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 (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 to 5-HIAA in the lungs. 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, particularly, those 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).

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. The tumors that behave more aggressively tend to cause nonspecific GI tract 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. These symptoms are at least partly caused by serotonin. Carcinoid syndrome is usually caused by midgut tumors, as foregut and hindgut neoplasms produce far less serotonin. 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, bypassing the extensive hepatic first-pass serotonin 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 urinary serotonin, urinary 5-HIAA (HIAA / 5-Hydroxyindoleacetic Acid, 24 Hour, Urine), and serum chromogranin A (CGAK / Chromogranin A, Serum), a peptide that is cosecreted alongside specific hormones by neuroectodermal cells.