Interpreting Normetanephrines-the Significance of Clinical Context

Abstract Introduction: Pheochromocytoma ranges in presentation, but the diagnostic hallmarks are increased catecholamine secretion in patients with an adrenal mass. However, interpretation requires consideration of the clinical state. Case: A 60-year-old man presented with 6 months of episodic flushing, night sweats, fatigue, back pain, and 20-pound weight loss. Vitals were notable for hypotension and mild tachycardia. He was thin with evidence of hyperpigmentation. Contrasted CT showed 15 cm heterogeneous masses of both adrenals and a rib lesion. Plasma normetanephrines were elevated on two separate measures (526 and 1,398 pg/mL, nl <=148). Plasma metanephrines were normal. Urine normetanephrines were increased 4-fold (2,165mcg/g Cr, n 108–524). Labs noted low DHEA-S (2 mcg/dL, n 38–313), high ACTH (204 pg/mL, n 6–50), random cortisol (5.2 mcg/dL, n 3.5–18.3), undetectable aldosterone, and high plasma renin activity (83 ng/mL/h, n 2.9–10.8). Cortisol peaked at 6.7 mcg/dL 1 hour after 250mcg of cosyntropin. MRI revealed over 15cm infiltrating masses arising from adrenals with modest flare on T2 imaging. Dotatate PET/CT showed mild uptake of bilateral adrenals and metastases to liver and bone. He was started on steroid replacement and doxazosin for presumed pheochromocytoma. He was transferred to our facility where he remained hypotensive despite adequate glucocorticoid and mineralocorticoid replacement. Once stabilized, repeat plasma normetanephrines were insignificant (218 pg/mL, n 0–145) and chromogranin was normal (68 ng/mL, n<93). Biopsy of the rib lesion confirmed diffuse large B-cell lymphoma. Discussion: Pheochromocytoma classically presents in the outpatient setting with palpitations, diaphoresis, pallor, and paroxysmal hypertension. Rarely, it results in hypertensive emergencies requiring hospitalization. In patients with catecholamine excess and an adrenal mass, pheochromocytoma is usually suspected. 3-fold or more increases of normetanephrines or metanephrines above upper cutoffs are rarely false-positives. However, this assumes clinical stability. Sympathoadrenal activation is a physiologic response to acute illness. Metanephrines in critically ill patients without pheochromocytoma approached those of pheochromocytoma in one study. Levels normalized upon recovery from illness, highlighting the importance of verifying biochemistries once the patient is stable. The degree of elevation in normetanephrines seen in this patient was a physiologic response to adrenal insufficiency and clinical instability. Pathology confirmed lymphoma rather than pheochromocytoma for which he was started on chemotherapy. Conclusion: Elevated normetanephrines is an appropriate physiological response in the acutely ill. Careful consideration of the clinical picture in conjunction with biochemical data is critical.

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Inappropriately High Plasma Renin Activity Accompanies Chronic Loss of Renal Function

American Journal of Nephrology ◽

10.1159/000169046 ◽

1996 ◽

Vol 16 (6) ◽

pp. 471-477 ◽

Cited By ~ 8

Author(s):

Nesmo L. Yeyati ◽

Horacio J. Adrogué

Keyword(s):

Renal Function ◽

Plasma Renin Activity ◽

Plasma Renin ◽

High Plasma ◽

Renin Activity

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Abstract P101: Primary Aldosteronism Screening In At-risk Populations

Hypertension ◽

10.1161/hyp.78.suppl_1.p101 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Winnie Nhan ◽

Caitlin Urban ◽

Yuxuan Chen ◽

Lili Zhao ◽

Lynn Holevinski ◽

...

Keyword(s):

At Risk ◽

Primary Aldosteronism ◽

Adrenal Mass ◽

Antihypertensive Agents ◽

Outpatient Setting ◽

Metabolic Complications ◽

Obstructive Sleep ◽

Academic Settings ◽

At Risk Populations ◽

End Stage

Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA is associated with higher rates of cardiovascular, metabolic, and renal comorbidities as compared to equivalent primary hypertension (HTN). Objective: To evaluate the rates and patterns of PA screening across various at-risk populations. Methods: We performed a retrospective review of adult patients seen in a university-based outpatient setting between 1/1/17-6/30/20, who had HTN plus at least one of the following criteria: 1) taking ≥3 antihypertensive agents (resistant HTN); 2) age <35; 3) obstructive sleep apnea (OSA); 4) hypokalemia; or 5) an adrenal mass. We excluded patients with adrenal insufficiency, congenital adrenal hyperplasia, severe renal disease, and end stage heart failure. Results: We identified 93,362 patients (54.6% men, mean age 64±16 y, 82.3% white, 12.8% black, 2.3% Asian) meeting at least one PA screening criterion. Of these, 3.4% were screened for PA. Screening occurred in 2.7% (1,813/66,185) of patients with resistant HTN; 4.2% of those with HTN and OSA (1,297/29,322) or hypokalemia (599/5,387); 5.1% of those <35 y (461/8,573); and 46.5% (452/972) of patients with HTN and an adrenal mass. Multiple logistic regression showed that the odds of screening were highest in patients with hypokalemia: OR: 3.4 (3.2-3.7), and were independent of having atrial fibrillation or myocardial infarction. Among patients with resistant HTN and those with HTN and OSA, women vs. men (OR: 1.2-1.4) and blacks vs. all other races (OR: 2-2.6, p <0.0001 for all) were more likely to be screened. Conversely, among patients <35 y and those with adrenal masses, there were no race or sex differences. Although ~8 years younger, patients with resistant HTN and HTN+OSA screened had higher prevalence of chronic kidney disease, cerebrovascular accidents, dyslipidemia, and diabetes than those not screened. Conclusions: PA remains vastly under-recognized, even in large academic settings. Consideration for PA is given more often after comorbidities have developed. Enhancing awareness and screening rates for PA are critical for preventing cardio-renal and metabolic complications in many patients with HTN.

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Influence of converting-enzyme inhibition on rat des-angiotensin I-angiotensinogen

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1984.246.2.e129 ◽

1984 ◽

Vol 246 (2) ◽

pp. E129-E133 ◽

Cited By ~ 1

Author(s):

E. Clauser ◽

J. Bouhnik ◽

M. F. Gonzalez ◽

P. Corvol ◽

J. Menard

Keyword(s):

Plasma Levels ◽

Renin Angiotensin System ◽

Plasma Renin ◽

High Plasma ◽

Angiotensin I ◽

Converting Enzyme Inhibition ◽

The Difference ◽

Indirect Assay ◽

Captopril Treatment ◽

Adrenalectomized Rats

The effects of high plasma renin levels on plasma levels of both total immunoreactive angiotensinogen (direct radioimmunoassay) and intact angiotensinogen measured by angiotensin I released by renin (indirect assay) were studied in sodium-depleted rats both with and without captopril treatment and in adrenalectomized rats. The direct assay measures both intact angiotensinogen and des-angiotensin I-angiotensinogen, its residue cleaved by renin. The indirect assay measures only intact angiotensinogen. Neither sodium depletion, captopril treatment, nor adrenalectomy modified the circulating levels of total angiotensinogen. However these treatments produced a decrease in intact angiotensinogen that was in proportion to the elevation of renin levels. The difference between the two assays for angiotensin represents the level of des-angiotensin I-angiotensinogen and correlated satisfactorily with the plasma levels of renin. Identical correlations were observed in adrenalectomized rats and captopril-treated rats. We conclude that des-angiotensin I-angiotensinogen levels are an index of activation of the renin-angiotensin system dependent on the circulating level of renin.

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Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90693.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. E343-E350 ◽

Cited By ~ 15

Author(s):

Jason D. Fowler ◽

Stacy B. Krueth ◽

David A. Bernlohr ◽

Stephen A. Katz

Keyword(s):

Adipose Tissue ◽

Cardiac Tissue ◽

Plasma Concentrations ◽

Renin Angiotensin System ◽

Plasma Renin ◽

Treated Group ◽

Rat Plasma ◽

High Plasma ◽

Tissue Growth

The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS.

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High plasma renin activity associates with obesity-related diabetes and arterial hypertension, and predicts persistent hypertension after bariatric surgery

Cardiovascular Diabetology ◽

10.1186/s12933-021-01310-w ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Lucia La Sala ◽

Elena Tagliabue ◽

Elaine Vieira ◽

Antonio E Pontiroli ◽

Franco Folli

Keyword(s):

Bariatric Surgery ◽

Glucose Tolerance ◽

Plasma Renin Activity ◽

Laparoscopic Gastric Banding ◽

Plasma Renin ◽

High Plasma ◽

Renin Activity ◽

Glucose Levels ◽

Before And After ◽

Severely Obese

Abstract Background Information about the renin–angiotensin–aldosterone system (RAAS) in obese individuals before and after bariatric surgery is scarce. Aim of this study was to analyze the RAAS in severely obese subjects, in relation to anthropometric and metabolic variables, with special reference to glucose tolerance. Methods 239 subjects were evaluated at baseline, and 181 one year after bariatric surgery [laparoscopic gastric banding (LAGB)]. Results At baseline, renin (plasma renin activity, PRA) was increased from normal to glucose tolerance and more in diabetes, also correlating with ferritin. After LAGB, the decrease of PRA and aldosterone was significant in hypertensive, but not in normotensive subjects, and correlatied with decrease of ferritin. PRA and glucose levels were predictive of persistent hypertension 1 year after LAGB. Conclusions These data support the role of RAAS in the pathophysiology of glucose homeostasis, and in the regulation of blood pressure in obesity. Ferritin, as a proxy of subclinical inflammation, could be another factor contributing to the cross-talk between RAAS and glucose metabolism.

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Primary aldosteronism due to aldosterone-producing adrenocortical adenoma with high plasma renin activity and massive elevation of plasma aldosterone concentration in a maintained hemodialysis patient

Nihon Toseki Igakkai Zasshi ◽

10.4009/jsdt.41.329 ◽

2008 ◽

Vol 41 (5) ◽

pp. 329-334

Author(s):

Soh Suzuki ◽

Toko Nakamura ◽

Makoto Hasegawa ◽

Norimasa Katayama ◽

Hidetaka Sumitomo ◽

...

Keyword(s):

Plasma Renin Activity ◽

Primary Aldosteronism ◽

Hemodialysis Patient ◽

Plasma Renin ◽

High Plasma ◽

Plasma Aldosterone ◽

Renin Activity ◽

Adrenocortical Adenoma ◽

Plasma Aldosterone Concentration

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High Plasma Renin Activities in Primary Aldosteronism with Malignant Hypertension

Japanese Heart Journal ◽

10.1536/ihj.21.423 ◽

1980 ◽

Vol 21 (3) ◽

pp. 423-428 ◽

Cited By ~ 4

Author(s):

Taisuke IWAOKA ◽

Teruhisa UMEDA ◽

Tatsuo SATO ◽

Shoichi KATSURAGI ◽

Tadao TAKEUCHI

Keyword(s):

Primary Aldosteronism ◽

Plasma Renin ◽

High Plasma ◽

Malignant Hypertension

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The Natural History of Hypertension in Turkeys

Clinical Science ◽

10.1042/cs055213s ◽

1978 ◽

Vol 55 (s4) ◽

pp. 213s-215s ◽

Cited By ~ 1

Author(s):

A. Pagnan ◽

A. C. Pessina ◽

G. Thiene ◽

C. Dal Palù

Keyword(s):

Natural History ◽

Salt Intake ◽

Pathological Finding ◽

Plasma Renin ◽

High Plasma ◽

Plasma Aldosterone ◽

Atherosclerotic Plaques ◽

High Salt Intake ◽

History Of ◽

High Concentrations

1. Variables involved in the genesis of hypertension in male broad-breasted white turkeys include social environment, obesity and high salt intake. 2. The hypertension is characterized by low plasma renin activity and, with increasing age, normal to high plasma aldosterone. 3. Medionecrosis of the abdominal aorta is a common pathological finding. 4. The absence of atherosclerotic plaques is probably related to the high concentrations of alpha-lipoproteins.

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Concurrence of thyrotoxicosis and Gitelman’s syndrome-associated hypokalemia-induced periodic paralysis

Pediatric Reports ◽

10.4081/pr.2012.e18 ◽

2012 ◽

Vol 4 (2) ◽

pp. 18 ◽

Cited By ~ 4

Author(s):

Shinsaku Imashuku ◽

Tomoko Teramura-Ikeda ◽

Naoko Kudo ◽

Shigehiro Kaneda ◽

Toshihiro Tajima

Keyword(s):

Plasma Renin ◽

High Plasma ◽

Periodic Paralysis ◽

Psychiatric Clinic ◽

Homozygous Mutation ◽

Gitelman's Syndrome ◽

Asian Men ◽

Old Japanese ◽

History Of ◽

Solute Carrier

A 16-year-old Japanese boy with a history of truancy had been treated at a psychiatric clinic. When the patient was referred to us for hypokalemia-associated paralysis, the diagnosis of thyrotoxic hypokalemic periodic paralysis was made, common in Asian men. Subsequently, the patient was found to have persistently high plasma renin and aldosterone levels. Thus, solute carrier family 12 member 3 gene (<em>SLC12A3</em>) analysis was performed. A novel missense homozygous mutation CTC->CAC at codon 858 (L858H) was found for which the patient was homozygous and his non-consanguineous parents heterozygote. These findings indicated that the patient developed hypokalemia-associated paralysis concurrently with thyrotoxicosis and Gitelman’s syndrome. This case underscores the importance of careful examinations of adolescents with complaints of truancy as well as of precise determinations of the causes of hypokalemia-associated paralysis.

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