Imaging as predictor of clinical response to teduglutide in adult patients with short bowel syndrome with chronic intestinal failure.

BACKGROUND: Teduglutide (TED) is a glucagon-like peptide 2 analogue approved in patients with short bowel syndrome with chronic intestinal failure. Bowel epithelial hyperplasia has been reported after TED treatment. OBJECTIVE: The aim of this study was to describe small bowel modifications at imaging in patients with SBS-CIF receiving TED and to assess their predictive value for clinical response. METHODS: Monocentric retrospective study including patients with SBS-CIF treated with TED from 2009 to 2018 with available computed tomography (CT) scans at baseline and during follow-up (≥12 mo). Small bowel (SB) wall thickness was measured as the average of 3 measurements on different SB segments. Clinical response to TED was defined as a ≥20% reduction of weekly parenteral support (PS) volume at 12 mo. RESULTS: Thirty-one patients [20 male (65%), median age 51 y (IQR: 37-59)] were included. Baseline weekly PS volume was a median 7500 mL (IQR: 3500-15,000). After a median (IQR) follow-up of 16 mo (14-27), 26 of 31 patients (84%) had a clinical response. During follow-up, patients underwent 1 (n = 18/31, 58%), 2 (10/31, 32%), or 3 (3/31 10%) CT scans. Median SB wall thickness was 4.0 mm (IQR: 2.8-4.7) and 8.5 mm (IQR: 6.1-9.8) at baseline and after treatment, respectively [paired P < 0.001, median +122% increase (IQR: +65% to +172%)]. Patients with a clinical response had a trend toward a higher SB wall thickness increase [median +133% (IQR: +70% to +176%) compared with +90% (IQR: +52% to +93%), P = 0.061]. All patients with a ≥95% SB wall thickness increase (n = 18) had a clinical response, whereas only 8 of 13 (62%) patients with a <95% SB thickness increase did (P = 0.008). CONCLUSIONS: Teduglutide induces a significant SB wall thickness increase that can be depicted by imaging <6 mo after treatment initiation, and the degree of such increase may be associated with clinical response. Bowel imaging in response to pharmacologic treatments may represent an important outcome to follow.

Small-Bowel Adaptation: A Case of Morphological Changes Induced by Teduglutide in Short-Bowel Syndrome With Intestinal Failure.

Teduglutide (TED) reduces the need for parenteral support (PS) in patients with short-bowel syndrome with intestinal failure (SBS-IF). It is a glucagon-like peptide-2 analog that improves absorption, induces the expansion of the absorptive epithelium in the small intestine, and may be used in patients with SBS-IF after a 6- to 12-month adaptation period, if PS is always necessary. We described the functional and morphological effect of TED in a 40-year-old female patient with SBS-IF due to Crohn's disease who underwent terminal jejunostomy after 12 months of drug exposition. Marked hypertrophy of the villi was detected by endoscopic capsule and confirmed by histological measurements. This is the first publication demonstrating an increase in intestinal absorption in an SBS-IF patient treated with TED because of a morphological adaptation of the small bowel, with hyperplasia confirmed by capsule endoscopy and histology. The capsule endoscopy, a noninvasive exploration of the gut, could be evaluated to monitor the real efficacy of treatments with growth factors in SBS patients.

Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure.

Widely used for their anti-inflammatory and immunosuppressive properties, glucocorticoids are nonetheless responsible for the development of diabetes and lipodystrophy. Despite an increasing number of studies focused on the adipocyte glucocorticoid receptor (GR), its precise role in the molecular mechanisms of these complications has not been elucidated. In keeping with this goal, we generated a conditional adipocyte-specific murine model of GR invalidation (AdipoGR knockout [KO] mice). Interestingly, when administered a corticosterone treatment to mimic hypercorticism conditions, AdipoGR-KO mice exhibited an improved glucose tolerance and insulin sensitivity. This was related to the adipose-specific activation of the insulin-signaling pathway, which contributed to fat mass expansion, as well as a shift toward an anti-inflammatory macrophage polarization in adipose tissue of AdipoGR-KO animals. Moreover, these mice were protected against ectopic lipid accumulation in the liver and displayed an improved lipid profile, contributing to their overall healthier phenotype. Altogether, our results indicate that adipocyte GR is a key factor of adipose tissue expansion and glucose and lipid metabolism control, which should be taken into account in the further design of adipocyte GR-selective modulators.

Postprandial lipid absorption in seven heterozygous carriers of deleterious variants of MTTP in two abetalipoproteinemic families.

BACKGROUND: Abetalipoproteinemia, a recessive disease resulting from deleterious variants in MTTP (microsomal triglyceride transfer protein), is characterized by undetectable concentrations of apolipoprotein B, extremely low levels of low-density lipoprotein cholesterol in the plasma, and a total inability to export apolipoprotein B-containing lipoproteins from both the intestine and the liver. OBJECTIVE: To study lipid absorption after a fat load and liver function in 7 heterozygous relatives from 2 abetalipoproteinemic families, 1 previously unreported. RESULTS: Both patients are compound heterozygotes for p.(Arg540His) and either c.708_709del p.(His236Glnfs*11) or c.1344+3_1344+6del on the MTTP gene. The previously undescribed patient has been followed for 22 years with ultrastructure analyses of both the intestine and the liver. In these 2 families, 5 relatives were heterozygous for p.(Arg540His), 1 for p.(His236Glnfs*11) and 1 for c.1344+3_1344+6del. In 4 heterozygous relatives, the lipid absorption was normal independent of the MTTP variant. In contrast, in 3 of them, the increase in triglyceride levels after fat load was abnormal. These subjects were additionally heterozygous carriers of Asp2213 APOB in-frame deletion, near the cytidine mRNA editing site, which is essential for intestinal apoB48 production. Liver function appeared to be normal in all the heterozygotes except for one who exhibited liver steatosis for unexplained reasons. CONCLUSION: Our study suggests that a single copy of the MTTP gene may be sufficient for human normal lipid absorption, except when associated with an additional APOB gene alteration. The hepatic steatosis reported in 1 patient emphasizes the need for liver function tests in all heterozygotes until the level of risk is established.

Teduglutide for treatment of adult patients with short bowel syndrome.

INTRODUCTION: The European Society for Clinical Nutrition has published recommendations on the 'definition and classification of intestinal failure (IF)'. Two criteria must be present: a 'decreased absorption of macronutrients and/or water and electrolytes due to a loss of gut function' and the 'need for parenteral support'. Home parenteral support (HPS) is the primary treatment for chronic IF but is associated with complications. Areas covered: The principal cause of chronic IF is short bowel syndrome (SBS). The aim of treatment is to maximize intestinal absorption and reduce or eliminate the need for HPS to achieve the best possible quality of life. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth, reducing intestinal loss and promoting intestinal absorption. This article provides an overview and opinion on teduglutide for SBS. Expert opinion: Teduglutide may provide a new treatment strategy for SBS patients with chronic IF. When prescribed, patients should be informed of the benefits and risks of the drug and must be closely monitored in an expert center. Furthermore, as this treatment is costly, cost-effectiveness analysis as well as the risk-benefit ratio needs to be better evaluated.

Signal inference with unknown response: calibration-uncertainty renormalized estimator.

The calibration of a measurement device is crucial for every scientific experiment, where a signal has to be inferred from data. We present CURE, the calibration-uncertainty renormalized estimator, to reconstruct a signal and simultaneously the instrument's calibration from the same data without knowing the exact calibration, but its covariance structure. The idea of the CURE method, developed in the framework of information field theory, is to start with an assumed calibration to successively include more and more portions of calibration uncertainty into the signal inference equations and to absorb the resulting corrections into renormalized signal (and calibration) solutions. Thereby, the signal inference and calibration problem turns into a problem of solving a single system of ordinary differential equations and can be identified with common resummation techniques used in field theories. We verify the CURE method by applying it to a simplistic toy example and compare it against existent self-calibration schemes, Wiener filter solutions, and Markov chain Monte Carlo sampling. We conclude that the method is able to keep up in accuracy with the best self-calibration methods and serves as a noniterative alternative to them.