eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Adrenal Insufficiency: Differential Diagnoses & Workup

Author: 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
Coauthor(s): Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Contributor Information and Disclosures

Updated: Feb 18, 2009

Differential Diagnoses

3-Beta-Hydroxysteroid Dehydrogenase Deficiency
Congenital Adrenal Hyperplasia
Adrenal Hypoplasia
Familial Glucocorticoid Deficiency
Birth Trauma
Hypopituitarism
Chronic Fatigue Syndrome
Pseudohypoaldosteronism

Other Problems to Be Considered

Adrenocorticotropic hormone (ACTH) receptor defect
Adrenoleukodystrophy and adrenomyeloneuropathy
Autoimmune polyglandular endocrinopathy syndromes
Infectious adrenalitis (eg, in association with HIV infection or tuberculosis [TB])
Adrenal hemorrhage
Lipoid adrenal hyperplasia
Wolman disease

Workup

Laboratory Studies

General considerations and tests

Clinical suspicion is important because the presentation of patients with adrenal insufficiency may be insidious and subtle.

When adrenal insufficiency is suspected, laboratory studies of the following measures help to establish the diagnosis:

  • Electrolyte levels
  • Fasting blood sugar concentration
  • Serum adrenocorticotropic hormone (ACTH) concentration
  • Plasma renin activity
  • Serum cortisol concentration, preferably obtained before 8:00 am
  • Serum aldosterone concentration

When hyponatremia or hyperkalemia is present, a simultaneous serum sample and spot urine or 24-hour urine measurement of sodium, potassium, and creatinine concentrations can be used to calculate the fractional excretion of sodium to determine whether inappropriate natriuresis is occurring. A plasma renin activity (PRA)–to–aldosterone ratio of more than 30 is suggestive of inadequate mineralocorticoid production.

Serum cortisol testing and the administration of cosyntropin

Interpret random serum cortisol concentrations in the context in which they were obtained. For example, adrenal insufficiency is unlikely in an otherwise healthy individual whose 8:00 am serum cortisol concentration is more than 10 mcg/dL. By contrast, a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient is suggestive of adrenal insufficiency, although some critically ill patients may have such cortisol concentrations due to lack of protein binding to cortisol (see Relative Adrenal Insufficiency).

Results diagnostic of adrenal insufficiency

A diagnosis of adrenal insufficiency is confirmed if the serum cortisol level is less than 18 mcg/dL in the presence of a markedly elevated serum ACTH concentration and plasma renin activity. Based on normative data of children of various ages, adrenal insufficiency is likely if the serum cortisol concentration is less than 18 mcg/dL 30-60 minutes after administration of 250 mcg of cosyntropin (synthetic ACTH 1-24).31

These criteria may not apply to premature or low-birth-weight infants, who have low cortisol secretion and, most likely, decreased cortisol binding to carrier proteins.32  Therefore, the diagnosis of adrenal insufficiency in premature infants remains problematic.

If the serum cortisol level is low but the ACTH value is elevated, measurement of antiadrenal antibodies may be informative. Antibodies to one or more steroidogenic enzymes, particularly 21-hydroxylase, are often found in patients with autoimmune adrenal disease.

The best dose of cosyntropin to administer for a cosyntropin stimulation test remains controversial.33,34,35,36 The standard dose is 250 mcg intravenously. Low doses (1 mcg or 0.5 mcg/m2) have been used in the belief that the low-dose test is more sensitive for central adrenal insuffficiency.37 A recent meta-analysis suggests that the low dose cosyntropin stimulation test is superior, but the difference was small.38 This issue remains unresolved in the pediatric age group. Because dilution of cosyntropin to 1 mcg is cumbersome and prone to error, and because all doses above are probably supraphysiologic, the author generally uses the standard dose or empirically adjusts the dose for patient size to 25 mcg for an infant, 50 mcg for a young child, 100 mcg for an older child, and 250 mcg for an adolescent or adult.

When a patient's serum cortisol response to cosyntropin is subnormal but his or her serum ACTH level is not elevated, the possibility of central adrenal insufficiency should be considered. Other indications of pituitary dysfunction, such as prior glucocorticoid exposure (suggesting a suppressed hypothalamic-pituitary-adrenal axis) or evidence of other pituitary dysfunction (suggesting hypopituitarism) are helpful. In central adrenal insufficiency, a 3-day stimulation with ACTH produces a normal cortisol response, indicating intact adrenal glands and implying that the initial low cortisol response to cosyntropin was related to chronic ACTH deficiency.  ACTH gel (ACTHar Gel) is administered at 25 U/m2 every 12 hours for 3 days. Plasma cortisol levels should increase to more than 40 mcg/dL in response. This procedure is now seldom performed.

Insulin-tolerance testing and metyrapone stimulation

If the patient has recent-onset (ie, <10 d) central adrenal insufficiency (eg, a patient who recently underwent surgery of the hypothalamus or pituitary regions), the relatively cumbersome and risky insulin-tolerance test or metyrapone stimulation test may be preferable to a cosyntropin challenge because the adrenal glands may not have had sufficient time to atrophy in the absence of ACTH stimulation. The insulin tolerance test is still considered the criterion standard.

An insulin-tolerance test requires an intravenous administration of insulin (usually regular insulin 0.05-0.15 U/kg) to induce a 50% reduction in blood sugar concentration. Cortisol and glucose concentrations are measured every 15 minutes for 60 minutes. The test is considered adequate if the blood sugars level decreases by at least 50%. In response to the hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 18-20 mcg/dL.

The insulin-tolerance test poses some risk of hypoglycemic seizure. Therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overtly symptomatic.

Standard metyrapone stimulation tests involve administering metyrapone 300 mg/m2 in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, which is involved in the last enzymatic step in cortisol synthesis, plasma levels of the cortisol precursor, 11-deoxycortisol, increase. A normal response is a rise in 11-deoxycortisol concentrations to more than 10.5 mcg/dL 4 hours after the last dose of metyrapone is given or a 2-fold to 3-fold increase in 24-hour urinary concentrations of 17-hydroxycorticosteroid (which include tetrahydro compound S, a urinary metabolite of 11-deoxycortisol) on the day of or the day after the administration of metyrapone. This test is cumbersome and carries some risk of inducing an adrenal crisis.

Test for antiadrenal antibodies

When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If results for antiadrenal antibodies are negative, search for another etiology, such as tuberculosis (TB), adrenal hemorrhage, or adrenoleukodystrophy.

Corticotropin-releasing hormone stimulation test

The standard ovine corticotropin-releasing hormone (CRH) stimulation test (1 mcg/kg over 1 min) may be helpful in the differential diagnosis of adrenal insufficiency. A lack of a 2-fold increase in serum ACTH concentration indicates pituitary dysfunction. A 2-fold or greater rise in ACTH without a concomitant rise in serum cortisol to more than 18-20 mcg/dL implies primary adrenal insufficiency.39 Ovine CRH is difficult to obtain, and this test is mainly performed for research purposes.

Imaging Studies

CT scanning is the imaging study of choice and helps in identifying adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT scanning. Abdominal radiography may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease. Ultrasonography is a poor imaging modality for investigating the adrenal glands. Iodocholesterol scanning is not particularly useful.

Procedures

CT-guided fine-needle aspiration sometimes helps in diagnosing the etiology of infiltrative adrenal disease.

Histologic Findings

Histologic findings depend on the underlying cause. In cases of autoimmune adrenal failure, lymphocytic infiltration destroys the adrenal gland. Granulomatous changes in the adrenal glands indicate TB-related adrenal insufficiency. Neoplastic infiltrations are caused by metastatic tumors. Hemorrhagic adrenal insufficiency results in hemorrhagic destruction of the adrenal glands. Fungal disease produces the typical picture of fungal infiltrates. Atrophy of the adrenals characterizes ACTH deficiency or resistance. Hyperplasia of the adrenals is characteristic of defects in steroidogenesis.

More on Adrenal Insufficiency

Overview: Adrenal Insufficiency
Differential Diagnoses & Workup: Adrenal Insufficiency
Treatment & Medication: Adrenal Insufficiency
Follow-up: Adrenal Insufficiency
Multimedia: Adrenal Insufficiency
References
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Further Reading

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Keywords

Addison disease, Addison's disease, adrenal crisis, adrenal insufficiency and adrenal crisis, glucocorticoid deficiency, familial glucocorticoid deficiency, hypoadrenalism, adrenal hypoplasia, hypocortisolism, adrenals, adrenal glands, adrenal failure, hormonal insufficiency, glucocorticoids, mineralocorticoids, androgens, primary adrenal insufficiency, secondary adrenal insufficiency, central adrenal insufficiency, dysfunctional adrenal gland

CRH, corticotropin-releasing hormone, adrenocorticotropic hormone, corticotropic hormone, ACTH, hypofunction of the adrenal cortex, congenital adrenal insufficiency, acquired adrenal insufficiency, tuberculosis, TB, autoimmune adrenal insufficiency, adrenal hypoplasia congenita, AHC, congenital adrenal hypoplasia, congenital adrenal hyperplasia, CAH

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Contributor Information and Disclosures

Author

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.

Coauthor(s)

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
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

Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital
Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

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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