Diagnostic Efficacy of Unconjugated Plasma Metanephrines for the Detection of Pheochromocytoma

Raber, Wolfgang; Raffesberg, Wolfgang; Bischof, Martin; Scheuba, Christian; Niederle, Bruno; Gasić, S; Waldhäusl, W.; Roden, Michael

doi:10.1001/archinte.160.19.2957

Cited by 167 publications

(141 citation statements)

References 16 publications

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“…The diagnosis is made by the measurement of urinary catecholamines and the identification of tumor by CT scanning, magnetic resonance imaging, or radionucleotide scanning with MIBG or octreotide [18]. Since 90% of the cases are derived from the adrenal medulla, the measurement of the levels of urinary metanephrine, a metabolite of E, is thought to be a sensitive biochemical screening test [19][20][21][22]. In the present case, we found an elevation of urinary normetanephrine, but not metanephrine levels and failed to locate the suspected adrenal tumor on either side.…”

Section: Discussionmentioning

confidence: 99%

A Case of Sleep Apnea Syndrome Manifesting Severe Hypertension with High Plasma Norepinephrine Levels

Makino¹,

Iwata²,

Fujiwara³

et al. 2006

Endocr J

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Abstract.A 55-year-old female was admitted to our hospital with severe hypertension (274/140 mmHg). Endocrinological examination revealed that her plasma levels of norepinephrine (NE) was elevated with high levels of urinary NE, normetanephrine and vanillylmandelic acid (VMA), suggesting the presence of pheochromocytoma. However, neither computed tomography nor MIBG scintigraphy detected any catecholamine-producing tumor in or outside the adrenal glands. She was screened with full polysomnography because of heavy snoring, and the diagnosis of severe obstructive sleep apnea syndrome (OSAS) was made. She was treated with calcium channel blocker for three weeks, but severe hypertension persisted. After treatment with nasal continuous positive airway pressure (CPAP) was added, her blood pressure gradually lowered week by week. Concomitantly, the levels of plasma and urinary NE, urinary normetanephrine and urinary VMA were normalized following nasal CPAP therapy for 2 weeks. Additional treatments with alphaadrenergic blocker further decreased her home blood pressure. After a year, she continued nasal CPAP therapy and her blood pressure was nearly below 160/100 mmHg. Urinary NE level was slightly above normal range and other catecholamines stayed within the normal range. This case shows that patients with OSAS could develop severe hypertension through elevated sympathetic tone, mimicking pheochromocytoma. Nasal CPAP therapy is recommended not only to improve hypertension and catecholamine excess but also to distinguish the condition from pheochromocytoma. THERE is a growing body of evidence showing that patients with obstructive sleep apnea syndrome (OSAS) have a high prevalence of hypertension [1][2][3] and that treatment with nasal positive airway pressure (CPAP) successfully lower blood pressure [4][5][6][7]. A major cause of hypertension in OSAS is thought to be the increased sympathetic activity due to apnea-related episodic hypoxemia and repeated arousal [8,9]. There are a number of studies demonstrating the elevated plasma or urinary norepinephrine (NE) or epinephrine (E) levels during sleep and wakefulness in OSAS [10][11][12]. Although it has been reported that nasal CPAP therapy reduces sympathetic activity [10,[13][14][15], the detailed analysis of catecholamine metabolites and the detailed time course of biochemical normalization during nasal CPAP therapy have not been fully examined. Recently, Hoy et al. reported 5 cases of OSAS with drug-resistant hypertension [16]. Catecholaminesecreting tumor could not be identified in any of these subjects, despite high urinary NE levels. Furthermore, treatment of OSAS with nasal CPAP led to normalization of both systemic blood pressure and urinary NE levels. The authors have proposed that pseudopheochromocytoma is a rare, but treatable, presentation of OSAS. Here, we present a similar rare case of the severe hypertensive OSAS patient showing high plasma and urinary catecholamine levels without evidence of catecholamine-secreting tumor. We examined the detailed profil...

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Section: Discussionmentioning

confidence: 99%

A Case of Sleep Apnea Syndrome Manifesting Severe Hypertension with High Plasma Norepinephrine Levels

Makino¹,

Iwata²,

Fujiwara³

et al. 2006

Endocr J

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“…Plasma cortisol (CVs Ͻ6%) was determined after extraction and charcoal-dextran separation by RIA (23). Plasma epinephrine and norepinephrine (CVs Ͻ 5%) were analyzed by reverse-phase HPLC using extraction tubes (ESA, Chelmsford, MA) for the isolation procedure (24). Gas chromatography-mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Hepatic Glycogen Metabolism in Type 1 Diabetes After Long-Term Near Normoglycemia

Bischof

Bernroider²,

Krššák³

et al. 2002

Diabetes

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We tested the impact of long-term near normoglycemia (HbA 1c <7% for >1 year) on glycogen metabolism in seven type 1 diabetic and seven matched nondiabetic subjects after a mixed meal. Glycemic profiles (6.2 ؎ 0.10 vs. 5.9 ؎ 0.07 mmol/l; P < 0.05) of diabetic patients were approximated to that of nondiabetic subjects by variable insulin infusion. Rates of hepatic glycogen synthesis and breakdown were calculated from the glycogen concentration time curves between 7:30 P.M. and 8:00 A.M. using in vivo 13 C nuclear magnetic resonance spectroscopy. Glucose production was determined with D-[6,6-2 H 2 ]glucose, and the hepatic uridine-diphosphate glucose pool was sampled with acetaminophen. Glycogen synthesis and breakdown as well as glucose production were identical in diabetic and healthy subjects: 7.3 ؎ 0.9 vs. 7.1 ؎ 0.7, 4.2 ؎ 0.5 vs. 3.8 ؎ 0.3, and 8.7 ؎ 0.5 vs. 8.4 ؎ 0.7 mol ⅐ kg ؊1 ⅐ min ؊1 , respectively. Although portal vein insulin concentrations were doubled, the flux through the indirect pathway of glycogen synthesis remained higher in type 1 diabetic subjects: ϳ70 vs. ϳ50%; P < 0.05. In conclusion, combined longand short-term intensified insulin substitution normalizes rates of hepatic glycogen synthesis but not the contribution of gluconeogenesis to glycogen synthesis in type 1 diabetes. Diabetes 51:49 -54, 2002 E arly studies on glycogen metabolism in type 1 diabetic patients using liver biopsies revealed controversial results, reporting either increased or decreased liver glycogen concentrations (1-4). When liver glycogen was continuously measured with 13 C nuclear magnetic resonance (NMR) spectroscopy, it became clear that under physiologic conditions of mixed meal ingestion, poorly controlled type 1 diabetic patients indeed exhibit a defect of net liver glycogen synthesis that accumulates throughout the day and is most pronounced after dinner (5). Furthermore, these authors reported higher contribution of the indirect (carbon 3 compounds 3 glucose 3 glucose-6-phosphate 3 glucose-1-phosphate 3 UDP-glucose 3 glycogen) compared with the direct pathway of glycogen synthesis (glucose 3 glucose-6-phosphate 3 glucose-1-phosphate 3 UDP-glucose 3 glycogen) (5,6). We recently found that type 1 diabetic subjects with poor metabolic control, as evidenced by an HbA 1c of ϳ9%, also present with reduced glycogen breakdown during the night after mixed meal ingestion (7). Short-term intensified insulin treatment for 24 h, resulting in near-normal plasma glucose concentrations, improved both defects in glycogen synthesis and breakdown that, however, were still ϳ52 and ϳ26% lower, respectively, compared with nondiabetic subjects.At present, even advanced insulin substitution regimens do not resemble the physiologic insulin secretion pattern, since peripheral administration of insulin distorts the portal-to-peripheral insulin gradient and thereby affects hepatic glycogen turnover (8). Furthermore, the physiologic inhibition of glucagon secretion by insulin is impaired (9), giving rise to the portal vein glucagon-to-insu...

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“…Correct understanding of the pathways of catecholamine metabolism has provided a rationale for many subsequent studies examining the utility of measurements of plasma free metanephrines for diagnosis of pheochromocytoma [5][6][7][8][9][10][11]. At the NIH, the superiority of plasma free metanephrines over other tests was established in a series of 3 published reports [5,6,8], culminating in a study involving over 850 patients, including 214 with pheochromocytoma [8].…”

Section: Current Progress In Diagnosismentioning

confidence: 99%

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

Eisenhofer¹,

Siegert²,

Kotzerke³

et al. 2008

Horm Metab Res

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Findings from five independent studies -with close to 350 patients with pheochromocytoma and more than 2 500 in whom the tumor was excluded -indicate that measurements of plasma free metanephrines provide an overall diagnostic sensitivity of 98 % and specificity of 92 %. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing truefrom false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with 131 I-labelled miodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies.

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Diagnostic Efficacy of Unconjugated Plasma Metanephrines for the Detection of Pheochromocytoma

Abstract: Plasma metanephrines offer improved efficacy for the diagnosis of pheochromocytoma. Less variability in response to external factors may favor plasma metanephrines in the screening for this disease. Arch Intern Med. 2000;160:2957-2963

Cited by 167 publications

References 16 publications

A Case of Sleep Apnea Syndrome Manifesting Severe Hypertension with High Plasma Norepinephrine Levels

A Case of Sleep Apnea Syndrome Manifesting Severe Hypertension with High Plasma Norepinephrine Levels

Hepatic Glycogen Metabolism in Type 1 Diabetes After Long-Term Near Normoglycemia

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

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