Postoperative Weight Loss Does Not Resolve After Esophagectomy Despite Normal Serum Ghrelin Levels

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1 GENERAL THORACIC Postoperative Weight Loss Does Not Resolve After Esophagectomy Despite Normal Serum Ghrelin Levels Masaru Koizumi, MD, PhD, Yoshinori Hosoya, MD, PhD, Katsuya Dezaki, MD, PhD, Toshihiko Yada, MD, PhD, Hiroshi Hosoda, MD, PhD, Kenji Kangawa, MD, PhD, Hideo Nagai, MD, PhD, Alan T. Lefor, MD, MPH, Naohiro Sata, MD, PhD, and Yoshikazu Yasuda, MD, PhD Departments of Surgery, Jichi Medical University School of Medicine, and Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Tochigi; Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka; and Department of Surgery, Ibaraki Prefectural Central Hospital, Ibaraki, Japan Background. Esophagectomy after gastric reconstruction leads to significant weight loss. Ghrelin is known to stimulate appetite and cause weight increase. The objective of this study is to examine the relationship of serum ghrelin levels and weight loss in patients after esophagectomy for cancer. Methods. Twenty-two patients underwent esophagectomy including gastric reconstruction. Serum ghrelin levels and weight were measured preoperatively and then postoperatively for 12 months in all patients. A questionnaire assessed appetite, amount of food eaten, satisfaction, and frequency of eating. Results. Preoperatively, the mean serum ghrelin level was (fmol/ml SD), and at 1, 3, 6, and 12 months after surgery were , , , and , respectively. Compared with preoperative values, the mean body mass index decreased by , , , at 1, 3, 6, and 12 months after surgery. While appetite score showed a decrease at 1 month ( ), appetite increased by 12 months postoperatively ( ) and showed a strong positive correlation (r 0.743) with serum ghrelin levels. There were no significant differences in ghrelin levels when patients were stratified by disease stage, recurrence, or administration of adjuvant chemotherapy. Conclusions. Esophagectomy resulted in temporary reduction of ghrelin levels, but while levels returned to normal 3 months later, weight loss persisted at 12 months. Further study is needed to elucidate the mechanisms of persistent weight loss and design therapeutic interventions to recover the weight lost. (Ann Thorac Surg 2011;91:1032 8) 2011 by The Society of Thoracic Surgeons Esophagectomy with gastric replacement may lead to significant weight loss and cause a variety of symptoms including dysphagia, gastroesophageal reflux, aspiration, choking, dyspnea, cough, and hoarseness [1 6]. Weight loss is a reliable indicator of postoperative malnutrition and profoundly affects overall postoperative quality of life [7, 8]. Significant weight loss after esophagectomy has been reported to be about 10% to 20% of preoperative weight [4, 5], similar to that after total gastrectomy [9, 10]. Ghrelin was first identified as a ligand for the growth hormone secretagogue receptor of the pituitary gland in 1999 [11]. Recent studies reveal that ghrelin stimulates not only growth hormone secretion from the pituitary gland but also the appetite signal in the hypothalamus, in opposition to leptin [12], an appetitesuppressing hormone [13]. Most ghrelin is secreted by the stomach, with only trace amounts from other Accepted for publication Nov 29, Address correspondence to Dr Koizumi, Jichi Medical University School of Medicine, Yakushiji Shimotsuke, Tochigi , Japan; mkoizumi@jichi.ac.jp. organs [14]. The discovery of ghrelin led to the novel concept of weight regulation by the stomach, which has been investigated in bariatric surgery and in patients after gastrectomy [15 17]. There is a single study of ghrelin levels after esophagectomy with gastric tube reconstruction, despite the fact that this procedure including anatomic translocation of the stomach and vagotomy may affect ghrelin production from the stomach [18]. This is a prospective study to examine the long-term relationship between serum ghrelin levels and weight loss in a single cohort of patients with thoracic esophageal squamous cell carcinoma after esophagectomy. Patients and Methods Patients This study was approved by the Institutional Review Board of Jichi Medical University, and individual consent obtained. Esophageal cancer patients who underwent resection at Jichi Medical University Hospital from 2004 through 2005 were enrolled. Inclusion criteria included 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg KOIZUMI ET AL 2011;91: GHRELIN LEVELS AFTER ESOPHAGECTOMY the following: (1) thoracic esophageal carcinoma; (2) reconstruction with a gastric tube; (3) no serious postoperative complication; (4) no other gastrointestinal diseases; (5) no serious dysfunction [white blood cell count 4,000 to 12,000/mm 3 ; platelet count 100,000 /mm 3 ; hemoglobin 8.0 g/dl; total bilirubin 1.5 mg/dl, glutamic-oxaloacetic acid transaminase 80 U/L; glutamic-pyruvic acid transaminase 80 U/L; alkaline phosphatase 2 times normal; creatinine 1.5 mg/dl]; and (6) informed consent. Surgical Procedure All patients underwent a right-sided thoracotomy and esophagectomy with lymph node dissection. A gastric tube was created along the greater curvature, approximately 5 cm in diameter. The finger bougie method to assure drainage of the vagotomized posterior mediastinal stomach was used. Reconstruction was performed using a retromediastinal and cervical anastomosis, or an intrathoracic anastomosis. Bilateral truncal vagotomy was performed distal to the bronchial branch. Jejunostomy tubes were not placed in any of the patients. Patients with lymph node metastases (stage III-IV) received adjuvant chemotherapy using two courses of 5-fluorouracil and cisplatin. Patients received individualized counseling and guidance regarding diet and eating habits in the postoperative period. Table 1. Postoperative Questionnaire (1) How does your appetite now compare with your appetite before surgery? Decreased 1 (points) Decreased slightly 2 Same as before 3 Increased slightly 4 Increased 5 (2) How much do you eat now, compared with before surgery? 1/4 or less 1 (points) 1/4 to 1/2 2 1/2 to 3/4 3 3/4 to same 4 Increased 5 (3) How many times do you eat each day? 1 time 1 2 times 2 3 times 3 4 times 4 5 times 5 (4) How full do you feel after eating a meal now, compared with before surgery (eating satisfaction)? Hungry 1 (points) Slightly hungry 2 Normal 3 Full (slightly) 4 Full Table 2. Patient Demographic Information and Perioperative Condition Total number of patients 22 Age (years), mean SD Range Gender Male 20 Female 2 Operation Esophagectomy 22 TNM stage I 2 II 13 III 5 IV 2 Preoperative BMI Range Preoperative comorbidities None 10 Hypertension 7 Anemia 2 Postmyocardial infarction 1 COPD 1 Chronic renal failure 1 Postcerebral hemorrhage 1 Hyperlipidemia 1 Benign prostatic Hypertrophy 1 Retinitis pigmentosa 1 Postoperative complications 5 Recurrent laryngeal nerve palsy 1 Wound infection 1 Liver dysfunction 1 Arrhythmia 1 Bronchial asthma 1 BMI body mass index; COPD chronic obstructive pulmonary disease; TNM tumor-nodes-metastasis. Measurement of Serum Ghrelin Measurement of serum ghrelin was performed preoperatively and at 1, 3, 6, and 12 months, postoperatively. A 10 ml fasting blood sample was collected from each patient on the day of measurement. Two rabbit polyclonal antisera were used including one against the COOH-terminal Cys-extended rat ghrelin, to recognize ghrelin with n-octanoylated Ser 3 (acylated ghrelin; ghrelin). Radioimmunoassay (RIA) using this antiserum, designated NH 2 -terminal radioimmunoassay, determined the concentration of acylated ghrelin. The other antiserum was raised against the NH 2 -terminal Cys-extended rat ghrelin to recognize both acylated ghrelin and desacyl-ghrelin [19]. Radioimmunoassay using this antiserum, COOH-terminal radioimmunoassay, determined the concentration of acylated ghrelin plus desacyl-ghrelin. Acylated ghrelin is described as GENERAL THORACIC

3 GENERAL THORACIC 1034 KOIZUMI ET AL Ann Thorac Surg GHRELIN LEVELS AFTER ESOPHAGECTOMY 2011;91: ghrelin and acylated ghrelin plus desacyl-ghrelin is described as total ghrelin in this study. Questionnaire Appetite, amount of food eaten, and satisfaction after eating were scored from 1 to 5 subjectively, comparing the patient s condition to their preoperative status (Table 1). Patients were asked how many times each day they ate. Weight (kg) and body mass index (BMI; kg/m 2 ) were measured preoperatively and at 1, 3, 6, and 12 months postoperatively. Statistical Analysis Statistical analysis was performed with the SPSS statistical package, version 14 (SPSS, Chicago, IL). Data are expressed as mean SD. Differences in each study variable were compared using one-way analysis of variance. A p value less than 0.05 was considered statistically significant. Results Twenty-two patients underwent esophagectomy, including 20 males and 2 females. The average age was 65.0 years (range 45 to 84). Patient demographic information is shown in Table 2. Serum Ghrelin Levels The mean concentration of serum total ghrelin and serum ghrelin are shown in Table 3. There is a significant (p 0.05) reduction at one month for both total ghrelin and ghrelin compared with the preoperative value. Total ghrelin and serum ghrelin levels at 12 months are significantly higher than at 1 month postoperatively, demonstrating a recovery of ghrelin level by 12 months after resection. Body Mass Index and Ghrelin Levels Preoperative BMI is shown in Table 2. Compared with preoperative BMI, the decrease in BMI was , , , and at 1, 3, 6, and 12 months after surgery, respectively, as shown in Table 3. These changes are all significantly lower than preoperative levels, but not significantly different at each time point documenting a persistent loss of weight. There was no correlation between preoperative BMI and serum ghrelin level. There was no correlation between the decrease in BMI and the serum ghrelin level postoperatively (correlation coefficient 0.01). Serum Albumin Level Serum albumin levels were measured preoperatively and at 1, 3, 6, and 12 months, and are shown in Table 3. Serum albumin was significantly lower at one month compared to the preoperative level. Serum albumin levels showed a significant increase at 6 months postoperatively, compared with the level at one month postoperatively. Pathologic Stage and Serum Ghrelin Levels The tumor-nodes-metastasis stage, using the Japanese Esophageal Society version 5, showed the following: stage I, n 2; stage II, 13; stage III, 5; and stage IV, 2. The serum concentration of total ghrelin showed no significant difference among any of the tumor stages at any time point, as shown in Table 4. Adjuvant Chemotherapy and Ghrelin Levels The serum concentration of total ghrelin was (fmol/ml SD) in those who received adjuvant chemotherapy (n 7) (AC ) and (fmol/ml SD) in patients who did not (n 15) (AC ), preoperatively. Serum total ghrelin levels stratified by the use of adjuvant chemotherapy is shown in Table 4, and there are no significant differences between the groups. Tumor Recurrence and Ghrelin Levels In patients with recurrent disease (n 3), the concentration of total ghrelin was (fmol/ml SD) and (fmol/ml SD) in patients without recurrence (n 19), preoperatively. The serum levels of total ghrelin stratified by recurrence are shown in Table 4 and there are no significant differences between the two groups. Table 3. Total Ghrelin, Ghrelin, Change in Body Mass Index (BMI) and Serum Albumin Parameter Preoperative 1 month 3 months 6 months 12 months Total Ghrelin (fmol/ml) a b (p 0.007) (p 0.008) Ghrelin (fmol/ml) a b (p 0.024) (p 0.03) BMI a a a a (p 0.016) (p 0.001) (p 0.004) (p 0.001) Albumin (mg/dl) a b (p 0.011) (p 0.023) a Result is significantly different compared with preoperative value, by ANOVA analysis. b Result is significantly different compared with that at 1 month, by ANOVA analysis. ANOVA analysis of variance.

4 Ann Thorac Surg KOIZUMI ET AL 2011;91: GHRELIN LEVELS AFTER ESOPHAGECTOMY Table 4. Serum Total Ghrelin Level (fmol/ml) Stratified by Clinical Course Clinical Parameter Preoperative 1 month 3 months 6 months 12 months Pathologic stage I II III IV Adjuvant chemotherapy Yes No Recurrent disease Yes No GENERAL THORACIC There were no significant differences in total ghrelin levels in any of the groups at any of the time points as analyzed by one-way analysis of variance. Questionnaire Appetite scores were based on a questionnaire (Table 1). The average appetite score (question 1) was at 1 month; it increased gradually to at 3 months, at 6 months, and at 12 months postoperatively. Scores are shown in Table 5, and changed significantly comparing the results at one month with those at six and 12 months after surgery (p 0.05). The amount consumed at each meal (question 2) decreased during the first month, but recovered to normal after that. There was a decrease in the frequency of meals (question 3), but it returned to the normal range after surgery (Table 5). There were significant changes at one and six months postoperatively. There were no significant changes in the sense of satisfaction score (question 4) after surgery (Table 5). Both appetite and ghrelin recovered over time, and there was a strong positive correlation (R 0.862) (Fig 1). Comment Ghrelin, secreted by the fundic glands of the stomach, increases weight by stimulating appetite and growth hormone secretion [11, 14], in a negative feedback loop in relation to weight. After surgery that affects gastric function, reduction of ghrelin levels may be related to postoperative weight loss. Gastric bypass surgery results in both weight loss and a reduction in serum ghrelin concentration, and probably appetite as well, while starvation reduces body weight but increases the ghrelin concentration with the sensation of hunger [15, 17]. Patients with gastric cancer typically have a reduction in serum ghrelin levels of 80% and a persistent loss of weight of about 20% after total gastrectomy [20, 21]. Resection of esophageal cancer includes resection of the upper part of the stomach, and gastric volume is reduced to create the gastric tube used for reconstruction. Vagotomy is also performed in the esophageal cancer operation. In theory, the concentration of serum ghrelin is reduced, and in fact it was reduced significantly after operation in this study. Ghrelin reduction after esophageal cancer surgery is likely a combination of the vagotomy and the partial of resection of the stomach. Significantly reduced serum ghrelin levels were seen at one month after surgery, but levels began to increase three months later. Subsequent increases in ghrelin levels may be due to the fact that the gastric fundus is still intact, in contrast to patients under- Table 5. Patient Responses to Satisfaction Questionnaire Question 1 Month 3 Months 6 Months 12 Months Appetite a a p p Amount Meal Frequency a a a p p p Satisfaction a Shows a significantly different (p 0.05) score compared with that at 1 month. Responses ona1to5point scale for each question at the time points shown. Fig 1. Correlation between total ghrelin level and appetite score. The correlation between total ghrelin and appetite score (points) was evaluated by a linear regression model, and shown by the regression line (Y 30.1X 8.79, R ). (e 1; 3; 6; Π12 months.)

5 GENERAL THORACIC 1036 KOIZUMI ET AL Ann Thorac Surg GHRELIN LEVELS AFTER ESOPHAGECTOMY 2011;91: going total gastrectomy and in whom ghrelin levels remain decreased at 12 months after resection (unpublished data). Performing a vagotomy may affect the neural influences on ghrelin production. The interaction between the vagus nerve and the fundus in regard to ghrelin production remain an area of active investigation. Transection of the vagus nerve has been reported to abolish the orexigenic effect of ghrelin in rodents [22, 23]. There are some reports that there is no relationship between ghrelin concentration and vagotomy in gastrectomy or esophagectomy [24, 25]. Doki and colleagues [18] reported the effect of esophagectomy on serum ghrelin and observed a correlation with ghrelin and postoperative body weight loss in esophageal cancer patients. They found a serum ghrelin concentration of 88.6 fmol/ml in the control group, which decreased to 58.8 fmol/ml 12 months postoperatively in the outpatient group. They concluded that the decline of ghrelin levels may play a role in weight loss after esophagectomy. The results of the present study are considerably different in that ghrelin levels returned to normal by 12 months postoperatively. One reason for the disparity of results may be that the data in the previous study were not analyzed continuously for the same group of patients. This is the only previous report about ghrelin and esophagectomy but the result is somewhat different from those in this prospective study in which all patients were followed continuously. This study was followed by a phase II clinical trial of ghrelin administration after esophagectomy [26], which showed a significantly increased food intake in patients receiving ghrelin compared with a placebo group, with attenuation of weight loss. Weight loss is a significant issue for patients after esophagectomy. Clinical trials looking at operative variables such as the route of reconstruction or type of gastric tube (whole or narrow tube) did not improve calorie intake or limit postoperative weight loss [27, 28]. In this study, the BMI significantly decreased at all time points measured compared with preoperative values, and persisted through the entire study period despite recovery of serum ghrelin levels. A wide variation in energy expenditure may contribute to the results observed. Responses to a questionnaire showed that appetite recovered chronologically, in parallel to the change in serum ghrelin levels. Serum ghrelin levels recovered early in the follow-up period, but did not synchronize with recovery of lost weight. About 70% of serum ghrelin is secreted from the stomach, so secretion may occur in the gastric tube during the postoperative period. There were no significant differences reported in the patients satisfaction after eating. Patients did report eating significantly more food at 12 months after surgery compared with the amount eaten at one month after surgery, correlating with increased ghrelin levels. This observation is consistent with the results of Yamamoto and colleagues [26], who found increased caloric intake in patients receiving exogenous ghrelin after esophagectomy. Further study will be needed to determine if a cause and effect relationship exists. Ghrelin enhances appetite and increases food intake in humans. This study shows a strong correlation between total serum ghrelin levels and appetite score. Ghrelin increases energy intake in patients with impaired appetite [29]. le Roux and colleagues reported that ghrelin does not stimulate food intake in patients after upper intestinal surgical procedures involving vagotomy (3 total gastrectomy, 1 partial gastrectomy, and 3 esophagectomy patients did not alter their energy intake with an infusion of ghrelin) [30]. This double blind, placebo-controlled trial supports the conclusions of this study; that ghrelin may not play an important role in reduced weight loss after esophagectomy. The stress of surgery alone could cause a change in ghrelin levels. In a study of patients after coronary artery bypass grafting, 17 patients were evaluated for ghrelin levels, including fasting and postprandial levels [31]. While fasting ghrelin levels were significantly increased postoperatively, postprandial ghrelin levels were suppressed. Peripheral ghrelin administration leads an increase in food intake and growth hormone release in humans [32]. The safety and usefulness of recombinant ghrelin have been confirmed in clinical trials for patients with heart failure [33]. Based on the results of the present study, the role of exogenous ghrelin requires further investigation. Weight loss may depend on other factors such as dysphagia, gastrointestinal reflux, aspiration, and diarrhea, which often accompany esophageal resection. Although serum ghrelin levels recover, patients do not recover weight lost postoperatively, suggesting that other factors are responsible for the persistent weight loss seen after esophageal resection. Future studies will include patient quality-of-life issues including gastrointestinal symptoms in searching for the factors responsible for weight loss, as well as other possible physiologic causes. Clinical trials using exogenous recombinant ghrelin therapy for patients after esophagectomy are necessary to more fully understand the complex physiology of weight loss after esophagectomy. References 1. 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6 Ann Thorac Surg KOIZUMI ET AL 2011;91: GHRELIN LEVELS AFTER ESOPHAGECTOMY 6. De Leyn P, Coosemans W, Lerut T. Early and late functional results in patients with intrathoracic gastric replacement after oesophagectomy for carcinoma. Eur J Cardiothorac Surg 1992;6: Demas GE, Drazen DL, Nelson RJ. Reductions in total body fat decrease humoral immunity. Proc Biol Sci 2003;270: Marinho LA, Rettori O, Vieira-Matos AN. Body weight loss as an indicator of breast cancer recurrence. Acta Oncol 2001;40: Bae JM, Park JW, Yang HK, Kim JP. Nutritional status of gastric cancer patients after total gastrectomy. World J Surg 1998;22: Braga M, Zuliani W, Foppa L, Di Carlo V, Cristallo M. Food intake and nutritional status after total gastrectomy: results of a nutritional follow-up. Br J Surg 1988;75: Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402: Shintani M, Ogawa Y, Ebihara K, et al. 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Gastroenterology 2001;120: Date Y, Murakami N, Toshinai K, et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002;123: Williams DL, Grill HJ, Cummings DE, Kaplan JM. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 2003;144: Banki F, Mason RJ, DeMeester SR et al. Vagal-sparing esophagectomy: a more physiologic alternative. Ann Surg 2002;236: Yamamoto K, Takiguchi S, Miyata H et al. Randomized phase II study of clinical effects of ghrelin after esophagectomy with gastric tube resection. Surgery 2010;148: Gawad KA, Hosch SB, Bumann D, et al. How important is the route of reconstruction after esophagectomy: a prospective randomized study. Am J Gastroenterol 1999;94: Collard JM, Tinton N, Malaise J, Romagnoli R, Otte JB, Kestens PJ. Esophageal replacement: gastric tube or whole stomach? Ann Thorac Surg 1995;60: Neary NM, Small CJ, Wren AM, et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004;89: le Roux CW, Neary NM, Halsey TJ, et al. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. J Clin Endocrinol Metab 2005;90: Nematy M, Brynes A, Hornick, et al. Postprandial ghrelin suppression is exaggerated following major surgery; implications for nutritional recovery. Nutr Metab (Lond) 2007;4: Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001;86: Nagaya N, Miyatake K, Uematsu M, et al. Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 2001;86: GENERAL THORACIC INVITED COMMENTARY Weight loss has been shown to be a significant predictor of survival in cancer patients. In patients with esophageal cancer undergoing esophagectomy, the weight loss is undoubtedly multifactorial, involving disturbed gastric emptying, gastroesophageal reflux, and depressed appetite as well as occasional swallowing dysfunction or anastomotic stricture. Recent interest has focused on the peptide hormone ghrelin and its role in enhancing eating and weight gain after gastroesophageal operations. Ghrelin, predominantly secreted by the stomach, has numerous biologic functions, including enhancing secretion of growth hormone, regulating energy balance, and promoting appetite. A randomized trial from Japan previously showed that supplementation of synthetic ghrelin postoperatively in patients after esophagectomy improved appetite and attenuated weight loss [1]. In the current study, Koizumi and colleagues [2] evaluated postoperative ghrelin levels after esophagectomy and related them to weight loss and appetite. They found that ghrelin levels decreased immediately after the operation, but returned to baseline levels by 3 months. Appetite scores steadily increased over the 12-month postoperative period as well. Body mass index, however, declined after the operation and failed to increase up to 1 year postoperatively. This was in a relatively lean patient cohort with a mean body mass index of only 21.7 kg/m 2. Although interesting, the study still leaves many questions to be answered regarding the role of ghrelin in gastroesophageal operations. The exact cause of de by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur