Changes in gut hormones, glycaemic response and symptoms after oesophagectomy

Abstract

Background: Oesophagectomy is associated with reduced appetite, weight loss and postprandial hypoglycaemia, the pathophysiological basis of which remains largely unexplored. This study aimed to investigate changes in enteroendocrine function after oesophagectomy.Methods: In this prospective study, 12 consecutive patients undergoing oesophagectomy were studied before and 10 days, 6, 12 and 52 weeks after surgery. Serial plasma total fasting ghrelin, and glucagon-like peptide 1 (GLP-1), insulin and glucose release following a standard 400-kcal mixed-meal stimulus were determined. CT body composition and anthropometry were assessed, and symptom scores calculated using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires. Results: At 1 year, two of the 12 patients exhibited postprandial hypoglycaemia, with reductions in bodyweight (mean(s.e.m.) 17⋅1(3⋅2) per cent, P < 0⋅001), fat mass (21.5(2.5) kg versus 25.5(2.4) kg before surgery; P = 0⋅014), lean body mass (51.5(2.2) versus 54.0(1.8) kg respectively; P = 0⋅003) and insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0⋅022). Mean(s.e.m.) fasting ghrelin levels decreased from postoperative day 10, but had recovered by 1 year (preoperative: 621⋅5(71⋅7) pg/ml; 10 days: 415⋅1(59⋅80) pg/ml; 6 weeks: 309⋅0(42⋅0) pg/ml; 12 weeks: 415⋅8(52⋅1) pg/ml; 52 weeks: 547⋅4(83⋅2) pg/ml; P < 0⋅001) and did not predict weight loss (P = 0⋅198). Postprandial insulin increased progressively at 10 days, 6, 12 and 52 weeks (mean(s.e.m.) insulin AUC 0-30 min : fold change 1⋅7(0⋅4), 2⋅0(0⋅4), 3⋅5(0⋅7) and 4⋅0(0⋅8) respectively; P = 0⋅001). Postprandial GLP-1 concentration increased from day 10 after surgery (P < 0⋅001), with a 3⋅3(1⋅8)-fold increase at 1 year (P < 0⋅001). Peak GLP-1 level was inversely associated with the postprandial glucose nadir (P = 0⋅041) and symptomatic neuroglycopenia (Sigstad score, P = 0⋅017, R 2 = 0⋅45). GLP-1 AUC predicted loss of weight (P = 0⋅008, R 2 = 0⋅52) and fat mass (P = 0⋅010, R 2 = 0⋅64) at 1 year.Conclusion: Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy.

PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia

“…Prevalence estimates range widely due to differing diagnostic criteria used, though the occurrence of severe hypoglycemia among postbariatric patients may be as high as 29% to 39% of patients undergoing Roux-en-Y gastric bypass (RYGB) and 10% to 23% of those undergoing vertical sleeve gastrectomy ( 9-12 ). Similar clinical presentations have been described following gastrectomy ( 13 ), esophagectomy ( 14 ), and Nissen fundoplication ( 15 ). Patients present at least 6 months postoperatively with frequent postprandial episodes of hypoglycemia accompanied by neuroglycopenic signs and symptoms, including altered mental status, visual changes, motor incoordination, loss of consciousness, and seizures, putting patients at risk for injury or death from falls, motor vehicle accidents, or prolonged hypoglycemia, and rendering many unable to drive, work, live alone, or care for dependents.…”

A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy

“…Prior longitudinal work in an esophagectomy cohort has shown that the exaggerated enteroendocrine response corresponds with important appetitive symptoms, such as early satiety, and correlates with Sigstad score (11). In this study, treatment with Octreotide LAR was associated with a 30% relative reduction in Sigstad score, reflective of acute post-prandial symptom burden.…”

“…This limits the ability to appropriately target treatment to patients who are most likely to derive benefit. Recent developments in our understanding of how alterations in gut-brain axis signaling may be implicated in the pathophysiology of post-esophagectomy symptomatology and malnutrition (11), should enable a more systematic approach to therapeutic interventions. Moreover, while studies at least suggest a compelling rationale for long-term nutritional benefit with the use of Octreotide LAR, through mitigation of the exaggerated post-operative gut hormone response, this remains to be proven.…”

“…These issues accentuate the psychosocial burden experienced by patients post esophagectomy, impairing physical function and long-term health-related quality of life (HRQL) (8)(9)(10). Though there are myriad drivers of weight loss following esophageal cancer surgery, the impact of exaggerated post-prandial gut hormone signaling on appetite and satiety has emerged as a novel modifiable factor (11). This has more thoroughly been researched in bariatric surgery contexts and is relatively understudied postesophagectomy (12)(13)(14).…”

Attribution of Ghrelin to Cancer; Attempts to Unravel an Apparent Controversy

“…Post-operative plasma ghrelin was lower than the pre-operative concentrations in esophageal cancer patients, which slightly recovered in 6–24 months. There was no relationship between circulating ghrelin and clinicopathologic features of tumor (45, 108).…”