C. Porter K.A. Venkataramanan R. Makowka L. et al.Transplantation of multiple abdominal viscera.JAMA. 1989; 261: 1449-1457Crossref PubMed Scopus (259) Google Scholar, 15Todo S. Tzakis A.G. Abu-Elmagd K. Reyes J. Nakamura K. Casavilla A. Selby R. Nour B.M. Wright H. Fung J.J. et al.Intestinal transplantation in composite visceral grafts or alone.Ann Surg. 1992; 216: 223-234Crossref PubMed Scopus (211) Google Scholar The graft was not routinely monitored for rejection, which was often diagnosed late. Little practical experience existed with regard to the diagnosis or treatment of rejection of the intestine, and success was limited by overwhelming rejection and infectious complications.16Starzl T.E. Todo S. Tzakis A. Alessiani M. Casavilla A. Abu-Elmagd K. Fung J.J. The many faces of multivisceral transplantation.Surg Gynecol Obstet. 1991; 172: 335-344PubMed Google Scholar In this early era, experience under immunosuppression with cyclosporine resulted in patient survival of only 57% and 50% at 1 and 3 years, even for only isolated intestinal transplant recipients; ultimately, the introduction of tacrolimus in 1989 improved isolated intestinal transplant survival to 83% and 47% at 1 and 3 years.17Grant D. Current results of intestinal transplantation. The International Intestinal Transplant Registry.Lancet. 1996; 347: 1801-1803Abstract PubMed Scopus (189) Google Scholar Intestinal failure can be defined as the inability of the native gastrointestinal tract to provide nutritional autonomy. Patients with intestinal failure require lifelong intravenous support to maintain caloric, fluid, or electrolyte homeostasis.18Mughal M. Irving M. Home parenteral nutrition in the United Kingdom and Ireland.Lancet. 1986; 2: 383-387Abstract PubMed Scopus (135) Google Scholar Replacement therapy in the form of parenteral nutrition, most often at home, permits survival for most patients.19Howard L. Hassan N. Home parenteral nutrition.Gastroenterol Clin North Am. 1998; 7: 481-512Abstract Full Text Full Text PDF Scopus (75) Google Scholar Home parenteral nutrition is therefore the primary long-term therapy for patients with intestinal failure. In 1992, it was estimated that more than 40,000 North American patients were receiving home parenteral nutrition.9Howard L. Ament M. Fleming C.R. Shike M. Steiger E. Current use and clinical outcome of home parenteral nutrition therapies in the United States.Gastroenterology. 1995; 109: 355-365Abstract Full Text PDF PubMed Scopus (449) Google Scholar It was further estimated that 15%–20% of patients on chronic parenteral nutrition could be candidates for transplantation.20Howard L. Current status of home parenteral nutrition in the United States.Transplant Proc. 1996; 28: 2691-2695PubMed Google Scholar Furthermore, it is estimated that, in western countries, approximately 2 new live births per million will eventually develop intestinal failure.21Van Gossum A. Preliminary results of the European survey of home parenteral nutrition.Presented to the European Society for Parenteral and Enteral Nutrition XVI Congress. 1994; (Birmingham, England, September 1)Google Scholar Thus, although the number of patients undergoing intestinal transplantation is currently small (approximately 100 per year in North America), the population for whom this transplant could be useful is potentially very large. Currently, patients considered for intestinal transplantation have intestinal failure and are receiving parenteral nutrition. Diseases that can lead to intestinal failure are categorized below as either loss of bowel length, loss of bowel function, or conventionally unresectable tumors involving the bowel. For each of these disease states, transplant candidacy is generally considered in the context of alternatives to transplantation, including the potential for rehabilitation of gastrointestinal function and weaning from parenteral nutrition or success with continuous lifelong parenteral nutrition.2Fishbein T.M. Schiano T. LeLeiko N. Facciuto M. Ben-Haim M. Emre S. Sheiner P.A. Schwartz M.E. Miller C.M. An integrated approach to intestinal failure results of a new program with TPN, bowel rehabilitation and transplantation.J Gastrointest Surg. 2002; 6: 554-562Crossref PubMed Scopus (48) Google Scholar Short-bowel syndrome, the loss of intestinal length and absorptive surface area due to surgical resection, is the most common cause of intestinal failure leading to intestinal transplantation.22Grant D. Intestinal transplantation 1997 report of the International Registry. Intestinal Transplant Registry.Transplantation. 1999; 67: 1061-1064Crossref PubMed Scopus (303) Google Scholar The loss of mucosal absorptive surface area is associated with malabsorption and rapid transit through the jejunoileum, with resultant malnutrition, recurrent dehydration, and electrolyte abnormalities. Short-bowel syndrome can be caused by a variety of diseases in adults, most of which result from vascular or ischemic insults (Figure 1). 23Messing B. Crenn P. Beau P. Boutron-Ruault M.C. Rambaud J.C. Matuchansky C. Long-term survival and parenteral nutrition dependence in adult patients with short-bowel syndrome.Gastroenterology. 1999; 117: 1043-1050Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 24Carbonnel F. Cosnes J. Chevret S. Beaugerie L. Ngo Y. Malafosse M. Parc R. Le Quintrec Y. Gendre J.P. The role of anatomic factors in nutritional autonomy after extensive small bowel resection.J Parenter Enteral Nutr. 1996; 20: 275-280Crossref PubMed Scopus (200) Google Scholar Adults frequently experience short-bowel syndrome due to trauma, thrombosis or embolism to the mesenteric vessels, inflammatory bowel disease, volvulus, radiation enteritis, or other causes of infarction. In children, disorders leading to intestinal failure include malrotation, volvulus, necrotizing enterocolitis, jejunoileal atresias, gastroschisis, omphalocele, and other congenital disorders.25Vargas J.H. Ament M.E. Berquist W.E. Long-term home parenteral nutrition in pediatrics ten years of experience in 102 patients.J Pediatr Gastroenterol Nutr. 1987; 6: 24-32Crossref PubMed Scopus (99) Google Scholar, 26Sigalet D.L. Short bowel syndrome in infants and children an overview.Semin Pediatr Surg. 2001; 10: 49-55Abstract Full Text PDF PubMed Scopus (117) Google Scholar Certain anatomic variables may also predict which patients with short-bowel syndrome will fail to wean from parenteral nutrition after resection. In a report by Messing et al.23Messing B. Crenn P. Beau P. Boutron-Ruault M.C. Rambaud J.C. Matuchansky C. Long-term survival and parenteral nutrition dependence in adult patients with short-bowel syndrome.Gastroenterology. 1999; 117: 1043-1050Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar on 124 adult patients with short-gut syndrome, <20% of patients with <100 cm of residual intestine or end jejunostomy could be weaned from parenteral nutrition even after 6 years. Additionally, patients with short-gut syndrome with underlying mucosal disease or higher metabolic demands due to larger body habitus have been shown to wean less successfully for a given length of bowel.27Sondheimer J.M. Asturias E. Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition.J Pediatr Gastroenterol Nutr. 1998; 27: 131-137Crossref PubMed Scopus (226) Google Scholar, 29Wilmore D.W. Lacey J.M. Soultanakis R.P. Bosch R.L. Byrne T.A. Factors predicting a successful outcome after pharmacologic bowel compensation.Ann Surg. 1997; 226: 288-293Crossref PubMed Scopus (86) Google Scholar In pediatric patients, less than approximately 30 cm of jejunoileum, lack of enterocolonic continuity, and lack of feeding tolerance early after birth correlate with failure of weaning from parenteral nutrition.25Vargas J.H. Ament M.E. Berquist W.E. Long-term home parenteral nutrition in pediatrics ten years of experience in 102 patients.J Pediatr Gastroenterol Nutr. 1987; 6: 24-32Crossref PubMed Scopus (99) Google Scholar, 28Pharaon I. Despres C. Aigrain Y. Grini A. Faure C. Matarazzo P. Navarro J. Cathelineau L. Cezard J.P. Long-term parenteral nutrition in children who are potentially candidates for small bowel transplantation.Transplant Proc. 1994; 26: 1442PubMed Google Scholar Functional disorders of the small intestine leading to intestinal failure include disorders of motility and disorders of enterocyte function. Motility disorders include chronic idiopathic intestinal pseudo-obstruction, visceral myopathy, visceral neuropathy, total intestinal aganglionosis, and some forms of mitochondrial respiratory chain disorders that affect gastrointestinal motor function (e.g., mitochondrial neurogastrointestinal encephalomyopathy or MNGIE syndrome).30Mousa H. Hyman P.E. Cocjin J. Flores A.F. Di Lorenzo C. Long-term outcome of congenital intestinal pseudoobstruction.Dig Dis Sci. 2002; 47: 2298-2305Crossref PubMed Scopus (87) Google Scholar Most are sporadic, and a high percentage of such patients (62%) may be dependent on parenteral nutrition.31Bardosi A. Creutzfeldt W. DiMauro S. Felgenhauer K. Friede R.L. Goebel H.H. Kohlschutter A. Mayer G. Rahlf G. Servidei S. Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder.Acta Neuropathol (Berl). 1987; 74: 248-258Crossref PubMed Scopus (147) Google Scholar Epithelial disorders causing intractable secretory diarrhea or failure of absorption in the intestine are more common in children, cause dependence on parenteral nutrition or death, and include microvillus inclusion disease, tufting enteropathy, and autoimmune enteritis.32Paramesh A.S. Fishbein T. Tschernia A. Leleiko N. Magid M.S. Gondolesi G.E. Kaufman S.S. Isolated small bowel transplantation for tufting enteropathy.J Pediatr Gastroenterol Nutr. 2003; 36: 138-140Crossref PubMed Scopus (30) Google Scholar, 33Goulet O.J. Brousse N. Canioni D. Walker-Smith J.A. Schmitz J. Phillips A.D. Syndrome of intractable diarrhoea with persistent villous atrophy in early childhood a clinicopathological survey of 47 cases.J Pediatr Gastroenterol Nutr. 1998; 26: 151-161Crossref PubMed Scopus (90) Google Scholar Tumors involving the base of the jejunoileal mesentery are often benign but are locally invasive and therefore lethal. Only complete resection of the tumor and sacrifice of the intestine can provide cure. The most common of these lesions are desmoid tumors in patients with familial adenomatous polyposis.34Olivier C. Retorri R. Baur O. Roux J. Homotransplantation orthotopique de l’intestin grele et des colons droit et transverse chez l’homme.J Chir (Paris). 1969; 98: 323-330PubMed Google Scholar, 35Chatzipetrou M.A. Tzakis A.G. Pinna A.D. Kato T. Misiakos E.P. Tsaroucha A.K. Weppler D. Ruiz P. Berho M. Fishbein T. Conn H.O. Ricordi C. Intestinal transplantation for the treatment of desmoid tumors associated with familial adenomatous polyposis.Surgery. 2001; 129: 277-281Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar This tumor is a leading cause of death among patients with intestinal polyposis syndromes after colon cancer, which is increasingly avoided with early detection and colectomy.36Galle T.S. Juel K. Bulow S. Causes of death in familial adenomatous polyposis.Scand J Gastroenterol. 1999; 34: 808-812Crossref PubMed Scopus (91) Google Scholar This tumor often involves the mesenteric vessels, foreshortens the mesentery, and requires exenteration of the small bowel for complete resection. Sometimes the tumors involve other foregut organs that provide portal flow to the liver, such as the pancreas, spleen, stomach, and duodenum. Removal of all these organs without concurrent intestinal transplantation would result in liver failure due to the absence of any portal blood supply. Therefore, patients with desmoid tumors sometimes do not have conventional intestinal failure and are not dependent on parenteral nutrition before resection and transplantation, which may be performed concurrently. Some evidence for a desmoid progression sequence similar to that of polyps and colon cancer exists; if this evidence accumulates, allowing early detection, late diagnosis with multiorgan involvement will hopefully decrease.37Clark S.K. Smith T.G. Katz D.E. Reznek R.H. Phillips R.K. Identification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis.Br J Surg. 1998; 85: 970-973Crossref PubMed Scopus (59) Google Scholar, 38Bertario L. Russo A. Sala P. Eboli M. Giarola M. D’amico F. Gismondi V. Varesco L. Pierotti M.A. Radice P. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.Int J Cancer. 2001; 95: 102-107Crossref PubMed Scopus (179) Google Scholar Indications for intestinal transplantation are those complications that lead to failure of parenteral therapy. Among these are parenteral nutrition-associated liver disease, loss of venous access, and recurrent sepsis. In fact, complications led to death in 10%–40% of patients with intestinal failure during the first 3–5 years on therapy.19Howard L. Hassan N. Home parenteral nutrition.Gastroenterol Clin North Am. 1998; 7: 481-512Abstract Full Text Full Text PDF Scopus (75) Google Scholar, 25Vargas J.H. Ament M.E. Berquist W.E. Long-term home parenteral nutrition in pediatrics ten years of experience in 102 patients.J Pediatr Gastroenterol Nutr. 1987; 6: 24-32Crossref PubMed Scopus (99) Google Scholar, 39Scolapio J. Fleming R. Kelly D. Wick D. Zinsmeister A. Survival of home parenteral nutrition treated patients 20 years of experience at Mayo Clinic.Mayo Clin Proc. 1999; 74: 217-222Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 40Van Gossum A. Vahedi K. Abdel-Malik Staun M. Pertkiewicz M. Shaffer J. Hebuterne X. Beau P. Guedon C. Schmit A. Tjellesen L. Messing B. Forbes A. ESPEN-HAN Working GroupClinical, social and rehabilitation status of long-term home parenteral nutrition patients results of a European multicentre survey.Clin Nutr. 2001; 20: 205-210Abstract Full Text PDF PubMed Scopus (117) Google Scholar Patients developing these complications can be considered to have failed parenteral therapy and may be candidates for intestinal transplantation. Additionally, some patients develop recurrent electrolyte disturbances, dehydration, and renal stone disease requiring recurrent hospitalizations. Patients with ultrashort gut (<50 cm), secretory diarrhea, and total jejunoileal loss are particularly prone to these latter disorders.41Fishbein T. Kaufman S. Schiano T. Gondolesi G. Florman S. Tschernia A. LeLeiko N. Miller C. Intestinal and multiorgan transplantation the Mount Sinai experience.Transplant Proc. 2002; 34: 891-892Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Such patients often have gastric or duodenal tubes draining upper intestinal contents externally, with no chance for establishment of enterocolonic continuity. Indications for transplantation as established by the Centers for Medicare and Medicaid Services are shown in Table 1. They include impending or overt liver failure due to TPN-induced liver injury, thrombosis of 2 or more central veins, the development of 2 or more episodes of systemic sepsis secondary to line infection per year that require hospitalization, a single episode of line-related fungemia, septic shock and/or acute respiratory distress, and frequent episodes of severe dehydration despite intravenous fluid supplementation in addition to TPN.1Health Care Financing Administration (HCFA), Program Memorandum Intermediaries/Carriers.Intestinal Transplantation. 2000; (December)Google Scholar Although anecdotal case reports of liver dysfunction during parenteral nutrition therapy previously constituted the only available natural history data, recent reports confirm the significant incidence of biologically relevant cholestasis.11Colomb V. Goult O. Ronbaud C. De Potter S. Long term parenteral nutrition in children liver and gallbladder disease.Transplant Proc. 1992; 24: 1054-1055PubMed Google Scholar, 42Chan S. McCowen K.C. Bistrian B.R. Thibault A. Keane-Ellison M. Forse R.A. Babineau T. Burke P. Incidence, prognosis, and etiology of end-stage liver disease in patients receiving home total parenteral nutrition.Surgery. 1999; 126: 28-34Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Cavicchi et al.43Cavicchi M, Beau P, Creen P, Degott C, Messing B. Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Ann Intern Med 132:525–532.Google Scholar recently reported an incidence of liver-related complications of more than 50% after 5 years of continuous use of parenteral nutrition in patients with intestinal failure. Factors that predicted such complications included ultra short-gut syndrome (<50 cm in adults), the presence of a jejunostomy, and parenteral formulas with lipid contents >1 g−1 · kg−1 · day−1. In children, the inability to wean from parenteral nutrition within 2 years after resection and early development of cholestasis are predictors of an early poor outcome.25Vargas J.H. Ament M.E. Berquist W.E. Long-term home parenteral nutrition in pediatrics ten years of experience in 102 patients.J Pediatr Gastroenterol Nutr. 1987; 6: 24-32Crossref PubMed Scopus (99) Google Scholar, 28Pharaon I. Despres C. Aigrain Y. Grini A. Faure C. Matarazzo P. Navarro J. Cathelineau L. Cezard J.P. Long-term parenteral nutrition in children who are potentially candidates for small bowel transplantation.Transplant Proc. 1994; 26: 1442PubMed Google Scholar, 44Kelly D.A. Liver complications of pediatric parenteral nutrition-etiology.Nutrition. 1998; 14: 153-157Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar Other factors affecting the probability of long-term survival with chronic parenteral nutrition are also recognized. The underlying primary intestinal disorder is one such factor, and various reports confirm that adults with underlying motility disorders are at higher risk for death on continuous parenteral nutrition than are adult patients with short-gut syndrome, with nearly 50% dying within 5 years.9Howard L. Ament M. Fleming C.R. Shike M. Steiger E. Current use and clinical outcome of home parenteral nutrition therapies in the United States.Gastroenterology. 1995; 109: 355-365Abstract Full Text PDF PubMed Scopus (449) Google Scholar, 39Scolapio J. Fleming R. Kelly D. Wick D. Zinsmeister A. Survival of home parenteral nutrition treated patients 20 years of experience at Mayo Clinic.Mayo Clin Proc. 1999; 74: 217-222Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar By contrast, Reyes et al.45Reyes J. Mazariegos G.V. Bond G.M. Green M. Dvorchik I. Kosmach-Park B. Abu-Elmagd K. Pediatric intestinal transplantation historical notes, principles and controversies.Pediatr Transplant. 2002; 6: 193-207Crossref PubMed Scopus (78) Google Scholar report that children developing intestinal failure who are younger than 1 year of age have only a 40% survival at 2 years but that patients with functional disorders appear to live longer than those with short-gut syndrome. A significant percentage of patients referred for intestinal transplantation die while waiting for an organ. In children, Bueno et al. reported that increased bilirubin level (>3 mg/dL) at the time of referral correlated with death on the transplant waiting list, as did histologic features of advanced liver disease.46Bueno J. Ohwada S. Kocoshis S. Mazariegos G.V. Dvorchik I. Sigurdsson L. Di Lorenzo C. Abu-Elmagd K. Reyes J. Factors inpacting the survival of children with intestinal failure referred for intestinal transplantation.J Pediatr Surg. 1999; 34: 27-33Abstract Full Text PDF PubMed Scopus (135) Google Scholar Therefore, it is important to bear in mind that early cholestasis should trigger referral or consultation with a center experienced in intestinal transplantation.27Sondheimer J.M. Asturias E. Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition.J Pediatr Gastroenterol Nutr. 1998; 27: 131-137Crossref PubMed Scopus (226) Google Scholar, 47Fecteau A. Atkinson P. Grant D. Early referral is essential for successful pediatric small bowel transplantation the Canadian experience.J Pediatr Surg. 2001; 36: 681-684Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 48Kaufman S.S. Atkinson J.B. Bianchi A. Goulet O.J. Grant D. Langnas A.N. McDiarmid S.V. Mittal N. Reyes J. Tzakis A.G. Indications for pediatric intestinal transplantation a position paper of the American Society of Transplantation.Pediatr Transplant. 2001; 5: 80-87Crossref PubMed Scopus (284) Google Scholar The degree of liver disease in patients with short-gut syndrome is often underestimated, and progression may be more rapid than anticipated. Because the portal flow largely comes from the mesenteric circulation, patients with short-gut syndrome have low portal flow. Consequently, the complications of portal hypertension such as variceal bleeding, ascites, and hepatorenal syndrome do not arise until late in the course of disease. In our experience, progressive thrombocytopenia and cholestasis are the most reliable indicators of developing liver dysfunction. Thus, in our program, we follow sequential platelet count and bilirubin levels and quantify spleen volumes every 2 months by ultrasonography. Progressive trends showing early development of splenomegaly or thrombocytopenia suggest development of liver disease, prompting listing for intestinal transplantation. We have recently witnessed reversal of even stage 3 fibrosis and severe cholestasis after successful isolated intestinal transplantation and discontinuation of parenteral nutrition (Fishbein et al., manuscript in submission).49The Intestinal Transplant Registry. 2003; (Available at: http://www.intestinaltransplant.org. Accessed January 13)Google Scholar Although early results of intestinal transplantation suggested improved results with liver-containing grafts, current results of both pooled data in the international registry and single-center results contradict these assertions.49The Intestinal Transplant Registry. 2003; (Available at: http://www.intestinaltransplant.org. Accessed January 13)Google Scholar Some have called for referral after development of irreversible liver failure, but the current worsening and sev