5-Hydroxy indoleacetic acid (5-HIAA) is the primary metabolite of serotonin. Serotonin is broken down into 5-hydroxy indoleacetic acid within the liver. 5-hydroxy indoleacetic acid is used as a proxy for serotonin measurement through a 24-hour urine test. 5-hydroxy indoleacetic acid's primary use is in diagnosing and monitoring carcinoid tumors, a subset of serotonin secreting neuroendocrine tumors.
5-hydroxy indoleacetic acid starts as tryptophan within cells. Tryptophan then converts to serotonin. After that, monoamine oxidase A (MAO-a) enzymatically deactivates serotonin by converting it to 5-hydroxy indoleacetic acid within the synaptic cleft. Serotonin generally gets metabolized by the liver before entering the general circulation and having more downstream effects. Serotonin may also be deactivated and taken out of circulation by the lungs.
5-hydroxy indoleacetic acid use as a proxy to measure serotonin levels is important because of serotonin’s systemic effects and prognostic capacity. Serotonin is mainly secreted by enterochromaffin cells in the gastrointestinal system and, to a lesser extent, by neurons within the nervous system. Serotonin secretion causes a cascade of effects as it is picked up by a variety of cells that store the hormone for later use. For example, platelets will store serotonin until the platelet is activated and releases the serotonin to induce local vasoconstriction and help stimulate an immune response. In carcinoid tumors, excessive serotonin is produced, thus raising the levels of urinary 5-hydroxy indoleacetic acid. 5-hydroxy indoleacetic acid is primarily a biomarker for midgut carcinoid tumors but may also be useful in characterizing a variety of diseases and disorders. Diseases or disorders in which urinary 5-hydroxy indoleacetic acid increases include intestinal neuroendocrine tumors, celiac disease, cystic fibrosis, and autism spectrum disorder. Diseases or disorders that display lower than normal urinary 5-hydroxy indoleacetic acid levels include obsessive-compulsive disorder, aromatic L-amino acid decarboxylation deficiency, sepiapterin reductase deficiency, and multiple sclerosis.
Measurement of 5-hydroxy indoleacetic acid levels is through a 24-hour urine sample; this requires the patient to collect all their urine produced over 24 hours. To prepare for an accurate urine sample of 5-hydroxy indoleacetic acid levels, ask your provider about food or medication restrictions needed before urine collection as well as any specific testing instructions. Testing instructions may include time collection strategies. For example, voiding one’s bladder in the morning after you wake up and mark that time, from then on, collecting urine until you reach 24 hours from that initial time mark.
The normal range for 5-hydroxy indoleacetic acid measured in urine is 3 to 15 mg/24 hours. The upper limit of 5-hydroxy indoleacetic acid measurements may vary depending on the laboratory used in the analysis.
Urine 5-hydroxy indoleacetic acid testing is useful for primary midgut carcinoid tumors, including jejunoileal, ascending colon, and appendiceal. In patients with primary midgut carcinoid tumors, 5-hydroxy indoleacetic acid levels may decrease during treatment, which may reflect the patient’s response to treatment. Increased or increasing 5-hydroxy indoleacetic acid levels indicate a non-response to treatment. Carcinoid tumors of the foregut and hindgut rarely secrete serotonin, so 5-hydroxy indoleacetic acid urine testing is not as useful for their detection. Foregut and hindgut carcinoid tumors cannot convert 5-HTP to serotonin because of DOPA decarboxylase deficiency.
5-hydroxy indoleacetic acid is essential in diagnosing and monitoring carcinoid tumors. Clinicians need to distinguish carcinoid tumors from carcinoid syndrome. Carcinoid tumors are a form of neuroendocrine tumor within the gastrointestinal or pulmonary system. Midgut carcinoid tumors secrete serotonin, whereas foregut and midgut carcinoid tumors do not. Carcinoid syndrome is a paraneoplastic syndrome secondary to carcinoid tumors with symptoms including but not limited to cutaneous flushing, diarrhea, nausea, vomiting, hepatomegaly, cardiac murmurs, coughing, shortness of breath, and wheezing. Furthermore, 5-hydroxy indoleacetic acid may be an essential biomarker for inborn errors of metabolism, diseases of malabsorption, as well as psychiatric conditions.