Case Report: Morphologic and Functional Characteristics of Intestinal Mucosa in a Child With Short Bowel Syndrome After Treatment With Teduglutide: Evidence in Favor of GLP-2 Analog Safety

Abstract

Teduglutide is a glucagon-like peptide-2 (GLP-2) analog employed in patients with short bowel syndrome (SBS) to reduce the need of parenteral nutrition in these patients, by virtue of its effects on enteric function. The experimental studies reported that the stimulating action of GLP-2 on epithelial turnover implies the potential development of dysplastic and neoplastic lesion. However, the clinical trials could not detect preneoplastic lesions on histologic material, and in a recent pilot study the occurrence of polyps was similar before and after treatment and included only low-grade dysplastic lesions. Another clue in GLP-2 function in stimulating mucosal restore is its enhancement through cooperation with epidermal growth factor (EGF). In this study, we analyzed gastroscopy and colonoscopy samplings from a child successfully weaned off parenteral nutrition with teduglutide. Villous and crypt structure was regular both in duodenal and in colonic samplings; in properly oriented villi, villus/crypt ratio was regular. The absorptive epithelium demonstrated a regular morphology. No atypia was detected in enterocytes, along epithelial structures. At the ultrastructural analysis, only a few enterocytes with vacuolized cytoplasm were observed. An S-phase marker Ki67 stained nuclei in the transitional amplifying zone, while nuclei stained by the cell cycle regulatory proteins p21 and p27 were placed in the differentiated epithelium of the duodenal villi and colonic crypts, as in the control cases. The counts of enterocytes immunostained with the same antisera, evaluated with image analysis software, were in the range of control cases. The ratio of the number of epidermal growth factor receptor (EGFR) signals/the number of centromere probe of chromosome 7 (CEP7) signals was less than 2. The findings available from this single patient are consistent with good preservation of functional capability of intestinal epithelium after treatment with GLP-2, given the histologic and ultrastructural features of enterocytes. In addition, the findings from cell cycle regulatory proteins immunolocalization and quantitative analysis show that cell renewal machinery in our case is comparable to control cases. The gene of the receptor EGFR is regularly expressed in enteric epithelium of our case. Morphologic and functional data from our patient improve evidence in favor of the safety of GLP-2 employ in SBS.

The assessment of the effectiveness and safety of teduglutide in the treatment of children with chronic intestinal insufficiency. A systematic review

“…Существенной клинико-социальной значимостью характеризуются так называемые субъективные критерии терапевтической эффективности ТЕД-терапии, определяемые понятием «качество жизни» пациентов, членов семьи, иных законных представителей интересов больного ребенка, включая режим дня, длительность сна, возможность социализации с посещением детских и образовательных учреждений и т. д. Острота данной проблемы в отечественной практике здравоохранения усугубляется несовершенством нормативно-правовой базы, прежде всего отсутствием регламента лечения детей с СКК на дому [2,5,6,8,33,35].…”

“…Данные явления не имели логически обусловленных причинно-следственных связей с проводимым лечением и могли определяться течением основного заболевания, однако в части наблюдений купировались при временном прекращении ТЕД-терапии. Это обстоятельство, по нашему мнению, требует целенаправленных исследований по заблаговременному выявлению предикторов повышенной индивидуальной чувствительности (непереносимости) к тедуглутиду [20,[29][30][31][32][33].…”

“…В дополнение к полнотекстовым оригинальным статьям мы считали необходимым представить клиническое наблюдение с описанием морфологических и функциональных характеристик слизистой оболочки кишечника у 11-летнего ребенка с СКК лечения тедуглутидом в течение 2 лет [33]. При морфологическом исследовании тонкой и толстой кишки установлено наличие ворсинок и крипт с хорошо структурированными энтероцитами и нормальной митотической активностью.…”

Predictive Potential of Biomarkers of Intestinal Barrier Function for Therapeutic Management with Teduglutide in Patients with Short Bowel Syndrome

“…The positive impact of GLP-2 on proliferation has been shown in many studies [10,41,74,75], while the information on Ki-67 as a proliferation marker in SBS patients is limited. In a case report for a pediatric SBS patient, no apparent changes in positive Ki-67 cells were seen during GLP-2 treatment [76]. In contrast, another study analyzing the effects of GLP-2 on the proliferation and apoptosis of intestinal epithelial cells in SBS rat models revealed an elevated percentage of Ki-67 expressing cells [77].…”