Clinical Information

Serotonin (5-hydroxytryptamine) is synthesized from the essential amino acid tryptophan via the intermediate 5-hydroxytryptophan (5-HTP). Serotonin production sites are the central nervous system (CNS), where it acts as a neurotransmitter, and neuroectodermal cells, chiefly gastrointestinal (GI) enterochromaffin cells (EC-cells). The CNS and peripheral serotonin pools are isolated from each other. EC-cell production accounts for 80% of the body's serotonin content.

Many different stimuli can release serotonin from EC-cells. Once secreted, in concert with other gut hormones, serotonin increases GI blood flow, motility, and fluid secretion. On first pass through the liver 30% to 80% of serotonin 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 serotonin are neuroectodermal tumors, in particular tumors arising from EC-cells, which are termed carcinoids. They are subdivided into foregut carcinoids, arising from respiratory tract, stomach, pancreas, or duodenum (approximately 15% of cases); midgut carcinoids, occurring within jejunum, ileum, or appendix (approximately 70% of cases); and hindgut carcinoids, which are found in the colon or rectum (approximately 15% of cases). The enzyme 5-HTP decarboxylase, which converts the intermediate 5-HTP to serotonin, is present in midgut tumors, but is absent or present in low concentrations in foregut and hindgut tumors.

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, or more, to the biogenic amines, chiefly serotonin, and peptide hormones secreted, as to local and distant spread. The symptoms of this so-called carcinoid syndrome consist of flushing, diarrhea, right-sided valvular heart lesions, and bronchoconstriction. All of these symptoms are at least partly caused by serotonin. The carcinoid syndrome is usually caused by midgut tumors, as foregut and hindgut neoplasms produce far lesser amounts of serotonin. Because midgut tumors drain into the portal circulation, which passes into the liver, undergoing extensive hepatic (first-pass) serotonin degradation, symptoms do not usually occur until liver or other distant metastases have developed, producing serotonin that bypasses the hepatic 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.

Diagnosis of carcinoid tumors with symptoms suggestive of carcinoid syndrome rests on measurements of circulating and urine serotonin, urine 5-HIAA (HIAA / 5-Hydroxyindoleacetic Acid [5-HIAA], 24 Hour, Urine), and serum chromogranin A (CGAK / Chromogranin A, Serum), a peptide that is cosecreted alongside specific hormones by neuroectodermal cells. Urine serotonin is, in most circumstances, the least likely marker to be elevated (see Interpretation).