Urinary 5-Hydroxyindoleacetic Acid

5-hydroxyindoleacetic acid (5-HIAA) is the main breakdown product of serotonin (5-hydroxytryptamine). Serotonin is made from tryptophan in enterochromaffin cells of the gut and is inactivated by monoamine oxidase in liver and lung, then excreted in urine as 5-HIAA. Serotonin secreting neuroendocrine tumours (carcinoid), mostly of the midgut, release large amounts, so 5-HIAA in urine rises.

It is measured in a 24-hour urine collection by high performance liquid chromatography or mass spectrometry, and reported in micromol/24 hours (mg/24 hours). Plasma 5-HIAA is an alternative that does not need a timed collection.

The test is used to diagnose carcinoid syndrome, to assess tumour burden and to monitor treatment of serotonin producing neuroendocrine tumours.

Neuroendocrine tumours have an incidence of about 5 to 7 per 100 000 people a year, and small bowel tumours are the commonest source of carcinoid syndrome. Carcinoid syndrome occurs in 20 to 30% of patients with midgut tumours and liver metastases, because the liver normally clears serotonin from the portal circulation. Carcinoid heart disease develops in about 20 to 50% of these patients.

Indications. Flushing, secretory diarrhoea, wheeze and right sided valvular heart disease (carcinoid syndrome), a small bowel or lung mass or liver metastases of unknown primary suggestive of neuroendocrine tumour, monitoring of a known midgut neuroendocrine tumour, and unexplained right heart valve disease.

Specimen. A complete 24-hour urine in a container with hydrochloric acid (usually 10 to 25 mL of 6 mol/L) or acetic acid to keep the pH between 2 and 4, kept refrigerated during the collection. For 3 days before and during the collection, avoid foods and drugs that raise or lower 5-HIAA. An acidified spot urine (5-HIAA to creatinine ratio) is less reliable.

Reference range. Adults: 10 to 47 micromol/24 hours (2 to 9 mg/24 hours), assay specific. Plasma 5-HIAA: under 123 nmol/L (under 24 microg/L) fasting.

Interpretation.

• Over 100 micromol/24 hours (over 20 mg/24 hours) with the clinical syndrome and an imaging mass: strongly supports carcinoid syndrome, and over 200 micromol/24 hours is virtually diagnostic.
• Values of 50 to 100 micromol/24 hours: indeterminate, and diet, drugs or malabsorption are checked, with a repeat.
• Sensitivity of 5-HIAA is about 70 to 75% overall and 80 to 90% for midgut tumours with carcinoid syndrome, with specificity of 90 to 100%. It is less sensitive in foregut tumours (bronchial, gastric) and hindgut tumours (rectal), which often lack serotonin production.
• Higher values correlate with tumour burden, with a risk of carcinoid heart disease (over 300 micromol/24 hours), and with progression of disease.
• A fall after resection or somatostatin analogue treatment suggests response, and a rise suggests progression. Imaging confirms.

Causes of false positive results.

• Foods rich in serotonin: bananas, plantains, pineapple, kiwi fruit, plums, tomatoes, avocado, walnuts, pecans, aubergine.
• Drugs: paracetamol on some methods, caffeine, guaifenesin, methocarbamol, phenacetin, reserpine, fluorouracil, melphalan, nicotine, and ephedrine.
• Disease: small bowel malabsorption (coeliac disease, Whipple disease, tropical sprue), and cystic fibrosis.

Causes of false negative results.

• Drugs: monoamine oxidase inhibitors, methyldopa, isoniazid, imipramine, levodopa, heparin, phenothiazines, aspirin, ethanol, and mephenesin.
• Poorly collected or unacidified urine, kidney failure (reduced excretion), foregut and hindgut tumours, and low bulk tumours.

Critical values and findings needing immediate action.

• Raised 5-HIAA with flushing, bronchospasm, hypotension and hypertension (carcinoid crisis), which can be provoked by anaesthesia, surgery and biopsy and needs intravenous octreotide.
• Dyspnoea, oedema and a murmur: carcinoid heart disease, requiring echocardiography.
• Raised 5-HIAA with bowel obstruction or mesenteric fibrosis, or with intestinal ischaemia.
• Pellagra like features (dermatitis, diarrhoea, dementia) from niacin deficiency in carcinoid syndrome.

Interferences and pitfalls.

• Diet and drugs are the commonest cause of false results. Dietary restriction for 3 days before and during collection is needed.
• Incomplete collection, delay in acidifying, and storage at room temperature give variable results.
• 5-HIAA is not a screening test and is not raised in all neuroendocrine tumours.
• Kidney impairment lowers urinary excretion.
• Carcinoid syndrome with a normal 5-HIAA is possible with intermittent secretion, and the test is repeated.
• Methods differ in range, and the same laboratory and method are used for serial tests.
• Plasma 5-HIAA is simpler and well correlated, but is not universally available and is also affected by diet and drugs.
• Chromogranin A and specific imaging complement the test.

Special groups.

• Children: rare, and reference ranges depend on age.
• Pregnancy: reference values are similar to non-pregnant adults.
• Patients on somatostatin analogues: values fall and the test is used to monitor control.
• Patients with malabsorption: false rises.
• Regions: the test may be limited by laboratory capacity, and diet rich in plantain (staple in parts of Africa) raises values.

Follow up tests. Plasma chromogranin A, somatostatin receptor PET-CT or scintigraphy, contrast CT or MRI of abdomen and liver, echocardiography with NT-proBNP, endoscopy and capsule endoscopy, biopsy with Ki-67 index and grading, niacin levels, and genetic testing (MEN1) in familial or multifocal disease.