Parenteral Nutrition-Dependent Short Bowel Syndrome Research Articles

Cost-effectiveness of teduglutide in adult patients with short bowel syndrome – a European socioeconomic perspective

BackgroundShort bowel syndrome with intestinal failure (SBS-IF) is a rare but devastating medical condition. An absolute loss of bowel length forces the patients into parenteral support dependency and a variety of medical sequelae, resulting in increased morbidity and mortality. Interdisciplinary treatment may include therapy with the effective but expensive intestinotrophic peptide teduglutide. ObjectivesA time-discrete Markov model was developed to simulate the treatment effect [lifetime costs, quality-adjusted life years (QALYs), and life years (LYs)] of teduglutide plus best supportive care compared with best supportive care alone in patients with SBS-IF. MethodsThe health status of the model was structured around the number of days on PS. Clinical data from 3 data sets were used: 1) an Austrian observational study (base case), 2) pooled observational cohort studies, and 3) a prospective study of teduglutide effectiveness in parenteral nutrition-dependent short bowel syndrome subjects. Direct and indirect costs were derived from published sources. QALYs, LYs, and costs were discounted (3% per annum). ResultsUnder the base case assumption, teduglutide is associated with costs of 2,296,311 € per patient and 10.78 QALYs (13.74 LYs) over a lifetime horizon. No teduglutide is associated with 1,236,816 € and 2.24 QALYs (8.57 LYs). The incremental cost-utility ratio (ICUR) amounts to 123,945 €. In case of the pooled clinical data set, the ICUR increases to 184,961 €. If clinical data based on the study of teduglutide effectiveness in parenteral nutrition-dependent short bowel syndrome subjects were used, the ICUR increased to 235,612 €. ConclusionsTeduglutide in treating patients with SBS-IF meets the traditional cost-effectiveness criteria from a European societal perspective. Nevertheless, the varying concentrations of teduglutide efficacy leave a degree of uncertainty in the calculations.

Featuring molecular regulation of bile acid homeostasis in pediatric short bowel syndrome.

Disturbed bile acid homeostasis may foster development of short bowel syndrome (SBS) associated liver disease during and after weaning off parenteral nutrition (PN). Our aim was to study hepatic molecular regulation of bile acid homeostasis in relation to serum and fecal bile acid profiles in pediatric SBS. Liver histopathology and mRNA expression of genes regulating synthesis, uptake and export of bile acids, and cellular receptors involved in bile acid signaling were measured in SBS patients (n=33, median age 3.2 years). Simultaneously, serum (n=24) and fecal (n=10) bile acid profiles were assessed. Sixteen patients were currently on PN. Results of patients were compared to healthy control subjects. Nine of ten (90%) patients with histological cholestasis received current PN, while portal inflammation was present in 60% (6/10) of patients with cholestasis compared to 13% (3/23) without cholestasis (P=0.01). In all SBS patients, hepatic synthesis and uptake of bile acids was increased. Patients on current PN showed widespread repression of hepatic FXR target genes, including downregulated canalicular (BSEP, MDR3) and basolateral (MRP3) bile acid exporters. Serum and fecal primary bile acids were increased both during and after weaning off PN. Bile acid homeostasis in SBS is characterized by interrupted enterohepatic circulation promoting increased hepatic synthesis and conservation of bile acids. In PN dependent SBS patients with hepatic cholestasis and inflammation, the molecular fingerprint of downregulated hepatocyte canalicular and basolateral bile acid export with simultaneously increased synthesis and uptake of bile acids could favor their accumulation in hepatocytes and predispose to liver disease.

Changes in Parenteral Nutrition Requirements and BMI in Patients with Parenteral Nutrition-Dependent Short Bowel Syndrome after Stopping Teduglutide-9 Years of Follow-Up.

Teduglutide (TED) is widely used in patients with short-bowel-syndrome-associated intestinal failure (SBS-IF) to enhance intestinal adaptation and reduce the need for parenteral support (PS). There are limited data on the effects of discontinuing TED. In this study, we describe the changes in parenteral nutrition (PN) requirements and body mass index (BMI) in a 9-year follow-up of patients receiving home parenteral nutrition after discontinuation of the TED treatment. We performed a retrospective analysis of changes in weekly PN orders and BMI in all patients with PN-dependent SBS from two Polish home parenteral nutrition (HPN) centers who received teduglutide between 2009 and 2013 and still required HPN 9 years after discontinuation of the TED treatment. Data included in the analysis were collected prospectively at mandatory visits to the HPN centers at 12, 24, 60, 84, and 108 months after drug discontinuation and compared with values before and after TED treatment. Weekly PN volume values varied significantly between all of the above time points from baseline to 9 years after TED discontinuation (χ2 = 34.860, p < 0.001). After an initial increase within the first year after treatment discontinuation (not statistically significant), the PN volume requirements remained stable for 4 years and increased 5–9 years after treatment discontinuation. The rate of patients requiring an increase in PN volume was 84.62% at 60 and 84 months and 92.30% at 108 months. At 9 years after cessation of the TED treatment, 53.85% of the study group required a 21.21% increase in PN volume compared with values before treatment. The need for PN volume in patients with PN-dependent SBS who discontinued the TED treatment increased within the first year and 4–5 years after treatment cessation, and in some cases might even exceed pretreatment values after 9 years.

Colon polyps in patients with short bowel syndrome before and after teduglutide: Post hoc analysis of the STEPS study series.

Teduglutide promotes intestinal growth and is approved for the treatment of short bowel syndrome and intestinal failure (SBS-IF). Based on the pharmacologic activity and preclinical findings, teduglutide can potentially induce proliferative colonic mucosal changes.The aim of this study is to report the occurrence of colorectal polyps in adult patients with SBS-IF who received teduglutide in clinical studies conducted to date. A post hoc analysis of the completed Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent Short Bowel Syndrome Subjects (STEPS) clinical study series (NCT00798967, EudraCT 2008-006193-15; NCT00930644, EudraCT 2009-011679-65; NCT01560403) evaluated electronic case report form data for baseline colonoscopies (performed before treatment) and for surveillance or end-of-study (performed after treatment with teduglutide 0.05mg/kg/day for 24 and 36 months) post-exposure procedures. In the STEPS studies, 73 patients treated with teduglutide had a baseline colonoscopy. No post-exposure colonoscopy was scheduled in STEPS. In STEPS-2/3, 50 of 65 patients with remnant colon (77%) underwent a protocol-mandated post-exposure colonoscopy. Colon polyps were reported at baseline in 12% (9/73) of patients and post-exposure in 18% (9/50) of patients. Two had polyps both at baseline and post-exposure. On histology, available for 7 patients, 5 had adenomas (1 serrated, 4 tubular) and none had malignancy or high-grade dysplasia. These data support recommendations for colonoscopic screening before teduglutide therapy and subsequent on-therapy colonoscopic surveillance for patients with SBS-IF. Further studies are required to assess the risk of polyp formation in patients with SBS-IF and the most appropriate colon polyp surveillance strategies.

Predictors of Response to Teduglutide Among Patients with Parenteral Nutrition–Dependent Short Bowel Syndrome

Introduction: The study aimed to identify factors associated with sustained parenteral nutrition (PN) volume reduction and early vs late responders among PN-dependent short bowel syndrome patients treated with teduglutide (TED). Methods: The study population was 43 patients receiving TED in a 24-week randomized placebo-controlled trial (STEPS: NCT00798967; EudraCT2008-006193-15) who could continue TED up to 24 months in the open-label extension (STEPS-2: NCT00930644; EudraCT2009-011679-65). Time to sustained PN volume reduction (i.e., PN volume reduction ≥20% at 2 consecutive visits) was calculated using Kaplan-Meier analysis. Multivariable Cox model was used to identify factors associated with sustained PN volume reduction. Among patients achieving sustained PN volume reduction, baseline characteristics were compared between early (PN volume reduction ≥20% at week 20 and 24) vs. late responders (sustained PN volume reduction at 2 consecutive visits after week 24). Results: The median time to sustained PN volume reduction was 4.2 months. Patients with stoma, compared to those without, were significantly more likely to achieve sustained PN volume reduction (hazard ratio [HR], 5.6; P = 0.01). Patients with an ileocecal valve, compared to those without (HR = 0.1; P = 0.03), and patients with major intestinal resection due to vascular disease, compared to those with Crohn’s disease (HR = 0.2; P = 0.02), were significantly less likely to achieve sustained PN volume reduction. Compared to late responders (n = 7), early responders (n = 27) were less likely to have colon-in-continuity (52% vs 100%; P = 0.02) and ileocecal valve (0% vs 29%; P < 0.01), and had smaller mean percentage of colon remaining (25% vs 57%; P = 0.02). The median time to sustained PN volume reduction was 3.7 months for early responders and 7.8 months for late responders. Conclusion: Presence of stoma and absence of ileocecal valve are good prognosis factors for achieving sustained PN volume reduction while vascular disease as cause of intestinal resection is a negative prognosis factor. Certain anatomical factors were significantly different between early and late responders. This research was funded by Shire Human Genetic Therapies, Inc., Lexington, MA, USA.

Predictors of Response to Teduglutide Among Patients with Parenteral Nutrition-Dependent Short Bowel Syndrome

Introduction: The study aimed to identify factors associated with sustained parenteral nutrition volume reduction and early vs. late responders among parenteral nutrition-dependent short bowel syndrome patients treated with teduglutide. Methods: The study population was 43 patients receiving teduglutide in a 24-week randomized placebocontrolled trial (STEPS: NCT00798967; EudraCT2008-006193-15) who could continue teduglutide up to 24 months in the open-label extension (STEPS-2: NCT00930644; EudraCT2009-011679-65). Time to sustained parenteral nutrition volume reduction (i.e., parenteral nutrition volume reduction ≥20% at 2 consecutive visits) was calculated using Kaplan-Meier analysis. Multivariable Cox model was used to identify factors associated with sustained parenteral nutrition volume reduction. Among patients achieving sustained parenteral nutrition volume reduction, baseline characteristics were compared between early (parenteral nutrition volume reduction ≥20% at week 20 and 24) vs. late responders (sustained parenteral nutrition volume reduction at 2 consecutive visits after week 24). Results: The median time to sustained parenteral nutrition volume reduction was 4.2 months. Patients with stoma, compared to those without, were significantly more likely to achieve sustained parenteral nutrition volume reduction (hazard ratio=5.6; P=0.01). Patients with an ileocecal valve, compared to those without (hazard ratio=0.1; P=0.03), and patients with major intestinal resection due to vascular disease, compared to those with Crohn's disease (hazard ratio=0.2; P=0.02), were significantly less likely to achieve sustained parenteral nutrition volume reduction. Compared to late responders (n=7), early responders (n=27) were less likely to have colon-in-continuity (52% vs. 100%; P=0.02) and ileocecal valve (0% vs. 29%; P=0.02). The median time to sustained parenteral nutrition volume reduction was 3.7 months for early responders and 7.8 months for late responders Conclusion: Presence of stoma and absence of ileocaecal valve are good prognosis factors for achieving sustained parenteral nutrition volume reduction, while vascular disease as the cause of intestinal resection is a negative prognosis factor. Certain anatomical factors were significantly different between early and late responders

SUN-P061: Clinical Status of Patients with Parenteral Nutrition-Dependent Short Bowel Syndrome 4 Years after Teduglutide Treatment

SUN-P061: Clinical Status of Patients with Parenteral Nutrition-Dependent Short Bowel Syndrome 4 Years after Teduglutide Treatment

Pharmacological strategies to enhance adaptation in intestinal failure.

Intestinal failure because of more or less extensive resection of parts of the small and large intestine (short bowel syndrome) results from the reduction of absorptive surface of the remaining intestine and frequently results in dependence on parenteral nutrition. Parenteral nutrition, although lifesaving, is associated with short and long-term complications as well as with reduced quality of life and overall survival. Pharmacological enhancement of the physiological intestinal adaptive response by subcutaneous application of the glucagon-like peptide 2 analogue teduglutide results in an improved, hyperadaptive response. This is reflected by decreased parenteral calorie and fluid requirements, decreased parenteral nutrition infusion days per week including complete weaning off parenteral nutrition with complete oral autonomy, improved quality of life, and metabolic and nutritional stability. The advent of teduglutide as an authority-approved specific medication for intestinal failure in parenteral nutrition-dependent short bowel syndrome offers an effective and beneficial treatment for these patients. As a result, patients are more stable whether for medical or further surgical management including intestinal transplantation. Long-term efficacy and safety still have to be proven.

Tis7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome.

Effective therapies are limited for patients with parenteral nutrition-dependent short bowel syndrome. We previously showed that intestinal expression of the transcriptional coregulator tetradecanoyl phorbol acetate-induced sequence 7 (tis7) is markedly increased during the adaptive response following massive small bowel resection and tis7 plays a role in normal gut lipid metabolism. Here, we further explore the functional implications of tis7 deletion in intestinal lipid metabolism and the adaptive response following small bowel resection. Intestinal tis7 transgenic (tis7(tg)), tis7(-/-), and wild-type (WT) littermates were subjected to 50% small bowel resection. Mice were fed a control or a high-saturated-fat (42% energy) diet for 21 days. Survival, body weight recovery, lipid absorption, mucosal lipid analysis, and the morphometric adaptive response were analyzed. Quantitative real-time PCR was performed to identify tis7 downstream gene targets. Postresection survival was markedly reduced in high-fat, but not control, diet-fed tis7(-/-) mice. Decreased survival was associated with anastomotic inflammation and intestinal obstruction postresection. High-fat, but not control, diet-fed tis7(-/-) mice had increased intestinal IL-6 expression. Intestinal lipid trafficking was altered in tis7(-/-) compared with WT mice postresection. In contrast, high-fat diet-fed tis7(tg) mice had improved survival postresection compared with WT littermates. High-fat diet feeding in the setting of tis7 deletion resulted in postresection anastomotic inflammation and small bowel obstruction. Tolerance of a calorie-rich, high-fat diet postresection may require tis7 and its target genes. The presence of luminal fat in the setting of tis7 deletion promotes an intestinal inflammatory response postresection.

Study of teduglutide effectiveness in parenteral nutrition-dependent short-bowel syndrome subjects

Loss of intestinal absorptive capacity from congenital defect, surgical resection or mucosal disease results in short bowel syndrome (SBS)-associated intestinal failure. In the past, few medical management options were available besides dietary modification, controlling diarrhea or high stomal output, and providing parenteral fluid, electrolyte and nutrient support (parenteral support). Recent research on strategies to enhance the intestinal absorptive capacity focused on glucagon-like peptide-2, an intestinotrophic hormone that has been shown to increase the villus height and crypt depth, and decrease gastric motility and intestinal secretory losses. STEPS is a Phase III randomized double-blinded controlled trial in which teduglutide, a recombinant analog of glucagon-like peptide-2, or placebo was given subcutaneously to SBS patients for 24 weeks. A clinically meaningful response, defined as a 20–100% reduction in parenteral support volume, was achieved in 63% of the treatment group compared with 30% in the placebo group (p = 0.002) without an increase in serious side effects. Teduglutide offers a new targeted approach to SBS-associated intestinal failure management. Its specific role in clinical practice remains to be evaluated.

Etiology and Initial Management of Short Bowel Syndrome

o he normal human small intestine ranges between 3 and 8 m in length, depending on whether measureent is made by radiologic or surgical techniques or at utopsy when the intestine may be desicated.1–5 Short owel syndrome is defined in adults as 200 cm of small ntestine. Although usually acquired because of one or ore enterectomies, short bowel syndrome may also be ongenitally acquired. Nutrient, electrolyte, and fluid bsorption is proportional to the amount of residual ntestine. The degree of intestinal function is better escribed in terms of energy absorption/loss rather than ength of residual intestine.6 Intestinal failure may be efined as the inability to sustain adequate nutritional, lectrolyte, or hydrational status in the absence of speialized nutritional support. This requires an increase in ral intake because absorption is compromised. Clinially, nutrient assimilation is a function of intake and bsorption. As such, some patients with short bowel yndrome will not have sufficient loss of functional caacity as to develop intestinal failure. Significant indiidual variability in jejunal absorption efficiency may be ncountered.7 The patients with the greatest risk for development of ehydration, generalized protein-calorie malnutrition, nd multiple nutrient deficiencies are those with a duoenostomy or jejunoileal anastomosis and 35 cm of esidual small intestine; jejunocolic or ileocoloic anastoosis, and 60 cm of residual small intestine; or end ejunostomy with 115 cm of residual small intesine.6,8–11 Those patients with residual colon in continuty will have enhanced energy and fluid absorption. ence, such patients can tolerate greater loss of small ntestine and retain their nutritional autonomy.

Living‐related intestinal transplantation for a patient with hypoganglionosis

A 14-yr-old boy with total parenteral nutrition-dependent short-bowel syndrome associated with hypoganglionosis underwent the LR-IT by using a 150 cm segment of distal ileum taken from a healthy donor. The graft vessels were connected to infrarenal aorta and inferior vena cava. The immunosuppressive regimen consisted of daclizumab, tacrolimus, and steroid. The graft surveillance for ACR was accomplished using zoom endoscopy and mucosal biopsy. The blood trough level of tacrolimus was maintained between 20 and 25 ng/mL for the first 2 months, followed by 15-20 ng/mL thereafter. The 50 mg of daclizumab was administered on the day of operation, and same dosage was repeated at 2-wk intervals. The first ACR occurred on POD-9 and was progressive, and required a 14-day course of OKT-3 injection. After the treatment with OKT-3, the graft recovered from the ACR, and began to function well enough to discontinue the intravenous nutrition on POD-55. No infectious complication has occurred. The patient was discharged in POD-112, and currently tolerates full oral intake without requiring intravenous nutritional or fluid supplementation. The donor was discharged without any complications. The LR-IT could successfully be performed with minimal risk to the donor, and it can be a treatment of choice for patients with short-gut syndrome associated with hypoganglionosis.

Low-dose growth hormone in adult home parenteral nutrition–dependent short bowel syndrome patients: A positive study

Background & Aims: Controversy surrounds a 3-week treatment with a high-dose (0.14 mg · kg −1 · day −1) growth hormone (GH), glutamine, and high carbohydrate diet in home parenteral nutrition (HPN)-dependent patients with short-bowel syndrome (SBS). This study assessed treatment with low-dose GH in these patients. Methods: Twelve adult HPN-dependent (duration, 7 ± 1 years; mean ± SEM) patients with SBS (small-bowel remnant length, 48 ± 11 cm) who were on an unrestricted hyperphagic diet were randomized in a double-blind, placebo-controlled, crossover study. Patients received daily low-dose GH (0.05 mg · kg −1 · day −1) and placebo for two 3-week periods separated by a 1-week washout period. Net intestinal absorption of macronutrients was assessed using a duplicate diet; nutritional assessment and blood tests were performed. Data from each group were compared using Wilcoxon rank sum test. Results: Treatment with GH increased intestinal absorption of energy (15% ± 5%, P < 0.002), nitrogen (14% ± 6%, P < 0.04), carbohydrates (10% ± 4%, P < 0.04), and fat (12% ± 8%, NS). The increased food absorption represented 37% ± 16% of total parenteral energy delivery. Body weight ( P < 0.003), lean body mass ( P < 0.006), D-xylose absorption ( P < 0.02), insulin-like growth factor 1 ( P < 0.002), and insulin-like growth factor binding protein 3 ( P < 0.002) increased, whereas uptake of GH binding protein decreased ( P < 0.01), without any major adverse effect. Conclusions: Three weeks of low-dose GH significantly improved intestinal absorption in HPN-dependent SBS patients who were on a hyperphagic western diet.