Approach

Primary adrenal insufficiency (PAI) can be difficult to diagnose. Clinical manifestations are based on the deficiency of adrenocortical hormones (glucocorticoids, mineralocorticoids) and adrenal androgens.[9] It presents with non-specific signs and symptoms, such as fatigue, weakness, and weight loss, that are also common to other diseases. Other manifestations include hyperpigmentation, postural hypotension due to salt loss and dehydration, hyponatraemia, hyperkalaemia, changes in blood count (anaemia, eosinophilia, and lymphocytosis), and hypoglycaemia.[2] A high percentage of patients are diagnosed after a life-threatening adrenal crisis.[2] Patients presenting with features of adrenal crisis (i.e., hypotension, circulatory failure) should be treated urgently.[26] Tests may be taken as baseline, but diagnostic tests should not delay treatment.[26]

Groups of patients with known causative factors for developing PAI should be viewed as being at high risk so that a diagnosis can be established early. Risk factors include female sex and known autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, pernicious anaemia, coeliac disease, vitiligo, or autoimmune thyroid disease.[3][9][13] Another risk factor for the development of PAI is the occurrence of adrenal haemorrhage or haemorrhagic infarction. This can be caused by thromboembolic and/or hypercoagulable states, such as antiphospholipid syndrome, sepsis, and heparin-induced thrombocytopenia.[9][17] Patients taking anticoagulants are at increased risk of adrenal haemorrhage.[2]

Secondary adrenal insufficiency can be associated with severe cortisol deficiency, but otherwise has a different clinical presentation (e.g., no increased pigmentation and only mild mineralocorticoid deficiency). Therefore, the finding of hypocortisolism is not unique to PAI. A history of treatment with glucocorticoid in recent months, or the possibility of hypothalamic-pituitary disease (e.g., concurrent emergence of other secondary pituitary deficiencies, such as thyroid or gonadal deficiencies), should prompt evaluation for secondary adrenal insufficiency.

History

Fatigue and lethargy (or weakness) are the most common presenting symptoms.[3] They are usually insidious and may be accompanied by variable degrees of generalised muscle weakness, myalgias, and arthralgias. Patients complain about gradual loss of energy as the day goes on.

Anorexia is often present and may lead to significant weight loss. Both are important features in patients with PAI.

Dizziness, arthralgia, and myalgia are less common.

Gastrointestinal symptoms including nausea, vomiting, and vague abdominal pain are non-specific presenting symptoms, and can suggest adrenal crisis if acutely worsening.[3] Salt craving may be present.[3]

History should be directed at establishing the underlying cause, such as a known history of autoimmune disease, HIV infection, possible tuberculosis infection, and current medication use.

Sudden alterations in glycaemic control and recurrent hypoglycaemia in patients with type 1 diabetes mellitus may suggest autoimmune polyglandular syndrome type 2 with co-existing diabetes and PAI.[9]

Physical examination

Most patients present with significant weight loss secondary to anorexia.

The most distinctive feature of PAI is generalised mucosal and cutaneous hyperpigmentation, which is more pronounced in areas of increased friction, such as palms, knuckles, and scars.[3] This is due to high levels of adrenocorticotrophic hormone (ACTH), which stimulate dermal melanocortin receptors. [Figure caption and citation for the preceding image starts]: Generally hyperpigmented young man with primary adrenal insufficiency: exaggerated pigmentation over pressure points on elbowsFrom the personal collection of T. Joseph McKenna, MD; used with permission [Citation ends].com.bmj.content.model.Caption@3b9209bf[Figure caption and citation for the preceding image starts]: Hands of patient with primary adrenal insufficiency showing: hyperpigmentation exaggerated on sun-exposed dorsal surface and creases; area of vitiligo in skin over left second metacarpophalangeal jointFrom the personal collection of T. Joseph McKenna, MD; used with permission [Citation ends].com.bmj.content.model.Caption@513ede98[Figure caption and citation for the preceding image starts]: Area of buccal hyperpigmentation where teeth pinch mucous membrane while chewingFrom the personal collection of T. Joseph McKenna, MD; used with permission [Citation ends].com.bmj.content.model.Caption@73dd184c

Postural hypotension caused by mineralocorticoid deficiency is common.[2][9]

In premenopausal women, loss of adrenal androgens results in significant loss of axillary and pubic hair.[2][9]

Other physical signs of autoimmunity, such as vitiligo, premature greying of the hair, and Hashimoto's thyroiditis goitre may be present.

Laboratory evaluation

In an emergency situation, the physician should not wait for the results of blood tests before administering treatment. In acutely ill patients with otherwise unexplained symptoms or signs suggestive of adrenal insufficiency, blood is drawn for baseline ACTH and cortisol level and treatment is administered immediately.[2] Further investigations are appropriate when in a less urgent situation to confirm the adrenal insufficiency and determine the aetiology.[2]

In addition to measurement of serum cortisol level, investigations focus on the integrity of the main peptide stimulating the adrenal cortex (plasma ACTH), as well as the classes of hormones secreted by the adrenal cortex: glucocorticoids (cortisol); mineralocorticoids (aldosterone); and adrenal androgens (dehydroepiandrosterone [DHEA], as well as its sulfated conjugate, DHEA-S).[3]

It is expected that with PAI there will be loss of cortisol, aldosterone, and DHEA/DHEA-S secretion from the adrenal cortex and that this will be associated with a compensatory rise in plasma ACTH. In contrast, patients with central adrenal insufficiency (that is, a secondary or tertiary cause), will lose ACTH secretion and consequently will have decreased secretion of cortisol as well as DHEA/ DHEA-S while mineralocorticoid function (aldosterone) remains relatively intact.[4]

  1. Measurements of cortisol and ACTH levels

    Cortisol

    • The first diagnostic test is measurement of serum cortisol level, preferably in the morning when it is expected to be normally the highest.[27] A random serum cortisol level is also acceptable as long as it is interpreted within the context of the patient’s activity and level of stress. This can be used as a test of exclusion.

    • Cortisol values vary according to the assay used, and use of the reference ranges provided by the relevant laboratory is recommended.[4] Serum cortisol is 80% bound to cortisol-binding globulin (CBG) and 10% to 15% to albumin, so disorders that affect CBG levels or albumin influence cortisol levels.[2] CBG levels are affected by oestrogen levels, some medical conditions (e.g., liver disease or nephrotic syndrome), and some heritable mutations.[8]

    • A level below 140 nanomols/L (5 micrograms/dL) is highly suggestive of adrenal insufficiency.[2] A lower cut-off of 85 nanomols/L (3 micrograms/dL) may reduce the number of patients requiring stimulation tests.[27]

    • A cortisol level above 500 nanomols/L (18 micrograms/dL) effectively excludes the diagnosis of adrenal insufficiency.[2][28]

    • Patients with suspected adrenal insufficiency and cortisol levels of 140 nanomols/L to 500 nanomols/L (5 to 18 micrograms/dL) require further testing with a high-dose ACTH stimulation test to confirm adrenal functioning.[4]

    ACTH

    • Plasma ACTH level should be determined along with a serum cortisol determination.

    • The presence of a low serum cortisol together with an elevated plasma ACTH (two-times the upper limit of the plasma ACTH reference interval) is indicative of PAI.[3][9] A similar biochemical set of data can at times be observed in patients recovering from chronic suppression of the hypothalamo-pituitary-adrenal (HPA) axis.

    • Patients with central adrenal insufficiency will have low or low-normal ACTH levels along with low/low normal cortisol values.[9]

  2. ACTH stimulation test

    • The optimal cortisol values need to be individualised depending on the assay used, as newer assays (e.g., monoclonal antibody immunoassays or mass spectrometry) may have a lower threshold and result in a false positive test.[29] The value of 500 nanomols/L (18 micrograms/dL) is derived from polyclonal antibody assays. Cut-off values also need to be individualised according to the type of ACTH stimulation test used.[30]

    • If cortisol levels below 500 nanomols/L (18 micrograms/dL) are found at either 30 or 60 minutes after ACTH stimulation, the diagnosis of adrenal insufficiency is highly likely.[2][4]

    • Cortisol levels exceeding 500 nanomols/L (18 micrograms/dL) at 30 or 60 minutes after administration of high-dose ACTH (250 micrograms) exclude the diagnosis of PAI in most instances.[8] However, some patients with mild or early PAI or partial central adrenal insufficiency manifest an adequate increase in cortisol levels after a high-dose ACTH stimulation test.[27][31] In situations where this is suspected, patients should have the stimulation test repeated using a low dose of ACTH (1 microgram).[28] A meta-analysis has concluded that the high-dose and low-dose ACTH stimulation tests are satisfactory for indicating the presence of secondary adrenal insufficiency but data in PAI are insufficient to estimate diagnostic accuracy, such that neither was reliable for consistently encoding the disorder.[32]

  3. Patients who have an abnormal ACTH stimulation test consistent with adrenal insufficiency require further laboratory evaluation to determine the type of adrenal insufficiency.

    • Plasma ACTH level should have been already measured. If high, the cause is PAI. A low or low-normal value would support a diagnosis of secondary adrenal insufficiency.[4][9]

    • Measurements of plasma renin activity and serum aldosterone levels are important when PAI is suspected.[2] In patients with PAI the entire adrenal cortex is involved, and biosynthesis of aldosterone is compromised in addition to that of cortisol. To compensate, renin levels become elevated, but they are ineffective. A low plasma aldosterone associated with a high simultaneously measured plasma renin activity is indicative of PAI.[2][4] In contrast, in secondary adrenal insufficiency the renin-angiotensin-aldosterone axis is intact, although slightly less responsive as a consequence of suppressed cortisol concentrations.

    • Measurement of DHEA/DHEA-S levels is helpful in the assessment of adrenal insufficiency as these adrenal androgens are the first to be lost when adrenal cortical function is impaired.[2][27] Levels below the lower limit of normal for age and sex are a useful initial sign of PAI, but cannot be used alone to make the diagnosis because levels may be low, especially in older age, without PAI.[2] Since the secretion of DHEA/DHEA-S is ACTH dependent, their levels will also be low in central adrenal insufficiency. Thus, a low DHEA-S level may indicate adrenal failure but will not identify whether it is primary or central in origin. Conversely, a normal serum DHEA-S level makes the diagnosis of adrenal insufficiency (primary or central) very unlikely.[33][34]

  4. Ancillary tests

    • Baseline blood tests (full blood count, electrolytes, urea, creatinine) should be performed, as destruction of the adrenal cortex, and especially deficiency in glucocorticoids and mineralocorticoids, leads to changes in fluid and electrolyte balance and changes in blood count.[2][4][26]

    • Autoimmune adrenalitis is the most common cause of adult cases of PAI.[2] Antibodies directed against the adrenal enzyme 21-hydroxylase are associated with autoimmune PAI, but although sensitive they are not necessary for the diagnosis.[2][4][35]

    • In patients where the underlying cause is still uncertain, imaging of the adrenals using computed tomography and magnetic resonance imaging is recommended to determine other causes, such as infection, haemorrhage, or metastatic disease.[4]

    • If secondary adrenal insufficiency is suspected, but the cortisol response to ACTH is not diagnostic, a test of the entire HPA axis may be helpful (e.g., the insulin tolerance test or the overnight metyrapone test). The insulin tolerance test measures the cortisol response to insulin-induced hypoglycaemia.[28][36] Vigilance is required, due to the fact that hypoglycaemia is an endpoint. The test is contraindicated in older adults and in people with cardiovascular disease or seizure disorder. Another option to investigate the HPA axis is the overnight metyrapone test which measures the 11-deoxycortisol and cortisol response to metyrapone.[37] Unfortunately, there is limited availability of metyrapone in the US; it can be obtained via a specialist pharmacy. In many countries, metyrapone is available through its manufacturer.

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