Approach

The key to diagnosis of iatrogenic adrenal suppression is eliciting exposure to exogenous glucocorticoids or other offending agents.

Patients receiving supraphysiologic doses of oral glucocorticoids for corticosteroid-responsive illnesses and having a cushingoid appearance (centripetal obesity with a round or moon facies, dorsocervical fat pads, and striae) should prompt recognition of possible hypothalamic-pituitary-adrenal (HPA) axis suppression.[37]​ HPA axis suppression has been described after only 4 to 5 days of corticosteroid therapy, and as a consequence of local glucocorticoid administration.[25][26]​ In patients receiving intra-articular glucocorticoid injections, recovery of the HPA axis can take 1 to 4 weeks depending on the dose and frequency of injections.[10]

Although some patients appear cushingoid, and some have obvious symptoms of adrenal insufficiency when the inciting corticosteroid agent is rapidly tapered or stopped, HPA axis suppression may be subtle. Not all patients appear cushingoid, and a high index of suspicion is necessary.

Patients with adrenal suppression are at risk of adrenal crisis if glucocorticoid treatment is suddenly ceased or if it is not increased during periods of increased stress (e.g., febrile illness, trauma, or surgery). Patients with a history compatible with adrenal suppression and presenting with features of adrenal crisis (i.e., hypotension, circulatory failure) should be treated urgently. Diagnostic tests should not delay treatment.[37][38]

History

Patients receiving supraphysiologic doses of glucocorticoids are at risk for adrenal suppression, especially if these are potent and/or administered for a prolonged period.[1][8][39]​​ However, nonsystemic corticosteroids may also cause adrenal suppression.[1]

Patients may need prompting; for example, asking specifically about eye drops, nasal sprays, inhalers for breathing problems, or injections for pain.

The history should be directed to elicit the pattern of glucocorticoid use. It is important to ask about diseases for which corticosteroids are commonly prescribed, and oral or alternate routes of administration such as:[10][11][12][13][14][15][16]

  • Inhaled corticosteroids for asthma or chronic obstructive pulmonary disease

  • Intranasal corticosteroids for allergic rhinitis

  • Topical corticosteroids for the treatment of dermatologic conditions

  • Intra-articular and epidural corticosteroids for rheumatologic or pain disorders.

Equivalent doses of hydrocortisone, prednisolone, prednisone, and dexamethasone are:

[Figure caption and citation for the preceding image starts]: Dose equivalency for glucocorticoidsCreated by MC Lansang and SL Quinn [Citation ends].com.bmj.content.model.Caption@70922ec3​Other sources of prescribed corticosteroids, such as enemas or rectal foam for inflammatory bowel disease, should also be sought. Additional information as to the type, dose, route of administration, and length of corticosteroid treatment should be obtained. Less commonly, patients give a history of taking drugs that act on the glucocorticoid receptor, such as megestrol or medroxyprogesterone.[1][17][18]​​

Note that nonprescription eczema treatments, skin-lightening creams, and herbal medicines may contain corticosteroids.

Patients should be asked about concomitant drugs. Some may interfere with glucocorticoid metabolism.[1] CYP3A4 is the primary pathway for the metabolism of most prescribed glucocorticoids, therefore CYP3A4 inhibitors will increase exposure to glucocorticoids.[1] For example, the antiretroviral drug ritonavir increases plasma concentrations of prednisone metabolites (prednisolone).[1] Other strong CYP3A4 inhibitors include antifungals such as itraconazole and ketoconazole, and cancer treatments such as ceritinib and idelalisib.[1] The anesthetic induction agent etomidate can interfere with adrenal steroid synthesis, and can increase the risk of adrenal insufficiency and mortality in patients with sepsis.[19]​ This list is not exhaustive; consult your local drug information source.

In patients with glucocorticoid-induced adrenal suppression, interaction with drugs that induce CYP3A4 will decrease synthetic glucocorticoid levels and may cause symptoms of adrenal insufficiency. Examples of agents that induce CYP3A4 include carbamazepine, phenobarbital, phenytoin, primidone, rifampin, and nafcillin.[1] This list is not exhaustive; consult your local drug information source

Rarely, patients have a history of removal of a pituitary adenoma or carcinoma that caused Cushing syndrome.[20][21]

Symptoms

Symptoms of adrenal insufficiency may be present, especially when the inciting agent is rapidly tapered or stopped.

Symptoms of adrenal insufficiency are generally vague. They include fatigue, anorexia, nausea and/or vomiting, and weight loss.[1][37]​​[38]​​[40]​ Dizziness, orthostatic symptoms, myalgias, and arthralgias may be present. Abdominal pain can be mild or severe enough to lead to a misdiagnosis of acute abdomen.[8][38]

Patients may report symptoms consistent with Cushing syndrome, including muscle weakness, central nervous system symptoms such as depression, agitation, or sleep disorders.[37]​ There may be a prior history of weight gain and increased appetite, round face, dorsocervical fat pads, and easy bruising.[37] Other medical disorders such as hypertension and diabetes may have become more difficult to control and less responsive to drug treatment.[8][41]

Adrenal suppression in the pediatric population can present as an adrenal crisis in times of stress, but it is more likely to be subtle. The nonspecific symptoms of adrenal suppression in children are similar to those seen in adults; however, children may also exhibit growth failure and hypoglycemia.[2][40]​​

Physical exam

Patients at risk of adrenal suppression who have suddenly ceased their glucocorticoid, or not increased the dose during periods of increased stress, can present with an acute adrenal crisis with collapse due to hypovolemic shock, hypotension, postural dizziness, and tachycardia.[37][38]

In less acute cases, patients may or may not appear cushingoid and hypertension may be present. Proximal muscle weakness may be present. The complexion may be plethoric with pigmented striae; thin, easily bruised skin; and acne. Features associated with elevations of adrenocorticotropic hormone (ACTH) such as mucosal or cutaneous hyperpigmentation will be absent. Likely also to be absent are other stigmata of autoimmune disorders associated with autoimmune adrenal insufficiency, such as vitiligo. These features help distinguish iatrogenic from endogenously induced adrenal suppression.

Suspected adrenal crisis

Diagnostic tests should not delay treatment in cases of acute adrenal crisis.[37][38]

Investigations for suspected adrenal crisis include close monitoring of blood pressure, fluid balance, and baseline bloods (complete blood count, electrolytes, urea, creatinine, thyroid function [hyperthyroidism can trigger adrenal crisis], cortisol, and ACTH level). If the patient is hemodynamically stable, consider a short ACTH stimulation test.[38]

Incidental laboratory findings such as hypo- or hyperglycemia, hypokalemia, hypomagnesemia, and a contraction alkalosis may raise suspicion of glucocorticoid use. Electrolyte abnormalities consistent with mineralocorticoid deficiency such as hyperkalemia are absent because the renin-angiotensin-aldosterone system remains intact.

So long as supraphysiologic corticosteroids continue, evaluation of adrenal function is not helpful.[37] 

Diagnostic testing in a patient discontinuing or reducing corticosteroid dose to physiologic or subphysiologic levels

Gradual corticosteroid tapering is recommended in patients who no longer require systemic corticosteroid therapy.[37][38]

Patients at risk for adrenal insufficiency during tapering (e.g., those with comorbidities), or who have symptoms of adrenal insufficiency, are candidates for a morning (between 9 and 10 a.m.) serum cortisol test. The test should be conducted only after reaching the range of a physiologic equivalent daily dose. Serum cortisol cutoffs serve as a guide. While higher serum cortisol values indicate recovery of the HPA axis, guidelines note that the value of morning serum cortisol should be viewed as a continuum.[37]

Random serum cortisol levels are not recommended as reliable indicators of adrenal status.

Salivary cortisol is of limited value in the diagnosis of adrenal insufficiency and is not routinely recommended.[42] It may be considered in patients in whom phlebotomy is impractical or difficult; or those with hepatic disease with hypoalbuminemia and cirrhosis, where salivary cortisol levels correlate better with adrenal function and plasma free cortisol than does total plasma cortisol.[43][44]​​​​​

Dynamic testing: ACTH stimulation test

A stimulation test may be considered in a patient with an indeterminate serum cortisol value.[37][38]​ Routine ACTH stimulation testing is not, however, recommended to assess HPA axis recovery in patients tapering or discontinuing corticosteroid therapy.[37]

The conventional dose ACTH (1-24) test (using 250 micrograms of cosyntropin by injection or infusion) measures serum cortisol levels (before and after administration of cosyntropin) to determine adrenal cortisol output. An appropriate increase in cortisol level within 60 minutes excludes adrenal insufficiency.

Guidelines suggest against the use of the low-dose protocol (using 1 microgram of cosyntropin) because of limited, or no, availability of commercially available formulations of this lower dose.[37] Furthermore, diagnostic accuracy using low-dose ACTH is not superior to that of the conventional dose test.

The ACTH stimulation test may be unreliable in patients with recent onset of HPA axis suppression where the adrenal glands have not had sufficient time to atrophy. If patients are taking hydrocortisone or prednisone, it is recommended to withhold the treatment for 24 hours before the test, to avoid false positives. Other corticosteroid preparations, such as dexamethasone, do not cross-react with the cortisol assay used for the ACTH stimulation test.

Less commonly used dynamic tests

The insulin tolerance test (ITT) and the overnight metyrapone test evaluate the entire HPA axis and are capable of assessing partial adrenal suppression.[45]​ 

The ITT can be used if there is a need to determine if the patient has concomitant growth hormone deficiency. Both ITT and metyrapone tests can be used to determine whether the patient has secondary adrenal insufficiency due to a recent pituitary insult (e.g., pituitary surgery). In this situation, the adrenal glands can still mount a normal response to the ACTH stimulation test up to 2 to 3 weeks after the pituitary insult because of adrenal reserve. However, the ITT may uncover that the pituitary gland is not capable of responding to stress.

The ITT relies on production of symptomatic hypoglycemia to stimulate cortisol release. There is, therefore, an associated risk of hypoglycemic seizures and the test must be performed under close observation. It is not recommended for frail or older patients with cardiovascular disease or seizures. The metyrapone may, theoretically, precipitate acute adrenal insufficiency.

Screening of urine for synthetic corticosteroids

In patients who have a vague recollection of being given local glucocorticoid preparations (such as epidural or intra-articular) suspected to be causing adrenal suppression, screening of urine for synthetic corticosteroids will confirm systemic absorption of exogenous glucocorticoids, but it is not diagnostic of adrenal suppression.

[Figure caption and citation for the preceding image starts]: Adrenal suppression tests tableCreated by MC Lansang and SL Quinn [Citation ends].com.bmj.content.model.Caption@180c1e32

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