Adrenal insufficiency - Wikipedia https://en.wikipedia.

org/wiki/Adrenal_insufficiency

Adrenal insufficiency is a condition in which the adrenal glands do

Adrenal insufficiency
not produce adequate amounts of steroid hormones, primarily cortisol;
but may also include impaired production of aldosterone (a
mineralocorticoid), which regulates sodium conservation, potassium
secretion, and water retention.[1][2] Craving for salt or salty foods due to
the urinary losses of sodium is common.[3]

Addison's disease and congenital adrenal hyperplasia can manifest as

adrenal insufficiency. If not treated, adrenal insufficiency may result in
severe abdominal pains, vomiting, profound muscle weakness and
fatigue, depression, extremely low blood pressure (hypotension), weight
loss, kidney failure, changes in mood and personality, and shock
(adrenal crisis).[4] An adrenal crisis often occurs if the body is subjected
to stress, such as an accident, injury, surgery, or severe infection; death
Adrenal gland
may quickly follow.[4]
Specialty Endocrinology
Adrenal insufficiency can also occur when the hypothalamus or the
pituitary gland does not make adequate amounts of the hormones that assist in regulating adrenal function.[1][5][6]
This is called secondary or tertiary adrenal insufficiency and is caused by lack of production of ACTH in the
pituitary or lack of CRH in the hypothalamus, respectively.[7]

1 Types
2 Signs and symptoms
3 Causes
3.1 Corticosteroid withdrawal
3.2 Adrenal dysgenesis Video explanation
3.3 Impaired steroidogenesis
3.4 Adrenal destruction
4 Pathophysiology
5 Diagnosis
5.1 Effects
6 Treatment
7 See also
8 References
9 External links

There are three major types of adrenal insufficiency.

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Primary adrenal insufficiency is due to impairment of the adrenal glands.

80% are due to an autoimmune disease called Addison's disease or autoimmune adrenalitis.
One subtype is called idiopathic, meaning of unknown cause.
Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus.[8] 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).[9] Causes can include brain tumors and sudden withdrawal from long-term
exogenous steroid use (which is the most common cause overall).[10]

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.[4] Eosinophilia may also occur.[11]

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.[12] The
latter is termed critical illnessrelated corticosteroid insufficiency.

For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease),
tuberculosis, AIDS, and metastatic disease.[12] Minor causes of chronic adrenal insufficiency are systemic
amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.[12]

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).[13] 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.[14]

Adrenoleukodystrophy can also cause adrenal insufficiency.[15]

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).[16]

Corticosteroid withdrawal
Use of high-dose steroids for more than a week begins to produce suppression of the person's adrenal glands

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because the exogenous glucocorticoids suppress 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.[17][18] Use of steroids joint
injections may also result in adrenal suppression after discontinuation.[19]

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.[16]

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,
17-hydroxylase, 11-hydroxylase and 3-hydroxysteroid dehydrogenase), lipoid CAH due to deficiency of StAR and
mitochondrial DNA mutations.[16] 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).[16]

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).[20] 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.[21]

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.[22]

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).[23]

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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 Addisons Disease, the auto-immune type of primary adrenal insufficiency, labs should be drawn to check
21-hydroxylase autoantibodies.

Effects

Hypothalamus Pituitary Adrenal glands

Type
(tertiary)1 (secondary) (primary)7
Tumor of the adrenal
Tumor of the pituitary
Abrupt steroid (adenoma), stress,
(adenoma),
withdrawal, Tumor of antibodies, environment,
antibodies,
Underlying the hypothalamus Addison's disease,
environment, head
causes (adenoma), antibodies, trauma, surgical removal
injury, surgical
environment (i.e. (resection), miliary
removal6, Sheehan's
toxins), head injury tuberculosis of the
syndrome
adrenal
CRH low high2 high
ACTH low low high
DHEA low low high
DHEA-S low low high
Cortisol low3 low3 low4
Aldosterone low normal low
Renin low low high
Sodium (Na) low low low
Potassium
low normal high
(K)

1 Automatically includes diagnosis of secondary (hypopituitarism)

2 Only if CRH production in the hypothalamus is intact
3 Value doubles or more in stimulation

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4 Value less than doubles in stimulation

5 Most common, does not include all possible causes
6 Usually because of very large tumor (macroadenoma)
7 Includes Addison's disease

Adrenal crisis

Intravenous fluids[4]
Intravenous steroid (Solu-Cortef/injectable hydrocortisone) later hydrocortisone, prednisone or
methylpredisolone tablets[4]
Rest
Cortisol deficiency (primary and secondary)

Hydrocortisone (Cortef)
Prednisone (Deltasone)
Prednisolone (Delta-Cortef)
Methylprednisolone (Medrol)
Dexamethasone (Decadron)
Mineralocorticoid deficiency (low aldosterone)

Fludrocortisone acetate

(To balance sodium, potassium and increase water retention)[4]

Addison's disease primary adrenocortical insufficiency

Cushing's syndrome overproduction of cortisol
Insulin tolerance test another test used to identify sub-types of adrenal insufficiency
Adrenal fatigue (hypoadrenia) a term used in alternative medicine to describe a believed exhaustion of the
adrenal glands

1. Eileen K. Corrigan (2007). "Adrenal Insufficiency (Secondary Addison's or Addison's Disease)"

(http://www.pituitary.org/disorders/addisons_disease.aspx). NIH Publication No. 90-3054.
2. Adrenal Insufficiency (https://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Adrenal+Insufficiency) at
the US National Library of Medicine Medical Subject Headings (MeSH)
3. Ten S, New M, Maclaren N (2001). "Clinical review 130: Addison's disease 2001" (http://jcem.endojournals.org
/cgi/content/full/86/7/2909). J. Clin. Endocrinol. Metab. 86 (7): 290922. doi:10.1210/jc.86.7.2909
(https://doi.org/10.1210%2Fjc.86.7.2909). PMID 11443143 (https://www.ncbi.nlm.nih.gov/pubmed/11443143).
4. Ashley B. Grossman, MD (2007). "Addison's Disease" (http://www.merck.com/mmhe/sec13/ch164
/ch164b.html). Adrenal Gland Disorders.
5. Brender E, Lynm C, Glass RM (2005). "JAMA patient page. Adrenal insufficiency" (http://jama.ama-assn.org
/cgi/content/full/294/19/2528). JAMA. 294 (19): 2528. doi:10.1001/jama.294.19.2528 (https://doi.org
/10.1001%2Fjama.294.19.2528). PMID 16287965 (https://www.ncbi.nlm.nih.gov/pubmed/16287965).
6. "Dorlands Medical Dictionary:adrenal insufficiency" (http://www.mercksource.com/pp/us
/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/four/000053970.htm).

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7. "Secondary Adrenal Insufficiency: Adrenal Disorders: Merck Manual Professional" (http://www.merck.com

/mmpe/sec12/ch153/ch153c.html).
8. "hypopituitary" (http://www.webmd.com/a-to-z-guides/hypopituitary). WebMD. 2006.
9. http://www.endotext.org/adrenal/adrenal13/adrenal13.htm
10. "Causes of secondary and tertiary adrenal insufficiency in adults" (https://www.uptodate.com/contents/causes-
of-secondary-and-tertiary-adrenal-insufficiency-in-adults#H9). Retrieved 10 November 2016.
11. 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): 25969.
doi:10.5858/arpa.2011-0597-RA (https://doi.org/10.5858%2Farpa.2011-0597-RA). PMID 23368869
(https://www.ncbi.nlm.nih.gov/pubmed/23368869).
12. Table 20-7 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic
Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.
13. Thomas A Wilson, MD (2007). "Adrenal Insufficiency" (http://www.emedicine.com/PED/topic47.htm). Adrenal
Gland Disorders.
14. 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"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880116). J Clin Endocrinol Metab (Practice Guideline.
Review). 101 (2): 36489. doi:10.1210/jc.2015-1710 (https://doi.org/10.1210%2Fjc.2015-1710). PMC 4880116
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880116) . PMID 26760044 (https://www.ncbi.nlm.nih.gov
/pubmed/26760044).
15. Thomas A Wilson, MD (1999). "Adrenoleukodystrophy" (http://healthlink.mcw.edu/article/921176192.html).
16. Ten S, New M, Maclaren N (2001). "Clinical review 130: Addison's disease 2001" (http://jcem.endojournals.org
/cgi/content/full/86/7/2909). The Journal of Clinical Endocrinology and Metabolism. 86 (7): 29092922.
doi:10.1210/jc.86.7.2909 (https://doi.org/10.1210%2Fjc.86.7.2909). PMID 11443143
(https://www.ncbi.nlm.nih.gov/pubmed/11443143).
17. Kaminstein, David S. William C. Shiel Jr., ed. "Steroid Drug Withdrawal" (http://www.medicinenet.com
/steroid_withdrawal/article.htm). MedicineNet. Retrieved 10 April 2013.
18. 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; Lot, XL (October 2010). "Use of
glucocorticoids in rheumatoid arthritis - pratical 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): 4517. PMID 20471886 (https://www.ncbi.nlm.nih.gov/pubmed/20471886).
19. Stitik, Todd P. (2010). Injection Procedures: Osteoarthritis and Related Conditions (https://books.google.ca
/books?id=sI7MZLDHcjQC&pg=PA47). Springer Science & Business Media. p. 47. ISBN 9780387765952.
20. Winqvist O, Karlsson FA, Kmpe O (June 1992). "21-Hydroxylase, a major autoantigen in idiopathic Addison's
disease". The Lancet. 339 (8809): 155962. doi:10.1016/0140-6736(92)91829-W (https://doi.org
/10.1016%2F0140-6736%2892%2991829-W). PMID 1351548 (https://www.ncbi.nlm.nih.gov/pubmed
/1351548).
21. Husebye ES, Perheentupa J, Rautemaa R, Kmpe O (May 2009). "Clinical manifestations and management of
patients with autoimmune polyendocrine syndrome type I". Journal of Internal Medicine. 265 (5): 51429.
doi:10.1111/j.1365-2796.2009.02090.x (https://doi.org/10.1111%2Fj.1365-2796.2009.02090.x). PMID 19382991
(https://www.ncbi.nlm.nih.gov/pubmed/19382991).
22. Kennedy, Ron. "Addison's Disease" (http://www.medical-library.net/content/view/570/41/). The Doctors' Medical
Library.
23. Schrier, R. W. (2006). "Body Water Homeostasis: Clinical Disorders of Urinary Dilution and Concentration".
Journal of the American Society of Nephrology. 17 (7): 182032. doi:10.1681/ASN.2006030240 (https://doi.org
/10.1681%2FASN.2006030240). PMID 16738014 (https://www.ncbi.nlm.nih.gov/pubmed/16738014).
24. Addison Disease~workup (http://emedicine.medscape.com/article/116467-workup) at eMedicine

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Classification ICD-10: E27.1

(http://apps.who.int
CAH (http://congenitaladrenalhyperplasia.org) - Congenital
adrenal hyperplasia /classifications/icd10/browse
Bornstein, SR; Allolio, B; Arlt, W; Barthel, A; Don- /2016/en#/E27.1)-E27.4
Wauchope, A; Hammer, GD; Husebye, ES; Merke, DP; (http://apps.who.int
Murad, MH; Stratakis, CA; Torpy, DJ (February 2016). /classifications/icd10/browse
"Diagnosis and Treatment of Primary Adrenal Insufficiency:
An Endocrine Society Clinical Practice Guideline". The /2016/en#/E27.4) ICD-9-CM:
Journal of Clinical Endocrinology and Metabolism. 101 (2): 255.4 (http://www.icd9data.com
36489. PMID 26760044 (https://www.ncbi.nlm.nih.gov /getICD9Code.ashx?icd9=255.4)
/pubmed/26760044).
MeSH: D000309
(https://www.nlm.nih.gov
/cgi/mesh
/2015/MB_cgi?field=uid&
term=D000309)
External eMedicine: emerg/16
resources (http://www.emedicine.com
/emerg/topic16.htm)

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