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Circulating Ghrelin Levels in Patients with Pancreatic and Gastrointestinal Neuroendocrine Tumors: Identification of One Pancreatic Ghrelinoma

Institute of Endocrine Sciences (S.C., V.C., A.L., P.B.-P., A.S.) and Department of Medical Sciences (M.P.), Ospedale Maggiore IRCCS, and Pathology Unit (E.L., L.V.), Department of Clinical Sciences, Ospedale L. Sacco, University of Milan, 20122 Milan, Italy

Address all correspondence and requests for reprints to: Anna Spada, M.D., Institute of Endocrine Sciences, Via F.Sforza, 35, 20122 Milan, Italy. E-mail: anna.spada{at}unimi.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. Although the expression of ghrelin has been demonstrated in most gastrointestinal carcinoids and pancreatic tumors, the circulating levels of this peptide have been marginally assessed in patients with these disorders. We measured plasma ghrelin levels in 16 patients with gastrointestinal carcinoid (10 with midgut and 6 with gastric carcinoid), 24 patients with pancreatic tumor (8 with gastrinoma, 2 with insulinoma, 2 with vipoma, 1 with glucagonoma, and 11 with nonfunctioning tumor), and 35 healthy controls. Plasma ghrelin levels recorded in patients with gastroenteropancreatic tumors were similar to controls (mean ± SE, 182.7 ± 66.5 pM in patients vs. 329 ± 32 pM in controls, P = not significant), and no significant difference between gastrointestinal and pancreatic, functioning and nonfunctioning, and metastatic and nonmetastatic tumors was observed. One patient with metastatic nonfunctioning pancreatic tumor had circulating ghrelin levels of 12,000 pM that were slightly reduced during chemotherapy and interferon therapy. Immunohistochemistry performed on peritoneal lesions showed an intense, focal cytoplasmic positivity for ghrelin. Despite the 50-fold increase in ghrelin concentrations, the patient had normal serum GH and IGF-I levels. In conclusion, the study showed that carcinoids and pancreatic tumors rarely cause ghrelin hypersecretion. However, in this series, 1 pancreatic ghrelinoma not associated with clinical features of acromegaly was identified.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
GHRELIN IS A 28-amino acid acylated peptide, recently isolated from the X/A-like neuroendocrine cells of the rat and human stomach, that exerts a wide range of metabolic functions (1, 2). This peptide stimulates GH release in humans and animals, probably by acting at both hypothalamic and pituitary levels (3). Ghrelin is an important regulator of energy balance, because it has been demonstrated to increase appetite and food intake and to modulate insulin secretion (4, 5). Consistent with the high homology with the novel motilin-related peptide, ghrelin stimulates gastric contractility and acid secretion (6, 7). Although ghrelin is highly expressed in the stomach, other minor sources for ghrelin production, such as bowel, hypothalamus, pituitary, and (more recently) pancreas, have been identified (8, 9). In the pancreas, ghrelin seems to be confined to pancreatic islets, where it colocalizes, in rats and humans, with glucagon in the A-cells (5, 9). As far as human tumors are concerned, the expression of ghrelin protein and/or messenger RNA has been recently identified in almost all gastric and intestinal carcinoids as well as in pancreatic neuroendocrine tumors (8, 10). Because only 1 recent study reported normal circulating ghrelin levels in 1 single patient with a ghrelin positive glucagonoma (11), the clinical impact of ghrelin expression in patients with these neuroendocrine tumors remains to be elucidated.

The aim of the study was to test the hypothesis that gastrointestinal carcinoids and pancreatic neuroendocrine tumors may release ghrelin in sufficient amounts to increase ghrelin concentrations in the circulation and to offer a new marker of these diseases.

	Patients and Methods

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Patients

Forty consecutive patients (25 women and 15 men, 17–81 yr old), referred to the Department of Medical Sciences with newly diagnosed untreated gastroenteropancreatic neuroendocrine tumors, were investigated. Ten had midgut carcinoid, 6 had gastric carcinoid with hypergastrinemia attributable to chronic atrophic gastritis, and 24 had pancreatic tumor (gastrinoma in 8 cases, insulinoma in 2, vipoma in 2, calcitoninoma in 1, and nonfunctioning tumor in 11). Seven patients with pancreatic tumors had multiple endocrine neoplasia type 1. Liver and/or lymph node metastasis were present in 7 patients with midgut carcinoids and in 8 with pancreatic tumors (2 also had peritoneal carcinomatosis). All patients had high plasma chromogranin A (CgA) levels, and 20 patients had elevated pancreatic polypeptide (PP) levels, whereas hypergastrinemia was present in 8 with gastrinoma and 6 with gastric carcinoid and chronic atrophic gastritis. In patients with midgut carcinoids, urinary 5-hydroxyindolacetic acid levels were elevated in 7 cases (Table 1). The study also included, as controls, 35 healthy subjects matched for age, sex, and body mass index.

Assays

After an overnight fast, blood was drawn from all patients into ice-chilled EDTA/aprotinin polypropylene tubes, immediately separated by centrifugation at 4 C, and stored in aliquots at -80 C until assay. Plasma ghrelin was measured with a commercially available RIA kit (Phoenix Pharmaceuticals, Inc., Belmont, CA) that uses a polyclonal antibody recognizing the C-terminal end of ghrelin, i.e. total ghrelin, as previously described (12). GH, IGF-I, CgA, and gastroenteropancreatic hormones levels were measured by commercial kits, as previously described (12, 13, 14).

Immunohistochemestry

Ghrelin immunostaining was performed on formalin-fixed and paraffin-embedded samples after microwave pretreatment (2x 5 min cycles in 0.01 M citric acid, 780 W) by incubating sections with a polyclonal antibody (Phoenix Pharmaceuticals, Inc.) diluted 1:1000 and incubated for 2 h at room temperature. The reaction product was revealed with a double indirect immunoperoxidase system, and diaminobenzidine was used as chromogen. It was followed by a weak nuclear counterstain with hematoxylin. Parallel sections of the sample studied were stained with CgA, secretogranin, and neuron-specific enolase.

Stastistics

The results are expressed as mean ± SE (range). Differences between groups were analyzed by two-tailed unpaired Student’s t test. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Plasma ghrelin levels recorded in patients with gastroenteropancreatic neuroendocrine tumors were similar to those observed in healthy controls [plasma ghrelin, 182.7 ± 66.5 (range, 108–486) in patients vs. 329 ± 32 pM (range, 75–662) in controls; P = not significant]. No significant difference between carcinoids and pancreatic tumors was observed (Table 1). Moreover, hypersecretion of bioactive peptides (such as insulin, glucagon, gastrin, or VIP) was not associated with changes in ghrelin levels. Similarly, there was no significant difference between metastatic and nonmetastatic tumors.

One patient with nonfunctioning pancreatic tumor had circulating ghrelin levels of 12,000 pM, consistent with the presence of a pancreatic ghrelinoma. She was a 66-yr-old woman (kg, 71; cm, 154; body mass index, 29.9 kg/m²) with arterial blood hypertension and type 2 diabetes mellitus by 5 yr. She was referred to a surgery department because of an episode of intestinal subocclusion. The imaging procedure, including octreoscan, showed a pancreatic neoplasia with concomitant multiple liver metastasis. Plasma samples from the patient showed increased CgA and PP levels (Fig. 1); normal values of gastrin and somatostatin; and a dramatic increase in ghrelin levels. However, despite the 50-fold increase in ghrelin concentrations, GH and IGF-I levels were within the normal range [1.8 ng/ml (normal value {nv}, <2.5) and 10.5 nM (nv. 12–37)], consistent with the absence of clinical features of acromegaly. Twenty-four-hour urine cortisol was within the normal range. She underwent an explorative surgical procedure, during which samples from liver, lymph nodes, and peritoneal metastasis were obtained and paraffin- embedded. Routine immunohistochemical reactions for the neuroendocrine markers CgA, secretogranin 2, and neuron-specific enolase were positive. Moreover, immunohistochemical reaction for ghrelin, performed on metastatic peritoneal lesions, showed an intense, focal cytoplasmic positivity in about half of the neoplastic cells (Fig. 2).

View larger version (22K): [in this window] [in a new window]   FIG. 1. Hormonal and clinical parameters of the patient with ghrelinoma from diagnosis and during the follow-up. CgA, nv. 2–18 U/liter; PP, nv. < 30 pM; ghrelin, nv. 329 ± 32 pM.

View larger version (125K): [in this window] [in a new window]   FIG. 2. Ghrelin immunostaining of a metastatic lesion. Immunohistochemical reaction with antighrelin antibody in a metastatic peritoneal lymph node demonstrated a strong cytoplasmic positivity (black) in about half of the neoplastic cells. No staining was observed in intratumoral stromal or inflammatory cells (immunoperoxidase, hematoxylin counterstain; x400).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In this retrospective study, we evaluated plasma ghrelin concentrations in a series of patients with gastrointestinal carcinoids and pancreatic neuroendocrine tumors and describe the first patient with a ghrelin-hypersecreting pancreatic tumor. Ghrelin is a novel gastrointestinal hormone, originally identified as a natural ligand of the GH secretagogue receptor and produced by gastric X-like neuroendocrine cells (2), that has been subsequently detected in most gastrointestinal carcinoids as well as pancreatic tumors (8, 10). With the exception of a recent study reporting normal circulating ghrelin levels in one patient with a ghrelin-positive glucagonoma (11), no information on circulating ghrelin levels in patients affected with these neoplasia is presently available. This study showed that plasma ghrelin levels from a large series of patients with gastrointestinal and pancreatic neuroendocrine tumors did not significantly differ from those reported in healthy subjects, vanishing the utility of circulating ghrelin as a marker for diagnosis or follow-up of these diseases. Accordingly, there was no difference in ghrelin levels regarding the hormonal production or the progression of the disease.

The evaluation of ghrelin secretion in patients with neuroendocrine tumors provided in vivo data on the influences of gastrointestinal hormones on ghrelin secretion. In our series, hypergastrinemia in patients with gastrinoma or chronic atrophic gastritis did not affect plasma ghrelin levels, suggesting that ghrelin-producing cells are not sensitive to gastrin, as observed in rats (15). Moreover, although several studies demonstrated a negative correlation between insulin and ghrelin levels (16, 17), in patients with insulinoma, ghrelin levels were within the normal range, suggesting that factors other than hyperinsulinemia per se are responsible for the low ghrelin levels typically observed in obese and type 2 diabetes patients (16).

Extremely high ghrelin levels were detected in one patient with nonfunctioning pancreatic tumor. Although the total removal of the tumor and metastatic tissues was not feasible, various evidence indicated that the pancreatic tumor was the source of ghrelin hypersecretion. To that conclusion pointed the strong ghrelin positivity in the metastasis and the extremely high circulating levels of the peptide. In fact, in physiological or pathological conditions characterized by high circulating ghrelin levels, such as starvation, anorexia nervosa (18), bulimia (19), and cachexia (20), ghrelin values were (at most) doubled, when compared with normal controls. The identification of a pancreatic ghrelinoma is reminiscent of the GHRH-secreting tumor that was first identified in the pancreas (21). However, though it is well established that GHRH-omas unequivocally cause acromegaly, the patient here described did not present acromegalic features, consistent with the normal levels of GH and IGF-I. Several events may account for this phenomenon. First, although ghrelin is the most potent GH secretagogue (3), the physiological relevancy of this peptide in controlling GH/IGF-I axis is still uncertain. Indeed, though it is known that the mice lacking GHRH signaling have a dwarf phenotype (22), the recently generated knockout mice for the ghrelin gene have a normal body size (23), suggesting a minor role for this peptide in GH secretion. Alternatively, the absence of GH axis activation in this patient might be attributable to the secretion of a bioinactive ghrelin molecule, because the commercially available RIA kits detected both octanoylated, active and nonoctanoylated, inactive ghrelin. Finally, down-regulation of GH secretagogue receptors in the presence of chronic ghrelin hypersecretion cannot be ruled out.

In conclusion, this study first describes a neoplastic ghrelin hypersecretion from a pancreatic tumor, not associated with clinical features of acromegaly. Moreover, data indicates that gastrointestinal carcinoids and pancreatic tumors are a rare cause of ghrelin hypersecretion.

	Footnotes

 
This work was supported in part by MURST Grant 2002068252 and Ricerca Corrente Funds of Ospedale Maggiore IRCCS.

Abbreviations: CgA, Chromogranin A; nv, normal value; PP, pancreatic polypeptide.

Received November 21, 2002.

Accepted March 16, 2003.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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