Adrenal insufficiency
Adrenal insufficiency | |
---|---|
Other names | adrenocortical insufficiency, hypocorticalism, hypocortisolism, hypoadrenocorticism, hypocorticism, hypoadrenalism |
Adrenal gland | |
Specialty | Endocrinology |
Adrenal insufficiency is a condition in which the
Adrenal insufficiency can be caused by dysfunction of the adrenal gland itself, whether by destruction (e.g.
Types
There are three major types of adrenal insufficiency, depending on the affected organ.
- Primary adrenal insufficiency is due to impairment of the adrenal glands, resulting in a lack of glucocorticoid production. Since the adrenal glands are directly affected, mineralocorticoid production is also reduced. Principal causes include:
- Autoimmune: e.g. autoimmune adrenalitis), which has been identified to be the cause of 80-90% of primary adrenal insufficiency cases since 1950.[2]
- Congenital: e.g. congenital adrenal hyperplasia, adrenoleukodystrophy[2]
- Infection: e.g. tuberculosis, CMV, histoplasmosis[2]
- Drugs: e.g.
- Vascular: e.g. hemorrhage from sepsis, adrenal vein thrombosis, hypercoagulable states such as heparin-induced thrombocytopenia and antiphospholipid syndrome[2]
- Neoplasia: e.g. adenoma (tumor) of the adrenal gland[2]
- Deposition disease: e.g.
- Idiopathic: undetermined cause
- Acquired: Bilateral Adrenalectomy to treat recurrent Cushing's Disease/Syndrome
- Autoimmune: e.g.
- Secondary adrenal insufficiency is caused by impairment of the pituitary gland, resulting in a lack of adrenocorticotropic hormone (ACTH) production and subsequent decreased adrenal stimulation. Since the adrenal glands are not directly affected, the effect on mineralocorticoid production is minimal, as ACTH primarily affects glucocorticoid production.[2][3] Principal causes include:
- Pituitary adenoma or craniopharyngioma: Tumors in the pituitary gland can suppress production of adrenocorticotropic hormone (ACTH).[2] High-dose irradiation (>30 Gy) to the hypothalamus or the pituitary gland can cause ACTH deficiency.[9]
- Surgery or radiation: Pituitary gland surgery and/or radiation can lead to destruction of ACTH-producing tissue.[2]
- Exogenous corticosteroid use: Exogenous corticosteroids suppress the stimulation of the hypothalamus and the pituitary gland to secrete CRH and ACTH, respectively.[2][3] These cases may present with symptoms of cortisol excess (see Cushing's syndrome).[3]
- Sheehan's syndrome: Loss of blood flow to the pituitary gland following childbirth[2]
- Pituitary apoplexy: Bleeding or impaired blood supply to the pituitary gland[2]
- Tertiary adrenal insufficiency is caused by impairment of the corticotropin-releasing hormone (CRH) production, causing downstream reduction in ACTH production and subsequently decreasing adrenal stimulation.[2] Since the adrenal glands are not directly affected, the effect on mineralocorticoid production is minimal, as ACTH primarily affects glucocorticoid production.[2][3]Principal causes include:
Signs and symptoms
Signs and symptoms include:
Pathophysiology
When functioning normally, the adrenal glands secrete
In adrenal insufficiency, there is a deficiency in cortisol production which may be accompanied by a deficiency in aldosterone production (predominantly 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), not ACTH.[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 (glucose production) in the liver, lipolysis (fat breakdown) in adipose tissue, and proteolysis (muscle breakdown) in muscle while increasing glucagon secretion and decreasing insulin secretion in the pancreas.[12] Overall, these actions cause the body to use fat stores and muscle for energy. Deficiency results in hypoglycemia, with associated nausea, vomiting, fatigue, and weakness.[2]
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.[13] The overproduction of α-MSH leads to the characteristic hyperpigmentation of Addison's disease.[14]
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).[15] 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.[15] 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.[15] 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.[15] This results in the absorption of sodium (with resulting retention of fluid) and the excretion of potassium.[15] Deficiency of aldosterone leads to urinary loss of sodium and effective circulating volume, as well as retention of potassium.[15] 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).[16]
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.[17] The latter is termed critical illness–related corticosteroid insufficiency.[18]
For chronic adrenal insufficiency, the major contributors are
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).[19]
Adrenal destruction
Autoimmune adrenalitis may be part of
Adrenal destruction is a feature of
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,
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
Adrenal dysgenesis
All causes in this category are genetic, and generally very rare. These include
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.[2][3] 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][29]
To confirm inappropriately low cortisol secretion, testing can include baseline morning cortisol level in the blood or morning cortisol level in the saliva.[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 | normal | low | low | low | tumor of the hypothalamus (adenoma), 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), 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, as well as treatment of any underlying cause.[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]
- typically hydrocortisone (Cortef) but dexamethasone (Decadron) may be used if diagnostic studies are necessary, as dexamethasone does not affect testing results[2][29]
- Supportive measures and correction of any additional issues such as electrolyte abnormalities[2][3]
- Chronic adrenal insufficiency treatment
- Glucocorticoid deficiency (low cortisol)
- Oral glucocorticoids[2][3]
- Hydrocortisone (brand name: Cortef), or
- Prednisone (brand name: Deltasone), or
- Dexamethasone (brand name: Decadron)
- Oral glucocorticoids[2][3]
- Mineralocorticoid deficiency (low aldosterone) treatment
- Sex hormone deficiency (low androgen)
- Oral androgens[2][3]
- Dehydroepiandrosterone (DHEA)
- Oral androgens[2][3]
- Glucocorticoid deficiency (low cortisol)
Prognosis
Primary adrenal insufficiency predisposes to higher risk of death, mostly due to infection, cardiovascular disease, and adrenal crisis.[2] Delayed diagnosis can impair quality of life, and lack of treatment brings high mortality.[2] However, with proper diagnosis, monitoring, and treatment, people with adrenal insufficiency can live normally.[3]
Epidemiology
The most common cause of
In children, congenital adrenal hyperplasia (CAH) is the most common cause of adrenal insufficiency, with an incidence 1 in 14,200 live births.[3]
See also
- 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
References
- ^ a b c d e f Ashley B. Grossman, MD (2007). "Addison's Disease". Adrenal Gland Disorders.
- ^ PMID 25905309, retrieved 2022-11-02
- ^ PMID 28722862, retrieved 2022-11-02
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- ^ 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.
- PMID 16287965.
- ^ "Dorlands Medical Dictionary:adrenal insufficiency".
- ^ "Secondary Adrenal Insufficiency - Endocrine and Metabolic Disorders". Merck Manuals Professional Edition.
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- ^ PMID 30855827, retrieved 2022-11-08
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- ^ Thomas A Wilson, MD (2007). "Adrenal Insufficiency". Adrenal Gland Disorders.
- PMID 26760044.
- ^ Thomas A Wilson, MD (1999). "Adrenoleukodystrophy".
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(help) - ^ Kennedy, Ron. "Addison's Disease". The Doctors' Medical Library. Archived from the original on 2013-04-12. Retrieved 2015-07-29.
- ^ Kaminstein, David S. William C. Shiel Jr. (ed.). "Steroid Drug Withdrawal". MedicineNet. Retrieved 10 April 2013.
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- ISBN 9780387765952.
- ^ a b Addison Disease~workup at eMedicine
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Further reading
- Bornstein, Stefan R.; Allolio, Bruno; Arlt, Wiebke; Barthel, Andreas; Don-Wauchope, Andrew; Hammer, Gary D.; Husebye, Eystein S.; Merke, Deborah P.; Murad, M. Hassan; Stratakis, Constantine A.; Torpy, David J. (February 2016). "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism. 101 (2): 364–389. PMID 26760044.