ABSTRACT

Ghrelin is a 28 amino acid, acylated peptide mainly produced in the P/D1 neuroendocrine cells of the stomach wall. The peptide stimulates growth hormone release by acting on both the pituitary and hypothalamus, but also stimulates ACTH and prolactin as well as gastric acid secretion and intestinal motility. Ghrelin also increases appetite and food intake. Expression of ghrelin protein and mRNA has been identified in high percentages of gastric neuroendocrine tumors (NETs) but also intestinal and pancreatic NETs. Theoretically, a ghrelinoma could cause acromegaly, diabetes mellitus, diarrhea and gastric acid hypersecretion. Small numbers of cases with elevated plasma ghrelin have been reported. However, patients often have non-specific symptoms, that do not resemble the theoretical syndrome of a ghrelinoma. This suggests a low biological activity of these elevated ghrelin levels, which could by related to the ratio of acylated ghrelin and unacylated ghrelin. At this time the clinical relevance of hyperghrelinemia for NETs remains limited. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

GHRELIN

Ghrelin is a 28 amino acid, acylated peptide mainly produced in the P/D1 neuroendocrine cells of the stomach wall (1,2). It was discovered in 1999 by Kojima and colleagues as a ligand for the growth-hormone secretagogues receptor 1a (GHS-R1a), purified from rat stomach extract (1). Ghrelin expression has been found in multiple organs including the bowel, adrenal gland, thyroid, ovary, testis, prostate, liver kidneys and myocardium (2-5). On top of this, ghrelin is produced in the central nervous system, particularly in the hypothalamus (6). Two isoforms of ghrelin can be found in equal amounts in the circulation: acylated ghrelin (AG) and unacylated ghrelin (UAG) (7). AG is formed when a hydroxyl group on one of UAGs serine residues is acylated by Ghrelin O-Acyltransferase (GOAT). The acylation allows AG to cross the blood-brain barrier and bind to the GHS-R1a and thereby stimulate growth hormone (GH) release in the pituitary and GHRH in the hypothalamus (8). Vice versa, GH infusion has been shown to decreases ghrelin levels (9). Other effects of ghrelin on the pituitary include stimulation of CRH dependent ACTH release, prolactin secretion and suppression of gonadotrophins (9). UAG does not bind to the GHS-R1a and was previously considered to be inactive, but currently both AG and UAG have been shown to influence glycemic regulation. When AG is administered to healthy individuals, insulin levels decline and plasma glucose levels increase. Coadministration of AG and UAG blunts the AG-induced alteration in insulin and glucose levels, suggesting UAG is an antagonist for AG (10). Ghrelin also has an important role in fasting. Plasma ghrelin levels rise preprandially and stimulates appetite, increases intestinal motility and gastric acid secretion (11). Acutely increased ghrelin levels stimulate lipolysis, however chronic administration of AG results in lipogenesis (12,13). Lastly, cardiovascular effects of ghrelin have been reported including vasodilation and an increased cardiac index and stroke volume (14). In Table 1 an overview of the effects of AG is provided.

GHRELIN AND NEUROENDOCRINE TUMORS

Based upon the physiologic effects of ghrelin one would expect that the clinical features of a ghrelinoma would include hyperglycemia (decreased insulin secretion) and GH excess with elevated IGF-1 and potentially features of acromegaly. Gastrointestinal symptoms could include hyperphagia and gastric acid hypersecretion (Table 1). The severity of these symptoms would probably also depend on the AG/UAG ratio. This complete syndrome has not been described in a patient to date, while tumor ghrelin immunoreactivity occurs frequently in neuroendocrine tumors (NETs) and in a small number of patients elevated plasma ghrelin levels have been found.

Expression of ghrelin protein and/or mRNA has been detected in a high percentage of gastric, intestinal and pancreatic NETs. Gastric NETs are regarded to derive from Enterochromaffin-Like (ECL) cells. They are classified as type 1 if they are associated with atrophic gastritis. Type 2 gastric NETs are associated with a gastrin-producing neuroendocrine tumors (Zollinger-Ellison syndrome) and type 3 gastric NETs are sporadic (15). Ghrelin expression is lacking in ECL cells in physiological conditions (2), but in gastric NETs ghrelin is frequently expressed. Rindi and colleagues used immunohistochemistry to identify the ghrelin peptide in 86% of type 1, 67% of type 2, and 50% of type 3 gastric NETs (16). Also, high ghrelin expression can be observed within neuroendocrine hyperplasia of the stomach (associated with type 1 and 2 NETs). Despite the expression of ghrelin, these hyperplastic neuroendocrine cells are currently still regarded to derive from ECL cells as they display VMAT2 immunoreactivity, which is a specific marker for ECL cells (17). It is hypothesized that ECL cells secrete ghrelin in proliferative states, potentially under the influence of gastrin.

In the same study, eight intestinal NETs didn’t express ghrelin immunohistochemically. Similar findings were reported by Papotti and colleagues, but they additionally detected ghrelin mRNA in 72% of intestinal carcinoids through in situ hybridization (18). These intestinal NETs were mostly negative for IHC suggesting that lower concentrations of ghrelin might be present, although below the detection limit of IHC or translation is absent. In pancreatic NETs, around 40% of tumors showed ghrelin immunoreactivity, whilst in situ hybridization revealed ghrelin mRNA in 68% of pNET, including non-functioning pNET, insulinoma, glucagonoma, and VIPoma (19,20). Normal pancreatic islet cells have also been demonstrated to express ghrelin peptide. The co-expression of ghrelin in a variety of NETs may also represent the common stem cell origin of the different enteroendocrine cell types (5).

Actual elevated plasma ghrelin levels in patients with a NET have only sporadically been measured (Table 2). In a study screening 26 patients with pNETs, mean plasma total ghrelin levels were similar between patients and healthy controls (20). However, plasma total ghrelin levels were elevated in a subset of 5 patients. These patients did not display features of acromegaly and mean body mass index of patients with hyperghrelinemia was similar to patients with normal ghrelin levels. Three other studies reported hyperghrelinemia in NET patients at a lower incidence of around 3% (total or acylated ghrelin; Table 2) (21-23). All patients with hyperghrelinemia had non-specific symptoms without evidence of GH excess or hyperglycemia. Again, mean plasma total ghrelin levels were similar in NET patients compared to controls and therefore ghrelin was found to be a poor screening tool for NETs (21,22).

Lastly, elevated ghrelin levels have been reported in three case reports. The first patient was a 60-year-old male, presenting with abdominal pain, weight loss, flushing and fatigue. There were no signs of diabetes mellitus or acromegaly. After being treated with a somatostatin analogue for four years and three cycles of temozolomide/capecitabine an elevated plasma total ghrelin level was measured. Four months later the patient developed symptomatic endogenous hyperinsulinism and passed away another four months later (24). A second patient with a presacral NET was also diagnosed with a ghrelinoma based on elevated plasma total ghrelin levels (25). Symptoms included back pain and intermittent attacks of weakness, shivering, tachycardia, numbness and profuse perspiration. While AG levels were stable through the course of the disease total ghrelin levels increased tenfold when the NET progressed. A third case report described a patient with a gastric NET with elevated total and acylated ghrelin. This patient reported frequent diarrhea and night sweats. During follow-up patient developed new-onset diabetes in the presence of normal IGF-1 levels (26).

In conclusion, while co-expression of ghrelin is a relative frequent finding in NETs, actual elevated plasma ghrelin levels has been described in small numbers of patients. The non-specific symptoms of a majority patients suggest limited biological activity of these elevated ghrelin levels, possibly related to the UAG/AG ratio. At this time the clinical relevance of hyperghrelinemenia for NETs remains limited.

REFERENCES

1.

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(6762):656–660. [PubMed: 10604470]

2.

Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141(11):4255–4261. [PubMed: 11089560]

3.

Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002;87(6):2988. [PubMed: 12050285]

4.

Kojima M, Hosoda H, Kangawa K. Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Horm Res. 2001;56 Suppl 1:93–97. [PubMed: 11786694]

5.

Beumer J, Gehart H, Clevers H. Enteroendocrine Dynamics - New Tools Reveal Hormonal Plasticity in the Gut. Endocr Rev. 2020;41(5) [PMC free article: PMC7320824] [PubMed: 32531023]

6.

Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37(4):649–661. [PubMed: 12597862]

7.

Tong J, Dave N, Mugundu GM, Davis HW, Gaylinn BD, Thorner MO, Tschop MH, D'Alessio D, Desai PB. The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects. Eur J Endocrinol. 2013;168(6):821–828. [PMC free article: PMC3740531] [PubMed: 23482590]

8.

Banks WA, Tschop M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther. 2002;302(2):822–827. [PubMed: 12130749]

9.

Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab. 2000;85(12):4908–4911. [PubMed: 11134161]

10.

Delhanty PJ, Neggers SJ, van der Lely AJ. Des-acyl ghrelin: a metabolically active peptide. Endocr Dev. 2013;25:112–121. [PubMed: 23652397]

11.

Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 2000;276(3):905–908. [PubMed: 11027567]

12.

Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194–198. [PubMed: 11196643]

13.

Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–913. [PubMed: 11057670]

14.

Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol. 2001;280(5):R1483–1487. [PubMed: 11294772]

15.

Delle Fave G, O'Toole D, Sundin A, Taal B, Ferolla P, Ramage JK, Ferone D, Ito T, Weber W, Zheng-Pei Z, De Herder WW, Pascher A, Ruszniewski P. all other Vienna Consensus Conference p. ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology. 2016;103(2):119–124. [PubMed: 26784901]

16.

Rindi G, Savio A, Torsello A, Zoli M, Locatelli V, Cocchi D, Paolotti D, Solcia E. Ghrelin expression in gut endocrine growths. Histochem Cell Biol. 2002;117(6):521–525. [PubMed: 12107502]

17.

Srivastava A, Kamath A, Barry SA, Dayal Y. Ghrelin expression in hyperplastic and neoplastic proliferations of the enterochromaffin-like (ECL) cells. Endocr Pathol. 2004;15(1):47–54. [PubMed: 15067176]

18.

Papotti M, Cassoni P, Volante M, Deghenghi R, Muccioli G, Ghigo E. Ghrelin-producing endocrine tumors of the stomach and intestine. J Clin Endocrinol Metab. 2001;86(10):5052–5059. [PubMed: 11600584]

19.

Volante M, Allia E, Gugliotta P, Funaro A, Broglio F, Deghenghi R, Muccioli G, Ghigo E, Papotti M. Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab. 2002;87(3):1300–1308. [PubMed: 11889202]

20.

Ekeblad S, Lejonklou MH, Grimfjard P, Johansson T, Eriksson B, Grimelius L, Stridsberg M, Stalberg P, Skogseid B. Co-expression of ghrelin and its receptor in pancreatic endocrine tumours. Clin Endocrinol (Oxf). 2007;66(1):115–122. [PubMed: 17201810]

21.

Corbetta S, Peracchi M, Cappiello V, Lania A, Lauri E, Vago L, Beck-Peccoz P, Spada A. Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors: identification of one pancreatic ghrelinoma. J Clin Endocrinol Metab. 2003;88(7):3117–3120. [PubMed: 12843152]

22.

van Adrichem RC, van der Lely AJ, Huisman M, Kramer P, Feelders RA, Delhanty PJ, de Herder WW. Plasma acylated and plasma unacylated ghrelin: useful new biomarkers in patients with neuroendocrine tumors? Endocr Connect. 2016;5(4):143–151. [PMC free article: PMC5002960] [PubMed: 27215920]

23.

Walter T, Chardon L, Hervieu V, Cohen R, Chayvialle JA, Scoazec JY, Lombard-Bohas C. Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases. Eur J Endocrinol. 2009;161(4):639–645. [PubMed: 19605542]

24.

Chauhan A, Ramirez RA, Stevens MA, Burns LA, Woltering EA. Transition of a pancreatic neuroendocrine tumor from ghrelinoma to insulinoma: a case report. J Gastrointest Oncol. 2015;6(2):E34–36. [PMC free article: PMC4311091] [PubMed: 25830049]

25.

Falkmer UG, Gustafsson T, Wenzel R, Wierup N, Sundler F, Kulkarni H, Baum RP, Falkmer SE. Malignant presacral ghrelinoma with long-standing hyperghrelinaemia. Ups J Med Sci. 2015;120(4):299–304. [PMC free article: PMC4816891] [PubMed: 26095011]

26.

Tsolakis AV, Portela-Gomes GM, Stridsberg M, Grimelius L, Sundin A, Eriksson BK, Oberg KE, Janson ET. Malignant gastric ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab. 2004;89(8):3739–3744. [PubMed: 15292299]

27.

Motta G, Allasia S, Zavattaro M, Ghigo E, Lanfranco F. Natural and Synthetic Growth Hormone Secretagogues☆. In: Huhtaniemi I, Martini L, eds. Encyclopedia of Endocrine Diseases (Second Edition). Oxford: Academic Press; 2018:127-141.