Adrenal insufficiency

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]

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 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.

  • 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:
  • 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.[2][3] Principal causes include:
    • Pituitary adenoma: Tumors in the pituitary gland can suppress production of adrenocorticotropic hormone (ACTH).[2]
    • 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]
    • 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 hypothalamus, resulting in a lack of 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.[2][3] Principal causes include:
    • Sudden withdrawal from long-term exogenous steroid use[2][3]
    • Brain tumors[2][3]

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

When functioning normally, the adrenal glands secrete glucocorticoids (in the zona fasciculata) and mineralocorticoids (in the zona glomerulosa) to regulate metabolism, blood pressure, and electrolyte balance. In adrenal insufficiency, there is a deficiency in glucocorticoid production which may be accompanied by a deficiency in mineralocorticoid 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 (in primary adrenal insufficiency) 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]

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).[10]

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.[11] 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.[11] Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.[11]

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).[12] 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.[13]

X-Linked Recessive Adrenoleukodystrophy can also cause adrenal insufficiency.[14]

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).[15]

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.[16][17] Use of steroids joint injections may also result in adrenal suppression after discontinuation.[18]

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]

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.[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 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).[19] 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.[20]

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.[21]

Diagnosis

The best diagnostic tool to confirm adrenal insufficiency is the ACTH stimulation test; however, 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.

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.[22]

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.

Effects
Source of pathologyCRHACTHDHEADHEA-ScortisolaldosteronereninNaKCauses5
hypothalamus
(tertiary)1		lowlowlowlowlow3lowlowlowlowtumor of the hypothalamus (adenoma), antibodies, environment (i.e. toxins), head injury
pituitary
(secondary)		high2lowlowlowlow3normallowlownormaltumor of the pituitary (adenoma), antibodies, environment, head injury,
surgical removal6, Sheehan's syndrome
adrenal glands
(primary)7		highhighhighhighlow4lowhighlowhightumor of the adrenal (adenoma), stress, antibodies, environment, Addison's disease, trauma, surgical removal (resection), miliary tuberculosis of the adrenal
1Automatically includes diagnosis of secondary (hypopituitarism)
2Only if CRH production in the hypothalamus is intact
3Value doubles or more in stimulation
4Value less than doubles in stimulation
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)[1]

See also

References
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  2. 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. Huecker, Martin R.; Bhutta, Beenish S.; Dominique, Elvita (2022), "Adrenal Insufficiency", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28722862, retrieved 2022-11-02
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Further reading
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