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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5392-5396
Copyright © 2004 by The Endocrine Society

Changes in Plasma Ghrelin Concentration Immediately after Gastrectomy in Patients with Early Gastric Cancer

Tae Yong Jeon, Sangyeoup Lee, Hyoung Hoi Kim, Yun Jin Kim, Han Chul Son, Dong Heon Kim and Mun Sup Sim

Department of Surgery (T.Y.J., D.H.K., M.S.S.), Obesity, Nutrition, and Metabolism Center, and Departments of Family Medicine (S.L., Y.J.K.) and Laboratory Medicine (H.H.K., H.C.S.), Pusan National University College of Medicine, and Medical Research Institute (T.Y.J., S.L., H.H.K., Y.J.K., H.C.S., D.H.K., M.S.S.), Pusan National University, Busan, 602-739 Korea

Address all correspondence and requests for reprints to: Sangyeoup Lee, M.D., Ph.D., Department of Family Medicine, Pusan National University Hospital, 1-10 Ami-dong Seo-gu, 602-739 Busan, Korea. E-mail: saylee{at}pnu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Although the majority of circulating ghrelin originates from the stomach, no prospective study of the proportion of ghrelin derived from the stomach has been reported. Patients with early gastric cancer who underwent gastric resection were divided into three groups according to the extent and site of gastric resection: subtotal gastrectomy group (n = 24), proximal gastrectomy group (n = 4), and total gastrectomy group (n = 12). Patients with advanced gastric cancer who underwent gastrojejunostomy without gastrectomy served as the bypass group (n = 5). Blood samples were collected from all patients preoperatively, at 1 h after gastric resection or gastrojejunostomy, and on postoperative d 1, 3, and 7. The plasma ghrelin level was determined in all samples and expressed as a percentage of the preoperative level. In the bypass group, no significant drop in the ghrelin level was observed at 1 h after gastrojejunostomy, and the ghrelin level remained stable through postoperative d 7. In the subtotal gastrectomy group, the ghrelin concentration reached a nadir of 38.8 ± 12.9% of preoperative levels at 1 h after gastric resection and then gradually increased to 88.1 ± 13.2% by postoperative d 7. In the proximal gastrectomy group, the nadir ghrelin level was 24.5 ± 15.4% at 1 h after gastric resection and was followed by a gradual recovery. However, the recovery rate was slower than that in the subtotal gastrectomy group, with the ghrelin level reaching only 47.6 ± 18.8% by postoperative d 7 (P < 0.05). In the total gastrectomy group, the nadir ghrelin level was 28.6 ± 11.1% at 1 h after gastric resection and remained at 30.0 ± 13.2% until postoperative d 7. These results suggest that compensatory ghrelin production can occur in the remnant stomach after the surgical removal of part of the stomach and that the proximal fundus is more important than the distal antrum and body in terms of the capacity for ghrelin production. The principal site of ghrelin production is clearly the stomach, which contributes 70% of the circulating ghrelin concentration.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN, A 28-AMINO-ACID peptide with an n-octanoylation indispensable for its biological activity, is a natural endogenous ligand for the GH secretagogue receptor (1). Ghrelin has been shown to regulate not only GH release from the pituitary gland but also to have other physiological functions, such as the regulation of food intake and energy homeostasis (2, 3, 4). The plasma concentration of ghrelin increases under conditions of negative energy balance, such as starvation, cachexia, and anorexia nervosa, whereas its expression decreases under conditions of positive energy balance, such as feeding, hyperglycemia, and obesity (5, 6, 7, 8, 9). Ghrelin is produced mainly by the stomach; substantially lower amounts are derived from the bowel, pancreas, kidney, and placenta (10, 11, 12, 13).

Gastrectomy, the surgical removal of all or part of the stomach, has been performed primarily to cure peptic ulcer disease or remove gastric cancer. Today, with advances in medical therapy, elective peptic ulcer surgery has been virtually abandoned, and surgery is restricted to cases of complicated peptic ulcer disease (14). However, surgical resection remains the treatment of choice for gastric cancer and offers the best chance of cure (15). Either a total gastrectomy or the removal of the distal two thirds of the stomach by subtotal gastrectomy is performed, depending on the site and extent of the primary tumor. Proximal gastrectomy, a limited resection for cancers in the upper third of the stomach, can be performed as an alternative to more radical surgery (16).

Because plasma ghrelin is predominantly derived from stomach, the plasma ghrelin concentration might change as a consequence of gastric resection. It is known that removing the entire stomach in humans and rats decreases the plasma concentration of ghrelin by 60–80% (17, 18). However, these results were obtained from animal experiments or retrospective studies comparing gastrectomized patients and control groups. No prospective study of the changes in plasma ghrelin concentrations before and after gastric resections in patients with early gastric cancers has been reported. To investigate the proportion of circulating ghrelin produced by the stomach and the ghrelin production capacity of the anatomic subdivisions of the stomach, the plasma concentration of ghrelin was serially measured before and after total or partial gastrectomy performed for the treatment of gastric cancer.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients with early gastric cancer who underwent gastric resection in Pusan National University Hospital between January 2001 and June 2003 comprised the study subjects. Early gastric cancer is defined by the Japanese Research Society for Gastric Cancer as cancer in which the tumor cells invade only the mucosal and submucosal layers (19). Forty-five patients with gastric cancer were studied (Table 1Go). Patients with early gastric cancer were divided into three groups after gastrectomy surgery, based on the extent and site of gastric resection: the subtotal gastrectomy group (n = 24), the proximal gastrectomy group (n = 4), and the total gastrectomy group (n = 12). Subtotal gastrectomy and proximal gastrectomy were defined as the surgical removal of the distal two thirds and proximal half of the stomach, respectively. The surgical removal of the entire stomach was defined as total gastrectomy. The restoration methods of digestive continuity after gastric resection were as follows: Billroth II anastomosis in subtotal gastrectomy, jejunal interposition between the esophagus and stomach in proximal gastrectomy, and Roux-en Y esophagojejunostomy in total gastrectomy. For gastrectomy, patients with endocrine diseases, such as diabetes mellitus, thyroid disease, and pituitary disease, were excluded from this study, as were patients with tumors larger than 2 cm in diameter. Patients with advanced gastric cancer who underwent gastrojejunostomy, rather than gastrectomy, owing to the direct invasion of the tumor into the pancreatic head comprised the bypass group (n = 5). Written informed consent was obtained from each subject before enrollment in this study. The study was approved by the institutional review board at the Medical Research Institute, Pusan National University, and was performed in accordance with the principles of the Declaration of Helsinki.


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  		TABLE 1. Characteristics of study subjects

 
Blood samples were collected from all patients preoperatively, at 1 h after gastric resection or gastrojejunostomy, and on postoperative d 1, 3, and 7. All blood samples were obtained at 0800 preprandially, except the sample taken at 1 h after gastric resection or gastrojejunostomy. All patients fasted from midnight before the day of surgery until postoperative d 3. Sips of water and a clear liquid diet were started on postoperative d 4 and 5, respectively. Thereafter, liquid diets were gradually increased, and patients were discharged on postoperative d 8–12.

The blood samples were analyzed for ghrelin, leptin, insulin, and GH. The plasma concentration of ghrelin was expressed as a percentage of the preoperative level for each patient. The proportion of circulating ghrelin produced by the stomach and the capacity for ghrelin production in the anatomic subdivisions of the stomach were investigated. Because the plasma concentration of ghrelin can be affected by leptin, insulin, and GH (8, 20), the concentrations of these hormones were also determined before and after gastric resection to examine any possible effect on ghrelin levels. Data from patients whose medical records showed surgical complications or an inability to follow a regular diet schedule were excluded from the analysis.

Blood samples were drawn into chilled tubes containing Na2EDTA (1 mg/ml) and aprotinin (500 U/ml). Plasma was immediately separated by centrifugation at 4 C and stored at –70 C until assayed. Plasma ghrelin was measured with a commercially available RIA kit (Phoenix Pharmaceuticals, Inc., Belmont, CA) using 125I-labeled bioactive ghrelin as a tracer molecule and a polyclonal rabbit antibody against full-length octanoylated human ghrelin, which measures total circulating ghrelin levels. The lower and upper limits of detection were 10 and 1280 pg/ml, respectively (21). The mean intra- and interassay coefficients of variation (CV) were 4.8 and 3.5%, respectively. The RIA did not show any cross-reaction with human leptin. Insulin levels were measured using RIA (Diagnostic Products, Los Angeles, CA) with antibody-coated tubes. The lower limit of detection was 6.6 pmol/liter. The mean intra- and interassay CV values were 4.2 and 6.3%, respectively. Plasma leptin concentrations were measured in duplicate using a double-antibody RIA (Linco Research Inc., St. Charles, MO). The lower limit of detection was 0.5 ng/ml, and the mean intra- and interassay CV were 3.4–8.3 and 3.0–6.2%, respectively. Plasma GH levels were measured using an electrochemiluminescence immunoassay (Nichols Institute Diagnostics, San Clemente, CA). The lower limit of detection was 0.2 U/ml (1.39 pmol/liter). The mean intra- and interassay CV values were 4.2 and 8.2%, respectively. All procedures were performed at 4 C.

The data were expressed as mean ± SD. ANOVA with Scheffé’s post hoc test was used to determine the statistical significance of the differences in ghrelin, leptin, insulin, and GH levels during the postoperative course among the four subject groups. We used SPSS 11.0 for Windows (SPSS Inc., Chicago, IL) for all statistical analyses. P < 0.05 was considered statistically significant. All statistical tests were two sided.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
There were no significant differences in the preoperative plasma ghrelin concentrations among the four groups (Table 1Go). There were also no significant differences in the preoperative plasma concentrations of leptin, insulin, and GH among the treatment groups (Figs. 1–3GoGoGo). The concentrations of ghrelin in plasma at 1 h after gastric resection or gastrojejunostomy and on postoperative d 1, 3, and 7 were expressed as percentages of the preoperative level for each patient (Fig. 4Go). In the subtotal gastrectomy group, the ghrelin level reached a nadir of 38.8 ± 12.9% at 1 h after gastric resection and gradually increased to 88.1 ± 13.2% by postoperative d 7. In the proximal gastrectomy group, the nadir ghrelin level was 24.5 ± 15.4% at 1 h after gastric resection and was followed by a gradual recovery. However, the recovery rate was slower than that in the subtotal gastrectomy group, with the ghrelin level reaching only 47.6 ± 18.8% by postoperative d 7. On postoperative d 3 and 7, the plasma ghrelin levels in the proximal gastrectomy group were significantly lower than those in the subtotal gastrectomy group. In the total gastrectomy group, the nadir ghrelin level was 28.6 ± 11.1% at 1 h after gastric resection and remained at 30.0 ± 13.2% through postoperative d 7. On postoperative d 1, 3, and 7, the plasma ghrelin levels in the total gastrectomy group were significantly lower than those in the subtotal gastrectomy group. In the bypass group, no significant drop in the ghrelin level was observed at 1 h after gastrojejunostomy, and the ghrelin level remained stable through postoperative d 7 (Fig. 4Go).



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  		FIG. 1. Changes in the concentration of leptin by treatment group. No significant differences (P > 0.05 by ANOVA with Scheffé’s post hoc test) were detected between treatment groups at any time. POD, Postoperative day.

 


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  		FIG. 2. Changes in the concentration of insulin by treatment group. No significant differences (P > 0.05 by ANOVA with Scheffé’s post hoc test) were detected between treatment groups at any time. POD, Postoperative day.

 


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  		FIG. 3. Changes in the concentration of GH by treatment group. No significant differences (P > 0.05 by ANOVA with Scheffé’s post hoc test) were detected between treatment groups at any time. POD, Postoperative day.

 


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  		FIG. 4. The plasma concentration of ghrelin by treatment group. The plasma concentration of ghrelin is expressed as a percentage of the preoperative levels. At 1 h after gastric resection, there were significant differences between the bypass group (B) and the three gastrectomized groups (P < 0.001). On postoperative day (POD) 1, there was a significant difference between the subtotal (S) and total (T) gastrectomy groups (P < 0.001). On POD 3 and 7, there were no differences between groups B and S, but significant differences were found between S and the other two gastrectomized groups (P < 0.001).

 
The plasma leptin concentrations of each of the groups remained relatively constant before and after gastric resection, within a range of 2–3 ng/ml. The plasma insulin concentrations declined transiently at 1 h after gastric resection in all groups and then gradually increased. The plasma GH concentrations increased transiently after surgery in all groups and declined thereafter to the preoperative levels by postoperative d 7. There were no significant differences in the concentrations of leptin, insulin, or GH among the treatment groups (Figs. 1–3GoGoGo).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The finding that ghrelin is produced mainly in the gastrointestinal tract strongly implies that there is a regulatory axis or a dialog between the gastrointestinal tract and the hypothalamic-pituitary unit (22). Because the gastrointestinal tract is the portal for nutrient absorption, the gastrointestinal tract should influence the hypothalamic regulation of food intake. Ghrelin provides this link by relaying information about nutritional and caloric intake to the hypothalamus and pituitary gland. In cases of abnormal ghrelin production, the information relayed to the brain is erroneous; consequently, the regulation of food intake and energy homeostasis can be changed. We hypothesized that gastric resection for treatment of gastric cancer would be one common clinical situation resulting in abnormal ghrelin production and examined whether the plasma concentration of ghrelin changed after gastric resection.

Gastric cancer is one of the leading causes of cancer-related deaths worldwide (15). Treatments for gastric cancer include surgery, chemotherapy, and radiation; however, surgery is the treatment of choice and offers the best chance of a cure. Surgical treatment varies according to the extent and site of the gastric cancer and may include total, subtotal, or proximal gastrectomy. Early gastric cancer, which is confined to the mucosa and submucosa, is often curable if surgery is performed at this stage. Although the correlation between gastric cancer and the plasma concentration of ghrelin has not been examined, advanced stages of gastric cancer or increased tumor size can influence the plasma ghrelin concentration. Previous studies have shown that the plasma concentration of ghrelin increases with the progression of cancer-related cachexia (23). Therefore, to exclude the influence of the tumor on the plasma concentration of ghrelin, the gastrectomized patients included in this study were limited to those with early gastric cancer and with tumors measuring less than 2 cm. The plasma concentration of ghrelin can be affected by endogenous hormones (24, 25); thus, gastrectomized patients with endocrine diseases, such as diabetes mellitus, thyroid disease, and pituitary disease, were also excluded from the study. To investigate the proportion of plasma ghrelin produced by the stomach and the capacity for the production of ghrelin in the anatomic subdivisions of the stomach, gastrectomized patients with early gastric cancer were divided into three groups based on the extent and site of gastric resection: the subtotal gastrectomy group, the proximal gastrectomy group, and the total gastrectomy group. The concentration of ghrelin in gastrectomy patients might be affected by perioperative factors, such as anesthesia, medications, fluid infusion, and operative stress. To rule out the influence of perioperative factors, patients with advanced gastric cancer who underwent gastrojejunostomy to treat the direct invasion of the pancreatic head by a tumor served as the bypass group, in which the patient management protocol was the same as that of gastrectomized patients. Plasma ghrelin was checked serially before and after gastrectomy or gastrojejunostomy.

The changes in the plasma concentration of ghrelin after gastric resection varied according to the extent and site of gastric resection. At 1 h after gastric resection or gastrojejunostomy, the plasma concentration of ghrelin in the subtotal gastrectomy group, the proximal gastrectomy group, and the total gastrectomy group had decreased to 38.8 ± 12.9, 24.5 ± 15.4, and 28.6 ± 11.1% of preoperative levels, respectively; the plasma concentration of ghrelin in the bypass group did not decrease. The plasma concentration of ghrelin was significantly lower in the gastrectomized groups than in the bypass group. These findings strongly indicate that gastric resection contributes to changes in plasma ghrelin levels. The removal of the entire stomach or the acid-producing part of the stomach in rats reduced the plasma concentration of ghrelin by 80%, supporting the view that the stomach is the main source of circulating ghrelin. In the current study, the removal of the entire stomach caused an abrupt decrease in plasma ghrelin to 28.6 ± 11.1% of preoperative levels by 1 h after gastric resection, again indicating that the principal site of ghrelin production is the stomach and that it contributes about 70% of the circulating ghrelin in humans. There is no information available regarding the half-life of plasma ghrelin, but the significant reductions in the plasma concentrations of ghrelin by 1 h after gastric resection in all of the gastrectomized groups suggest that the half-life of plasma ghrelin is very short, consistent with its hypothesized regulatory role.

A subtotal gastrectomy involves the removal of the distal two thirds of the stomach, sparing the fundus. In contrast, in proximal gastrectomy, the proximal half of the stomach is removed, and the antrum and part of the body are spared. A study in rats indicated that the expression of ghrelin in the stomach is strictly localized to the X/A-like endocrine cells of the oxyntic mucosa, which are found mainly in the fundus (26). In subtotal gastrectomy, which preserves the fundus, the ghrelin production capacity might be conserved. However, in proximal gastrectomy, which removes the fundus, the ghrelin production capacity might be reduced. In this study, the concentration of ghrelin gradually recovered after resection in both the subtotal gastrectomy and proximal gastrectomy groups. However, the rate of recovery in the proximal gastrectomy group was slower than that in the subtotal gastrectomy group, and the concentration reached only 47.6 ± 18.8% of preoperative levels by postoperative d 7. In other words, a partial gastrectomy that spared the fundus permitted a largely compensatory production of ghrelin, whereas the compensatory production was significantly diminished after a more limited resection removing the fundus. These results suggest that compensatory production of ghrelin can occur in the remnant stomach after the surgical resection of cancerous tissue and that the proximal fundus is more important than the distal antrum and body in terms of ghrelin production. In the total gastrectomy group, ghrelin decreased to 28.6 ± 11.1% of preoperative levels by 1 h after gastric resection and remained at 30.0 ± 13.2% through postoperative d 7. The compensatory production of ghrelin, which was observed in the subtotal gastrectomy and proximal gastrectomy groups, did not occur in the total gastrectomy group. This suggests that when the entire stomach is removed, any potential compensatory production of ghrelin by other tissues, such as bowel, pancreas, kidney, and placenta, does not occur before postoperative d 7.

Total gastrectomy is followed by a variety of symptoms and impairments, referred to as postgastrectomy syndrome. One important feature of postgastrectomy syndrome is weight loss. The average loss is approximately 25% of preoperative body weight, leaving 60–70% of patients permanently below their ideal body weight (27). However, the reason for this weight loss is not clear. A reduced caloric intake and malabsorption are considered the most important factors contributing to weight loss after total gastrectomy (28). Hosoda et al. (29) reported that the plasma concentration of ghrelin after total gastrectomy was gradually normalized and suggested that other tissues compensate to maintain circulating ghrelin levels after total gastrectomy. However, Ariyasu et al. (17) compared 13 total gastrectomized patients with sex- and age-matched control subjects and found that the average plasma concentration of ghrelin in gastrectomized patients remained at only 35% that of control subjects for 1–8 yr after surgery. Therefore, further long-term studies are necessary to determine whether the reduction of ghrelin production in total gastrectomized patients is persistent. If circulating ghrelin participates in the adaptive response to weight loss, its levels would be expected to remain low after gastric resection. In addition, because ghrelin is produced mainly by the stomach, weight loss after total gastrectomy should be accompanied by impaired ghrelin production. Although the evidence in the current study supports the possibility that the reduced circulating ghrelin concentration in gastrectomized patients contributes to weight loss, future clinical studies should further clarify this hypothesis.

The plasma leptin, insulin, and GH levels were measured to exclude the possibility of influences on the plasma concentration of ghrelin. The plasma concentration of leptin in each of the groups remained constant at approximately 2–3 ng/ml before and after gastric resection. Maintenance of the plasma concentration of leptin, which is secreted by adipocytes, indicates that no significant change in the body fat composition occurred during the first 7 d after gastric resection. The plasma concentration of insulin in each of the groups declined transiently by 1 h after gastric resection and gradually increased thereafter. The transient reduction of plasma insulin due to surgical stress recovered after the infusion of glucose-containing fluids. The concentration of GH in each of the groups increased transiently before declining again to preoperative levels by postoperative d 7. Transient elevations of plasma GH owing to surgical stress gradually recovered as the body shifted from a catabolic to an anabolic phase. There were no significant differences in the plasma concentrations of leptin, insulin, or GH among the treatment groups, suggesting that these hormones do not affect the changes in the plasma concentration of ghrelin after gastric resection.

In summary, we have shown that the plasma concentration of ghrelin is altered after gastric resection and that the principal site of ghrelin production is the stomach, which contributes 70% of the circulating concentration of ghrelin. Compensatory ghrelin production might occur in the remnant stomach after the surgical removal of part of the stomach. The proximal fundus is more important than the distal antrum and body in terms of the capacity to produce ghrelin.


   Footnotes
 
This work was supported by a Medical Research Institute Grant (2003-21) from Pusan National University, Busan, Korea.

Abbreviation: CV, Coefficient of variation.

Received May 10, 2004.

Accepted August 6, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals