Serotonin, Whole Blood

Whole blood, frozen

10 mL EDTA/ascorbic acid mixture (see Collection below)

Lavender-top (EDTA) tube and transport tube (LabCorp N° 33314) containing 75 mg ascorbic acid

Monoamine oxidase inhibitor drugs should be discontinued for at least one week prior to sampling since they tend to increase the level of serotonin.

Serotonin measurement is used in conjunction with urinary 5-hydroxyindoleacetic acid (5-HIAA) and/or serum chromogranin A in the diagnosis of carcinoid syndrome.

The majority of gastroenteropancreatic neuroendocrine, carcinoid tumors do not produce elevated whole blood or serum serotonin levels. In most cases, 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A are superior tests for the assessment of carcinoid syndrome^.1-4 In rare instances, a deficiency of aromatic amino acids decarboxylase in carcinoid tumor cell limits the conversion of 5-HTP into serotonin.¹⁷

Several medications (lithium, monoamine oxidase inhibitors, methyldopa, morphine, and reserpine) can produce elevation in serotonin concentration. Selective serotonin reuptake inhibitors can cause a reduction in serum and whole blood serotonin levels. Tryptophan-rich food (avocados, bananas, plums, walnuts, pineapple, eggplant, plantain, tomatoes, hickory nuts, kiwi, dates, grapefruit, cantaloupe, and honeydew melon) do not contribute to serum or blood serotonin measurements.^12,13

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

Liquid chromatography/tandem mass spectrometry (LC/MS-MS)

See table.

Reference Interval developed by in-house study.

Carcinoid tumors are slow-growing neuroendocrine tumors derived from enterochromaffin cells that are widely distributed throughout the body.^1-4 Approximately 65 percent of carcinoid tumors are found in the gastrointestinal tract from the foregut, midgut, and hindgut, and another 25 percent originate in the bronchopulmonary tract.^3,4 The primary site for one in 10 cases remain undetermined.³ About a quarter of cases present with distant metastases, half of which have unknown primary tumor location.³

Carcinoid tumors secrete a variety of peptides and small molecules.^1,4-6 Midgut carcinoid tumors frequently produce serotonin. Serotonin secreting carcinoids from other locations are less common. Serotonin (5-hydroxytryptamine) is synthesized from the essential amino acid tryptophan via the intermediate 5-hydroxytryptophan (5-HTP). Serotonin secretion in the gut causes an increase in gastrointestinal blood flow, motility, and fluid secretion. In healthy individuals, the great majority of serotonin made by the gut is converted by the liver and lungs to 5-hydroxyindoleacetic acid (5-HIAA) via first pass metabolism prior to entering the general circulation. Almost the entirety of the small amount of serotonin that survives the first pass metabolism is taken up by platelets. Platelets store serotonin until it is released as part of the clotting process to promote platelet aggregation.

Serotonin secreting carcinoid tumors are relatively slow growing, and in most cases, asymptomatic.^1,4,6 The local, paracrine effect of increased serotonin on the gut intestine can cause diarrhea, malabsorption and tumor mass producing discomfort.^4,7 Since most serotonin produced by carcinoid tumors is metabolized prior to reaching the circulation, the metabolic product, 5-HIAA, in urine is usually the most important marker for carcinoid tumors.⁴

In cases where a larger amount of serotonin reaches the systemic circulation (advanced disease with liver metastases bypassing first pass metabolism), patients can present with a constellation of symptoms referred to as the carcinoid syndrome. The carcinoid syndrome can also occur in the absence of liver metastases in cases where tumor pathology causes direct venous drainage of serotonin bypassing first pass liver metabolism.^5,8 Carcinoid syndrome is relatively rare and is most commonly associated with midgut carcinoid tumors^.2,4 Carcinoid syndrome occurs in 20% of cases of well-differentiated endocrine tumors of the jejunum or ileum.^5,8 Carcinoid syndrome occurs less often with neuroendocrine tumors of other origins and is very rare in association with rectal NETs.^5,8

Carcinoid syndrome is characterized by one or more symptoms including diarrhea, dry flushing without sweating with or without palpitations, and intermittent abdominal pain.⁵ Some patients also experience lacrimation and rhinorrhea. ^5,8 Advance or long-standing carcinoid syndrome can lead to carcinoid heart disease involving the tricuspid and pulmonary valves of the heart.^7,9 Other cardiovascular complications include bowel ischemia and hypertension.⁷ Approximately one in five patients with carcinoid syndrome sent with heart disease at diagnosis.^5,8 Carcinoid tumors are classified similarly whether they produce symptoms of the carcinoid syndrome or not.¹⁰

The primary laboratory tests for the diagnosis and assessment of carcinoid tumors are serum chromogranin A and, in the case of tumors presenting with carcinoid syndrome, urinary 5-HIAA. Direct measurement of serotonin is considered a secondary test for this condition.^14-16 Whole blood serotonin is measured because most circulating serotonin is contained in platelets and whole blood levels correlated with platelet levels. Alternatively, serum serotonin levels can be measured because the process of blood clotting causes the release of all platelet serotonin in to the serum.

In healthy individuals, approximately 99 percent of dietary tryptophan is metabolized by the oxidative pathway into nicotinic acid (vitamin B3).⁴ In carcinoid tumors, excessive conversion of tryptophan to serotonin can cause result in vitamin B3 deficiency referred to as pellagra, a condition that is characterized by the triad of symptoms; diarrhea, dementia, and dermatitis.¹¹