Role of trophic factors

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Many SBS patients are unable to be weaned completely from PN even after implementation of an optimized diet and medical care as described. Despite advances in the provision of PN, this mode of nutritional support carries with it significant risks to the patient such as catheter sepsis, venous thrombosis and liver disease. This expensive, invasive therapy has also been shown to impair a patient's quality of life. As a consequence, there has been intense investigation to identify treatments that maximize intestinal absorption/adaptation with the goal of eliminating or at least minimizing the need for PN. Recent investigations in humans have focused on the use of trophic substances such as growth factors [e.g., growth hormone (GH) and glucagon-like peptide-2 (GLP-2)] and nutrients (e.g., glutamine).

A number of pharmacological agents including GH, glutamine and GLP-2 have been demonstrated to induce trophic properties on the intestinal epithelium in animal models of SBS. These encouraging reports have been followed by conflicting reports of efficacy in humans regarding the enhancement of intestinal absorption, adaptation and PN weaning. Several only uncontrolled trials with PN weaning as the primary endpoint using a combination of GH, glutamine and an optimized diet have been published [71-73]. Byrne et al. treated 47 patients, most of whom had a colon in continuity, with a combination of GH, oral glutamine and an optimized diet for 3 weeks followed by continued use of the diet and glutamine. With follow-up for as long as 5 years, they showed that 40% of patients could be weaned completely from PN, while another 40% could make significant reductions in their PN use. In a more recent uncontrolled, prospective case series, Zhu et al. used a similar treatment program and demonstrated very similar, long-lasting results [74]. Nevertheless, due to conflicting findings on nutrient absorption reported in three prospective, randomized, controlled trials [34, 75, 76], the role of this combination of trophic factors and diet remains controversial [77, 78].

Byrne and colleagues have recently completed a randomized, controlled, prospective study of this combination treatment approach in 41 PN-dependent SBS patients (most with colon in continuity) in which PN reduction was the primary endpoint [79]. The control group was treated with an optimized diet supplemented with glutamine. They demonstrated a significant reduction in PN requirements in all groups studied; however, the extent of reduction was greatest in the group in which GH was administered in addition to the diet and glutamine. The effect of this treatment on nutrient absorption and bowel morphology was not studied in this trial. On the basis of this evidence and the safety of the treatment program, the United States Food and Drug Administration recently approved the use of recombinant-human growth hormone [Zorbtiveâ„¢, somatropin [rDNA origin] for injection; Serono Inc., Rockland, MA] in patients with SBS on PN as an aid for PN weaning. While encouraging, further controlled studies investigating the optimal dose, duration and timing of administration in relation to the onset of SBS are needed before this therapy can be routinely advocated for SBS patients [80].

Glucagon-like peptide-2, secreted from distal small intestine and colonic mucosal L-cells after eating, appears to be a promising hormone that plays a role in adaptation [81]. GLP-2 administration induces epithelial proliferation in the stomach, small bowel and colon by stimulating crypt cell proliferation and inhibiting enterocyte apoptosis [82, 83]. Additional effects of GLP-2 include its abilities to increase absorptive capacity [84] and inhibit gut motility and secretion [85, 86]. In a small, open-label trial investigating the effects of GLP-2 in humans with SBS, eight patients including four without a colon and receiving PN and four without a colon who did not require PN, received 400 ^g GLP-2 twice daily for 35 days [87]. An increase in overall energy absorption, decrease in fecal wet weight, slowing of gastric emptying and nonsignificant trend toward increased jejunal villus height and crypt depth were demonstrated. More recently, a longer acting GLP-2 analogue, teduglutide (NPS Pharmaceuticals, Salt Lake City, UT), was shown to be safe, well-tolerated, intestinotrophic and significantly increase intestinal wet weight, but not energy absorption in 16 SBS patients with an end-jejunostomy or a colon in continuity [88]. Although there are currently no data on teduglutide's utility in PN weaning, a large, multinational, randomized, controlled trial to study this issue is currently in progress.

Peptide YY levels, also produced by L-cells in the distal small bowel and colon, are markedly elevated in patients with short-bowel syndrome [89]. Since this hormone inhibits gastrointestinal motility, peptide YY might play a role in functional adaptation. Although a peptide YY analogue is available, it has yet to be studied in humans with SBS [90].

Glutamine is a "conditionally essential" amino acid that is a primary energy source for the enterocyte and has been shown to prevent mucosal atrophy and deterioration of gut permeability in patients receiving PN [91]. In a study in which glutamine was added to an ORS provided to SBS patients with an end-jejunostomy, no benefit was seen in terms of fluid or sodium absorption [92]. In a recent randomized, controlled, crossover study, the role of oral glutamine was evaluated in eight patients with SBS. No difference in small bowel morphology, transit time, D-xylose absorption or stool output was seen [93]. Despite these negative studies, there is evidence that glutamine may have a synergistic effect with GH with regards to intestinal adaptation and PN weaning [79, 94, 95].

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