Michiel N. Kerstens

6-[F-18]Fluoro-l-Dihydroxyphenylalanine Positron Emission Tomography Is Superior to Conventional Imaging with 123I-Metaiodobenzylguanidine Scintigraphy, Computer Tomography, and Magnetic Resonance Imaging in Localizing Tumors Causing Catecholamine Excess

CONTEXT Catecholamine excess is rare, but symptoms may be life threatening. OBJECTIVE The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET), compared with (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess. DESIGN AND SETTING All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible. PATIENTS Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three. MAIN OUTCOME MEASURES Sensitivities and discordancy between (18)F-DOPA PET, (123)I-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of (18)F-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard. RESULTS (18)F-DOPA PET showed lesions in 43 patients, (123)I-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for (18)F-DOPA PET, (123)I-MIBG, and CT/MRI was 90, 65, and 67% (P < 0.01 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 1.0 (123)I-MIBG vs. CT/MRI). Lesion-based sensitivities were 73, 48, and 44% (P < 0.001 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 0.51 (123)I-MIBG vs. CT/MRI). The combination of (18)F-DOPA PET with CT/MRI was superior to (123)I-MIBG with CT/MRI (93 vs. 76%, P < 0.001). Whole-body metabolic burden measured with (18)F-DOPA PET correlated with plasma normetanephrine (r = 0.82), urinary normetanephrine (r = 0.84), and metanephrine (r = 0.57). CONCLUSION To localize tumors causing catecholamine excess, (18)F-DOPA PET is superior to (123)I-MIBG scintigraphy and CT/MRI.

Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical‐risk profiles. Presentation, age‐dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4–86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon‐associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. Hum Mutat 31:1–8, 2010.

111In-Octreotide Is Superior to 123I-Metaiodobenzylguanidine for Scintigraphic Detection of Head and Neck Paragangliomas

In this study, we evaluated the diagnostic yield of somatostatin receptor scintigraphy (SRS), I-metaiodobenzylguanidine (MIBG) scintigraphy, and morphologic imaging (CT or MRI) in patients with head and neck paragangliomas. Methods: In a university hospital setting, patients considered to have head and neck paraganglioma were referred to the outpatient endocrinology department and underwent CT or MRI, SRS, and MIBG imaging. For validation, we used a composite reference standard consisting of clinical and histologic data and CT or MRI, with which SRS and MIBG imaging were compared. Urinary metanephrine and normetanephrine measurements were also obtained. Results: Twenty-nine consecutively referred patients (17 women and 12 men) were included and were found to have paraganglioma. Both morphologic and SRS were positive in 27 patients (sensitivity, 93%, and 95% confidence interval [CI], 77%–98%, compared with the composite reference standard), whereas MIBG was positive in only 13 patients (44%; 95% CI, 23%–61%) (P < 0.001, compared with SRS). On a lesion-based analysis, morphologic imaging detected 31 lesions (sensitivity, 82%; 95% CI, 65%–92%), SRS detected 34 (89%; 95% CI, 75%–97%), and MIBG detected 15 (42%; 95% CI, 26%–59%). SRS was superior to MIBG (P = 0.001). With SRS, a previously unknown carcinoid tumor was detected in 1 patient, and a carcinoid was suspected in another patient. MIBG detected an additional adrenal pheochromocytoma in 1 patient. Urinary metanephrine or normetanephrine excretion was elevated in 6 patients. The number of lesions on SRS and MIBG per patient correlated with the levels of abnormal metanephrine or normetanephrine excretion (P = 0.005 and P = 0.02, respectively). Conclusion: SRS was superior to MIBG in patients with highly suspected head and neck paraganglioma.

Adrenocortical carcinoma: A population-based study on incidence and survival in the Netherlands since 1993

BACKGROUND The reported annual incidence of adrenocortical carcinoma (ACC) is 0.5-2.0 cases per million individuals. Updated population-based studies on incidence are lacking. The aim of this nationwide survey was to describe the incidence and survival rates of ACC in the Netherlands. Secondary objectives were to evaluate changes in both survival rates and the number of patients undergoing surgery. METHODS All ACC patients registered in the Netherlands Cancer Registry (NCR) between 1993 and 2010 were included. Data on demographics, stage of disease, primary treatment modality and survival were evaluated. RESULTS Included were 359 patients, 196 of whom were female (55%). Median age at diagnosis was 56 years (range 1-91). The 5-year age-standardised incidence rate decreased from 1.3 to 1.0 per one million person-years. Median survival for patients with stage I-II, stage III and stage IV disease was 159 months (95% confidence interval (CI) 93-225 months), 26 months (95% CI: 4-48 months) and 5 months (95% CI: 2-7 months), respectively (P<0.001). Improvement in survival was not observed, as reflected by the lack of association between survival and time of diagnosis. The percentage of patients receiving treatment within 6 months after diagnosis increased significantly from 76% in 1993-1998 to 88% in 2005-2010 (P=0.047), mainly due to an increase in surgery for stage III-IV patients. CONCLUSION These nationwide data provide an up-to-date survey of the epidemiology of ACC in the Netherlands. A trend towards a decreasing overall incidence rate was observed. Survival rates did not change during this period despite an increased number of surgical procedures.

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency

Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial

BACKGROUND The distinction between unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia as causes of primary aldosteronism is usually made by adrenal CT or by adrenal vein sampling (AVS). Whether CT or AVS represents the best test for diagnosis remains unknown. We aimed to compare the outcome of CT-based management with AVS-based management for patients with primary aldosteronism. METHODS In a randomised controlled trial, we randomly assigned patients with aldosteronism to undergo either adrenal CT or AVS to determine the presence of aldosterone-producing adenoma (with subsequent treatment consisting of adrenalectomy) or bilateral adrenal hyperplasia (subsequent treatment with mineralocorticoid receptor antagonists). The primary endpoint was the intensity of drug treatment for obtaining target blood pressure after 1 year of follow-up, in the intention-to-diagnose population. Intensity of drug treatment was expressed as daily defined doses. Key secondary endpoints included biochemical outcome in patients who received adrenalectomy, health-related quality of life, cost-effectiveness, and adverse events. This trial is registered with ClinicalTrials.gov, number NCT01096654. FINDINGS We recruited 200 patients between July 6, 2010, and May 30, 2013. Of the 184 patients that completed follow-up, 92 received CT-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist) and 92 received AVS-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist). We found no differences in the intensity of antihypertensive medication required to control blood pressure between patients with CT-based treatment and those with AVS-based treatment (median daily defined doses 3·0 [IQR 1·0-5·0] vs 3·0 [1·1-5·9], p=0·52; median number of drugs 2 [IQR 1-3] vs 2 [1-3], p=0·87). Target blood pressure was reached in 39 (42%) patients and 41 (45%) patients, respectively (p=0·82). On secondary endpoints we found no differences in health-related quality of life (median RAND-36 physical scores 52·7 [IQR 43·9-56·8] vs 53·2 [44·0-56·8], p=0·83; RAND-36 mental scores 49·8 [43·1-54·6] vs 52·7 [44·9-55·5], p=0·17) for CT-based and AVS-based treatment. Biochemically, 37 (80%) of patients with CT-based adrenalectomy and 41 (89%) of those with AVS-based adrenalectomy had resolved hyperaldosteronism (p=0·25). A non-significant mean difference of 0·05 (95% CI -0·04 to 0·13) in quality-adjusted life-years (QALYs) was found to the advantage of the AVS group, associated with a significant increase in mean health-care costs of €2285 per patient (95% CI 1323-3248). At a willingness-to-pay value of €30 000 per QALY, the probability that AVS compared with CT constitutes an efficient use of health-care resources in the diagnostic work-up of patients with primary aldosteronism is less than 0·2. There was no difference in adverse events between groups (159 events of which nine were serious vs 187 events of which 12 were serious) for CT-based and AVS-based treatment. INTERPRETATION Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. This finding challenges the current recommendation to perform AVS in all patients with primary aldosteronism. FUNDING Netherlands Organisation for Health Research and Development-Medical Sciences, Institute of Cardiology, Warsaw.

Randomized Trial on the Influence of the Length of Two Insulin Pen Needles on Glycemic Control and Patient Preference in Obese Patients with Diabetes

OBJECTIVE This study determined the influence of needle length for insulin administration on metabolic control and patient preference in obese patients with diabetes mellitus. METHODS In this multicenter, open-label crossover study, insulin pen needles of two different lengths (5 mm and 8 mm) were compared. A total of 130 insulin-treated type 1 and type 2 diabetes patients with a body mass index ≥30 kg/m(2) were randomized, and 126 patients completed the study. Patients started using the 5-mm needle for 3 months, after which they switched to injecting insulin with the 8-mm needle for another 3 months, or vice versa. Hemoglobin A1c (A1C), fructosamine, and 1,5-anhydroglucitol were measured, and self-reported side effects and patient preference were recorded. RESULTS No within-group changes were observed with respect to A1C, serum fructosamine, 1,5-anhydroglucitol, hypoglycemic events, bruising, and pain. When data of all 126 subjects were pooled, there was a small, but significant, difference between needle lengths (5-mm, A1C 7.47 ± 0.9%; 8-mm, 7.59 ± 1.0%; P = 0.02). Patients reported less bleeding with the 5-mm needle (P = 0.04) and less insulin leakage from the skin with the 8-mm needle (P = 0.01). There were no significant differences in patient preference, with 46% of the patients preferring the 5-mm needle, 41% the 8-mm needle, and 13% not preferring a particular needle length. CONCLUSIONS A 5-mm needle is similar to an 8-mm needle in obese patients with diabetes with respect to metabolic control, injection-related complaints, or patient preference and can be used safely.

Short-term moderate sodium restriction induces relative hyperfiltration in normotensive normoalbuminuric Type I diabetes mellitus.

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is associated with an increased extracellular volume. Sodium restriction might seem a logical form of treatment but data on its renal effects is conflicting. We therefore studied the effects of sodium restriction on renal haemodynamics in uncomplicated Type I diabetes mellitus. Methods. Uncomplicated Type I diabetic patients (n = 24) and matched control subjects (n = 24) were studied twice in random order: after a week of 50 mmol or after 200 mmol sodium intake, respectively. The diabetic patients were studied under normoglycaemic clamp conditions. Glomerular filtration rate and effective renal plasma flow were measured as the clearances of iothalamate and hippuran, respectively. Results. During liberal sodium intake, glomerular filtration, effective renal plasma flow and filtration fraction were similar between the diabetic patients and the control subjects. Sodium restriction decreased the effective renal plasma flow in both groups, whereas glomerular filtration rate only decreased in the control subjects. Consequently, in the diabetic patients, the filtration fraction was increased on low sodium (4.1 ± 8.4 %, p < 0.05 vs liberal sodium). As a consequence, filtration fraction (24.0 ± 2.6 vs 22.1 ± 2.0 %, p < 0.05) and glomerular filtration (119 ± 14 vs 110 ± 13 ml/min, p < 0.05) were higher in the diabetic patients than in the control subjects during sodium restriction. Conclusion/interpretation. Short-term moderate sodium restriction induces relative hyperfiltration in uncomplicated Type I diabetes. This could indicate an increased intraglomerular pressure. Sodium restriction could be an unfavourable preventive approach in diabetes mellitus but its long-term effects are not known. [Diabetologia (2002) 45: ▪–▪]

Pubertal Presentation in Seven Patients with Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

Adolescents with oxidoreductase deficiency present with impaired pubertal development, manifesting in girls with hypergonadotropic hypogonadism and ovarian cysts while boys may show delayed but spontaneous pubertal progression.

Reference Values for Aldosterone-Renin Ratios in Normotensive Individuals and Effect of Changes in Dietary Sodium Consumption

BACKGROUND Determination of the aldosterone-to-renin ratio (ARR) in blood is the preferred screening test for primary aldosteronism. Renin can be measured as the plasma renin activity (PRA) or the plasma renin concentration (PRC). Consequently, the ARR can be measured either based on the PRA (ARR(pra)) or based on the PRC (ARR(prc)). In contrast with the ARR(pra), the data on reference values for the ARR(prc) are limited. Moreover, whether the ARR(pra) or ARR(prc) is affected by variations in salt intake is unknown. METHODS We measured the PRA, the PRC, and serum aldosterone in 100 normotensive individuals between 20 and 70 years of age before and after a 3-day oral sodium-loading test (SLT). Participants were stratified according to age and sex. Data are presented as the median and interquartile range (IQR). RESULTS Urinary sodium excretion after the SLT was ≥200 mmol/24 h in all participants. Serum aldosterone, PRA, and PRC values were significantly reduced after the SLT. PRC and PRA results were highly correlated [Spearman rank correlation r(s) = 0.80 and 0.74 before and after SLT, respectively; P < 0.001 for both]. The central 95% reference intervals for ARR(pra) before and after SLT were 0.07-1.45 h(-1) and 0.06-1.84 h(-1), respectively. The corresponding reference intervals for ARR(prc) were 4.1-81.3 pmol/ng and 3.9-74.8 pmol/ng. The median ARR(prc) decreased after the SLT from 19.5 pmol/ng (IQR, 13.0-29.4 pmol/ng) to 18.6 pmol/ng (IQR, 9.4-27.1 pmol/ng) (P = 0.005), whereas the median ARR(pra) did not change (P = 0.12). Both the ARR(prc) and ARR(pra) at baseline were higher in women than in men, whereas no sex difference was observed after sodium loading. CONCLUSIONS We present reference values for the ARR(prc) for healthy individuals. The ARR is affected to a variable degree by sex and sodium intake.