clinical topic updates
Serotonin Metabolism in Carcinoid Syndrome
Our featured expert describes how serotonin metabolism is relevant to both the diagnosis and treatment of carcinoid syndrome.
Professor and Chief
Division of Medical Oncology
Department of Medicine
Member, UK Markey Cancer Center
University of Kentucky
“When serotonin is broken down into 5-HIAA within the liver, it creates a useful proxy for serotonin measurement through a 24-hour urine test.”
Neuroendocrine tumors (NETs) that cause carcinoid syndrome, which are commonly of small bowel origin, secrete serotonin and other substances that give rise to the symptoms of carcinoid syndrome. Serotonin is thought to have an important role in the diarrhea and in the mesenteric and cardiac valvular fibrosis of carcinoid syndrome, while the episodic flushing of carcinoid syndrome may reflect the influence of other active peptides and tachykinins, such as substance P.
Tryptophan is the precursor of serotonin, and serotonin is synthesized via the enzyme tryptophan hydroxylase, for which there are 2 isoforms that are expressed in distinct cell types throughout the body. TPH1 is mainly expressed in the gut, while TPH2 is primarily expressed in neurons in the brain stem and in a subset of neurons in the enteric nervous system.
When serotonin is broken down into 5-hydroxyindoleacetic acid (5-HIAA) within the liver, it creates a useful proxy for serotonin measurement through a 24-hour urine test. However, if a patient has an elevated 5-HIAA, there may be some uncertainty regarding the cause. The dietary intake of certain foods and medications can cause 5-HIAA levels to rise, so a patient might be asked to adhere to a tryptophan-free diet for 48 hours prior to testing.
In terms of our treatments, we use somatostatin analogues such as octreotide to try to block NETs from producing serotonin and other amines. Telotristat is a tryptophan hydroxylase inhibitor that is sometimes used to help control diarrhea when added to somatostatin analogue therapy. When we add telotristat, we are blocking serotonin production in the tumor, but we are not blocking serotonin production in the brain because that is a separate compartment. Serotonin does not readily cross the blood-brain barrier; thus, patients with carcinoid syndrome do not have anything akin to a built-in selective serotonin reuptake inhibitor (SSRI). Likewise, when the tryptophan gets converted to serotonin in the brain, that serotonin is circulating in the brain and does not cross back over.
A common clinical question—and an area of controversy—is: Can SSRIs be used to treat mood disorders in patients with carcinoid syndrome? An analysis by Isenberg-Grzeda and colleagues found no evidence of serious adverse outcomes related to serotonin-mediated antidepressant usage in patients with NETs, many of whom had carcinoid syndrome. Researchers concluded that their findings do not support the conclusions drawn by previous authors that SSRIs should be avoided in patients with NETs. They did note, however, that, as with the use of antidepressants in all patients, individuals with NETs who are on antidepressant therapy should be monitored for worsening symptoms.
Burks ML, Bao S. The 24-hour urinary 5-HIAA: a simple test with a common pitfall. AACE Clin Case Rep. 2016;2(3):e186-e188. doi:10.4158/EP15794CR
Chan DL, Singh S. Developments in the treatment of carcinoid syndrome - impact of telotristat. Ther Clin Risk Manag. 2018;14:323-329. doi:10.2147/TCRM.S126143
Clement D, Ramage J, Srirajaskanthan R. Update on pathophysiology, treatment, and complications of carcinoid syndrome. J Oncol. 2020;2020:8341426. doi:10.1155/2020/8341426
de Celis Ferrari ACR, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e490s. doi:10.6061/clinics/2018/e490s
Isenberg-Grzeda E, MacGregor M, Bergel A, et al. Antidepressants appear safe in patients with carcinoid tumor: results of a retrospective review [published correction appears in Eur J Surg Oncol. 2018;44(9):1453]. Eur J Surg Oncol. 2018;44(6):744-749. doi:10.1016/j.ejso.2018.03.010
Isenberg-Grzeda E, MacGregor M, Matsoukas K, Chow N, Reidy-Lagunes D, Alici Y. Must antidepressants be avoided in patients with neuroendocrine tumors? Results of a systematic review. Palliat Support Care. 2020;18(5):602-608. doi:10.1017/S147895152000005X
Jones LA, Sun EW, Martin AM, Keating DJ. The ever-changing roles of serotonin. Int J Biochem Cell Biol. 2020;125:105776. doi:10.1016/j.biocel.2020.105776
Lenchner JR, Santos C. Biochemistry, 5 hydroxyindoleacetic acid. StatPearls. StatPearls Publishing; 2022.
Pandit S, Annamaraju P, Bhusal K. Carcinoid syndrome. StatPearls. StatPearls Publishing; 2022.