Biochemistry, 5 Hydroxyindoleacetic Acid
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.
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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.
- Strenuous exercise may raise 5-HIAA levels.
- 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.
- Medicines that lower urine 5-HIAA levels include risperidone and acetaminophen. The mechanism by which acetaminophen decreases urinary 5-HIAA, and conversely increases brain serotonin levels, is by inhibiting hepatic tryptophan 2,3-dioxygenase.
- Medicines that lower CSF 5-HIAA levels are: desipramine and zimeldine.
- Dialysis has been shown to decrease CSF levels of 5-HIAA.
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.
- 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%.
- 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.
- Elevated levels of 5-hydroxy indoleacetic acid occur in patients of autism spectrum disorder.
- Lower levels have correlated with aggressive or violent behavior, depression, and obsessive-compulsive disorder.
- Diseases of malabsorption may present with increased urinary 5-hydroxy indoleacetic acid.
- 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.
- 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.
- Altered levels of 5-hydroxy indoleacetic acid are present in IBS patients vs. controls.
- 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. Increased levels of 5-hydroxy indoleacetic acid are present in patients with celiac disease. 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.
- 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.
- 5-hydroxy indoleacetic acid levels were found to be positively correlated with FEV1/FVC and negatively correlated with bronchial inflammatory marker, eNO.
- 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.
Deacon AC. The measurement of 5-hydroxyindoleacetic acid in urine. Annals of clinical biochemistry. 1994 May:31 ( Pt 3)():215-32 [PubMed PMID: 7520678]
Adaway JE, Dobson R, Walsh J, Cuthbertson DJ, Monaghan PJ, Trainer PJ, Valle JW, Keevil BG. Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement. Annals of clinical biochemistry. 2016 Sep:53(Pt 5):554-60. doi: 10.1177/0004563215613109. Epub 2015 Oct 5 [PubMed PMID: 26438520]
Hart CM, Block ER. Lung serotonin metabolism. Clinics in chest medicine. 1989 Mar:10(1):59-70 [PubMed PMID: 2650964]
Hilaire G, Voituron N, Menuet C, Ichiyama RM, Subramanian HH, Dutschmann M. The role of serotonin in respiratory function and dysfunction. Respiratory physiology & neurobiology. 2010 Nov 30:174(1-2):76-88. doi: 10.1016/j.resp.2010.08.017. Epub 2010 Aug 27 [PubMed PMID: 20801236]
Melancon MO, Lorrain D, Dionne IJ. Exercise and sleep in aging: emphasis on serotonin. Pathologie-biologie. 2014 Oct:62(5):276-83. doi: 10.1016/j.patbio.2014.07.004. Epub 2014 Aug 4 [PubMed PMID: 25104243]
Tohmola N, Johansson A, Sane T, Renkonen R, Hämäläinen E, Itkonen O. Transient elevation of serum 5-HIAA by dietary serotonin and distribution of 5-HIAA in serum protein fractions. Annals of clinical biochemistry. 2015 Jul:52(Pt 4):428-33. doi: 10.1177/0004563214554842. Epub 2014 Sep 23 [PubMed PMID: 25249663]
Feldman JM. Urinary serotonin in the diagnosis of carcinoid tumors. Clinical chemistry. 1986 May:32(5):840-4 [PubMed PMID: 2421946]
Aymard N, Viala A, Clement MN, Jacquot M, Vacheron MN, Gauillard J, Caroli F. Long-term pharmacoclinical follow-up in schizophrenic patients treated with risperidone. Plasma and red blood cell concentrations of risperidone and its 9-hydroxymetabolite and their relationship to whole blood serotonin and tryptophan, plasma homovanillic acid, 5-hydroxyindoleacetic acid, dihydroxyphenylethyleneglycol and clinical evaluations. Progress in neuro-psychopharmacology & biological psychiatry. 2002 Jun:26(5):975-88 [PubMed PMID: 12369274]
Daya S, Anoopkumar-Dukie S. Acetaminophen inhibits liver trytophan-2,3-dioxygenase activity with a concomitant rise in brain serotonin levels and a reduction in urinary 5-hydroxyindole acetic acid. Life sciences. 2000 Jun 8:67(3):235-40 [PubMed PMID: 10983867]
Potter WZ, Scheinin M, Golden RN, Rudorfer MV, Cowdry RW, Calil HM, Ross RJ, Linnoila M. Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites. Archives of general psychiatry. 1985 Dec:42(12):1171-7 [PubMed PMID: 2416297]
Sullivan PA, Murnaghan D, Callaghan N, Kantamaneni BD, Curzon G. Effect of dialysis on plasma and CSF tryptophan and CSF 5-hydroxyindoleacetic acid in advanced renal disease. Journal of neurology, neurosurgery, and psychiatry. 1980 Aug:43(8):739-43 [PubMed PMID: 6159456]
Jayamohananan H, Manoj Kumar MK, T P A. 5-HIAA as a Potential Biological Marker for Neurological and Psychiatric Disorders. Advanced pharmaceutical bulletin. 2019 Aug:9(3):374-381. doi: 10.15171/apb.2019.044. Epub 2019 Aug 1 [PubMed PMID: 31592064]
Tirosh A, Nilubol N, Patel D, Kebebew E. Prognostic Utility of 24-Hour Urinary 5-HIAA Doubling Time in Patients With Neuroendocrine Tumors. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2018 Aug:24(8):710-717. doi: 10.4158/EP-2018-0022. Epub 2018 Aug 7 [PubMed PMID: 30084688]
Ito T, Lee L, Jensen RT. Carcinoid-syndrome: recent advances, current status and controversies. Current opinion in endocrinology, diabetes, and obesity. 2018 Feb:25(1):22-35. doi: 10.1097/MED.0000000000000376. Epub [PubMed PMID: 29120923]Level 3 (low-level) evidence
Chojnacki C, Błońska A, Kaczka A, Chojnacki J, Stępień A, Gąsiorowska A. Evaluation of serotonin and dopamine secretion and metabolism in patients with irritable bowel syndrome. Polish archives of internal medicine. 2018 Nov 30:128(11):711-713. doi: 10.20452/pamw.4364. Epub 2018 Nov 6 [PubMed PMID: 30398468]
Papamichael MM, Katsardis C, Erbas B, Itsiopoulos C, Tsoukalas D. Urinary organic acids as biomarkers in the assessment of pulmonary function in children with asthma. Nutrition research (New York, N.Y.). 2019 Jan:61():31-40. doi: 10.1016/j.nutres.2018.10.004. Epub 2018 Oct 13 [PubMed PMID: 30683437]
Maroun J, Kocha W, Kvols L, Bjarnason G, Chen E, Germond C, Hanna S, Poitras P, Rayson D, Reid R, Rivera J, Roy A, Shah A, Sideris L, Siu L, Wong R. Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group. Current oncology (Toronto, Ont.). 2006 Apr:13(2):67-76 [PubMed PMID: 17576444]
Feldman JM, O'Dorisio TM. Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. The American journal of medicine. 1986 Dec 22:81(6B):41-8 [PubMed PMID: 2432780]
Laskaratos FM,Diamantopoulos L,Walker M,Walton H,Khalifa M,El-Khouly F,Koffas A,Demetriou G,Caplin M,Toumpanakis C,Mandair D, Prognostic Factors for Survival among Patients with Small Bowel Neuroendocrine Tumours Associated with Mesenteric Desmoplasia. Neuroendocrinology. 2018; [PubMed PMID: 29320779]
Ruggeri B, Sarkans U, Schumann G, Persico AM. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology. 2014 Mar:231(6):1201-16. doi: 10.1007/s00213-013-3290-7. Epub 2013 Oct 6 [PubMed PMID: 24096533]
Spreux-Varoquaux O, Alvarez JC, Berlin I, Batista G, Despierre PG, Gilton A, Cremniter D. Differential abnormalities in plasma 5-HIAA and platelet serotonin concentrations in violent suicide attempters: relationships with impulsivity and depression. Life sciences. 2001 Jun 29:69(6):647-57 [PubMed PMID: 11476186]
Ballo P, Dattolo P, Mangialavori G, Ferro G, Fusco F, Consalvo M, Chiodi L, Pizzarelli F, Zuppiroli A. Acute inflammatory bowel disease complicating chronic alcoholism and mimicking carcinoid syndrome. Case reports in gastroenterology. 2012 May:6(2):545-9. doi: 10.1159/000341588. Epub 2012 Aug 16 [PubMed PMID: 22949895]Level 3 (low-level) evidence
Saito J,Suzuki E,Tajima Y,Takami K,Horikawa Y,Takeda J, Increased plasma serotonin metabolite 5-hydroxyindole acetic acid concentrations are associated with impaired systolic and late diastolic forward flows during cardiac cycle and elevated resistive index at popliteal artery and renal insufficiency in type 2 diabetic patients with microalbuminuria. Endocrine journal. 2016 [PubMed PMID: 26567921]
Manegold C, Hoffmann GF, Degen I, Ikonomidou H, Knust A, Laass MW, Pritsch M, Wilichowski E, Hörster F. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. Journal of inherited metabolic disease. 2009 Jun:32(3):371-80. doi: 10.1007/s10545-009-1076-1. Epub 2009 Jan 28 [PubMed PMID: 19172410]
Abeling NG, Duran M, Bakker HD, Stroomer L, Thöny B, Blau N, Booij J, Poll-The BT. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Molecular genetics and metabolism. 2006 Sep-Oct:89(1-2):116-20 [PubMed PMID: 16650784]
Challacombe DN, Brown GA, Black SC, Storrie MH. Increased excretion of 5-hydroxyindoleacetic acid in urine of children with untreated coeliac disease. Archives of disease in childhood. 1972 Jun:47(253):442-5 [PubMed PMID: 5034674]
Coleman NS, Foley S, Dunlop SP, Wheatcroft J, Blackshaw E, Perkins AC, Singh G, Marsden CA, Holmes GK, Spiller RC. Abnormalities of serotonin metabolism and their relation to symptoms in untreated celiac disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2006 Jul:4(7):874-81 [PubMed PMID: 16797248]
Hallert C, Sedvall G. Improvement in central monoamine metabolism in adult coeliac patients starting a gluten-free diet. Psychological medicine. 1983 May:13(2):267-71 [PubMed PMID: 6192458]
Partington MW, Ferguson AC. Serotonin metabolism in cystic fibrosis. Archives of disease in childhood. 1977 May:52(5):386-90 [PubMed PMID: 869568]
Kollberg H, Schöni M, Türler K, Käser H, Bardón A, Ceder O, Stanghelle JK, Maehlum S, Skyberg D. Dopamine and catecholamines in cystic fibrosis in response to a marathon race. International journal of sports medicine. 1988 Feb:9 Suppl 1():56-9 [PubMed PMID: 3360546]
Schöni MH, Türler K, Käser H, Kraemer R. Plasma and urinary catecholamines in patients with cystic fibrosis. Pediatric research. 1985 Jan:19(1):47-52 [PubMed PMID: 3969312]
Markianos M, Koutsis G, Evangelopoulos ME, Mandellos D, Karahalios G, Sfagos C. Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis. Journal of neurochemistry. 2009 Jan:108(1):158-64. doi: 10.1111/j.1471-4159.2008.05750.x. Epub 2008 Nov 12 [PubMed PMID: 19014375]