Introduction

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.[1][2] 5-hydroxy indoleacetic acid's primary use is in diagnosing and monitoring carcinoid tumors, a subset of serotonin secreting neuroendocrine tumors. 

Fundamentals

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.[3][4]

Issues of Concern

1. Strenuous exercise may raise 5-HIAA levels.[5]
2. Certain foods and drugs affect 5-HIAA levels if eaten within 48 hours of the test. Foods that may increase urine 5-HIAA levels include pineapple, banana, kiwi fruit, tomato, or walnuts.[6][7]
3. Medicines that lower urine 5-HIAA levels include risperidone and acetaminophen.[8] The mechanism by which acetaminophen decreases urinary 5-HIAA, and conversely increases brain serotonin levels, is by inhibiting hepatic tryptophan 2,3-dioxygenase.[9]
4. Medicines that lower CSF 5-HIAA levels are: desipramine and zimeldine.[10]
5. Dialysis has been shown to decrease CSF levels of 5-HIAA.[11]

Function

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.[12][13][14] 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.[15][16] 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.

Testing

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.[17]

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.[17]

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.[7]

Pathophysiology

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.

Clinical Significance

1. Elevated levels of 5-hydroxy indoleacetic acid are present in carcinoid tumors, carcinoid syndrome. For carcinoid tumors, 5-hydroxy indoleacetic acid urine test has a specificity of 100% and sensitivity of 73%.[14][18]
2. Urinary 5-hydroxy indoleacetic acid levels over five times the upper limit of normal were found to be a weak prognostic indicator for patients with small intestine neuroendocrine tumors.[19]
3. Elevated levels of 5-hydroxy indoleacetic acid occur in patients of autism spectrum disorder.[20][12]
4. Lower levels have correlated with aggressive or violent behavior, depression, and obsessive-compulsive disorder.[21]
5. Diseases of malabsorption may present with increased urinary 5-hydroxy indoleacetic acid.[22]
6. Increased 5-hydroxy indoleacetic acid levels correlate with type 2 diabetes patients with microalbuminuria that developed renal insufficiency and impaired blood flow to their lower extremities.[23]
7. A shorter 5-hydroxy indoleacetic acid DT in patients with small intestine or unknown primary neuroendocrine tumors correlated with a higher risk of disease progression.[13]
8. Altered levels of 5-hydroxy indoleacetic acid are present in IBS patients vs. controls.[15]
9. Levels of 5-hydroxy indoleacetic acid undergo alteration in various inborn errors of metabolism. Decreased levels of 5-hydroxy indoleacetic acid are present in aromatic L-amino acid decarboxylation deficiency, sepiapterin reductase deficiency.[24][25] Increased levels of 5-hydroxy indoleacetic acid are present in patients with celiac disease.[26] Additionally, celiac disease patients were found to have increased numbers of enterochromaffin cells and platelet 5-HT stores. Treatment with a gluten-free diet was shown to help normalize urinary 5-hydroxy indoleacetic acid levels in celiac patients.[27][28]
10. Cystic fibrosis patients were found to have higher blood serotonin levels and normal 5-HIAA urinary excretion levels in one study, but in other studies, CSF and urinary 5-hydroxy-indoleacetic acid levels were found to have increased in cystic fibrosis patients.[29][30][31]
11. 5-hydroxy indoleacetic acid levels were found to be positively correlated with FEV1/FVC and negatively correlated with bronchial inflammatory marker, eNO.[14]
12. Urinary 5-hydroxy indoleacetic acid levels were found to be lower in patients with multiple sclerosis. Furthermore, levels of 5-hydroxy indoleacetic acid were found to relate to the severity of disease symptoms in relapsing-remitting multiple sclerosis patients.[32]