eMedicine Specialties > Endocrinology > Adrenal Gland

Conn Syndrome: Differential Diagnoses & Workup

Author: Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University
Contributor Information and Disclosures

Updated: May 21, 2009

Differential Diagnoses

C-11 Hydroxylase Deficiency
C-17 Hydroxylase Deficiency
Cushing Syndrome
Hypertension
Hypertension, Malignant
Renovascular Hypertension

Other Problems to Be Considered

Liddle syndrome - This is a rare autosomal dominant disorder resulting in a continuously activated sodium channel with excessive sodium reabsorption in the renal distal tubule. Levels of renin and aldosterone are low.

Renin-secreting tumor - These are rare tumors arising from the juxtaglomerular apparatus.

Exogenous mineralocorticoid

Excessive licorice intake - In this situation, the glycyrrhizinic acid component inhibits 11beta-hydroxysteroid dehydrogenase, impairing conversion of cortisol to cortisone in the kidneys; hence, cortisol binds to mineralocorticoid receptors and acts as a mineralocorticoid.

Workup

Laboratory Studies

Routine laboratory studies can show hypernatremia, hypokalemia, and metabolic alkalosis resulting from the action of aldosterone on the distal tubule of the kidney (ie, enhancing sodium reabsorption and potassium and hydrogen ion excretion).

Almost 20% of patients have impaired glucose tolerance resulting from the inhibitory affect of hypokalemia on insulin action and secretion; however, diabetes mellitus is rare.

Normokalemia does not exclude primary hyperaldosteronism. Several studies have shown that 7-38% of patients with primary hyperaldosteronism have baseline serum levels of potassium that are in the reference range. The hypokalemia becomes evident with liberalization of dietary sodium intake.

Typically, renin levels are suppressed to less than 1 ng/mL/h in patients with primary hyperaldosteronism, and levels do not stimulate above 2 ng/mL/h with diuretics and upright posture.

Because of this finding, some experts suggest that suppressed renin levels should be used as a screen for detecting primary hyperaldosteronism. However, in a 1993 series by Bravo, 30% of patients had renin levels that rose to greater than 2 ng/mL/h when appropriately stimulated by sodium deprivation.3

  • Thus, a nonsuppressed renin level in the setting of diuretic administration does not exclude a diagnosis of primary aldosteronism.
  • Furthermore, a subnormal renin level (<2 ng/mL/h) can be found in 30% of patients with essential hypertension; thus, a low renin level is not specific for primary aldosteronism.
  • In order to improve the sensitivity of a screening test for primary hyperaldosteronism, a ratio of plasma aldosterone (PA) activity to PRA can be calculated.

PA/PRA ratio (obtained in the morning) 20 or greater (with a PA ≥15 ng/dL) provide a sensitivity of 100% and a specificity of 80%, indicating the need for further study.

  • Others use a ratio greater than 30 and a PA level greater than 20 ng/dL, with a sensitivity of 90% and a specificity of 91%.
  • Note, however, that this ratio should be calculated when the patient is not taking interfering medications. Spironolactone should be stopped for 6 weeks prior to testing. Eplerenone, another aldosterone receptor antagonist, can also interfere with testing and should be stopped for at least 2 weeks before.
  • Alpha blockers, such as doxazosin, do not interfere with the PA/PRA ratio. Beta blockers and calcium channel blockers do not affect the diagnostic accuracy of the ratio in most cases.
  • Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) can falsely elevate PRA, leading to a lower PA/PRA ratio; therefore, the presence of suppressed PRA in a patient treated with a diuretic or, especially, an ACE inhibitor or ARB, is a strong predictor for primary hyperaldosteronism.
  • Because of limited specificity, a positive screening test result should be followed by a confirmatory test.

When the PA/PRA ratio is 20 or greater with a PA 15 ng/dL or greater, confirmatory tests need to be performed. The most commonly used confirmatory test is a 24-hour urine aldosterone level obtained after 3 days of salt loading. The patient can be instructed to maintain a sodium intake of at least 200 mEq/d (1 teaspoon of salt 3 times daily) for 3 days.

Care must be taken to ensure that potassium stores are replete and that the patient is normokalemic at the time of testing, because hypokalemia can inhibit aldosterone release and salt loading can exacerbate hypokalemia.

A 24-hour aldosterone excretion rate of greater than 14 mcg (with a concomitant 24-h urine sodium >200 mEq) is diagnostic of primary hyperaldosteronism.

Imaging Studies

Computed tomography (CT) scanning4

  • Once the diagnosis of primary hyperaldosteronism is confirmed, the next step is to differentiate the subtypes and to identify surgically curable disease. For practical purposes, this means distinguishing between an adrenal adenoma and bilateral hyperplasia.
  • In general, patients with adenomas are younger, have more severe hypertension and hypokalemia, and have higher urinary aldosterone levels than patients with hyperplasia. However, these clinical parameters are not reliable enough to accurately distinguish unilateral disease from bilateral disease.
  • Abdominal CT scanning is considered the procedure of choice.
  • Some investigators suggest that when a solitary unilateral macroadenoma (>1 cm) is detected in the setting of unequivocal hyperaldosteronism in a young patient, unilateral adrenalectomy is indicated.
  • Because of the age-dependent risk that a solitary unilateral adrenal macroadenoma may be a nonfunctioning adenoma, some experts believe that adrenal vein sampling4 should be performed in patients older than 40 years.
  • The problem arises with lesions that are smaller than 1 cm, which may be missed by CT scanning. Furthermore, bilateral lesions are not always diagnostic of adrenal hyperplasia because of the high incidence of adrenal incidentaloma. In these cases, adrenal vein sampling is the only way to make a firm diagnosis.
  • Overall, CT scanning has a sensitivity of 67-85% in patients with primary hyperaldosteronism.

Scanning with iodine I-131 iodocholesterol (NP-59, a precursor of aldosterone): This has also been used to detect unilateral functional adrenal lesions. In experienced hands, NP-59 scanning has a sensitivity of 88%. However, this procedure is not widely available, requires careful patient preparation, is very expensive, and rarely detects lesions larger than 1.5 cm. See the image below.

Scintigram obtained by using iodine-131-6β-i...

Scintigram obtained by using iodine-131-6β-iodomethylnorcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.

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Scintigram obtained by using iodine-131-6β-i...

Scintigram obtained by using iodine-131-6β-iodomethylnorcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.


Magnetic resonance imaging (MRI) - MRI is not more sensitive than CT scanning. See the image below.

Magnetic resonance imaging (MRI) scan in a patien...

Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.

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Magnetic resonance imaging (MRI) scan in a patien...

Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.


Other Tests

Postural studies are cumbersome to perform in most office settings and have proven less useful since the recognition of a renin-responsive subtype of adrenal adenoma. They are rarely used in current practice.

Procedures

Because of the difficulties in distinguishing hyperplastic lesions from adenomatous lesions, adrenal venous sampling4 has become the preferred diagnostic approach in patients with equivocal findings after CT scanning.

  • The adrenal veins are catheterized via a percutaneous femoral venous approach.
  • Right and left venous catheters should be placed in the ipsilateral adrenal veins to prevent errors in handling the samples.
  • Blood is obtained from both adrenal veins and the inferior vena cava and is then assayed for aldosterone and cortisol. Cannulation of the right adrenal vein is technically difficult because of the short length of this vessel. The left adrenal vein is longer, allowing for more stable catheter placement.
  • In order to document placement of the catheters within the adrenal veins, an adrenal-to – vena cava cortisol ratio (post-corticotropin) is obtained and should be greater than 5-10. Because the secretion of aldosterone from either an adenoma or hyperplasia may be pulsatile, samples are obtained under maximum stimulation following cosyntropin (corticotropin) infusion. Several different protocols have been used. In a 1996 article, Doppman and Gill recommended a 250-mcg bolus of corticotropin (Cortrosyn) followed by a corticotropin infusion, with samples collected at baseline and 15 minutes following the infusion.5 An aldosterone-to-cortisol ratio, post-corticotropin, can then be calculated for each sampling site. Most patients with a unilateral source of aldosterone have adrenal-to-adrenal aldosterone-to-cortisol ratios greater than 4. Ratios less than 3 suggest hyperplasia, and values of 3-4 are indeterminate results.

More on Conn Syndrome

Overview: Conn Syndrome
Differential Diagnoses & Workup: Conn Syndrome
Treatment & Medication: Conn Syndrome
Follow-up: Conn Syndrome
Multimedia: Conn Syndrome
References
Further Reading
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References

  1. Born-Frontsberg E, Reincke M, Rump LC, et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn's Registry. J Clin Endocrinol Metab. Apr 2009;94(4):1125-30. [Medline].

  2. Bernini G, Galetta F, Franzoni F, et al. Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism. J Hypertens. Dec 2008;26(12):2399-405. [Medline].

  3. Bravo EL. Primary aldosteronism: new approaches to diagnosis and management. Cleve Clin J Med. Sep-Oct 1993;60(5):379-86. [Medline].

  4. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. Sep 2008;93(9):3266-81. [Medline].

  5. Doppman JL, Gill JR Jr. Hyperaldosteronism: sampling the adrenal veins. Radiology. Feb 1996;198(2):309-12. [Medline].

  6. Carey RM. Primary aldosteronism. Horm Res. Jan 2009;71 Suppl 1:8-12. [Medline].

  7. Wu VC, Chang HW, Liu KL, et al. Primary aldosteronism: diagnostic accuracy of the losartan and captopril tests. Am J Hypertens. May 14 2009;[Medline].

  8. Letavernier E, Peyrard S, Amar L, et al. Blood pressure outcome of adrenalectomy in patients with primary hyperaldosteronism with or without unilateral adenoma. J Hypertens. Sep 2008;26(9):1816-23. [Medline].

  9. Al Fehaily M, Duh QY. Clinical manifestation of aldosteronoma. Surg Clin North Am. Jun 2004;84(3):887-905. [Medline].

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  11. Gill JR. Primary aldosteronism: Strategies for diagnosis and treatment. The Endocrinologist. 1991;1:365-9.

  12. Hirohara D, Nomura K, Okamoto T, et al. Performance of the basal aldosterone to renin ratio and of the renin stimulation test by furosemide and upright posture in screening for aldosterone-producing adenoma in low renin hypertensives. J Clin Endocrinol Metab. Sep 2001;86(9):4292-8. [Medline].

  13. Jabbour SA, De Papp AE. Pitfalls in the diagnosis and management of primary hyperaldosteronism. The Endocrinologist. 1999;9:395-8.

  14. Montori VM, Schwartz GL, Chapman AB, et al. Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. Mayo Clin Proc. Sep 2001;76(9):877-82. [Medline].

  15. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. Mar 2004;89(3):1045-50. [Medline].

  16. Rose BD, Kaplan NM. Approach to the patient with hypertension and hypokalemia. UpToDate [CD-ROM and online]. 1997;1-8.

  17. Seiler L, Rump LC, Schulte-Monting J, et al. Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication. Eur J Endocrinol. Mar 2004;150(3):329-37. [Medline].

  18. Vallotton MB. Primary aldosteronism. Endocrine Investigation. 1996;45:47-60.

  19. Weinberger MH, Fineberg NS. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med. Sep 27 1993;153(18):2125-9. [Medline].

  20. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. Feb 8 2007;356(6):601-10.

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Keywords

Conn syndrome, Conn's syndrome, adrenal, adrenal gland, adrenal glands, hyperaldosteronism, aldosteronism, adenoma, spironolactone, renin, primary hyperaldosteronism, adrenalectomy, hypertension, hypokalemia, adrenal hyperplasia, unilateral aldosterone-producing adenoma, bilateral adrenal hyperplasia, idiopathic hyperaldosteronism, increased aldosterone secretion, primary hypersecretion of aldosterone, secondary hypertension, renin-responsive adenoma, primary adrenal hyperplasia, glucocorticoid-remediable aldosteronism

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Contributor Information and Disclosures

Author

Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University
Serge A Jabbour, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Thyroid Association, Endocrine Society, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Barry J Goldstein, MD, PhD, Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Professor, Department of Internal Medicine, Thomas Jefferson University
Barry J Goldstein, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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