Excretion Of 5-hydroxyindoleacetic Acid Research Articles

Urinary 5-Hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy

Highly emetogenic drugs such as cisplatin induce an increase in the urinary 5-hydroxyindoleacetic acid (5-HIAA) level, the main metabolite of serotonin (5-HT), within the first 24h following a single infusion, thus providing a possible cause for acute emesis and an explanation for the action of 5-HT3 antagonists. No further excretion peaks have been observed, suggesting that additional or serotonin-independent mechanisms cause delayed emesis. Our aim was to study the mechanisms behind emesis seen during a highly emetogenic chemotherapy regimen given as a continuous infusion over several days. Seven women treated with a 4-day high-dose chemotherapy (HDCT) regimen for breast cancer entered the study. Pooled urine samples were collected prior to and during chemotherapy for determining 5-HIAA excretion. An excretion peak in the urinary 5-HIAA level was observed within the first 24h with no further peaks thereafter. Thus, the mechanisms behind the emesis experienced during this highly emetogenic multiple-day chemotherapy regimen from days 2–3 onwards would appear to be at least partially serotonin independent and would not be expected to be completely relieved by 5-HT3 antagonists alone.

5-Hydroxyindoleacetic acid (5-HIAA) and cortisol excretion as predictors of chemotherapy-induced emesis.

This study evaluated the relationship between prechemotherapy cortisol and 5-hydroxyindoleacetic acid (5-HIAA) excretion and chemotherapy-induced emesis. The urinary excretion of cortisol and the serotonin metabolite 5-HIAA in the night before chemotherapy administration were measured in 28 and 49 female patients receiving > 300 mg m-2 carboplatin. Vomiting and nausea were documented over a 3 day observation period. Lower basal cortisol excretion was significantly correlated with vomiting with or without nausea occurring within the observation period. 5-HIAA showed only a weak correlation with emesis on days 1-3, but low 5-HIAA excretion was correlated with a higher proportion of patients vomiting on days 2-3 following chemotherapy. Low basal cortisol excretion might be useful as a predictor for chemotherapy-induced emesis and therefore should be evaluated prospectively in future studies.

High serum levels of the thyrotropin-releasing hormone-like peptide pyroglutamyl-glutamyl-prolineamide in patients with carcinoid tumors.

The TRH-like peptide pGlu-Glu-Pro-NH2 ( < EEP-NH2) has been identified in the prostate, the anterior pituitary, and a human neuroblastoma cell line. We here report the determination of TRH-like immunoreactivity (TRH-LI) in serum of control subjects and patients with carcinoid tumors. TRH-LI was distinguished from authentic TRH (pGlu-His-Pro-NH2) in RIAs using the nonspecific antiserum 4319, which recognizes most peptides with the structure pGlu-X-Pro-NH2, or the TRH-specific antiserum 8880. TRH levels were undetectable ( < 25 pg/mL) in unextracted serum from healthy subjects, whereas the TRH-LI level was 42 +/- 22 pg/mL (mean +/- SD; n = 175). TRH levels were also undetectable in unextracted serum from 60 patients with carcinoid tumors, whereas TRH-LI levels ranged from less than 10 to 2540 pg/mL, being elevated in 27 of 60 (45%) patients. Serum TRH-LI was significantly correlated with 1) the number of tumor localizations (tumor load), 2) the presence of liver metastases, and 3) urinary 5-hydroxyindoleacetic acid excretion. Serum TRH-LI was completely extracted with methanol, and its identity was analyzed in serum extracts from 3 patients with carcinoid tumors by QAE-Sephadex A-25 anion exchange chromatography and reverse phase high performance liquid chromatography. With both techniques, TRH-LI predominantly coeluted with synthetic < EEP-NH2, suggesting secretion of this peptide by carcinoid tumors. The mechanism of < EEP-NH2 production by these tumors and its possible biological function remain to be determined.

The role of serotonin as a mediator of emesis induced by different stimuli.

The aim of this work was to evaluate the impact of changes in serotonin metabolism on the pathophysiology of different types of emesis: pregnancy-induced emesis, emesis associated with inner-ear dysfunction, and cisplatin-induced emesis. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, was measured in 13 women with pregnancy-induced emesis, 12 patients who had nausea and vomiting following inner-ear dysfunctions, 27 patients with cisplatin-induced emesis and a control group of 21 women. 5-HIAA was measured with a fluorescence polarization immunoassay (Abbott) and corrected for varying urine concentrations. Both patients with emesis associated with inner-ear dysfunction and patients with pregnancy-associated emesis showed a similar 5-HIAA excretion pattern compared with the control group. No correlation between intensity of nausea or vomiting and changes in 5-HIAA excretion could be detected. In patients receiving cisplatin, the 5-HIAA excretion increased rapidly within the 12 h following cisplatin administration and returned to baseline levels after 24 h. There was a parallel increase of 5-HIAA excretion and numbers of emetic episodes in the first 12 h, but delayed emesis was not associated with elevated 5-HIAA excretion. Our results provide evidence that serotonin is involved in the pathophysiology of cisplatin-induced acute emesis. Cisplatin-induced delayed emesis, pregnancy-associated emesis, and emesis due to inner-ear dysfunction are not associated with elevated levels of 5-HIAA excretion. The serotonin pathway probably represents only one of many different afferent mechanisms capable of initiating the emesis cascade.

Clinical effects of octreotide compared to placebo in patients with gastrointestinal neuroendocrine tumours Report on a double‐blind, randomized trial

To compare the effect of octreotide with f placebo on symptoms, tumour marker and quality of life in patients with gastrointestinal neuroendocrine tumours and liver metastases. A blinded, placebo-controlled, cross-over study was performed. The number of flushing epidodes and diarrhoea episodes were registered for 1 week prior to the study and for the 8-week duration of the study. Quality of life and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured before the start, and at 4 and 8 weeks. Quality of life was registered with the Psychosocial Adjustment to Illness Scale (PAIS) and 5-HIAA measured by high-performance chromatography with electrochemical detection. 5-HIAA values exceeding 45 mumol 24 h-1 were considered to be elevated. The study was performed in a tertiary referral centre. Twelve patients were approached; eleven patients were included, with a mean age of 56.5 (range 30-72) years. The primary tumour originated from the small intestine in nine and from the pancreas in two patients. The main symptoms were diarrhoea, flushing and nausea. The 24-h excretion of 5-HIAA was increased in all patients. Patients were treated for 4 weeks with octreotide (100 micrograms) subcutaneously, twice daily, and for 4 weeks on placebo (octreotide vehicle) in random starting order. The main outcome measures were the number of episodes of the main clinical symptom(s) and 24-h 5-HIAA excretion. Octreotide lowered diarrhoea and flushing frequency significantly compared to placebo. 5-HIAA excretion was reduced during treatment with the active drug. Two domains of the PAIS were significantly improved, indicating that the reduction of tumour marker and symptoms were clinically important. The clinical effect of octreotide on symptoms in patients with neuroendocrine tumours was demonstrated in a controlled, prospective trial.

ＣＤＤＰおう吐に対する抗セロトニン薬の効果

The efficacy of ondansetron, an antagonist of serotonin 5HT3-receptor, was compared with that of metoclopramide, an antagonist of dopamin D2-receptors, in the contorol of nausea and vomiting induced by cisplatin treatment in 30 patients with head and neck cancers. Nausea and vomiting were significantly in those treated with ondansetron less than in those receiving metoclopramide. It was concluded that ondansetron is an effective agent for the control of cisplatin-induced nausea and vomiting. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, was significantly increased in the patients who received cisplatin chemotherapy. There was a significant positive correlation between the degree of nausea induced by cisplatin and the urinary excretion of 5-HIAA, suggesting that the release of serotonin induced by cisplatin causes emesis.

An Unusual Cause of Acute Gastroenteritis

A 51 -year-old man came to the Mayo Clinic approximately 6 weeks after a 3-day episode of severe watery diarrhea (25 bowel movements per day). Because of associated pronounced abdominal distention, use of a long intestinal tube had been necessary while he was hospitalized. Small bowel roentgenography demonstrated a diffuse inflammatory process from the stomach to the ileocecal valve, suggestive of Crohn's disease. The patient had had a similar episode of diarrhea 1 xh years previously. At that time, roentgenograms showed a diffuse inflammatory process of the small bowel, again suggestive of Crohn's disease. Findings on a roentgenogram 1 month later were normal. During the interim between the two episodes and since the last one, the patient had been asymptomatic. On admission to our institution, the patient's vital signs were normal. Results of abdominal and rectal examinations were normal. The following laboratory studies yielded normal results: routine urinalysis, 24-hour urinary excretion of 5-hydroxyindoleacetic acid, complete blood cell count, erythrocyte sedimentation rate, chemistry group, serum protein electrophoresis, and total thyroxine. Elicitation of a detailed dietary history from the patient and his wife revealed a sporadic habit of eating jalapeno peppers. His wife confirmed that he had ingested 40 to 50 jalapeno peppers the evening before each of the two episodes

A study of some components of the serotoninergic system in psychopathic subjects during depression

It is shown that the platelet serotonin level and the maximum rate of uptake of labeled serotonin by platelets in the groups of patients with anxious-depressive and depressive-hysterical syndromes is markedly higher than in the control (patients with psychopathy without signs of depression) and in the group with the asthenodepressive syndrome. In all groups of patients with depressions the excretion of 5-hydroxyindoleacetic acid is reduced as compared to the control.

Effects of inhibition of serotonin synthesis on 5-hydroxyindoleacetic acid excretion, in healthy subjects.

The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, reflects the content and turnover of gastrointestinal (GI) serotonin. Employing longitudinal measurements of 5-HIAA, the authors investigated in healthy subjects (n = 43) how manipulations of serotonin synthesis affect GI serotonin. Under conditions of serotonin-free diets, the intersubject and intrasubject variability (coefficient of variation) for 5-HIAA excretion averaged 33% and 14%, respectively. Dietary tryptophan restrictions to 50% of minimal daily requirements (which is equivalent to a 10-fold reduction in baseline tryptophan intake) decreased by half the urinary excretion of 5-HIAA, irrespective of the caloric content of diet. Restoration to the regular tryptophan intake produced a rapid normalization of the 5-HIAA excretion. Neutral amino acids are known to compete with the intestinal transport absorption mechanisms of tryptophan. Administration of neutral amino acids (1.8 g, by mouth, three times a day, before each meal) or of carbidopa (50 mg, by mouth, three times a day for 3 days) to a normal tryptophan diet failed to alter significantly the 5-HIAA excretion. Further, neutral amino acids failed to enhance the reduction in 5-HIAA produced by the low-tryptophan diet. The failure of these treatments to reduce 5-HIAA excretion could be due to large capacity transport and decarboxylation systems for tryptophan. Other possibilities are discussed. In summary, dietary tryptophan is essential for the maintenance of GI serotonin. Reductions or increases in dietary tryptophan are the easiest and most effective method to alter GI serotonin.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromogranin A and pancreastatin-like immunoreactivity in human carcinoid disease

Objective: To evaluate chromogranin A (CgA) and pancreastatin-like immunoreactivity (PST-LI) as tumor markers in human carcinoid disease, compared with urinary excretion of 5-hydroxyindole acetic acid (5-HIAA), and to evaluate their role as indicators of survival. Patients and methods: Urinary 5-HIAA excretion was determined by a spectrophotometric method, while serum CgA and PST-LI were determined by radioimmunoassay methods in 38 patients with midgut, 10 with foregut and one with hindgut carcinoids. Results: In midgut carcinoid patients levels of 5-HIAA, CgA and PST-LI were raised by 76, 82 and 76%, respectively. The median CgA level in midgut carcinoid patients was significantly higher than in the controls (193 compared with 12ng/ml; P<0.01). In the midgut carcinoid patients, the median CgA value was significantly higher in women who died (1990 ng/ml) than in those who survived (46ng/ml; P<0.01), and significantly higher than in men, either survivors or non-survivors. The median PST-LI value was significantly higher in midgut carcinoid patients than in the control group (2282 compared with 33 pg/ml; P< 0.01). In women, the median PST-LI level was significantly higher in non-survivors than in survivors (9088 compared with 1337 pg/ml; P<0.01), and significantly higher than in male survivors and non-survivors. In foregut carcinoid patients, levels of CgA, PST-LI and 5-HIAA were increased in nine, eight and one patient, respectively. The median CgA and PST-LI levels in the foregut group were similar to the midgut group. Conclusion: CgA and PST-LI are useful markers in the diagnosis of both midgut and foregut carcinoids. They are as good as, or more sensitive than, 5-HIAA.

Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea.

The pathophysiology of diarrhea in patients with the carcinoid syndrome is not understood. Possible causes include tumor production of neurohumoral substances, such as serotonin and substance P, which stimulate small-bowel and colonic motility, and intestinal abnormalities, such as lymphangiectasia and bacterial overgrowth. We undertook this study to determine whether carcinoid diarrhea is associated with abnormal motor function in the small intestine and colon. We measured the gastric, small-bowel, and colonic transit of radiolabeled solid residue and estimated the volume of the ascending colon in 16 patients with the carcinoid syndrome and diarrhea and 16 normal subjects. We also measured colonic tone and phasic pressure activity by intracolonic multilumen manometry and with an electronic barostat in seven patients and six normal subjects. The patients with the carcinoid syndrome had elevated 24-hour urinary excretion of 5-hydroxyindoleacetic acid and elevated fasting plasma serotonin concentrations. Transit times in the small bowel and colon were two times (P < 0.001) and six times (P = 0.001) faster in the patients than in the normal subjects. The volume of the ascending colon was approximately 50 percent smaller in the patients than in the normal subjects (P < 0.001). The patients had normal fasting colonic tone; their mean postprandial colonic tone was markedly increased as compared with the values in the normal subjects (mean increase, 41 percent vs. 24 percent; P = 0.03). Patients with the carcinoid syndrome who have diarrhea have major alterations in gut motor function that affect both the small intestine and colon.

Recent Developments in Diagnosis and Treatment of Metastatic Carcinoid Tumours

In carcinoid patients a tumour of enterochromaffin cell origin is present, which dependent on the site of origin can result in increased serotonin production. Metastasized carcinoids are often diagnosed by measuring 5-hydroxyindoleacetic acid excretion in the urine. This excretion, however, can be influenced by food intake. On the other hand, serotonin measured in blood platelets is unaffected by food intake and, in addition, is found to be more sensitive. Therapy of metastasized carcinoids is directed at tumour reduction or only reduction of symptoms. Tumour reduction can be achieved surgically or by embolization. Combination chemotherapy has a maximum response percentage of about 33%. Over the last few years, both octreotide and interferon alpha have been used in these patients. They rarely result in a reduction of the tumour size (10-20%). Symptom reduction is achievable in most patients with these agents, however. Recently, increasing knowledge obtained concerning the various serotonin receptors and their antagonists is now being used in the treatment of patients with a metastasized carcinoid. In the future it is expected that the different modalities will be combined increasingly.

Changes in serotonin metabolism in cancer patients: its relationship to nausea and vomiting induced by chemotherapeutic drugs.

The metabolism of serotonin was studied in cancer patients of their first day of their first course of chemotherapeutic drugs either with strongly or moderately emetogenic regimens. It was observed that strongly emetogenic treatments induce greater increases in serotonin release than moderately emetogenic regimens. High-dose cisplatinum (75 +/- 5 or 83.8 +/- 5 mg m-2) produced a marked increase in the plasma levels and in the urinary excretion of 5-hydroxyindole acetic acid (5-HIAA). Neither platelet nor plasma (platelet-free plasma) serotonin were significantly modified by high-dose cisplatinum. Dacarbazine (283 +/- 22 mg m-2), another strongly emetogenic agent, induced acute nausea and emesis paralleled by marked increases in the urinary excretion of 5-HIAA. Both for high-dose cisplatinum and dacarbazine, the increases in serotonin metabolism occurred with a similar time-course than those of vomiting, and lasted for a period of 4 to 8 h. Low-dose cisplatinum (30.8 +/- 3 mg m-2) as well as cyclophosphamide-based chemotherapies (520 +/- 30 mg m-2) produced very small increases in the urinary excretion of 5-HIAA. Platelet and plasma serotonin levels failed to increase in cyclophosphamide-treated patients. Octreotide, a long-acting somatostatin analog, did not inhibit the increase in urinary 5-HIAA and the nausea and vomiting produced by high-dose cisplatinum. These results suggest that for treatments that induce marked increases in serotonin release such as high-dose cisplatinum or dacarbazine: (a) the amount and time course of serotonin release induced by chemotherapeutic drugs determines the severity, time of onset and pattern of emesis observed; (b) platelet serotonin play no role in chemotherapy-induced emesis; (c) strongly emetogenic regimens release serotonin from enterochromaffin cells; and (d) intestinal release of serotonin is the consequence of the damage induced by the chemotherapeutic drugs on the gut mucosa.

Relationship of Urinary Serotonin Excretion to Cigarette Smoking and Respiratory Symptoms: The Normative Aging Study

The relationship of 2-h urinary excretion of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) to cigarette smoking and respiratory symptoms was examined among 631 male participants in the Normative Aging Study (age range, 44 to 85 years). The amount of serotonin excreted in urine was inversely related to age (p less than 0.001). Mean 2-h excretion of serotonin varied from 8.01 micrograms for men 40 to 49 years of age to 5.84 micrograms for those 70 years of age or over. No clear relationship was evident between the amount of 5-HIAA excreted in urine and age. After adjustment for age, current smokers were found to excrete more serotonin (p less than 0.001) and 5-HIAA (p = 0.001) than never smokers. Former smokers did not differ significantly from never smokers in these respects. After adjustment for age and smoking status in a multivariate model, chronic cough was a significant predictor of serotonin excretion (p = 0.005); chronic cough was less predictive of 5-HIAA excretion (p = 0.07). Other respiratory symptoms were unrelated to urinary excretion of serotonin and 5-HIAA. The mechanisms underlying the observed relationships of urinary serotonin and 5-HIAA excretion to smoking and to chronic cough and their potential relevance to chronic bronchitis remain to be determined.

Improved Diagnosis of Carcinoid Tumors by Measurement of Platelet Serotonin

Carcinoid patients are diagnosed biochemically on the basis of increased urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA); urinary and platelet serotonin concentrations are considered to provide complementary information. Using established HPLC methods with fluorometric detection, we evaluated the clinical usefulness of measurements of urinary 5-HIAA and urinary, plasma, and platelet serotonin in 30 consecutive patients with histologically proven carcinoid tumors of fore-, mid-, and hindgut origin before treatment. Ten patients showed no signs of serotonin overproduction; 14 had increased concentrations of urinary 5-HIAA and platelet serotonin; and platelet serotonin, but not urinary 5-HIAA, was increased in 6. None had increased urinary 5-HIAA excretion without an increase in platelet serotonin content. In cases with high rates of tumor serotonin secretion, platelet serotonin reached a maximum and did not correlate with serotonin secretion rate, whereas urinary 5-HIAA was correlated. Increased platelet serotonin was correlated with increased plasma serotonin and with occurrence of carcinoid syndrome. Increased urinary serotonin, allegedly caused by increases in circulating 5-hydroxytryptophan, almost invariably coincided with increased platelet serotonin, but not necessarily with above-normal urinary 5-HIAA excretion. From these results and long-term monitoring of three patients during treatment, we conclude that platelet serotonin is more sensitive than urinary 5-HIAA for detecting carcinoids that secrete only small amounts of serotonin.

158. Effect of salt intake on serotonin and 5-hydroxyindole acetic acid excretion in man

158. Effect of salt intake on serotonin and 5-hydroxyindole acetic acid excretion in man

Autoimmunity after Alpha-Interferon Therapy for Malignant Carcinoid Tumors

To determine the incidence of autoantibodies and autoimmune disease and their influence on therapeutic results during alpha-interferon treatment in patients with malignant midgut carcinoid tumors. Consecutive sample of patients. University hospital. One hundred thirty-five patients (70 women, 65 men; median age, 59 years) with biopsy-proven tumors, liver metastases, and no autoimmune disease. Leukocyte alpha-interferon (n = 88) or alpha-interferon 2b (n = 47) three times a week. Signs and symptoms of autoimmune disease or development of autoantibodies to thyroid antigens, nuclear antigens, or gastric parietal cells. Tumor responses were determined by reduced liver metastases or reduced urinary 5-hydroxyindole acetic acid excretion, or both. Twenty-five patients (19%) developed the following autoimmune disorders after a median of 9 months of therapy: thyroid disease (n = 18), systemic lupus erythematosus (n = 1), pernicious anemia (n = 4), and vasculitis (n = 2). Antibodies to microsomal thyroid antigen or thyroglobulin were detected in 16 patients before therapy and in another 11 patients during therapy. Antinuclear antibodies were detected in 16 patients before and in another 19 patients during therapy. Clinical thyroid disease developed in more than 60% of patients who had or developed thyroid antibodies but in only 7% of initially autoantibody-negative patients. Autoimmunity did not correlate with objective tumor response. Patients with malignant carcinoid tumors may develop autoimmune disease during alpha-interferon therapy, especially when autoantibodies are present. They should therefore be monitored for autoimmunity, which does not appear, however, to influence tumor responses.

Extended Experience with Recombinant a-2b Interferon with OR Without Hepatic Artery Embolization in the Treatment OF Midgut Carcinoid Tumours A preliminary report

Thirty-six patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily interferon therapy 5 x 10(6) IU s.c. for one or two years. All had the primary tumour removed at laparotomy, and whenever technically possible, an embolization of the hepatic arteries was performed prior to interferon start. Recombinant human alpha 2b interferon from Schering-Plough was employed. When interferon was given alone, 24% responded after one year, judged from a 50% reduction in excretion of 5-hydroxyindoleacetic acid in the urine. Three patients had died. Stable disease was found in 43%, while 19% progressed. Survival rate was 40% after 5 years from start of therapy. The median survival time from start of therapy was 3 years and 4 months. When embolization of the liver arteries had been performed prior to the start of interferon treatment, the response rate was 60% after one year, 20% had stable disease and 20% progressed. Survival rate was 75% up to 5 years of observation. We conclude that interferon is an effective treatment of malignant metastatic midgut carcinoid and that survival might be prolonged compared with historical controls. Embolization of the liver arteries seems to increase the response rate after one year. Kaplan-Meier plots suggest prolonged survival when interferon treatment is combined with embolization.

158. Effect of salt intake on serotonin and 5-hydroxyindole acetic acid excretion in man

Thlede, Hans-Michael; Sharma, Arya M.; Wengerzink, E.; Distler, Armin Author Information

Treatment of Metastatic Carcinoid Tumors and the Carcinoid Syndrome with Recombinant interferon Alpha

Fourteen patients with metastatic carcinoid tumors were treated with recombinant interferon alpha-2b at a dosage of 3-4 x 10(6) IU s.c. daily or every second day. No objective tumor regression was observed. Six out of 8 patients with carcinoids of the ileum and the caecum showed stable disease lasting for a median of 25 months (range 4-57). In 3 out of 6 patients with carcinoids of rectum, lung and of unknown primary site, stable disease was observed lasting for 2-7 months. The remaining patients had progressive disease. Six out of 9 evaluable patients had a more than 50% reduction of urinary 24 h 5-hydroxyindoleacetic acid excretion lasting for a median of 4 months (range 2-11). Decrease of flushing was noticed in 3 out of 6 evaluable patients and decrease of diarrhea in 5 out of 9 evaluable patients. In 4 patients dose reduction was necessary due to confusion and fatigue.