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Serotonin

Serotonin (5-hydroxytryptamine; 5-HT) is synthesized from the essential amino acid tryptophan. 5-HT production sites are the central nervous system (CNS) and gastrointestinal tract enterochromaffin cells (EC-cells). The CNS and peripheral 5-HT pools are isolated from each other. EC-cell production accounts for 80% of the body’s 5-HT content.

Many different stimuli can release 5-HT from EC-cells. Once secreted, in concert with other gut hormones, 5-HT increases GI blood flow, motility, and fluid secretion. On first pass through the liver, between 30 and 80% of 5-HT is metabolized, predominately to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted by the kidneys. Ninety-percent of the remainder is metabolized in the lungs, also to 5-HIAA. Of the remaining 10%, almost all is taken up by platelets, where it remains until it is released during clotting, promoting further platelet aggregation.

The main diseases that may be associated with measurable increases in 5-HT are neuroectodermal tumors, in particular those arising from EC-cells, which are termed carcinoids. They are subdivided into:

  • Foregut carcinoids, arising from respiratory tract, stomach, pancreas or duodenum (15% of cases)
  • Midgut carcinoids, occurring within jejunum, ileum, or appendix (70% of cases)
  • Hindgut carcinoids, which are found in the colon or rectum (15% of cases)

Carcinoids display a spectrum of aggressiveness with no clear distinguishing line between benign and malignant. The majority of carcinoid tumors do not cause significant clinical disease. Those tumors that behave more aggressively tend to cause nonspecific GI disturbances, such as intermittent pain and bloating, for many years before more overt symptoms develop. In advanced tumors, morbidity and mortality relate as much to secretion of 5-HT and peptide hormones as to local and distant spread. The symptoms of the carcinoid syndrome consist of:

  • Flushing
  • Diarrhea
  • Right-sided valvular heart lesions
  • Bronchoconstriction

The carcinoid syndrome is usually caused by midgut tumors, because foregut and hindgut neoplasms produce far lesser amounts of 5-HT. Since midgut tumors drain into the portal circulation, which passes into the liver, symptoms do not usually occur until liver or other distant metastases have developed, subverting the extensive hepatic first-pass 5-HT degradation.

Serotonin production by disseminated carcinoid tumors can sometimes be so substantial that body tryptophan stores become depleted and clinical tryptophan deficiency, resembling pellagra (triad of diarrhea, dementia, and dermatitis), develops.

To achieve maximum sensitivity in the initial diagnosis of suspected carcinoid tumors, 5-HT in blood, 5-HIAA in urine, and serum chromogranin A should all be measured. The latter is a peptide secreted by neuroectodermal cells. In most cases, if none of these 3 analytes is elevated, carcinoids can be excluded as a cause of symptoms suggestive of carcinoid syndrome. For some cases, additional tests, such as urinary 5-HT measurement might be required. These analytes will not be elevated in patients with small carcinoid tumors (>95% of cases) that are not producing the carcinoid syndrome. Blood 5-HT levels >400 ng/mL are suggestive of carcinoid tumors as the cause of carcinoid syndrome-like symptoms. Metastatic midgut carcinoid tumors usually produce blood or serum 5-HT concentrations >1,000 ng/mL.

In patients with more advanced tumors, circulating 5-HT is elevated in nearly all patients with midgut tumors, but only in approximately 50% of those with foregut carcinoids, and 20% of individuals with hindgut tumors.

Urinary 5-HIAA is elevated in almost all carcinoid-syndrome patients with midgut tumors, in about 30% of individuals with foregut carcinoids, but almost never in hindgut tumors.

Serum chromogranin A measurements are particularly suited for diagnosing hindgut tumors, being elevated in nearly all cases, even though 5-HT and 5-HIAA are often normal. Chromogranin A is also elevated in 80-90% of patients with foregut and midgut tumors.

Disease progression can be monitored in patients with serotonin-producing carcinoid tumors by measurement of 5-HT in blood. However, at levels above approximately 5,000 ng/mL, the serotonin storage capacity of platelets becomes limiting, and there is no longer a linear relationship between tumor burden and blood 5-HT levels. Urinary 5-HIAA and serum chromogranin A continue to increase in proportion to the tumor burden to much higher 5-HT production levels, and are therefore better suited for follow-up in patients with extensive disease.

Since most circulating 5-HT is contained in platelets, the preferred specimens for measurement either include all or most of the platelets, such as whole blood or serum from completely clotted specimens. Clotting releases most of the 5-HT from platelets.

Medications that may elevate serotonin concentrations include lithium, MAO-inhibitors, methyldopa, morphine, and reserpine. The observed levels are usually <400 ng/mL. Selective serotonin reuptake inhibitors (e.g., fluoxetine) can lead to depletion of platelet serotonin levels and result in false-negative blood 5-HT tests. The effects of drugs are more marked on urinary 5-HT and 5-HIAA levels than on blood 5-HT levels.

Serotonin- or tryptophan-rich foods (avocados, bananas, plums, walnuts, pineapple, eggplant, plantain, tomatoes, hickory nuts, kiwi, dates, grapefruit, cantaloupe, and honeydew melon) do not contribute significantly to blood 5-HT measurements, but can elevate urinary 5-HT and urinary 5-HIAA levels up to 10-fold.

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