Roland Därr

Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions.

To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine.

Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma

Background Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochro-mocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. Methods Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. Results Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. Conclusions These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.

Pheochromocytoma - update on disease management

Pheochromocytomas are rare endocrine tumors that can present insidiously and remain undiagnosed until death or onset of clear manifestations of catecholamine excess. They are often referred to as one of the ‘great mimics’ in medicine. These tumors can no longer be regarded as a uniform disease entity, but rather as a highly heterogeneous group of chromaffin cell neoplasms with different ages of onset, secretory profiles, locations, and potential for malignancy according to underlying genetic mutations. These aspects all have to be considered when the tumor is encountered, thereby enabling optimal management for the patient. Referral to a center of specialized expertise for the disease should be considered wherever possible. This is not only important for surgical management of patients, but also for post-surgical follow up and screening of disease in patients with a hereditary predisposition to the tumor. While preoperative management has changed little over the last 20 years, surgical procedures have evolved so that laparoscopic resection is the standard of care and partial adrenalectomy should be considered in all patients with a hereditary condition. Follow-up testing is essential and should be recommended and ensured on a yearly basis. Managing such patients must now also take into account possible underlying mutations and the appropriate selection of genes for testing according to disease presentation. Patients and family members with identified mutations then require an individualized approach to management. This includes consideration of distinct patterns of biochemical test results during screening and the appropriate choice of imaging studies for tumor localization according to the mutation and associated differences in predisposition to adrenal, extra-adrenal and metastatic disease.

Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma

BACKGROUND Reports conflict concerning measurements of plasma metanephrines (MNs) for diagnosis of pheochromocytomas/paragangliomas (PPGLs) by immunoassays compared with other methods. We aimed to compare the performance of a commercially available enzyme-linked immunoassay (EIA) kit with liquid chromatography-tandem mass spectrometric (LC-MS/MS) measurements of MNs to diagnose PPGLs. METHODS In a substudy of a prospective, multicenter trial to study the biochemical profiles of monoamine-producing tumors, we included 341 patients (174 males and 167 females) with suspected PPGLs (median age 54 years), of whom 54 had confirmed PPGLs. Plasma MNs were measured by EIA and LC-MS/MS, each in a specialized laboratory. RESULTS Plasma normetanephrine (NMN) and MN were measured 60 and 39% lower by EIA than by LC-MS/MS. Using upper cut-offs stipulated for the EIA, diagnostic sensitivity was only 74.1% at a specificity of 99.3%. In contrast, use of similar cut-offs for MN and overall lower age-adjusted cut-offs for NMN measured by LC-MS/MS returned a diagnostic sensitivity and specificity of 98.1 and 99.7%. Areas under receiver-operating characteristic curves, nevertheless, indicated comparable diagnostic performance of the EIA (0.993) and LC-MS/MS (0.985). Diagnostic sensitivity for the EIA increased to 96.2% with a minimal loss in specificity (95.1%) following use of cut-offs for the EIA adapted to correct for the negative bias. CONCLUSIONS The EIA underestimates plasma MNs and diagnostic sensitivity is poor using commonly stipulated cut-offs, resulting in a high risk for missing patients with PPGLs. Correction of this shortcoming can be achieved by appropriately determined cut-offs resulting in comparable diagnostic performance of EIA and LC-MS/MS assays.

Combined Use of 68Ga-DOTATATE and 18F-FDG PET/CT to Localize a Bronchial Carcinoid Associated with Ectopic ACTH Syndrome

Division of Endocrinology, Department of Medicine III (R.D., G.E., V.K., S.R.B., L.C.H.), Department of Nuclear Medicine (K.Z.), Institute of Clinical Chemistry and Laboratory Medicine (G.E.), Institute for Diagnostic Radiology (N.A.), Department of Surgery (J.G.), and Institute of Pathology (K.W.), Dresden Technical University Medical Center, 01307 Dresden, Germany; and Department of Internal Medicine (V.J.), Dobeln General Hospital, 04720 Dobeln, Germany

Accuracy of recommended sampling and assay methods for the determination of plasma-free and urinary fractionated metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review

PurposeTo determine the accuracy of biochemical tests for the diagnosis of pheochromocytoma and paraganglioma.MethodsA search of the PubMed database was conducted for English-language articles published between October 1958 and December 2016 on the biochemical diagnosis of pheochromocytoma and paraganglioma using immunoassay methods or high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection for measurement of fractionated metanephrines in 24-h urine collections or plasma-free metanephrines obtained under seated or supine blood sampling conditions.ResultsApplication of the Standards for Reporting of Diagnostic Studies Accuracy Group criteria yielded 23 suitable articles. Summary receiver operating characteristic analysis revealed sensitivities/specificities of 94/93% and 91/93% for measurement of plasma-free metanephrines and urinary fractionated metanephrines using high-performance liquid chromatography or immunoassay methods, respectively. Partial areas under the curve were 0.947 vs. 0.911. Irrespective of the analytical method, sensitivity was significantly higher for supine compared with seated sampling, 95 vs. 89% (p < 0.02), while specificity was significantly higher for supine sampling compared with 24-h urine, 95 vs. 90% (p < 0.03). Partial areas under the curve were 0.942, 0.913, and 0.932 for supine sampling, seated sampling, and urine. Test accuracy increased linearly from 90 to 93% for 24-h urine at prevalence rates of 0.0–1.0, decreased linearly from 94 to 89% for seated sampling and was constant at 95% for supine conditions.ConclusionsCurrent tests for the biochemical diagnosis of pheochromocytoma and paraganglioma show excellent diagnostic accuracy. Supine sampling conditions and measurement of plasma-free metanephrines using high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection provides the highest accuracy at all prevalence rates.

[Diagnosis of pheochromocytoma and paraganglioma: the clonidine suppression test in patients with borderline elevations of plasma free normetanephrine]

BACKGROUND Measurements of plasma free metanephrines provide a sensitive test for the diagnosis of pheochromocytoma/paraganglioma (P/PGL), with highly elevated levels diagnostic of the disease. However, there is less diagnostic certainty in patients with mild elevations of these catecholamine metabolites. PATIENTS AND METHODS Here we report use of the clonidine suppression test (CST) as a second-tier diagnostic test in 24 patients with mild elevations of plasma free metanephrines and/or catecholamines. Blood samples before and 3 hours after clonidine were analyzed for plasma concentrations of metanephrines and catecholamines with a negative test result defined as either a clonidine-induced fall in normetanephrine or noradrenaline by more than 40 % and 50 % respectively or to below the upper cut-offs of reference intervals. RESULTS P/PGLs were confirmed in 9 patients and excluded in 15 by independent criteria. More than half of the patients without P/PGL showed normalized plasma concentrations of normetanephrine at baseline before clonidine compared to initial screening; all showed appropriate clonidine-induced falls in normetanephrine and noradrenaline or levels after the drug below upper cut-offs, indicating a diagnostic specificity of 100 % (CI 78-100 %). However, similar responses for noradrenaline were noted in 7 patients with P/PGL, indicating a diagnostic sensitivity of only 22 % (CI 2,8-60 %) compared to 100 % (CI 66-100 %) for normetanephrine. CONCLUSION These results support use of the CST in combination with measurements of normetanephrine for confirming or excluding P/PGL in patients with borderline elevated test results, which should, however, first be confirmed by sampling blood under standardized resting conditions.

Macroglossia as the only presenting feature of amyloidosis due to MGUS

Macroglossia is a well-known complication of primary (AL) amyloidosis and considered a pathognomonic feature of the disease. However, the finding of an enlarged tongue as the only clinical abnormality may be similar for various diseases. An elderly woman with a tongue ulcer was seen elsewhere by an oromaxillofacial surgeon. Progressive and painless enlargement of the tongue occurring over the past year had responded to systemic glucocorticoids. Her medical history included arterial hypertension, and she was taking valsartan. A biopsy of the lesion revealed chronic inflammation. She reported no pain, dyspnea, or dysphagia. Laboratory tests excluded inflammation, hypothyroidism, and hereditary or acquired angioedema. High-dose therapy with up to 1000 mg per day of prednisolone resulted in prompt improvement. When seen here, the patient’s swollen tongue protruded from her mouth (Fig. 1A) affecting her ability to speak, swallow, and breathe. The ulcer had healed, there were no local masses, and her physical examination was otherwise normal. Laboratory investigations, including serum levels of vitamin B12, growth hormone, insulin-like growth factor1 and thyroid function tests, were normal. Magnetic resonance imaging of the head, neck, and chest revealed a large mediastinal goiter and no pituitary tumor. Reassessment of the tongue biopsy specimen obtained 13 months earlier and immunohistopathology revealed extensive AL amyloid deposits of k-light chain origin (Fig. 1B–D). Further investigations showed monoclonal elevation of serum k-light chains at 78 mg/dL (normal < 2.6 mg/dL), a decrease in the serum j/k-light chain ratio at 0.01 (normal 0.26–1.65), and 5–10% of plasma cells in the bone marrow. There were no signs of other lymphoproliferative disorders or abnormal urinary protein excretion. Red blood cell count, renal function testing, serum ionized calcium, and a skeletal survey were normal, establishing the diagnosis of primary (AL) amyloidosis associated with monoclonal k-light chain gammopathy of undetermined significance (MGUS). The patient received chemotherapy with melphalan and dexamethasone, and 10 months later, the macroglossia had slightly improved. This report illustrates the clinical case of AL amyloidosis secondary to MGUS in a patient with progressive macroglossia as the sole symptom. Chemotherapy with melphalan and dexamethasone is a therapeutic option for patients ineligible for stem-cell transplantation. Establishing the correct diagnosis may be delayed in patients with amyloidosis, and our case offers valuable lessons. (I) Initial response to glucocorticoids did not unravel the underlying cause and may have delayed the diagnosis. (II) The fact that an often systemic disease only presented as a large tongue led to management by an oromaxillofacial specialist with selective cognition and an organ-centered rather than a systemic approach.

Functional Imaging Experience in a Germline Fumarate Hydratase Mutation–Positive Patient With Pheochromocytoma and Paraganglioma

ABSTRACT Objective: To report the functional imaging experience with a 29-year-old woman carrying a mutation in the fumarate hydratase (FH)-encoding gene and a history of a pheochromocytoma (PHEO) and retroperitoneal paraganglioma (PGL). Methods: The patient was found to have a splice-site mutation in the FH gene at intron 2, c.268-2A>G. To confirm this, immunohistochemical staining was performed on tumor tissue slides from the patients previous surgeries. The patient underwent biochemical testing for PHEO/PGL, which included chromogranin A and plasma methoxytyramine. The patients tumors were also imaged using several imaging modalities, including computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography (PET)/CT studies using [18F]-fluorodeoxyglucose ([18F]-FDG), [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), and [68Ga]-tetraazacyclododecanetetraacetic acid–[Tyr3]-octreotate ([68Ga]-DOTATATE) as tracers. Results: The patient ...

Dipping in Ambulatory Blood Pressure Monitoring Correlates With Overnight Urinary Excretion of Catecholamines and Sodium

Nondipping blood pressure (BP) is associated with increased morbidity and mortality. This study examines the relationship of “dipping” in 24‐hour ambulatory BP monitoring (ABPM) with awake and sleeping urinary norepinephrine (NE) and epinephrine (EPI), and that of urinary NE and EPI with urinary sodium (UNa). Fifty nondippers and 65 dippers were included in the present study. Collected data included age, sex, body mass index, history of hypertension, current antihypertensive treatment, ABPM data, and NE, EPI, and UNa values. Hierarchical multiple regression analysis with the night‐to‐day ratio (NDR) of systolic BP as a dependent variable showed that the composite term of the NDRs of urinary NE and EPI was a significant predictor for dipping. Results also show a differential role of NE and EPI in circadian UNa excretion in dippers and nondippers. These results indicate that the sympathetic nervous system is involved in the regulation of circadian BP variations and UNa excretion.