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==Pathophysiology==
==Pathophysiology==
⚫
[[File:HPA axis combined.jpg|thumb|660x660px|Diagram detailing the hypothalamus-pituitary-adrenal axis in the normal state, primary adrenal insufficiency, secondary adrenal insufficiency, and tertiary adrenal insufficiency. ]]
When functioning normally, the adrenal glands secrete [[Glucocorticoid|glucocorticoids]] (primarily, [[cortisol]]) in the ''[[zona fasciculata]]'' and [[Mineralocorticoid|mineralocorticoids]] (primarily, [[aldosterone]]) in the ''[[zona glomerulosa]]'' to regulate metabolism, blood pressure, and electrolyte balance.<ref name=":2">{{Citation |last=Thau |first=Lauren |title=Physiology, Cortisol |date=2022 |url=http://www.ncbi.nlm.nih.gov/books/NBK538239/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30855827 |access-date=2022-11-08 |last2=Gandhi |first2=Jayashree |last3=Sharma |first3=Sandeep}}</ref> Adrenal hormone production is controlled by the [[Hypothalamic–pituitary–adrenal axis|hypothalamic-pituitary-adrenal axis]], in which the hypothalamus produces [[Corticotropin releasing hormone|corticotropin-releasing hormone]] (CRH), which stimulates the pituitary gland to produce [[adrenocorticotropic hormone]] (ACTH), which stimulates the adrenal gland to produce cortisol.<ref name=":2" /> High levels of cortisol inhibit the production of both CRH and ACTH, forming a negative feedback loop.<ref name=":2" /> The types of adrenal insufficiency thus refer to the level of the axis in which the dysfunction originates: primary, secondary, and tertiary for adrenal glands, pituitary gland, and hypothalamus, respectively.<ref name=":0" /><ref name=":1" />
When functioning normally, the adrenal glands secrete [[Glucocorticoid|glucocorticoids]] (primarily, [[cortisol]]) in the ''[[zona fasciculata]]'' and [[Mineralocorticoid|mineralocorticoids]] (primarily, [[aldosterone]]) in the ''[[zona glomerulosa]]'' to regulate metabolism, blood pressure, and electrolyte balance.<ref name=":2">{{Citation |last=Thau |first=Lauren |title=Physiology, Cortisol |date=2022 |url=http://www.ncbi.nlm.nih.gov/books/NBK538239/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30855827 |access-date=2022-11-08 |last2=Gandhi |first2=Jayashree |last3=Sharma |first3=Sandeep}}</ref> Adrenal hormone production is controlled by the [[Hypothalamic–pituitary–adrenal axis|hypothalamic-pituitary-adrenal axis]], in which the hypothalamus produces [[Corticotropin releasing hormone|corticotropin-releasing hormone]] (CRH), which stimulates the pituitary gland to produce [[adrenocorticotropic hormone]] (ACTH), which stimulates the adrenal gland to produce cortisol.<ref name=":2" /> High levels of cortisol inhibit the production of both CRH and ACTH, forming a negative feedback loop.<ref name=":2" /> The types of adrenal insufficiency thus refer to the level of the axis in which the dysfunction originates: primary, secondary, and tertiary for adrenal glands, pituitary gland, and hypothalamus, respectively.<ref name=":0" /><ref name=":1" />

⚫
[[File:HPA axis combined.jpg|center|thumb|660x660px|Diagram detailing the hypothalamus-pituitary-adrenal axis in the normal state, primary adrenal insufficiency, secondary adrenal insufficiency, and tertiary adrenal insufficiency. ]]
In adrenal insufficiency, there is a deficiency in cortisol production which may be accompanied by a deficiency in aldosterone production (primarily in primary adrenal insufficiency).<ref name=":0" /><ref name=":1" /> Depending on the cause and type of adrenal insufficiency, the mechanism of the disease differs. Generally, the symptoms manifest through the systemic effects of cortisol and aldosterone.<ref name=":0" /><ref name=":1" /> In secondary and tertiary adrenal insufficiency, there is no effect on the production of aldosterone within the ''zona glomerulosa'' as this process is regulated by the [[Renin–angiotensin system|renin–angiotensin–aldosterone system]] (RAAS).<ref name=":1" />
In adrenal insufficiency, there is a deficiency in cortisol production which may be accompanied by a deficiency in aldosterone production (primarily in primary adrenal insufficiency).<ref name=":0" /><ref name=":1" /> Depending on the cause and type of adrenal insufficiency, the mechanism of the disease differs. Generally, the symptoms manifest through the systemic effects of cortisol and aldosterone.<ref name=":0" /><ref name=":1" /> In secondary and tertiary adrenal insufficiency, there is no effect on the production of aldosterone within the ''zona glomerulosa'' as this process is regulated by the [[Renin–angiotensin system|renin–angiotensin–aldosterone system]] (RAAS).<ref name=":1" />


Revision as of 20:23, 14 November 2022

This article is about medically-recognized chronic adrenal insufficiency. For a term used in alternative medicine, see Adrenal fatigue.
Adrenal insufficiency
Other namesadrenocortical insufficiency, hypocorticalism, hypocortisolism, hypoadrenocorticism, hypocorticism, hypoadrenalism
Adrenal gland
SpecialtyEndocrinology

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androgens.[1][2][3] Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes (in mild cases) to organ failure and shock (in severe cases).[1][2][3] An adrenal crisis may occur if the body is subjected to stress, such as an accident, injury, surgery, or severe infection; death may quickly follow.[1]

Adrenal insufficiency can be caused by dysfunction of the adrenal gland itself, whether by destruction (e.g. Addison's disease), failure of development (e.g. adrenal dysgenesis), or enzyme deficiency (e.g. congenital adrenal hyperplasia).[2][3] Adrenal insufficiency can also occur when the pituitary gland or the hypothalamus do not produce adequate amounts of the hormones that assist in regulating adrenal function.[4][5][6] This is called secondary adrenal insufficiency (when caused by lack of production of adrenocorticotropic hormone (ACTH) in the pituitary gland) or tertiary adrenal insufficiency (when caused by lack of corticotropin-releasing hormone (CRH) in the hypothalamus).[2][3][7]

Types

There are three major types of adrenal insufficiency, depending on the affected organ.

Signs and symptoms

Signs and symptoms include: hypoglycemia, hyperpigmentation, 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.[1] Eosinophilia may also occur.[8] Hyponatremia is a sign of secondary insufficiency.[9]

Pathophysiology

Diagram detailing the hypothalamus-pituitary-adrenal axis in the normal state, primary adrenal insufficiency, secondary adrenal insufficiency, and tertiary adrenal insufficiency.

When functioning normally, the adrenal glands secrete glucocorticoids (primarily, cortisol) in the zona fasciculata and mineralocorticoids (primarily, aldosterone) in the zona glomerulosa to regulate metabolism, blood pressure, and electrolyte balance.[10] Adrenal hormone production is controlled by the hypothalamic-pituitary-adrenal axis, in which the hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to produce cortisol.[10] High levels of cortisol inhibit the production of both CRH and ACTH, forming a negative feedback loop.[10] The types of adrenal insufficiency thus refer to the level of the axis in which the dysfunction originates: primary, secondary, and tertiary for adrenal glands, pituitary gland, and hypothalamus, respectively.[2][3]

In adrenal insufficiency, there is a deficiency in cortisol production which may be accompanied by a deficiency in aldosterone production (primarily in primary adrenal insufficiency).[2][3] Depending on the cause and type of adrenal insufficiency, the mechanism of the disease differs. Generally, the symptoms manifest through the systemic effects of cortisol and aldosterone.[2][3] In secondary and tertiary adrenal insufficiency, there is no effect on the production of aldosterone within the zona glomerulosa as this process is regulated by the renin–angiotensin–aldosterone system (RAAS).[3]

Adrenal insufficiency can also affect the zona reticularis and disrupt production of androgens, which are precursors to testosterone and estrogen.[2][3] This leads to a deficiency of sex hormones and can contribute to symptoms of depression and menstrual irregularities.[2][3]

Cortisol deficiency

Cortisol increases blood sugar by inducing gluconeogenesis in the liver, lipolysis in adipose tissue, and proteolysis in muscle while increasing glucagon secretion and decreasing insulin secretion in the pancreas.[10] Deficiency results in hypoglycemia, with associated nausea, vomiting, fatigue, and weakness. Over time, the breakdown of fat and muscle can cause weight loss (in severe cases, anorexia) and muscle aches.[citation needed]

Cortisol potentiates the effectiveness of angiotensin II and catecholamines such as norepinephrine in vasoconstriction. Thus, a deficiency can contribute to hypotension, though this effect is most pronounced in mineralocorticoid deficiency.[2]

In primary adrenal insufficiency, the lack of negative feedback from cortisol leads to increased production of CRH and ACTH.[2][3] ACTH is derived from pro-opiomelanocortin (POMC), which is cleaved into ACTH as well as α-MSH, which regulates production of melanin in the skin.[citation needed] The overproduction of α-MSH leads to the characteristic hyperpigmentation of Addison's disease.[11]

Aldosterone deficiency

Although the production of aldosterone occurs within the adrenal cortex, it is not induced by adrenocorticotropic (ACTH); instead, it is regulated by the renin–angiotensin-aldosterone system (RAAS).[12] Renin production in the juxtaglomerular cells of the kidney is induced by decreased arterial blood pressure, decreased sodium content in the distal convoluted tubule, and increased sympathetic tone.[12] Renin initiates the downstream sequence of cleavage of angiotensinogen to angiotensin I to angiotensin II, in which angiotensin II stimulates aldosterone production in the zona glomerulosa.[12] Thus, dysfunction of the pituitary gland or the hypothalamus does not affect the production of aldosterone.[2][3] However, in primary adrenal insufficiency, damage to the adrenal cortex (e.g. autoimmune adrenalitis a.k.a. Addison's disease) can lead to destruction of the zona glomerulosa and therefore a loss of aldosterone production.

Aldosterone acts on mineralocorticoid receptors on epithelial cells lining the distal convoluted tubule, activating epithelial sodium channels (ENaC) and the Na⁺/K⁺-ATPase pump.[12] This results in the absorption of sodium (with resulting retention of fluid) and the excretion of potassium.[12] Deficiency of aldosterone leads to urinary loss of sodium and effective circulating volume, as well as retention of potassium.[12] This can cause hypotension (in severe cases, shock), dizziness (from orthostatic hypotension), dehydration, and salt craving.

Differently from mineralocorticoid deficiency, glucocorticoid deficiency does not cause a negative sodium balance (in fact a positive sodium balance may occur).[13]

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.[14] The latter is termed critical illness–related corticosteroid insufficiency.[citation needed]

For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease), tuberculosis, AIDS, and metastatic disease.[14] Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.[14]

Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. These are adrenal destruction (disease processes leading to glandular damage), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol), or adrenal dysgenesis (the gland has not formed adequately during development).[15]

Adrenal destruction

Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialised world, causing 80-90% of primary adrenal insufficiency cases since 1950.[2] Autoimmune destruction of the adrenal cortex is caused by an immune reaction against the enzyme 21-hydroxylase (a phenomenon first described in 1992).[16] 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.[17]

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).[18] 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.[19]

Adrenal destruction is a feature of adrenoleukodystrophy (ALD).[20] Destruction also occurs 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.[21]

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.[verification needed]

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.[15] 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).[15]

Adrenal insufficiency can also result when a patient has a brain mass in the pituitary gland (e.g. pituitary adenoma, craniopharyngioma) which can take up space and interfere with the secretion of pituitary hormones such as ACTH, therefore leading to decreased adrenal stimulation (secondary adrenal insufficiency).[2] The same can occur with masses in the hypothalamus (tertiary adrenal insufficiency).[2]

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.[22][23] Use of steroids joint injections may also result in adrenal suppression after discontinuation.[24]

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.[15]

Diagnosis

The first step of diagnosing adrenal insufficiency is confirming inappropriately low cortisol secretion.[2] This is followed by determining the origin of dysfunction (adrenal glands, pituitary gland, or hypothalamus) and therefore the type of adrenal insufficiency (primary, secondary, or tertiary).[2] After narrowing down the source, further testing can elucidate the cause of insufficiency.[2]

If a patient is suspected to be experiencing 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.[citation needed] Dexamethasone should be used as the corticosteroid of choice in these cases as it is the only corticosteroid that will not affect diagnostic test results.[2][25]

To confirm inappropriately low cortisol secretion, testing can include basal morning serum cortisol concentration or morning salivary cortisol concentration.[2] Cortisol levels typically peak in the morning; thus, low values indicate true adrenal insufficiency.[2] Urinary free cortisol can also be measured, but are not necessary for diagnosis.[2]

To determine the origin of dysfunction, the ACTH stimulation test is the best initial test as it can differentiate between primary and secondary adrenal insufficiency.[2] If cortisol levels remain low following ACTH stimulation, then the diagnosis is primary adrenal insufficiency.[2] If cortisol levels increase following ACTH stimulation, then the diagnosis is either secondary or tertiary adrenal insufficiency.[2] The corticotropin-releasing hormone test can then differentiate between secondary and tertiary adrenal insufficiency.[2] Additional testing can include basal plasma ACTH, renin, and aldosterone concentrations, as well as a blood chemistry panel to check for electrolyte imbalances.[2]

Depending on the type of adrenal insufficiency, there are many possible causes and therefore many different avenues of testing (see Causes above). For primary adrenal insufficiency, the most common cause is autoimmune adrenalitis (Addison's disease); therefore, 21-hydroxylase autoantibodies should be checked.[2] Structural abnormalities of the adrenal glands can be detected on CT imaging.[2] For secondary and tertiary adrenal insufficiency, an MRI of the brain can be obtained to detect structural abnormalities such as masses, metastasis, hemorrhage, infarction, or infection.[2]

Effects

Source of pathology CRH ACTH DHEA DHEA-S cortisol aldosterone renin Na K Causes5
hypothalamus
(tertiary)1		 low low low low low3 low low low low tumor of the hypothalamus (adenoma), antibodies, environment (i.e. toxins), head injury
pituitary
(secondary)		 high2 low low low low3 normal low low normal tumor of the pituitary (adenoma), antibodies, environment, head injury,
surgical removal6, Sheehan's syndrome
adrenal glands
(primary)7		 high high high high low4 low high low high tumor of the adrenal (adenoma), stress, antibodies, environment, Addison's disease, trauma, surgical removal (resection), miliary tuberculosis of the adrenal
1 Automatically includes diagnosis of secondary (hypopituitarism)
2 Only if CRH production in the hypothalamus is intact
3 Value doubles or more in stimulation
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

Treatment

In general, the treatment of adrenal insufficiency requires replacement of deficient hormones.[2][3] All types of adrenal insufficiency will require glucocorticoid repletion.[2][3] Many cases (typically, primary adrenal insufficiency) will also require mineralocorticoid repletion.[2][3] In rarer cases, repletion of androgens may also be indicated, typically in female patients with mood disturbances and changes in well-being.[2][3]

  • Adrenal crisis (acute) treatment
    • Intravenous fluids[1][2][3]
    • Intravenous glucocorticoids[1][2][3]
    • Supportive measures and correction of any additional issues such as electrolyte abnormalities[2][3]
  • Chronic adrenal insufficiency treatment

See also

References

  1. ^ a b c d e f Ashley B. Grossman, MD (2007). "Addison's Disease". Adrenal Gland Disorders.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf Nicolaides, Nicolas C.; Chrousos, George P.; Charmandari, Evangelia (2000), Feingold, Kenneth R.; Anawalt, Bradley; Boyce, Alison; Chrousos, George (eds.), "Adrenal Insufficiency", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID 25905309, retrieved 2022-11-02
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Huecker, Martin R.; Bhutta, Beenish S.; Dominique, Elvita (2022), "Adrenal Insufficiency", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28722862, retrieved 2022-11-02
  4. ^ Eileen K. Corrigan (2007). "Adrenal Insufficiency (Secondary Addison's or Addison's Disease)". NIH Publication No. 90-3054.
  5. ^ Brender E, Lynm C, Glass RM (2005). "JAMA patient page. Adrenal insufficiency". JAMA. 294 (19): 2528. doi:10.1001/jama.294.19.2528. PMID 16287965.
  6. ^ "Dorlands Medical Dictionary:adrenal insufficiency".
  7. ^ "Secondary Adrenal Insufficiency - Endocrine and Metabolic Disorders". Merck Manuals Professional Edition.
  8. ^ 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.
  9. ^ Jessani, Naureen; Jehangir, Waqas; Behman, Daisy; Yousif, Abdalla; Spiler, Ira J. (April 2015). "Secondary Adrenal Insufficiency: An Overlooked Cause of Hyponatremia". Journal of Clinical Medicine Research. 7 (4): 286–288. doi:10.14740/jocmr2041w. PMC 4330026. PMID 25699130.
  10. ^ a b c d Thau, Lauren; Gandhi, Jayashree; Sharma, Sandeep (2022), "Physiology, Cortisol", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30855827, retrieved 2022-11-08
  11. ^ Nieman, Lynnette K.; Chanco Turner, Maria L. (July–August 2006). "Addison's disease". Clinics in Dermatology. 24 (4): 276–280. doi:10.1016/j.clindermatol.2006.04.006. ISSN 0738-081X. PMID 16828409.
  12. ^ a b c d e f Arai, Keiko; Papadopoulou-Marketou, Nektaria; Chrousos, George P. (2000), Feingold, Kenneth R.; Anawalt, Bradley; Boyce, Alison; Chrousos, George (eds.), "Aldosterone Deficiency and Resistance", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID 25905305, retrieved 2022-11-08
  13. ^ 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.
  14. ^ a b c 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.
  15. ^ a b c d Ten, Svetlana; New, Maria; Maclaren, Noel (July 2001). "Addison's Disease 2001". The Journal of Clinical Endocrinology & Metabolism. 86 (7): 2909–2922. doi:10.1210/jcem.86.7.7636. PMID 11443143.
  16. ^ 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. S2CID 19666235.
  17. ^ Husebye, E. S.; 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): 514–529. doi:10.1111/j.1365-2796.2009.02090.x. PMID 19382991.
  18. ^ Thomas A Wilson, MD (2007). "Adrenal Insufficiency". Adrenal Gland Disorders.
  19. ^ 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.
  20. ^ Thomas A Wilson, MD (1999). "Adrenoleukodystrophy". {{cite journal}}: Cite journal requires |journal= (help)
  21. ^ Kennedy, Ron. "Addison's Disease". The Doctors' Medical Library. Archived from the original on 2013-04-12. Retrieved 2015-07-29.
  22. ^ Kaminstein, David S. William C. Shiel Jr. (ed.). "Steroid Drug Withdrawal". MedicineNet. Retrieved 10 April 2013.
  23. ^ Dernis, Emmanuelle; Ruyssen-Witrand, Adeline; Mouterde, Gaël; Maillefert, Jean-Francis; Tebib, Jacques; Cantagrel, Alain; Claudepierre, Pascal; Fautrel, Bruno; Gaudin, Philippe; Pham, Thao; Schaeverbeke, Thierry; Wendling, Daniel; Saraux, Alain; Loët, Xavier Le (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. 77 (5): 451–457. doi:10.1016/j.jbspin.2009.12.010. PMID 20471886.
  24. ^ Stitik, Todd P. (2010). Injection Procedures: Osteoarthritis and Related Conditions. Springer Science & Business Media. p. 47. ISBN 9780387765952.
  25. ^ a b Addison Disease~workup at eMedicine

Further reading

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