Intestinal failure is a condition requiring the use of parenteral nutrition as long as it persists. Causes of severe protracted intestinal failure include short bowel syndrome, congenital diseases of enterocyte development, and severe motility disorders (total or subtotal aganglionosis or chronic intestinal pseudo-obstruction syndrome). Intestinal failure may be irreversible in some patients, thus requiring permanent parenteral nutrition. Liver disease may develop with subsequent end-stage liver cirrhosis in patients with intestinal failure as a consequence of both underlying digestive disease and unadapted parenteral nutrition. Death will occur if combined liver-intestine transplantation is not performed. Catheter-related sepsis and/or extensive vascular thrombosis may impede the continuation of a safe and efficient parenteral nutrition and may also require intestinal transplantation in some selected cases. Thus management of patients with intestinal failure requires an early recognition of the condition and the analysis of its risk of irreversibility. Timing of referral for intestinal transplantation remains a crucial issue. As a consequence, management should include therapies adapted to each stage of intestinal failure based on a multidisciplinary approach in centers involving pediatric gastroenterology, parenteral nutrition expertise, home parenteral nutrition program, pediatric surgery, and liver intestinal transplantation program.

Intestinal transplantation has become a standard treatment for intestinal failure in patients with life-threatening complications of TPN. Although the long-term survival of patients with continued parenteral nutrition is higher than after intestinal transplantation, the 1 and 2 year survival is comparable. Here we examine other aspects of the treatment options available for patients with intestinal failure including the cost of the therapy and the quality of life. The cost of parenteral nutrition compared to intestinal transplantation reveals that transplantation is cost-effective in patients that maintain graft function within 1 to 3 years after surgery. The quality of life after transplantation is probably equal to or better than quality of life on TPN and children report quality of life similar to normal school children. Although currently reserved for those with life-threatening complications, intestinal transplantation may soon be an option for any patient permanently dependent on parenteral nutrition.

Current treatment options for patients suffering from intestinal insufficiency include all forms of intestinal replacement therapy (IRT). Parenteral nutrition has achieved extended success for the majority of patients requiring interval treatment, however, complications leading to failure of this treatment increases with the duration of therapy. There is currently no consensus as to the appropriate timing for transplantation of the intestine or the timing of referral for evaluation at a center experienced with this therapy. Certain patient characteristics warrant evaluation. Those patients with no jejunoileum who have guaranteed lifelong parenteral dependence, both adult and pediatric, should be immediately referred to a transplant center due to the high likelihood of the development of liver disease. Patients with metastatic infectious complications from catheter sepsis, patients with cholestasis seen intermittently with sepsis episodes, patients who are not successfully weaning and who demonstrate progressive thrombocytopenia, and patients with motility disorder experiencing deterioration should also warrant early referral to an intestinal rehabilitation and transplant program. The objective of evaluation is to maximize the opportunities for rehabilitation while not missing the critical window of opportunity for successful transplantation when needed. We favor an aggressive directed approach to rehabilitation, coupled with psychological preparation for both transplantations and other options. Early referral requires trust between the patient, referring physician, and the transplant team to assure that a rush to judgment will not lead to a premature transplant. The current wait list mortality is high, mandating early referral and listing with an approach aimed at maximizing both the success of gastrointestinal support, as well as of transplantation when necessary.

The short bowel state is treatable, with acceptable long-term quality of life. Management during the first 6-12 months of life is critical but, presently, frequently compromises long-term survival and prospects. At first presentation, primary caregivers, working with specialists at designated intestinal failure centers, should develop a structured individual-oriented management plan. Preservation of venous access, "hepatosparing" parenteral nutrition, and avoidance of liver sepsis are crucial to survival. Early surgery should be limited to conservation of autologous bowel, even short bowel lengths having great potential, and to facilitating natural intestinal adaptation. Bowel expansion may be relevant prior to delayed bowel reconstruction with single or combined techniques that include bowel lengthening and/or tailoring, reversed segments, and colon interposition. Bowel transplantation, as yet not recommended for primary management, offers survival and opportunity to those with no prospect of autologous bowel autonomy or following failed autologous gastrointestinal reconstruction. This paper reviews current surgery for the short bowel state and concludes that it is presently appropriate before bowel transplantation to offer autologous gastrointestinal reconstruction, with its prospect of enteral autonomy with quality life. It emphasizes the need for an individual-oriented management plan, developed jointly at the time of first presentation between the primary caregivers and a designated multidisciplinary intestinal failure center, to enhance the prospects for enteral autonomy preferably on autologous bowel. Autologous gastrointestinal reconstruction is in its infancy and requires resources, commitment, and research from dedicated bowel reconstructive surgeons toward a better opportunity for the child and family with short bowel.

Although long-term parenteral nutrition is lifesaving in patients with intestinal failure, it is expensive and associated with serious complications such as catheter sepsis, venous occlusions, and liver failure and severely impairs the quality of life in the short bowel patients. Therefore, treatments that increase the absolute intestinal absorption, thereby eliminating or minimizing the need for parenteral support, are needed. In this respect, glucagon-like peptide 2 (GLP-2) has received attention. In this review, the nature of the short bowel syndrome is described, and the antisecretory, transit-modulating, but also intestinotrophic effects of GLP-2 are presented. As illustrated in 2 pilot studies, one using native GLP-2 and the other a degradation-resistant analogue, teduglutide, these new agents may prove important in optimizing remnant intestinal function, thereby eliminating the need for parenteral support and improving quality of life in short bowel patients with intestinal failure.

There has been recent clinical enthusiasm for treating short bowel patients with either human recombinant growth hormone alone or in combination with glutamine and diet in hopes of reducing their parenteral nutrition requirements. Part of this interest has been the result of studies done in short bowel animal models showing increased bowel growth and function following such treatment. Since 1995, 5 key clinical studies have been published in peer-reviewed literature reporting the effects of growth hormone alone or in combination with glutamine and diet in patients with short bowel syndrome. Three of these controlled studies have reported negative results, and 1 controlled and 1 uncontrolled study reported positive results. This review discusses each of these articles and provides some explanation on how these studies and results may have differed.

This review examines the preclinical rationale for using glutamine supplements and reviews the prospective randomized trials using glutamine to improve outcomes in patients. A special role for glutamine in gut physiology and in management of a variety of serious illnesses has been suggested, because it is the most abundant extracellular amino acid, and is used at high rates by the gut, liver, central nervous system, and immune cells. A state of relative Gln deficiency has been postulated in humans based on the decrease in plasma Gln in acute critical illness, but the decrease in plasma Gln is not specific for that amino acid, predicts only poorer outcome, and has not been validated to identify a deficiency state. Current evidence does not necessarily predict a special need or role for Gln in critical illness. Clinical efficacy of supplemental Gln has been difficult to demonstrate, possibly related to the lack of a Gln deficiency state, the wide range of end points used that reflect the lack of certainty of the predicted effect of supplementation, the heterogeneous patient populations studied, the lack of stable clinical course during the study, the lack of adequate power, and the relatively short follow-up period. Prospective randomized clinical trials of Gln supplementation were reviewed in patients with short-bowel syndrome, during cancer chemotherapy and in bone marrow transplantation, and in surgical, burn, and intensive care unit patients. No firm recommendation can be made at this time. Future studies should seek to develop a more standard and stable design for intervention in sufficiently powered studies.

In 1984, Barry Marshall and Robin Warren proposed a role for bacterial infections in the pathogenesis of gastroduodenal disease, which triggered an avalanche of research intended to prove or disprove their theory. The result has been a series of advances that have enhanced our understanding of these diseases and completely modernized the clinical approach to their management. In just over 20 years, many aspects of the immunopathogenesis of these diseases have been dissected at the molecular level, with key pathogenic mechanisms being validated by the identification of genes that are associated with the development of gastric cancer. There has been particular emphasis on understanding the molecular structures associated with Helicobacter pylori and their role in modifying the host responses. Gastric immune and inflammatory responses have emerged as key elements in the pathogenesis of gastritis and epithelial cell damage. This review summarizes important findings emanating from basic research primarily related to the immunopathogenesis of H pylori that have advanced the practice of medicine or our understanding of gastroduodenal disease.

Progression of cancer is dependent on acquisition of vascular networks within the tumor. Tumor angiogenesis is dependent on up-regulation of angiogenesis stimulators to overcome the endogenous anti-angiogenic barrier. Such disruption of angiogenesis balance to favor neovascularization is a key step for progression of tumor growth and metastasis. In this regard, the vascular basement membrane and the extracellular matrix have been found to be rich sources of angiogenesis stimulators and inhibitors that become bioavailable on proteolysis of the matrix by tumor microenvironment-related enzymes. In this review the subgroup of endogenous angiogenesis stimulators and inhibitors is discussed, and their mechanism of action during tumor angiogenesis is evaluated. The role in regulating tumor growth and the possibility of using them as prognostic markers for human gastrointestinal cancers is discussed. Furthermore, we specifically address the role of vascular endothelial growth factor in human gastrointestinal cancers and discuss the development and use of bevacizumab (Avastin; anti-vascular endothelial growth factor antibody [Genentech, CA]) in the treatment of colorectal and other gastrointestinal cancers.