5-Hydroxyindoleacetic Acid (Urine)

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Auckland Te Toka Tumai

Test Guide

5-Hydroxyindoleacetic Acid (Urine)

Testing Laboratory

Auckland Te Toka Tumai | Auckland Hospital

Department

Chemical Pathology

Delphic Registration Code (Alpha Code)

HIAA

Test Code (Numeric Code)

629

Laboratory Handling

Registration

For casual collection, register for HIAA then give specimen to HPLC technical staff with a copy of the form

Laboratory

LabPLUS High Performance Liquid Chromatography

Sample Stability

Urine 5-HIAA is unstable unless collected and stored into an acidified container (20 mL of 6 mol/L HCl in 2L bottle).
Casual collects must be acidified to pH less than 3 on receipt in the lab.
Once acidified, samples are stable at room temperature or refrigerated.

Associated Tests

Chromogranin A (Blood)

Synonyms

5-hydroxyindole acetic acid, 5-HIAA, HIAA

Turnaround Time

1 week

Performed Weekly

Specimen Type

24hr Urine

Specimen Requirements

Tube/Container Type:

Preferred

Acidified 24hr Urine Container

Paediatric Specimen Requirements

Tube/Container Type:

Preferred

Acidified 24hr Urine Container

Pre-testing Requirements

The following foods and supplements interfere with the test and should be avoided for at least 48, and preferably up to 72 hours prior to and during the urine collection.

Tryptophan or Hydroxytryptophan containing supplements

Chocolate
Walnuts / Hickory nuts
Pineapple, banana, tomatoes, kiwifruit, plum, avocado, dates, grapefruit
Eggplant (controversial)

Additional Specimen Information

Acid preservative is essential.

24 hour urine samples are unsuitable for analysis if they have not been collected into acid.

Diagnostic Use

Serotonin (5 hydroxytryptamine or 5-HT) is derived from dietary amino acid Tryptophan. About 10% of serotonin is located in neurons while 90% is located in the enterochromaffin (neural crest derived) cells of the gut. Serotonin is metabolised by hepatic monoamine oxidase to 5-HIAA, which is renally excreted.

Tryptophan is a precursor to serotonin, but normally only 1-3% is metabolised through the serotonin pathway – the majority being used for protein synthesis or for production of nicotinamide adenine dinucleotide (NAD/NADP). However in carcinoid tumours, up to 60% of tryptophan can be diverted to the serotonin pathway, resulting in niacin deficiencies (frank pellagra rare, <1%). A flow diagram of the Tryptophan metabolic pathway can be found in “Vitamin B3” entry in this test guide. 24 hour urine 5 HIAA test is primarily used to confirm the presence of midgut carcinoid tumours (sensitivity 76%, specificity around 90-100%). It is less sensitive to detect foregut carcinoid (sensitivity 31%). Pancreatic neuroendocrine tumours occasionally increase urine 5-HIAA (~1-8%, depending on series) but are rare to induce carcinoid syndrome. Hindgut carcinoid tumours rarely secrete serotonin or 5-HIAA and do not normally cause carcinoid syndrome. In comparison, plasma chromogranin A though non-specific if raised, has about 80-100% sensitivity for carcinoid tumours regardless of site. Carcinoid syndrome typically comprises episodes of diarrhoea, flushing, bronchoconstriction and cardiac manifestations (valvular/endocardial fibrosis; predominantly right-sided). Serotonin plays a major role in mediating diarrhoea symptoms and fibrosis (cardiac and non-cardiac). On the other hand, the exact mediator of flushing is unclear although in gastric carcinoid, it can be attributed to excess histamine. Carcinoid heart disease (CHD) occurs in 20-50% of patients with carcinoid syndrome. It is a major source of morbidity and mortality. 24-h urine 5-HIAA >300 umol/day and also >3 episodes of flushing per day are independent risk factors in predicting the development or progression of CHD. NT-proBNP is a useful screening test for CHD, with level >31 pmol/L having 92% sensitivity and 91% specificity in one study.

Overall, carcinoid syndrome only occurs in about 1.7-18.7% of patients with carcinoid tumours (depending on series). Mid-gut carcinoids only manifest symptomatically as carcinoid syndrome when the tumour bulk is large and with liver metastases. Rarely, carcinoid syndrome can be encountered in patients with primary ovarian, lung/bronchial or pancreatic carcinoid tumours without liver metastases, or in mid-gut carcinoids with retroperitoneal metastases.

Platelet (as whole blood) serotonin is an alternative marker for diagnosis of mid-gut carcinoids. Diagnostic performance is comparable to 24 hour urine 5-HIAA. Unlike the urine test, it is not affected by short term consumption of serotonin rich food thus prior dietary restriction is not necessary. In foregut carcinoids or in those with residual carcinoid tumours where there is a low rate of serotonin production, platelet serotonin is more sensitive than urine 5-HIAA.

Interpretation

Phaeochromocytomas or paragangliomas can induce a mild increase in 5-HIAA urine excretion. However head and neck paragangliomas are unlikely to do so.

Conversely, some carcinoids can express catecholamine synthesizing enzymes, resulting in elevated metanephrine, 3 methoxy-tyramine (3MT) and catecholamine levels, and raising the possibility of phaeochromocytoma or paragangliomas.

Two series of patients with mid-gut carcinoids revealed that although the median urine levels of normetanephrine, metanephrine and 3MT were not noticeably raised, the normetanephrine and metanephrine could be up to 2 times and 3MT up to 5 times above their corresponding upper reference limits in some patients.

However, platelet serotonin concentration is affected by platelet count and is saturable at high serotonin secretion rate, hence urine 5-HIAA and chromogranin A are preferred as markers for monitoring. Platelet serotonin level is also age dependent, about 30% lower in those older than 65 years compared with younger adults or children.

Like urine 5-HIAA, platelet serotonin has no proven value in diagnosis or monitoring of depression or treatments such as SSRI’s.

Platelet serotonin measurements require pathologist approval. Special collection requirements apply – platelet serotonin is unstable unless stored frozen within 2 hours of collection.

Reference Intervals

Adults:

≤ 50 umol/day

≤4.1 umol/mmol creatinine

Paediatric:

3 – 8 years	≤ 9.6 umol/mmol creatinine
9 – 12 years	≤ 5.2 umol/mmol creatinine

Ref: Soldin et al. Paediatric Reference Ranges, 3rd ed.

Test Method

Liquid Chromatography Mass Spectrometry (LCMS)

Limitations / Interference

Untreated coeliac disease and some small intestinal diseases e.g. Whipple's disease can increase 24 hr urine 5-HIAA by about 2-3 times the above upper reference limit.

Foods - Tryptophan or serotonin rich foods can increase urine 5-HIAA, hence the above recommended 2 days dietary restriction recommendation before and during urine collection. Daily intake of 100mg of 5 hydroxytryptophan containing over-the-counter supplements e.g. for mood stabilisation, insomnia or even claiming to treat flushing, can increase urine 5-HIAA up to 10 times above upper reference limit. A relevant history of supplement use is useful and a normal plasma chromogranin A level is also suggestive.

Drugs - A number of common drugs can interfere analytically with older methods of 5HIAA measurement. Traditionally medications such as glyceryl guaiacolate containing cough mixture or Naproxen (causing falsely high results), phenothiazines, aspirin or L-dopa (causing falsely low results) have been described to cause analytical interference. HPLC system can also be interfered by sulfasalazine, mesalazine (via 5 aminosalicylic acid). Our LC-MS assay is not analytically interfered with by these medications.

It is unclear if methyldopa or carbidopa-levodopa exhibit in-vivo inhibition of L-aromatic amino acid (DOPA) decarboxylase, and thus may reduce 5-hydroxytryptophan metabolism to serotonin, or if aspirin's anti-platelet effect reduces serotonin release from platelets in-vivo.

There is no hard data to support the notion that psychiatric medications affecting serotonin metabolism (e.g. monoamine oxidase inhibitors, serotonin reuptake inhibitors or serotonin receptor antagonists) in therapeutic doses significantly alter 5-HIAA excretion in humans, causing possible false diagnosis of neuroendocrine tumours. This may be because the amount of serotonin alteration in the central nervous system is relatively low (about 10%) compared with the much larger serotonin pool in gut neuroendocrine cells. Urine 5-HIAA has no place in the diagnosis and monitoring of such patients.

Uncertainty of Measurement

14%

References (for Diagnostic Use, Interpretation and Limitations/Interferences):

Adaway JE et al. Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement. Ann Clin Biochem 2016; 53(Pt 5): 554-560

Allen KR et al. Monitoring the treatment of carcinoid disease using blood serotonin and plasma 5-hydroxyindoleacetic acid: three case examples. Ann Clin Biochem 2007; 44:300-307

Bhattacharyya S et al. Risk factors for the development and progression of carcinoid heart disease Am J Cardiol 2011; 107:1121-1226

Boudreaux JP et al. The NANETS consensus guidelines for the diagnosis and management of neuroendocrine tumours. Pancreas 2010; 39:753-766

Evaluation of whole blood serotonin and plasma and urine 5-hydroxyindole acetic acid in diagnosis of carcinoid disease. Ann Clin Biochem 2002; Nov 39 (Pt 6): 577-82

Challacombe DM et al. Measurement of urine 5-hydroxyindoleacetic acid/creatinine ratio in the urine of patients with coeliac disease. Hepatogastroenterology 1981; 28:160-162

Corcuff J-B et al. Urinary sampling for 5HIAA and metanephrines determination: revisiting the recommendations. Endocrine Connections 2017; 6:R87-R98

Coward S et al. Sulfasalazine interference with HPLC assay of 5 hydroxyindole-3-acetic acid. Clin Chem 1995; 41(5): 765-766

Davar J et al. Diagnosing and managing carcinoid heart disease in patients with neuroendocrine tumors ? an expert statement. J Am Coll Cardiol (JACC) 2017; 69(10): 1288-1304

Flachaire E et al. Determination of reference values for serotonin concentration in platelets of healthy newborns, children, adults and elderly subjects by HPLC with electrochemical detection. Clin Chem 1990; 36: 2117-20

Ito T et al. Carcinoid-syndrome: recent advances, current status and controversies. Curr Opin Endocrinol Diabetes Obes. 2018 February ; 25(1): 22?35. doi:10.1097/MED.
Joy T et al. Increase of urinary 5-hydroxyindoleacetic acid excretion but not serum chromogranin A following over the counter 5 hydroxytryptophan intake. Can J Gastroenterol 2008; 22(1): 49-53

Kema IP et al. Serotonin, Catecholamines, histamine and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors. Clin Chem 1994; 40:86-95
Lips CJM et al. The spectrum of carcinoid tumours and carcinoid syndromes Ann Clin Biochem 2003; 40:612-627

Meijer WG et al Catecholamine synthesizing enzymes in carcinoid tumors and pheochromocytomas. Clin Chem 2003; 49(4): 586-593

Van Hulstein LT et al. Urinary 5 HIAA excretion is not increased in patients with head and neck paraganglioma. Int J Biol Markers 2012; 27(2): e160-3

Last updated: 28/10/2026

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5-Hydroxyindoleacetic Acid (Urine)

Overview

Testing Laboratory

Department

Delphic Registration Code (Alpha Code)

Test Code (Numeric Code)

Laboratory Handling

Registration

Laboratory

Sample Stability

Associated Tests

Synonyms

Turnaround Time

Specimen

Specimen Type

Specimen Requirements

Tube/Container Type:

Preferred

Paediatric Specimen Requirements

Tube/Container Type:

Preferred

Pre-testing Requirements

Additional Specimen Information

Referral

Aliquot Instructions

Sample Type

Transport to Lab

Additional Referral/Aliquot Information

Clinical Information/Test Method

Diagnostic Use

Interpretation

Reference Intervals

Test Method

Limitations / Interference

Uncertainty of Measurement

Additional Information

Contact Information

Contact Information

Enquiry Form

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