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Adrenal insufficiency (AI) is a life-threatening condition characterized by the failure of adrenocortical function. This failure results in impaired secretion of glucocorticoids (GCs) only, or of GCs and mineralocorticoids (MCs) and adrenal androgens, which are crucial for energy, salt and fluid homeostasis, and androgenic activity. The disorder may be caused by adrenocortical disease, primary adrenal insufficiency (PAI), known as Addison’s disease, which is a rare disease with a reported prevalence in Europe ranging from 39 cases/million in England in 1968 () to 221 cases/million in Iceland in 2016 (), the highest prevalence reported. Depending on the study, the annual incidence of AI in Europe is estimated to range between 4.4 and 6.2 new cases per million people (,). AI may be secondary in the setting of conditions affecting the pituitary gland and the secretion of adrenocorticotropic hormone (ACTH) (secondary AI) and/or the hypothalamus and the secretion of corticotropin-releasing hormone (CRH) and/ or other ACTH secretagogues such as vasopressin (tertiary AI). Central AI is estimated to have a prevalence between 150 and 280 per million, making it more prevalent than PAI (-). The prevalence of AI after pituitary surgery varies, with higher rates of up to 90% after craniopharyngioma surgery, while hypopituitarism has a high prevalence after cranial radiation for non-pituitary tumors, but may take several years to develop.

The clinical manifestations of AI depend upon the extent of loss of adrenal function, and whether MCs and androgen production are preserved, whereby the renin-angiotensin-aldosterone system (RAAS) is intact in central AI. The presentation can be acute or insidious, depending on the underlying cause of the adrenal failure. The diagnosis may be delayed until an intercurrent illness such as serious infection, acute stress, bilateral adrenal infarction or hemorrhage, precipitates a life-threatening adrenal crisis. The symptoms of PAI are pleiotropic and generally non-specific, except for salt craving with primary adrenal failure ().

Adrenal crisis is an acute deterioration in health which is associated with hypotension, acute abdominal symptoms and marked laboratory abnormalities, which will resolve after parenteral glucocorticoid administration if provided expeditiously. In PAI, the patients may have more severe symptoms which are due to concomitant MC deficiency. This condition is commonly presented in PAI, but less common in central AI, in which a typical example would be pituitary apoplexy. Retrospective and prospective analysis revealed the prevalence of adrenal crises 6.6-8.3 cases/100 patient-years, with a mortality 0.5/100 patient-years, and occurs mainly due to gastrointestinal or other infectious diseases ().A recent retrospective case-control analysis of the European Adrenal Insufficiency Registry (EU-AIR) reported an incidence of adrenal crisis of 6.53 cases per 100 patient-years for PAI and 3.17 cases per 100 patient-years for central AI ().

A significant feature to clinically differentiate PAI from central AI is skin pigmentation, which is nearly always present in long-standing PAI. The most probable cause of the pigmentation seems to be the increased stimulation of the melanocortin-1 receptor (MC1R) by elevated levels of ACTH itself with its intrinsic α-melanocyte stimulating hormone activity. The rest of the clinical features of secondary and tertiary AI are similar to those of PAI (). Rarely, the presentation may be more acute in patients with pituitary apoplexy. Hyponatremia and compensatory water retention may be the result of an “inappropriate” increase in vasopressin secretion. The clinical manifestations of a pituitary or hypothalamic tumor, such as symptoms and signs of deficiency of other anterior pituitary hormones, headache or visual field defects, may also be present. Another condition with a dissociation in GCs and MCs secretion presenting as AI is congenital adrenal hyperplasia (CAH), with a frequency of adrenal crisis of 5.8 cases/100 patient-years (4.9 cases/100 patient-years after correction for a neonatal salt-wasting crisis) and often respiratory infections, firstly in early childhood, followed by gastrointestinal infections at older ages ().

The majority of cases of PAI are the result of gradual destruction of all three layers of the adrenal cortex. Clinical manifestations of this condition appear when the loss of the adrenocortical tissue of the combined glands is greater than 90%. In the initial phase of chronic gradual destruction, adrenal reserve is decreased, and although the basal steroid secretion is normal, the secretion in response to stress is suboptimal, resulting in inadequate GCs, MCs and androgen production, leading to partial ΑΙ; this is manifested by an inadequate cortisol response during stress. Any major or even minor stressor can precipitate an acute adrenal crisis, followed by complete AI, since with further loss of adrenocortical tissue, even basal steroid secretion is decreased, leading to the clinical manifestations of the disease. Adrenal hemorrhage or infarction may lead to adrenal crisis, a medical emergency manifesting as hypotension and acute circulatory failure crisis due to MC deficiency when the appropriate doses of GCs are not met to cover MCs requirements. On the other hand, GC deficiency may also contribute to hypotension by decreasing vascular responsiveness to angiotensin II, norepinephrine/ noradrenaline, and other vasoconstrictive hormones, reducing the synthesis of renin substrate, and increasing the production and effects of prostacyclin and other vasodilatory hormones. Combined GC and MC deficiency leads to increased urinary sodium loss and hypovolemia resulting in hypotension and electrolyte imbalance including hyponatremia and hyperkalemia. ‘Inappropriate’ anti-diuretic hormone (ADH) release and action on the renal tubule due to GCs deficiency contributes to the hyponatremia, although it could be argued that this attempt at volume maintenance is far from inappropriate. Low plasma cortisol concentrations reduce GC negative feedback, which in turn increases the production and secretion of ACTH and other POMC-peptides. These mechanisms are responsible for the well-recognized hyperpigmentation by acting on the MC1R in the skin.

Conversely, ACTH deficiency in central AI leads to decreased secretion of cortisol and adrenal androgens, while MC production remains normal, as MCs are principally regulated by the RAAS. In the early stages, basal ACTH secretion is normal, while its stress-induced release is impaired. With further loss, there is atrophy of zonae fasciculata and reticularis of the adrenal cortex. Therefore, basal cortisol secretion is decreased but aldosterone secretion by the zona glomerulosa is preserved. However, hypotension in central AI may still occur due to decreased vascular tone because of reduced vascular responsiveness to angiotensin II and noradrenaline.

When an adrenal crisis is present, there is no need for immediate investigation to confirm AI, but treatment should be initiated without delay as soon as clinically suspected. Clinical suspicion could be the case of a cancer patient under treatment with immunotherapy, particularly with the anti-CTLA-4 agent ipilimumab and signs and/or symptoms suspicious for AI, where the differential diagnosis of the rare metastatic involvement of adrenal or pituitary gland has to be also considered (,). In any case, confirmatory testing should be deferred until the patient has been stabilized; however, a blood sample taken at this time for cortisol and ACTH levels is extremely helpful for later assessment. In cases of insidious presentation, clinical suspicion of AI should be followed by diagnostic dynamic tests to confirm the inappropriately low cortisol secretion and whether cortisol deficiency is dependent or independent of ACTH deficiency by measuring ACTH levels (). In PAI, cortisol deficiency results in decreased feedback to the HPA axis, leading to increased secretion of ACTH to stimulate the adrenal cortex. Simultaneously, MC deficiency causes increased release of renin by the juxtaglomerular apparatus of the kidneys.

In a non-acute setting, the diagnosis should be suspected based on the patient’s history and physical examination along with low morning cortisol levels and confirmed by an ACTH stimulation test. Basal morning cortisol levels lower than 3μg/dL suggest ACTH deficiency. Conversely, morning cortisol higher than 15μg/dL indicates sufficient ACTH reserve. However, random cortisol levels are not advised for the diagnosis of AI. Additional tests are required to establish the diagnosis of AI if the cortisol levels are in the range of these cut-offs. Based on the pathophysiology, different dynamic tests have been proposed to diagnose this condition.

The classic short Synacthen test (SST; 250μg of ACTH [1-24], i.m. or i.v.) is considered the standard diagnostic method to detect AI, with a sensitivity of 92% (95% confidence interval, 81–97%) for the diagnosis of AI (). On the other hand, no statistically significant difference was found between low-dose and high-dose ACTH stimulation tests (,). Low levels for age and sex of dehydroepiandrosterone sulphate (DHEAS) concentration (or less frequently, dehydroepiandrosterone, DHEA) represents an additional marker to increase the level of suspicion of PAI but are not per se diagnostic. A CRH test may also be used, but is less common and has limited availability, while a prolonged ACTH stimulation test is rarely required other than to distinguish secondary or tertiary deficiency ().

The insulin-induced hypoglycemia or insulin tolerance test (ITT), also previously known as the gold standard test, is performed by injecting 0.1 or 0.15u/kg of short-acting insulin intravenously after overnight fast, followed by serial measurements of venous glucose and cortisol over 2hours. Importantly, this procedure must only be used if there are adequate supervision and experienced carers. However, the ITT is beneficial in assessing growth hormone (GH) response simultaneously in patients with suspected co-existing deficiency in secondary AI, in which GH may not exceed 3-5μg/dL. It should be emphasized that all normative values quoted are assay-dependent, and using immunoassays o liquid chromatography with tandem mass spectrometry (LC-MS/MS) may result in a lower cut-off than the historic value of 18μg/dL derived from polyclonal antibody assay (). Further investigations such as imaging studies, auto-antibodies, or microbiological screening should be arranged accordingly to identify the underlying cause of AI.

The notion of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) emerged to describe impairment of the HPA axis during critical illness that is characterized by the dysregulated systemic inflammation caused by the inadequate intracellular GC-mediated anti-inflammatory activity. The Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) have updated the guideline for the diagnosis and management of CIRCI, which was originally proposed in 2008 ().The task force makes no recommendation as to whether to use delta cortisol after SST or random plasma cortisol levels of less than 10μg/dL to diagnose CIRCI. However, some cohort studies found that patients with CIRCI had poorer outcomes than patients without CIRCI when total cortisol levels are less than 10μg/dL or delta cortisol after SST <9μg/dL. This evidence may be helpful in deciding upon replacement treatment when CIRCI is suspected () (-). Other diagnostic tests, such as salivary cortisol or serum ACTH, are not recommended to diagnose this condition. Additionally, markers of inflammation and coagulation, morbidity, length of intensive care unit (ICU) stay and mortality, should be taken into consideration. Nevertheless, this whole concept has been questioned, especially since cortisol-binding globulin and albumin are invariably decreased in severe critical illness, implying that simple measurement of total cortisol is likely to be an inaccurate reflection of the true state of the HPA axis. However, the guideline cautions against using plasma free cortisol levels rather than plasma total cortisol levels to diagnose CIRCI. Most recent evidence suggests that CIRCI is not a useful diagnostic or therapeutic description, and that during the acute phase of the response to severe sepsis there is no failure of the HPA axis and no need for corticosteroid therapy, although in the recovery phase this may become important.

Regarding patients with CAI resulting from steroid use, when confirming the recovery of the HPA axis is necessary, the 2024 European Society of Endocrinology and Endocrine Society Joint Clinical Guideline recommends using morning cortisol as the initial test. A cortisol level above 10μg/dL suggests HPA axis recovery (). However, if the cortisol result remains indeterminate, more dynamic tests, such as SST, and less commonly, overnight metyrapone, and ITT, may be considered. The choice of these tests depends on their availability, feasibility, costs, and regional accessibility. On the other hand, routine testing for adrenal insufficiency is not advised in patients receiving supraphysiologic steroid doses or requiring steroid for treatment of their underlying condition. In the context of the different diseases associated with AI, additional investigations may be necessary (). CT scanning of adrenals should be performed to identify infectious diseases such as tuberculosis, tumors, or adrenal hemorrhage.