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Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications

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Abstract

Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient’s quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.

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Abbreviations

5-HIA:

5-Hydroxyindole Acetaldehyde

5-HIAA:

5-Hydroxyindole Acetic Acid

5-HTP:

5-Hydroxytryptophan

GTOL:

5-Hydroxytryptophol Glucuronide

5-HTOL:

5-Hydroxytryptophol

ADH:

Alcohol Dehydrogenase

ALR:

Aldehyde Reductase

AADC:

Aromatic Acid Decarboxylase

CHD:

Carcinoid Heart Disease

CaS:

Carcinoid Syndrome

CNS:

Central Nervous System

EC :

Enterochromaffin Cell

HPLC :

High-Performance Liquid Chromatography

HIOMT :

Hydroxyindole O-Methyltransferase

TRP :

L-Tryptophan

TPH :

L-Tryptophan-5-Hydroxilase

LC :

Liquid Chromatography

MS :

Mass Spectrometry

MEL:

Melatonin

MAO :

Monoamine Oxidase

NAS :

N-Acetyl-Serotonin

NEN:

Neuroendocrine Neoplasm

SERT :

Serotonin Transporter

5-HT :

Serotonin, 5-Hydroxytryptamine

SNAT :

Serotonin-N-Acetyltransferase

TE:

Telotristat etiprate

UGT:

UDP-Glucuronosyltransferase

U-5-HIAA:

Urinary 5-Hydroxyindole Acetic Acid

VMATs:

Vesicular Monoamine Transporters

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Acknowledgements

This review is part of the ‘Neuroendocrine Tumours Innovation Knowledge and Education’ project led by Prof. Annamaria Colao and Prof. Antongiulio Faggiano, which aims at increasing the knowledge on neuroendocrine tumours. We would like to acknowledge all the Collaborators of this project: Manuela Albertelli, Barbara Altieri, Elena Ambrosetti, Antonio Bianchi, Lena Bottiglieri, Severo Campione, Silvia Carra, Federica De Cicco, Carla Di Dato, Sergio Di Molfetta, Antonella Di Sarno, Giuseppe Fanciulli, Diego Ferone, Francesco Ferraù, Marco Gallo, Elisa Giannetta, Federica Grillo, Elia Guadagno, Valentina Guarnotta, Andrea Isidori, Pasqualino Malandrino, Chiara Martini, Erika Messina, Roberta Modica, Giovanna Muscogiuri, Genoveffa Pizza, Paola Razzore, Laura Rizza, Manila Rubino, Concetta Sciammarella, Giovanni Vitale, Maria Chiara Zatelli.

Authorship

All authors made substantial contributions to the conception of the article, literature search and data analysis. The manuscript was drafted by Giuseppe Fanciulli and Rosaria M. Ruggeri and all authors commented on previous versions of the manuscript. Antongiulio Faggiano, Andrea Isidori and Annamaria Colao critically revised the work for important intellectual content. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Author notes

  1. Giuseppe Fanciulli and Rosaria M. Ruggeri contributed equally to this work.

Authors and Affiliations

  1. Department of Medical, Surgical and Experimental Sciences, University of Sassari - Endocrine Unit, AOU Sassari, Sassari, Italy

    Giuseppe Fanciulli

  2. Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Messina, Messina, Italy

    Rosaria M. Ruggeri

  3. S.C. Endocrinologia, ASST Grande Ospedale Metropolitano, Niguarda, Milan, Italy

    Erika Grossrubatscher

  4. Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy

    Fabio Lo Calzo & Annamaria Colao

  5. Department of Chemistry, University at Buffalo, Buffalo, NY, USA

    Troy D. Wood

  6. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Antongiulio Faggiano & Andrea Isidori

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  1. Giuseppe Fanciulli
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Fanciulli, G., Ruggeri, R.M., Grossrubatscher, E. et al. Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications. Rev Endocr Metab Disord 21, 599–612 (2020). https://doi.org/10.1007/s11154-020-09547-8

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