Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Serotonin (5-hydroxytryptamine: 5-HT) is synthesized from the essential amino acid tryptophan via the intermediate 5-hydroxytryptophan (5-HTP). 5-HT production sites are the central nervous system (CNS), where it acts as a neurotransmitter, and neuroectodermal cells, chiefly gastrointestinal (GI) enterochromaffin cells (EC-cells). The CNS and peripheral 5-HT pools are isolated from each other. EC-cell production accounts for 80% of the body's 5-HT content.
Many different stimuli can release 5-HT from EC-cells. Once secreted, in concert with other gut hormones, 5-HT increases GI blood flow, motility, and fluid secretion. On first pass through the liver, 30% to 80% of 5-HT is metabolized, predominately to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted by the kidneys. Ninety-percent of the remainder is metabolized in the lungs, also to 5-HIAA. Of the remaining 10%, almost all is taken up by platelets, where it remains until it is released during clotting, promoting further platelet aggregation.
The main diseases that may be associated with measurable increases in 5-HT are neuroectodermal tumors, in particular, tumors arising from EC-cells, which are termed carcinoids. They are subdivided into foregut carcinoids, arising from respiratory tract, stomach, pancreas, or duodenum (approximately 15% of cases); midgut carcinoids, occurring within jejunum, ileum, or appendix (approximately 70% of cases); and hindgut carcinoids, which are found in the colon or rectum (approximately 15% of cases). Carcinoids display a spectrum of aggressiveness with no clear distinguishing line between benign and malignant. The majority of carcinoid tumors do not cause significant clinical disease. Those tumors that behave more aggressively tend to cause nonspecific GI disturbances, such as intermittent pain and bloating, for many years before more overt symptoms develop. In advanced tumors, morbidity and mortality relate as much, or more, to the biogenic amines, chiefly 5-HT, and peptide hormones secreted, as to local and distant spread. The symptoms of this so-called carcinoid syndrome consist of flushing, diarrhea, right-sided valvular heart lesions, and bronchoconstriction. All of these symptoms are at least partly caused by 5-HT. The carcinoid syndrome is usually caused by midgut tumors, as foregut and hindgut neoplasms produce far lesser amounts of 5-HT. Since midgut tumors drain into the portal circulation, which passes into the liver, symptoms do not usually occur until liver or other distant metastases have developed, bypassing the extensive hepatic first-pass 5-HT degradation.
Serotonin production by disseminated carcinoid tumors can sometimes be so substantial that body tryptophan stores become depleted and clinical tryptophan deficiency, resembling pellagra (triad of diarrhea, dementia, and dermatitis), develops.
Diagnosis of carcinoid tumors with symptoms suggestive of carcinoid syndrome rests on measurements of circulating and urinary 5-HT, urinary 5-HIAA (HIAA / 5-Hydroxyindoleacetic Acid [5-HIAA], 24 Hour, Urine), and serum chromogranin A (CGAK / Chromogranin A, Serum), a peptide that is cosecreted alongside specific hormones by neuroectodermal cells.
In conjunction with, or as an alternative to, 5-hydroxyindoleacetic acid (5-HIAA) or serum chromogranin A measurements as a first-line test in the diagnosis of carcinoid syndrome, including the differential diagnosis of isolated symptoms suggestive of carcinoid syndrome, in particular flushing
As a second-line test (5-HIAA and serum chromogranin A measurement are first-line tests) in the follow-up of patients with known or treated carcinoid tumors
Metastasizing midgut carcinoid tumors usually produce blood or serum 5-hydroxytryptamine (5-HT) concentrations >1,000 ng/mL. However, elevations >400 ng/mL are suggestive of carcinoid tumors as the cause of carcinoid syndrome-like symptoms. Lesser increases may be nonspecific or drug-related (see Cautions).
Only a minority of patients with carcinoid tumors will have elevated 5-HT levels. It is usually impossible to diagnose small carcinoid tumors (>95% of cases) without any symptoms suggestive of carcinoid syndrome by measurement of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), or chromogranin A.
In patients with more advanced tumors, circulating 5-HT is elevated in nearly all patients with midgut tumors, but only in approximately 50% of those with foregut carcinoids, and in no more than 20% of individuals with hindgut tumors. Foregut and hindgut tumors often have low or absent 5-hydroxytryptophan (5-HTP) decarboxylase activity and, therefore, may produce little if any 5-HT. Urinary 5-HIAA is elevated in almost all carcinoid-syndrome patients with midgut tumors, in about 30% of individuals with foregut carcinoids, but almost never in hindgut tumors. Serum chromogranin A measurements are particularly suited for diagnosing hindgut tumors, being elevated in nearly all cases, even though 5-HT and 5-HIAA are often normal. Chromogranin A is also elevated in 80% to 90% of patients with foregut and midgut tumors. Therefore, to achieve maximum sensitivity in the initial diagnosis of suspected carcinoid tumors, 5-HT in serum/blood, 5-HIAA in urine, and serum chromogranin A should all be measured. In most cases, if none of these 3 analytes is elevated, carcinoids can be excluded as a cause of symptoms suggestive of carcinoid syndrome. For some cases, additional tests, such as urinary 5-HT measurement will be required. An example would be a nonchromogranin-secreting foregut tumor that only produces 5-HTP, rather than 5-HT. In this case, circulating chromogranin, 5-HT levels, and urinary 5-HIAA levels would not be elevated. However, the kidneys can convert 5-HTP to 5-HT, leading to high urinary 5-HT levels.
Disease progression can be monitored in patients with serotonin-producing carcinoid tumors by measurement of 5-HT in blood. However, at levels above approximately 5,000 ng/mL, the serotonin storage capacity of platelets becomes limiting, and there is no longer a linear relationship between tumor burden and blood 5-HT levels. Urinary 5-HIAA and serum chromogranin A continue to increase in proportion to the tumor burden to much higher 5-HT production levels, and are therefore better suited for follow-up in patients with extensive disease.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Since most circulating 5-hydroxytryptamine (5-HT) is contained in platelets, the preferred specimens for measurement either include all or most of the platelets (ie, whole blood and platelet-rich plasma) or consist of serum from completely clotted specimens, a process that releases nearly all 5-HT from platelets. "Ordinary" or platelet-poor plasma specimens are not suitable.
Medications that may elevate serotonin concentrations include lithium, monoamine oxidase inhibitors, methyldopa, morphine, and reserpine. The observed levels are usually <400 ng/mL. Selective serotonin reuptake inhibitors (eg, fluoxetine) can lead to depletion of platelet serotonin levels and result in false-negative serum and blood 5-HT tests. The effects of drugs are more marked on urinary 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels than on serum and blood 5-HT levels.
Serotonin- or tryptophan-rich foods (avocados, bananas, plums, walnuts, pineapple, eggplant, plantain, tomatoes, hickory nuts, kiwi, dates, grapefruit, cantaloupe, and honeydew melon) do not contribute significantly to serum or blood 5-HT measurements, but can elevate platelet-poor plasma 5-HT, urinary 5-HT, and urinary 5-HIAA levels markedly (up to 10-fold).
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
< or =330 ng/mL
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Kema IP, Schellings AM, Meibotg G, et al: Influence of a serotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem 1992;38:1730-1736
2. Kema IP, de Vries EGE, Muskiet FAJ: Clinical chemistry of serotonin and metabolites. J Chromatogr B Biomed Appl 2000;747:33-48
3. Meijer W, Kema I, Volmer M, et al: Discriminating capacity of indole markers in the diagnosis of carcinoid tumors. Clin Chem 2000;46:1588-1596
4. Ganim RB, Norton JA: Recent advances in carcinoid pathogenesis, diagnosis and management. Surg Oncol 2000;9:173-179