Investigational: Trophic Factors and Intestinal AdaptationAn increasing number of factors have been identified which can promote epithelial growth, increase epithelial absorptive function and effect intestinal growth Table 1. This section highlights three of the most well-described of these factors: Glucagon-like peptide 2 (GLP-2), epidermal growth factor (EGF) and human growth hormone (GH). As an introduction to these state of art lectures, below is a brief introduction to humoral growth factors and several points which must be taken into consideration prior to the usage of these factors in a clinical setting. Humoral Factors after Formation of SBSThe large number of factors which promote intestinal epithelial cell growth, and the marked redundancy of the system, clearly emphasizes the importance of this action, Table 1. The appreciation that the system is truly redundant is best shown by demonstrating normal intestinal development with the production of IGF-1, IGF-1 receptor or IGF-2 knockout mice.1 An important question regarding the role of these humoral factors during adaptation is what happens to levels of these factors post-resection? Interestingly, the expression of some of these factors have been shown to decrease, including the finding that GH levels are depressed in many SBS patients.2 Whereas many other humoral factors are markedly increased after the development of SBS, including IGF-1, KGF, GLP-1 and 2, and EGF 3-7. It appears that levels of some of these factors may help predict the clinical status of SBS patients. SBS patients with failure to thrive have been correlated to lower IGF-1 levels.8 Further the levels of GLP-2 has been correlated to the ability to wean infants off of TPN.9 As illustrated by Jeppesen, using exogenous delivery of humoral factors, the gastrointestinal tract appears to have the potential to further the adaptive process beyond that mediated by the normal adaptive process.10 Table 1 Click here to Download a PDF of Table 1 
The Effect of Multiple FactorsAlthough most studies have dealt with predominately single humoral growth factors, this strategy clearly does not replicate the normal adaptive process, whereby a number of these factors are simultaneously expressed. The combination of growth factors, or growth factors and enteral factors, may have a greater effect than isolated factors. This is well-illustrated by the studies of Iannoli, et al where a combination of GH and EGF were given in a rabbit SBS model.11, 12 In these study, the combination of these two growth factors, led to a greater increase in microvillus height and enhanced nutrient transport, than could be achieved by either single factor. Additionally, although the administration of either GH or EGF had no benefit in promoting villus hypertrophy, the combination improved enterocyte function.12 This additive effect of factors may help to explain the lack of observed action in some reports.13 Additionally, enteral factors may also work in conjunction with humoral growth factors to augment the adaptive process. In a study by Ziegler, et al, the combination of glutamine (GLN) and IGF-1 was examined in rats.14 In this study, adaptation was increased (as measured by DNA content) with either agent. However, the combination of both factors had an additional benefit of synergistically increasing the plasma levels of IGF-1 above those found in non-resected rats. Similarly, Zhou, et al showed that a combination of fiber and GH can also act synergistically to improve SBS adaptation.15 Therapeutic Use of Humoral FactorsEpidermal growth factor has been extensively studied in several animal models.16 In addition to demonstrating that EGF is increased in a mouse SBS model, these authors have nicely shown that receptors to EGF (EGFR and another EGFR family member ErbB2 (c-neu)), increased significantly in this model. The distribution of these receptors was quite interesting, being found predominantly in the crypt of the mucosa, but as well within the muscularis of the gut wall. The mechanism by which the action of EGF is mediated may go beyond induction of proliferation, but as well a modulation of the expression of bcl-2 proteins, to reduce the rate of apoptosis.
The clinical efficacy of GLP-2 in patients with SBS has been studied in two clinical studies in adult SBS patients, and shows extremely encouraging results. In a non-masked study of 8 SBS patients, a number of positive effects of GLP-2 were noted.17 These patients lacked a distal small bowel and colon, and thus had very little endogenous GLP-2; and were without the normal post-prandial elevation in GLP-2 levels. Nutrient absorption was carefully measured in this study, and was found to increase by 3.5%. A significant increase in protein absorption, and a non-significant increase in carbohydrate absorption was noted; however, no significant change was found in fat absorption. Morphometric analysis of the small intestine demonstrated an increase in villus height and crypt depth in the majority of their patients. In a follow-up study of 10 SBS patients using the dipeptidyl peptidase IV resistant recombinant human GLP-2 analog, teduglutide, for a 21 day period, similar increases in wet nutrient absorption were noted, however intestinal energy absorption was not found to be significant. Results of an on-going multi-institutional study of this agent should provide critical information on the clinical applicability of this agent.
Growth hormone (GH) has been studied in 5 clinical studies. Three of these have been controlled trials which failed to show efficacy, and 2 trials (one controlled the other uncontrolled) showed efficacy. The perceived weight gain in some of these patients was due to extracellular water accumulation as opposed to actual anabolism - which emphasizes the importance of detailed measurements of nutrient absorption in the performance of these trials. The benefits of GH in the two latter studies maintain the possibility that GH may have clinical applications. The fact that human GH is the only FDA approved drug emphasizes the importance of his review, and all clinicians considering use of this agent should carefully read this section. Considerations for Clinical Application of Humoral FactorsClearly, bringing the use of these factors to the clinical setting has finally come to fruition with the FDA approval of human GH in the treatment of patients with SBS, and advancement of human trials for GLP-2. Still, there are numerous areas which need to be addressed. Little attention has been directed to the pediatric SBS patient in many of these studies - a group which bears some of the highest rates of morbidity and mortality.18, 19 Additionally, several other growth modulating factors may also be applicable for clinical study; including: KGF; EGF; and HGF - none of which have even undergone Phase I trials. Obstacles to the use of many of these factors is the small targeted population, which may have little appeal for many pharmaceutical companies. Another obstacle is the fact that some of these factors (e.g., EGF) no longer have an active patent. Another consideration is defining what outcome measures should be used to determine clinical efficacy. As noted above, humans do not show the marked degree of villus hypertrophy observed in rodents, dogs and other laboratory animals. Additionally, some humoral factors may be efficacious on one aspect of adaptation, but not others. Finally, some of these 'growth' factors have many other properties including anti-apoptotic effects and anti-oxidative injury actions - which have not been routinely examined in many clinical trials.16, 20, 21 Thus, a negative effect may be due to selecting an incorrect or non-applicable outcome measure. Finally, it is possible that a lack of observed efficacy may be due to a deficiency of another enteral or humoral factor which acts synergistically with the factor being studied (e.g., use of GH with glutamine and a modified enteral diet). Potential Risks with the Usage of These FactorsAnother potential obstacle to bringing humoral factors to clinical usage is the fear that use of agents which promote epithelial growth may lead to inappropriate levels of proliferation, or potentially carcinomatous changes, either within the gastrointestinal tract or elsewhere. Clearly, agents such as EGF have been shown to promote growth of several tumor lines; and the ErbB receptors for EGF have been closely linked to the invassivness of breast carcinoma.22 Thus, caution must be exercised with the use of some of these agents, particularly on a long-term nature. Additionally, many of these factors, including IGF-1, KGF, IL-11 and EGF can also promote epithelial proliferation outside of the gastrotintestinal tract. As an example, early trials of KGF for treatment of mucositis in patients receiving chemotherapy have been associated with development pancreatitis and airway narrowing due to the epithelial proliferative response.23 Another critical question is how long an individual must remain on these growth factors. In Jeppesen's studies, the patients were treated for no more than 5 weeks. Although clinical benefit was observed, it is not known whether these benefits (increased nutrient absorption and villus hypertrophy) remain after termination of GLP-2. In the studies by Byrne, et al, long-lasting effects were noted (40% remained off TPN at 1 year); however, these studies did involve more than just a humoral factor - including optimization of enteral feeding and glutamine supplementation as well.24 In studies of GH alone, the improvement in nutrient absorption was lost after the drug was discontinued.25 Thus, it is possible that the decision to use humoral factors in SBS patients may commit such patients to life-long therapy with these agents. Finally, one must consider the great costs that many of these factors will contribute to the overall care of SBS patients. Clearly, one would want to see not just a measurable improvement with the use of these factors, but a true ability to impact on cost-reduction before advocating for the wide-spread usage of these drugs. Nevertheless, as pointed out in the review by Warner, even a 5% reduction in the usage of TPN by SBS patients could result in a 50 million dollar annual reduction in health-related costs. In conclusion, a growing number of humoral growth factors have been shown to have the potential to augment intestinal adaptation in patients suffering from SBS. Recent clinical trials offer the potential of a new modality to care for such patients. Selection of appropriate patients for these new therapies, and ensuring efficacy of these factors will be important objectives over the next several years. Below is a partial listing of some of the more established humoral factors which promote SBS adaptation. Actions may be via epithelial proliferation, reduction in epithelial apoptosis, and/or increase in epithelial function. Source of the factor has been separated between derived from the small bowel versus a distal source. In many cases this distinction is difficult to make, as the factor may be derived from several sources. Mucosal-derived humoral factors:
Distantly-derived humoral factors:
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