Higher 5-HIAA Research Articles

The role of central serotonergic markers and estradiol changes in perinatal mental health.

Women have an increased risk for mental distress and depressive symptoms in relation to pregnancy and birth. The serotonin transporter (SERT) may be involved in the emergence of depressive symptoms postpartum and during other sex-hormone transitions. It may be associated with cerebrospinal fluid (CSF) levels of the main serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). In 100 healthy pregnant women, who were scheduled to deliver by cesarean section (C-section), we evaluated 5-HIAA and estradiol contributions to mental distress 5 weeks postpartum. Eighty-two women completed the study. CSF collected at C-section was analyzed for 5-HIAA, with high performance liquid chromatography. Serum estradiol concentrations were quantified by liquid chromatography tandem mass spectrometry before C-section and postpartum. Postpartum mental distress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS). Associations between EPDS, 5-HIAA, and Δestradiol were evaluated in linear regression models adjusted for age, parity and SERT genotype. Higher levels of postpartum mental distress symptoms were negatively associated with a large decrease in estradiol concentrations (βΔE2 =0.73, p=0.007) and, on a trend level, positively associated with high antepartum 5-HIAA levels (β5-HIAA =0.002, p=0.06). In a cohort of healthy pregnant women, postpartum mental distress was higher in women with high antepartum 5-HIAA (trend) and lower in women with a large perinatal estradiol decrease. We speculate that high antepartum 5-HIAA is a proxy of SERT levels, that carry over to the postpartum period and convey susceptibility to mental distress. In healthy women, the postpartum return to lower estradiol concentrations may promote mental well-being.

Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization.

Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs ≥ 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted β = 0.010, 95% CI 0.001-0.019). In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.

Serotonin-Secreting Neuroendocrine Tumours of the Pancreas.

Background: Serotonin-secreting pancreatic neuroendocrine tumours (5-HT-secreting pNETs) are very rare, and characterised by high urinary 5-hydroxyindole-acetic acid (5-HIAA) levels (or high serum 5-HT levels). Methods: Patients with 5-HT-secreting pancreatic neoplasms observed in our unit (1986–2015) were included. Diagnosis was based on urinary 5-HIAA or serum 5-HT levels. Results: Seven patients were enrolled (4 M/3 F), with a median age of 64 (range 38–69) years. Two patients had a carcinoid syndrome. Serum 5-HT was elevated in four patients. Urinary 5-HIAA levels were positive in six patients. The median tumour size was 4.0 (range 2.5–10) cm. All patients showed liver metastases at diagnosis. None underwent resective surgery; lymph node/liver biopsies were taken. Six lesions were well-differentiated tumours and one a poorly differentiated carcinoma (Ki67 range 3.4–70%). All but one patient received chemotherapy. Four patients received somatostatin analogues; three patients underwent ablation of liver metastases. One patient is alive with disease 117 months after observation. All the others died from disease progression after a follow-up within 158 months. Conclusions: Primary 5-HT-secreting pNETs are mostly metastatic to the liver; patients are not amenable to resective surgery. Despite high 5-HIAA urinary levels, few patients present with carcinoid syndrome. A five-year survival rate of 42.9% may be achieved with multimodal treatment.

P55 Carcinoid syndrome on etanercept and subsequent treatment with secukinumab in a patient with psoriatic arthritis

Abstract Background Psoriatic arthritis requires early recognition and treatment for prevention of disease progression. Conventional disease modifying drugs are first-line agents followed by biologic DMARDs for patients with active disease. TNF-alpha blockers are first line biologic agents in the UK. Th17 inhibitors are used since the elucidation of Th17 pathway. Safety and efficacy profiles of biologic agents inhibiting the Th17 pathway, including secukinumab (IL-17A) and ustekinumab (IL-12/23p40) have been studied. Methods We report a case of carcinoid syndrome in a lady on etanercept for psoriatic arthritis, carcinoid as a potential TNF alpha side effect. We also report safety of Th17 (secukinumab) inhibitors in the patient to date (&amp;gt;1 year). Results A female with a history of acne rosacea, was diagnosed with psoriatic arthritis in 2000 age 32. Initial sulphasalazine failed, then received methotrexate until 2011, when her arthritis flared. She was commenced on etanercept which proved effective. After 4 years of etanercept and methotrexate, her liver profile became deranged. Investigations off treatment included ultrasound abdomen demonstrating a liver mass, which resembled focal nodular hyperplasia on magnetic resonance imaging. Further screening revealed high urinary 5HIAA (527 umol/24h) and raised chromogranin A &amp; B levels (1574 pmol/L and 373 pmol/L respectively). She had no symptoms suggestive of carcinoid, although facial flushing could have been camouflaged by her rosacea. Octreotide scan was positive, CT enterogram showed a distal ileal neuroendocrine tumour with adjacent lymphadenopathy. She underwent right hemihepatectomy and hemicolectomy. Her liver profile deteriorated again on methotrexate, leflunomide was ineffective. In November 2017 she was started on ustekinumab, which was ineffective and was withdrawn after 8 months. There was no alteration in carcinoid blood markers and no CT changes. In July 2018, she was commenced on secukinumab, which has allowed reduction in steroids. The patient is aware of lack of safety data in her circumstances. Regular surveillance has shown no recurrence of carcinoid with serial negative 5HIAA and chromogranin levels. There are no progressive CT changes at 1 year. Conclusion This is a case of carcinoid tumour occurring on TNF-alpha blockers and may represent a rare complication. Screening biomarkers including 5HIAA and chromogranin levels can be useful if disease is suspected. We could not find other similar case reports to guide further management. Within time limited data available - ustekinumab had no effect on the carcinoid. Th17 inhibitors can be safe options for treating psoriatic arthritis and psoriasis with highly sustained efficacy and favourable safety profile seen in large clinical trials. In this case, after &amp;gt; one year of secukinumab treatment - there is no adverse effect on carcinoid syndrome. Disclosures A.S.F. Sheikh None. S.G. Srivastva None. F. Wood None.

Maternal neglect and the serotonin system are associated with daytime sleep in infant rhesus monkeys.

Environmental and biological factors contribute to sleep development during infancy. Parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. We hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. Subjects were nursery-reared infant rhesus macaques (n = 287). During the first month of life, daytime sleep-wake states were rated bihourly (0800-2100). Infants were considered neglected (n = 16) if before nursery-rearing, their mother repeatedly failed to retrieve them. Serotonin transporter genotype and concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) were used as markers of central serotonin system functioning. t tests showed that neglected infants were observed sleeping less frequently, weighed less, and had higher 5-HIAA than non-neglected nursery-reared infants. Regression revealed that serotonin transporter genotype moderated the relationship between 5-HIAA and daytime sleep: in subjects possessing the Ls genotype, there was a positive correlation between 5-HIAA and daytime sleep, whereas in subjects possessing the LL genotype there was no association. These results highlight the pivotal roles that parents and the serotonin system play in sleep development. Daytime sleep alterations observed in neglected infants may partially derive from serotonin system dysregulation.

Behavioral, hormonal, and neurochemical outcomes of neonatal repeated shaking brain injury in male adult rats

It is well known that an abusive environment in childhood is related to individual anxiety behavior in adulthood. Though an imbalance of adrenocorticosteroid receptors and a dysfunction of monoaminergic neuron systems have been proposed, the underlying mechanisms are not fully understood. To address these problems, we recently developed a new model of shaking brain injury (SBI) in neonatal rats. These model rats showed transient microhemorrhages in the gray matter of the cerebral cortex and hippocampus. Using this model, we assessed the effects of neonatal repeated mild SBI on subsequent behavior and the stress response, and we further examined the possible contribution of adrenocorticosteroid receptors in the hippocampus and central monoaminergic neuron systems mediating such abnormalities. Behavioral screening examination with a novel open-field test showed that the rats with postnatal day (P) 3–7 shaking had significantly reduced locomotor activity and exploration behaviors than those with late (P8–14) shaking periods, indicating a critical period for neonatal SBI. In the elevated plus maze (EPM) and the light/dark transition (L/D) tests, the model rats spent less time in the open arm of the EPM and the light box of the L/D test, indicating anxiety-like behavior as adults. In adults, the novel EPM-induced adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) responses were significantly increased by neonatal SBI. Further experiments showed that the expression of mineralocorticoid receptor (MR), but not glucocorticoid receptor (GR), was significantly downregulated in the hippocampus of this model rat. These results suggest that neonatal SBI-induced downregulation of MRs in the hippocampus attenuates negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which results in abnormal secretion of ACTH and CORT. Furthermore, the neurochemical analysis showed that shaken rats had higher dopamine (DA), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and noradrenaline (NA) levels in the dorsal part of the medial prefrontal cortex (dmPFC). In the amygdala, higher 5-HIAA and lower NA levels were observed. Both areas are known to be anxiety and stress-related. Taken together, the effects of neonatal SBI on the monoaminergic systems may also be involved in the changes of behavioral and hormonal responses in this model.

TACE-Associated Hepatic Encephalopathy in the Absence of Decompensated Liver Disease

Hepatic encephalopathy is a common presentation of decompensated liver disease in patients with HCC, but occurs rarely outside the context of diffuse cirrhosis. We describe a case of severe encephalopathy in the setting of a routine TACE procedure for metastatic neuroendocrine tumor. This report seeks to raise awareness of the essential predilection for hepatic encephalopthy (HE) in patients with metastatic neuroendocrine tumor (NET), and may help to illuminate the mechanism of hepatic encephalopathy in the setting of NET. A 68 year old male with Grade II well-differentiated carcinoid tumor metastatic to the liver presented for chemoembolization of a hypervascular tumor in segment 4. He was known to have extremely high 5-HIAA and carcinoid syndrome. He had several ill-defined lesions in his liver without evidence of cirrhosis. Over the next 24 hours developed new confusion, dysarthria, and non-focal weakness. MRI was negative for any evidence of acute stroke or TIA. EEG revealed diffuse slowing and he was noted to have significant asterixis and clonus on exam. The patient did not have significantly elevated liver enzymes or fulminant hepatic failure. After several days he became increasingly obtunded with no localizing source. Lactulose was initiated for acute hepatic encephalopathy with gradual improvement in his asterixis, drowsiness, and confusion. Discussion We describe an unusual case of hepatic encephalopathy which occurred following localized chemoembolization of a NET in the absence of cirrhosis or widespread tumor burden. HE is known to occur in approximately 1% of patients with cirrhosis who undergo TACE, but occurs very rarely in the absence of cirrhosis. The exception to this is in patients with NET, who are known to have a poorly-understoond predilection for HE. In contrast to cirrhosis, patients with NET typically have well-preserved synthetic and detoxification function attributable to the remaining healthy hepatic tissue. This patient did not exhibit diffuse liver injury or elevated ammonia, but developed severe HE after TACE. This raises interesting questions about the mechanism of HE in NET -- arguing for a greater role of 5HIAA release in NET-associated HE, rather than transtumoral intrahepatic shunting of ammonia. Clinicians should be aware of the predilection towards hepatic encephalopathy in metastatic neuroendocrine tumors, and consider this etiology when neurologic symptoms arise in patients who have undergone recent embolization.2428 Figure 1 No Caption available.

Association between neuroendocrine tumors biomarkers and primary tumor site and disease type based on total 68Ga-DOTATATE-Avid tumor volume measurements.

To determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by 68Ga DOTATATE PET/CT imaging. A retrospective analysis of a prospective database of patients with NETs. Fasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total 68Ga-DOTATATE-avid tumor volume (TV) was analyzed. The analysis included 232 patients. In patients with pancreatic NETs (n = 112), 68Ga-DOTATATE TV correlated with CgA (r = 0.6, P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39), 68Ga-DOTATATE TV correlated with glucagon (r = 0.5, P = 0.01) and PP levels (r = 0.5, P = 0.049). In patients with von Hippel-Lindau (n = 24), plasma VIP (r = 0.5, P = 0.02) and PP levels (r = 0.7, P < 0.001) correlated with 68Ga-DOTATATE TV. In patients with small intestine NET (SINET, n = 74), 68Ga-DOTATATE TV correlated with CgA (r = 0.5, P = 0.02) and 5-HIAA levels (r = 0.7, P < 0.001), with 5-HIAA ≥8.1 mg/24 h associated with metastatic disease with high positive (81.8%) and negative (85.7%) predictive values (P = 0.001). 68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8, P = 0.002 and r = 0.7, P = 0.02 respectively). Our data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET.

Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders.

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.

Primary Carcinoid Tumors of the Pancreas: Report of Eight Cases

Context Primary pancreatic carcinoid tumors (foregut) are very rare. A typical carcinoid syndrome with diarrhea and flushing may be present. The diagnosis is based on the high urinary 5-HIAA (5-hydroxyndole acetic acid) levels (or high serum serotonin levels) or the immunostaining of serotonin (5-HT) in the tumor cells. Objective We evaluated clinical presentation, endocrine tumor markers, histology, therapeutic approach and follow up. Methods From 1986 to 2011 in our department we observed 211 neuroendocrine (NE) pancreatic tumors and 8 of them (3.8%) were primary carcinoid tumors (5 males and 3 females; averaging 55.8 years, range: 38-69 years). Follow up was updated until December 2012. Results Among the eight patients enrolled, 3 were symptomatic. Seven had high serum 5-HT or high urinary 5-HIAA, and one was asymptomatic with immunostaining of 5-HT in tumor cells. Location: 6 body-tail. All were malignant tumors: 7 liver and 1 single nodal metastases. Markers: 4 high serum 5-HT (up to 176 µmol/L), 7 high urinary 5-HIAA (up to 522 µmol/L). Surgery: 1 left pancreatectomy, 7 biopsy. Histology: 7 NE tumor, 1 negative pancreatic biopsy (liver metastases). Other therapy: 3 treated with somatostatin analogues (SST-A) and chemotherapy (CT), 1 CT and radiometabolic therapy after hepatic artery embolization (HAE), 1 HAE and SST-A, 1 CT. Follow up: 6 dead for disease progression (mean survival 52 months), 2 alive (1 without disease 78 months after surgery; 1 asymptomatic with high 5-HIAA 33 months after SST-A and CT). Conclusion Most of primary pancreatic carcinoids are locally advanced tumors or have liver metastases at time of diagnosis, then patients are not amenable to surgery. Although most patients had high 5-HIAA urinary excretion, few patients had carcinoid syndrome. A long term survival may be achieved with multimodal approach, including chemotherapy, in foregut carcinoid tumors.

Monoamine Neurotransmitter Metabolites in the Cerebrospinal Fluid of a Group of Hybrid Baboons (Papio hamadryas × P. anubis)

Comparatively little is known about the pathways of proximate causation that link divergent genotypes, via neurophysiological differences, to distinct, species-specific social behaviors and systems. One approach to the problem compares gross activity levels of monoamine neurotransmitters (norepinephrine, dopamine, and serotonin), evidenced by their metabolites —3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively— in cerebrospinal fluid (CSF). We have applied this method to Papio hamadryas and P. anubis, closely related baboon species with divergent social behavior, living in the Awash National Park (ANP), Ethiopia. We had previously shown that adult males of the two species differ in the ratio of HVA to 5-HIAA, and in concentrations of MHPG and HVA, but not 5-HIAA. Here, we compare monoamine metabolite levels of the parental species with those of 49 members of a naturally formed, multigenerational hamadryas × anubis hybrid group. We cage-trapped the baboons in July 1998, sampled their CSF by cisternal puncture, and assayed monoamine metabolites by high-performance liquid chromatography. Previous findings suggested, anomalously, that hybrid males showed the high 5-HIAA levels predicted by the low-serotonin–early-dispersal hypothesis (originally based on observation of rhesus macaques, Macaca mulatta), while hamadryas did not. The present study failed to find higher 5-HIAA levels in hybrids, resolving the anomaly, but leaving the previous result unexplained. Among adult females (underrepresented in our sample) and juveniles, metabolite levels of the hybrids did not differ significantly from either parental species. Overall, adult male hybrids resembled anubis in HVA and HVA/5-HIAA ratio, but did not show the low MHPG levels characteristic of that species. Consistent with a significant genetic influence on species differences in these metabolites, the adult hybrids showed intermediate means and greater intra-population diversity than the parental species for most variables, but showed no indication of hybrid dysgenesis in the form of low intermetabolite correlation. To the contrary, an enhanced HVA–MHPG correlation in the hybrids suggested a species-associated factor (not necessarily genetic) influencing both of these monoamine neurotransmitter systems.

Dosing patterns for octreotide LAR in neuroendocrine tumor (NET) patients: NCCN NET outcomes database.

4142 Background: Among patients (pts) with neuroendocrine histology, 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks is FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration is often prescribed for pts who experience refractory symptoms (e.g., flushing and/or diarrhea) on the maximal labeled dose. Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations, clinical characteristics, reasons for dose increase, and maximal dose. Results: Among 1,886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n=82) and 23% of pNET pts (n=15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. The primary tumor sites among carcinoid pts receiving above label dosing were small bowel (n=40), colorectal (n=4), and unknown (n=34). Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n=53, 65%), tumor progression (n=21, 25%), high urine 5-HIAA (n=1, 1%) and unknown (n=7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%), 40 mg every 3 weeks (15 pts, 18%), and 30 mg every 2 weeks (14 pts 17%). Among pNET pts, reasons for change included uncontrolled symptoms (n=5, 33%), tumor progression (n=9, 60%), and unknown (n=1, 7%). The most common maximal dose/frequency combinations among pNET pts were 40mg every 4 weeks (n=5, 33%), 30mg every 2 weeks (n=4, 27%), and 60 mg every 4 weeks (n=4, 27). Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.

Is urinary 5-hydroxyindoleacetic acid helpful for early diagnosis of acute appendicitis?

ObjectiveAcute appendicitis is the most common abdominal emergency in children and young adults. There are a lot of serotonin-containing cells in the appendix, which release serotonin into the bloodstream in response to inflammation. Consequently, serotonin is converted to 5-hydroxyindoleacetic acid (5-HIAA) and secreted into the urine. On this basis, urinary 5-HIAA could be a marker for acute appendicitis. In this study, we investigated the value of 5-HIAA levels in spot urine in the diagnosis of acute appendicitis. MethodsThe urinary 5-HIAA was measured by an enzyme-linked immunosorbent assay in the spot urine of 70 patients who presented to the emergency department with a clinical picture of acute appendicitis. Urine concentration results were correlated to final histopathologic reports, and the diagnostic value of this factor was measured. ResultsDiagnosis of appendicitis was confirmed by histopathologic reports in 59 of 70 patients with presumptive diagnosis of appendicitis. Considering 5.25 mg/L as the cutoff point for urinary 5-HIAA, 28 patients had high urinary 5-HIAA levels, whereas 42 patients had values within reference range. The sensitivity and specificity of this test was 44% and 81%, respectively. ConclusionsThe measurement of urinary 5-HIAA levels is not an ideal diagnostic tool for ruling out or determination of acute appendicitis.

FC04-03 - Serotonin, trauma and violence in attempted suicide

IntroductionSerotonin is implicated in impaired impulse control, aggression and suicidal behaviour. Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in violent suicide attempters, suicide victims and in violent offenders. CSF 5-HIAA concentrations have both genetic and environmental determinants. Childhood trauma may have an effect on central monoamine function as an adult.AimsThe aim of this study was to assess the relationship of CSF 5-HIAA and the exposure to and the expression of violence in childhood and during adult life measured with the Karolinska Interpersonal Violence Scale (KIVS).Methods42 medication free suicide attempters underwent lumbar puncture and were assessed with the Karolinska Interpersonal Violence Scale (KIVS) to assess history of childhood exposure to violence and lifetime expressed violent behaviour.ResultsIn women CSF 5-HIAA showed a significant negative correlation to exposure to violence during childhood. Furthermore, suicide attempters with low CSF 5-HIAA were more prone to commit violent acts as an adult if exposed to violence as a child compared to suicide attempters with high CSF 5-HIAA. In the non-traumatized group, CSF 5-HIAA showed a significant negative correlation to expressed violent behaviour in childhood.ConclusionsAlthough central serotonergic function has important genetic determinants, exposure to childhood trauma may also affect serotonergic function. Low serotonergic function may facilitate aggression dyscontrol in traumatized suicide attempters.

CSF 5-HIAA and exposure to and expression of interpersonal violence in suicide attempters

Serotonin is implicated in impaired impulse control, aggression and suicidal behaviour. Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in violent suicide attempters, suicide victims and in violent offenders. CSF 5-HIAA concentrations have both genetic and environmental determinants. Childhood trauma may have an effect on central monoamine function as an adult. The aim of this study was to assess the relationship of CSF 5-HIAA and the exposure to and the expression of violence in childhood and during adult life measured with the Karolinska Interpersonal Violence Scale (KIVS). 42 medication free suicide attempters underwent lumbar puncture and were assessed with the Karolinska Interpersonal Violence Scale (KIVS) to assess history of childhood exposure to violence and lifetime expressed violent behaviour. In women, but not in men, CSF 5-HIAA showed a significant negative correlation to exposure to violence during childhood. Furthermore, suicide attempters with low CSF 5-HIAA were more prone to commit violent acts as an adult if exposed to violence as a child compared to suicide attempters with high CSF 5-HIAA. In the non-traumatized group, CSF 5-HIAA showed a significant negative correlation to expressed violent behaviour in childhood. Although central serotonergic function has important genetic determinants, exposure to childhood trauma may also affect serotonergic function. Low serotonergic function may facilitate impaired aggression control in traumatized suicide attempters.

Long-standing malignant pancreatic carcinoid treated with octreotide

A male presented with a metastatic, plasma serotonin-secreting (high 5-HIAA in urine), malignant pancreatic carcinoid with a carcinoid-like syndrome, and was assessed using ultrasounds (US), computerized tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) and Octreoscan; he sequentially received chemotherapy, interferon and octreotide, with long-term, 12-year survival after diagnosis. Given this unusual case, the second reported in our country, the overall literature is reviewed.

Central Nervous System Serotonin and Clustering of Hostility, Psychosocial, Metabolic, and Cardiovascular Endophenotypes in Men

To use measures of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and genotype of a functional polymorphism of the monoamine oxidase A gene promoter (MAOA-uVNTR) to study the role of central nervous system (CNS) serotonin in clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes. In 86 healthy male volunteers, we evaluated CSF levels of the primary serotonin metabolite 5HIAA and MAOA-uVNTR genotype for association with a panel of 29 variables assessing hostility, other psychosocial, metabolic, and cardiovascular endophenotypes. The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those of men with less active alleles for 15 of the 29 endophenotypes. MAOA-uVNTR genotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, body mass index, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles. These findings indicate that, in men, indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, whereas decreased CNS serotonin function is associated with a less favorable profile.

Effects of group size and repeated social disruption on the serotonergic and dopaminergic systems in two genetic lines of White Leghorn laying hens

Farm practices such as increasing group size (GS) and mixing unfamiliar chickens may result in repeated social disruption (RSD) and affect the well-being of hens. To examine whether there are genetic differences in response to social stress, 2 genetic strains of White Leghorn hens were used [i.e., high group production and survivability (HGPS) and DeKalb XL commercial strain (DXL). At 50 wk of age, social stress was created by increasing GS from 4 hens (control) to 8 hens (experimental) per cage and removing hens within the stressed groups to create 4 treatments (control-HGPS, control-DXL, GS/RSD-HGPS, and GS/RSD-DXL). For RSD, 2 hens per cage were moved weekly among the experimental cages within the same treatment. At 58 wk of age, blood sample and brain were collected from 1 hen per cage (n = 10 per treatment). Whole-blood tryptophan and serotonin (5-HT) and plasma norepinephrine (NE), epinephrine (EP), and dopamine (DA) were analyzed by HPLC. The raphe nuclei and the hypothalamus (HYP) were dissected and analyzed by HPLC for the central NE, EP, DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid, 5-hydroxyindoleacetic acid (5-HIAA), 5-HT, and the ratios of DOPAC:DA and 5-HIAA:5-HT. There were no line differences in the concentrations of peripheral tryptophan, 5-HT, EP, NE, and DA in response to GS-RSD (P > 0.10). However, neuronal transmitters were regulated differently in the different central nuclei between the lines. In the raphe nuclei, control-HGPS tended to have a higher 5-HIAA:5-HT ratio than the control-DXL (P = 0.09). Concentrations of EP were increased in the DXL hens (P < 0.01), whereas the HGPS hens had decreased levels of DOPAC (P < 0.05) and DA turnover (DOPAC:DA, P < 0.01) post GS-RSD. In the HYP, compared with relative controls, there were no significant differences in the concentrations of 5-HT, whereas the levels of 5-HIAA were reduced (P < 0.01) after GS-RSD, suggesting that GS-RSD led to a lower 5-HT turnover in the HYP. The results indicate that selection for docility and productivity alters serotonergic and catecholamine homeostasis in hens in response to social stress, GS-RSD.

Plasma serotonin is a predictor for deterioration of urinary albumin excretion in men with type 2 diabetes mellitus

We performed an observational study to investigate if plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of serotonin (5-hydroxytryptamine), concentration could be a predictor for deterioration of urinary albumin excretion. The relationship between baseline plasma 5-HIAA concentration and changes in urinary albumin excretion for 24 months was investigated in 162 male patients with type 2 diabetes mellitus. Patients were divided into tertiles according to plasma 5-HIAA concentration. Greater changes in urinary albumin excretion were seen in patients with high plasma 5-HIAA concentration (112.8 ± 36.2 mg/g creatinine) than in patients with low plasma 5-HIAA concentration (7.6 ± 8.0 mg/g creatinine, P = .0011) or in patients with intermediate plasma 5-HIAA concentration (25.6 ± 15.0 mg/g creatinine, P = .0070) after adjustment for baseline values of urinary albumin excretion. A positive correlation was observed between log (plasma 5-HIAA concentration) and changes in urinary albumin excretion ( r = 0.314, P < .0001). Multiple regression analysis demonstrated that log (plasma 5-HIAA concentration) ( β = .284, P = .0013) was an independent determinant of changes in urinary albumin excretion. In conclusion, plasma 5-HIAA concentration was positively correlated with changes in urinary albumin excretion, which may indicate causality in diabetic nephropathy in male patients with type 2 diabetes mellitus and high plasma 5-HIAA concentration.

HPLC–mass spectrometry method for quantitative detection of neuroendocrine tumor markers: Vanillylmandelic acid, homovanillic acid and 5-hydroxyindoleacetic acid

Background The urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) can be increased in the presence of neuroblastic and carcinoid tumors. The former is characterized by defective catecholamine metabolism which results in high urinary levels of VMA and HVA. The latter shows an altered metabolism of tryptophan and an increased synthesis of serotonin, producing high 5-HIAA urinary concentrations. Methods We describe an HPLC-tandem mass spectrometric method for the simultaneous quantification of VMA, HVA and 5-HIAA in human urine. The chromatographic separation is performed on a reversed-phase C18 column. Instrumental analysis is performed on a Q-Trap 2000 triple quadrupole/ion trap mass spectrometer. Results The method is fast and does not require sample pre-treatment. Multiple calibration curve exhibited consistent linearity and reproducibility. Linear responses were observed in the concentration range 0–50 mg/l for each analyte. Limits of detection were 0.001 mg/l for VMA, 0.015 mg/l for 5-HIAA and 0.050 mg/l for HVA with a signal-to-noise ratio of 3. Limits of quantification were 0.005 mg/l for VMA, 0.050 mg/l for 5-HIAA and 0.1 mg/l for HVA with a signal-to-noise ratio of 10. Conclusions This method can be proposed as a tool for neuroendocrine tumor markers detection.