Addison's disease laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Diagnosis of Addison's disease is made by routine blood tests and specific tests. ACTH stimulation test is a specific test employed to determine the function of adrenal glands and to diagnose Addison's disease. The prominent finding of a rapid ACTH stimulation test includes failure of cortisol to rise in response to ACTH injection. Other routine laboratory tests employed include plasma cortisol level, serum ACTH level, plasma renin activity, aldosterone levels and serum biochemistry.

Laboratory Findings

Diagnosis of Addison's disease is made by routine blood tests and specific tests. The aim of these tests is to determine the levels of cortisol and then to establish the cause of deficiency.

• Specific tests to determine the function of adrenal glands include:
  • ACTH stimulation test
  • CRH stimulation test
• Routine blood tests
  • Plasma cortisol level
  • Serum ACTH level
  • Plasma renin activity and aldosterone levels
  • Serum biochemistry

Diagnostic decision

Clinical setting	Best initial test
Non-acute	8AM cortisol
Acute illness	Random plasma cortisol and ACTH levels Followed by cortisol levels 30 and 60 minutes after cosyntropin administration.

Specific tests to determine adrenal gland function

ACTH Stimulation Test (Rapid ACTH Stimulation Test)

• This is the most specific test for diagnosing Addison's disease.
• In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection.
• It is called short, or rapid ACTH test because measurement of cortisol in blood is repeated 30 to 60 minutes after an intravenous ACTH injection.
• 250 µg synthetic ACTH (cosyntropin) is administered intravenously or intramuscularly.
• The normal response after an injection of ACTH is a rise in blood and urine cortisol levels.
• Those with primary adrenal insufficiency fail to increase cortisol levels above 18 µg/dL; those with secondary or tertiary adrenal insufficiency also fail to achieve cortisol levels above 18 µg/dL as long as their condition has been present long enough to allow adrenal atrophy (about 2-4 weeks).
• If a subnormal cortisol response occurs, ACTH measurement and other tests should distinguish between primary and secondary and tertiary causes
• Patients with either form of adrenal insufficiency respond poorly or do not respond at all.

8 am cortisol

>15Ug/dL

3-15Ug/dL

<3Ug/dL

Adrenal insufficiency is ruled out

Measure ACTH

30 min cortisol during cosyntropin stimulation test

>18Ug/dL

<18Ug/dL

Adrenal insufficiency is ruled out

Adrenal insufficiency confirmed

Measure ACTH

Low/normal

Elevated

Secondary Adrenal insufficiency

Primary Adrenal insufficiency

CRH Stimulation Test

• When the response to the short ACTH test is abnormal, a "long" CRH stimulation test is required to determine the cause of adrenal insufficiency.
• In this test, 1 μg synthetic CRH is injected intravenously and blood cortisol is measured before and 30, 60, 90, and 120 minutes after the injection.
• There is some evidence that the low-dose ACTH test is more sensitive than the standard 250 μg test in identifying partial or mild cases of secondary or tertiary adrenal insufficiency
• Patients with primary adrenal insufficiency have high ACTHs but do not produce cortisol.
• Patients with secondary adrenal insufficiency have deficient cortisol responses but absent or delayed ACTH responses.
• Absent ACTH response points to the pituitary as the cause; a delayed ACTH response points to the hypothalamus as the cause.

Routine investigations

Routine investigations include

• Plasma cortisol level
• Serum ACTH level
• Plasma renin activity and aldosterone levels
• Serum biochemistry

Test	Advantage	Normal values	Laboratory Finding
Plasma cortisol	Screening test for adrenal insufficiency	Plasma cortisol: >18 µg/dL at 8AM	<3 µg/dL: suggests evidence of adrenal insufficiency 3-18 µg/dL: non-diagnostic, although levels <10 µg/dL raise suspicion of adrenal insufficiency >18 µg/dL precludes the diagnosis of adrenal insufficiency
Serum ACTH level	Helps to distinguish primary from secondary/tertiary adrenal insufficiency	ACTH: 5-30 ng/mL	In Addison disease: ACTH elevated (usually >60 ng/mL) in the face of a low or low-normal cortisol In secondary/tertiary adrenal insufficiency: ACTH is low (usually <5 ng/mL) in the face of low cortisol
Plasma renin activity and aldosterone levels	A compensatory increase in PRA is the earliest response to mild aldosterone deficiency.	Normal PA (ng/dL) to PR (ng/mL/h) is less than 20 with plasma aldosterone levels less than 15 ng/dL.	Patients with Addison disease have increased aldosterone levels Plasma renin activity exhibits a compensatory rise
Serum biochemistry	Simple, widely available test	Sodium: 135-145 mEq/L Potassium: 3.8-5.5 mEq/L Chloride: 95-105 mEq/L BUN: 8-18 mg/dL Creatinine: 0.6-1.2 mg/dL	In Addison disease: Sodium and chloride levels may be decreased Potassium levels may be increased BUN-to-creatinine ratio may be increased (prerenal azotemia) Mild non–anion-gap metabolic acidosis