Adrenal Insufficiency

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Symptoms consistent with adrenal insufficiency (eg, hypotension, weakness)
  • Presence of disease process associated with adrenal insufficiency

Laboratory Testing

  • Initial testing
    • Measure early morning serum cortisol
      • Cortisol ≥5 µg/dL makes primary adrenal insufficiency less likely
        • If serious consideration is given to this diagnosis, perform stimulation testing
    • Follow abnormal cortisol results with adrenocorticotropic hormone (ACTH) testing
      • If ACTH >300 pg/dL – adrenal failure likely
      • If ACTH <10 pg/dL – pituitary failure likely
      • If ACTH between 10 pg/dL and 300 pg/dL – administer ACTH (cosyntropin) stimulation test
  • Testing based on ACTH result
    • ACTH stimulation test (cosyntropin)
      • Measures cortisol response to cosyntropin (250 µg using serial cortisol measures at 0, 30, and 60 minutes)
        • Cortisol <5 µg/dL – primary severe adrenal failure
        • Cortisol >20 µg/dL – normal; adrenal insufficiency unlikely
        • Cortisol ≤20 µg/dL but ≥5 µg/dL – evaluate for pituitary failure; secondary adrenal insufficiency likely
      • Evaluation for pituitary failure
        • Insulin tolerance testing (ITT)
          • Not recommended in children <6 years
        • Metyrapone overnight testing
          • If 11 deoxycortisol >7 µg/dL – adrenal failure unlikely; MRI/CT of adrenal glands
          • If 11 deoxycortisol ≤7 µg/dL – pituitary failure likely; order MRI/CT
            • If still not clear – corticotropin releasing hormone (CRH) stimulus testing
              • If ACTH <10 pg/mL – pituitary failure likely
  • Autoimmune etiology confirmation – presence of 21-hydroxylase antibodies confirm autoimmune etiology

Imaging Studies

  • MRI/CT based on stimulation testing results
    • If stimulation testing or absolute cortisol suggests adrenal failure – MRI/CT of adrenal glands
    • If stimulation testing suggests pituitary failure – MRI/CT of pituitary

Differential Diagnosis

Adrenal insufficiency is defined as hypofunction of the adrenal gland with decreased or absent cortisol secretion.

Epidemiology

  • Incidence – estimated at 5-10/100,000 (Charmandari, 2014)
  • Sex – M:F, equal

Classification

  • Primary or secondary insufficiency

Etiology

  • Primary adrenal insufficiency
    • Autoimmune
      • Addison disease
        • Frequent association with other endocrine diseases
        • Autoantibodies to 21-hydroxylase – frequently present
      • Autoimmune polyendocrine syndromes
        • Epidemiology
          • Incidence – 1-2/100,000
          • Age – 30s
          • Sex – M<F, 1:3
        • Classification
          • Type 1 associated characteristics
          • Type 2 associated characteristics
          • Type 4 associated characteristics
            • Other  autoimmune disorders excluding thyroid disease and type 1 DM
          • Types 1 and 2 may also include other autoimmune disorders – vitiligo, chronic atrophic gastritis, alopecia
    • Infection
    • Anatomic destruction of the gland
      • Surgical removal
      • Bilateral hemorrhage into the gland – may be associated with anticoagulant therapy
      • Invasion of the gland
        • Metastases – lung, stomach, breast, and colon most common
        • Infiltrative disorders – lymphoma, amyloid iron overload
    • Genetic disorders (eg, adrenoleukodystrophy, congenital adrenal hyperplasia [CAH])
    • Medications – etomidate, ketoconazole, metyrapone
  • Secondary adrenal insufficiency (central insufficiency)
    • Drug induced (eg, corticosteroids)
    • Hypopituitarism
      • Postpartum hemorrhage – Sheehan syndrome
      • Pituitary radiation
      • Pituitary surgery
      • Acute interruption of prolonged corticosteroids
      • Pituitary infiltrative disease – sarcoidosis, granulomatosis with polyangiitis
      • Traumatic brain injury
    • Lymphocytic hypophysitis – may be part of autoimmune polyendocrine syndrome

Pathophysiology

  • Primary – combined glucocorticoid and mineralocorticoid deficiency
  • Secondary – glucocorticoid deficiency

Clinical Presentation

  • Insidious onset of fatigue, weakness, anorexia, nausea and emesis
  • Cutaneous hyperpigmentation – diffuse tan, brown or bronzing
    • Does not occur in secondary insufficiency
  • Orthostatic hypotension
  • Diarrhea, abdominal pain
  • Acute presentation may occur in patients with mild adrenal insufficiency who are stressed (eg, critical illness, surgery)
    • Hypotension which is unresponsive to fluids
    • Mainly attributable to mineralocorticoid deficiency
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cortisol by LC-MS/MS, Serum or Plasma 2003250
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Recommended Use 

Use for evaluation of adrenal axis disorders

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use 

Aid in the diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors

Limitations 

Some types of synthetic ACTH are not detected by this assay

11-Deoxycortisol Quantitative by HPLC-MS/MS, Serum or Plasma 0092331
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Recommended Use 

Measured after metyrapone testing

21-Hydroxylase Antibody 0070265
Method: Quantitative Radioimmunoassay

Recommended Use 

Secondary testing after adrenal insufficiency established to diagnose autoimmune disease

The presence of 21-hydroxylase antibodies (>1.0 U/mL) is indicative of primary adrenal insufficiency (Addison’s disease); results should be interpreted in the context of clinical symptoms, including functional adrenal testing

In males with adrenal insufficiency and 21-hydroxylase antibodies within the reference interval (<1.0 U/mL), X-linked adrenoleukodystrophy (X-ALD) should be excluded by ordering Very Long-Chain and Branched-Chain Fatty Acids Profile in plasma

Guidelines

Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, Falorni A, Gan EH, Hulting A, Kasperlik-Zaluska A, Kämpe O, Løvås K, Meyer G, Pearce SH. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014; 275(2): 104-15. PubMed

General References

Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical diagnosis of adrenal insufficiency: the added value of dehydroepiandrosterone sulfate measurements. Endocr Pract. 2011; 17(2): 261-70. PubMed

Betterle C, Morlin L. Autoimmune Addison's disease. Endocr Dev. 2011; 20: 161-72. PubMed

Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014; 383(9935): 2152-67. PubMed

Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010; 95(11): 4855-63. PubMed

Majeroni BA, Patel P. Autoimmune polyglandular syndrome, type II. Am Fam Physician. 2007; 75(5): 667-70. PubMed

Michels A, Michels N. Addison disease: early detection and treatment principles. Am Fam Physician. 2014; 89(7): 563-8. PubMed

Wallace I, Cunningham S, Lindsay J. The diagnosis and investigation of adrenal insufficiency in adults. Ann Clin Biochem. 2009; 46(Pt 5): 351-67. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

La'ulu SL, Roberts WL. Performance characteristics of the Architect cortisol immunoassay. Clin Chim Acta. 2008; 388(1-2): 219-21. PubMed

Medical Reviewers

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Last Update: July 2017