TY - JOUR
AU - le Roux, C W
AB - 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 AUC0–30 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, R2 = 0·45). GLP-1 AUC predicted loss of weight (P = 0·008, R2 = 0·52) and fat mass (P = 0·010, R2 = 0·64) at 1 year. Conclusion Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy. This prospective study evaluated changes in enteroendocrine physiology, appetite and glycaemia in patients undergoing oesophagectomy. Fasting ghrelin was inappropriately attenuated early after surgery, but recovered over the first postoperative year, with concurrent improvements in appetite. However, after a meal challenge, patients exhibited a persistently exaggerated postprandial gut hormone and insulin response, associated with early satiety, weight loss and reactive hypoglycaemia. Graphical Abstract Open in new tabDownload slide Targets for treatment? Introduction Advances in neoadjuvant protocols and perioperative care have improved oncological outcomes for patients with oesophageal cancer treated with curative intent1,2. The CROSS study3 established a modern benchmark, achieving a 47 per cent 5-year survival rate among patients with locally advanced disease treated with multimodal therapy. With such welcome advances with respect to oncological outcome, there is increasingly a focus on functional recovery and health-related quality of life (HR-QoL) in survivorship, as the attritional impact of oesophagectomy is widely appreciated4,5. Progressive loss of fat mass (FM) and lean body mass (LBM) occurs after oesophagectomy. Sarcopenia, determined by CT, was present in 35 per cent of disease-free patients at 1 year after surgery, a fivefold increase from the time of diagnosis6. Interestingly, progression of sarcopenia after surgery occurred independently of postoperative complications or final pathological stage6, implicating changes in dietary intake and nutrient handling as key drivers of nutritional decline. In this regard, recovery after oesophagectomy is commonly confounded by altered appetite and postprandial symptoms. An altered desire to eat and eating difficulties are major predictors of long-term weight loss7, whereas postprandial hypoglycaemia and symptoms of neuroglycopenia, so-called ‘late dumping’, may affect up to 30 per cent of patients8. Such changes in the patient's experience of eating may result in reduced oral nutrient intake, progressive postoperative weight loss and sarcopenia9,10, and affect participation in the social aspects of eating, reinforcing a persistent illness identity11,12. Accordingly, altered appetite and postprandial symptoms represent a significant barrier to functional recovery in survivorship. However, the mechanisms underpinning these phenomena remain poorly understood, and thus therapeutic options are limited. Clinical and experimental models in obesity and bariatric surgery have generated major insights into regulation of appetite, bodyweight and glycaemia. Short-term regulation of feeding is primarily under the control of the gut–brain axis (Fig. 1). The only known orexigenic or ‘hunger’ gut hormone, ghrelin, is secreted from the Gr-cells of the gastric fundus during fasting, and is attenuated in response to ingested nutrients13. On the other hand, meal termination and satiety are mediated by secretion of anorectic gut hormones such as glucagon-like peptide (GLP) 1, which are secreted by enteroendocrine cells of the small and large intestine following direct interaction of ingested nutrients with taste and fatty acid receptors on their luminal surfaces14. Importantly, GLP-1 and other gut peptides also serve to enhance postprandial nutrient utilization, through both stimulation of insulin secretion and increased peripheral insulin sensitivity15. Fig. 1 Open in new tabDownload slide The enteroendocrine system regulates nutrient ingestion and postprandial glucose utilization Enteroendocrine L-cells of the small and large intestine produce postprandial gut hormones in response to luminal nutrients and bile. Glucagon-like peptide (GLP) 1 is a prototypical small intestinal gut hormone with incretin and satiety gut hormone properties. Secreted GLP-1 diffuses into the lamina propria and enters the systemic circulation via the hepatic portal vein, and acutely augments the postprandial insulin response, enhancing islet cell insulin production and increasing hepatic and peripheral insulin sensitivity. Chronically, a possible trophic effect on the pancreatic islet has also been demonstrated in rodent models, increasing β-cell proliferation and differentiation, and inhibiting apoptosis. Circulating GLP-1 also inhibits food intake, simultaneously stimulating anorexigenic pro-opiomelanocortin and inhibiting appetitive neuropeptide Y (NPY) and agouti-related peptide neurones (AgRP) in the hypothalamic arcuate nucleus. The only orexigenic gut peptide, ghrelin, is secreted from the Gr-cells of the gastric fundus in the fasted state and inhibited in the postprandial state by luminal nutrients and small intestinal gut hormones. Traversing the blood–brain barrier via a saturable transport system, endogenous or peripherally administered ghrelin exerts orexigenic effects via activation of NPY/AgRP neurones to increase hypothalamic NPY expression, and other central nervous system sites. Ghrelin also regulates growth hormone (GH) secretion, as well as GH-releasing hormone, prolactin, adrenocorticotropic hormone and somatostatin. Solid arrows indicate stimulatory effect; dashed arrow indicates inhibitory effect. PYY, peptide YY; OXM, oxyntomodulin; GIP, gastric inhibitory peptide. It was demonstrated recently16,17 that an exaggerated postprandial GLP-1 response is associated with early satiety and postprandial symptoms among patients 3 months after oesophagectomy; however, long-term changes in enteroendocrine physiology have not been studied prospectively. The aim of the present study was to characterize changes in enteroendocrine physiology, and their effect on satiety, postingestive symptoms, weight and body composition over the first year following oesophagectomy. Methods Study participants The Oesophageal and Gastric Centre at St James's Hospital, Dublin, is a high-volume national centre, and detailed clinicopathological, treatment and follow-up data are maintained prospectively for all patients. Consecutive patients scheduled to undergo potentially curative oesophagectomy between March and July 2015 were identified at the weekly tumour board and invited before surgery to participate in the study. Patients with significant dysphagia, major co-morbidity, neuropsychiatric illness, substance misuse or previous gastrointestinal surgery were considered ineligible. All patients underwent surveillance CT 1 year after surgery, and those with disease recurrence during the study interval were excluded. Treatment Neoadjuvant therapy During the study interval, patients with locally advanced adenocarcinoma were treated with either preoperative and postoperative chemotherapy, as per the MAGIC regimen (etoposide–cisplatin–fluorouracil or capecitabine)18, or neoadjuvant chemoradiotherapy, as per the CROSS protocol (carboplatin–paclitaxel, 41·4 Gy in 23 fractions) as part of the ongoing Neo-AEGIS trial19,20. Patients with locally advanced squamous cell carcinoma received neoadjuvant chemoradiotherapy as per the CROSS protocol20. Surgery was undertaken approximately 6 weeks after completion of neoadjuvant therapy. Surgery All patients with adequate respiratory function underwent radical abdominothoracic en bloc oesophagectomy with thoracic or cervical anastomosis, whereas those with significant respiratory co-morbidity had transhiatal resection with cervical anastomosis, as described previously21. Reconstruction was with a posterior mediastinal gastric conduit approximately 5 cm in width, with hand-sewn anastomosis, and pyloroplasty (Fig. S1, supporting information). Nutritional assessment and support All patients were reviewed in the multidisciplinary clinic and received detailed dietetic consultation and assessment before surgery according to European Society for Clinical Nutrition and Metabolism (ESPEN) best practice guidelines22. A 10-Fr needle catheter jejunostomy (NCJ) was placed routinely at surgery, and NCJ feeding commenced on the first postoperative day. Patients began oral intake on postoperative day 4 or 5. Overnight NCJ feeding was continued for approximately 6 weeks after surgery, when ongoing requirements for supplemental nutrition were assessed. NCJ feeding was withheld the evening before study assessments. Study design and protocol (Fig. S2, supporting information) The institutional research ethics committee approved the study (REC 2014/12/11) and all patients provided written informed consent. The study was registered with ClinicalTrials.gov before recruitment of the first participant (NCT02381249). Participants were studied before surgery and at 10 days, 6 weeks, 3 months and 1 year after operation. At each outpatient assessment they attended the clinical research facility at 09·00 hours after a 12-h fast. On day 10 after surgery participants were assessed on the surgical ward. Blood was collected from a peripheral intravenous cannula 5 min before and at 15, 30, 60, 90, 120, 150 and 180 min after a standardized 400-kcal semiliquid meal (160 g (184 ml): 27·2 g fat, 32·3 g carbohydrate, 6·7 g protein). At each outpatient assessment participants completed Sigstad23 and HR-QoL questionnaires (EORTC QLQ-C30 and disease-specific module QLQ-OG25)24. The Sigstad score comprises a 16-symptom questionnaire with each symptom differentially weighted. A score above 7 may be considered indicative of dumping syndrome, representing symptoms consistent with rapid gastric emptying and/or reactive hypoglycaemia, whereas a score below 4 suggests an alternative diagnosis. Each HR-QoL item comprised four categories on a Likert scale, and linear transformation of Likert scores for answers in each conceptual area was performed as per EORTC recommendations, and was also applied to the scores for ‘early satiety’ (QLQ-OG25 item 5) and ‘trouble enjoying eating’ (QLQ-OG25 item 4)24,25. Scores comprise a numerical value from 0 to 100, with higher symptom scores indicating more pervasive symptoms and higher function scores indicating preserved function. Body composition Serial height, body anthropometry and bodyweight measurements were obtained in the fasting state with participants wearing light indoor clothing after voiding urine26. As described previously6, PET–CT or CT scans were obtained routinely before surgery and at 1 year after surgery using a Discovery ST™ PET/CT scanner (GE Healthcare, Little Chalfont, UK) or multislice Somatom Sensation scanner (Siemens Healthcare, Erlangen, Germany). Images at L3 were analysed by a single blinded investigator to determine the cross-sectional area of each tissue compartment using a Siemens Leonardo PACS Workstation (Siemens Healthcare), applying an automated algorithm utilizing Hounsfield unit thresholds of −29 to +150 for skeletal muscle and − 50 to −150 for adipose tissue27–29. LBM and FM were derived using validated formulas27,29. Plasma analysis All blood samples were immersed immediately in ice, centrifuged at 2500 r.p.m. for 10 min at 4 °C, and plasma was stored at −80 °C to minimize gut hormone degradation. Plasma total GLP-1 and ghrelin levels were measured by enzyme-linked immunosorbent assay (ELISA) (Multi-Species GLP-1 Total ELISA and Human Ghrelin (Total) ELISA; Merck Millipore, Darmstadt, Germany), validated for detection in the picomolar range with intra-assay and interassay variability of less than 5 and 12 per cent, and less than 1·9 and 7·7 per cent, respectively. Plasma glucose and insulin were determined by automated analyser (Cobas® 8000; Roche Diagnostics, Basel, Switzerland). Homeostatic model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-%β) and insulin sensitivity (HOMA-%S) were calculated from fasting plasma insulin and glucose values using open-source software (https://www.dtu.ox.ac.uk/homacalculator/). The HOMA model estimates steady state β-cell function and insulin sensitivity versus a normal reference population. These measures have been validated against estimates of β-cell function and insulin sensitivity derived from stimulatory models such as the hyperinsulinaemic and hyperglycaemic clamp, and intravenous and oral glucose tolerance tests30. Statistical analysis Data were analysed using GraphPad Prism® version 6.0 for Windows® (GraphPad Software, San Diego, California, USA) and are presented as mean(s.e.m.) unless otherwise specified. Area under the curve (AUC) was calculated using the trapezoidal rule. Univariable within-group comparisons were analysed with paired Student's t or Wilcoxon signed rank test, as appropriate. Univariable between-group comparisons were performed using the Student's t or Mann–Whitney U test for continuous variables and χ2 or Fisher's exact test for categorical variables. Relationships between continuous variables were interrogated using linear regression. One-way repeated-measures ANOVA with post hoc Dunnett's test was used to analyse differences in single data point measures over time from baseline, and two-way repeated-measures ANOVA with post hoc Holm–Sidak's test was applied to assess for differences in multiple-response data over time. All statistical analyses were two-tailed with the threshold of significance set at P < 0·050. Results Sixteen participants with a median age of 62 years were recruited between March and July 2015. Two participants withdrew from the study and two developed recurrent disease within the first postoperative year. Clinicopathological characteristics of the 12 patients in the final study population are shown in Table S1 (supporting information). Assessments were carried out a mean(s.e.m.) of 7(2) days before surgery, and 10(0), 38(2), 106(5) and 367(6) days after surgery. Nutritional status Weight loss occurred over the first year after surgery, with 17·1(3·2) per cent bodyweight loss (%BWL) from preillness weight observed at 1 year (P < 0·001) (Fig. 2a). Ten of the 12 patients experienced more than 10%BWL and five had more than 20%BWL at 1 year. Body composition analysis demonstrated significant loss of both FM (25·5(2·4) kg before surgery versus 21.5(2.5) kg at 1 year after surgery; P = 0·014) and LBM (54.0(1.8) versus 51.5(2.2) kg respectively; P = 0·003) (Fig. 2b,c). A complete nutritional profile of participating subjects is provided in Table 1. Fig. 2 Open in new tabDownload slide Weight and body composition a Significant weight loss from preillness weight (bodyweight 87·9(4·5) kg) occurred from time of diagnosis (83·3(4·3) kg) and progressed at 6 weeks (75·8(2·9) kg) 3 months (73·3(3·0) kg) and 1 year (72·1(3·4) kg) after surgery. Weight loss was reflected by significant loss of both b lean body mass and c fat mass during the first year after surgery. Values are mean(s.e.m.). aP < 0·001 (one-way repeated-measures ANOVA with post hoc Dunnett's test: *P < 0·050, †P < 0·001); bP = 0·003, cP = 0·014 (paired Student's t test). Table 1 Nutritional and metabolic assessment . Before surgery . 1 year after surgery . P* . Anthropometry Weight (kg) 80·4(3·5) 72·1(3·4) 0·021 BMI (kg/m2) 27·3(1·1) 24·5(1·1) 0·018 Waist circumference (cm) 97·8(4·8) 89·0(3·8) 0·076 Hip circumference (cm) 105·9(3·2) 97·3(2·1) 0·029 Body composition Lean body mass (kg) 54·0(1·8) 51·5(2·2) 0·003 Skeletal muscle index (cm2/m2) 55·1(6·3) 50·4(2·5) 0·001 Fat mass (kg) 25·5(2·4) 21·5(2·5) 0·014 Metabolic profile Fasting glucose (mmol/l) 5·24(0·31) 5·25(0·25) 0·949 Fasting insulin (units/ml) 8·39(1·42) 5·90(1·13) 0·007 HOMA-IR 1·16(0·20) 0·84(0·17) 0·022 HOMA-%S 124·7(26·5) 160·7(26·0) 0·002 HOMA-%β 103·1(15·7) 70·8(5·8) 0·038 Thyroid-stimulating hormone (munits/l) 1·52(0·34) 1·68(0·63) 0·177 Thyroxine (pmol/l) 16·2(0·9) 15·9(0·92) 0·515 Nutritional profile Haemoglobin (g/dl) 13·5(0·4) 12·9(0·4) 0·335 Haematocrit (l/l) 0·40(0·01) 0·39(0·01) 0·572 Mean cell volume (fl) 90·5(1·5) 92·2(1·3) 0·167 Vitamin B12 (ng/l) 406·1(63·7) 477·3(147·4) 0·642 Folate (μg/l) 12·6(2·6) 9·2(1·0) 0·124 Ferritin (μg/l) 152·3(61·5) 50·8(19·4) 0·002 Urea (mmol/l) 4·6(0·4) 5·1(0·4) 0·193 Creatinine (μmol/l) 70·5(2·6) 79·1(1·9) 0·013 Albumin (g/l) 43·0(1·0) 41·5(1·1) 0·108 Total protein (g/l) 67·1(1·0) 65·4(1·6) 0·397 Sodium (mmol/l) 140·6(0·6) 140·3(0·5) 0·651 Potassium (mmol/l) 4·2(0·1) 4·6(0·1) 0·119 Corrected calcium (mmol/l) 2·30(0·03) 2·34(0·02) 0·188 Magnesium (mmol/l) 0·79(0·03) 0·82(0·04) 0·504 Phosphate (mmol/l) 1·15(0·06) 1·19(0·05) 0·319 Prothrombin time (s) 11·0(0·3) 11·2(0·4) 0·557 Vitamin A (μmol/l) 3·20(1·48) 1·81(0·17) 0·619 Vitamin D (nmol/l) 48·5(11·6) 51·6(4·5) 0·406 Vitamin E (μmol/l) 23·3(4·8) 28·7(2·3) 0·661 C-reactive protein (mg/l) 3·3(1·0) 1·8(0·5) 0·020 . Before surgery . 1 year after surgery . P* . Anthropometry Weight (kg) 80·4(3·5) 72·1(3·4) 0·021 BMI (kg/m2) 27·3(1·1) 24·5(1·1) 0·018 Waist circumference (cm) 97·8(4·8) 89·0(3·8) 0·076 Hip circumference (cm) 105·9(3·2) 97·3(2·1) 0·029 Body composition Lean body mass (kg) 54·0(1·8) 51·5(2·2) 0·003 Skeletal muscle index (cm2/m2) 55·1(6·3) 50·4(2·5) 0·001 Fat mass (kg) 25·5(2·4) 21·5(2·5) 0·014 Metabolic profile Fasting glucose (mmol/l) 5·24(0·31) 5·25(0·25) 0·949 Fasting insulin (units/ml) 8·39(1·42) 5·90(1·13) 0·007 HOMA-IR 1·16(0·20) 0·84(0·17) 0·022 HOMA-%S 124·7(26·5) 160·7(26·0) 0·002 HOMA-%β 103·1(15·7) 70·8(5·8) 0·038 Thyroid-stimulating hormone (munits/l) 1·52(0·34) 1·68(0·63) 0·177 Thyroxine (pmol/l) 16·2(0·9) 15·9(0·92) 0·515 Nutritional profile Haemoglobin (g/dl) 13·5(0·4) 12·9(0·4) 0·335 Haematocrit (l/l) 0·40(0·01) 0·39(0·01) 0·572 Mean cell volume (fl) 90·5(1·5) 92·2(1·3) 0·167 Vitamin B12 (ng/l) 406·1(63·7) 477·3(147·4) 0·642 Folate (μg/l) 12·6(2·6) 9·2(1·0) 0·124 Ferritin (μg/l) 152·3(61·5) 50·8(19·4) 0·002 Urea (mmol/l) 4·6(0·4) 5·1(0·4) 0·193 Creatinine (μmol/l) 70·5(2·6) 79·1(1·9) 0·013 Albumin (g/l) 43·0(1·0) 41·5(1·1) 0·108 Total protein (g/l) 67·1(1·0) 65·4(1·6) 0·397 Sodium (mmol/l) 140·6(0·6) 140·3(0·5) 0·651 Potassium (mmol/l) 4·2(0·1) 4·6(0·1) 0·119 Corrected calcium (mmol/l) 2·30(0·03) 2·34(0·02) 0·188 Magnesium (mmol/l) 0·79(0·03) 0·82(0·04) 0·504 Phosphate (mmol/l) 1·15(0·06) 1·19(0·05) 0·319 Prothrombin time (s) 11·0(0·3) 11·2(0·4) 0·557 Vitamin A (μmol/l) 3·20(1·48) 1·81(0·17) 0·619 Vitamin D (nmol/l) 48·5(11·6) 51·6(4·5) 0·406 Vitamin E (μmol/l) 23·3(4·8) 28·7(2·3) 0·661 C-reactive protein (mg/l) 3·3(1·0) 1·8(0·5) 0·020 Values are mean(s.e.m.). HOMA-IR, homeostatic model assessment of insulin resistance; HOMA-%β, homeostatic model assessment of β-cell function; HOMA-%S, homeostatic model assessment of insulin sensitivity. * Paired Student's t test or Wilcoxon matched-pairs signed rank test, as appropriate. Open in new tab Table 1 Nutritional and metabolic assessment . Before surgery . 1 year after surgery . P* . Anthropometry Weight (kg) 80·4(3·5) 72·1(3·4) 0·021 BMI (kg/m2) 27·3(1·1) 24·5(1·1) 0·018 Waist circumference (cm) 97·8(4·8) 89·0(3·8) 0·076 Hip circumference (cm) 105·9(3·2) 97·3(2·1) 0·029 Body composition Lean body mass (kg) 54·0(1·8) 51·5(2·2) 0·003 Skeletal muscle index (cm2/m2) 55·1(6·3) 50·4(2·5) 0·001 Fat mass (kg) 25·5(2·4) 21·5(2·5) 0·014 Metabolic profile Fasting glucose (mmol/l) 5·24(0·31) 5·25(0·25) 0·949 Fasting insulin (units/ml) 8·39(1·42) 5·90(1·13) 0·007 HOMA-IR 1·16(0·20) 0·84(0·17) 0·022 HOMA-%S 124·7(26·5) 160·7(26·0) 0·002 HOMA-%β 103·1(15·7) 70·8(5·8) 0·038 Thyroid-stimulating hormone (munits/l) 1·52(0·34) 1·68(0·63) 0·177 Thyroxine (pmol/l) 16·2(0·9) 15·9(0·92) 0·515 Nutritional profile Haemoglobin (g/dl) 13·5(0·4) 12·9(0·4) 0·335 Haematocrit (l/l) 0·40(0·01) 0·39(0·01) 0·572 Mean cell volume (fl) 90·5(1·5) 92·2(1·3) 0·167 Vitamin B12 (ng/l) 406·1(63·7) 477·3(147·4) 0·642 Folate (μg/l) 12·6(2·6) 9·2(1·0) 0·124 Ferritin (μg/l) 152·3(61·5) 50·8(19·4) 0·002 Urea (mmol/l) 4·6(0·4) 5·1(0·4) 0·193 Creatinine (μmol/l) 70·5(2·6) 79·1(1·9) 0·013 Albumin (g/l) 43·0(1·0) 41·5(1·1) 0·108 Total protein (g/l) 67·1(1·0) 65·4(1·6) 0·397 Sodium (mmol/l) 140·6(0·6) 140·3(0·5) 0·651 Potassium (mmol/l) 4·2(0·1) 4·6(0·1) 0·119 Corrected calcium (mmol/l) 2·30(0·03) 2·34(0·02) 0·188 Magnesium (mmol/l) 0·79(0·03) 0·82(0·04) 0·504 Phosphate (mmol/l) 1·15(0·06) 1·19(0·05) 0·319 Prothrombin time (s) 11·0(0·3) 11·2(0·4) 0·557 Vitamin A (μmol/l) 3·20(1·48) 1·81(0·17) 0·619 Vitamin D (nmol/l) 48·5(11·6) 51·6(4·5) 0·406 Vitamin E (μmol/l) 23·3(4·8) 28·7(2·3) 0·661 C-reactive protein (mg/l) 3·3(1·0) 1·8(0·5) 0·020 . Before surgery . 1 year after surgery . P* . Anthropometry Weight (kg) 80·4(3·5) 72·1(3·4) 0·021 BMI (kg/m2) 27·3(1·1) 24·5(1·1) 0·018 Waist circumference (cm) 97·8(4·8) 89·0(3·8) 0·076 Hip circumference (cm) 105·9(3·2) 97·3(2·1) 0·029 Body composition Lean body mass (kg) 54·0(1·8) 51·5(2·2) 0·003 Skeletal muscle index (cm2/m2) 55·1(6·3) 50·4(2·5) 0·001 Fat mass (kg) 25·5(2·4) 21·5(2·5) 0·014 Metabolic profile Fasting glucose (mmol/l) 5·24(0·31) 5·25(0·25) 0·949 Fasting insulin (units/ml) 8·39(1·42) 5·90(1·13) 0·007 HOMA-IR 1·16(0·20) 0·84(0·17) 0·022 HOMA-%S 124·7(26·5) 160·7(26·0) 0·002 HOMA-%β 103·1(15·7) 70·8(5·8) 0·038 Thyroid-stimulating hormone (munits/l) 1·52(0·34) 1·68(0·63) 0·177 Thyroxine (pmol/l) 16·2(0·9) 15·9(0·92) 0·515 Nutritional profile Haemoglobin (g/dl) 13·5(0·4) 12·9(0·4) 0·335 Haematocrit (l/l) 0·40(0·01) 0·39(0·01) 0·572 Mean cell volume (fl) 90·5(1·5) 92·2(1·3) 0·167 Vitamin B12 (ng/l) 406·1(63·7) 477·3(147·4) 0·642 Folate (μg/l) 12·6(2·6) 9·2(1·0) 0·124 Ferritin (μg/l) 152·3(61·5) 50·8(19·4) 0·002 Urea (mmol/l) 4·6(0·4) 5·1(0·4) 0·193 Creatinine (μmol/l) 70·5(2·6) 79·1(1·9) 0·013 Albumin (g/l) 43·0(1·0) 41·5(1·1) 0·108 Total protein (g/l) 67·1(1·0) 65·4(1·6) 0·397 Sodium (mmol/l) 140·6(0·6) 140·3(0·5) 0·651 Potassium (mmol/l) 4·2(0·1) 4·6(0·1) 0·119 Corrected calcium (mmol/l) 2·30(0·03) 2·34(0·02) 0·188 Magnesium (mmol/l) 0·79(0·03) 0·82(0·04) 0·504 Phosphate (mmol/l) 1·15(0·06) 1·19(0·05) 0·319 Prothrombin time (s) 11·0(0·3) 11·2(0·4) 0·557 Vitamin A (μmol/l) 3·20(1·48) 1·81(0·17) 0·619 Vitamin D (nmol/l) 48·5(11·6) 51·6(4·5) 0·406 Vitamin E (μmol/l) 23·3(4·8) 28·7(2·3) 0·661 C-reactive protein (mg/l) 3·3(1·0) 1·8(0·5) 0·020 Values are mean(s.e.m.). HOMA-IR, homeostatic model assessment of insulin resistance; HOMA-%β, homeostatic model assessment of β-cell function; HOMA-%S, homeostatic model assessment of insulin sensitivity. * Paired Student's t test or Wilcoxon matched-pairs signed rank test, as appropriate. Open in new tab Appetite and gastrointestinal quality of life On HR-QoL analysis, physical and role function scores remained persistently reduced 1 year after surgery (Table S2, supporting information). Although participants scored highly for lack of appetite in the short term after surgery, scores were not statistically significant different from preoperative measurements by 1 year. Early satiety scores, however, remained persistently raised at 1 year (12·1(6·8) before surgery, 63·9(9·6) at 6 weeks, 41·7(9·3) at 3 months, and 33·3(8·2) at 1 year; P = 0·007). Similarly, participants reported persistent discomfort and pain associated with eating (1·5(1·5), 27·8(5·6), 30·6(6·4) and 26·4(5·9) respectively; P = 0·002) and the Sigstad score remained increased versus baseline (0·3(0·5), 6·2(1·6), 8·6(1·7) and 7·6(1·6) respectively; P < 0·001). At 1 year, four participants met the diagnostic criteria for dumping syndrome, reporting clinical features suggestive of postprandial neuroglycopenia. Ghrelin Fasting total ghrelin was reduced from day 10 after surgery (415·1(59·8) pg/ml versus 621.5(71.7) pg/ml before surgery; P < 0·050), and, despite weight loss, remained inappropriately attenuated at 6 weeks (309·0(42·0) pg/ml, P < 0·001) and 3 months (415·8(52·1) pg/ml, P < 0·050) after surgery (Fig. 3). Fasting total ghrelin levels did recover to baseline at 1 year after surgery (547·4(83·2) pg/ml), and at 1 year there was no relationship between fasting total ghrelin and %BWL (P = 0·198, R2 = 0·19). Fig. 3 Open in new tabDownload slide Changes in fasting total ghrelin after oesophagectomy Fasting total ghrelin concentration was reduced from day 10 after surgery, remained reduced at 6 weeks and 3 months, but recovered to baseline at 1 year. Values are mean(s.e.m.). P < 0·001 (1-way repeated-measures ANOVA with post hoc Dunnett's test: *P < 0·050, †P < 0·001). Glucagon-like peptide 1 The postprandial total GLP-1 response was significantly increased from day 10 after surgery (P < 0·001) (Fig. 4a), with a doubling of the GLP-1 AUC (P < 0·001) (Fig. 4b) and a mean threefold increase in peak postprandial total GLP-1 (3·3(1·8)-fold, P < 0·001) (Fig. 4c), persisting for up to 1 year after surgery. At 1 year, the magnitude of the postprandial total GLP-1 AUC was predictive of %BWL (P = 0·008, R2 = 0·52) and loss of FM (P = 0·010, R2 = 0·64). Fig. 4 Open in new tabDownload slide Postprandial total glucagon-like peptide 1 response after oesophagectomy a The postprandial total glucagon-like peptide (GLP) 1 response was increased from day 10 after surgery, with b a doubling of the GLP-1 area under the curve (AUC) and c an approximate threefold increase in the postprandial peak total GLP-1, changes that persisted for up to 1 year. Values are mean(s.e.m.). aP < 0·001 (2-way repeated-measures ANOVA with post hoc Holm–Sidak's multiple comparisons test); b,cP < 0·001 (1-way repeated-measures ANOVA with post hoc Dunnett's test: *P < 0·010, †P < 0·001). Glucose and insulin Fasting glucose levels were unchanged at 1 year (P = 0·9495) (Fig. 5c). However, consistent with loss of LBM and FM, fasting insulin levels were reduced significantly at 1 year versus before surgery (5.90(1.13) versus 8.39(1.42) units/ml respectively; P = 0·007), with reduced insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0·022) and increased insulin sensitivity (HOMA-%S: 160.7(26.0) versus 124.7(26.5); P = 0·002). After administration of the test meal, no statistically significant initial change in the early postprandial insulin response was observed at 10 days (AUC0–30 min: 844.8(198.7) versus 509.7(76.0) before surgery) or 6 weeks (997·8(201·3)) after surgery. However, the magnitude of the early postprandial insulin response increased progressively over time and was significantly greater at 3 months (1799·0(371·3), P < 0·050) and 1 year (2040·0(402·0), P < 0·050), with a fold change of 1·7(0·4), 2·0(0·4), 3·5(0·7) and 4·0(0·8) at each time point respectively (P = 0·001). Fig. 5 Open in new tabDownload slide Postprandial insulin and glucose levels after oesophagectomy a Postprandial insulin response after a meal. b No change in the postprandial insulin response was observed at 10 days or 6 weeks after surgery, but the early area under the curve (AUC) increased progressively and was significantly greater at 3 months and 1 year compared with the AUC before surgery. c,d This occurred in the context of a rapid and transient postprandial increase, and subsequent decrease, in glucose levels from day 10 after surgery. Values are mean(s.e.m.). a,cP < 0·001 (2-way repeated-measures ANOVA with post hoc Holm–Sidak's multiple comparisons test); bP = 0·001, dP = 0·021 (1-way repeated-measures ANOVA with post hoc Dunnett's test: *P < 0·050). This occurred in the context of a rapid and transient postprandial increase, and subsequent decrease, in glucose levels from day 10 after surgery, with two patients experiencing biochemical postprandial hypoglycaemia after the test meal at 1 year. The postprandial peak GLP-1 was inversely associated with the postprandial glucose nadir (P = 0·041, R2 = 0·39) and symptomatic neuroglycopenia after eating (Sigstad score: P = 0·017, R2 = 0·45). Discussion This study demonstrates the evolution of gut hormone and glycaemic responses after oesophagectomy, and their association with postoperative changes in appetite, postprandial symptoms, altered glycaemic profile, weight and body composition. Understanding the role of satiety gut hormones as mediators of energy intake and weight loss in patients undergoing bariatric surgery for morbid obesity has facilitated the development of practical, targeted, therapeutic interventions, as evidenced by the recent SCALE trial, which demonstrated weight loss and improved glycaemic control among patients treated with liraglutide, a GLP-1 analogue31–33. However, the relevance of such insights in gastrointestinal cancer surgery, where postoperative changes in appetite and glycaemia represent a critical challenge affecting the recovery of nutritional well-being and HR-QoL, as yet remains largely uninvestigated and hence targeted treatment approaches are lacking. GLP-1 is a prototypical small intestinal gut hormone secreted by the enteroendocrine L-cells of the small and large intestine in response to luminal contents, such as glucose, fatty acids, specific amino acids and peptones, and microbial metabolites, and demonstrating both incretin and satiety gut hormone properties (Fig. 1)34. Entering the systemic circulation via the hepatic portal vein, GLP-1 acutely enhances the pancreatic β-cell response and increases peripheral insulin sensitivity, in a pulsatile fashion. Circulating GLP-1 can also diffuse across fenestrated capillaries near the hypothalamic arcuate nucleus, where it inhibits further food intake, simultaneously stimulating anorexigenic pro-opiomelanocortin and inhibiting appetitive neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurones. Some of these actions are shared by other postprandial gut hormones, such as gastric inhibitory peptide, which acts primarily as an incretin hormone, augmenting postprandial insulin secretion and hence utilization of glucose, and oxyntomodulin and peptide YY (PYY), which function as satiety gut hormones34. Conversely, ghrelin, the only known orexigenic gut peptide, is secreted primarily from the Gr-cells of the gastric fundus during fasting, and is suppressed postprandially by luminal amino acids and long- and medium-chain fatty acids. Circulating total ghrelin levels are inversely correlated with bodyweight, with increased circulating ghrelin levels observed after diet-induced weight loss34. Ghrelin traverses the blood–brain barrier and exerts orexigenic effects via activation of NPY/AgRP neurones to increase hypothalamic NPY expression, while additionally recruiting pathways involved in reward-based eating behaviours. Ghrelin further regulates growth hormone (GH) secretion, as well as GH-releasing hormone, prolactin, adrenocorticotropic hormone and somatostatin. As such, ghrelin represents an endocrine link between the gastrointestinal tract and the pituitary, whereby anabolism and growth may be modulated in response to nutrient availability34. It was demonstrated previously that patients exhibit an exaggerated postprandial satiety gut hormone response early after oesophagectomy17, with increased postprandial total GLP-1 and PYY levels observed approximately 2 years after surgery16. From the present study, which characterized prospectively the gut hormone profile of patients undergoing oesophagectomy for up to 1 year after surgery, a number of observations can be made. Consistent with previous reports6,35, patients demonstrated significant weight loss, with reductions in both LBM and FM after oesophagectomy (Fig. 2). Initially, this occurred in the context of a lack of hunger with an inappropriate reduction in fasting ghrelin levels, consistent with loss of Gr-cell mass consequent to formation of the gastric conduit. However, by 1 year, both fasting ghrelin and hunger scores had recovered to baseline (Fig. 3; Table S2, supporting information), and fasting ghrelin levels were unrelated to weight loss. This is consistent with cross-sectional data indicating normalization of fasting ghrelin concentrations among patients in the long term after oesophagectomy16,36–38, and with rodent studies demonstrating increased production of ghrelin from extragastric sites after gastrectomy39. Despite improvements in hunger (the motivation to eat after a period of fasting), at 1 year after surgery patients persistently experienced early satiety – the premature onset of the central perception of fullness after eating. Of greatest relevance, the postprandial total GLP-1 response was markedly exaggerated from the tenth postoperative day, with a threefold increase in the total GLP-1 peak and a twofold increase in the postprandial GLP-1 AUC (Fig. 4). The mechanism underlying the exaggerated satiety gut hormone response in this cohort remains uncertain, although altered nutrient and bile transit leading to early postprandial small intestinal L-cell hyperstimulation may play a role. This is supported by the finding of rapidly and transiently increasing plasma glucose at all postoperative time points (Fig. 5c). Notably, gastrointestinal transit times correlate inversely with postprandial GLP-1 levels in patients after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy40,41. Moreover, rapid gastric emptying has been associated with an increased GLP-1 response after oesophagectomy8. In the present study, the magnitude of the postprandial GLP-1 response predicted postoperative loss of bodyweight and FM, suggesting that the exaggerated postprandial satiety gut hormone response may be a key driver of reduced nutrient intake and resultant malnutrition in this cohort. The discordant trajectories of ghrelin and GLP-1 release have potential therapeutic significance. Phase II trials, and the subsequent phase III ROMANA 1 and 2 studies, have demonstrated the safety and efficacy of anamorelin, a novel, orally bioavailable, high-affinity, selective ghrelin receptor agonist, in improving appetite and augmenting LBM among patients with cancer cachexia42–45. The present data, however, suggest caution in the application of these findings to patients following oesophagectomy, for whom the primary barrier to eating in the long term appears to be early satiety and postprandial symptoms, rather than a lack of hunger per se. In this regard, it has been demonstrated previously16 that administration of the somatostatin analogue octreotide attenuates the exaggerated postprandial satiety gut hormone response among patients after oesophagectomy, with a 1·5-fold increase in ad libitum energy intake, and the present data support the rationale for further study of the impact of somatostatin analogues on eating behaviour, bodyweight and composition, and gastrointestinal HR-QoL in this population. Another important finding relates to the insulin response. In the early postoperative period, no significant change was observed in the postprandial insulin response; however, the insulin response appeared to increase progressively, and was markedly exaggerated by 1 year after surgery, with a 2·5-fold increase in the postprandial insulin peak and a fourfold increase in the AUC. Although the postprandial insulin response increased, peripheral insulin resistance decreased in keeping with loss of FM, and by 1 year four of the 12 patients reported symptoms suggestive of postprandial neuroglycopenia in their daily life, and two exhibited biochemically confirmed postprandial hypoglycaemia in response to the mixed meal. This progressive and physiologically inappropriate increase in the postprandial insulin response may indicate the development of pancreatic β-cell adaptation and/or β-cell hyperresponsiveness to glucose46–48. Consistent with a role for GLP-1 in promoting this response, the magnitude of the postprandial GLP-1 peak predicted the subsequent glucose nadir. There are parallels with bariatric surgery, as hyperinsulinaemic hypoglycaemia has also been observed in patients following RYGB (who typically exhibit a similar gut hormone profile but greater insulin resistance), a phenomenon that is abolished after administration of the GLP-1 receptor antagonist exendin(9–39)46 and by somatostatin analogues47,49. These data support the primary role of GLP-1 in mediating hyperinsulinaemic hypoglycaemia in these cohorts, and, as such, competitive antagonism at the GLP-1 receptor may represent an important future therapeutic strategy. A phase II multicentre, randomized, single-blind, placebo-controlled crossover study to assess the efficacy and safety of subcutaneous exendin(9–39) in patients with postbariatric hypoglycaemia is currently underway (PREVENT study, NCT03373435), and there is rationale for further investigation in patients who have undergone oesophagectomy. Some limitations are acknowledged. First, although only the postprandial total GLP-1 response has been characterized, it is likely that these patients would exhibit similar changes in other postprandial satiety gut hormones such as oxyntomodulin and PYY, as indicated by previous cross-sectional data16. In addition, given the likely role of rapid gastrointestinal nutrient transit, the impact of pyloric management requires further study. Finally, it is possible that other barriers to eating, such as oropharyngeal dysphagia and anastomotic hold-up, may have contributed to weight loss in this cohort. Notwithstanding, the study provides novel data exploring the impact of oesophageal cancer surgery on the physiological systems regulating hunger and satiety, and highlights potential therapeutic targets. Early postoperative ghrelin deficiency and a persistently raised postprandial GLP-1 response may mediate altered appetite and weight loss after oesophagectomy. Furthermore, progressive GLP-1-mediated increases in the postprandial insulin response, in concert with diminished insulin resistance related to reduced FM, may have precipitated postprandial hypoglycaemia in this cohort. Therefore, manipulation of enteroendocrine physiology, specifically attenuation of postprandial satiety and incretin signalling, may represent a key therapeutic target to improve nutritional status, glycaemia and gastrointestinal HR-QoL in recovery and survival. Acknowledgements The authors acknowledge the assistance and support of: the Wellcome Trust–Health Research Board Clinical Research Facility at St James's Hospital, Dublin, in providing a dedicated environment for the conduct of high-quality clinical research activities; the Health Research Board, Ireland, which funded this study through a fellowship award to J.A.E. (HPF 2015-1013); Science Foundation Ireland, which provided funding to C.W.l.R (12/YI/B2480); and P. 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes Presented to the Patey Prize Session at the Annual Meeting of the Society of Academic and Research Surgery, Nottingham, UK, January 2018; published in abstract form as Br J Surg 2018; 105(Suppl 1): 82 © 2019 BJS Society Ltd Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2019 BJS Society Ltd Published by John Wiley & Sons Ltd
TI - Changes in gut hormones, glycaemic response and symptoms after oesophagectomy
JF - British Journal of Surgery
DO - 10.1002/bjs.11118
DA - 2019-04-11
UR - https://www.deepdyve.com/lp/oxford-university-press/changes-in-gut-hormones-glycaemic-response-and-symptoms-after-nodOvp0wcO
SP - 735
EP - 746
VL - 106
IS - 6
DP - DeepDyve
ER -