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Background: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis., Methods: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay., Results: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises., Conclusion: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To compare health-related quality of life (HRQoL), anxiety, depression, and impulsivity scores in patients with and without carcinoid syndrome (CS), and correlated them with serum 5-hydroxyindoleacetic acid (5-HIAA) levels., Methods: Patients with advanced gastroenteropancreatic neuroendocrine tumours (GEPNET), with and without CS completed HRQoL QLQ-C30 and QLQ-GI.NET21, Hospital Anxiety and Depression Scale (HADS) and Barratt Impulsivity Scale (BIS) questionnaires. Two-sample Wilcoxon test was applied to assess differences in serum 5-HIAA levels, two-sample Mann-Whitney U test for HRQoL and BIS, and proportion test for HADS, between those with and without CS., Results: Fifty patients were included; 25 each with and without CS. Median 5-HIAA in patients with and without CS was 367nmol/L and 86nmol/L, respectively ( P = 0.003). Scores related to endocrine symptoms were significantly higher amongst patients with CS ( P = 0.04) and scores for disease-related worries approached significance in the group without CS, but no other statistically-significant differences were reported between patients with and without CS in responses on QLQ-C30 or QLQ-GI.NET21. Fifteen patients (26%) scored ≥ 8/21 on anxiety scale, and 6 (12%) scored ≥ 8/21 on depression scale. There was no difference in median 5-HIAA between those scoring < or ≥ 8/21 on anxiety scale ( P = 0.53). There were no statistically significant differences between groups in first or second-order factors (BIS) or total sum ( P = 0.23)., Conclusion: Excepting endocrine symptoms, there were no significant differences in HRQoL, anxiety, depression or impulsivity between patients with advanced GEPNET, with or without CS. Over one quarter of patients had high anxiety scores, unrelated to peripheral serotonin metabolism., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to declare.

Objectives: Inappropriate calcitonin (CT) release, a major feature of medullary thyroid cancer (MTC), may occur in neuroendocrine tumors (NETs). The aims of this retrospective study were to assess i) the characteristics and prognosis of CT-producing NETs, and ii) the value of CT monitoring during follow-up., Methods: All patients with NETs in whom serum CT was assayed between 2010 and 2012 were included. MTCs were excluded. Clinical, biological, and histological characteristics were studied., Results: Twenty-one (12%) of 176 patients in whom serum CT was systematically assayed had concentrations >100  ng/l, with tumours predominantly of bronchial or pancreatic origin (P<0.0001), and of high grade (P=0.0006). Poor prognosis was linked to high CT levels, poor differentiation, and grade 3. In a total group of 24 patients with serum CT >100  ng/l, symptoms potentially attributable to CT were recorded in eight, with occasional overlap with the carcinoid syndrome among other secretory syndromes. Immunohistochemistry could be performed in six tumor specimens, CT being detected in five. In 11 patients with five or more successive CT assays, hormone levels were fairly well correlated with clinical courses., Conclusion: Serum CT levels may be raised in some patients with NETs, especially from foregut origin, and of high grade. The suggested value of CT monitoring during follow-up must be confirmed in further studies., (© 2016 European Society of Endocrinology.)

Context: Gut-derived serotonin has been proposed as a regulator of bone formation, and inhibition of gut serotonin synthesis increases bone formation in rodents. Carcinoid neuroendocrine tumors can produce very high levels of circulating serotonin and so offer a model of serotonin excess in humans., Objectives: The objective of the study was to determine whether patients with carcinoid syndrome have lower bone formation markers, lower bone density, or poor bone structure compared with healthy controls., Design: We conducted a cross-sectional study of 25 patients with carcinoid syndrome and 25 healthy controls, individually matched to carcinoid patients by gender, age, height, and body mass index., Outcome Measures: We measured circulating serotonin in blood and plasma and 5-hydroxyindoleacetic acid (5HIAA) in plasma and urine. We measured lumbar spine and hip bone mineral density by dual-energy x-ray absorptiometry, the distal radius and tibia with high-resolution peripheral quantitative computed tomography, and bone turnover with serum osteocalcin, amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX)., Results: All measures of serotonin and 5HIAA were higher in carcinoid patients than in controls. No measures of bone density or bone structure differed significantly between cases and controls. Osteocalcin was higher in the cases than controls (26.0 vs 21.1 ng/mL, P = .02). PINP and CTX did not differ between cases and controls. In patients with carcinoid syndrome, plasma 5HIAA was positively correlated with osteocalcin. In controls, whole-blood serotonin was positively correlated with osteocalcin, PINP, and CTX (R values = 0.40-0.47, all P < .05.)., Conclusions: High circulating serotonin in carcinoid syndrome is not associated with clinically significant lower bone density, poorer bone structure, or lower bone formation markers.

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 (>50 μmol/24 h, 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs)., Method: TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients., Results: All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels., Conclusion: We found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is, to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.

Gastro-intestinal carcinoids are slow growing tumors arising from enterochromaffin or Kulchitsky cells. Their clinical presentation depends on what combination of bioactive substances is secreted. Midgut carcinoid can present with the carcinoid syndrome in the presence of liver metastases. Its most typical clinical manifestations include cutaneous flushing and diarrhea. A nonspecific biochemical tumor marker for carcinoid tumors is serum chromogranin A and a specific marker for the carcinoid syndrome is the increased urinary excretion of 5-hydroxy indole acetic acid (5-HIAA). Localizing studies in carcinoid tumors/syndrome are: transabdominal ultrasonography (US), endoscopy, endoscopic US, videocapsule endoscopy, computerized tomography, magnetic resonance imaging, selective abdominal angiography, 111In-pentetreotide scintigraphy (and intraoperative radionuclide probe), 123I (131I)-metaiodobenzylguanidine (MIBG) scintigraphy, bone scintigraphy and 11C-5-HT positron emission tomography (PET). Therapies for carcinoid tumors/syndrome are: surgery, somatostatin analogs, interferon-alpha, radiotherapy, liver dearterialization, liver (chemo, or radio)-embolization, alcohol sclerotherapy of liver metastases, radiofrequency ablation of liver metastases, cryosurgery of liver metastases, occasionally liver transplantation, radiotherapy-coupled somatostatin analogs, 131I-MIBG and occasionally chemotherapy.

Objective: Carcinoid cancer patients often have elevated levels of serotonin or its precursor 5-hydroxytryptophan. Normally, serotonin synthesis accounts for a small fraction of tryptophan catabolism, which should be directed along a pathway that allows partial conversion to niacin; hence, increased diversion of tryptophan toward serotonin could cause variable degrees of niacin deficiency in carcinoid patients. Therefore, the prevalence of niacin deficiency among carcinoid patients was investigated by clinical assessment of pellagra and biochemical assessment of whole blood niacin number, a ratio derived from two biologically active forms of niacin (NAD/NADP x 100)., Methods: Clinical and biochemical niacin status were assessed in a cohort of newly diagnosed carcinoid patients with carcinoid syndrome (CCS, n = 36), carcinoid patients without carcinoid syndrome (CWCS, n = 32) and noncarcinoid controls (n = 24) recruited at two primary care clinics. Other aspects of serotonin metabolism were measured by analyses of plasma serotonin and tryptophan and urinary excretion of 5-hydroxyindoleacetic acid., Results: Biochemical niacin deficiency (niacin number < 130) was significantly more common in CCS patients (10 out of 36) compared to controls (p < 0.05, Fisher's exact test), while CWCS patients displayed an incidence that was not significantly elevated (4 out of 32). Only one CCS patient, who was also identified biochemically as niacin deficient, was clinically diagnosed with pellagra., Conclusion: Biochemical niacin deficiency is more prevalent among newly diagnosed CCS patients than in controls. Manifestation of pellagra is a less sensitive indicator, and dependence on this endpoint could lead to a lack of appropriate nutritional support for this group of patients.

Asthma-like symptoms, infrequently, may be secondary to other diseases like: gastro-esophageal reflux, allergic bronchial-pulmonary aspergillosis, Churg-Strauss syndrome, sarcoidosis or carcinoid syndrome. The diagnosis is often made after months of unsuccessful treatment. The authors discuss clinical picture and diagnostic problems in case of symptomatic bronchial asthma in course of hyperserotoninemia.

Purpose: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing., Patients and Methods: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population., Results: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups., Conclusion: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.

Objectives: Previous studies showed increased plasma motilin and substance P concentrations and accelerated motor function in the small bowel and colon in patients with carcinoid diarrhea. Octreotide is beneficial in patients with carcinoid syndrome. Our hypothesis was that octreotide inhibits accelerated motility and gut neuropeptides in carcinoid syndrome., Methods: In 12 patients with metastatic carcinoid syndrome, we investigated the effect of octreotide 50 microg s.c. t.i.d (n = 6) or placebo (n = 6) on postprandial symptoms, GI transit, colonic motility, and circulating levels of selected circulating peptides and amines., Results: Octreotide reduced postprandial flushing (p = 0.03) but not pain. Octreotide significantly retarded overall colonic transit and proximal colonic emptying (p < 0.05); it tended to prolong small bowel transit time (p = 0.13) and to reduce postprandial colonic tone (p = 0.08) compared with placebo. Octreotide also reduced circulating levels of peptide YY, neurotensin, vasoactive intestinal polypeptide, and substance P but had no effect on plasma motilin, neuropeptide Y, calcitonin gene-related peptide, or histamine after meal ingestion., Conclusion: Octreotide ameliorates gut motor dysfunctions that characterize carcinoid diarrhea; the potential role of specific antagonism of serotonin, substance P, and vasoactive intestinal polypeptide alone or in combination with agents that inhibit their release in carcinoid diarrhea deserves further study.

Objective: To characterize a disorder of episodes of flushing and increased levels of 5-hydroxyindoleacetic acid (5-HIAA) in men with secondary hypogonadism who respond to testosterone therapy., Material and Methods: We present detailed case reports of three male patients who had flushing, secondary hypogonadism, and increased urinary 5-HIAA levels and describe their clinical and laboratory features before and after treatment with testosterone. In addition, six male patients with hypogonadism (three with primary and three with secondary hypogonadism) without flushing were assessed., Results: The three patients with flushing and secondary hypogonadism (serum total testosterone 5.45 +/- 0.63 nmol/L, free testosterone 89.3 +/- 7.0 pmol/L, follicle-stimulating hormone 3.85 +/- 0.58 IU/L, and luteinizing hormone 4.41 +/- 0.98 IU/L) had increased urinary 5-HIAA levels (98.5 +/- 12.2 micromol/24 h) but normal blood serotonin levels (9.66 +/- 1.58 micromol/L). During a pentagastrin-calcium stimulation test, serum calcitonin and blood serotonin values were normal in patients with secondary hypogonadism and flushing. Detailed investigation showed no evidence of a carcinoid tumor. Urinary 5-HIAA levels became normal (16.6 +/- 1.73 micromol/24 h) after treatment with testosterone. When testosterone therapy was discontinued in two patients, flushing and increased urinary 5-HIAA levels recurred. Furthermore, flushing and the elevated urinary 5-HIAA values resolved when testosterone treatment was reinitiated. The six patients with hypogonadism without flushing had normal urinary 5-HIAA levels (14.9 +/- 3.31 micromol/24 h)., Conclusion: Male patients with flushing and increased urinary 5-HIAA levels should undergo assessment for hypogonadism after screening for carcinoid tumor. If hypogonadism is diagnosed, resolution of flushing and normalization of 5-HIAA may be achieved with testosterone treatment. We suggest that pseudocarcinoid syndrome associated with hypogonadism be the descriptive label used for this combination of clinical features.

Background/aims: Serotonin is the diagnostic hallmark of midgut carcinoids, but the pathophysiology of spontaneous flushing is unknown. The aim of this study was to assess to what extent serotonin and catecholamine blood levels are related in time with spontaneous midgut carcinoid flush., Methods: Using specific radioenzymatic assays, we measured prospectively before, during, and after spontaneous flushing platelet-poor plasma and whole blood serotonin and plasma catecholamines and their metabolites in 10 patients with primary midgut carcinoids. Blood was drawn simultaneously from a forearm vein and an external jugular vein draining the flushing area., Results: During flushing, plasma serotonin and norepinephrine levels increased (P < 0.001) over preflush levels at both sampling sites. Intraflush serotonin and norepinephrine were twice as high (P < 0.01) in external jugular (9.57 +/- 1.40 ng/mL and 857 +/- 33 pg/mL, respectively) than in antecubital plasma (4.59 +/- 0.73 ng/mL and 471 +/- 26 pg/mL). Preflush and postflush levels were similar at both venous sites., Conclusions: Vein plasma serotonin and norepinephrine levels do increase during midgut carcinoid flush, especially in the flushing area. This may reflect a local release secondary to flush but also suggests a role for these bioamines in the pathogenesis of flushing.

We monitored long-term (median 11 months) concentrations of platelet serotonin and urinary serotonin, 5-hydroxyindoleacetic acid, and seven catecholamine metabolites in 44 patients with carcinoid tumors. Tumor serotonin and catecholamine contents (11 patients) and urinary histamine and N-methylhistamine (15 patients) were determined. Consistently increased concentrations of indoles, notably platelet serotonin, were observed in 96%, 43%, and 0% of patients with mid-, fore-, and hindgut carcinoids, respectively. Urinary dopamine metabolites, notably 3-methoxytyramine, were consistently increased in 38%, 20%, and 7% of patients with mid-, hind-, and foregut carcinoids, respectively. For urinary norepinephrine/epinephrine metabolites, notably normetanephrine and metanephrine, these data were 33%, 20%, and 14%, respectively. Midgut carcinoid tumors had the highest serotonin contents, whereas concentrations of catecholamines were independent of primary localization. There was no consistent relation between biogenic amine contents in tumors and urinary excretion of the amine metabolites. Occurrence of carcinoid syndrome was related to increased serotonin production rate. Increased histamine production is not an important feature in patients with lung carcinoids or liver-metastasized ileum carcinoids.

Endocrine cells of the GI tract derive from stem cells of the neurocrest. They belong to the diffuse endocrine system as defined by Feyrter and share common features, such as the capacity for APUD cells. From these regulatory peptide-producing cells, endocrine tumors may develop with specific clinical symptoms. In some other endocrine GI tumors, no hormone secretion has yet been found, and for some regulatory peptides, no specific clinical entity has yet been identified. Diagnosis can be confirmed by hormone measurements and by specific immunohistochemistry or electron microscopy of the tumor tissue. Metastases synthesize and secrete peptide hormones like those of the primary tumors. The principal target organ for metastases is the liver. Several approaches to treatment of hepatic tumor deposits may reduce tumor mass with consequent reduction of effective plasma hormone levels. There are also systemic treatments for neuroendocrine tumors from the GEP system.

The effects of synthetic cyclic somatostatin 14 were studied in two patients with the carcinoid syndrome. The 3-hour intravenous administration of somatostatin (250 micrograms X h-1), a) resulted in the disappearance of flushing in the first patient but was without any clinical effect in the second subject who remained chronically colored; b) lowered plasma levels of motilin, prostaglandins (E1, E2 and F2 alpha) and to a lesser extent of catecholamines in both patients whereas the serotonin level was not altered; c) was followed by a rebound effect with recurrence of severe flushing in the first patient and was associated with a dramatic increase of prostaglandin, substance P and catecholamine levels in both patients. The inhibitory effect of somatostatin and the occurrence of a rebound effect at the end of infusion were confirmed by infusing somatostatin (6 mg per day) during 48 h in the first patients. These results: a) show that somatostatin is an effective drug in carcinoid syndrome with severe flushing; b) confirm that several mediators are affected in carcinoid syndrome. However it could not be excluded that increased circulating levels of prostaglandins, substance P and catecholamines may represent unrelated secondary events; c) suggest that somatostatin primarily inhibits the release rather than the synthesis of tumor products. Owing to the severity of the rebound effect, treatment of the carcinoid syndrome with somatostatin must be undertaken with precaution until specific long-acting analogs are available.

Release of hormones peri-operatively in patients with metastatic carcinoids may lead to severe circulatory and respiratory disturbances. Fourteen patients with liver metastases were studied during 16 operations with a modified neurolept anaesthesia in order to evaluate the central haemodynamic and respiratory functions as well as plasma serotonin levels. The premedication in five patients was supplemented with levopromazine. During the 11 operations performed on patients not pretreated with levopromazine, no major significant fluctuations in circulatory or respiratory functions were recorded although big variations in serotonin plasma levels were measured. In the patients treated with levopromazine, however, significant changes were observed in heart rate, mean pulmonary artery pressure, cardiac index, and left and right ventricular stroke work especially during flushing episodes. However, these changes did not correlate with the changes in plasma serotonin levels. Modified neurolept anaesthesia without levopromazine pretreatment combined with careful monitoring seems to be a safe procedure for carcinoid patients. Using this type of anaesthetic procedure only one major complication occurred in connexion with 16 major operations and then in the postoperative period.

We report the case of a patient with functioning bronchial carcinoid tumor found as a solitary nodule. Acute carcinoid syndrome developed during transbronchial biopsy, and life-threatening hypotension occurred during operation. We emphasize that carcinoid tumors should be considered in the differential diagnosis of solitary nodules, and such a complication should be kept in mind when endobronchial or transbronchial biopsy is performed.

This simplified determination of serotonin in human plasma involves "high-performance" liquid chromatography with electrochemical detection. Deproteinated samples of platelet-poor plasma are injected directly into the chromatograph without preliminary chromatographic purification. The limit of quantitative detection of serotonin in plasma is 5 nmol/L (equivalent to 250 fmol injected). Intra- and inter-assay CVs ranged from 5.6% to 7.7% and 3.5% to 14.9%, respectively, for concentrations of serotonin from 0.02 to 10.0 mumol/L. Results agreed well with those by spectrofluorometry, both for plasma standards (r = 0.985, range 100 nmol/L to 100 mumol/L) and for pathological samples obtained from four carcinoid syndrome patients (r = 0.964). The method is also applicable to the concurrent measurement of 5-hydroxytryptophan and 5-hydroxyindoleacetic acid.

Detailed studies of protein metabolism were undertaken in a patient with pellagra and hypoproteinemia associated with the carcinoid syndrome both before and after treatment. The synthesis of albumin improved from 82 mg per kg per day to 135 mg per kg per day with little change in the daily excretion of 5-hydroxyindole acetic acid. After treatment with nicotinamide the patient made good progress with a complete resolution of the signs of pellagra and protein malnutrition. These results support the hypothesis that a reduced availability of the essential amino acid L-tryptophan may limit the synthesis of albumin and nicotinic acid in patients with the carcinoid syndrome who become anoretic.

A 56-year-old woman was admitted with carcinoid crisis and became comatose. Blood tryptophan at this stage was 5 micrograms/ml; after treatment with 3.4 g tryptophan daily her level of consciousness improved and blood tryptophan increased to 10 micrograms/ml. The carcinoid syndrome was not exacerbated by tryptophan. Tryptophan may have a supportive role in the management of carcinoid crisis.

The levels of 5-hydroxytryptamine (serotonin, 5-HT) and substance P (SP) were assayed (using high performance liquid chromatography-electron capture and radioimmunoassay methods) in the peripheral blood of 17 patients with known mid-gut carcinoids, 16 of whom had hepatic metastases. All patients had supranormal basal levels of 5-HT and SP. The clinical and hormonal changes induced by two provocation tests, intravenous pentagastrin (PG) and calcium infusion, were compared. Pentagastrin caused flushing in all the patients, induced gastrointestinal symptoms in all but one of the patients with hepatic involvement, and universally elevated circulating 5-HT levels. Pretreatment with a 5-HT2-receptor blocking agent, ketanserin, abolished the gastrointestinal effects but had virtually no influence on either 5-HT levels or flushing induced by intravenous pentagastrin. In contrast, calcium infusion induced carcinoid symptoms in only two of six patients, and this was consistently associated with stimulation of circulating serotonin levels. The authors conclude that 1) 5-HT may be responsible for the gastrointestinal symptoms in carcinoid patients, but it does not seem to play any role in flushing; 2) ketanserin may be a useful therapeutic agent in alleviating gastrointestinal symptoms in carcinoid patients; 3) differential responses to PG suggests that SP is released from a site different from that of 5-HT; 4) it is possible that SP may contribute to the mediation of flushing, but it cannot be the sole agent causing this symptom; and 5) the pentagastrin test with measurements of 5-HT levels in peripheral blood seems to be superior to calcium infusion as a provocative test in documenting the diagnosis of carcinoid disease.

Six patients with the carcinoid syndrome (C.S) had serum luteinizing hormone (LH) concentrations that were greater than age and sex matched control subjects. The serum follicle stimulating hormone (FSH) and testosterone concentrations of the groups did not differ. Four of the 5 C.S. patients tested had an increase in serum testosterone after human chorionic gonadotropin administration and 5 of the 5 subjects tested had an increase in serum LH after clomiphene citrate administration. One of the 4 subjects treated with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA) had a reduction in serum testosterone. He was also receiving methysergide. The other 3 subjects treated with PCPA did not have any persistent alterations in serum testosterone.

The plasma concentrations of various tachykinins were measured before and during flushing episodes in 16 patients with metastatic carcinoid tumors. The flushing attacks were induced by iv injection of pentagastrin or ingestion of food or alcohol. Tachykinins, such as neurokinin A (NKA) and neuropeptide K (NPK), increased 2-fold during flushing episodes in 12 patients, and the plasma concentrations of substance P increased to a varying extent in 3 patients. Chromatographic analysis of plasma samples taken before and during flushing episodes in 2 patients indicated the presence of individual spectra of tachykinins. In addition, the plasma concentration of tachykinin [TKLI(K12)], using an assay that detects NKA, NPK, kassinin, eledoisin, and NKB, but not substance P and physalaemin, and the urinary excretion of 5-hydroxyindole acetic acid (5-HIAA) were measured in 20 patients with midgut carcinoid tumors before and during treatment with human leucocyte interferon. The overall changes in the 2 tumor markers were concordant in 18 of the 20 patients. Thus, the Spearman correlation coefficient between the percent changes in urinary 5-hydroxyindole acid excretion and plasma TKLI(K12) was 0.54 (P less than 0.001). The patients who had a decrease in the tumor markers also had a decrease in flushing episodes and diarrhea. Plasma TKLI(K12) is a convenient tumor marker for the diagnosis and follow-up of patients with carcinoid tumors of midgut origin. The combined use of both tumor markers strengthens the diagnosis and may improve the evaluation of response during treatment.

We evaluated the effect of intravenous (i.v.) glucose on the plasma tryptophan (TRP) and tyrosine (TYR) concentration of 12 normal subjects, six patients with carcinoid tumors and the carcinoid syndrome (carcinoid syndrome), and five patients with carcinoid tumors without the carcinoid syndrome (tumor.) Following i.v. glucose administration, the plasma Trp concentration of the normal subjects and the tumor patients incresed, while the plasma Trp concentration of the carcinoid syndrome patients decreased. Following i.v. glucose administration, the plasma Tyr concentration of the normal subjects and the tumor patients decreased, while the plasma Tyr concentration of the carcinoid syndrome patients did not change. The response to i.v. insulin differed in some respects from the response to i.v. glucose: the plasma Trp of normal subjects did not change while the plasma Trp of carcinoid syndrome patients decreased; the plasma Tyr of the normal subjects increased while the plasma Tyr concentration of the carcinoid syndrome patients did not change. The carcinoid syndrome patients had high serum serotonin concentrations and impaired glucose tolerance and insulin secretion as compared to both normal subjects and tumor patients. We conclude that under appropriate experimental conditions, glucose administration can increase the plasma Trp concentration of normal human subjects.

Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed.

Plasma atrial natriuretic peptide (ANP) concentration was determined and cardiac ultrasound studies were performed in 50 patients with malignant mid-gut carcinoid tumors. The extent of carcinoid-related heart disease varied among the patients. The patients with the most severe right-sided heart disease, who often had signs of right ventricular failure, had significantly (p less than 0.001) higher plasma ANP concentrations than either patients with less or no abnormal ultrasound findings or age- and sex-matched healthy control subjects. ANP levels were serially determined for 0.5 to 4 years (median 2.1) in 12 patients. The levels increased above the reference range in patients with clinical findings of right ventricular failure. In patients without cardiac decompensation the levels remained within the reference range. In 3 patients who had successful tricuspid and pulmonary valve replacements, signs and symptoms of right ventricular failure disappeared and plasma ANP levels declined and normalized. Five patients with progressive right ventricular failure and increasing plasma ANP levels during follow-up eventually died from cardiac decompensation. This study demonstrates the predictive value of serial determinations of plasma ANP in carcinoid heart disease. Such measurements can be an additional guide in the clinical management of these patients.

Bradykinin and structurally related peptides are potent vasodilators and a role for these kinins in the aetiology of the carcinoid flush has been proposed. Using an antiserum directed against the COOH-terminal region of bradykinin in radioimmunoassay, the concentrations of bradykinin-like immunoreactivity in extracts of peripheral blood were compared in patients with carcinoid syndrome (n = 11) and healthy subjects (n = 6). In the fasted state, the concentrations of bradykinin-like immunoreactivity in the patients (10 +/- 5 ng/l) were not significantly different from the concentrations in healthy subjects (6 +/- 3 ng/l). An intravenous injection of pentagastrin (0.6 micrograms/kg) provoked a flush of differing degrees of severity in all patients. In four patients, the flush was concurrent with large rises (277-, 26-, 11- and 10-fold over mean basal values) in bradykinin-like immunoreactivity that was resolved by high performance liquid chromatography into lysyl-bradykinin and bradykinin (approximate ratio 1:2). In two patients, small rises in immunoreactivity (2.4- and 1.7-fold) occurred after the flush and in the remaining five patients no rise in bradykinin-like immunoreactivity was measured. In the healthy subjects, the pentagastrin injection did not provoke a flush and no rises in bradykinin-like immunoreactivity were observed. The data support earlier results obtained using bioassays that the carcinoid flush in some patients is associated with the appearance in blood of bradykinin-related peptides. It has been shown, however, that these kinins cannot be the sole causative agent of the flush. It is suggested, therefore, that the aetiology of the flush is probably multi-factorial.

We treated nine patients who had carcinoid tumors of the small intestine, six of whom had the carcinoid syndrome, with daily intramuscular doses of leukocyte interferon--3 X 10(6) U per day for one month and 6 X 10(6) U per day for another two months. Seven patients had previously been treated with streptozocin and fluorouracil, without benefit. Treatment with interferon ameliorated the manifestations of the carcinoid syndrome and led to prompt and continuing decreases in urinary levels of 5-hydroxyindoleacetic acid and serum levels of human chorionic gonadotropin subunits and pancreatic polypeptide in all six patients with liver metastases, but it had no clear effect in two of three patients with only lymph-node involvement. After the treatment period, five of the six responders had relapses in clinical manifestations and increases in hormone levels. We conclude that interferon is of benefit in treating metastatic small intestinal carcinoid tumors in patients with the carcinoid syndrome.

The carcinoid syndrome, a common feature of small intestinal carcinoid tumors with liver metastases, includes flushing, diarrhea, bronchoconstriction, and right heart failure. The etiology of the carcinoid syndrome is not well understood, but serotonin seems to be involved in the diarrhea, whereas tachykinins may play a role in the flush reaction. In a double blind placebo-controlled study, we studied the effect of octreotide in 20 patients with midgut carcinoid tumors and liver metastases. A sc injection of 50 micrograms octreotide caused a significant (P less than 0.001) decrease in median plasma tachykinins and serum pancreatic polypeptide, GH, and insulin for up to 4 h. Administration of octreotide (50 micrograms, twice daily, sc) caused a 26% decrease in urinary 5-hydroxyindoleacetia acid excretion, but the number of flushing attacks or bowel movements did not change significantly. A typical flush was provoked by pentagastrin, and plasma tachykinin and serotonin levels were measured. The flush reaction was graded on a 10-point visual analog scale. Octreotide (50 micrograms, sc) given 45 min before flush stimulation prevented tachykinin release completely and significantly reduced the median flushing score from 8.5 to 2. Placebo administered in the same way did not prevent tachykinin release after pentagastrin administration. Thus, octreotide prevents pentagastrin-induced flushing and the related hormonal changes in patients with the carcinoid syndrome.

To determine if patients with chronic hyperserotoninaemia from the carcinoid syndrome have increased basal adrenocortical function, I have determined the urinary free cortisol excretion of seventeen patients with carcinoid tumours and the carcinoid syndrome, twelve patients with carcinoid tumours without the carcinoid syndrome and seventeen normal subjects. There was no significant difference in the urinary free cortisol excretion of the patients with carcinoid tumours and the carcinoid syndrome (133 +/- 20.0 nmoles/24 h), patients with carcinoid tumours without the carcinoid syndrome (115 +/- 29 nmoles/24 h) and the normal subjects (96 +/- 9 nmoles/24 h). There was no correlation between the urinary free cortisol secretion and urinary 5-hydroxyindoleacetic acid or serum serotonin concentration in the patients with the carcinoid syndrome. There was a suggestion that patients with 5-hydroxytryptophan (5-HTP) secreting carcinoid tumours had higher urinary free cortisol excretion than patients with predominantly serotonin (5-HT) secreting carcinoid tumours. This may be due to the fact that the non-polar 5-HTP molecule penetrates the blood-brain barrier more effectively than the polar 5-HT molecule. 5-HTP is then converted to 5-HT within the brain. None of the twenty-nine patients with carcinoid tumours had clinical or laboratory evidence of the ectopic ACTH syndrome.

Cardiac ultrasound investigation of 68 prospectively studied patients with histologically proven midgut carcinoid tumors showed right heart disease in 66%. The abnormal findings included morphologic and functional aberrations of the tricuspid valve in 52% and 83%, respectively, right atrial and ventricular enlargement in 53% and 30%, and paradoxical systolic septal contractions in 19%. The patients with the most pronounced right heart disease had significantly higher (p less than .01) plasma levels of the tachykinins neuropeptide K and substance P as well as higher (p less than .001) urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid. These patients also had the most extensive tumor disease. The occurrence of echocardiographic abnormalities of the left heart was similar to that in healthy individuals of the same age, but abnormalities were less frequent among the patients with severe right heart disease. Electrocardiographic changes were nonspecific. Right heart disease thus seems to be present more often than previously reported in patients with malignant midgut carcinoid tumors. The severity of cardiac involvement does not seem to be related to the duration of carcinoid disease but more to the extent of the disease, i.e., higher plasma levels of serotonin and tachykinins.

Platelets and megakaryocytes from 11 patients with the carcinoid syndrome have been studied by transmission electron microscopy. Cells fixed in phosphate-buffered glutaraldehyde are oval to discoid, with pseudopods, a dilated open-channel system, and a prominent dense tubular system as defined by peroxidase activity and alkaline bismuth stain. Atypical with hexagonal lattices and treaded substructures and large (diameter greater than 0.5 mum), phosphatase-positive, debris-containing vacuoles are four times more numerous than in normal platelets. Incubation of platelets in a 0.05% suspension of latex results in particle incorporation into phagosomes and the debris-containing vacuoles. Molybdate-dichromate stain reveals two classes of dense bodies, one of which (with a reticular core) is 20 times more numerous than in normal platelets. Bone marrow megakaryocytes lack both dense bodies and debris vacuoles analogous to those found in circulating platelets. These results suggest autophagy or endocytosis abnormalities and provide evidence for multiple types of dense bodies in carcinoid platelets.

Plasma tryptophan (Trp) is reported to be decreased in some patients with the carcinoid syndrome. To determine if the plasma levels of other amino acids are also altered in the carcinoid syndrome, we used a fas-liquid chromatographic method to determine the plasma amino acid concentration of nine patients with the carcinoid syndrome and nine age-matched healthy control subjects. In comparison to the control subjects, the patients with the carcinoid syndrome had decreased plasma concentration of valine (Val), isoleucine (Ile), lysine (Lys), and ornithine (Orn), and an increased plasma concentration of methionine (Met). With the exception of a decrease in urinary excretion of proline (Pro) and hydroxyporline (Hyp), the patients with the carcinoid syndrome had normal quantities of amino acids in their urine. Plasma Met returned to normal when serotonin production by the tumor was reduced 60% by parachlorophenylalanine (PCPA); the other amino acid abnormalities persisted. Further studies are needed to determine the significance of these amino acid abnormalities.

The effect of a 550-kcal mixed meal and of an intravenous injection of pentagastrin (0.06 microgram/kg body wt) upon peripheral blood serotonin concentrations has been compared in 10 carcinoid patients with hepatic metastases and healthy subjects. The fasting concentrations of blood serotonin in the patients (range 790-4500 ng/ml) were elevated compared with healthy subjects (range 71-310 ng/ml; n = 15). Urinary output of 5-hydroxyindole acetic acid was elevated in 8 patients but was in the healthy range for 2 patients. The healthy subjects (n = 9) responded to food with an increase in blood serotonin (maximum rise over mean basal of 32% +/- 4%) that was significant at 60, 75, 90, and 105 min postcibal. All carcinoid patients responded to food with a comparable (25% +/- 11% over basal) rise in serotonin but the pattern of release was erratic. All patients with tumor metastases exhibited symptoms of the carcinoid flush after eating, but there was no correlation between occurrence and severity of the flush and occurrence and magnitude of the rise in serotonin. Intravenous pentagastrin evoked a flush in all carcinoid patients, but there was no significant increase in peripheral blood serotonin either in the patients or in healthy subjects.

Serotonin and substance P circulate in high concentrations in patients with the carcinoid syndrome. These studies were performed to evaluate the effects of intravenous infusions of serotonin and substance P to reproduce carcinoid levels of these agents on central hemodynamics, regional blood flow (using the radioactive microsphere technique), and endogenous hormone release. Serotonin did not affect mean arterial pressure but it significantly increased cardiac output, decreased systematic vascular resistance, and redistributed regional blood flow, increasing blood flow to the heart, adrenals, fundus, and antrum. Substance P significantly decreased mean arterial pressure and systemic vascular resistance, increased cardiac output, and increased blood flow to adrenal, fundus, antrum, liver, and all muscular layers of the stomach and small bowel. Neither serotonin nor substance P affected skin blood flow, nor altered circulating levels of glucose, insulin, or gastrin. Although both of these agents seem to participate in the pathogenesis of the carcinoid syndrome, our studies suggest that it is not possible to ascribe all the hemodynamic abnormalities to either.

Bradykinin concentrations in peripheral venous blood were measured in seven patients with carcinoid syndrome. The diagnosis was based on typical symptoms and raised urinary excretion of 5-hydroxy-3-indole acetic acid; the carcinoid tumour was verified histologically. Two patients were flushing constantly and the other patients had flushing attacks two to 10 times daily. Several blood samples were taken at weekly intervals from six of seven patients. During 30 sampling procedures the patients were flushing during sampling in 12 instances. Bradykinin was measured by a sensitive solid phase radioimmunoassay technique. Blood bradykinin concentration was normal in all patients. Bradykinin is unlikely to be the vasoactive mediator of flushing.