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Technical Briefs |
1 National Research Council, Rome, Italy; Departments of2 Public Health Science,3 Pediatrics, and 4 Anesthesia and Intensive Care, "La Sapienza" University of Rome, Rome, Italy;
aaddress correspondence to this author at: Department of Pediatrics, "La Sapienza" University of Rome, Viale Regina Elena, 324 00161 Rome, Italy; fax 39-06-4997-9215, e-mail claudio.chiesa{at}uniroma1.it
Secreted predominantly from the stomach (1), ghrelin is a peptide identified in 1999 as an endogenous ligand of the growth hormone (GH) secretagogue receptor located on the pituitary gland, thus fulfilling the criteria of a brain–gut peptide (2)(3). The brain–gut axis serves as an effector of anabolism by regulating growth, feeding, and metabolism via vagal afferent-mediating ghrelin signaling (2)(4). The role of ghrelin as a brain–gut peptide emphasizes the significance of afferent vagal fibers as a major pathway to the brain, serving the purpose of maintaining physiologic homeostasis (2)(4). The importance of ghrelin as a "hunger hormone" with orexigenic effects mediated by the hypothalamic peptides, agouti-related peptide, and neuropeptide Y, and the fact that it is the most potent peripheral signal of diminishing energy stores, implies that ghrelin release might be the most important of the many redundant mechanisms ensuring human survival in times of famine (4). However, the wide tissue distribution of ghrelin suggests that it may have other functions as well (5). Further characterization of the functions of ghrelin is fundamental to discovering new approaches to the diagnosis and treatment of different disease entities, including those related to the catabolic response to surgical trauma (2). In this preliminary study, we report the pattern of ghrelin secretion in different perioperative periods in patients undergoing elective cholecystectomy.
Thirty patients [17 females; age range, 20–45 years; body mass index (BMI), 18–25 kg/m2] with ultrasound-confirmed cholecystolithiasis undergoing elective cholecystectomy via laparoscopy or laparotomy at the Surgical Department at the Hospital Umberto I° of Rome were recruited to the study. All patients presented a low surgical risk (American Society of Anesthetists’ score 1 or 2). Patients with a diagnosis of choledocholitiasis, jaundice, acute cholecystitis, and pancreatitis; those with a history of metabolic, endocrine, hepatic, cardiac, or renal disease; those who, before surgery, received medication known to interfere with hormonal responses to stress; and those with a history of tobacco use or substance abuse were not eligible for the study. The study was approved by the Hospital Ethical Committee, and each participant gave informed consent to be included in the study.
After an overnight fast, between 0830 and 0900 in the morning, 20 study patients (13 females) underwent laparoscopic cholecystectomy (LC) by a 4-trocar technique, whereas 10 (4 females) underwent open cholecystectomy (OC) via a right subcostal incision. No LC patient required conversion to OC. There were no significant differences in the mean duration of surgery (time elapsed from the end of the induction of anesthesia until exsufflation or incision closure) between LC [mean (SD), 91.9 (36.8) min; range, 40–190 min] and OC [108 (30.9) min; range, 80–165 min] groups. All patients had an uneventful postoperative clinical course. Induction of anesthesia consisted of intravenous fentanyl (2 µg/kg), thiopental (5 mg/kg), and vecuronium (0.08 mg/kg). Anesthesia was maintained with 1% sevoflurane in a mixture of 60% nitrous oxide and 40% oxygen and intravenous fentanyl and vecuronium. Fluid replacement was performed with normal saline solution during surgery (7 mL · kg–1 · h–1) and throughout the postoperative course (1 mL · kg–1 · h–1) until the next morning after surgery (see below) when the seventh blood sample was taken.
Blood samples were collected from each patient at 
60 min before induction of anesthesia (sampling time t1); after induction of anesthesia (t2); at 30 min intraoperatively (t3); at the end of surgery, i.e., at exsufflation or incision closure (t4); in the first postoperative hours [t5 and t6: 6 h (afternoon) and 10 h (evening) after the start of surgery]; and on the morning (0800) of the first postoperative day (t7). Serum concentrations of immunoreactive ghrelin were measured in duplicate with an RIA that recognizes both the acylated and des-acyl forms (Phoenix Pharmaceuticals; lower limit of detection, 10 ng/L; inter- and intraassay CVs, 9.0%–13.6% and 4.5%–5.3%, respectively, as reported by the manufacturer).
A frequency distribution of the 30 measured ghrelin concentrations at each of the 7 time points was constructed and inspected. Given that every frequency distribution was positively skewed, the natural logarithm of each observed value was calculated, and these logarithms were used in all subsequent calculations. To investigate how the mean ghrelin concentration changed between the first and the seventh and last observation, we applied 2-way ANOVA (in which the rows represented the patients and the columns were the 7 time points) to the logarithms of the ghrelin concentrations to determine whether there were significant differences between the mean concentrations at times t1 to t7. We compared the differences between the observed values at times t2 to t7 with the baseline value (t1) by paired t-test and used regression analysis to investigate whether the patients’ sex and the type of operation influenced the mean logarithmic values of the ghrelin concentrations.
The 2-way ANOVA revealed highly significant (P <0.00005) differences between the mean values at times t1 to t7. The geometric mean concentrations of ghrelin at sampling times t1 to t7 are shown in Table 1
. After induction of anesthesia, at t2, the geometric mean ghrelin concentrations decreased by 5%, but this difference was not statistically significant compared with baseline values. By time t3, ghrelin had decreased by 23% (P = 0.035) compared with baseline values, and by time t4, the concentration had decreased by 30% (P = 0.01), reaching a minimum at t5 with a decrease of 39% (P <0.00005) compared with baseline values. At time t6, the concentrations had increased slightly, and by t7 they had returned to baseline values.
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In regression analysis, sex, duration of surgery, and type of surgical procedure had no significant effect on log ghrelin concentrations when adjusted for patients and times.
To our knowledge, this is the first report on the characteristics of ghrelin secretion in different perioperative periods of a cohort of adult patients undergoing elective cholecystectomy. The novel finding of our study is that ghrelin may be added to the list of substances whose concentrations remain stable until after the induction of anesthesia, at time t2 (6). However, the finding of a significant decrease in ghrelin concentrations from baseline during the intraoperative period, as well as over the course of several hours after surgery, was somewhat surprising. In general, ghrelin concentrations are inversely correlated with positive energy balance, BMI, body fat mass, adipocyte size, and leptin concentrations (7)(8)(9), whereas they are lower in obese persons than in controls (9). Pima Indians, known for their propensity to develop type II diabetes and obesity, also have lower circulating ghrelin concentrations, independent of BMI, compared with matched controls (9). Patients with anorexia nervosa have higher plasma ghrelin concentrations than age- and sex-matched controls, and weight gain lowers their increased ghrelin concentrations (10). Thus, fluctuations in plasma ghrelin concentrations may reflect physiologic adaptation to long-term alterations in energy balance (4).
Although ghrelin concentrations may increase in response to short-term fasting, the effects of a more prolonged fast on ghrelin have not been well characterized (11)(12). Only a very few studies have evaluated ghrelin concentrations in humans who have fasted completely and therefore have lost the meal-related pattern. Using single measurements, Norrelund et al. (13), in a study of healthy individuals and GH-deficient patients during a 36-h fast, found no significant changes in ghrelin concentrations in either group. In contrast, Muller et al. (14) reported that healthy nonobese individuals who fasted for 3 days developed a diurnal rhythm in ghrelin characterized by low concentrations in the morning with subsequent increases in the afternoon and at midnight. This study was, however, difficult to evaluate because a synthetic GH secretagogue was administered before and during fasting and plasma ghrelin was measured every 6 h in a relatively small number of individuals (n = 10). Recently, Chan et al. (11) described the circadian profiles of ghrelin in healthy lean persons who had fasted for 72 h (n = 6) and who had blood samples taken every 15 min for 24 h; the authors found minimal variation in ghrelin during the day before concentrations increased in the evening, followed by a significant decrease between 0200 and 0400. More recently, Espelund et al. (12) studied 33 healthy young adults (17 lean and 16 obese) with blood sampling every 3 h from 12 to 84 h of fasting. In contrast to the data from Chan et al. (11), Espelund et al. (12) found that serum ghrelin showed a marked diurnal rhythm with a nadir in the morning (0800), maximum values in the afternoon, and a gradual decrease during the night. This pattern was preserved during the entire fasting period and was independent of sex and obesity.
Considering this background, the ghrelin kinetics observed in our clinical setting involving a combination of fasting and uncomplicated surgical injury were quite different from any of the above-mentioned ghrelin patterns observed in response to the metabolic stress of fasting by itself in healthy individuals. Patients who undergo elective cholecystectomy do not appear to follow the circadian meal-independent rhythm of ghrelin secretion. The ghrelin response to surgical injury may be interpreted as an appropriate adaptation to an acute stress to help maintain homeostasis (15). Indeed, adaptation to starvation or caloric restriction may be the primary physiologic need for which ghrelin evolved as a peripheral regulator of energy balance (16)(17). On the other hand, it may be an adaptive response to inflammation. Consistent with the latter possibility are the recent findings by Dixit et al. (18) in a murine model of lipopolysaccharide (LPS)-induced endotoxemia, a well-recognized model associated with anorexia resulting from excessive production of proinflammatory mediators and a refractory catabolic state. The authors demonstrated that ghrelin infusion in LPS-challenged mice leads to a significant inhibition of the proinflammatory cytokines in circulation as well as in various organs. They also demonstrated that LPS-induced inflammatory anorexia is also significantly reduced in ghrelin-treated mice. Their data complement those reported previously by Basa et al. (19) and Hataya et al.(20) in rats. Whereas Basa et al. (19) showed that LPS-induced endotoxemia leads to inhibition of ghrelin secretion, Hataya et al. (20) found that ghrelin infusion increases body weight in septic animals. Considering these data, it seems plausible that inhibition of ghrelin secretion after LPS challenge might exacerbate the ongoing inflammatory insult and promote the development of a catabolic state. Thus, the decrease in ghrelin that we have found in the present study may be associated with the transition from an inflammatory immune response to an adaptive immune response, and future studies of the prognostic role of ghrelin after elective and nonelective surgery, with and without a complicated postoperative course, are warranted.
Acknowledgments
We thank Gino Davì for excellent technical assistance.
References
The following articles in journals at HighWire Press have cited this article:
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  L. Pacifico, C. Anania, J. F Osborn, E. Ferrara, E. Schiavo, M. Bonamico, and C. Chiesa Long-term effects of Helicobacter pylori eradication on circulating ghrelin and leptin concentrations and body composition in prepubertal children Eur. J. Endocrinol., March 1, 2008; 158(3): 323 - 332. [Abstract] [Full Text] [PDF]
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 C. Chiesa, J. F. Osborn, C. Haass, F. Natale, M. Spinelli, E. Scapillati, A. Spinelli, and L. Pacifico Ghrelin, Leptin, IGF-1, IGFBP-3, and Insulin Concentrations at Birth: Is There a Relationship with Fetal Growth and Neonatal Anthropometry? Clin. Chem., March 1, 2008; 54(3): 550 - 558. [Abstract] [Full Text] [PDF]
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L. Pacifico, L. Di Renzo, C. Anania, J. F Osborn, F. Ippoliti, E. Schiavo, and C. Chiesa Increased T-helper interferon-{gamma}-secreting cells in obese children. Eur. J. Endocrinol., May 1, 2006; 154(5): 691 - 697. [Abstract] [Full Text] [PDF]
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