5-Hydroxyindoleacetic Acid (5-HIAA)

5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin, a chemical/neurotransmitter that is needed by the nervous system, mainly the brain, and also needed by special cells in the lung and gastrointestinal tract. After the body uses serotonin, it is degraded in the liver and is broken down to its metabolites, including 5-HIAA, which is excreted in the urine.

Normal findings

24-hour urine for 5-HIAA: 2-8 mg/24 hr or 10-40 μmol/day (SI units) ^[1]

Female levels are lower than those of males. Also note that the urine and plasma levels of 5-HIAA vary with the intake of certain foods rich in serotonin and medications that either increase or decrease serotonin levels. Therefore, pretest education for the patient is very important, as is preparation before the test for inpatients.

Urine spot/random urine 5-HIAA test

Creatinine is the best option when the urine sample is random, the urine sample is not collected over 24 hours, or urine volume is less than 400 mL/24 h. Creatinine is dependent on urine creatinine (24 h). The reference range varies according to age and sex, as listed in the Table below. ^[2]

Table 1. Reference Ranges Based on Age and Sex (Open Table in a new window)

 

24-hour urine 5-HIAA test

With elevated values, levels greater than 25 mg/24 h or greater than 131 µmol/day indicate large carcinoid tumors, especially when in ileal, biliary, pancreatic, or duodenal tumors. ^{[3, 4]}

With intermediate values, levels of 7-25 mg/24 h are found in celiac and tropical sprue, cystic fibrosis, foregut and midgut carcinoid tumors, small cell carcinoma of the bronchus, Whipple disease, and ovarian carcinoid tumors.

With low values, levels less than 2 mg/24 h are found in depressive illness, Hartnup disease, mastocytosis, phenylketonuria, renal disease, and related small intestine resection (related to a decrease in enterochromaffin-producing cells).

Plasma 5-HIAA levels

levels greater than 22 np/mL are considered elevated, and these levels correlate well with urine (24-h) 5-HIAA values. ^[2]

Foods and medications that can alter 5-HIAA levels

Medications/factors that decrease 5-HIAA levels are as follows:

• Aspirin

• Corticotropin

• Ethanol

• Isoniazid

• Homogentisic acid

• Imipramine

• Monoamine oxidase inhibitors (MAOIs)

• Methyldopa

• Promethazine

• Phenothiazines

• Perchlorperazine

• Octreotide

• Fluoxetine: Recent data show that patients on fluoxetine have lower 5-HIAA levels, as this medication decreases the body’s level of serotonin and hence decreases the 5-HIAA levels. Patients can have false-negative or low levels while on this medication, and patients should be off this medication when 5-HIAA testing is planned as a screening test for an underlying etiology.

Medications/factors that increase 5-HIAA levels are as follows:

• Recent surgery

• Stress

• Acetaminophen

• Caffeine

• Diazepam

• Ephedrine

• 5-Fluorouracil

• Guaifenesin

• Melphalan

• Naproxen

• Nicotine

• Phenobarbitone

• Phentolamine

• Reserpine

Foods that interfere with test results are as follows:

• Avocado

• Various herbal remedies

• Banana

• Eggplant

• Pineapple

• Plum

• Tomato

• Walnut

All medications and foods that alter the 5-HIAA levels should be discontinued at least 72 hours before the test.

Collection and panels information for the urine (24 h) 5-HIAA is as follows:

• Pretest preparation: 72 hours before testing, avoid foods and medications that alter 5-HIAA levels

• Specimen: Urine

• Container: Plastic leakproof container, with preservative (15 mL of 50% acetic acid if patient aged < 5 y; if patient is aged >5 y, then 25 mL of 50% acetic acid; keep pH at 2.0-4.0; see the image below)

  Plastic leakproof container for 24-hour urine sample, with a volume of 5 mL.

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• Collection method: For timed study, empty the bladder, discard the voided sample, and note the start time; collect all urine voided for specified period; at the end of the collection period, note the time and add the last voided sample to the container; refrigerate the sample during the collection; upon completion of the test, freeze the sample

• Stability: Refrigerated, longer than 1 week; frozen, longer than 2 weeks

Collection and panels information for the plasma 5-HIAA test is as follows:

• Pretest preparation: 72 hours before testing, avoid foods and medications that alter 5-HIAA levels

• Specimen type: Fasting sample, 10 mL of plasma

• Container: Special Z tube (ISI); separate as soon as possible and freeze quickly

• Transport: On dry ice

• Frozen Z (ISI) tube plasma is the only acceptable sample for this assay

Description

5-HIAA is a metabolite of serotonin, a chemical/neurotransmitter that is needed by the nervous system, mainly the brain, and also needed by special cells in the lung and gastrointestinal tract. After the body uses serotonin, it is degraded in the liver and is broken down to its metabolites, including 5-HIAA, which is excreted in the urine.

In healthy patients, 5-HIAA is usually present in very small amounts in the urine. Large quantities of serotonin and 5-HIAA may be produced, however, by some neuroendocrine tumors (NETs)/carcinoid tumors. Carcinoid tumors are slow-growing benign or malignant neuroendocrine masses that can form in the GI tract, on the appendix, and in the lungs. About 2 out of every 3 carcinoid tumors are found in the GI tract, with most of the rest occurring in the lungs.

Approximately 10% of carcinoid tumors produce enough serotonin to cause symptoms. Symptoms are typically gastrointestinal and have liver involvement. The symptoms, collectively termed carcinoid syndrome, include facial flushing, diarrhea, rapid heart rate, and wheezing. Continuous or intermittent release of serotonin results in carcinoid syndrome, and this release results in excessive quantities of 5-HIAA in the urine. The production and metabolism of serotonin correlates with the origin of the tumor, with midgut, ileal, and other masses of the large colon not accurately reflecting urine 5-HIAA because of little metabolism.

Foregut carcinoid tumors rarely manifest with high 5-HIAA levels because the foregut lacks decarboxylase, so serotonin does not convert to 5-HIAA. Tumor of hindgut with metastasis to liver is symptomatic with urine 5-HIAA levels greater than 25 mg per 24 hours. 5-HIAA levels can be elevated in conditions other than carcinoid syndrome. Twenty-four hour urine 5-HIAA is a screening test for carcinoid tumors. More tests, like serotonin assay, chromagraffin A levels, and octreotide scans are performed to confirm the presence of carcinoid tumor in the body and its location for resection.

Indication and application

Indications are as follows:

• Symptomatic carcinoid tumor presenting with dry flushing (ie, flushing with no sweating) as opposed to wet flushing (flushing with sweating), rapid heart rate, wheezing, coughing, shortness of breath, and nighttime diarrhea (or nocturnal diarrhea)

• Tumor re-evaluation

• Monitoring the response to treatment given for carcinoid tumor

If the patient has an indwelling catheter, the 24-hour urine sample can be easily collected. In the absence of an indwelling catheter, urine collection involves discarding the first morning sample and including the next early morning sample. The total volume of urine collected must be noted, and 10 mL of the total 24-hour sample is used, with preservative added, for the 5-HIAA measurement.

Urine spot 5-HIAA levels may not be as accurate because few neuroendocrine tumors secrete serotonin intermittently; thus, the diagnosis may be missed if the urine spot 5-HIAA test is used. In addition, the results are dependent on the creatinine level in urine, with consideration of the reference range variation of creatinine as affected by age and sex, among other factors.

The 24-hour urine 5-HIAA test can be cumbersome and time-consuming, and an alternative is plasma 5-HIAA screening using high-performance liquid chromatography with fluorescence detection technology. This method is recommended as a faster and less complicated test, with comparable results.

Consideration

Of neuroendocrine tumors, whether symptomatic or secreting, 73% are detected using the 24-hour urine 5-HIAA assay. The only limitation to this test is that the procedure is too cumbersome and time-consuming. Additionally, 15-70% of active/secreting neuroendocrine tumors are missed with this test. The neuroendocrine tumors that are missed by the 24-hour urine 5-HIAA screening are detected by a serotonin assay. Serotonin assays detect 90% of the neuroendocrine tumors secreting serotonin.

High-performance liquid chromatography with fluorescence detection technology that uses plasma 5-HIAA rather than urine 5-HIAA may be an alternative. Advantages with the plasma test are that results can also be used for diagnostic purposes. However, cost and availability limit wide use of this test as the first screening test for carcinoid and neuroendocrine tumors.

To confirm the diagnosis of neuroendocrine tumor, the following tests are performed:

• Serotonin assay

• Chromagraffin A level

• Octreotide scanning

These tests can detect 73-80% of the symptomatic or secreting neuroendocrine tumors.