Adrenal insufficiency

Adrenal insufficiency
Forty-nine year-old with signs of adrenal insufficiency. Appearance shows lack of facial hair, dehydration, loss of the outer eyebrow (panel A), pale skin, muscular and weight loss, and loss of body hair (panel B).[1]
SpecialtyEndocrinology
SymptomsWeakness, lightheadedness with standing, darkening skin, weight loss, vomiting, intolerance to the cold, salt cravings[2]
ComplicationsAdrenal crisis[3]
TypesPrimary, secondary, tertiary
CausesPrimary: Addison disease, congenital adrenal hyperplasia, adrenal hemorrhage, certain medications[3]
Secondary: Panhypopituitarism, Sheehan’s syndrome[4][5]
Tertiary: Brain tumors, long term corticosteroid use[3][5]
Diagnostic methodBased on symptoms, confirmed by blood tests[4]
TreatmentHydrocortisone, prednisone, fludrocortisone[2]
PrognosisOften good with treatment[3]
FrequencyPrimary: 5 in 100,000[6]
Secondary: 22 per 100,000[5]

Adrenal insufficiency is a condition in which the adrenal glands do not produce enough of the hormone cortisol and potentially aldosterone.[3] Symptoms vary from mild to severe.[3] Mild symptoms may include weakness, tiredness, lightheadedness with standing, and darkening skin.[2] More severe symptoms may include low blood pressure and weight loss.[2] There may also be vomiting, abdominal pain, intolerance to the cold, and salt cravings.[2][7] Complications may include an adrenal crisis.[3]

The causes of adrenal insufficiency are divided into primary, secondary, and tertiary.[3] Primary causes are due to the adrenal gland and include Addison disease, congenital adrenal hyperplasia, adrenal hemorrhage, and certain medications.[3] Secondary causes involve decreased ACTH from the pituitary and include panhypopituitarism and Sheehan’s syndrome.[3][4][5] Tertiary causes involve decreased CRH from the hypothalamus and include brain tumors and long term corticosteroid use.[3][5] Diagnosis is suspected based on symptoms and confirmed by blood tests.[4]

Treatment is generally with hydrocortisone or prednisone.[2][4] In primary disease fludrocortisone is also required.[2] Larger doses of hydrocortisone are required during physical stress, such as infections, and people are generally given injectable forms to self administer as soon as they feel sick.[2] Outcomes are often good with treatment.[3]

Primary adrenal insufficiency affects about 5 per 100,000 people.[6] Secondary adrenal insufficiency affects about 22 per 100,000 people.[5] Women are affected about twice as often as men.[6][5] The condition was first described in 1855 by Thomas Addison.[5]

Signs and symptoms

Signs and symptoms include: hypoglycemia, dehydration, weight loss, and disorientation. Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse, muscle aches, nausea, vomiting, and diarrhea. These problems may develop gradually and insidiously. Addison's disease can present with tanning of the skin that may be patchy or even all over the body. Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa). Goitre and vitiligo may also be present.[8] Eosinophilia may also occur.[9]

Causes

Causes of acute adrenal insufficiency are mainly sudden withdrawal of long-term corticosteroid therapy, Waterhouse–Friderichsen syndrome, and stress in people with underlying chronic adrenal insufficiency.[10] The latter is termed critical illness–related corticosteroid insufficiency.

For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease), tuberculosis, AIDS, and metastatic disease.[10] Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.[10]

Autoimmune adrenalitis may be part of Type 2 autoimmune polyglandular syndrome, which can include type 1 diabetes, hyperthyroidism, and autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto's thyroiditis, and Hashimoto's disease).[11] Hypogonadism may also present with this syndrome. Other diseases that are more common in people with autoimmune adrenalitis include premature ovarian failure, celiac disease, and autoimmune gastritis with pernicious anemia.[12]

Adrenoleukodystrophy can also cause adrenal insufficiency.[13]

Adrenal insufficiency can also result when a patient has a craniopharyngioma, which is a histologically benign tumor that can damage the pituitary gland and so cause the adrenal glands not to function. This would be an example of secondary adrenal insufficiency syndrome.

Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. These are adrenal dysgenesis (the gland has not formed adequately during development), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol) or adrenal destruction (disease processes leading to glandular damage).[14]

Corticosteroid withdrawal

Use of high-dose steroids for more than a week begins to produce suppression of the person's adrenal glands because the exogenous glucocorticoids suppress release of hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid. During this recovery time, the person is vulnerable to adrenal insufficiency during times of stress, such as illness, due to both adrenal atrophy and suppression of CRH and ACTH release.[15][16] Use of steroids joint injections may also result in adrenal suppression after discontinuation.[17]

Adrenal dysgenesis

All causes in this category are genetic, and generally very rare. These include mutations to the SF1 transcription factor, congenital adrenal hypoplasia due to DAX-1 gene mutations and mutations to the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome). DAX-1 mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes.[14]

Impaired steroidogenesis

To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include Smith–Lemli–Opitz syndrome and abetalipoproteinemia.

Of the synthesis problems, congenital adrenal hyperplasia is the most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations.[14] Some medications interfere with steroid synthesis enzymes (e.g. ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin).[14]

Adrenal destruction

Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialised world. Autoimmune destruction of the adrenal cortex is caused by an immune reaction against the enzyme 21-hydroxylase (a phenomenon first described in 1992).[18] This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected.[19]

Adrenal destruction is also a feature of adrenoleukodystrophy (ALD), and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g. in Waterhouse–Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis.[20]

Pathophysiology

Adrenal gland

Hyponatremia can be caused by glucocorticoid deficiency. Low levels of glucocorticoids leads to systemic hypotension (one of the effects of cortisol is to increase peripheral resistance), which results in a decrease in stretch of the arterial baroreceptors of the carotid sinus and the aortic arch. This removes the tonic vagal and glossopharyngeal inhibition on the central release of ADH: high levels of ADH will ensue, which will subsequently lead to increase in water retention and hyponatremia.

Differently from mineralocorticoid deficiency, glucocorticoid deficiency does not cause a negative sodium balance (in fact a positive sodium balance may occur).[21] Aldosterone regulates sodium conservation, potassium secretion, and water retention.[22][23]

Diagnosis

a) Heterogeneously enhancing adrenal mass b) Paracoccidioides brasiliensis yeast cells in the adrenal gland of individual with adrenal insufficiency

The best diagnostic tool to confirm adrenal insufficiency is the ACTH stimulation test; however, if a patient is suspected to be suffering from an acute adrenal crisis, immediate treatment with IV corticosteroids is imperative and should not be delayed for any testing, as the patient's health can deteriorate rapidly and result in death without replacing the corticosteroids.

Dexamethasone should be used as the corticosteroid if the plan is to do the ACTH stimulation test at a later time as it is the only corticosteroid that will not affect the test results.[24]

If not performed during crisis, then labs to be run should include: random cortisol, serum ACTH, aldosterone, renin, potassium and sodium. A CT of the adrenal glands can be used to check for structural abnormalities of the adrenal glands. An MRI of the pituitary can be used to check for structural abnormalities of the pituitary. However, in order to check the functionality of the Hypothalamic Pituitary Adrenal (HPA) Axis the entire axis must be tested by way of ACTH stimulation test, CRH stimulation test and perhaps an Insulin Tolerance Test (ITT). In order to check for Addison's Disease, the auto-immune type of primary adrenal insufficiency, labs should be drawn to check 21-hydroxylase autoantibodies.

Types

There are three major types of adrenal insufficiency.

  • Primary adrenal insufficiency is due to impairment of the adrenal glands.
  • Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus.[25] Its principal causes include pituitary adenoma (which can suppress production of adrenocorticotropic hormone (ACTH) and lead to adrenal deficiency unless the endogenous hormones are replaced); and Sheehan's syndrome, which is associated with impairment of only the pituitary gland.
  • Tertiary adrenal insufficiency is due to hypothalamic disease and a decrease in the release of corticotropin releasing hormone (CRH).[26] Causes can include brain tumors and sudden withdrawal from long-term exogenous steroid use (which is the most common cause overall).[27]

Effects

TypeHypothalamus
(tertiary)1		Pituitary
(secondary)		Adrenal glands
(primary)7
Underlying causesAbrupt steroid withdrawal, Tumor of the hypothalamus (adenoma), antibodies, environment (i.e. toxins), head injuryTumor of the pituitary (adenoma), antibodies, environment, head injury, surgical removal6, Sheehan's syndromeTumor of the adrenal (adenoma), stress, antibodies, environment, Addison's disease, trauma, surgical removal (resection), miliary tuberculosis of the adrenal
CRHlowhigh2high
ACTHlowlowhigh
DHEAlowlowhigh
DHEA-Slowlowhigh
Cortisollow3low3low4
Aldosteronelownormallow
Reninlowlowhigh
Sodium (Na)lowlowlow
Potassium (K)lownormalhigh
1Automatically includes diagnosis of secondary (hypopituitarism)
2Only if CRH production in the hypothalamus is intact
5Most common, does not include all possible causes
6Usually because of very large tumor (macroadenoma)
7Includes Addison's disease

Treatment

(To balance sodium, potassium and increase water retention)[8]

See also

References

  1. ↑ Streetz-van der Werf, C; Karges, W; Blaum, M; Kreitschmann-Andermahr, I (15 May 2015). "Addisonian Crisis after Missed Diagnosis of Posttraumatic Hypopituitarism". Journal of clinical medicine. 4 (5): 965–9. doi:10.3390/jcm4050965. PMID 26239458.
  2. 1 2 3 4 5 6 7 8 "Addison Disease - Endocrine and Metabolic Disorders". Merck Manuals Professional Edition. Archived from the original on 26 May 2021. Retrieved 21 October 2020.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Huecker, MR; Dominique, E (January 2020). "Adrenal Insufficiency". PMID 28722862. {{cite journal}}: Cite journal requires |journal= (help)
  4. 1 2 3 4 5 "Secondary Adrenal Insufficiency - Endocrine and Metabolic Disorders". Merck Manuals Professional Edition. Archived from the original on 23 October 2020. Retrieved 21 October 2020.
  5. 1 2 3 4 5 6 7 8 Nicolaides, NC; Chrousos, GP; Charmandari, E; Feingold, KR; Anawalt, B; Boyce, A; Chrousos, G; de Herder, WW; Dungan, K; Grossman, A; Hershman, JM; Hofland, HJ; Kaltsas, G; Koch, C; Kopp, P; Korbonits, M; McLachlan, R; Morley, JE; New, M; Purnell, J; Singer, F; Stratakis, CA; Trence, DL; Wilson, DP (2000). "Adrenal Insufficiency". PMID 25905309. {{cite journal}}: Cite journal requires |journal= (help)
  6. 1 2 3 Ferri, Fred F. (2014). Ferri's Clinical Advisor 2015 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 63. ISBN 978-0-323-08430-7. Archived from the original on 27 August 2021. Retrieved 21 October 2020.
  7. ↑ Ten S, New M, Maclaren N (2001). "Clinical review 130: Addison's disease 2001". J. Clin. Endocrinol. Metab. 86 (7): 2909–22. doi:10.1210/jc.86.7.2909. PMID 11443143. Archived from the original on 2009-08-22. Retrieved 2008-08-25.
  8. 1 2 3 4 Ashley B. Grossman, MD (2007). "Addison's Disease". Adrenal Gland Disorders. Archived from the original on 2008-09-15. Retrieved 2008-08-22.
  9. ↑ Montgomery ND, Dunphy CH, Mooberry M, Laramore A, Foster MC, Park SI, Fedoriw YD (2013). "Diagnostic complexities of eosinophilia". Archives of Pathology & Laboratory Medicine. 137 (2): 259–69. doi:10.5858/arpa.2011-0597-RA. PMID 23368869. S2CID 17918640.
  10. 1 2 3 Table 20-7 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 8th edition.
  11. ↑ Thomas A Wilson, MD (2007). "Adrenal Insufficiency". Adrenal Gland Disorders. Archived from the original on 2008-09-15. Retrieved 2008-08-25.
  12. ↑ Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. (2016). "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab (Practice Guideline. Review). 101 (2): 364–89. doi:10.1210/jc.2015-1710. PMC 4880116. PMID 26760044.
  13. ↑ Thomas A Wilson, MD (1999). "Adrenoleukodystrophy". Archived from the original on 2008-09-15. Retrieved 2008-08-25. {{cite journal}}: Cite journal requires |journal= (help)
  14. 1 2 3 4 Ten S, New M, Maclaren N (2001). "Clinical review 130: Addison's disease 2001". The Journal of Clinical Endocrinology and Metabolism. 86 (7): 2909–2922. doi:10.1210/jc.86.7.2909. PMID 11443143. Archived from the original on 2009-08-22. Retrieved 2008-08-25.
  15. ↑ Kaminstein, David S. William C. Shiel Jr. (ed.). "Steroid Drug Withdrawal". MedicineNet. Archived from the original on 2 April 2013. Retrieved 10 April 2013.
  16. ↑ Dernis, E; Ruyssen-Witrand, A; Mouterde, G; Maillefert, JF; Tebib, J; Cantagrel, A; Claudepierre, P; Fautrel, B; Gaudin, P; Pham, T; Schaeverbeke, T; Wendling, D; Saraux, A; Loët, XL (October 2010). "Use of glucocorticoids in rheumatoid arthritis - practical modalities of glucocorticoid therapy: recommendations for clinical practice based on data from the literature and expert opinion". Joint, Bone, Spine : Revue du Rhumatisme. 77 (5): 451–7. doi:10.1016/j.jbspin.2009.12.010. PMID 20471886.
  17. ↑ Stitik, Todd P. (2010). Injection Procedures: Osteoarthritis and Related Conditions. Springer Science & Business Media. p. 47. ISBN 9780387765952. Archived from the original on 2021-04-14. Retrieved 2020-06-03.
  18. ↑ Winqvist O, Karlsson FA, Kämpe O (June 1992). "21-Hydroxylase, a major autoantigen in idiopathic Addison's disease". The Lancet. 339 (8809): 1559–62. doi:10.1016/0140-6736(92)91829-W. PMID 1351548.
  19. ↑ Husebye ES, Perheentupa J, Rautemaa R, Kämpe O (May 2009). "Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I". Journal of Internal Medicine. 265 (5): 514–29. doi:10.1111/j.1365-2796.2009.02090.x. PMID 19382991.
  20. ↑ Kennedy, Ron. "Addison's Disease". The Doctors' Medical Library. Archived from the original on 2013-04-12. Retrieved 2015-07-29.
  21. ↑ Schrier, R. W. (2006). "Body Water Homeostasis: Clinical Disorders of Urinary Dilution and Concentration". Journal of the American Society of Nephrology. 17 (7): 1820–32. doi:10.1681/ASN.2006030240. PMID 16738014.
  22. ↑ Eileen K. Corrigan (2007). "Adrenal Insufficiency (Secondary Addison's or Addison's Disease)". NIH Publication No. 90-3054. Archived from the original on 2008-09-15. Retrieved 2008-08-22.
  23. ↑ Adrenal+Insufficiency at the US National Library of Medicine Medical Subject Headings (MeSH)
  24. ↑ Addison Disease~workup at eMedicine
  25. ↑ "hypopituitary". WebMD. 2006. Archived from the original on 2008-09-13. Retrieved 2008-08-26.
  26. ↑ "Archived copy". Archived from the original on 2010-06-13. Retrieved 2010-03-31.{{cite web}}: CS1 maint: archived copy as title (link)
  27. ↑ "Causes of secondary and tertiary adrenal insufficiency in adults". Archived from the original on 10 November 2016. Retrieved 10 November 2016.
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