Rebecca Dobson

External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals

BACKGROUND AND AIMS Simple clinical algorithms including the fatty liver index (FLI) and lipid accumulation product (LAP) have been developed as surrogate markers for non-alcoholic fatty liver disease (NAFLD), constructed using (semi-quantitative) ultrasonography. This study aimed to validate FLI and LAP as measures of hepatic steatosis, as determined quantitatively by proton magnetic resonance spectroscopy (1H-MRS). METHODS Data were collected from 168 patients with NAFLD and 168 controls who had undergone clinical, biochemical and anthropometric assessment. Values of FLI and LAP were determined and assessed both as predictors of the presence of hepatic steatosis (liver fat>5.5%) and of actual liver fat content, as measured by 1H-MRS. The discriminative ability of FLI and LAP was estimated using the area under the receiver operator characteristic curve (AUROC). As FLI can also be interpreted as a predictive probability of hepatic steatosis, we assessed how well calibrated it was in our cohort. Linear regression with prediction intervals was used to assess the ability of FLI and LAP to predict liver fat content. Further validation was provided in 54 patients with type 2 diabetes mellitus. RESULTS FLI, LAP and alanine transferase discriminated between patients with and without steatosis with an AUROC of 0.79 (IQR=0.74, 0.84), 0.78 (IQR=0.72, 0.83) and 0.83 (IQR=0.79, 0.88) respectively although could not quantitatively predict liver fat. Additionally, the algorithms accurately matched the observed percentages of patients with hepatic steatosis in our cohort. CONCLUSIONS FLI and LAP may be used to identify patients with hepatic steatosis clinically or for research purposes but could not predict liver fat content.

Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity

Background:The term ‘metabolically healthy obese (MHO)’ is distinguished using body mass index (BMI), yet BMI is a poor index of adiposity. Some epidemiological data suggest that MHO carries a lower risk of cardiovascular disease (CVD) or mortality than being normal weight yet metabolically unhealthy.Objectives:We aimed to undertake a detailed phenotyping of individuals with MHO by using imaging techniques to examine ectopic fat (visceral and liver fat deposition) and myocardial function. We hypothesised that metabolically unhealthy individuals (irrespective of BMI) would have adverse levels of ectopic fat and myocardial dysfunction compared with MHO individuals.Subjects:Individuals were categorised as non-obese or obese (BMI ⩾30 kg m−2) and as metabolically healthy or unhealthy according to the presence or absence of metabolic syndrome.Methods:Sixty-seven individuals (mean±s.d.: age 49±11 years) underwent measurement of (i) visceral, subcutaneous and liver fat using magnetic resonance imaging and proton magnetic resonance spectroscopy, (ii) components of metabolic syndrome, (iii) cardiorespiratory fitness and (iv) indices of systolic and diastolic function using tissue Doppler echocardiography.Results:Cardiorespiratory fitness was similar between all groups; abdominal and visceral fat was highest in the obese groups. Compared with age- and BMI-matched metabolically healthy counterparts, the unhealthy (lean or obese) individuals had higher liver fat and decreased early diastolic strain rate, early diastolic tissue velocity and systolic strain indicative of subclinical systolic and diastolic dysfunction. The magnitude of dysfunction correlated with the number of components of metabolic syndrome but not with BMI or with the degree of ectopic (visceral or liver) fat deposition.Conclusions:Myocardial dysfunction appears to be related to poor metabolic health rather than simply BMI or fat mass. These data may partly explain the epidemiological evidence on CVD risk relating to the different obesity phenotypes.

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.

Diagnosing and Managing Carcinoid Heart Disease in Patients With Neuroendocrine Tumors: An Expert Statement

Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is responsible for substantial morbidity and mortality. The pathophysiology of carcinoid heart disease is poorly understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors. Despite recognition, international consensus guidelines specifically addressing the diagnosis and management of carcinoid heart disease are lacking. Furthermore, there is considerable variation in multiple aspects of screening and management of the disease. The aim of these guidelines was to provide succinct, practical advice on the diagnosis and management of carcinoid heart disease as well as its surveillance. Recommendations and proposed algorithms for the investigation, screening, and management have been developed based on an evidence-based review of the published data and on the expert opinion of a multidisciplinary consensus panel consisting of neuroendocrine tumor experts, including oncologists, gastroenterologists, and endocrinologists, in conjunction with cardiologists and cardiothoracic surgeons.

The clinical presentation and management of carcinoid heart disease

Carcinoid heart disease is a major cause of morbidity and mortality in patients with metastatic neuroendocrine tumours (NETs). Although cases of carcinoid syndrome and severe carcinoid heart disease requiring urgent intervention are well described, many patients with significant carcinoid heart disease may have insidious symptoms or even be asymptomatic. As haemodynamically significant carcinoid heart disease may be clinically silent, specific and individualised considerations must be made as to the most appropriate clinical criteria and time point at which surgical valve replacement should be undertaken in patients with carcinoid heart disease.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

Background:Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs.Methods:Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression.Results:One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l−1 increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l−1 increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%.Conclusions:The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

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 m2. 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.

Variation in Cardiac Screening and Management of Carcinoid Heart Disease in the UK and Republic of Ireland

AIMS Screening for carcinoid heart disease is an important, yet frequently neglected aspect of the management of patients with neuroendocrine tumours (NETs). Screening is advocated in international guidelines, although recommendations on the modality and frequency are poorly defined. We mapped current practice for the screening and management of carcinoid heart disease in specialist NET centres throughout the UK and Republic of Ireland. MATERIALS AND METHODS Thirty-five NET centres were invited to complete an online questionnaire outlining the size of NET service, patient selection criteria for carcinoid heart disease screening and the modality and frequency of screening. RESULTS Twenty-eight centres responded (80%), representing over 5500 patients. Eleven per cent of centres screen all patients with any NET, 14% screen only patients with midgut NETs, 32% screen all patients with liver metastases and/or carcinoid syndrome and 43% screen all patients with evidence of syndrome or raised urinary/serum/plasma 5-hydroxyindoleacetic acid (5HIAA). The mode of screening included clinical examination, echocardiography and biomarker measurement: 89% of centres carry out echocardiography, ranging from at initial presentation only (24%), periodically without clearly defined intervals (28%), annually (36%) or less than annually (12%); three centres use a scoring system to report their echocardiograms. Fifty per cent of centres utilise biomarkers for screening (chromogranins, plasma/urinary 5HIAA or most commonly N-terminal pro-brain natriuretic peptide) at varying time intervals. CONCLUSION There is considerable heterogeneity across the UK and Ireland in multiple aspects of screening and management of carcinoid heart disease.

The optimal use of cardiac imaging in the quantification of carcinoid heart disease

Carcinoid heart disease is a rare cause of right-sided valvular dysfunction, primarily mediated by serotonin. It is an important complication in patients with carcinoid syndrome and occurs in 20-50% of such patients. Echocardiography is the main technique used for the assessment of carcinoid heart disease, but other imaging modalities are also important, particularly in the quantification of the severity of the disease. We sought to review the role of cardiac imaging in the assessment of carcinoid heart disease.

Exercise training reduces the frequency of menopausal hot flushes by improving thermoregulatory control

Objective:Postmenopausal hot flushes occur due to a reduction in estrogen production causing thermoregulatory and vascular dysfunction. Exercise training enhances thermoregulatory control of sweating, skin and brain blood flow. We aimed to determine if improving thermoregulatory control and vascular function with exercise training alleviated hot flushes. Methods:Twenty-one symptomatic women completed a 7-day hot flush questionnaire and underwent brachial artery flow-mediated dilation and a cardiorespiratory fitness test. Sweat rate and skin blood flow temperature thresholds and sensitivities, and middle cerebral artery velocity (MCAv) were measured during passive heating. Women performed 16 weeks of supervised exercise training or control, and measurements were repeated. Results:There was a greater improvement in cardiorespiratory fitness (4.45 mL/kg/min [95% CI: 1.87, 8.16]; P = 0.04) and reduced hot flush frequency (48 hot flushes/wk [39, 56]; P < 0.001) after exercise compared with control. Exercise reduced basal core temperature (0.14°C [0.01, 0.27]; P = 0.03) and increased basal MCAv (2.8 cm/s [1.0, 5.2]; P = 0.04) compared with control. Sweat rate and skin blood flow thresholds occurred approximately 0.19°C and 0.17°C earlier, alongside improved sweating sensitivity with exercise. MCAv decreased during heating (P < 0.005), but was maintained 4.5 cm/s (3.6, 5.5; P < 0.005) higher during heating after exercise compared with control (0.6 cm/s [−0.4, 1.4]). Conclusions:Exercise training that improves cardiorespiratory fitness reduces self-reported hot flushes. Improvements are likely mediated through greater thermoregulatory control in response to increases in core temperature and enhanced vascular function in the cutaneous and cerebral circulations.