ACHAIKI IATRIKI | 2023; 42(2):99–111
Review
Anastasia K. Armeni, Anastasia Theodoropoulou
Division of Endocrinology, Patras University Medical School, Patras, Greece
Received: 09 Mar 2023; Accepted: 23 May 2023
Corresponding author: Anastasia Theodoropoulou, Tel.: +30 2613603845, E-mail: theodorop@upatras.gr
Key words: Αdrenal insufficiency addison disease ηypothalamic-pituitary-adrenal axis
Abstract
Adrenal insufficiency (AI) is defined by a complete or partial lack of adrenal glucocorticoids with or without concomitant lack of mineralocorticoids and adrenal androgens. Primary adrenal insufficiency is an uncommon and serious disease of loss of function of the adrenal glands. Secondary AI (SAI) is more common and is brought on by conditions that affect the pituitary, whereas tertiary AI (TAI) is brought on by conditions that affect the hypothalamus. TAI is the most common kind due to withdrawal of exogenous glucocorticoids. The lack of cortisol, adrenal androgen precursors, and aldosterone (particularly in PAI) are linked to the non-specific, frequently missed, or incorrectly diagnosed symptoms of AI. The assessment of adrenal corticosteroid hormones, their regulatory peptide hormones, and stimulation tests serve as the foundation for diagnosis. Establishing a hormone-replacement regimen that closely resembles the body’s natural diurnal cortisol secretion rhythm and is adapted to the patient’s daily needs is the main objective of therapy.
INTRODUCTION
Adrenal hypofunction, which results in insufficient synthesis of glucocorticoids, particularly cortisol, characterises the endocrine condition known as adrenal insufficiency (AI). According to the underlying aetiology, AI can be primary, secondary, or tertiary. Hence, the synthesis of mineralocorticoids and adrenal androgens may also be impacted [1]. When the adrenal glands are damaged or destroyed, it results in primary adrenal insufficiency (PAI), which is a direct failure of the adrenal glands. The most common cause of PAI, particularly in high-income countries, is autoimmune adrenalitis, also known as Addison disease. In contrast, the proportion of patients with PAI whose AI is caused by infectious diseases, such as tuberculosis or human immunodeficiency virus (HIV), is high in nations with high prevalence of these infections [2–4]. The condition known as secondary adrenal insufficiency (SAI) results from conditions affecting the pituitary or the hypothalamus, such as tumours of the pituitary and/or hypothalamus and the treatment options (surgery and/or radiation), hypophysitis, or granulomatous infiltration. Tertiary adrenal insufficiency (TAI) is characterised by hypothalamic anomalies or dysfunction, which results in decreased corticotropin-releasing hormone (CRH) output. Similar to SAI, the subsequent absence of adrenocorticotropic hormone (ACTH) stimulation results in decreased cortisol and dehydroepiandrosterone (DHEA) release. As a result, TAI is frequently referred to as SAI without any further distinction between the two terms. TAI often develops from the persistent use of supraphysiological amounts of exogenous glucocorticoids, which suppresses the hypothalamic-pituitary-adrenal (HPA) axis [5].
The clinical manifestations of AI that frequently occur gradually over a lengthy period of time are associated with the corresponding hormone shortage. Fatigue, hypotension, and weight loss are three major symptoms especially linked to cortisol deficit; nevertheless, because they are vague, they frequently cause diagnostic delays and incorrect diagnoses [6]. Particularly, unexplained hyponatraemia and hyperpigmentation or hair loss in the pubis and axillae may point to AI. Adrenal crisis is a severe emergency that can also appear as AI. Patients with unknown AI and those receiving established replacement treatment run the danger of suffering a life-threatening adrenal crisis due to the critical protective role of cortisol under stressful circumstances [7]. Hence, one of the main objectives of long-term management is to prevent adrenal crises.
Iatrogenic causes of AI have significant implications for several medical specialties. Opioids and glucocorticoids, which are known to impede the HPA axis’s function, are commonly utilized to treat a variety of illnesses. The incidence of AI has further increased due to the more widespread use of immune checkpoint inhibitors (ICIs), which are linked to autoimmune hypophysitis and infrequently to autoimmune adrenalitis.
Hypothalamus-Pituitary Axis
Adrenal glands consist of adrenal cortex and medulla. Zonas fasciculata, glomerulosa, and reticularis make up the three zones of the cortex. Cortisol is produced by the zona fasciculata, mineralocorticoids (aldosterone) are produced by the zona glomerulosa, and sex hormones are produced by the zona reticularis. Catecholamines are produced by the adrenal medulla. Adrenal glands use cholesterol as a starting material to create steroid hormones.
The hypothalamus-pituitary axis regulates the adrenal cortex’s ability to secrete cortisol. The paraventricular nucleus (PVN) of the hypothalamus secretes both arginine vasopressin and CRH. PVN produces and releases CRH and vasopressin in response to stress inputs from other brain nuclei as well as circadian input from the hypothalamic suprachiasmatic nucleus. Portal vein CRH stimulates pituitary corticotroph cells to secrete ACTH. Cortisol, DHEA, and, to a lesser extent, aldosterone secretion are stimulated by ACTH when it binds to certain receptors in the adrenal cortex (melanocortin-2-receptor-MC2R) [8]. A negative feedback loop regulates cortisol secretion by binding to particular receptors in the brain and the pituitary and preventing ACTH secretion [9]. While ACTH release from pituitary corticotroph cells precedes cortisol peaks, the circadian rhythm of cortisol secretion is characterized by increased levels in the morning (peak after awakening) and nadir levels in the evening (before bedtime) [10]. A negative brief feedback loop between cortisol and ACTH controls the release of cortisol as well (ultradian rhythmicity) [11].
Cortisol acts by binding to particular cytoplasmatic receptors, and this complex then moves to the nucleus, where it binds to particular glucocorticoid and mineralocorticoid response elements. This process results in the transcription or repression of particular genes, which is necessary for cortisol’s physiological function. By its interaction with particular glucocorticoid receptors and mineralocorticoid receptors, cortisol plays a role in a number of physiological processes including metabolism, stress response, reproduction, immunity, and cognition [12,13]. Plasma proteins bind to cortisol once it has been secreted into the bloodstream, keeping it inactive. 80–90% of cortisol is bound to corticosteroid-binding globulin (CBG), the most significant binding protein. Many variables, like body temperature or inflammation, have an impact on CBG levels. A decrease in CBG affinity and an increase in free cortisol are observed in a variety of pathologic conditions, such as fever or inflammation [14,15].
The mineralocorticoids are secreted by the zona glomerulosa of the adrenal glands (aldosterone). The renin-angiotensin system and potassium are the primary regulators of aldosterone secretion. The renin-angiotensin system controls electrolyte balance, blood volume, and blood pressure. When sodium concentration is low or when renal perfusion pressure is reduced, the kidneys produce renin. Angiotensinogen is processed by renin into angiotensin I, which is then transformed into angiotensin II by the angiotensin-converting enzyme. Angiotensin II increases the release of aldosterone from the adrenal cortex by binding to angiotensin receptors. Aldosterone production is stimulated by elevated serum potassium levels. Moreover, ACTH stimulates aldosterone secretion, whereas glucocorticoids inhibit it [16–18].
The C19 steroids produced by the adrenal glands include DHEA and DHEAS, which have received the most attention as potential indicators of excessive androgen production in the adrenal glands. DHEAS is the most abundant C19 steroid secreted by the adrenal glands, according to recent measurements of steroids using liquid chromatography/tandem mass spectrometry in samples taken directly from the adrenal veins. However, it is shown that the adrenal gland is the source of other C19 steroids. ACTH seems to be the main mediator, even if the processes that control the synthesis of adrenal C19 steroid have not yet been fully understood. Contrary to the testis, which is a highly effective androgen generator, the adrenal gland only contributes minimally to the production of active androgen in males. However, the adrenal gland is a significant source of androgen and androgen precursors in women and pre-pubertal children, which have physiologic and pathologic functions. The adrenal glands’ participation in the synthesis of pathologic androgen is crucial in a number of conditions. Future research is required to determine the mechanisms governing adrenal C19 steroidogenesis control and dysregulation in both normal and pathologic production.
A. EPIDEMIOLOGY AND PATHOGENESIS
The types of adrenal insufficiency are depicted in Figure 1.
Figure 1. Types of adrenal insufficiency.
Primary Adrenal Insufficiency
The prevalence and range of underlying causes of PAI have varied throughout the past century, according to the epidemiology of the condition. With an incidence of 10–20 cases per 100,000 people, PAI is a rare condition with several possible causes. In industrialized countries, Addison’s disease accounts for about 90% of non-congenital adrenal hyperplasia (CAH) cases, but primary adrenal insufficiency from infections (tuberculosis, Cytomegalovirus, HIV) is more prevalent in developing countries [4,19–22]. CAH is a typical contributor to primary adrenal insufficiency [3,23]. The prevalence of Addison’s disease varies by region, from 1.4 cases per 100,000 people in South Africa to 9–22 cases per 100,000 people in Europe [24–26]. Addison’s disease can develop at any age, but its average onset age is between 20 and 50 years. It also occurs more frequently in people with other autoimmune disorders, such as those with type 1 diabetes mellitus, compared to the general population [27]. The most prevalent inherited form of PAI is CAH, which is brought on most commonly by a 21-hydroxylase deficiency. One in fifty patients with CAH, an autosomal recessive condition, have a CYP21A2 mutation (encoding 21- hydroxylase). Between 0.5 and 1 cases of classic CAH are found in every 10,000 people, depending on the population. Adrenoleukodystrophy, adrenal hypoplasia congenita, and autoimmune polyglandular syndrome (APS) type 1 are additional, less common hereditary causes of PAI [28]. Because CAH lacks 21-hydroxylase, there is less cortisol produced, which in turn causes the pituitary to secrete more ACTH. The reactions catalysed by 21-hydroxylase are the conversion of progesterone in 11-deoxycorticosterone and of 17-OH progesterone in deoxycortisol. Adrenocortical hyperplasia and the release of steroidogenic products upstream of the enzymatic block, such as adrenal androgens, are induced by increasing ACTH. The underlying mutation and the remaining enzyme activity determine the severity of CAH. Neonates have low levels of cortisol and aldosterone when the enzyme activity is less than 2%. In addition to having defective aldosterone synthesis, the severe type of CAH, known as salt-wasting syndrome, also causes virilization of the external genitalia in female infants as a result of excessive adrenal androgen production [29]. There are symptoms of virilization, premature pseudopuberty, or growth arrest in less severe mutations. Milder forms of CAH, often known as “non-classic CAH” or “late-onset” CAH, are more prevalent. Aldosterone synthesis is normal, cortisol insufficiency may be slight or nonexistent, and adrenal androgens are overproduced in this variant of CAH [30]. A number of autoimmune comorbidities, including autoimmune thyroid disease (which affects 40% of patients), premature ovarian failure (5–16%), type 1 diabetes mellitus (11%), pernicious anemia (10%), vitiligo (6%), and celiac disease (2%), coexist with Addison disease [31].
Autoantibodies against 21-hydroxylase are typically detected in people with autoimmune Addison disease. It appears that CD4+ and CD8+ T lymphocytes that are active against 21-hydroxylase are responsible for adrenal cortex destruction. Antibodies to 21-hydroxylase can be found with great specificity and sensitivity, and their finding can occur several years before the manifestation of the disease. Additional research has linked specific major histocompatibility complex (MHC) genotypes, including DR3-DQ2 and DR4-DQ8, to Addison disease. The genetic causes of Addison disease make it another inherited illness [32–36]. The production of mineralocorticoids is impaired in primary adrenal illness, which also involves the zona glomerulosa. Lack of aldosterone causes salt loss, decreased fluid volume, and hypotension, which affects the electrolyte balance. The darkening of the skin (bronzing), which is particularly pronounced in sun-exposed areas and over pressure points like the elbows, scars, knees, and the oral mucosa, is a defining symptom of people with Addison disease. Hyperpigmentation of the skin and mucous membrane can precede over other signs by months to years. Lack of cortisol feedback causes increased release of pro-opiomelanocortin (POMC), as well as peptides generated from it, such as ACTH and melanocyte stimulating hormone (MSH). Increased MSH stimulates melanocortin receptor 1 to cause hyperpigmentation [37] (Table 1).
Secondary Adrenal Insufficiency
It has been suggested that SAI is more widespread than PAI, with a prevalence of up to 42 cases per 100,000 people. Only rarely can SAI have a genetic basis (for instance, mutations of the transcription factor TPIT). Usually, it is reported in people with disorders that affect the pituitary, such as tumours, autoimmune hypophysitis, trauma, or after radiotherapy of intracranial tumors [38,39] (Table 2).
Because of the pituitary gland’s mass effect from the tumour, SAI will manifest in 10–62% of individuals with pituitary adenoma; the risk rises with pituitary surgery or radiotherapy. Pituitary insufficiency after radiotherapy is usually seen many years later and is dose dependent [40]. Moreover, SAI has been documented in 26–57% of patients with hypophysitis, compared to 23% of individuals with any type of pituitary stalk lesion [41–43].
In patients receiving immune checkpoint inhibitor therapy for various forms of cancer, hypophysitis is a relatively frequent finding (13%) [44].
Chronic opiate use, even with low doses of morphine, is another factor that contributes to secondary adrenal insufficiency that is iatrogenic and results from pituitary insufficiency. It is a pathological syndrome that is underestimated and not well understood. It may be caused by both an opioid’s detrimental impact on the production of adrenal glucocorticoids and a disruption of the circadian rhythm of glucocorticoids. Long-term opioid usage can also damage the gonadotroph axis and cause secondary hypogonadism [45,46].
Tertiary Adrenal Insufficiency
Endogenous causes such as tumours, radiation, or inflammatory processes that impact the hypothalamus may contribute to tertiary AI. Chronic exogenous glucocorticoid injection is the main cause of TAI. In the majority of individuals, glucocorticoid-induced TAI, also known as iatrogenic or exogenous AI, is a transient condition. The risk of developing TAI varies depending on the dose and the route of glucocorticoid administration. Intranasal administration is stated to carry a 4.2% risk of TAI, inhalation is claimed to carry a 20% risk, oral administration a 49% risk, and intra-articular delivery a 52% risk. With short-term, low-dose glucocorticoid usage, the risk of AI is lowest, while with long-term, high-dose glucocorticoid use, the risk is highest. Yet, the relationship between TAI and glucocorticoid seems to be multifactorial, suggesting that other factors may also affect a person’s vulnerability [47]. Every patient receiving glucocorticoid medication must be thought of as having a TAI risk; as a result, the dosage must be carefully tapered and the patient must receive counseling. This advice is further backed by the higher death rate seen in the first three months after stopping glucocorticoid medication [48]. Restoration of HPA axis function is usually observed after 24 months of cessation of glucocorticoid treatment, however, some individuals may experience a longer recovery period of up to 4 years [49,50] (Table 3).
Adrenomedullary function in AI
Catecholamine production under physiological settings and in response to stress is impaired in patients with primary and secondary adrenal insufficiency [51,52]. In particular, norepinephrine levels rise while epinephrine output falls. The root reason is not entirely known. It is well known that high local glucocorticoid concentrations from the adrenal cortex via a rich blood supply are necessary for the action of the enzyme PNMTase, which catalyses the conversion of norepinephrine to epinephrine [53]. In patients with adrenal insufficiency, it appears that glucocorticoid replacement may not achieve the requisite glucocorticoid levels for enzyme activation. It is unclear what clinical significance low epinephrine levels have. Apparently, it may be responsible for the diminished well-being, the cognitive impairment, and the diminished glucose counter-regulatory response to hypoglycaemia [54,55].
Adrenal androgens
The zona reticularis of the adrenal glands produces DHEA. Due to the loss of the zona reticularis in the first case and the impairment of ACTH production in the second, it is seen that primary adrenal insufficiency (apart from CAH) and secondary adrenal insufficiency have impaired DHEA secretion. Symptoms of DHEA deficiency are observed in women, given that testosterone production in men is preserved. Adrenal androgens’ physiological function is not entirely known. The DHEA effects are direct and indirect. Indirect actions result in the conversion of these adrenal androgen precursors into active androgens or estrogens in the target organs such as gonads. The direct actions are related to the immunomodulatory action and to the neuroprotective effect in the brain and this may be one of the reasons for the impairment of well-being in patients with adrenal insufficiency [56].
B. CLINICAL MANIFESTATIONS
Adrenocortical hormones are vital to the organism and their deficiency causes a host of symptoms affecting almost all systems. Symptoms vary depending on the cause of the adrenal insufficiency, as shown in Table 4.
C. DIAGNOSIS
Primary Adrenal Insufficiency
The importance of raising awareness of PAI is highlighted by the fact that the majority of patients experience non-specific symptoms such as fatigue, poor health, postural dizziness, nausea, and weight loss for years before being diagnosed, and that these symptoms are frequently attributed to other causes. Diagnostic tests should never be run (or the results of tests should never be awaited before starting treatment for suspected acute manifestations of AI).
Typical symptom of primary adrenal insufficiency is changes in skin pigmentation. Skin hyperpigmentation is a characteristic finding of primary adrenal insufficiency, but the degree of hyperpigmentation varies among patients. Another cardinal finding in these patients is low blood pressure and orthostatic hypotension, because of aldosterone deficiency. Common laboratory findings are hyponatraemia, hyperkalaemia and hypoglycaemia. DHEA deficiency is accompanied by loss of pubic and axillary hairs and decreased libido in women, while men do not manifest similar disorders. Adrenal crisis could be the first presentation of the disease.
A coupled assessment of blood cortisol and plasma ACTH serves as the diagnostic test for suspected PAI. When combined with elevated ACTH levels (twice the upper normal limit), a morning serum cortisol level of less than 5 g/dl indicates PAI. It is advised to confirm the reference ranges with the appropriate laboratory because cortisol concentrations fluctuate depending on the assay utilized [57]. Due to improved test specificity, mass spectrometry analyses have been demonstrated to detect lower cortisol concentrations than immunoassays [58]. In patients with cortisol values >5 µg/dl, confirmation of the diagnosis is made using ACTH stimulation test (Synacthen test or corticotropin-stimulation test, 250-μg dose of synthetic ACTH 1–24). A peak serum cortisol concentration of <16 µg/dl min 30 after ACTH, or a peak <18 µg/dl 60 min after ACTH confirms the diagnosis [59]. To determine the presence of mineralocorticoid deficit, which is characterised by low or low-to-normal aldosterone in the presence of elevated levels of renin, combined plasma renin and aldosterone levels should be tested. The aetiology should be looked into, once PAI has been diagnosed. Patients should be examined for the presence of 21-hydroxylase autoantibodies in the serum in areas with a high frequency of Addison disease. Patients who have autoantibody tests that are positive should be checked for concurrent autoimmune comorbidities. However, testing negative for 21-hydroxylase autoantibodies does not rule out autoimmune PAI. To rule out inflammatory processes, adrenal gland destruction due to haemorfrhage or infiltration, such as bilateral extra-adrenal cancer metastases, in patients with negative autoantibody tests, CT imaging of the adrenal region is recommended [60]. Adrenoleukodystrophy should be ruled out in men with negative 21-hydroxylase autoantibodies by checking the serum levels of very long chain fatty acids.
Secondary Adrenal Insufficiency
In secondary adrenal insufficiency, in addition to symptoms of glucocorticoid deficiency, there are also symptoms from the absence of other pituitary hormones (hypothyroidism, hypogonadism) or symptoms due to pressure of the tumor in the adjacent structures (headache, visual field disturbances).
In individuals with known or suspected pituitary illness, determining the HPA axis’ stress reactivity is crucial. With structural pituitary pathology, such as tumours or injuries, the corticotropic axis is often one of the last anatomical units to be destroyed after the thyrotropic axis, albeit autoimmune hypophysitis can result in solitary ACTH insufficiency. Hyponatraemia with a history of stroke or traumatic brain injury and symptoms of attention and cognitive deficits, nausea, vomiting, disorientation, headache, somnolence, and seizures should warrant additional testing for a possible SAI [61].
Although serum cortisol > 16 μg/dl precludes secondary adrenal insufficiency, a morning serum cortisol 3,6 g/dl and a low or low-normal ACTH level are indicative of the condition [61]. The insulin tolerance test is the gold standard test to assess the integrity of the hypothalamus-pituitary axis. A severe stress reaction and the release of hormones that counteract it, including cortisol and growth hormone, are brought on by hypoglycemia. The test is not safe for people who have a history of cardiovascular illness, stroke, or epilepsy due to the extreme hypoglycaemia that is induced. The test is carried out in specialist facilities as a result. The ACTH test is the most often utilized test since it is reliable and secure. Peak serum cortisol levels above 18 g/dl are regarded as normal. The ACTH test should be administered six weeks after pituitary surgery when it’s necessary to assess cortisol reserve following transsphenoidal surgery for a pituitary adenoma, because, the adrenal cortisol response to an ACTH test seems to be normal for a brief period of time. Synthetic CRH testing is a great way to assess hypothalamic function, but it doesn’t seem to be any better than ACTH stimulation testing, and some facilities have restrictions on its use. Metyrapone and the glucagon test are additional tests for cortisol reserve evaluation, but they are rarely used. Measuring basal salivary cortisol and salivary cortisone is a potential technique for the diagnosis and screening of secondary adrenal insufficiency due to the simplicity of the procedure and independence from binding proteins like albumin or CBG.
Under stressful physical or psychological settings, patients with undiagnosed adrenal insufficiency are susceptible to developing a life-threatening adrenal crisis. For this reason, it’s critical to include adrenal deficiency in the differential diagnosis for all patients who have unexplained hyponatraemia, hypotension, vomiting, or diarrhea as well as those who present with atypical symptoms. When there is a clinical suspicion of Addison disease, patients with other autoimmune disorders such as type 1 diabetes, hypothyroidism, premature ovarian failure, pernicious anemia, etc. should be examined [61–65].
D. MANAGEMENT
According to the European Society of Endocrinology a successful treatment aim to achieve an optimal glucocorticoid dosing regimen in order to avoid complications from overtreatment such as metabolic syndrome, cardiovascular disease and osteoporosis, but also to ensure a good quality of life and daily performance and to prevent adrenal crisis [66].
Glucocorticoid replacement
The purpose of hormone replacement is to mimic the diurnal sleep pattern of cortisol secretion as closely as possible. Until now there is no therapeutic preparation that mimics the cortisol secretion profile. The optimal glucocorticoid dosing is based primarily on the patient’s symptoms, since there are no biological markers indicating cortisol sufficiency or not. Cortisol measurement is not a reliable indicator of ideal glucocorticoid replacement, specifically when prednisolone is used. It is recommended that titration of the glucocorticoid dose should be based on patient symptoms of cortisol deficiency and excess. Usually patients with insufficient glucocorticoid replacement complain of fatigue, weight loss and nausea, while glucocorticoid overtreatment induce a picture of iatrogenic Cushing with increased abdominal fat, thin skin, easy bruising, hypertension and type 2 diabetes mellitus. Usually patients with PAI require greater glucocorticoid replacement compared to patients with SAI, owing to residual ACTH secretion.
The pharmaceutical preparation indicated for the treatment of adrenal insufficiency is hydrocortisone. Hydrocortisone is administered 2 or 3 times daily, because plasma half-life is ~90 min. The highest dose is taken in the morning, the next dose at lunch and the third at afternoon, depending on the patient’s needs, in order to replicate cortisol circadian rhythm. Recently a new formulation is available, Plenadren, which may be administered once daily. This formulation consists of two layers, an outer layer responsible for immediate release of the drug, and an internal layer responsible for prolonged release [67]. Open-label studies have shown that it does not affect the BMI of the patients and the lipid profile, but all these findings may be the results of the reduced bioavailability in relation to hydrocortisone [68]. Patients with poor compliance could be administered prednisolone, which has a longer half-life (150 min) but less mineralocorticoid activity than hydrocortisone. A 40-mg dose of hydrocortisone exerts mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Dexamethasone, because of the complete lack of mineralocorticoid activity, it is not recommended as replacement therapy in patients with adrenal insufficiency. Chronocort, is a newly formulation under development, which tries to mimic the circadian rhythm [69]. For patients with CAH, a CRFR1 antagonist is under study, with the aim to reduce ACTH secretion and minimize glucocorticoid replacement treatment [70].
Plenadren is a modified-release tablet of hydrocortisone that releases hydrocortisone over a longer period of time, allowing once daily dosing. Chronocort is modified-release tablet of hydrocortisone, designed for patients with CAH and in order to mimic the circadian rhythm of cortisol, given twice daily. CRF is the primary regulator of the hypothalamic-pituitary axis, acting directly on specific receptors on pituitary corticotroph cells for ACTH production. CRF antagonists have shown to reduce ACTH release both in vivo and in vitro.
Mineralocorticoid Replacement
Administration of mineralocorticoids is necessary for patients with impaired aldosterone secretion such as Addison disease or the salt-wasting form of CAH or after bilateral adrenalectomy. The therapeutic objective is to maintain normal blood pressure and normal electrolyte levels and to prevent salt craving [71]. Account should be taken of that ~13% of patients with Addison disease show residual aldosterone secretion. The formulation commonly used today is 9α-fluorocortisol (fludrocortisone) which has a 200–400-fold higher mineralocorticoid potency than hydrocortisone [72]. Fludrocortisone exerts its action through specific mineralocorticoid receptors sparse in different tissues, and is very effective to restore electrolyte balance and hypotension. The proper dosage of daily fludrocortisones is achieved by measuring blood pressure, examining for the presence of peripheral oedema and by measuring serum potassium and sodium levels. Renin determination could be useful for dose monitor, but it should take in consideration that it is affected by the use of oestrogens [73]. Signs of mineralocorticoid overtreatment are, high blood pressure, rapid weight gain, oedema and hypokalaemia. Monitoring of the results of the dose changing should be done 2-4 weeks later.
Patients with PAI under treatment with phenytoin, phenobarbital, rifampicin and mitotane, need increased doses of fludrocortisone and hydrocortisone, because the CYP3A4 induction by the drugs, results in rapid inactivation of cortisol (Table 3). In areas with hot climates, especially in the summer months, an increase in mineralocorticoid replacement may be necessary [74].
In the case that the patient under mineralocorticoid develops hypertension, the dosage of glucocorticoids and mineralocorticoids should be reassessed. Anti-hypertensive treatment of choice in patients with PAI, are direct vasodilator (calcium antagonist), while diuretics and especially aldosterone antagonists (spironolactone or eplerenone), should be avoided. In patients with PAI the occurrence of heart failure can be treated with angiotensin-converting enzyme inhibitors, angiotensin II antagonists or β-blockers, while administration of mineralocorticoid receptor antagonists and/or discontinuation of fludrocortisone should be individualized [75].
DHEA Replacement
DHEA replacement does not seem to be necessary in patients with adrenal insufficiency. Various studies have shown that they can have beneficial effects on mood and on libido (specifically in women) [76]. There is some evidence that oral DHEA possesses a role in immunomodulation, restoring the levels of regulatory T cells in patients with Addison disease. Administration of DHEA is personalised and targeted mainly in women with impaired well being, reduced libido and dry skin.
E. ADRENAL CRISIS
Adrenal crisis may be the first symptom of adrenal insufficiency, or may be the result of inadequate treatment in patients with known adrenal insufficiency when the demand of the organism for glucocorticoids is greater than their availability. Adrenal crisis is more common among patients with primary adrenal insufficiency than in those with secondary adrenal insufficiency [25,77]. The incidence among patients with known adrenal insufficiency is 5–10 events per 100 patient-years [7]. The mortality of adrenal crisis is rare and is 0.5 per 100 patient-years. Increased risk of premature death is observed among patients < 40 years old [78].
Risk factors for the occurrence of adrenal crisis are older age (>65 years) or adolescence and young adulthood, previous crises, and comorbidities [79,80]. Patients on low-dose, short- acting glucocorticoids are in increased risk for adrenal crisis [81], as well as patients treated with drugs that reduce cortisol production (steroidogenesis inhibitors) or increase the metabolic clearance of cortisol (compounds that induce CYP3A4). Generally, the risk of adrenal crisis is low among patients receiving glucocorticoids treatment [82]. Special attention should be made in patients with thyroid disease. Initiation of thyroxine treatment or the onset of hyperthyroidism in patients with adrenal insufficiency could precipitate an adrenal crisis, because of more rapid inactivation of cortisol [83].
Precipitating factors
In patients with adrenal insufficiency who are receiving replacement treatment, the precipitating factors that may cause adrenal crisis are any kind of severe acute inflammation or sepsis [84]. The most common cause is gastroenteritis, although there is a percentage of patients where no precipitating factor is found (10%) [85]. In this case there is an imbalance between the availability and the demand for cortisol, due to the reduced absorption of orally administered glucocorticoids in these patients.
Other precipitating factors could be a reduction in the dose of administered glucocorticoids or the use of different glucocorticoid preparation or even an intense psychological stress. The pathophysiology of adrenal crisis is multifactorial and is not fully understood. Glucocorticoids affect the immune system. The inflammatory reaction is characterized by the release of cytokines, IL-1, TNF and IL-6. Under normal conditions these cytokines stimulate hypothalamic-pituitary-adrenal axis and increase cortisol secretion [86]. Increased cortisol levels in turn inhibit further cytokine release and action [87,88]. Cortisol thereby prevents a cytokine cascade due to a hyperinflammatory response [89].
Cortisol deficiency observed in adrenal insufficiency leads to increased inflammatory cytokines. In addition, cortisol deficiency is aggravated by a cytokine-induced glucocorticoid receptor resistance. The hypovolemia seen in primary adrenal insufficiency due to aldosterone deficiency, is further aggravated by the reduced action of catecholamines in blood vessels. The hypotension that occurs may be aggravated by vomiting and diarrhea [90].
Lack of cortisol leads to metabolic alterations such as reduced production of fatty acids from adipose tissue, reduced amino-acid liberation from muscles and reduced gluconeogenesis from liver. The result of these changes leads to decreased energy reserves.
Management of adrenal crisis
If an adrenal crisis is suspected, treatment should be promptly initiated, without waiting for laboratory test results that document cortisol deficiency. A rapid patient’s medical history, such as the abrupt discontinuation of chronic exogenous glucocorticoids use, or the occurrence of an infection in patients with known AI, increases the index of suspicion for an adrenal crisis.
Initially must be administered intravenous or intramuscular bolus injection of 100 mg hydrocortisone, followed by continuous intravenous infusion of 200 mg of hydrocortisone per 24 hours, or alternatively, by intravenous or intramuscular bolus injections of 50 mg of hydrocortisone every 6 hours.
Intravenous administration of fluids (isotonic saline), under tight control to avoid either exacerbation or too-rapid correction of hyponatraemia. Sometimes, especially in children it is necessary to treat hypoglycemia. It is very important to identify the precipitating factor and to cure it. Once the recovery of the patient is achieved the hydrocortisone dose should be tapered according to the clinical situation of the patient. A delay of the treatment of an adrenal crisis increases the risk of death. Adrenal insufficiency is a rare disease, but misdiagnosis could be potentially fatal. All patients with AI need education in order to recognize signs and symptoms of adrenal crisis, they must be equipped with a hydrocortisone self-injection kit for emergency management and with a steroid emergency card [91].
Conflict of interest
None to declare
Declaration of funding sources
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