Clonidine Suppression Endocrine Dynamic Function Protocols

Clonidine Suppression Endocrine Dynamic Function Protocols

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Clonidine Suppression

Clonidine Suppression

Rationale: This test has been used to diagnose pheochromocytoma and those paragangliomas that may secrete epinephrine, norepinephrine, or both. Such tumors may cause paroxysmal or persistent hypertension. The test is useful in the investigation of hypertensive patients, especially younger individuals, particularly when hypertension is paroxysmal, suggesting pheochromocytoma.1 Several definitions of a normal plasma catecholamine response to clonidine have been postulated:

  1. A minimum plasma norepinephrine level ≤500 pg/mL2
  2. ≥50% norepinephrine decline from baseline, and a norepinephrine level ≤500 pg/mL3
  3. A minimum plasma total catecholamine (norepinephrine + epinephrine) concentration ≤500 pg/mL4

Sjoberg et al5 have concluded that minimal suppression occurs two to three hours after clonidine administration with the greatest diagnostic accuracy (92%) obtained when the normal response is defined as a level of total plasma catecholamine ≤500 pg/mL. Taylor et al6 have demonstrated an increase in false-positive results by using the 50% reduction criteria. This is especially true if the baseline results are within the established reference interval. Plasma levels are useful if elevated, especially during or immediately following an episode of hypertension, but false-negative results occur when the specimen is drawn during an uneventful period. Normotensive pheochromocytoma has been reported.7 False-positive results are common. Epinephrine secretion increases in response to cold and hypoglycemia.

Protocol: The patient should fast overnight and abstain from smoking. Thirty minutes after the insertion of the indwelling catheter, blood is drawn for the baseline catecholamine determination. Clonidine hydrochloride (0.3 mg) is given orally, and repeat specimens for plasma catecholamines are collected two and three hours later.5 Collection of a fourth tube at four hours is optional.

Note: Several medications have been shown to prevent clonidine suppression, thus rendering false-positive results. These include β-adrenergic blockers, tricyclic antidepressants, and thiazide diuretics. If possible, these drugs should be discontinued 48 hours before collection. The α-adrenergic blocking agents do not interfere with clonidine suppression. Drugs that may affect plasma norepinephrine levels include α-adrenergic and β-adrenergic blockers, vasodilators, clonidine, bromocriptine, theophylline, phenothiazine, tricyclic antidepressants, labetalol, calcium channel blockers, converting enzyme inhibitors, bromocriptine, chlorpromazine, haloperidol, and cocaine.

Walnuts, bananas, and interfering medications should be avoided for a week prior to specimen collection. An indwelling heparinized catheter is recommended, as venipuncture can cause an increase in the substances for which testing is being performed. The patient should remain recumbent during the entire collection procedure.

Orderable Tests: Clonidine Suppression Test (Three-hour) (123133)  , Clonidine Suppression Test (Four-hour) (123158)

Note: For each collection time interval, draw blood into lavender-top (EDTA) tubes. Invert tubes to allow preservatives to mix thoroughly. Centrifuge and transfer the plasma to labeled plastic transport tubes (4 mL each; 2 mL minimum). Freeze immediately and ship frozen. The time between blood collection and the preparation of plasma is critical; if the time exceeds one hour, catecholamine values increase (when blood is refrigerated) or decrease (when kept at room temperature).8

References

1. Sheps SG, Jiang NS, Klee GG, van Heerden JA. Recent developments in the diagnosis and treatment of pheochromocytoma. Mayo Clin Proc. 1990 Jan; 65(1):88-95. PubMed 1967325

2. Bravo EL, Tarazi RC, Fouad FM, Vidt DG, Gifford RW Jr. Clonidine-suppression test: A useful aid in the diagnosis of pheochromocytoma. N Engl J Med. 1981 Sep 10; 305(11):623-626. PubMed 7266587

3. Manger WM, Gifford RW Jr, Hoffman BB. Pheochromocytoma: A clinical and experimental overview. Curr Probl Cancer. 1985 May; 9(5):1-89. PubMed 3021396

4. Bravo EL, Gifford RW Jr. Current concepts. Pheochromocytoma: diagnosis, localization, and management. N Engl J Med. 1984 Nov 15; 311(20):1298-1303. PubMed 6149463

5. Sjoberg RJ, Simcic KJ, Kidd GS. The clonidine suppression test for pheochromocytoma. A review of Its utility and pitfalls. Arch Intern Med. 1992 Jun; 152(6):1193-1197. PubMed 1599347

6. Taylor HC, Mayes D, Anton AH. Clonidine suppression test for pheochromocytoma: Examples of misleading results. J Clin Endocrinol Metab. 1986 Jul; 63(1):238-242. PubMed 3711261

7. Feldman JM, Blalock JA, Zern RT, et al. Deficiency of dopamine-beta-hydroxylase. A new mechanism for normotensive pheochromocytomas. Am J Clin Pathol. 1979 Aug; 72(2):175-185. PubMed 474494

8. Boomsma F, Alberts G, van Eijk L, Man in ‘t Veld AJ, Schalekamp MA. Optimal collection and storage conditions for catecholamine measurements in human plasma and urine. Clin Chem. 1993 Dec; 39(12):2503-2508. PubMed 8252722

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Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma

Article (PDF Available)in Journal of human hypertension 25(7):451-6 · July 2011with 54 Reads
DOI: 10.1038/jhh.2010.78 · Source: PubMed

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Abstract
The aim of this study is to review the experience of the clonidine suppression test in a regional endocrine centre and to compare the diagnostic sensitivity and specificity using various previous published criteria. The design used is retrospective study. The subjects include 56 patients in whom clonidine suppression tests had been performed from 1995 to 2000: 15 with phaeochromocytoma and 41 patients in whom the diagnosis was excluded using a combination of biochemical testing, abdominal computed tomography scanning and clinical follow-up. Plasma catecholamines were measured by high pressure liquid chromatography on basal samples and at hourly intervals for 3 h after the administration of clonidine 300 μg orally and the following diagnostic criteria were applied: plasma noradrenaline+adrenaline>2.96 nmol l(-1) at 3 h post-clonidine or a baseline plasma adrenaline plus noradrenaline>11.82 nmol l(-1); plasma noradrenaline>2.96 nmol l(-1) at 3 h post-clonidine and plasma noradrenaline>2.96 nmol l(-1) and <50% fall in noradrenaline at 3 h post-clonidine. The results obtained is that mean plasma noradrenaline plus adrenaline fell across the test in 40/41 patients in the non-phaeochromocytoma patients and was lowest at 3 h (basal 2.28 ± 0.14 vs 1.36 ± 0.11 nmol l(-1), P<0.001). In the phaeochromocytoma group, clonidine had a variable effect on adrenaline plus noradrenaline levels with increases in 7/15. Using an abnormal result as a 3 h level of noradrenaline plus adrenaline>2.96 mmol l(-1) gave a sensitivity of 93% and specificity of 95%. When a 3 h noradrenaline>2.96 mmol l(-1) was used, sensitivity was 87% and specificity 95%. Using the former criteria, noradrenaline plus adrenaline>2.96 mmol l(-1), 1/15 in the phaeochromocytoma group had a normal result after clonidine suppression testing. Two of 41 in the non-phaeochromocytoma group had a false-positive result. Under carefully controlled conditions, the clonidine suppression test is well tolerated, safe and accurate for use in the investigation of patients with suspected phaeochromocytoma.

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Figures – uploaded by Albert Brew Atkinson
Author content

All content in this area was uploaded by Albert Brew Atkinson

Plasma total noradrenaline + adrenaline in individual patients before and 3 h after a single oral dose of clonidine.
Plasma total noradrenaline + adrenaline in individual patients before and 3 h after a single oral dose of clonidine.
… 
Sensitivity and specificity of clonidine suppression test results using varying diagnostic thresholds
Sensitivity and specificity of clonidine suppression test results using varying diagnostic thresholds
… 
Content uploaded by Albert Brew Atkinson
Author content

All content in this area was uploaded by Albert Brew Atkinson on Jan 11, 2016

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  • Diagnosis of Pheochromocytoma and Paraganglioma
    Chapter
    • May 2018
    • William F Young

      William F Young

    There has been a dramatic evolution in both the clinical presentation and the methods used to diagnose pheochromocytoma and paraganglioma (PPGL) over the past nine decades. Due to the advances in biochemical testing and cross-sectional computed imaging, we have progressed from prior to 1970 when 90% of patients with PPGL were detected because of symptoms (paroxysms or hypertension) to 2018 when 60% of patients with PPGL are diagnosed due to an incidental discovery on cross-sectional imaging done for other reasons. Thus, the clinician should recognize the imaging phenotype typical for a pheochromocytoma. The differential diagnosis for those patients who present with symptoms spans the field of medicine. Biochemical case detection testing relies on measurement of fractionated metanephrines and catecholamines by tandem mass spectrometry or high-pressure liquid chromatography. The clinician should assess the relative likelihood of pheochromocytoma in each patient. Decisions for the type of test performed may be subject to clinical availability, cost, clinical experience of the ordering physician, and the local laboratory. However, it is key to understand the medications and clinical situations that may cause false-positive biochemical testing.

  • Störungen der Nebennierenfunktion
    Chapter
    • Sep 2014
    • Carl-Joachim Partsch Prof. Dr. med

      Carl-Joachim Partsch Prof. Dr. med

    • Felix Riepe Prof. Dr. med

      Felix Riepe Prof. Dr. med

    Die Nebennieren bestehen aus der vom Mesoderm abstammenden Nebennierenrinde (NNR) und dem vom Ektoderm stammenden Nebennierenmark (NNM). Während der Fetalzeit ist die NNR deutlich größer als postnatal. Im 2. Fetalmonat ist das Größenverhältnis von Nebenniere zu Niere 2 : 1, im 6. Monat 1 : 1 und beim Erwachsenen 1 : 28. In der fetalen NNR finden sich eine breite Innenschicht, die als transitorische fetale Rinde (Fetokortex) bezeichnet wird, und eine schmale Außenzone (Neokortex), aus der die permanente, letztlich dreischichtige NNR hervorgeht. Während der Neokortex durch ACTH stimulierbar ist, scheint der Fetokortex in der 1. Schwangerschaftshälfte unter dem Einfluss von plazentarem hCG (humanes Choriongonadotropin) zu stehen. Er produziert bereits ab der 6. Schwangerschaftswoche (SSW) aus plazentarem Pregnenolon vorwiegend Dehydroepiandrosteron-Sulfat (DHEA-Sulfat) und 16-OH-DHEA-Sulfat, welche als direkte Vorstufen der hoch aktiven Östriolsynthese in der Plazenta dienen. Da einige der hierfür nötigen Enzyme nur in der fetalen NNR, andere aber nur in der Plazenta vorhanden sind, ist die Östrogenproduktion in der Schwangerschaft sowohl von einer funktionierenden Plazenta als auch von einer intakten und hormonell aktiven fetalen NNR abhängig (sog. fetoplazentare Einheit). Daher dient die Östriolkonzentration im Plasma oder Urin der Schwangeren als Parameter für die Vitalität des Fetus. Bereits um den 8. Schwangerschaftsmonat beginnt eine Involution des Fetokortex, welche postpartal etwa im 6. Monat abgeschlossen ist. Im Neokortex differenziert sich erst nach der 10. SSW die Zona fasciculata. Ab der 20. SSW ist auch eine schmale Zona glomerulosa abgrenzbar. Die Steroidbiosynthese (Kortisol, Aldosteron) im Neokortex erfolgt in nennenswertem Umfang jedoch erst ab der 32. SSW. Die Zona reticularis demarkiert sich erst im Rahmen der Adrenarche vor der Pubertät (Kap. 66). Man unterscheidet somit von innen nach außen 3 Zonen in der maturen Nebennierenrinde: Zona reticularis, Zona fasciculata und Zona glomerulosa.

  • Störungen der Nebennierenfunktion bei Kindern und Jugendlichen
    Chapter
    • Jan 2015
    • Carl-Joachim Partsch

      Carl-Joachim Partsch

    • Felix G Riepe

      Felix G Riepe

    Die Nebennieren bestehen aus der vom Mesoderm abstammenden Nebennierenrinde (NNR) und dem vom Ektoderm stammenden Nebennierenmark (NNM). Während der Fetalzeit ist die NNR deutlich größer als postnatal. Im 2. Fetalmonat ist das Größenverhältnis von Nebenniere zu Niere 2:1, im 6. Monat 1:1 und beim Erwachsenen 1:28. In der fetalen NNR finden sich eine breite Innenschicht, die als transitorische fetale Rinde (Fetokortex) bezeichnet wird, und eine schmale Außenzone (Neokortex), aus der die permanente, letztlich dreischichtige NNR hervorgeht. Während der Neokortex durch ACTH stimulierbar ist, scheint der Fetokortex in der 1. Schwangerschaftshälfte unter dem Einfluss von plazentarem hCG (humanes Choriongonadotropin) zu stehen. Er produziert bereits ab der 6. Schwangerschaftswoche (SSW) aus plazentarem Pregnenolon vorwiegend Dehydroepiandrosteron-Sulfat (DHEA-Sulfat) und 16-OH-DHEA-Sulfat, welche als direkte Vorstufen der hoch aktiven Östriolsynthese in der Plazenta dienen. Da einige der hierfür nötigen Enzyme nur in der fetalen NNR, andere aber nur in der Plazenta vorhanden sind, ist die Östrogenproduktion in der Schwangerschaft sowohl von einer funktionierenden Plazenta als auch von einer intakten und hormonell aktiven fetalen NNR abhängig (sog. fetoplazentare Einheit). Daher dient die Östriolkonzentration im Plasma oder Urin der Schwangeren als Parameter für die Vitalität des Fetus. Bereits um den 8. Schwangerschaftsmonat beginnt eine Involution des Fetokortex, welche postpartal etwa im 6. Monat abgeschlossen ist. Im Neokortex differenziert sich erst nach der 10. SSW die Zona fasciculata. Ab der 20. SSW ist auch eine schmale Zona glomerulosa abgrenzbar. Die Steroidbiosynthese (Kortisol, Aldosteron) im Neokortex erfolgt in nennenswertem Umfang jedoch erst ab der 32. SSW. Die Zona reticularis demarkiert sich erst im Rahmen der Adrenarche vor der Pubertät. Man unterscheidet somit von innen nach außen 3 Zonen in der maturen Nebennierenrinde: Zona reticularis, Zona fasciculata und Zona glomerulosa.

  • Recurrence of Phaeochromocytoma and Abdominal Paraganglioma After Initial Surgical Intervention
    Article
    Full-text available
    • May 2015
    • Ulster Med J
    • Steven J Hunter

      Steven J Hunter

    • Albert Brew Atkinson

      Albert Brew Atkinson

    • Karen R Mullan

      Karen R Mullan

    • Philip Johnston

      Philip Johnston

    Clinical and biochemical follow up after surgery for phaeochromocytoma is essential with long term studies demonstrating recurrence frequencies between 6% and 23%.
    To examine the characteristics and frequency of tumour recurrence in a regional endocrine referral centre, in patients with surgical resection of phaeochromocytoma (P) and abdominal paraganglioma (AP).
    We identified a cohort of 52 consecutive patients who attended our Regional Endocrinology & Diabetes Centre and retrospectively reviewed their clinical, biochemical and radiological data (between 2002 and 2013). After confirmation of early post-operative remission by negative biochemical testing, tumour recurrence was defined by demonstration of catecholamine excess with confirmatory imaging.
    Phaeochromocytoma was confirmed histologically in all cases (43:P, 9:AP, mean-age:53years). Open adrenalectomy was performed in 20 cases and laparoscopically in 32. Hereditary phaeochromocytoma was confirmed by genetic analysis in 12 (23%) patients. Median follow up time from initial surgery was 47 months, (range: 12 – 296 months), 49 patients had no evidence of tumour recurrence at latest follow-up. Three patients (6%) demonstrated tumour development, one in a patient with VHL which occurred in a contralateral adrenal gland, one sporadic case had local recurrence, and an adrenal tumour occurred in a patient with a SDHB gene mutation who had a previous bladder tumour. After initial surgery, the tumours occurred at 8.6, 12.0 and 17.7 years respectively.
    In this study tumour development occurred in 6% of patients. Although tumour rates were low, careful and sustained clinical and biochemical follow up is advocated, as new tumour development or recurrence may occur long after the initial surgery is performed.

  • Recurrence of phaeochromocytoma and abdominal paraganglioma after initial surgical intervention
    Article
    Full-text available
    • May 2015
    • Ulster Med J
    • Steven J Hunter

      Steven J Hunter

    • Philip Johnston

      Philip Johnston

    Background:Clinical and biochemical follow up after surgery for phaeochromocytoma is essential with long term studies demonstrating recurrence frequencies between 6% and 23%.
    Aim: To examine the characteristics and frequency of tumour recurrence in a regional endocrine referral centre, in patients with surgical resection of phaeochromocytoma (P) and abdominal paraganglioma (AP).
    Methods: We identified a cohort of 52 consecutive patients who attended our Regional Endocrinology & Diabetes Centre and retrospectively reviewed their clinical, biochemical and radiological data (between 2002 and 2013). After confirmation of early post-operative remission by negative biochemical testing, tumour recurrence was defined by demonstration of catecholamine excess with confirmatory imaging.
    Results: Phaeochromocytoma was confirmed histologically in all cases (43:P, 9:AP, mean-age:53). Open adrenalectomy was performed in 20 cases and laparoscopically in 32. Hereditary pheochromocytoma was confirmed by genetic analysis in 12 (23%) patients. Median follow up time from initial surgery was 47 months, (range: 12 – 296 months), 49 patients had no evidence of tumour recurrence at latest follow-up. Three patients (6%) demonstrated tumour development, one in a patient with VHL which occurred in a contralateral adrenal gland, one sporadic case had local recurrence, and an adrenal tumour occurred in a patient with a SDHB gene mutation who had a previous bladder tumour. After initial surgery, the tumours occurred at 8.6, 12.0 and 17.7 years respectively.
    Conclusion: In this study tumour development occurred in 6% of patients. Although tumour rates were low, careful and sustained clinical and biochemical follow up is advocated, as new tumour development or recurrence may occur long after the initial surgery is performed.

  • Diagnostic correlation between RET proto-oncogene mutation, imaging techniques, biochemical markers and morphological examination in MEN2A syndrome: Case report and literature review
    Article
    Full-text available
    • Jun 2014
    • Rom J Morphol Embryol
    • Mihaela Galatâr

      Mihaela Galatâr

    • Carmen Georgescu

      Carmen Georgescu

    • Alina Sovrea

      Alina Sovrea

    • Eleonora Dronca

      Eleonora Dronca

    Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant monogenic disorder caused mostly by missense mutations in the RET (REarranged during Transfection) proto-oncogene on chromosome 10q11.2. MEN2A represents more than 50% of all MEN2 cases, having a regular pattern with medullary thyroid carcinoma (MTC) incidence of 90-100%, bilateral pheochromocytoma (PCC) incidence of 40-50% and primary hyperparathyroidism (HPT) incidence of 10-25%. Until recently, the diagnosis of MTC was most frequently based on fine-needle aspiration of thyroid nodules, after an ultrasound examination and endocrine evaluation of serum calcitonin levels. Nowadays, RET gene screening (starting with exons 10 and 11) is a mandatory test used for identification of both symptomatic and non-symptomatic MTC carriers or for exclusion of healthy individuals from subsequent periodical clinical÷biochemical screening. In this context, and in the idea of PCC preceding MTC, the early detection of germline RET mutations are highly suggestive for hereditary disease. PCC diagnosis is established in classical manner by abdominal ultrasound imaging or computed tomography confirming the presence of adrenal gland masses, elevated plasma metanephrines and normetanephrines values and histopathological examination. Additional HPT diagnosis is acknowledged by serum ionized calcium and parathormone levels. Here we report a hereditary case of MEN2A in a two-generation Romanian family, along with data presenting the importance of correlative plurifactorial diagnostic scheme in this syndrome and a short literature review.

  • Diagnosis of pheochromocytoma and paraganglioma: The clonidine suppression test in patients with borderline elevations of plasma free normetanephrine
    Article
    • Jan 2013
    • Jacques Lenders

      Jacques Lenders

    • G Eisenhofer

      G Eisenhofer

    • K. Stange

      K. Stange

    • Roland Wolfgang Darr

      Roland Wolfgang Darr

    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.

  • Pheochromocytoma: Implications in tumorigenesis and the actual management
    Article
    Full-text available
    • Jun 2012
    • Minerva Endocrinol
    • Urvi A Shah

      Urvi A Shah

    • Karel Pacak

      Karel Pacak

    • Alessio Giubellino

      Alessio Giubellino

    Pheochromocytomas and paragangliomas are rare neuroendocrine catecholamine producing tumors with varied clinical presentations, biochemistries and genetic makeup. These features outline the complexity and the difficulties in studying and understanding the oncogenesis of these tumors. The study of families with genetically inherited mutations in pheochromocytoma susceptibility genes has greatly enhanced our understanding of the pathophysiology and mechanisms of oncogenesis of the disease, and consequently changed our clinical approach. Several molecular pathways and mutations in their important regulatory proteins have been identified. Such mutations are responsible for the dysregulation of metabolic pathways involved in oxygen and nutrient sensing, apoptosis regulation, cell proliferation, migration and invasion. The knowledge derived from the study of these pathways will be fundamental in the future clinical management of these patients. As a rare disease that often masks its clinical presentation, the diagnosis is frequently missed and a high level of suspicion is required. Management of this disease requires a multidisciplinary team approach and will be discussed along with advances in its treatment.

  • A comparison of plasma-free metanephrines with plasma catecholamines in the investigation of suspected pheochromocytoma
    Article
    • Dec 2011
    • Graham R Lee

      Graham R Lee

    • Steven J Hunter

      Steven J Hunter

    • Albert Brew Atkinson

      Albert Brew Atkinson

    • Philip Johnston

      Philip Johnston

    To compare the diagnostic performance of plasma metanephrines by ELISA and plasma catecholamine measurements by HPLC in patients selected for clonidine suppression testing.
    Plasma catecholamines adrenaline (ADR) and noradrenaline (NOR) were measured by HPLC and metanephrine with normetanephrine (NMN) by ELISA (n = 67). The diagnostic performance of metanephrines was determined by receiver operating characteristic (ROC) curve analysis.
    Phaeochromocytoma was confirmed by histological analysis in 14 patients and excluded in 53 patients by a negative clonidine suppression test (CST), abdominal computerized tomography scan and clinical follow-up (median 2.5 years). A sensitivity and specificity of 100 and 96%, respectively, was obtained by using our current CST diagnostic criteria for ADR and NOR values. ROC curve analysis revealed optimum sensitivity and specificity for plasma-free metanephrines using a threshold of 784 pmol/l at baseline and 663 pmol/l at 180 min. Baseline measurements of metanephrine with NMN showed 100% sensitivity and 98% specificity, as assessed by ROC curve analysis-derived criteria or when evaluated against published decision thresholds. A sensitivity and specificity of 100% was obtained for the combined measurements of metanephrine with NMN at 180 min.
    Plasma metanephrines (metanephrine with NMN) were equally effective as plasma catecholamines during CST. This study supports the use of measuring plasma metanephrines by ELISA as a less labour-intensive and equally effective biochemical test for phaeochromocytoma in patients with a high clinical suspicion. There was still overlap between groups with and without phaeochromocytoma at baseline under controlled conditions and clinically some patients still need to undergo clonidine suppression testing.

  • In Search of Pheochromocytomas
    Article
    • Sep 2003
    • J CLIN ENDOCR METAB
    • William M Manger

      William M Manger

  • High blood pressure. A side effect of drugs, poisons, and food
    Article
    • Jul 1979
    • ARCH INTERN MED
    • E D Frohlich

      E D Frohlich

    • F H Messerli

      F H Messerli

    Arterial hypertension, either transient or persistent, may be induced or aggravated by ingestion of various chemical agents, such as drugs, poisons, and food. Most of these agents either cause sodium retention and expand extracellular fluid volume or act as direct or indirect sympathomimetics. Others act directly on arteriolar smooth muscle. For a few agents, no precise mechanism has been ascertained. Hypertensive reactions may also occur as a result of drug interactions or food and drug interactions. In addition, paradoxical increases in pressure may be encountered during or after discontinuance of antihypertensive therapy. In general, these pressure increases are small and transient; however, a few have been associated with severe hypertension involving encephalopathy, strokes, and irreversible renal failure. Careful review of a patient's drug regimen, including over-the-counter preparations, may avoid chemically induced hypertension. Identification of any offending or incriminating agent will prevent the labeling of a chronic illness and obviate the need for lifelong antihypertensive therapy.

  • Glucagon and clonidine testing in the diagnosis of Pheochromocytoma
    Article
    • Jul 1991
    • Hypertension
    • H R Keiser

      H R Keiser

    • Aaron Hoffman

      Aaron Hoffman

    • David S. Goldstein

      David S. Goldstein

    • Ehud Grossman

      Ehud Grossman

    We assessed the sensitivity and specificity of glucagon stimulation and clonidine suppression tests in the diagnosis of pheochromocytoma in 113 hypertensive patients, 39 with and 74 without the tumor. In the glucagon stimulation test, blood was sampled 2 minutes after intravenous injection of 0.28 mumol (1 mg) glucagon, and in the clonidine suppression test, blood was sampled 3 hours after administration of oral clonidine, 1.30 mumol (0.3 mg)/70 kg body wt. Baseline levels of catechols in antecubital venous blood were abnormal, with norepinephrine greater than 7.10 nmol/l (1,200 pg/m), epinephrine greater than 1.51 nmol/l (276 pg/ml), norepinephrine/dihydroxyphenylglycol (DHPG) ratio greater than 1.09, or dopa greater than 35.53 nmol/l (7,000 pg/ml), in 30 of 39 patients with pheochromocytoma (sensitivity 77%) and 1 of 74 patients without pheochromocytoma (specificity 99%). Results of the glucagon test were abnormal (norepinephrine greater than 11.83 nmol/l [2,000 pg/ml] or more than threefold increase from baseline) in 25 of 31 patients with pheochromocytoma (sensitivity 81%) and 0 of 72 patients without pheochromocytoma (specificity 100%). Results of the clonidine test were abnormal (after clonidine norepinephrine greater than 2.96 nmol/l [500 pg/ml] or less than 50% decrease from baseline) in 29 of 30 patients with pheochromocytoma (sensitivity 97%) and in 7 of 30 patients without pheochromocytoma (specificity 67%). Very high baseline levels of catechols therefore indicated the presence of pheochromocytoma, but there were several false-negative results when normal levels were obtained. The glucagon test alone was highly specific but not sensitive, and the clonidine test was highly sensitive but less specific.(ABSTRACT TRUNCATED AT 250 WORDS)

  • Pheochromocytoma: A clinical and experimental overview
    Article
    • Jun 1985
    • CURR PROB CANCER
    • B B Hoffman

      B B Hoffman

    • W M Manger

      W M Manger

    • Ray W. Gifford

      Ray W. Gifford

  • Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase
    Article
    Full-text available
    • Dec 1986
    • CLIN CHEM
    • G Eisenhofer

      G Eisenhofer

    • Irwin J Kopin

      Irwin J Kopin

    • David S. Goldstein

      David S. Goldstein

    • R Stull

      R Stull

    This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines.

  • Reduced specificity of the clonidine suppression test in patients with normal plasma catecholamine levels
    Article
    • Apr 1988
    • AM J MED
    • Michael Murphy

      Michael Murphy

    • William J. Elliott

      William J. Elliott

    Although originally devised to discriminate between patients with pheochromocytoma and those with elevated plasma catecholamine levels for other reasons, the clonidine suppression test has recently been used in patients with normal resting catecholamine levels. Upon review of 49 patients evaluated for pheochromocytoma, 26 had elevated plasma norepinephrine levels and underwent clonidine suppression testing. Only one of 13 patients with sustained elevated norepinephrine levels before clonidine administration had a false-positive clonidine test result, in contrast to five of 13 patients whose pre-clonidine norepinephrine levels had decreased into the normal range. This difference was statistically significant (by chi-square) at p less than 0.05. Clonidine suppression testing for pheochromocytoma should be performed only in patients with elevated catecholamine levels, because it carries a higher false-positive rate in patients with normal resting norepinephrine levels; a more accurate diagnosis may be made in such patients using glucagon stimulation tests.

  • Dopamine-secreting pheochromocytoma: An unrecognized entity? Classification of pheochromocytomas according to their type of secretion
    Article
    • Jan 1987
    • SURGERY
    • Patricia Fontaine

      Patricia Fontaine

    • C Proye

      C Proye

    • P Cecat

      P Cecat

    • P Fossati

      P Fossati

    A pheochromocytoma that exclusively secretes dopamine (DA) rather than predominantly DA among a blend of catecholamines is as yet unreported. Of the 50 patients with pheochromocytoma who have undergone surgery, 32 underwent treatment within the last 5 years (when DA assay has been available). One half of these patients (15/32) exhibited DA secretion either in mixed catecholamines (12 patients) or exclusively (three patients). All three patients with exclusive DA-secreting tumors were normotensive. Without hypertension, the clinical investigation was a diagnostic challenge (unexplained cough or flank mass with inflammatory features). All three tumors were malignant and two were ectopic. Five of the 12 patients with mixed catecholamine-secreting tumors whose secretions included DA were hypertensive. Five other patients had flank mass and one had an unexplained cough. Tumors were rather large, and three of the tumors with mixed secretion were ectopic. Of the 12 patients, seven had tumors that were judged to be malignant. Three patients exhibited a dramatic decrease in blood pressure under alpha-blockade, which was not used in subsequent cases. Predominant or exclusive secretion of DA would explain the lack of hypertension due to its antiadrenergic action that inhibits the vasoconstrictive effects of other amines. Hypertension in patients with pheochromocytoma might depend on the ratio of DA/noradrenaline + adrenaline.

  • Parathyroid tumors
    Article
    • Dec 1985
    • CURR PROB CANCER
    • S Werner

      S Werner

    • Bjorn Cedermark

      Bjorn Cedermark

    • P O Granberg

      P O Granberg

    • Lars-Ove Farnebo

      Lars-Ove Farnebo

  • Pheochromocytoma: Diagnosis, Localization and Management
    Article
    • Dec 1984
    • NEW ENGL J MED
    • Emmanuel L. Bravo

      Emmanuel L. Bravo

    • Ray W. Gifford

      Ray W. Gifford

    THE early diagnosis of pheochromocytoma is important, not only because it offers the possibility of curing hypertension but also because unrecognized pheochromocytoma is a potentially lethal condition. Hypertensive crisis or shock or both leading to death have been precipitated by drugs, anesthetic agents, parturition, or surgery for an unrelated condition. Moreover, 8 to 10 per cent of the tumors are malignant. The detection of pheochromocytoma requires a high degree of clinical alertness. Although rare cases have been reported in which the tumor was not associated with hypertension, especially in patients with familial tumors, elevation of blood pressure, either continuous or . . .

  • Clonidine-Suppression Test: A Useful Aid in the Diagnosis of Pheochromocytoma
    Article
    • Oct 1981
    • NEW ENGL J MED
    • Gifford, R.W., Jr

      Gifford, R.W., Jr

    • Emmanuel L. Bravo

      Emmanuel L. Bravo

    • R C Tarazi

      R C Tarazi

    • Fetnat M. Fouad

      Fetnat M. Fouad

    We have devised a safe and simple test involving the ability of clonidine to suppress plasma norepinephrine levels in normal human beings by stimulating central α-adrenergic receptors. Since a physiologic increase in catecholamines depends on activation of the sympathetic nervous system, whereas release from a tumor is presumed to be autonomous, these studies were designed to assess the possibility that specific inhibition of neurogenically mediated catecholamine release might differentiate sympathetic hyperactivity from pheochromocytoma. In 10 patients with proved pheochromocytoma, a single oral dose of 0.3 mg of clonidine had no effect on plasma norepinephrine after 180 minutes. By contrast, plasma norepinephrine was suppressed in each of 15 hypertensive patients who were free of pheochromocytoma but had suggestive symptoms. Both groups had similar reductions in supine blood pressure and heart rate. We conclude that the clonidine method is a useful adjunctive test to rule out pheochromocytoma in hypertensive patients with suggestive symptoms and borderline catecholamine values.

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A comparison of plasma-free metanephrines with plasma catecholamines in the investigation of suspect…

December 2011 · Journal of Hypertension
  • Graham R Lee
  • Steven J Hunter

    Steven J Hunter

  • Albert Brew Atkinson

    Albert Brew Atkinson

  • […]
  • Philip Johnston

    Philip Johnston

To compare the diagnostic performance of plasma metanephrines by ELISA and plasma catecholamine measurements by HPLC in patients selected for clonidine suppression testing.
Plasma catecholamines adrenaline (ADR) and noradrenaline (NOR) were measured by HPLC and metanephrine with normetanephrine (NMN) by ELISA (n = 67). The diagnostic performance of metanephrines was determined by receiver … [Show full abstract] operating characteristic (ROC) curve analysis.
Phaeochromocytoma was confirmed by histological analysis in 14 patients and excluded in 53 patients by a negative clonidine suppression test (CST), abdominal computerized tomography scan and clinical follow-up (median 2.5 years). A sensitivity and specificity of 100 and 96%, respectively, was obtained by using our current CST diagnostic criteria for ADR and NOR values. ROC curve analysis revealed optimum sensitivity and specificity for plasma-free metanephrines using a threshold of 784 pmol/l at baseline and 663 pmol/l at 180 min. Baseline measurements of metanephrine with NMN showed 100% sensitivity and 98% specificity, as assessed by ROC curve analysis-derived criteria or when evaluated against published decision thresholds. A sensitivity and specificity of 100% was obtained for the combined measurements of metanephrine with NMN at 180 min.
Plasma metanephrines (metanephrine with NMN) were equally effective as plasma catecholamines during CST. This study supports the use of measuring plasma metanephrines by ELISA as a less labour-intensive and equally effective biochemical test for phaeochromocytoma in patients with a high clinical suspicion. There was still overlap between groups with and without phaeochromocytoma at baseline under controlled conditions and clinically some patients still need to undergo clonidine suppression testing.

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Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients…

April 2006 · European Journal of Endocrinology
  • Stephan Petersenn
  • C Pitt
  • N Unger
  • […]
  • I Lopez Schmidt
Pheochromocytomas are neoplasms generally characterized by the autonomous production of catecholamines. This study compared various biochemical parameters for the diagnosis of adrenal pheochromocytoma in patients with adrenal mass.
One hundred and fifty subjects were studied, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas … [Show full abstract] and 30 nonfunctioning adrenal masses, 16 patients with essential hypertension and 42 healthy normotensive volunteers. Spontaneous blood samples and 24-h urine samples were collected prospectively.
Plasma and urinary epinephrine and norepinephrine levels were measured by high performance liquid chromatography, whereas plasma and urinary metanephrine and normetanephrine levels were determined by radioimmunoassay (RIA). Putative ratio thresholds were calculated by receiver operating characteristic (ROC) analysis to balance between sensitivity and specificity.
Plasma normetanephrine was found to be the best single parameter with the highest sensitivity (91.7%) and specificity (95.6%) using a threshold of 126 pg/ml. In combination, plasma normetanephrine and metanephrine had a higher sensitivity of 95.8% with lower specificity (79.4%). All other combinations of plasma and/or urinary parameters demonstrated a lower accuracy.
Plasma metanephrines measured by RIA are reliable screening parameters for the diagnosis of pheochromocytoma.

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Article

The Value of Immunoassays for Metanephrines in the Biochemical Diagnosis of Pheochromocytomas

July 2009 · Hormone and Metabolic Research
  • N Unger
  • S Petersenn
  • Timo Deutschbein

    Timo Deutschbein

  • […]
  • Martin K Walz

    Martin K Walz

An undiagnosed pheochromocytoma may result in life-threatening consequences. The diagnosis of pheochromocytoma is based on the overproduction of catecholamines. Highly sensitive biochemical assays are essential to avoid false-negative results. Determinations of 24-h urinary epinephrine and norepinephrine levels are established diagnostic tools. However, they may be falsely negative in patients … [Show full abstract] with a biochemically-silent or periodically-secreting pheochromocytoma. Metanephrines, which are metabolites of catecholamines, have been suggested as an alternative diagnostic tool. Urinary metanephrines are determined by high-pressure liquid chromatography (HPLC) in an increasing number of laboratories, whereas plasma metanephrines measured by HPLC are available in specialised centres only. The different HPLC methods may be cost- and time-intensive. Immunoassays such as radio- or enzyme-immunoassays may be alternative procedures. Measurement of metanephrines instead of catecholamines by either technique improved the diagnostic accuracy for the diagnosis of pheochromocytomas. Determination of plasma free metanephrines demonstrated a higher accuracy than their urinary counterparts. The use of immunoassays may be an alternative to the laborious HPLC, although the method needs to be evaluated in more detail.

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Article
Full-text available

Biochemical Diagnosis of Pheochromocytoma: Which Test Is Best?

April 2002 · JAMA The Journal of the American Medical Association
  • Karel Pacak
  • Jacques W M Lenders
  • Graeme Eisenhofer
  • […]
  • Mcclellan Walther

    Mcclellan Walther

Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined.
To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma.
Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between … [Show full abstract] 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor.
Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid.
Sensitivities of plasma free metanephrines (99% [95% confidence interval [CI], 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines.
Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.

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Article
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Low Sensitivity of Glucagon Provocative Testing for Diagnosis of Pheochromocytoma

November 2009 · The Journal of Clinical Endocrinology and Metabolism
  • Karel Pacak
  • Jacques W M Lenders
  • Graeme Eisenhofer
  • […]
  • Thanh Truc Huynh

    Thanh Truc Huynh

Pheochromocytomas can usually be confirmed or excluded using currently available biochemical tests of catecholamine excess. Follow-up tests are, nevertheless, often required to distinguish false-positive from true-positive results. The glucagon stimulation test represents one such test; its diagnostic utility is, however, unclear.
The aim of the study was to determine the diagnostic power of the … [Show full abstract] glucagon test to exclude or confirm pheochromocytoma.
Glucagon stimulation tests were carried out at three specialist referral centers in 64 patients with pheochromocytoma, 38 patients in whom the tumor was excluded, and in a reference group of 36 healthy volunteers.
Plasma concentrations of norepinephrine and epinephrine were measured before and after glucagon administration. Several absolute and relative test criteria were used for calculating diagnostic sensitivity and specificity. Expression of the glucagon receptor was examined in pheochromocytoma tumor tissue from a subset of patients. Results: Larger than 3-fold increases in plasma norepinephrine after glucagon strongly predicted the presence of a pheochromocytoma (100% specificity and positive predictive value). However, irrespective of the various criteria examined, glucagon-provoked increases in plasma catecholamines revealed the presence of the tumor in less than 50% of affected patients. Diagnostic sensitivity was particularly low in patients with pheochromocytomas due to von Hippel-Lindau syndrome. Tumors from these patients showed no significant expression of the glucagon receptor.
The glucagon stimulation test offers insufficient diagnostic sensitivity for reliable exclusion or confirmation of pheochromocytoma. Because of this and the risk of hypertensive complications, the test should be abandoned in routine clinical practice.

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