Generalized Cytokine Increase in the Setting of a Multisystem Clinical Disorder and Carcinoid Syndrome Associated with a Novel NLRP12 Variant.

BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms. AIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features. METHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed. RESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1ß, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10. CONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.

A prospective study of the pathophysiology of carcinoid crisis.

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.

Health-related quality of life, anxiety, depression and impulsivity in patients with advanced gastroenteropancreatic neuroendocrine tumours.

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.

Neuroendocrine tumors producing calcitonin: characteristics, prognosis and potential interest of calcitonin monitoring during follow-up.

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.

Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.

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.

Carcinoid syndrome: diagnosis and medical management.

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.

Tachykinins in carcinoid tumors: their use as a tumor marker and possible role in the carcinoid flush.

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.

The effects of octreotide on basal and stimulated hormone levels in patients with 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.

Plasma atrial natriuretic peptide in carcinoid heart disease.

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.

Pseudocarcinoid syndrome associated with hypogonadism and response to testosterone therapy.

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.

Ultrastructural cytochemistry of platelets and megakaryocytes in the carcinoid syndrome.

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.

Effect of intravenous glucose and insulin on plasma tryptophan and tyrosine concentrations in normal subjects and patients with carcinoid tumors.

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.

Acute carcinoid syndrome: a complication of flexible fiberoptic bronchoscopy.

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.

Tryptophan in the treatment of carcinoid crisis.

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.

[Effects of the administration of somatostatin 14 in the carcinoid syndrome. Clinical and biological study of 2 cases]. / Effets de l'administration de somatostatine 14 sur le syndrome carcinoïdien. Etude clinique et biologique de deux observations.

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.

[Hyperserotoninemia as a cause of symptomatic bronchial asthma]. / Hiperserotoninemia jako przyczyna objawowej astmy oskrzelowej.

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.

Circulating serotonin and bone density, structure, and turnover in carcinoid syndrome.

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.

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 (>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.