5-HIAA Excretion Research Articles

Characterization of a human placental clearance system to regulate serotonin levels in the fetoplacental unit

BackgroundSerotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells.MethodsWe employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells.ResultsUsing the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance.ConclusionsTaken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs.

A Reduced Tryptophan Diet in Patients with Diarrhoea-Predominant Irritable Bowel Syndrome Improves Their Abdominal Symptoms and Their Quality of Life through Reduction of Serotonin Levels and Its Urinary Metabolites.

(1). An essential component of any treatment for patients with irritable bowel syndrome (IBS) is an adequate diet. Currently, a low FODMAP diet is recommended as a first-line therapy, but it does not relieve abdominal discomfort in all patients, and alternative nutritional treatment is required. The purpose of this study was to evaluate the effect of a tryptophan-lowering diet (TRP) on abdominal and mental symptoms in patients with irritable bowel syndrome with predominant diarrhea (IBS-D). (2). The study included 40 patients with IBS-D, and 40 healthy subjects served as a baseline for IBS-D patients, after excluding comorbidities. The TRP intake was calculated using the nutritional calculator. The severity of abdominal symptoms was assessed using the gastrointestinal symptom rating scale (GSRS-IBS). Mental state was assessed using the Hamilton anxiety rating scale (HAM-A), the Hamilton depression rating scale (HAM-D), and the insomnia severity index (ISI). The serum levels of serotonin and melatonin and the urinary excretion of their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and 6-sulfatoxymelatonin (aMT6) were determined by the ELISA method. The severity of symptoms and laboratory data were analyzed before and after a 12 week diet with tryptophan restricted to a daily dose 10 mg per kilogram body weight. (3). Compared to the control group, patients with IBS-D had a higher serum level of serotonin (198.2 ± 38.1 vs. 142.3 ± 36.4 ng/mL; p < 0.001) but a similar level of melatonin (8.6 ± 1.1 vs. 9.4 ± 3.0 pg/mL; p > 0.05). The urinary excretion of 5-HIAA was also higher in patients with IBS-D patients (7.7 ± 1.5 vs. 6.0 ± 1.7 mg/24 h; p < 0.001). After nutritional treatment, both the serum serotonin level and the urinary 5-HIAA excretion significantly decreased (p < 0.001). The severity of the abdominal symptoms and anxiety also decreased, while the HAM-D score and the ISI score remained unchanged (4). Lowering the dietary intake of tryptophan may reduce abdominal complaints and does not alter the mental state of IBS-D patients.

Application of Wastewater-Based Epidemiology for Tracking Human Exposure to Deoxynivalenol and Enniatins.

Wastewater-based epidemiology (WBE) is a promising biomonitoring approach with the potential to provide direct information on human intake and exposure to food contaminants and environmental chemicals. The aim of this study was to apply WBE while employing the normalization method for exploring human exposure to selected mycotoxins according to population biomarker 5-hydroxyindoleacetic acid (5-HIAA). This type of normalization technique has been previously used to detect various other compounds. However, to the best of our knowledge, this is the first study tracking human exposure to mycotoxins. A sensitive analytical methodology was developed to achieve reliable quantification of deoxynivalenol, enniatins, and beauvericin in wastewater (WW) samples. The applicability of the method was evaluated by testing 29 WW samples collected at WW treatment plants in Latvia. With frequency of detection greater than 86%, enniatins B, B1, A, and A1 were revealed in WW samples. The estimated total daily intake for enniatins was in the range of 1.8–27.6 µg/day per person. Free deoxynivalenol (DON) was determined in all analysed WW samples. Based on the average 5-HIAA excretion level and the determined 5-HIAA content in the samples, the intake of DON by the human population of Riga was estimated at 325 ng/kg b.w. day.

Mesenteric fibrosis and palliative surgery in small intestinal neuroendocrine tumours.

Mesenteric fibrosis (MF) surrounding a mesenteric mass is a hallmark feature of small intestinal neuroendocrine tumours (SI-NETs). Since this can induce intestinal obstruction, oedema and ischaemia, prophylactic resection of the primary tumour and mesenteric mass is often recommended. This study assessed the predictors for mesenteric metastasis and fibrosis and the effect of MF and palliative surgery on survival. A retrospective analysis of 559 patients with pathologically proven SI-NET and available CT-imaging data was performed. Clinical characteristics, presence of mesenteric mass and fibrosis on CT imaging and the effect of palliative abdominal surgery on overall survival were assessed. We found that MF was present in 41.4%. Older age, 5-HIAA excretion ≥67 μmol/24 h, serum CgA ≥121.5 μg/L and a mesenteric mass ≥27.5 mm were independent predictors of MF. In patients ≤52 years, mesenteric mass was less often found in women than in men (39% vs 64%, P = 0.002). Corrected for age, tumour grade, CgA and liver metastasis, MF was not a prognostic factor for overall survival. In patients undergoing palliative surgery, metastasectomy of mesenteric mass or prophylactic surgery did not result in survival benefit. In conclusion, we confirmed known predictors of MF and mesenteric mass and suggest a role for sex hormones as women ≤52 years have less often a mesenteric mass. Furthermore, the presence of MF has no effect on survival in a multivariate analysis, and we found no benefit of metastasectomy of mesenteric mass or prophylactic surgery on overall survival.

Incidence and prognostic value of serotonin secretion in pancreatic neuroendocrine tumours.

Serotonin secretion occurs in approximately 1%-4% of patients with a pancreatic neuroendocrine tumour (PNET), but the incidence is not well defined. The aim of this study was to determine the incidence of serotonin secretion with and without carcinoid syndrome and the prognostic value for overall survival (OS). Data were collected from 255 patients with a PNET if 24-hours urinary 5-hydroxyindoleacetic acid excretion (5-HIAA) was assessed. Patients were diagnosed with serotonin secretion if 24-hours urinary 5-HIAA excretion was more than 3× the upper limit of normal (ULN) of 50μmol/24hours during follow-up. The effect of serotonin secretion on OS was estimated with uni- and multivariate analyses using a Cox regression. Two (0.8%) patients were diagnosed with carcinoid syndrome, and another 20 (7.8%) had a serotonin-secreting PNET without symptoms. These patients mostly had ENETS stage IV disease with high chromogranin A (CgA). Serotonin secretion was a negative prognostic factor in univariate analysis (HR 2.2, 95% CI: 1.27-3.81), but in multivariate analysis, only CgA>10× ULN (HR: 1.81, 95% CI: 1.10-2.98) and neuron-specific enolase (NSE) >ULN (HR: 3.51, 95% CI: 2.26-5.46) were predictors for OS. Immunohistochemical staining for serotonin was positive in 28.6% of serotonin-secreting PNETs (one with carcinoid syndrome) and negative in all controls. Carcinoid syndrome is rare in patients with a PNET, but serotonin secretion occurs often. This is a negative prognostic factor for OS, but after correction for CgA and NSE, it is no longer a predictor and probably only a "not-so innocent bystander" in patients with high tumour burden.

A 17-year-old male with a Small Bowel Neuroendocrine Tumor: flushing differential diagnosis

Background Neuroendocrine tumors (NETs) are heterogeneous neoplasms that originate from cells with a secretory function. Small bowel NETs (SB-NETs) are related to serotonin hypersecretion which causes: flushing, diarrhea, abdominal pain, bronchoconstriction and heart involvement, also known as carcinoid syndrome (CS). CS can be confused with an allergic reaction and thus should be considered as a differential diagnosis in the allergy consult. We present the case of a pediatric patient initially referred under the suspicion of food allergies.Case presentation We present the case of a 17-year-old male with evanescent non-pruriginous erythematous lesions- flushing that appeared with food consumption, associated with conjunctival injection, warmth and diaphoresis after the lesions disappeared. He denied abdominal pain, diarrhea, cough or wheezing. The 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion was elevated. The CT scan showed thickening of the distal ileum and multiple lesions on both hepatic lobules and the colonoscopy revealed a tumor in the ileocecal valve. Hepatic and intestinal biopsies reported a well-differentiated NET of the ileocecal valve with hepatic metastasis. He was started on octreotide and underwent a wide hepatectomy and right hemicolectomy with improvement of symptoms.Conclusions NETs can present as carcinoid syndrome (flushing, diarrhea, abdominal pain, wheezing), which constitutes vague symptomatology and represents a challenging diagnosis for physicians. They can be confused with an allergic reaction and the allergist should consider it as a differential diagnosis. Accurate diagnostic tests will help to diagnose NETs earlier and potentially prevent carcinoid heart disease, bowel obstruction, and improve quality of life and mortality in these patients.

Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours.

To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers. Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2× upper limit of normal (ULN), 2-10× ULN, or >10× ULN. For neuron-specific enolase (NSE), this was the reference range or >1× ULN. OS was compared using Kaplan-Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses. A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10× ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10× ULN was a negative predictor (HR 1.62, 95% CI: 1.09-2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01-1.08), grade 3 disease (HR 5.09, 95% CI: 2.20-11.79), NSE >1× ULN (HR 2.36, 95% CI: 1.34-4.14) and CgA >10× ULN (HR 3.61, 95% CI: 1.56-8.34) remained as the predictors. Urinary 5-HIAA excretion >10× ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value.

Serotonin and melatonin secretion in postmenopausal women with eating disorders.

Postmenopausal women manifest emotional disorders associated with an increase in appetite. The aim of the study was to assess the serotonin and melatonin secretion and metabolism in postmenopausal women in relation to eating disorders. Sixty postmenopausal women and 30 women without hormonal disturbances were enrolled into the study and divided into three groups: group I (control) - women without menstrual disorders, group II - postmenopausal women without appetite disorders and change in body weight, and group III - postmenopausal women with increased appetite and weight gain. Serum melatonin, serotonin, urinary 6-sulfatoxymelatonin (aMT6s), and 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured. Serum serotonin and melatonin levels in groups II and III were lower compared to group I. Urinary 5-HIAA and aMT6s excretion was lower in overweight women. In group III the correlation between the serum level of serotonin, melatonin, and BMI was negative; a high statistical significance was found between BMI and urinary aMT6s excretion. Melatonin supplementation and use of drugs modulating the serotonin homeostasis together with female hormones have a beneficial effect in complex treatment of disorders of eating in postmenopausal women. (Endokrynol Pol 2016; 67 (3): 299-304).

The 24-Hour Urinary 5-HIAA: A Simple Test With a Common Pitfall

ABSTRACT Objective: 5-Hydroxyindoleacetic acid (5-HIAA) is the principal metabolite of serotonin, and the quantitative urinary excretion of 5-HIAA is the most useful way to diagnose serotonin overproduction by carcinoid tumors. The test carries a high specificity; however, many serotonin-rich foods, such as pineapple, banana, kiwi, and walnuts, will also increase urinary 5-HIAA excretion. We present a case which demonstrates that consumption of these foods prior to the 24-hour collection will falsely elevate the test results. Methods: Case report with literature review. Results: A 39-year-old female presented to endocrine clinic with episodes of hot “flushing.” She had no diarrhea, diaphoresis, skin rash, muscle weakness, or purple striae. Her primary doctor was concerned for carcinoid syndrome after a 24-hour urine 5-HIAA level was elevated to 22.7 mg/24 hours (normal, <6 mg/24 hours). After negative computed tomography and octreotide scans, it was felt that the patient's 24-hour urine 5-HIAA test was fa...

Microscopic Carcinoid: An Unusual Presentation of Gastric Carcnioid

51 year old Caucasian male with history of hyperlipidemia presented with complain of melena. Patient had noticed one episode of bright red blood per rectum. On questioning patient also complained of feeling tired lately with generalized body aches. He also had some numbness and tingling in both lower extremities which had been gradually worsening. Neurological exam showed decreased sensation, vibration and position sensation in both lower extremities. Digital rectal exam was positive for frank blood in rectal vault. Initial laboratory work up showed hemoglobin of 8.5 with MCV of 110. Patient underwent upper endoscopy which showed non-bleeding gastric ulcer. Also there were few scattered small focal areas of erythematous lesions in gastric cardia and proximal body with significant loss of the gastric folds. Biopsy of the lesions showed increase in fibrous tissue with moderate active inflammation of lamina propria and Chronic atrophic gastritis while rapid urease test was negative. Interestingly, carcinoid changes with chronic intestinal metaplasia were found on biopsy suspicious for carcinoid tumor. Given the finding on biopsy, fasting serum Gastrin Chromogranin A levels, Parietal cell antibodies, Intrinsic Factor antibodies, 24 hour urine for 5-HIAA, Computerized tomography (CT) scan of the abdomen and pelvis, and Octreotide scan were ordered to look for primary location of carcinoid tumor. Fasting serum Gastrin Chromogranin A levels, Parietal cell antibodies, Intrinsic Factor antibodies were found to be elevated the diagnosis of Carcinoid Tumor but there were no mass lesions but only scattered cells in the stomach. Patient subsequently underwent frequent endoscopies with biopsies which reconfirmed well differentiated carcinoid tumor cells scattered in the stomach but no mass lesion. Meanwhile patient underwent extensive work up for peripheral neuropathy and was found to have vitamin B12 deficiencies in setting of atrophic gastritis leading towards diagnosis of pernicious anemia which was likely cause of the underlying carcinoid changes. Patient is currently treated with vitamin B12 with marked improvement in his symptoms and is undergoing Surveillance endoscopies of carcinoid changes. Discussion: Carcinoid tumors Originate from Enterochromaffin-like (ECL) cells, found in gastric wall. There are three types of gastric carcinoid tumors. Type 1 are smaller and less than 1 cm, multiple, polypoid lesions with central ulceration associated with chronic atrophic gastritis and pernicious anemia. Type 2 occurs in association with gastrinomas (Zollinger-Ellison syndrome), often in setting of MEN type 1 and are mostly indolent in nature. While type 3 are Sporadic as they occur in the absence of atrophic gastritis or the Zollinger-Ellison /MEN1 syndromes and are very aggressive in nature. They are characterized by normal gastrin level. Diagnosis for carcinoid tumors include biochemical testing including urinary excretion of 5-HIAA, Chromogranin level, Blood serotonin concentration, Gastrin level and Anti parietal cell antibodies. Tumor localization is done by CT, Magnetic resonance Imaging, Octreotide scan. Type 1 and 2 are treated with endoscopic resections and survelliant endoscopies. Treatment for type 3 gastric carcinoid tumors is partial or total gatstrectomy considering the aggressive nature. Conclusions: Carcinoid tumors usually appear as discrete masses but microscopic carcinoid tumor in stomach is a very rare.

Celiac Crisis: A Rare Manifestation of a Common Disease

Introduction: Celiac crisis is a rare and life threatening manifestation of celiac disease. Case presentation: We present a 46 year old male with a history of DM1 complicated by ESRD on HD and a recent diagnosis of Bell's Palsy who was admitted from a dialysis center with hypotension and voluminous diarrhea. Reported up to 20 watery, nonbloody bowel movements per day x 7 days. The diarrhea was associated with LLQ crampy pain. Denied fevers. +Nocturnal diarrhea. The diarrhea did not improve with fasting. Denied recent weight loss.Figure 1Figure 2Figure 3Vital Signs and PE: Afebrile BP 55/42 Pulse 102. Dry mucous membranes. Mild LLQ tenderness with hyperactive bowel sounds. A rectal tube was in place with voluminous light brown watery stool identified. Inital laboratory results and imaging. 6.8/11\173. 130 | 98 | 98. 4.6 | 19 | 13.4. pH 7.27 Alb 2.9 Ca 7.2 C. Diff PCR negative CT abdomen and pelvis with IV contrast revealed mild thickening of proximal small bowel loops, suspicious for enteritis. Further pertinent labs: Stool 0 + P and culture negative. Lactoferrin: positive. ESR and CRP elevated. TTG IgA 80 (0-19). Gliadin IgA 39 (0-19). Stool Osmolar gap 36 Gastrin and VIP normal 5HIAA excretion normal. Over a 24 hour period, the patient required 13 L's of IVF's to keep up with GI losses and maintain blood pressure. An esophagogastroduodenoscopy revealed scalloping in the duodenal bulb and 2nd part of the duodenum. Biopsies were obtained and revealed villous atrophy, increased intraepithelial lymphocytes, and crypt hyperplasia (Marsh 3C). The diagnosis of celiac crisis was made based on the endoscopic and serologic results in conjuction with the dramatic presentation. After 3 days of gluten withdrawal our patients bowel movement frequency and caliber improved dramatically. Discussion: In this rare manifestation of celiac disease marked metabolic derangements are encountered. It is unclear what triggers this more aggressive disease course, however it has been suggested to be a combination of severe mucosal inflammation and immune activation.1 In our case, we propose that his recent diagnosis of Bell's Palsy precipitated an immune activation leading to the crisis. Celiac disease should be considered in adults presenting with acute voluminous diarrhea and profound electrolyte abnormalities.

Determination of urinary 5-hydroxyindoleacetic acid as a metabolomics in gastric cancer.

The aim of this paper is to study urinary5-hydroxyindoleacetic acid (5-HIAA) in gastric cancer patients with a biochemical method and compare this metabolite with normal control and individuals with chronic gastritis. The subjects were 48 histologically proven gastric adenocarcinoma patients. They were 10 women and 38 men with mean age of 63.73 years. For determination of urinary excretion of 5-HIAA, a biochemical method was applied. According to kit protocol, the patients' fresh urine was added to the reagent material, and the color of the sediment that was the result of interaction between 5-HIAA and the mercury salt was compared with the standard colorimetric plate of the kit. The same method was also performed for a group of 47 patients with chronic gastritis and also a group of 50 normal individuals (age and sex matched). Urinary 5-HIAA was significantly higher in gastric cancer patients compared to individuals with chronic gastritis and normal controls (P value <0.001), but no association was detected in urinary 5-HIAA based on age, sex, or site of tumor and tumor grade in gastric cancer patients group. Also, no significant difference was noted in 5-HIAA excretion between chronic gastritis and normal control groups. Urinary excretion of 5-HIAA is significantly higher in the gastric cancer patients in comparison with that of chronic gastritis patients or normal individuals. So, this test could be regarded as a tumor marker in conjunction with other modalities in diagnosis of gastric cancer.

Serum and ascitic fluid serotonin levels and 5-hydroxyindoleacetic acid urine excretion in the liver of cirrhotic patients with encephalopathy

The excess and deficit of serotonin can be the cause of somatic and mental disorders. The aim of this study was to evaluate serotonin levels in blood and ascitic fluid as well as excretion of 5-hydroxyindoleacetic acid (5-HIAA) in urine in patients with hepatic encephalopathy (HE). The study included 75 alcoholic cirrhotic patients divided into 3 groups (HE1, HE2, HE3), 25 patients each, with grade 1, 2 and 3 of hepatic encephalopathy according to West-Haven classification. The control group (C) included 25 clinically healthy volunteers. Venous blood and ascitic fluid were collected in fasting. On the same day a 24-hour urine collection was performed. Immunoenzymatic method was used to determine the serotonin level in serum and ascitic fluid, and 5-HIAA in urine (IBL-RE-59121, RE-59131). In the control group, mean serum serotonin level (ng/ml) was 155.5 ± 38.1 and in the 3 study groups: HE1 - 175.2 ± 32.4 (NS), HE2 - 137.2 ± 28.6 (NS), HE3 - 108.3 ± 46.3 (p<0.001). Serotonin concentration in ascitic fluid was on the average about 25% of its level in serum. The excretion of 5-HIAA in urine (mg/24h) in all groups, was: C - 5.9 ± 2.1, HE1 - 5.8 ± 1.8 (NS), HE2 - 4.8 ± 1.2(NS), HE3 - 4.3 ± 1.3 (p<0.05). The results of our study indicate that serum and ascitic fluid level of serotonin and urine excretion of 5-HIAA depends on the grade of hepatic encephalopathy. In patients with severe hepatic encephalopathy serotonin concentration in blood is decreased which can affect some clinical manifestation of this disease.

‘Sweet Dreams’, ‘Happy Days’ and elevated 24-h urine 5-hydroxyindoleacetic acid excretion

We report two patients with markedly elevated 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) excretion due to over-the-counter (OTC) self-medication with 5-hydroxytryptophan (5-HTP). It is important to recognize that OTC medication may cause increased 'false-positive' 5-HIAA excretion to prevent undue patient anxiety and unnecessary further investigation for carcinoid disease. Discordance between chromogranin A and 24-h urine 5-HIAA results should alert to the possibility of false-positive or -negative laboratory results.

Serotonin and melatonin secretion and metabolism in patients with liver cirrhosis

Hepatic encephalopathy is one of the symptoms of liver failure. The exact causes of encephalopathy are complex and still unclear. Apart from elevated blood ammonia levels, the role of numerous other factors is being considered. The aim of the study was to determine the serum level of serotonin and melatonin and the urinary excretion of their metabolites (5-hydroxyindoleacetic acid [5-HIAA] and 6-sulfatoxymelatonin [6-HMS]) in patients with various stages of liver cirrhosis. The study comprised 75 patients with alcohol-induced liver cirrhosis and 25 healthy subjects (control group). Based on the Child-Pugh classification, 3 groups of 25 patients each were distinguished - group A, B, and C with grade A, B, and C of liver failure, respectively. Blood samples were drawn at fasting at 9 a.m., and 24-hour urine collection was performed. Immunoenzymatic assays were used to determine serum melatonin and serotonin levels as well as urine 5-HIAA and 6-HMS concentrations. Serum serotonin levels were 159.8 ± 23.1 ng/ml in controls, 179.3 ± 21.1 ng/ml in group A (P >0.05), 143.2 ± 22.8 ng/ml in group B (P >0.05), and 114.5 ± 37.6 ng/ml in group C (P <0.01). Serum melatonin levels were 10.6 ± 1.7 in controls, 31.2 ± 9.8 pg/ml in group A (P <0.01), 49.8 ± 12.2 pg/ml in group B (P <0.001), and 94.8 ± 22.6 pg/ml in group C (P <0.001). Urinary 5-HIAA excretion was 5.9 ± 2.1 mg/24 h in controls, 5.9 ± 1.9 mg/24 h in group A (P >0.05), 4.8 ± 1.2 mg/24 h in group B (P >0.05), and 4.6 ± 1.4 mg/24 h in group C (P <0.05). Urinary 6-HMS excretion was 26.6 ± 15.1 μg/24 h in controls, 23.2 ± 7.9 μg/24 h in group A (P >0.05), 18.3 ± 10.6 μg/24 h in group B (P >0.05), and 6.5 ± 3.6 μg/24 h in group C (P <0.001). Disturbances in serotonin and melatonin homeostasis observed in patients with liver cirrhosis may be associated with advanced encopaholopathy.

Urinary 5-HIAA Excretion is not Increased in Patients with Head and Neck Paragangliomas

Case reports have documented carcinoid-like features in head and neck paragangliomas (HNPGLs), which, in addition to catecholamine storing granules, may also contain granules with serotonin. Serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA). To assess the urinary excretion rates of 5-HIAA and catecholamines in HNPGL patients. In 114 consecutive HNPGL patients, normetanephrine, metanephrine, norepinephrine, epinephrine, VMA, dopamine, 3-methoxytyramine and 5-HIAA excretion rates were measured in two 24-hour urinary samples. Increased excretion rates were defined as an increase of the average hormone excretion rate of 2 urine samples above the reference range. In all patients with catecholamine excess, intrathoracic and abdominal paragangliomas were excluded by 123I-MIBG scintigraphy, MRI and/or CT. Genetic screening for mutations in genes of the succinate dehydrogenase (SDH) family was performed. Mean urinary 5-HIAA excretion rate was 14±9 μmol/24 hours (reference range 10-44 μmol/24 hours). Urinary 5-HIAA excretion was slightly increased in only 1 patient (48 μmol/24 hours). None of the 50 patients (44%) with increased urinary excretion rates of catecholamines and/or their metabolites had elevated 5-HIAA excretion. Urinary 5-HIAA excretion is within the normal reference range in almost all HNPGL patients. Therefore, this parameter has no clinical relevance in the routine clinical assessment of HNPGL patients.

5-HIAA excretion is not associated with bone metabolism in carcinoid syndrome patients

In patients with a carcinoid syndrome and neuroendocrine tumors of the digestive tract (carcinoids), elevated circulating serotonin (5-hydroxytryptamine, 5-HT) levels can be demonstrated. It can be hypothesized that bone metabolism will be affected in these patients, since serotonin receptors are expressed on bone cells and serotonin effects on bone have been demonstrated. However, to date, no data are available on bone metabolism parameters in patients with neuroendocrine tumors of the digestive tract (carcinoids). In the current retrospective study we have measured serum bone formation markers P1CP (pro-collagen type I C-terminal), and osteocalcin, and the bone resorption marker NTx (collagen breakdown product N-terminal), in a group of 61 carcinoid patients with increased circulating serotonin levels as demonstrated by increased excretion of the serotonin breakdown product, 5-hydroxy indole acetic acid (5-HIAA), in the urine (>50μmol/24h, so-called “hyper-secretors”) and a control group of 23 carcinoid patients, without increased 5-HIAA excretion (so-called non-secretors). The 24-h urinary excretion of 5-HIAA reflects the 24-h production of serotonin. Measurements of markers of bone metabolism were performed in serum samples obtained before the start of medical treatment. The hypersecretor group had on average a 10-fold higher urinary 5-HIAA excretion than the control (non-secretor) group. No significant differences in bone metabolism parameters could be demonstrated between hyper-secretors and controls (non-secretors). Correlation and regression analyses could not demonstrate significant age- and sex-adjusted correlations between urinary 5-HIAA excretion and any of the markers for bone turnover. A limitation is that the exposure time to elevated levels of serotonin is unknown, which might have been too short to induce effects on bone metabolism. Treatment of human pre-osteoblasts SV-HFO with serotonin didn't change alkaline phosphatase activity throughout differentiation as well as mineralization.In conclusion, the current study in a unique group of untreated carcinoid patients could not demonstrate a major role for circulating serotonin in the control of bone metabolism.

Chromogranin A as Serum Marker for Gastroenteropancreatic Neuroendocrine Tumors: A Single Center Experience and Literature Review

The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio) during routine follow-up in the years 2000–2009. CgA showed a higher sensitivity for midgut (68%) than pancreatic (54%) NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs.

Urinary Excretion of 5-Hydroxy-3-Indoleacetic Acid in Dystimic/Depressed, Adult Obese Women: What Correlations to Hepatic Steatosis?

The synthesis of serotonin at CNS level is influenced by diet. Moreover, insulin resistance is associated with lower serotonin levels. Visceral obesity, strictly linked to hepatic steatosis is specifically associated with mild to severe somatic affective-depressive symptom clusters. Previous data support the view that depression involves serotonergic systems, reflecting low levels of urinary 5- hydroxy-3-indoleacetic acid (5-HIAA). The 24-h urinary excretion of 5-HIAA was evaluated in 76 dystimic/depressed, obese/overweight females, divided into two groups, i.e., on a hyper-caloric diet, associated with a life style characterized by leisure time sedentary behavior (LTSB, 35 women), or on a normo-caloric diet, assisted by program-based strategies aimed at promoting physical activity participation (PAP, 41 women). Beck Depression Inventory (BDI) was carried out to score the severity of dystimia/depression. Anthropometric measures, metabolic indices, severity of hepatic steatosis at sonography and HOMA were studied. Urinary levels of 5-HIAA in controls and PAP groups were comparable with a great overlap, while in the LTSB group the urinary excretion of 5-HIAA was significantly reduced in respect to that of the PAP group and obviously compared to that of the control group, 3.4±1.4 mg/L versus 6.2±2.7 mg/L and 6.4±2.6 mg/L, respectively, ANOVA test, P= 0.001. Among metabolic indices, cholesterol, HDL-cholesterol, triglycerides and uric acid were not able to predict urinary concentrations of 5-HIAA, which were not associated with hepatic steatosis; vice versa, ferritin levels, and mainly HOMA values, were independent predictors of the urinary excretion of 5-HIAA (β=0.235 and 0.45, respectively). Dystimia/depression severity was negatively predicted by urinary 5-HIAA levels in the sense that the highest BDI values were forecast by the lowest values of urinary 5-HIAA (β= -0.72).The importance of measuring the 24-h urinary excretion of 5-HIAA in follow-ups could rely on a method simultaneously mirroring the well-being status, the adherence to physical activity, which leads to improved insulin sensitivity, and the eating habits acquired by dystimic/depressed overweight/obese patients. In contrast, the significance of the urinary 5-HIAA is reduced in evaluating the severity of hepatic steatosis, likely because it is a structured process.

LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin

LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10(-8) -10(-7) mol L(-1) range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750 mg q.i.d.; the median T(1/2) for elimination is ∼ 20 h, and repeat administration for 14 days doubles C(max) . In ascending-single-dose and multiple-dose (14 days) trials in healthy volunteers, LX-1031, 2-4 g day(-1) significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14 day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4 weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.