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

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