5-Hydroxyindoleacetic Acid (HIAA), Quantitative, 24-Hour Urine

CPT: 83497
Print Share

Test Details

Synonyms

  • 5-HIAA, Quantitative, 24-Hour Urine
  • Serotonin Metabolite, 24-Hour Urine

Limitations

Levels of 5-HIAA may not be elevated in nonfunctional tumors. Because flushing is mediated by different hormones in foregut and midgut tumors, some patients with a neuroendocrine tumors will have symptoms of flushing with low or normal levels of 5-HIAA. A number of substances interfere with determination of urinary 5-HIAA.1

Causes of Elevated 5-HIAA:

Foods: Avocado, bananas, eggplant, kiwi fruit, nuts (hickory nuts, pecans, walnuts), pineapple, plums, tomato products.

Drugs: Acetaminophen (Tylenol®), antihistamines (nasal drops and spray), antihypertensives, antipsychotics, caffeine, cough suppressants, diazepam (Valium®), muscle relaxants, nicotine, warfarin (Coumadin®)

Causes of Diminished 5-HIAA:

• Alcohol, aspirin, antidepressants (imipramine, monoamine oxidase inhibitors), herbal products: Diadzin (active compound in kudzu, a Chinese herbal treatment for alcohol abuse), St John's wort

Methodology

Liquid chromatography/tandem mass spectrometry (LC/MS-MS)

Reference Interval

0.0−14.9 mg/24 hours

If a borderline elevation of 5-HIAA is found, sample should be recollected following withdrawal of dietary and medication sources that might elevate 5-HIAA (see Patient Preparation). Nontropical sprue may cause a slight increase in urinary 5-HIAA. 5-HIAA levels are lowered by renal insufficiency and after small bowel resection. When a patient strongly suspected for carcinoid syndrome shows normal or borderline increases of 5-HIAA, two possibilities should be considered: one, that large amounts of serotonin produced are not being metabolized, in which case blood levels of serotonin are required to document the diagnosis; and two, that secretion of 5-HIAA by the tumor is intermittent, in which case repeat timed specimen collections are needed to demonstrate the abnormality.

Additional Information

Serotonin measurement is used in conjunction with urinary 5-hydroxyindoleacetic acid (5-HIAA) and/or serum chromogranin A in the diagnosis of carcinoid syndrome. Carcinoid tumors are slow-growing neuroendocrine tumors derived from enterochromaffin cells that are widely distributed throughout the body.1-4 Approximately 65% of carcinoid tumors are found in the gastrointestinal tract from the foregut, midgut, and hindgut and another 25% originate in the bronchopulmonary tract.2,4 About a quarter of cases present with distant metastases, half of which have unknown primary tumor location.2 Carcinoid tumors secrete a variety of peptides and small molecules.1,4,5,6 Midgut carcinoid tumors frequently produce serotonin. Serotonin-secreting carcinoids from other locations are less common. Serotonin (5-hydroxy-tryptamine) is synthesized from the essential amino acid tryptophan via the intermediate 5-hydroxytryptophan (5-HTP). Serotonin secretion in the gut causes an increase in gastrointestinal blood flow, motility, and fluid secretion. In healthy individuals, the great majority of serotonin made by the gut is converted by the liver and lungs to 5-hydroxy-indoleacetic acid (5-HIAA) via first pass metabolism prior to entering the general circulation.

Serotonin secreting carcinoid tumors are relatively slow growing, and in most cases, asymptomatic.1,4,5 The local, paracrine effect of increased serotonin on the gut intestine can cause diarrhea, malabsorption, and tumor mass producing discomfort.4,7 Since most serotonin produced by carcinoid tumors is metabolized prior to reaching the circulation, the metabolic product, 5-HIAA in a 24-hour urine collection is usually the most important marker for diagnosing and monitoring treatment of the carcinoid syndrome.4,8 The severity of carcinoid syndrome symptoms correlates with the level of 5-HIAA in urine. Urine 5-HIAA has been shown to have a sensitivity of 73% and specificity of 100% for diagnosing well-differentiated functional gastroenterohepatic neuroendocrine tumors.9 Compared with patients having normal urinary 5-HIAA levels, patients with elevated levels, whether symptomatic or not, tend to have poorer prognosis.10-12

In cases where a larger amount of serotonin reached the systemic circulation (advanced disease with liver metastases bypassing first pass metabolism), patients can present with a constellation of symptoms referred to as the carcinoid syndrome. The carcinoid syndrome can also occur in the absence of liver metastases in cases where tumor pathology causes direct venous drainage of serotonin bypassing first pass liver metabolism.6,13 Carcinoid syndrome is relatively rare and is most commonly associated with midgut carcinoid tumors.3,4 Carcinoid syndrome occurs in 20% of cases of well-differentiated endocrine tumors of the jejunum or ileum.6,13 Carcinoid syndrome occurs less often with neuroendocrine tumors of other origins and is very rare in association with rectal neuroendocrine tumors.6,13 Carcinoid syndrome is characterized by one or more symptoms, including diarrhea, dry flushing without sweating with or without palpitations, and intermittent abdominal pain.6 Some patients also experience lacrimation and rhinorrhea.6,13 Advanced or long-standing carcinoid syndrome can lead to carcinoid heart disease involving the tricuspid and pulmonary valves of the heart.7 Significant elevations in urine 5-HIAA have been associated with carcinoid heart disease.14-16 Other cardiovascular complications include bowel ischemia and hypertension.7 Approximately one in five patients with carcinoid syndrome present with heart disease at diagnosis.6,13 Carcinoid tumors are classified similarly, whether they produce symptoms of the carcinoid syndrome or not.17

In healthy individuals, approximately 99% of dietary tryptophan is metabolized by the oxidative pathway into nicotinic acid (vitamin B3).4 In carcinoid tumors, excessive conversion of tryptophan to serotonin can cause result in vitamin B3 deficiency referred to as pellagra, a condition that is characterized by a triad of symptoms: diarrhea, dementia, and dermatitis.18

Specimen Requirements

Specimen

Urine (24-hour)

Volume

4 mL aliquot

Minimum Volume

1 mL aliquot

Container

Plastic urine container, no preservative (Note: 1 g/L boric acid may be added as a preservative for other tests without harm to 5-HIAA.)

Patient Preparation

Avoid avocado, bananas, eggplant, kiwi fruit, nuts (hickory nuts, pecans, walnuts), pineapple, plums, tomato products, and interfering drugs (see Limitations) for a 72-hour period prior to and during the collection.

Collection

Instruct the patient to void at 8 AM and discard the specimen. Then collect all urine including the final specimen voided at the end of the 24-hour collection period (ie, 8 AM the next morning). Screw the lid on securely. Label container with patient's name, date, and time. Measure and record total urine volume. Mix well; send aliquot.

Storage Instructions

Room temperature

Stability Requirements

Temperature

Period

Room temperature

7 days

Refrigerated

14 days

Frozen

14 days

Freeze/thaw cycles

Stable x3

Causes for Rejection

pH <2

Clinical Information

Special Instructions

Measure and record total 24-hour urine volume on the request form.

Footnotes

1. Aggarwal G, Obideen K, Wehbi M. Carcinoid tumors: What should increase our suspicion? Cleve Clin J Med. 2008 Dec; 75(12):819-855. 2421946
2. Modlin IM, Lye KD, Kidd M. A 50-year analysis of 562 gastric carcinoids: Small tumor or larger problem? Am J Gastroenterol. 2004 Jan; 99(1):23-32. 2421946
3. Robertson RG, Geiger WJ, Davis NB. Carcinoid tumors. Am Fam Physician. 2006 Aug 1; 74(3):429-434. 2421946
4. Zuetenhorst JM, Taal BG. Metastatic carcinoid tumors: A clinical review. Oncologist. 2005 Feb; 10(2):123-131. 2421946
5. Ghevariya V, Malieckal A, Ghevariya N, Mazumder M, Anand S. Carcinoid tumors of the gastrointestinal tract. South Med J. 2009 Oct; 102(10):1032-1040. 2421946
6. Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012 Jan; 61(1)6-32. 2421946
7. van der Horst-Schrivers AN, Wymenga AN, Links TP, Willemse PH, Kema IP, de Vries EG. Complications of midgut carcinoid tumors and carcinoid syndrome. Neuroendocrinology. 2004; (80 Suppl)1:28-32. 2421946
8. Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumours. Cancer. 1999 Sep 1; 86(5):858-865. 2421946
9. Feldman JM, O'Dorisio TM. Role of neuropeptides and serotonin in the diagnosis of carcinoid tumours. Am J Med. 1986 Dec 22; 81(6B):41-48. 2421946
10. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol 2005 Mar 1; 89(3):151-160. 2421946
11. Agranovich AL, Anderson GH, Manji M, Acker BD, Macdonald WC, Threlfall WJ. Carcinoid tumour of the gastrointestinal tract: prognostic factors and disease outcome. J Surg Oncol. 1991 May; 47(1):45-52. 2421946
12. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol. 1997 Jul; 8(7):685-690. 2421946
13. Pape UF, Perren A, Niederle B, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology. 2012; 95(2):135-156. 2421946
14. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993 Apr; 87(4):1188-1196. 2421946
15. Lundin L, Norheim I, Landelius J, Oberg K, Theodorsson-Norheim E. Carcinoid heart disease:relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation. 1988 Feb; 77(2):264-269. 2421946
16. Denney WD, Kemp WE Jr, Anthony LB, Oates JA, Byrd BF 3rd. Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease. J AM Col Cardiol. 1998 Oct; 32(4):1017-1022. 2421946
17. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: A review of nomenclature, grading, and staging systems. Pancreas. 2010 Aug; 39(6):707-712. 2421946
18. Castiello RJ, Lynch PJ. Pellagra and the carcinoid syndrome. Arch Dermatol. 1972 Apr; 105(4):574-577. 2421946

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
004069 5-HIAA,Quant.,24 Hr Urine 004070 5-HIAA, Urine mg/L 31203-3
004069 5-HIAA,Quant.,24 Hr Urine 004071 5-HIAA, Urine, 24hr mg/24 hr 1695-6
Reflex Table for 5-HIAA, Urine, 24hr
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 700471 Disclaimer: 700471 Disclaimer: N/A

For Providers

Please login to order a test.

 

© 2017  Laboratory Corporation of America® Holdings and Lexi-Comp Inc. All Rights Reserved.

CPT Statement/Profile Statement

The LOINC® codes are copyright © 1994-2017, Regenstrief Institute, Inc. and the Logical Observation Identifiers Names and Codes (LOINC) Committee. Permission is granted in perpetuity, without payment of license fees or royalties, to use, copy, or distribute the LOINC® codes for any commercial or non-commercial purpose, subject to the terms under the license agreement found at https://loinc.org/license/. Additional information regarding LOINC® codes can be found at LOINC.org, including the LOINC Manual, which can be downloaded at LOINC.org/downloads/files/LOINCManual.pdf