Clinical Characteristics of Inflammatory Bowel Disease Patients Requiring Long-Term Parenteral Support in the Present Era of Highly Effective Biologic Therapy.

BACKGROUND: Despite advances in the medical management of inflammatory bowel disease (IBD), a subset of patients may require extensive surgery, leading to short-bowel syndrome/intestinal failure requiring long-term home parenteral nutrition (PN) or customized intravenous fluid (IVF) support. Our aim was to further define the characteristics of IBD patients requiring home PN/IVF. METHODS: This is an observational study from a prospective IBD research registry. Patients receiving long-term home PN/IVF support during 2009-2015 were identified and compared with remaining IBD patients. Demographics, surgical history, smoking, narcotic use, IBD treatment, healthcare charges, and presence of biomarkers were reviewed. The IBD-PN group was stratified into 3 groups based on median healthcare charges. RESULTS: Of 2359 IBD patients, there were 25 (1%, 24 with Crohn's disease) who required home PN/IVF, and 250 randomly selected IBD patients matched for disease type formed the control population. Median duration of PN use was 27 months (interquartile range, 11-66). PN use was significantly associated with smoking, narcotic use, IBD-related operations, and lower quality-of-life scores. Among IBD-PN patients, 7 of 25 (28%, 3 after use of teduglutide) were able to successfully discontinue this modality. Median healthcare charges in the IBD-PN group were $51,456 annually. Median charges in the controls were $3427. Period prevalence mortality was 11.5% in IBD-PN and 3.8% in controls. CONCLUSIONS: IBD patients requiring long-term home PN/IVF support are a small minority in the present era of immunomodulator/biologic therapy. These refractory patients have a 15-fold increase in annual median healthcare charges compared with control IBD patients.

The Need to Reassess Dietary Fiber Requirements in Healthy and Critically Ill Patients.

This article provides evidence that current dietary fiber intake levels may be insufficient to maintain colonic mucosal health and defense, and reduce inflammation and cancer risk in otherwise healthy people. Current commercial tube feeds generally overlook the metabolic needs of the colon and may predispose patients to dysbiosis, bacterial overgrowth with pathogens such as Clostridium difficile, and acute colitis. These results raise concern about the wide-scale use of prophylactic antibiotics in the intensive care unit and the use of elemental, fiber-depleted tube feeds. Nutrition support is not complete without the addition of sufficient fiber to meet colonic nutritional needs.

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.

Therapeutic efficacy of intestinal and multivisceral transplantation: survival and nutrition outcome.

The clinical introduction of intestinal transplantation has added a new dimension and offered a valid therapeutic option for patients with irreversible intestinal failure. In the year 2000, the Center for Medicare & Medicaid Services (CMS) recognized intestinal, combined liver-intestinal, and multivisceral transplantation as the standard of care for patients with irreversible intestinal and parenteral nutrition (PN) failure. Accordingly, the indications for the procedure are currently limited to those who develop life-threatening PN complications. However, a recent improvement in survival similar to other solid organ transplant recipients should justify lifting the current restricted criteria, and the procedure should be considered before the development of PN failure. Equally important is the awareness of the recent evolution in nutrition management and outcome after transplantation. Early and progressive enteral feeding using a complex polymeric formula is safe and effective after successful transplantation. Full nutrition autonomy is universally achievable among most intestinal and multivisceral recipients, with enjoyment of unrestricted oral diet. Such a therapeutic benefit is commonly maintained among long-term survivors, with full rehabilitation and restoration of quality of life.

Physiological evaluation of the severity of pancreatic exocrine dysfunction during endoscopy.

OBJECTIVES: Despite the advances in pancreatic imaging, there continues to be a need to measure exocrine function to determine which patient requires enzyme supplementation. To evaluate the potential use of a rapid endoscopic test that can be conducted by nonacademic centers, we investigated whether concentration of trypsin in food-stimulated secretion is related to trypsin synthesis and secretion. METHODS: Subjects include 22 chronic pancreatitis patients (10 mild, 5 moderate, and 7 severe radiological disease) and 11 healthy controls. During upper gastrointestinal endoscopy, pancreatic secretion was stimulated by a single 30-mL duodenal injection of an enteral diet, followed 5 minutes later by periampullary juice aspiration (endoscopic pancreatic function test [ePFT]). This was followed by a conventional 2-hour marker-perfusion diet-stimulated pancreatic trypsin secretion and synthesis study (2-hour PFT [2hPFT]). RESULTS: Severity of radiological disease was associated with a progressive loss of enzyme secretion measured by the 2hPFT. The endoscopic PFT correlated positively with 2hPFT (r2 = 0.48; P < 0.0001) and an activity of less than 5% of the average normal had a 96% specificity and 75% sensitivity for the detection of pancreatic insufficiency as defined by a loss of greater than 90% of pancreatic secretion. CONCLUSIONS: The diagnostic power of endoscopy may be enhanced by the collection of a pancreatic juice sample after enteral feed stimulation because measurement of the trypsin content will identify chronic pancreatitis patients who will be benefited by enzyme supplementation.

Nutrition and quality of life following small intestinal transplantation.

BACKGROUND: The outcome from small bowel transplantation (SBTx) has improved progressively over the past decade raising questions as to whether indications should be broadened from those currently followed based on "TPN (total parenteral nutrition) failure." OBJECTIVE AND METHODS: To assess current outcome, we studied the effect of transplantation on nutritional autonomy, organ function, and quality of life (QoL) measured by a validated self-administered questionnaire containing 26 domains and 130 questions, for a minimum of 12 months in a cohort of 46 consecutively transplanted patients between June 2003 and July 2004. The majority of transplanted patients (76%) had intestinal failure because of extreme short bowel, the remainder having either chronic pseudo-obstruction or porto-mesenteric vein thrombosis (PMVT). All but the PMVT patients were dependent on home TPN (HPN) (median 2, range 0-25 yr) and had developed serious recurrent infective complications with (25%) or without central vein thrombosis and liver failure. Sixty-one percent received a liver in addition to a small intestine. RESULTS: Follow-up was for a mean of 21 (range 12-36) months. Five patients died, two with chronic graft rejection. All the remaining patients have graft survival with an average of 1.2 (range 0-5) episodes of acute rejection. All patients were weaned from TPN by a median of 18 days (range 1-117 days) and from tube feeding by day 69 (range 22-272 days). There was a significant improvement in overall assessment of QoL and in 13 of 26 of the specific domains examined. CONCLUSION: Our results confirm the claim that a new era has dawned for SBTx, such that, with continued progress, it can potentially become an alternative to HPN for the management of permanent intestinal failure, rather than a last-chance treatment for "TPN failure."

p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold.

A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.

Small bowel transplantation.

Until very recently, outcomes from small bowel transplantation (SBTx) lagged behind those in liver, heart, and kidney transplantation because of the magnitude of the immunologic burden; the strong expression of histocompatibility antigens; and the contamination in grafts by bacterial organisms. With novel techniques of immune-induction therapies, such as recipient "preconditioning" with lymphocyte reduction, followed by the more subtle use of immunosuppression-based single-agent tacrolimus, graft and host 1-year survival is now over 90% in the most active US centers, a finding that parallels the outcomes in liver and kidney transplantation. In contrast to the alternative therapy for permanent intestinal failure, home total parenteral nutrition (TPN), SBTx improves quality of life and restores digestive and absorptive function, making patients nutritionally autonomous. With survival beyond 1 to 3 years, the procedure is cost-effective. Current results support expansion of the indications for SBTx from use as salvage therapy for patients with TPN failure to preemptive therapy for patients at risk of developing TPN failure.

Treatment of intestinal failure: home parenteral nutrition.

Intestinal failure can result from surgical resection, obstruction, dysmotility, congenital deficiencies or disease-associated loss of absorption. Before the development of intravenous feeding in the late 1960s, the condition was fatal, but by the 1990s approximately 40,000 patients were being successfully managed on long-term home parenteral nutrition (HPN) annually in the US. Survival on HPN depends on the nature of the underlying medical condition: over 80% of Crohn's disease patients survive for 5 years, but only 20% of cancer patients survive for 1 year. Although a patient's nutritional status is easy to maintain, there are serious long-term complications that arise from bypassing the gut and infusing nutrients directly into the systemic circulation. Catheter sepsis occurs about once per year (range 0-12 times). Abnormalities in liver function tests are common, but end-stage liver disease is rare. Central venous thrombosis develops in nearly all patients after 5 years. Although approximately 80% of patients on HPN are completely rehabilitated at home, their quality of life is impaired by the perpetual dependence on nocturnal intravenous infusions (every 8-12 h). In conclusion, HPN has allowed patients with previously fatal intestinal failure to survive and lead relatively normal lives at home, but their quality of life remains impaired by the dependence on intravenous infusions and complications that progress with time.

Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans.

Prolonged infusions of lipid and heparin that achieve high physiological free fatty acid (FFA) concentrations inhibit hepatic (and peripheral) insulin sensitivity in humans. These infusions are composed largely of polyunsaturated fatty acids (PUFA; linoleic and linolenic). It is not known whether fatty acid composition per se affects hepatic glucose metabolism in humans. To address this issue, we examined the impact of enteral infusions of either palm oil (48% palmitic, 35% oleic, and 8% linoleic acids) or safflower oil (6% palmitic, 12% oleic, 74% linoleic acids) in 14 obese nondiabetic subjects. (2)H(2)O was administered to determine the contribution of gluconeogenesis to endogenous glucose production (EGP), and a primed continuous infusion of [6,6-(2)H]glucose was administered to assess glucose appearance. As a result of the lipid infusions, plasma FFA concentrations increased significantly in both the palm oil (507.5 +/- 47.4 to 939.3 +/- 61.3 micromol/l, P < 0.01) and safflower oil (588.2.0 +/- 43.0 to 857.8 +/- 68.7 micromol/l, P < 0.01) groups after 4 h. EGP was similar at baseline (12.4 +/- 1.8 vs. 11.2 +/- 1.0 micromol x kg FFM(-1) x min(-1)). During a somatostatin-insulin clamp, the glucose infusion rate was significantly lower (AUC glucose infusion rate 195.8 +/- 50.7 vs. 377.8 +/- 38.0 micromol/kg FFM, P < 0.01), and rates of EGP were significantly higher (10.7 +/- 1.4 vs. 6.5 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < 0.01) after palm oil compared with safflower oil, respectively. Baseline rates of gluconeogenesis and glycogenolysis were also similar. However, after lipid infusion, rates of glycogenolysis were suppressed by safflower oil but not by palm oil. Thus these studies demonstrate, for the first time in humans, a differential effect of saturated fatty acids and PUFA on hepatic glucose metabolism.