Medical Analysis

5 – HIAA – Hydroxy Indole Acetic Acid Overview and Clinical Significance By Dr. Dipak Ladda M.D.

Introduction to Serotonin and 5-Hydroxyindoleacetic Acid Diagnostic Markers

Serotonin is broken down into 5-hydroxy indoleacetic acid within the liver [1]. 5-hydroxy indoleacetic acid is used as a proxy for serotonin measurement through a 24-hour urine test [1, 2]. It functions as a tumor marker and is used to diagnose and monitor midgut carcinoid tumor [9]. It is measured mainly in urine as it is excreted through it [12].

Biochemistry and Metabolic Pathways of Serotonin and Tryptophan Breakdown

The biochemistry of 5-HIAA is derived from tryptophan metabolism [1]. The pathway proceeds where serotonin breaks down into 5-Hydroxyindoleacetic acid via Monoamine oxidase (MAO), and is subsequently excreted in urine [1]. The interconnected biochemical cascade involves the Serotonin Pathway, Kynurenine Pathway, and Indole Pathway [1]. Within the Serotonin Pathway, Melatonin converts to N-acetylserotonin, then to Serotonin, and finally via Monoamine oxidase (MAO) into 5-HIAA, alongside 5-HTP originating from Tryptophan [1]. Simultaneously, the Kynurenine Pathway processes Tryptophan through Tryptophan-2,3-dioxygenase (TDO) and Indoleamine-2,3-dioxygenase (IDO) to form Kynurenine, which branches into Kynurenic Acid, Xanthrenic Acid, 3H-KYN, 3-HAA, Picolinic Acid, Quinolinic Acid, and ultimately NAD [1]. The abbreviations denote essential enzymes: MAO representing monoamine oxidase, TDO representing tryptophan-2,3-dioxygenase, and IDO representing indoleamine-2,3-dioxygenase [1].

Clinical Indications and Diagnostic Applications for Neuroendocrine Tumors

The clinical indications encompass diagnosis and monitoring treatment of carcinoid tumor [2], differential diagnosis for GI symptoms, unexplained flushing of face and neck, and diarrhea, abdominal pain, nocturnal diarrhea, vomiting, and nausea [5], prognostic indicator where high levels suggest poor outcome [7], paediatric neuroendocrine tumor, and research purpose.

Patient Preparation Protocols Before Clinical Sample Collection

The preparation before collection of sample requires specific dietary restrictions applied 3 days before and during collection involving bananas, walnuts, pineapples, avocados, tomatoes, kiwi, plums, and eggplant [2]. Patients must avoid alcohol minimum 3 days before collection [2]. Drug interference involves medications such as acetaminophen, caffeine, methyldopa, and guaifenesin, and one needs to stop these medications at least 3 days before testing [2]. Furthermore, 24 hours urine collection requires proper instructions given to the patient [2].

Method of Collection for 24 Hours Urine Sample and Preservation Techniques

The method of collection for 24 hrs urine sample involves instructing the patient properly for 24 hrs urine collection [2]. One must add preservative as 10 ml of N/10 HCl or alternatively use 6 N hydrochloric acid prepared by adding 5.15 ml concentrated HCl to 4.85 ml water, or Boric Acid at 25-50 mgs/L to avoid bacterial growth and degradation of analytes [2]. Refrigerate 24-hour specimens during collection [2]. Measure volume properly before submitting for further testing and make proper calculation before releasing report [2].

Analytical Methods of Assay for Urinary 5-HIAA Measurement

The methods of assay for 24 hrs urinary 5-HIAA include acidification and extraction with organic solvents, high performance liquid chromatography (HPLC), gas chromatography mass spectrometry (GCMS), and ELISA assay [12]. An important note specifies that calibration with known standards is a must [12].

Specimen Collection Parameters and Laboratory Specifications

Specimen collection can utilize 24-hour or random urine [2]. Give proper instructions to the patient for 24 hrs urine collection [2]. Refrigerate 24-hour specimens during collection and add preservative to the 24 hrs urine specimen collection container before starting collection to prevent microbial growth and degradation of analytes [2].

Normal Reference Ranges for 24 Hours Urine HIAA Test Results

Serum 5-HIAA Diagnostic Value and Plasma Biomarkers

A serum 5-HIAA test measures levels of this serotonin metabolite in the blood, though a 24-hour urine test remains the standard method for diagnosing and monitoring carcinoid tumours [2]. A specific reference range for serum 5-HIAA is not widely established in clinical practice [2]. However, an optimal cutoff of 139.4 nmol/L for diagnosing carcinoid syndrome is established and is demonstrating a strong correlation with urine levels [2]. Serum 5-HIAA serves as a quicker alternative to the 24-hour urine test [2].

Urine HIAA to Creatinine Ratio Calculations and Interpretation

Generally, HIAA to creatinine ratio is not reported if a 24 hrs sample is submitted [2]. However, if the sample is a random one or 24 hrs collection is less than 400 ml, then it will be mandatory to report HIAA creatinine ratio [2]. The reference range is 2-14 mgs/Gm creatinine [2].

Paediatric and Adult Creatinine Urine 24 Hours Reference Values

Comprehensive Clinical Significance of 5-HIAA Biomarker Findings

Etiology and Physiological Causes of Low Serotonin Levels

Causes of low serotonin include genetics, chronic stress, poor diet, nutritional deficiencies, lack of sunlight, certain medications and drugs, irritable bowel syndrome (IBS), chronic fatigue, lack of exercise, and depression [1].

Important Clinical Reminders Regarding Factors Influencing 5-HIAA Test Results

Strenuous exercise may raise 5-HIAA levels [2]. Foods increasing 5-HIAA levels if eaten within 48 hours of test include pineapple, banana, kiwi fruit, tomato, or walnuts [2]. Drugs that lower urine 5-HIAA levels and increase brain serotonin levels include risperidone and acetaminophen by inhibiting hepatic tryptophan 2,3-dioxygenase [2]. Medicines that lower CSF 5-HIAA levels are desipramine and zimeldine [2]. Dialysis decreases CSF levels of 5-HIAA [2].

Technical Limitations and Patient Compliance Challenges in Laboratory Testing

Limitations involve inconvenience and cumbersome nature, and it can be difficult for patients [2]. Dietary restrictions on tryptophan or serotonin-rich foods and certain medications are necessary to avoid false results [2]. Patient compliance with the diet and the collection process is crucial for accuracy [2]. Factors like strenuous exercise, chronic kidney disease, and certain medications can interfere with results [2]. Trusted insights curated by Dr. Dipak Ladda [2].

For Non-Medicos

What Is a 5-HIAA Test and Why Doctors Order It

Welcome to an easy-to-understand breakdown of the 5-HIAA test. When your body processes a chemical messenger called serotonin, it breaks it down into a waste product known as 5-hydroxyindoleacetic acid, or 5-HIAA for short [1]. This waste product travels through your bloodstream and filters out through your kidneys into your urine [1, 2]. Doctors use a 24-hour urine test to measure 5-HIAA levels because it acts as an important warning sign or tumor marker for rare neuroendocrine growths called carcinoid tumors, particularly those located in the middle part of your intestines [9]. If you have been experiencing unexplained symptoms like sudden flushing of your face and neck, frequent watery diarrhea, abdominal pain, or nausea, your physician may order this test to investigate what is happening inside your digestive system [5].

How to Prepare for Your Urine Test and Avoid False Alarms

Preparing properly for your 5-HIAA test is critical because many common foods and medications can alter your results and cause false alarms [2]. For three days before and during your urine collection period, you must avoid eating serotonin-rich foods such as bananas, walnuts, pineapples, avocados, tomatoes, kiwi fruits, plums, and eggplants [2]. You should also stay away from alcohol for at least three days prior to testing [2]. Certain medications—including acetaminophen, caffeine, methyldopa, and guaifenesin—can interfere with the lab analysis and must be paused under your doctor’s supervision [2]. Strenuous exercise should also be avoided because heavy physical exertion can temporarily push your 5-HIAA numbers higher [2].

Collecting Your 24-Hour Urine Sample Step-by-Step

Collecting urine over a full 24-hour period requires careful attention to detail to ensure accuracy [2]. Your laboratory or healthcare provider will give you a specialized jug containing a special preservative liquid, usually a diluted acid or boric acid, which prevents bacteria from growing and breaking down the sample over the day [2]. To start your collection correctly, empty your bladder into the toilet first thing in the morning and flush it away; note down this exact start time [2]. From that moment on, every single drop of urine you pass over the next 24 hours must be collected inside the provided container, which you should keep stored in a refrigerator or a cool dark place [2]. Exactly 24 hours after your start time, pass urine one final time and add it to the container, then take the whole labeled sample to your laboratory so they can measure the total volume and run the assay [2].

Understanding Your Test Results and What They Mean

Once the laboratory analyzes your sample, they will look at how many milligrams of 5-HIAA you excreted over the 24-hour window [2]. A normal result is typically 10 milligrams or less per day, indicating healthy serotonin metabolism [1]. If your results fall into a borderline range between 10 and 25 milligrams, the test may be inconclusive, and your doctor might ask you to repeat it while strictly following the dietary rules [2]. Numbers exceeding 25 milligrams often suggest the presence of a carcinoid tumor or serotonin-secreting neuroendocrine condition, while very high levels above 50 to 100 milligrams strongly point toward active carcinoid syndrome [2, 5]. Managing these conditions relies heavily on accurate initial measurements, proper patient compliance, and expert medical evaluation by specialists like Dr. Dipak Ladda [2].

References:

1. Lenchner, J. R., & Hassan, M. (2023). Biochemistry, 5 Hydroxyindoleacetic Acid. StatPearls Publishing.

2. Feldman, J. M. (1986). Urinary 5-hydroxyindoleacetic acid excretion in patients with carcinoid tumors. Clinical Chemistry, 32(5), 840–844.

3. Moattari, A. R., O’Dorisio, T. M., Vinik, A. I., & Warner, R. R. (1989). Carcinoid tumors: treatment of carcinoid syndrome with somatostatin analog. The American Journal of Surgery, 157(1), 168–179.

4. Oberg, K., & Eriksson, B. (1991). Endocrine gastrointestinal tumors. Current Opinion in Oncology, 3(1), 79–87.

5. Ahlman, H., & Nilsson, O. (2002). The carcinoid syndrome: serotonin, tachykinins and associated symptoms. Gastroenterology Clinics of North America, 31(1), 21–42.

6. Ramage, J. K., Ahmed, A., Ardill, J., Evers, E., Maxwell, J. D., & McArdle, B. (2005). Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut, 54(Suppl 4), iv1–iv16.

7. Eriksson, B., Oberg, K., & Stridsberg, M. (2000). Tumor markers in neuroendocrine tumors. Digestive Diseases, 18(3), 142–149.

8. Boyce, A. M., & Rosenberg, A. F. (2012). Evaluation and management of neuroendocrine tumors. Clinical Endocrinology, 76(4), 481–488.

9. Strosberg, J. R., Cheema, A., Shah, M., & Kvols, L. K. (2007). Carcinoid tumors of the midgut. Current Treatment Options in Oncology, 8(4), 276–286.

10. Modlin, I. M., Lye, K. D., & Kidd, M. (2003). A 5-decade analysis of 13,715 carcinoid tumors. Cancer, 97(4), 934–959.

11. Buxbaum, J. L., & El-Serag, H. B. (2010). The epidemiology of carcinoid tumors. Seminars in Oncology, 37(6), 504–510.

12. Kema, I. P., de Jong, P. E., & Muskiet, F. A. (1993). Clinical chemistry of serotonin and related compounds. Clinical Chemistry, 39(12), 2445–2452.

13. Plöckinger, U., Rindi, G., Arnold, R., Eriksson, B., Krenning, E. P., & de Herder, W. W. (2004). Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. Neuroendocrinology, 80(6), 394–424.

14. Vinik, A. I., & McLeod, M. K. (1989). Carcinoid tumors and their syndrome. Metabolism, 38(2), 217–228.

15. Jensen, R. T. (1999). Carcinoid and neuroendocrine tumors. Current Opinion in Gastroenterology, 15(4), 312–322.

FAQ’s:

1. What is 5-HIAA?
Serotonin’s liver breakdown waste product measured via urine as a tumor marker.

2. Why is this test ordered?
To diagnose and monitor midgut carcinoid tumors and related symptoms.

3. Which foods should be avoided?
Bananas, walnuts, pineapples, avocados, tomatoes, kiwi, plums, and eggplants.

4. What medications interfere with testing?
Acetaminophen, caffeine, methyldopa, guaifenesin, risperidone, and certain antidepressants.

5. How is the urine collected?
Over a 24-hour period using a specialized container with a preservative.

6. What is normal urine output?
Typically ten milligrams or less of 5-HIAA per 24 hours.

7. What indicates elevated test results?
Levels exceeding 25 milligrams per 24 hours suggest carcinoid tumors.

8. Can blood tests replace urine?
Serum 5-HIAA is a quicker alternative, though urine remains standard.

9. What causes low serotonin levels?
Genetics, chronic stress, poor diet, nutritional deficiencies, and lack of exercise.

Related Tests

• Serotonin Test
• Liver Function Test (LFT)