Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis.

Aim: Elevated serotonin in patients with neuroendocrine tumors (NETs) may impact heart failure incidence but a quantitative relationship has not been established. Materials & methods: Systematic review and meta-analysis of studies assessing 24-h urinary 5-hydroxyindoleacetic acid (u5-HIAA) and mortality in patients with NETs (2007-2017) with a primary outcome of 1-year mortality risk and 24-h u5-HIAA. Results: We identified 1715 records of which 12 studies including 755 patients (3442 person-years with 376 deaths) were eligible for meta-analysis. Mean u5-HIAA was 149.2 mg/24 h (standard deviation: 96.6) and mortality was 13.0%. The meta-regression equation showed an 11.8% (95% CI: 8.9-17.0%; I2  = 93.0%) increase in 1-year mortality for every ten-unit increase in u5-HIAA. Conclusion: Serotonin measured by its metabolite u5-HIAA is predictive of 1-year all-cause mortality in patients with NETs.

Carcinoid heart disease involving the left heart: a case report and biomarker analysis.

Herein, we report the case of a 67-year-old woman who was admitted to our hospital because of dyspnoea and oedema of the lower extremities. Transthoracic echocardiography revealed severe tricuspid and mitral regurgitation, and the leaflets of the tricuspid valve were found to be rigid and almost immobile. The plasma concentrations of serotonin and chromogranin A were elevated, and hence, suspicion for carcinoid heart disease was raised. In addition to the diagnostic workup and medical and surgical treatment, we analysed levels of novel cardiovascular biomarkers throughout the entire follow-up by means of enzyme-linked immunosorbent assay. A dopa positron emission tomography (DOPA-PET) was conducted and showed a neoplasm in the terminal ileum. Tricuspid valve replacement, mitral valve repair, and a closure of the patent foramen ovale (PFO) were conducted. Two months later, hemicolectomy and liver segment resection were performed. The tumour was resected, and the diagnosis of a neuroendocrine tumour (NET) was confirmed. Throughout the follow-up, we observed a decrease in the plasma levels of novel biomarkers [e.g. interleukin-8 (IL-8), soluble suppression of tumorigenicity-2 (sST2), and heart-type fatty acid-binding protein (H-FABP)] over the follow-up period. In our case, carcinoid heart disease resulted in a severe tricuspid regurgitation as commonly seen in these patients. Moreover, a pre-existent mitral regurgitation was likely aggravated by fibrotic remodelling, because a PFO has led to a right-to-left shunt and might have caused left heart involvement. As IL-8 was associated with adverse outcomes in patients with NETs, and sST2 and H-FABP were associated with adverse outcomes in patients with heart failure previously, these biomarkers could aid in the risk stratification of patients with NET.

Carcinoid heart disease: Diagnosis and management.

Hedinger syndrome refers to carcinoid valvular heart disease. The disease is believed to be triggered by vasoactive substances that result in valvular fibrosis. It classically occurs in patients with metastatic carcinoid and preferentially involves the right sided cardiac valves. Affected valves become thickened and retracted, exhibiting regurgitation and sometimes, stenosis. Echocardiography is recommended in patients with carcinoid syndrome and a follow up study is advisable in those who develop a murmur or other symptoms or signs of valvular heart disease. For appropriately selected patients, valve replacement surgery appears to improve outcomes.

Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement.

BACKGROUND: Neuroendocrine tumours are slow growing tumours known to secrete a variety of vasoactive peptides which give rise to symptoms of the carcinoid syndrome. The diagnosis and monitoring of patients with neuroendocrine tumours is undertaken in many centres using 24 h urinary measurement of 5-hydroxyindoleacetic acid. However, 5-hydroxyindoleacetic acid can also be quantified in plasma and serum. METHODS: We measured 5-hydroxyindoleacetic acid concentration in 134 paired EDTA plasma and urine samples from 108 patients with known neuroendocrine tumours and 26 healthy volunteers. We also compared 5-hydroxyindoleacetic acid concentrations in paired serum and plasma samples (n = 63), then analysed paired urine and serum samples (n = 97). Furthermore, we examined the impact of renal impairment on serum 5-hydroxyindoleacetic acid by analysing 5-hydroxyindoleacetic acid in patients without neuroendocrine tumours in different stages of chronic kidney disease, as indicated by the estimated glomerular filtration rate. RESULTS: Plasma and urine 5-hydroxyindoleacetic acid had very similar diagnostic sensitivities and specificities, with areas under the curve on ROC analysis of 0.917 and 0.920, respectively. Serum and plasma 5-hydroxyindoleacetic acid values showed good correlation but serum results demonstrated a positive bias, indicating the necessity for different serum and plasma reference intervals. There was an inverse correlation between estimated glomerular filtration rate and serum 5-hydroxyindoleacetic acid concentration, with 5-hydroxyindoleacetic acid increasing once the estimated glomerular filtration rate falls below 60 mL/min/1.73 m(2). CONCLUSION: The measurement of both serum and plasma 5-hydroxyindoleacetic acid can be used for the diagnosis and monitoring of patients with neuroendocrine tumours. Provided renal function is taken into consideration, either of these tests should be incorporated into standard practice as an alternative assay to urinary 5-hydroxyindoleacetic acid.

Determination of the optimal echocardiographic scoring system to quantify carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) is an important complication of metastatic neuroendocrine disease, requiring regular monitoring to enable intervention prior to right heart failure. We aimed to identify the most appropriate echocardiographic scoring systems for the quantitative assessment of CHD. METHODS: In this prospective study conducted between April and October 2012 in two European Neuroendocrine Tumor Society (ENETS) Centres of Excellence, patients with neuroendocrine tumours with liver metastases and/or carcinoid syndrome underwent transthoracic echocardiography and blood sampling for serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA). Each patient was assessed according to six echocardiographic scoring systems. The individual scoring systems' feasibility, observer variability, sensitivity, specificity and correlation with the concentration biomarkers were determined. RESULTS: 100 patients were included; 21% had echocardiographic evidence of CHD. All scores discriminated highly between those with/without CHD, with no single score performing significantly better than another. The severity, determined using all of the scoring systems, correlated with the concentration of both biomarkers, but the strongest correlations were seen between the Bhattacharyya score and serum NT-proBNP. CONCLUSION: All scoring systems are comparable in terms of sensitivity and specificity for the detection of CHD. There is a variation in the feasibility of the scoring systems due to varying complexity of the score components. All scores correlate with NT-proBNP and plasma 5-HIAA. The Westberg score appears to be the most optimal scoring system for use in screening of CHD whereas the more complex scoring systems are more suited to the patient with established disease who may require surgical intervention.

Circulating plasma and platelet 5-hydroxytryptamine in carcinoid heart disease: a pilot study.

BACKGROUND AND AIM OF THE STUDY: Carcinoid heart disease (CaHD) is a rare form of valvular heart disease in patients with carcinoid syndrome (CS). The role of 5-hydroxytryptamine (5-HT) in the pathogenesis of CaHD is unclear. The study aim was to evaluate the association between platelet 5-HT (5-HTplt) and plasma 5-HT (5-HTpls) and valvular dysfunction. METHODS: Twelve patients with CaHD, 18 with CS and 10 'normal' subjects were recruited. Patients with CaHD underwent cardiac catheterization and echocardiography. 5-HTplt and 5-HTpls was sampled in blood from the femoral vein, right and left ventricle, and left antecubital fossa vein. RESULTS: Levels of 5-HTpls and 5-HTplt were significantly higher in patients with CaHD (median 5-HTpls 325 nmol/l and 5-HTplt 18.9 nmol/10(9) platelets) and CS (median 5-HTpls 155 nmol/l and 5-HTplt 16.4 nmol/10(9) platelets) when compared to healthy controls (median 5-HTpls 9 nmol/l and 5-HTplt 3.7 nmol/10(9) platelets; p < 0.0001 and p = 0.003, respectively). There was a significant increase in 5-HTplt and 5-HTpls between the femoral vein and right heart (p = 0.007 and p = 0.0002, respectively). There was no significant difference in 5-HTplt or 5-HTpls between the right and left side of the heart, irrespective of the presence of a patent foramen ovale or of left-sided CaHD. CONCLUSION: Plasma and platelet 5-HT levels are elevated in patients with CaHD. Despite exposure to similar levels of intracardiac plasma and platelet 5-HT, the development of valve dysfunction is heterogeneous. This suggests that individual heart valves have a susceptibility to the development of valvular dysfunction which is not related solely to plasma or platelet 5-HT levels.

The association of a panel of biomarkers with the presence and severity of carcinoid heart disease: a cross-sectional study.

PURPOSE: Metastatic neuroendocrine tumors secrete serotonin and other vasoactive substances that are responsible for carcinoid syndrome and carcinoid heart disease. We sought to evaluate the discriminatory utility of diagnostic biomarkers in determining the presence and severity of carcinoid heart disease in patients with metastatic neuroendocrine tumors. PATIENTS AND METHODS: A cross-sectional study of patients with neuroendocrine tumors with documented liver metastases and/or carcinoid syndrome between April 2009-October 2012 in 5 tertiary referral centers. Serum was analyzed for Chromogranin A, Chromogranin B and N-terminal pro Brain Natriuretic Peptide (NT-proBNP). Plasma was analyzed for Neurokinin A and 5-Hydroxyindoleacetic acid (5HIAA). Echocardiography was used to determine the presence and severity of carcinoid heart disease. Non-parametric receiver operating characteristic curves were constructed for biomarkers, and the area under the curve determined. The severity of cardiac involvement was correlated with the concentration of each biomarker. RESULTS: A total of 187 patients were identified of whom 37 (20%) had carcinoid heart disease. Significantly higher median values of all biomarkers were found in the patients with cardiac involvement. NT-proBNP and plasma 5HIAA had the highest areas under the curve for the prediction of carcinoid heart disease [NT-proBNP 0.82 (95% confidence interval 0.74-0.90, p<0.0001) and 5HIAA 0.85 (95% confidence interval 0.78-0.92, p<0.0001]. NT-proBNP was moderately correlated (r = 0.48, p<0.001) whereas plasma 5HIAA was only weakly correlated (r = 0.34, p<0.001) with the echocardiographic severity score. CONCLUSION: NT-proBNP and plasma 5HIAA are both sensitive and specific biomarkers for the presence of carcinoid heart disease whereas only NT-proBNP is moderately correlated with disease severity.

Risk factors for the development and progression of carcinoid heart disease.

The development of valvular heart disease in patients with carcinoid syndrome is thought to be related to the secretion of vasoactive substances by a tumor. We sought to identify modifiable risk factors for the development of carcinoid heart disease because this may help define strategies to attenuate the disease process. Two hundred fifty-two patients with carcinoid syndrome were prospectively followed with serial echocardiograms at 6-month intervals. Clinical characteristics, biochemical markers, and radiologic markers were measured at set intervals. An echocardiographic scoring system was applied. Patients were defined as having progression of carcinoid heart disease if the echocardiographic score increased by ≥25%. After a median follow-up of 29 months, 44 patients developed carcinoid heart disease or had progression of existing valvular dysfunction. At time of progression of carcinoid heart disease compared to the previous 6 months, there was a significant increase in median levels of 5-hydroxyindoleacetic acid (5-HIAA; 791 vs 460.5 µmol/24 hours) and flushing episodes (4.5 vs 2 episodes per day). Independent predictors of the development or progression of carcinoid heart disease were a 5-HIAA level ≥ 300 µmol/24 hours and ≥ 3 episodes of flushing per day. 5-HIAA levels of ≥ 300 to 599, 600 to 899, and > 900 µmol/24 hours conferred 2.74, 3.16, and 3.40 times the risk of progression of carcinoid heart disease, respectively. In conclusion, a 5-HIAA level ≥ 300 µmol/24 hours and ≥ 3 flushing episodes per day are predictors of the development or progression of carcinoid heart disease.

Activin A in carcinoid heart disease: a possible role in diagnosis and pathogenesis.

BACKGROUND/AIMS: Carcinoid heart disease (CHD), a complication of neuroendocrine tumors (NETs), is characterized by right heart fibrotic lesions. Though serotonin is likely involved, the pathogenesis of CHD remains unclear. Cytokines and growth factors with fibrogenic properties may play a role. We sought to examine the relationship between plasma levels of fibrogenic cytokines and growth factors and CHD, both to provide further insight into possible biomarkers of CHD as well as into the possible pathogenesis of CHD. METHODS: Plasma samples obtained from 71 patients with NETs and 18 controls were analyzed using enzyme immunoassays. All patients underwent echocardiography. RESULTS: 15 patients (21%) had CHD, all of whom had carcinoid syndrome compared to 82% of those without CHD. CHD patients were older (p = 0.01), had larger (p = 0.007) and more numerous liver metastases (p = 0.04), and had elevated 24-hour urinary 5-hydroxyindoleacetic acid (U-5HIAA) (p = 0.03) and serum chromogranin A levels (p = 0.02). CHD patients had higher plasma levels of C-reactive protein (p = 0.03), osteoprotegerin (p = 0.005), and activin A (p = 0.005) than patients without CHD. A significant direct correlation between activin A and U-5HIAA levels was observed in the total patient group (r = 0.30, p = 0.02). Activin A ≥0.34 ng/ml (odds ratio (OR) 5.35 [1.01; 28.17], p = 0.048) and age ≥69.5 (OR 6.10 [1.60; 23.24], p = 0.008) were independent predictors of CHD. Activin A levels were elevated to the same degree in both early and advanced CHD. Activin A ≥0.34 ng/ml had 87% sensitivity and 57% specificity for detecting CHD (p = 0.006). CONCLUSION: Elevated plasma activin A levels are associated with the presence of CHD.

Evaluation of treatment with bosentan in patients with carcinoid heart disease: single center study.

BACKGROUND: The primary aim of this study was to evaluate a combined therapeutic intervention, including the dual endothelin receptor antagonist bosentan, in patients with carcinoid heart disease (CaHD). The efficacy of the treatment protocol was investigated using serological, echocardiographic, and clinical markers. PATIENTS AND METHODS: Since 2003, 40 patients with neuroendocrine tumours were identified; 14 had echocardiographic findings consistent with CaHD. Six of the 14 patients with CaHD and a New York Heart Association (NYHA) functional class >or= III received bosentan and were eligible for inclusion in this study. RESULTS: N-terminal pro-brain natriuretic peptide (NT-pro-BNP) had decreased 6 months after treatment with bosentan (median: 646 pg/ml vs. 400.5 pg/ml; p = 0.02); the right ventricular systolic pressure had decreased after 3 and 6 months (median: 69 mmHg vs. 61 mmHg, p = 0.02; median: 69 mmHg vs. 48.5 mmHg, p = 0.02); the 6-minute walk distance (6MWD) had significantly improved after 3 and 6 months of treatment (median: 293.5 vs. 406.5 m; p = 0.02; median: 293.5 vs. 578.5 m; p = 0.02). The NYHA functional class improved in 5/6 patients receiving bosentan. CONCLUSIONS: Combined treatment with bosentan is effective in patients with CaHD, based on functional class, 6MWD, and NT-pro-BNP. Further clarification of the CaHD fibrosis pathogenesis is needed to facilitate development of targeted antifibrotic therapeutic agents.

Chromogranin-A and N-terminal pro-brain natriuretic peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor.

PURPOSE: For the last decade chromogranin-A (CgA) has been a well-established marker for neuroendocrine tumor (NET), and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been a useful marker for left ventricular dysfunction. This study examined the diagnostic value of CgA and NT-proBNP for carcinoid heart disease (CHD), and their prognostic value for overall survival in NET patients. PATIENTS AND METHODS: Serum samples were obtained and cardiac ultrasound studies performed in 102 NET patients. The criterion for mild and severe CHD was tricuspid regurgitation stage I/II and III/IV, respectively. Proportional odds and Cox proportional hazards models were constructed respectively to identify the association between CHD and overall survival with patient characteristics and the two markers. RESULTS: Severe CHD was found in 15 (15%) of 102 patients, 13 of whom had elevated NT-proBNP levels. In the univariate proportional odds model CHD was correlated with age (P = .007), CgA (P = .002), and NT-proBNP (P < .001), whereas in the multivariate model NT-proBNP and CgA were significantly associated with CHD (P < .001 and P = .01). In the univariate Cox models, age (P = .04), sex (P = .03), CgA (P = .003), and NT-proBNP (P = .04) were related to overall survival, and in the multivariate model CgA and NT-proBNP remained significantly related to overall survival (P = .002 and P = .04, respectively). CONCLUSION: NT-proBNP and CgA are very important markers in the diagnosis of CHD in patients with NET. Furthermore, patients with elevated NT-proBNP in addition to elevated CgA levels showed worse overall survival than patients with elevated CgA alone.

Usefulness of N-terminal pro-brain natriuretic peptide as a biomarker of the presence of carcinoid heart disease.

We sought to investigate whether N-terminal pro-brain natriuretic peptide (NT-pro-BNP) can be used as a biomarker for the detection of carcinoid heart disease (CHD); 200 patients with carcinoid syndrome were screened for CHD using transthoracic echocardiography. A carcinoid score was formulated to quantify severity of CHD. NT-pro-BNP was measured in all patients before echocardiography. Patients were categorised into New York Heart Association class. CHD was present in 39 patients (19.5%). NT-pro-BNP was significantly higher in those with CHD (median 1,149 pg/ml) than in those without CHD (median 101 pg/ml, p <0.001). The sensitivity and specificity of NT-pro-BNP at a cut-off level of 260 pg/ml for detection of CHD were 0.92 and 0.91, respectively. NT-pro-BNP positively correlated both with carcinoid score (r = 0.81, p <0.001) and New York Heart Association class (p <0.001). The number of patients screened to diagnose 1 case of CHD decreased from 5.1 to 1.4. In conclusion, NT-pro-BNP seems to be an excellent biomarker of CHD. A high negative predictive value may allow it to provide a screening test for CHD.

Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography.

BACKGROUND: Although serotonin has been postulated as an etiologic agent in the development of carcinoid heart disease, no direct evidence for different ambient serotonin levels in cardiac and noncardiac patients has been reported to date. METHODS AND RESULTS: The present study reviews our experience with 604 patients in the Duke Carcinoid Database. Nineteen patients with proven carcinoid heart disease (by cardiac catheterization and/or echocardiogram) were compared with the remaining 585 noncardiac patients in the database with regard to circulating serotonin and its principal metabolite, 5-hydroxyindole acetic acid (5-HIAA). No significant demographic differences existed between the cardiac and noncardiac groups; however, typical carcinoid syndrome symptoms (ie, flushing and diarrhea) were almost threefold more common in the cardiac group (P < .001). Compared with the noncardiac group, heart disease patients demonstrated strikingly higher (P < .0001) mean serum serotonin (9750 versus 4350 pmol/mL), plasma serotonin (1130 versus 426 pmol/mL), platelet serotonin (6240 versus 2700 pmol/mg protein), and urine 5-HIAA (219 versus 55.3 mg/24 h) levels. The spectrum of heart disease among the 19 patients showed a strong right-sided valvular predominance, with tricuspid regurgitation being the most common valvular dysfunction (92% by cardiac catheterization; 100% by echocardiogram). CONCLUSIONS: These data suggest that serotonin plays a major role in the pathogenesis of the cardiac plaque formation observed in carcinoid patients.

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.

Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities.

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.

Heart involvement in metastatic carcinoid disease.

Sixteen patients with metastatic carcinoid tumors of ileal or cecal origin were studied in order to evaluate the frequency and degree of cardiac involvement in a nonselected patient group. We have also studied the correlation between plasma hormone levels (e.g., 5-hydroxytryptamine (5-HT) and substance P) and the degree of cardiac involvement. The patients underwent physical examinations, electrocardiograms, chest x-rays, cardiac catheterization, and echocardiography. Plasma levels of 5-HT and substance P were analyzed. Carcinoid heart involvement was found in 3 of 16 patients (19%) but no patient had subjective symptoms associated with heart disease. Four patients (25%) had slight pulmonary hypertension. No left-sided heart lesions were seen. No correlation between blood levels of 5-HT or substance P and heart involvement was found. Eight patients died during the follow-up period, but in none of these was the cause of death cardiac failure. Carcinoid heart disease is not as common in our patients as in patients selected on a cardiological basis described in earlier studies. Echocardiography appears to be the most efficient technique for detection of even subclinical heart involvement and a useful tool for following its progress.