eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hyperaldosteronism: Differential Diagnoses & Workup

Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece
Coauthor(s): Antony Lafferty, MB ChB, FRACP, Senior Lecturer of Pediatric Endocrinology, Monash University Department of Pediatrics, National Institutes of Health, Bethesda, MD, and Princess Margaret Hospital for Children, Perth, Western Australia
Contributor Information and Disclosures

Updated: Mar 4, 2009

Differential Diagnoses

Congenital Adrenal Hyperplasia

Other Problems to Be Considered

Secondary hyperaldosteronism
Apparent mineralocorticoid excess (types I and II)
Liddle syndrome
Glucocorticoid resistance
Exogenous mineralocorticoid excess
Drug-induced apparent mineralocorticoid excess

Workup

Laboratory Studies

The evaluation of a patient in whom hyperaldosteronism is suggested has several distinct stages. The finding of hypertension, hypokalemia, or both most commonly precipitates the decision to screen. The presence of these 2 features together has a 50% predictive value. The first step entails confirmation that hyperaldosteronism is present and, if it is not present, exclusion of other conditions that produce a similar picture. The next step involves differentiating primary from secondary causes of hyperaldosteronism.

  • Aldosterone-to-renin ratio
    • The aldosterone-to-renin ratio (ARR) is the most sensitive means of differentiating primary from secondary causes of hyperaldosteronism. It can be obtained under random conditions of sodium intake.
    • Values obtained in the upright position (standing for 2 h) have greater sensitivity than supine test results. Patients should be normokalemic because hypokalemia suppresses aldosterone secretion. A ratio of plasma aldosterone (ng/dL) to plasma renin activity (ng/mL/h) of more than 20 with a plasma aldosterone level greater than 15 ng/dL is highly suggestive of primary aldosteronism.
    • The principle behind this test is that as aldosterone secretion rises, plasma renin activity (PRA), a measure of the rate of production of angiotensin I from endogenous angiotensinogen, in ex vivo testing should fall because of sodium retention. This negative feedback response should occur when the aldosterone levels are supraphysiologic for that individual patient, and PRA may fall well before plasma aldosterone is clearly increased.
    • When using this screening test, the aldosterone must be elevated in addition to having an elevated ARR because, with the more sensitive PRA assays, having an ARR in excess of 20 without having an elevated aldosterone is possible.
    • The most important factors that can interfere with the diagnostic reliability of the ARR test are drugs and renal impairment. Beta-blockers can reduce PRA levels, leading to a falsely elevated ratio, and dihydropyridine calcium antagonists (eg, nifedipine) can reduce aldosterone levels, tending to lead to a falsely normal ratio in some patients with primary aldosteronism. Diuretics tend to induce secondary aldosteronism. Spironolactone, an aldosterone receptor antagonist, can raise plasma renin levels. Spironolactone and diuretics should be withheld for 6 weeks, and beta-blockers and dihydropyridine calcium antagonists should be withheld for 5-7 days before testing. Patients' hypertension can be controlled with diltiazem and alpha-blockers when testing for primary aldosteronism. Renal impairment can lead to a high aldosterone-to-renin ratio in patients without primary aldosteronism because fluid retention suppresses PRA and hyperkalemia stimulates aldosterone secretion.
    • After a positive screening test result, subsequent testing is directed at confirming aldosterone secretory autonomy and differentiating an aldosterone-producing adenoma (APA), for which surgery is currently the first line of treatment, from idiopathic hyperaldosteronism (IHA), which is usually treated medically. The possibility of glucocorticoid-remediable aldosteronism (GRA), which accounts for approximately 1% of primary aldosteronism, should be kept in mind.
  • Saline infusion test
    • The saline infusion test can confirm autonomous aldosterone secretion. Other tests described include the measurement of urine aldosterone excretion during oral salt loading or the fludrocortisone suppression test. All tests rely on the principle that a lack of suppression of aldosterone excretion with intravascular expansion is indicative of aldosterone production.
    • The saline infusion test is performed by infusing 1140 mL/m2 body surface area (BSA) of 0.9% saline over 4 hours. Plasma aldosterone and cortisol are measured before and at the end of infusion. Those without primary aldosteronism should have a fall in plasma aldosterone levels to less than 10 ng/dL. Plasma aldosterone values greater than 10 ng/dL confirm primary aldosteronism, and levels from 5-10 may be considered borderline.
    • Cortisol levels are taken to exclude an adrenocorticotropic hormone (ACTH)-mediated rise in aldosterone.
    • Consider the risks of fluid expansion or hypokalemia in susceptible patients.
  • Oral salt loading
    • The oral salt loading test consists of administering 12 g/1.7m2 BSA of sodium chloride tablets and ad libitum diet for 3 days followed by a 24-hour urinary aldosterone measurement.
    • Urinary aldosterone values greater than 10-14 mcg/d with a urine sodium excretion greater than 250 nmol/d are considered diagnostic of primary aldosteronism.
  • Captopril test
    • The captopril test has also been used for screening. Its use is based on the principle that inhibition of angiotensin II production should not affect autonomous secretion of aldosterone in primary aldosteronism.
    • Application of the 60-minute aldosterone-to-renin ratio after 25 mg of oral captopril yielded a sensitivity of 100% and specificity of 83% for diagnosis of primary aldosteronism, but the test was only marginally better than baseline values. Somewhat lower sensitivity was noted in a larger study using aldosterone and PRA 90 minutes after a 50-mg dose of captopril.
  • Fludrocortisone suppression test: The fludrocortisone suppression test uses fludrocortisone (0.1 mg q6h) and salt loading. It is less frequently used and was described by Gordon et al in 1995.5,6
  • Tests to differentiate between an APA and other forms of primary aldosteronism
    • Postural testing: Postural testing is best performed after overnight recumbency. An intravenous catheter is inserted at 7 am, and baseline aldosterone, cortisol, and PRA are obtained at 8 am. After 2 hours of ambulation, repeat aldosterone, cortisol, and PRA are obtained. Typically, APAs are angiotensin II unresponsive, and a fall in aldosterone over 2 hours is observed in parallel with reduced circadian ACTH and cortisol release. A rise in aldosterone is observed in IHA. Cortisol levels are used to validate the test, and a rise in cortisol release suggests an ACTH surge, which invalidates the test. Diagnostic accuracy of 85% is reported.
    • 18-Hydroxycorticosterone: Levels of 18-hydroxycorticosterone are typically elevated (>100 ng/dL) in APA and are significantly lower in patients with IHA. Although a diagnostic accuracy of 82% is reported, 18-hydroxycorticosterone levels have been noted to parallel the severity of aldosteronism, and levels of aldosterone and clinical severity are greater in APA than IHA.
    • Dexamethasone suppression
      • In cases of bilateral aldosterone secretion or when the diagnosis is suspected on the basis of family history, GRA can be excluded with a 4-day dexamethasone suppression test (0.5 mg q6h).
      • The aldosterone and renin levels can be measured before testing, at 2 days, and at 4 days of suppression testing. The typical response in patients without GRA is for the aldosterone levels to fall by approximately 50% and return to the reference range by the end of testing; however, persistent suppression of aldosterone levels to less than 4 ng/dL are reported in GRA.
      • The test achieves a sensitivity of 92% and a specificity of 100% for the diagnosis of GRA compared with direct genetic testing.
      • Biochemically unique, markedly elevated levels of 18-oxocortisol and 18-hydroxycortisol (>100 nmol/d) are also observed in GRA.
      • Mutation analysis for the hybrid gene that gives rise to GRA is now available by Southern blotting or a long–polymerase chain reaction (PCR) technique. This is likely to supersede the time-intensive dexamethasone suppression test.

Imaging Studies

  • CT scanning of the adrenal glands
    • Adrenal CT scanning is 70% sensitive in detecting APAs. Mean APA size was 1.8 cm in one large series; however, 19% of these tumors were less than 1 cm.
    • Adrenal incidentalomas are very uncommon in children, meaning that in the presence of hyperaldosteronism, a positive finding on adrenal CT scanning makes the diagnosis of an adenoma very likely.
    • Aldosteronomas are typically lipid-rich and commonly appear as homogeneous lesions with a low Hounsfield number consistent with this high lipid content.
  • Adrenal scintigraphy has insufficient diagnostic accuracy for routine use in diagnosing adrenal adenomas.

Procedures

  • Adrenal venous sampling
    • Adrenal venous sampling requires considerable skill. It can be performed as an outpatient procedure, although younger children may need general anesthesia.
    • Infusion of ACTH into a peripheral vein (50 mcg/h, starting 30 min before sampling) masks the effects of confounding ACTH peaks during sampling.
    • Venography is avoided to reduce the risk of adrenal hemorrhage.
    • With comparison of simultaneous aldosterone, cortisol ratios in the adrenal veins and the inferior vena cava allow detection of unilateral or bilateral sources of aldosterone hypersecretion.
    • Although the cut-off for lateralization is controversial, both 5:1 and 10:1 have been advocated. Nevertheless, adrenal venous sampling is the criterion standard for the differential diagnosis of primary aldosteronism.

Histologic Findings

  • APA
    • Unlike cortisol-producing adrenocortical tumors, in which the remaining ipsilateral and contralateral glands are commonly atrophic, the nontumorous cortex may show hyperplasia of the zona glomerulosa, forming either a broad zone locally or thickening of the entire cortex, with tongues of glomerulosalike cortex extending inward from the subcapsular region.
    • This appearance has been reported in up to one third of patients with aldosteronoma and suggests that the tumor has arisen from within an area that was hyperplastic, although neither an external stimulus nor an intrinsic defect has been found to date.
  • IHA
    • IHA is a disease of the zona glomerulosa with a variable macroscopic appearance that can range from hyperplasia with micronodules and macronodules, hyperplasia without nodules, and normal appearing zona glomerulosa with micronodules. The glands may be normal in weight or heavy.
    • The normal microscopic appearance of the zona glomerulosa is of small discontinuous subcapsular nests of cells. In hyperplasia, the zona glomerulosa may form continuous bands of cells that may be visibly thickened, as either a continuous sheet or focally extending as tongues into the adjacent cortex. This process may be focal or diffuse and may vary from one part of the gland to another, requiring multiple sections.
  • Glucocorticoid remediable hyperaldosteronism (FH-I): This disorder is the result of formation of a hybrid gene that leads to ACTH-mediated mineralocorticoid synthesis by the zona fasciculata. Histologically, evidence suggests hyperplasia of this zone in addition to the zona glomerulosa.
  • Nonglucocorticoid remediable hyperaldosteronism (FH-II and III): This autosomal dominant disorder (FH-II) has been linked to a locus on chromosome 7p22. Histologically, evidence suggests adrenocortical hyperplasia and/or hypertrophy and the presence of adenomas.

More on Hyperaldosteronism

Overview: Hyperaldosteronism
Differential Diagnoses & Workup: Hyperaldosteronism
Treatment & Medication: Hyperaldosteronism
Follow-up: Hyperaldosteronism
Multimedia: Hyperaldosteronism
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

hyperaldosteronism, aldosteronism, primary aldosteronism, primary hyperaldosteronism, familial hyperaldosteronism type I, FH-I, glucocorticoid remediable aldosteronism, GRA, familial hyperaldosteronism type II, FH-II, secondary hyperaldosteronism, idiopathic hyperaldosteronism, IHA, hyperkalemia, hypertension, hypoalbuminemia, cardiac output states, nephrotic syndrome, bilateral adrenal hyperplasia, adenoma, diabetes mellitus, cardiac fibrosis, headaches, facial flushing, constipation, polyuria, polydipsia, Wilms tumor, anxiety attacks, neurofibromatosis, multiple endocrine neoplasia type 2, MEN, MEN 2A, MEN 2B, von Hippel-Lindau syndrome, Wilms tumor, hepatomegaly, splenomegaly, ascites

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Contributor Information and Disclosures

Author

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece
George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Antony Lafferty, MB ChB, FRACP, Senior Lecturer of Pediatric Endocrinology, Monash University Department of Pediatrics, National Institutes of Health, Bethesda, MD, and Princess Margaret Hospital for Children, Perth, Western Australia
Antony Lafferty, MB ChB, FRACP is a member of the following medical societies: Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds PI, also occasional consultant

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

 
 
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