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CLINICAL RECOGNITION
Adrenal insufficiency (AI) is a disorder characterized by the failure of adrenocortical function resulting mainly in impaired secretion of glucocorticoids (GCs) only or of GCs and mineralocorticoids (MCs), hormones crucial for energy, salt and fluid homeostasis. The disorder may be caused by an adrenocortical disease (primary AI, known as Addison’s disease), which is a rare disease with a prevalence 100-140 cases/106 inhabitants and an incidence of 4 cases/106/year. In addition, AI may be secondary in the setting of conditions affecting the pituitary gland and the secretion of adrenocorticotropin 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). The prevalence of secondary AI is estimated to be 150–280/106 inhabitants. The prevalence of AI after pituitary surgery varies (higher rates up to 90% after craniopharyngioma surgery), while hypopituitarism has 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 is preserved (in cases of secondary and tertiary AI where the renin-angiotensin-aldosterone (RAA) axis is intact). 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 (serious infection, acute stress, bilateral adrenal infarction, or hemorrhage) precipitates a life-threatening adrenal crisis (AC). Consequently, except for salt craving, the symptoms of primary AI are pleiotropic and non-specific (Table 1). Adrenal crisis is less common in secondary AI (pituitary apoplexy) or tertiary AI, but it is commonly present in primary AI. Retrospective and prospective analysis revealed a prevalence of 6.6-8.3 AC/100 patient-years, with mortality 0.5/100 patient-years, mainly due to gastrointestinal and other infectious diseases.
A significant feature to clinically differentiate primary AI from secondary AI is skin pigmentation, which is nearly always present in long-standing primary AI. The most probable cause of the pigmentation seems to be the increased stimulation of the melanocortin receptor by elevated levels of ACTH. The rest of the clinical features of secondary and tertiary AI are similar to those of primary AI form (Table 1,2). Rarely, the presentation may be more acute in patients with pituitary apoplexy. Hyponatremia and increased intravascular volume 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 in pediatric populations of 5.8 adrenal crisis/100 patient-years (4.9 AC/100 patient-years after correction for a neonatal salt-wasting crisis) and reported respiratory infections firstly in early childhood followed by gastrointestinal infections at older ages.
Table 1.
Symptoms, Physical Findings, and Laboratory Findings Associated with Adrenal Insufficiency
| SYMPTOMS AND PHYSICAL FINDINGS | |
| Adrenal crisis: hypotension (<110mmHg systolic) and syncope/ shock (>90%); volume depression Non-specific symptoms: Gastrointestinal symptoms- abdominal pain (flank, back, or lower chest pain: 86%- may mimic acute abdomen) Fever (66%) Anorexia (early feature), nausea, vomiting (47%) Abdominal rigidity or rebound tenderness (22%) diarrhea, which may alternate with constipation Neuropsychiatric symptoms- Confusion, lethargy, disorientation, coma (42%) | PAI>SAI/TAI |
| Psychiatric symptoms (memory impairment, depression, anxiety, psychosis, reduced consciousness, delirium) | Chronic AI |
| General malaise, weakness, fatigue, lassitude, generalized weakness | PAI/SAI |
| Hypoglycemia; ↑ risk: children/ thin women/ alcohol abuse/ GH deficiency | SAI>>PAI |
| Sudden severe headache, loss of vision or visual field defect | SAI (pituitary apoplexy) |
| Skin- hyperpigmentation: sun-exposed or pressure areas, recent scars (after AI manifestation), axillae, nipples, palmar creases, mucous membranes as buccal mucosa | Chronic PAI |
| Postural hypotension (due to dehydration or improvement in blood pressure control in previously hypertensive patients); postural dizziness Salt craving (22%) | PAI>>SAI |
| Autoimmune manifestations (vitiligo) | PAI |
| Weight loss | Chronic PAI/SAI |
| Decreased axillary and pubic hair, loss of libido in females (DHEA deficiency), amenorrhea in women (in 25% due to chronic illness, weight loss or associated premature ovarian failure) | PAI/SAI |
| Auricular calcification | |
| Low grade fever | PAI |
| Vitiligo (as marker of autoimmune disease) | PAI/SAI |
| Associated endocrinopathies (in the context of autoimmune polyglandular syndrome) | |
| LABORATORY FINDINGS | |
| Electrolyte abnormalities: Hyponatremia: 85-90% (PAI: MCs deficiency; SAI: dilutional) Hyperkalemia: 60-65% due to MCs deficiency Metabolic acidosis Mild hypercalcemia (uncommon) | PAI/SAI |
| Azotemia | PAI |
| Liver enzymes abnormalities | |
| Changes in blood count: mild anemia (normocytic normochromic) eosinophilia lymphocytosis | |
| ↑TSH with normal or low normal T4 (transient with ↑ACTH; permanent with autoimmune thyroiditis | PAI |
| ↓ blood bicarbonate (metabolic acidosis in primary adrenal insufficiency) | |
| ↑ Erythrocyte Sedimentation Rate | |
ACTH: adrenocorticotropin hormone; AI: adrenal insufficiency; DHEA: dehydroepiandrosterone); GCs: glucocorticoids; GH: growth hormone; MCs: mineralocorticoids; PAI: primary AI, SAI: secondary AI, T4: thyroxine; TAI: tertiary AI; TSH: thyrotropin stimulating hormone
PATHOPHYSIOLOGY
Primary AI results from gradual destruction of all three layers of the adrenal cortex. Clinical manifestations of the 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 a complete AI, since with further loss of adrenocortical tissue, even basal steroid secretion is decreased, leading to the clinical manifestations of the disease. Hence, an adrenal hemorrhage or infarction may lead to adrenal crisis which represents 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 MC requirements. On the other hand, GC deficiency may also contribute to hypotension by decreasing vascular responsiveness to angiotensin II, norepinephrine 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 (hyponatremia and hyperkalemia). Inappropriate anti-diuretic hormone (ADH) release and action on the renal tubule due to GC deficiency contributes to the hyponatremia, although one could argue that this attempt at volume maintenance is far from inappropriate. Low plasma cortisol concentrations reduce GC negative feedback increasing the production and secretion of ACTH and other POMC-peptides; these are responsible for the well-recognized hyperpigmentation by acting on the melanocortin receptor in the skin.
On the other hand, ACTH deficiency in secondary AI leads to decreased secretion of cortisol and adrenal androgens, while MC production remains normal, as MCs are principally regulated by the RAA axis. However, in the early stages, basal ACTH secretion is normal, while its stress-induced release is impaired. Moreover, 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 SAI may still occur and it is due to decreased vascular tone as a result of reduced vascular responsiveness to angiotensin II and norepinephrine.
DIAGNOSIS and DIFFERENTIAL DIAGNOSIS
Table 2.
Etiology of Adrenal Insufficiency
| Primary Adrenal Insufficiency | |
| Acute presentation | |
| Hemorrhage (trauma, anticoagulants) | |
| Waterhouse-Friedrichson syndrome (meningococcal septicemia) | |
| Acute or insidious presentation | |
| Autoimmune AI or Addison’s disease (AD) (up to 90% in developed countries) |
|
| Infection |
|
| Metastases | from lung, breast, kidney, colon cancers, melanoma, lymphoma |
| Infiltrations | Sarcoidosis/ Amyloidosis/ Hemochromatosis |
| Intra-adrenal hemorrhage |
|
| Infarction | anti-phospholipid/ anti-cardiolipin/ lupus anti-coagulant syndrome |
| Hematological disorders | Lymphoma |
| Adrenoleukodystrophy (inherited disorder of long chain fatty acid metabolism, presents in childhood, may progress to severe neurological problems and dementia)/ Adrenomyeloneuropathy | |
| Mitochondrial disease (rare) | |
| Wolman’s disease | |
| CAH most forms can cause salt loss; commonest cause of PAI in children (80%); may be diagnosed in older individuals; 21-Hydroxylase deficiency: commonest type of CAH with associated hyperandrogenism; 11β-hydroxylase deficiency: hyperandrogenism, hypertension (in older children and adults); 3β-hydroxysteroid dehydrogenase II deficiency: ambiguous genitalia in boys, hyperandrogenism in girls; P450 side-chain cleavage deficiency (CYP11A1 mutations): XY sex reversal; P450 oxidoreductase deficiency: skeletal malformations, abnormal genitalia; Congenital lipoid adrenal hyperplasia (StAR mutations): XY sex reversal | |
| Congenital adrenal hypoplasia | DAX-1 mutations; X-linked NROB1, Xp21 deletion (with Duchenne’s muscular deficiency), SF-1 mutations (XY sex reversal), IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities) |
| Congenital unresponsiveness to ACTH syndromes (various mutations, MCs usually spared) | Type 1: ACTH receptor, melanocortin 2 receptor gene (MC2-R) Type 2: melanocortin 2 receptor accessory protein (MARP) Familial glucocorticoid deficiency (MCM4, NNT, TXNRD2) Triple A (Allgrove’s) syndrome, achalasia, AD, alacrima, AAAS gene mutation |
| Iatrogenic | Bilateral adrenalectomy/ steroid synthesis inhibitors/ adrenolytic agents (mitotane, suramin)/ GC antagonists (mifepristone) |
| Drugs | Ketoconazole or fluconazole or etomidate or aminoglutethimide, mitotane (inhibition of cortisol synthesis), phenytoin, phenobarbital, L-T4, mitotane, or St John’s wort (increased GCs metabolism), rifampicin, CTLA-4 inhibitors (enhancing autoimmunity) |
| Secondary and Tertiary Adrenal Insufficiency | |
| Iatrogenic |
|
| Idiopathic hypopituitarism | |
| Pituitary and hypothalamic lesions |
|
| Pituitary-hypothalamic hemorrhage |
|
| Tumors | |
| Inflammation | |
| Infections | |
| Autoimmune lesions | |
| Hemochromatosis | |
| Granulomatous infiltration |
|
| Trauma to the pituitary; Traumatic Brain Injury | |
| Secondary tumor deposits | Breast, lung cancers |
| Acquired isolated ACTH deficiency (rare, except in lymphocytic hypophysitis) | |
| Familial corticosteroid-binding-globulin deficiency | |
| Lymphocytic hypophysitis | |
| Langerhans cell histocytosis | |
| Congenital aplasia/ hypoplasia/ dysplasia/ ectopy | |
| POMC processing defect | |
| POMC gene mutations | |
AC: adrenal crisis; ACTH: adrenocorticotropin hormone; AD: Addison’s disease; AI: adrenal insufficiency; CAH: congenital adrenal hyperplasia; DHEA: dehydroepiandrosterone; GCs: glucocorticoids; HPA: hypothalamo-pituitary-adrenal; MCs: mineralocorticoids; PAI: primary AI; PGA: polyglandular autoimmune syndromes; POMC: pro-opiomelanocortin; T4: thyroxine; TSH: thyrotropin stimulating hormone
When an adrenal crisis is present there is no need for immediate investigation to confirm AI but treatment should be initiated without any delay as soon as suspected clinically, and confirmatory testing should be deferred till the stabilization of the patient; however, a blood sample taken at this time for cortisol and ACTH is extremely helpful for later assessment. In cases of insidious presentation, the 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 the level of ACTH (Table 3). In primary AI, cortisol deficiency results in a decreased feedback to the hypothalamo-pituitary-adrenal (HPA) axis which results in increased secretion of ACTH to stimulate in turn the adrenal cortex. On the other hand, MC deficiency results in increased release of renin by the juxtaglomerular apparatus of the kidneys.
In a non-acute setting, the diagnosis should be suspected by the patient’s history and physical examination along with a low morning cortisol concentration, and is confirmed by a cortisol stimulation test. The classic short Synacthen test (SST; 250ug of ACTH [1-24], im or iv), considered as the ‘gold standard’ diagnostic method to detect primary AI, has a sensitivity of 92% (95% confidence interval, 81–97%) for the diagnosis of primary AI (Table 3). 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 primary AI, but it is not per se diagnostic. A CRH test may also be used but is not in frequent use or availability, while a prolonged ACTH stimulation test is not usually needed other than to confirm secondary or tertiary deficiency (Table 3). The gold standard’ is insulin-induced hypoglycemia, where short-acting insulin 0.1 or 0.15u/Kg, is injected and the peak cortisol measured over 2-3h. However, this must only be performed where there is adequate supervision and experience in its use. It must be emphasized that all normative values quoted are assay-dependent, and with the increasing use of GCMS to measure cortisol they may change again. Further investigations such as imaging studies, auto-antibodies or microbiological screening should be arranged accordingly to identify the underlying cause of AI.
Table 3.
Diagnostic Tests Used to Diagnose and Differentiate AI
| Test/ procedure | Interpretation of the result/ comments | Cortisol physiologic response | |
| Short Synacthen test (SST or cosyntropin test or ACTH test)- sampling at 9am for cortisol and ACTH level following by 250 mcg Synacthen for adults, children ≥ 2 y of age (15mcg/ kg for infants, 125 mcg for children <2 y of age) ACTH i.v. or i.m.; collect samples at 30’/ 60’ for cortisol level | Indication when morning cortisol levels 3-15mcg/dl; recent onset secondary AI may produce a normal response; testing at least 18–24 h after the last HC dose or longer for GCs; SST can be done at any time of the day | >430-500nmol/L (18µg/dL) (assay dependent) at 30 or 60 minutes Pregnancy: higher diagnostic cortisol cutoffs of 700 nmol/L (25 mcg/ dL), 800 nmol/L (29 mcg/dL), and 900 nmol/L (32 mcg/dL) for the first, second, and third trimesters, respectively | |
| Serum cortisol secretion at 09:00h in combination with plasma ACTH if SST is not feasible until confirmatory testing with SST is available | 9am cortisol <140 nmol/L (5 mcg/dL) suggests AI; can be useful in recent onset SAI (2 weeks); in severe stress such as sepsis a ‘normal’ level may still indicate AI ↑ ACTH 300 ng/L (66pmol/L) or > 2-fold the ULN confirms primary AI; ↓ACTH level (<10ng/L) confirms secondary or tertiary AI; ACTH 10-20ng/L can be equivocal, consider long synacthen test | Normal (100% sensitivity) > 400nmol/L (>285-480) or>15 μg/dL (10.3-17); suggestive AI: likely AI:<10µg/dL (275nmol/L) PAI: ↓cortisol + ↑ACTH; SAI/TAI: ↓morning + ↓ACTH; partial AI normal both | |
| Random cortisol; collect random serum cortisol level if AI is suspected, prior to steroid replacement | Undetectable level suggests AI; not very reliable, unless very low | ||
| Simultaneous measurement of plasma renin and aldosterone in primary AI to determine MC | early phase of evolving primary AI, MC deficiency may predominate and may be the only sign | ↑plasma renin activity or concentration in combination with an (inappropriately) normal or ↓serum aldosterone concentration: suggestive PAI | |
| low-dose SST 1mcg ACTH i.v.; collect samples at 30’ for cortisol level | Is suggested when the substance itself is in short supply: better for secondary AI? Better for critical ill patients? | >18 µg/dL (500nmol/L) | |
| CRH stimulation test iv bolus 1µg/kg or 100µg h-/o-CRH | Tertiary AI: ↑↑ACTH | ||
| Diagnostic tests not commonly used to diagnose and differentiate AI | |||
| Prolonged ACTH stimulation test; administer 1mg depot Synacthen i.m. or iv infusions 250mcg cosyntropin over 8hrs(A): cortisol/ 24hr urinary cortisol/ 17OHCS before and after infusion or over 24hrs on 2(or3) consecutive days(B); take blood sample for 9am cortisol and ACTH level; collect blood sample for serum cortisol level at 30, 60, 120min, 4, 8, 12 and 24 hours | Progressive rise in cortisol response in secondary AI; little or no response in primary AI; useful in differentiating primary from secondary AI when ACTH level is equivocal | A:24hr urinary 17-OHCS excretion ↑3-5-fold; >20μg/dL (550nmol/L) at 30’60’; 25μg/dL (690 nmol/L) at 6-8hrs post-initiation infusion; B:at 4hrs >1000nmol/L (36μg/dL) beyond this time, no further↑; secondary AI: delayed response at 24 and 48hrs than 4hrs; primary AI no response at either time | |
| ITT; sampling after overnight fast, insert cannula, take venous blood for basal glucose and cortisol, administer i.v. soluble insulin 0.1-0.15 U/kg; collect blood samples at 30, 45, 60, 90 and 120min for glucose and cortisol with adequate clinical and biochemical hypoglycemia Repeat insulin dose if glucose does not fall <2.2mmol/L at 45 min | Fall of glucose <2.2 mmol/L with corresponding failure of cortisol response >450-500nmol/L confirms AI Contraindications: Basal cortisol <100nmol/L; untreated hypothyroidism; abnormal ECG; ischemic heart disease; seizure; craniotomy; age >70 (uncertain); “Gold standard” test; sensitive test for recent onset secondary AI. | >500nmol/L (18μg/dL) | |
| overnight metyrapone test 30 mg/kg (max 3g) at midnight; cortisol/ 11-deoxycortisol measured at 8.00h the following morning | ↑ACTH+ peak; 11-deoxycortisol >7 mg/dL | ||
ACTH: adrenocorticophin hormone; AI: adrenal insufficiency; CBG: cortisol-binding globulin; CRH: corticotrophin releasing hormone; h-CRH: human CRH; GCs: glucocorticoids; IHD: ischemic heart disease; i.m.: intramuscular; ITT: insulin tolerance test; i.v.: intravenous; MCs: mineralocorticoids; o-CRH: ovine CRH; PAI: primary AI; SAI: secondary AI; SST: short synacthen test; TAI: tertiary AI; ULN: upper limit of normal
The notion of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) emerged to describe impairment of the HPA axis (stress response) during critical illness that is characterized by the dysregulated systemic inflammation caused by the inadequate intracellular GC-mediated anti-inflammatory activity. Recently, the Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) have issued guidelines for the diagnosis and management of CIRCI in critically ill patients. A specific test, such as post-SST cortisol at 60 min of <9 mcg/dL and a random plasma cortisol of <10 mcg/dL, may be helpful to make decision upon replacement treatment when AI is suspected (Table 4). Additionally, markers of inflammation and coagulation, morbidity, length of intensive care unit (ICU) stay, and mortality should be taken in consideration. Nevertheless, this whole concept has been questioned, especially as cortisol-binding proteins are invariably decreased in severe critical illness, such that simple measurement of total cortisol is likely to be an inaccurate reflection of the true state of the HPA axis. Because of the decrease in cortisol binding proteins the plasma total cortisol level may be decreased but plasma free cortisol levels may be normal. A marked decrease in serum albumin levels suggests that cortisol binding proteins are decreased.
Table 4.
Tests Used to Diagnose Adrenal Insufficiency in Critical Illness (but see text above)
| Test | Response |
| Cortisol | AI <275nmol/L (10μg/dL); normal: >900nmol/L (33μg/dL) |
| SST | Delta peak/basal <250nmol/L (9 mg/dL):AI → needs replacement |
AI: adrenal insufficiency; SST: short synacthen test
In the context of the different diseases associated with AI, additional investigations may be necessary (Table 5). When autoantibody against CYP21A2 is not detected, CT scanning of the adrenals should be performed to identify infectious diseases such as tuberculosis and tumors, or adrenal hemorrhage.
-
Table 5.
Additional Studies Used in Patients with AI
| Primary AI | |
| Radioimmunoassay (caution since the autoantibodies are not standardized) | autoantibodies against the 21-hydroxylase (CYP21A2), side-chain-cleavage enzyme and 17-hydroxylase for autoimmune PAI |
| Autoimmune markers and hormonal assays for evidence of other organ-specific autoimmune disease (APS) | Several autoantibodies/ clinical features (thyroid function for autoimmune hypothyroidism; plasma glucose for diabetes type 1; serum calcium and PTH for autoimmune hypoparathyroidism; anti-parietal cell antibody and intrinsic factor antibody for pernicious anemia; endomyseal antibody or tissue transglutaminase for celiac disease; liver function for autoimmune hepatitis; antibodies to interferon ω or α have a high diagnostic sensitivity and specificity for APS-1 |
| Microbial and serological tests | Tuberculosis (tuberculin testing, early morning urine samples cultured for Mycobacterium tuberculosis) or other infective cause |
| CT / MRI scan | Calcified adrenals: infection/hemorrhage/ malignancy Large adrenals with or without calcification seen in tuberculosis and metastatic deposits Small atrophic glands in autoimmune primary AI, but can also be seen in chronic secondary AI Adrenal hemorrhage and adrenal vein thrombosis (MRI better than CT) |
| Chest radiograph | Tuberculosis |
| CT guided adrenal biopsy | Adrenal metastases |
| Adrenoleukodystrophy | measuring circulating levels of VLCFA (frequently in boys 2 to 10 years) |
| 17-OH progesterone and 24-hour urine steroid profile | Classic CAH, in neonates |
| Secondary AI | |
| Hormonal assessment | Pituitary hormone deficiency |
| Pituitary MRI scans | Pituitary cause |
| Biopsy of pituitary | Occasionally necessary |
| Other Investigations | |
| Plasma renin activity | ↑ in PAI due to mineralocorticoid deficiency |
| DHEAS | ↓ in women |
AI: adrenal insufficiency; APS: autoimmune polyglandular syndrome; CAH: congenital adrenal hyperplasia; CT: computerized tomography; DHEAS: dehydroepiandrosterone sulfate; MRI: magnetic resonance imaging; VLCFA: very long-chain fatty acids
As noted above, caution should be given in the interpretation of laboratory tests in specific situation such as the conditions that affect CBG concentration (↓: inflammation, nephrotic syndrome, liver disease, immediate postoperative period or requiring intensive care, rare genetic disorders; ↑: estrogen, pregnancy, mitotane). Systemic estrogens should be discontinued at least for 4 weeks prior to testing (estrogen patches will not affect CBG). Different criteria may apply according to the cortisol assay. If on GC replacement, omit the steroid dose before the test (hold off evening and morning dose: for HC or prednisolone, longer for the other synthetic GCs). In pregnancy, higher diagnostic cortisol cutoffs of 700 nmol/L (25 mcg/dL), 800 nmol/L (29 mcg/dL), and 900 nmol/L (32 mcg/dL) should be considered for the first, second, and third trimesters, respectively. In pituitary diseases, testing of GC sufficiency is suggested before and after initiation of GH replacement or upon documentation of an improvement in pre-existing diabetes insipidus (DI).
THERAPY
Acute Adrenal Insufficiency (Adrenal Crisis)
Adrenal insufficiency is a potentially life-threatening medical emergency when presenting as adrenal crisis, which requires prompt treatment with hydrocortisone (HC) and fluid replacement. Once clinically suspected, treatment should be initiated and not be delayed while waiting for definitive proof of diagnosis. Blood samples should be obtained for measurement of cortisol concentrations later, and the management approach should be similar to the resuscitation of any critically ill patient (Table 6).
Table 6.
Treatment of Acute Adrenal Insufficiency (Adrenal Crisis) During Patient’s Admission- Management of Resuscitation of Critically Ill Patient
| Maintain airway and breathing | Treat hypotension: correct hypovolemia, reverse electrolyte abnormalities + cortisol deficiency; measurement central/ peripheral venous pressure + chest auscultation avoid fluid overload (↓infusion rate); clinical improvement (blood pressure), within 4-6h; caution should be taken in correcting chronic hyponatremia (not more than 12mmol in 24 h, preferably < 8) to prevent central pontine myelinolysis Τhe half- life of HC is 90-120 min after i.v. injection, and more prolonged after i.m. administration; switch to oral HC with a tapering dose (usually 20mg-10mg-10mg) after 48 hours if oral intake is resumed and there is no other major illness; some recommend dexamethasone while dynamic tests are awaited, as dexamethasone does not interfere with the assay, but HC is preferred for its MC activity (negligible with dexamethasone), in correcting the electrolyte imbalances; no need for fludrocortisone replacement in an acute crisis since the MC activity of HC and 0.9% saline infusion is sufficient to correct electrolyte imbalances |
| Establish i.v. access with two large bore cannula | |
| Collect venous blood samples for urea and electrolytes, glucose, full blood count, bicarbonate, infection screen, store samples (cortisol/ ACTH (plasma measurement) | |
| Rapid infusion of 1L isotonic saline within the 1st hour or 5% glucose in isotonic saline, followed by continuous i.v. isotonic saline guided by individual patient needs; usually infuse 1-3 L normal saline NaCl (0.9%) within 12 hours; normal saline to be continued, guided by volume status and urine output, for 24-48 hours or 50g/L (5%) dextrose in NaCl (0.9%l) if there is evidence of hypoglycemia (rare in adults); children, rapid bolus of normal saline (0.9%) 20 mL/kg; can repeat up to a total of 60 mL/kg within 1 h for shock | |
| Inject i.v. 100mg HC immediately (50-100 mg/m2 for children) and then fluids followed by 200 mg/d (50–100 mg/m2 /d for children divided q 6h) of HC/24h (via continuous i.v. therapy or 6 hourly injection) for 24- 48 h, reduce to HC 100 mg/d the following day; if unavailable use prednisolone; dexamethasone is the least preferred and should be given i.v. 4mg immediately | |
| Use additional supportive measures as needed | |
| For hypoglycemia | Dextrose 0.5–1 g/kg of dextrose or 2–4 mL/kg of D25W (maximum single dose 25 g) infused slowly at rate of 2-3 mL/min. Alternatively, 5–10 mL/kg of D10W for children >12 y old |
| Cardiac monitoring | |
| MC replacement is not required if the HC dose exceeds 50 mg/24 hours | |
ACTH: adrenocorticotropic hormone; HC: hydrocortisone; i.m.: intramuscular; i.v.: intravenous; MC: mineralocorticoid
Table 7.
Treatment of Acute Adrenal Insufficiency (Adrenal Crisis) After Patient Stabilization
| Continue i.v. NaCl (0.9%)→ slower rate for 24-48hr |
| Search for and treat possible infectious precipitating causes of the AC; treat any associated condition |
| Perform SST to confirm the diagnosis |
| Differential diagnosis if needed |
| Taper parenteral glucocorticoids over 3-4 days→ oral maintenance dosage→ after 24hrs, ↓HC-50mg im every 6hr→ oral HC 40mg morning+ 20mg afternoon→ rapidly ↓maintenance dose 20mg on awaking/10mg at 18.00hrs |
| Begin MC replacement with fludrocortisone (0.1mg by mouth daily) when saline infusion ceased to prevent sodium loss, intravascular volume depletion and hyperkalemia |
AC: adrenal crisis; ACTH: adrenocorticophin hormone; HC: hydrocortisone; i.m.: intramuscular; i.v.: intravenous; MC: mineralocorticoid; SST: short Synacthen test
Management of Chronic or Insidious Onset of Adrenal Insufficiency
The aim of replacement treatment in AI is to mimic the normal cortisol secretion rate. Initially this was thought to be approximately 25-30 mg/day, but normal cortisol production rates seem to be of the order of 8 to 15 mg/day. Most patients can cope with <30 mg/day (usually 15-25 mg/day in divided doses). Doses are usually given on waking with a smaller dose in afternoon; most patients feel better on three-a-day dosing. There is some evidence that three or four daily doses mimic better physiological cortisol secretion and that weight-adjusted dosing may be associated with a better safety profile. Despite the various types of cortisol replacement regimens, no head–to-head comparison data are available to advocate one over the other. Decisions regarding the form of GCs and the doses of replacement therapy are based on crude end-points such as weight, well-being, and blood pressure, as well as on local availability, cost and clinical need (Table 8). Bone mineral density may be reduced on conventional doses of 30mg/day HC, highlighting the need to target for effective but safe doses. Long-duration GCs can be administered once daily but may be associated with higher risk of side effects. Patients should be monitored for clinical symptoms.
Table 8.
Glucocorticoid Replacement Schemes
| Commonly used doses | ||
| HC | Short acting, given in 2-3 divided doses; this approximately mimics the endogenous diurnal rhythm; obese individuals may require more GC replacement than lean individuals; higher frequency regimes and size-based dosing may be beneficial in individual cases; high doses in the evening may disturb sleep and alter metabolism | 15-25 mg or 5-8 mg/m2/day; the highest dose in the morning on wakening, the next in the early afternoon (2 h after lunch) (2-dose regime) or at lunch and afternoon-not later than 4-6hours before bedtime) (3-dose regime); usually 10mg waking, 5mg at lunchtime and 5mg in the late afternoon |
| Slow-release HC | Available in some countries | usually 20mg once-daily |
| Cortisone acetate | Short acting (but longer than HC); metabolized in liver to active form, HC; no i.v. preparation | 20-35mg in 2-3 divided doses |
| Prednisolone (alternative to HC) /prednisone | Long-acting, once-daily dose is sufficient; some may need additional 2.5mg in the evening; does not mimic diurnal rhythm of endogenous cortisol; better choice in patients non-compliant with multiple daily dose or in patients with no good quality of life on HC replacement; cross-reacts in most cortisol assays | 3-5 mg once daily on waking |
| Dexamethasone | Inter-individual variable metabolism makes it difficult to predict the adequate dose; dose needs to be ↑ if patient is on hepatic enzyme inducing medications; it is not recommended in primary AI because of risk of Cushingoid side effects due to difficulties in dose titration | 0.25-0.75 mg once daily |
| MC replacement therapy | Required only in primary AI; may need to ↑ dose in hot weather; available in oral preparation only; if parenteral action required, use DOCA if available | 50-200mcg (median 100mcg) (starting dose, 50–100 mcg in adults) fludrocortisone (9α-fluorohydrocortisone) daily; do not restrict salt intake |
| Androgen replacement | A trial can be offered to women with low energy, low mood and low libido, despite otherwise optimized GCs and MCs replacement; some evidence of benefit; not generally available on prescription, but obtained as a ‘health food’ supplement. | 25–50 mg as a single oral dose in the morning; initial trial of 6 months of DHEA replacement; if no benefit after 6 months, it should be discontinued. |
AI: adrenal insufficiency; DHEA: dehydroepiandrosterone; DOCA: deoxycorticosterone acetate; GCs: glucocorticoids; i.m.: intramuscular; i.v.: intravenous; HC: hydrocortisone; MCs: mineralocorticoids
It should be noted that while HC and prednisolone are active GCs, cortisone acetate and prednisone require activation via hepatic 11β-hydroxysteroid dehydrogenase type 1 to be biologically active. A novel dual-release HC preparation can be administered once daily and slow-release preparations of HC are in clinical development.
One important aspect of the management of chronic primary AI is patient and family education. Careful instructions should be given to double the daily dose in the event of intercurrent febrile illness, accident, or severe mental stress such as an important examination. If the patient is vomiting and cannot take medication by mouth, parenteral HC must be given urgently. Ideally, patients should wear a ‘medical-alert’ bracelet or necklace and carry the Emergency Medical Information Card, which should provide information on the diagnosis, the medications and daily doses, and the physician involved in the patient’s management. Patients should also have supplies of dexamethasone sodium phosphate, HC or methylprednisolone for emergencies, and should be educated about how and when to administer them by the i.m. route. However, it has been shown that subcutaneous self-injection was their preferred route of administration; the delay in time to reach peak cortisol concentrations with this later formulation was off-set by the time to find another person to administrate the GC by i.m. route. Rectal suppositories (prednisolone 100 mg suppository) or enemas (prednisolone 20 mg/100mL or HC acetate enema 10%) have been also used, but they are clearly not useful when diarrhea co-exists.
Table 9.
Glucocorticoid Replacement Schemes During Illness
| Examples of commonly used schemes | ||
| During minor illness | ↑up to 3 times usual dosage for 3 days; do not change MC dose | HC 25-75 mg /24h in 2 doses orally or i.v.; taper rapidly as patient recovers (usually 1-2 d); children, i.m. HC 50 mg/m2 or HC replacement doses doubled or tripled |
| During minor surgery | 50-100mg HC with premedication | |
| During major illness or major surgery | ↑up to 10 times usual dosage; continuous infusion of 10mg HC/ h (or equivalent dexamethasone/ prednisolone. Half dose 2nd postoperative day, maintenance dose 3rd postoperative day. | HC 100mg i.v. /8hr for 24hr; taper rapidly ↓by half/ day |
| Major surgery | HC 100mg i.v. just before induction of anesthesia followed by continuous i.v. infusion of 200 mg HC/24h (alternatively 50 mg every 6 h i.v. or i.m.); taper rapidly, ↓ by half/day and switch to oral regime depending on clinical state; children: HC 50 mg/m2 i.v. followed by HC 50–100 mg/m2/d divided every 6 h. Weight-appropriate continuous i.v. fluids with 5% dextrose and 0.2 or 0.45% NaCl. | |
| Uncomplicated, outpatient dental procedures under local anesthesia and most radiologic studies | No extra supplementation | |
| Severe stress or trauma | Inject prefilled dexamethasone (4-mg) syringe | |
| Moderately stressful procedures (barium enema, endoscopy, or arteriography) | 100mg i.v. dose of HC just before | |
| Pregnancy | ↑5-10mg/day of HC usually in the last trimester (20–40% from the 24th week onward); ↑dose of fludrocortisone; HC is preferred over the other GCs but dexamethasone is not suggested since it is not inactivated in the placenta | Labor - HC stress dosing (bolus injection of 100 mg HC iv followed by continuous infusion of 200 mg HC/24 h (well hydrated +saline drip +HC 50mg im/6h until delivery) similar to major surgical stress; thereafter, rapidly taper to pre-pregnancy levels |
HC: hydrocortisone; i.m.: intramuscularly; i.v.: intravenously; GCs: glucocorticoids
Regarding MC replacement therapy, the dose of fludrocortisone is titrated individually based on clinical examination (mainly body weight and blood pressure) and the levels of plasma renin activity (PRA). Patients receiving prednisone (less MC activity) or dexamethasone (no MC activity) may require higher doses of fludrocortisone, as opposed to those receiving HC (125 time less), which has some MC activity. After the acute phase has passed, the adequacy of MC replacement should be assessed by measuring electrolytes, supine and erect blood pressure, and PRA; too little fludrocortisone may cause postural hypotension with elevated PRA, whereas too much causes the converse. Mineralocorticoid replacement therapy is all too frequently neglected in patients with adrenal failure. The dose may have to be increased in the summer along with an increase in salt intake, particularly if patients are exposed to temperatures above 30ºC (85ºF) or other conditions causing increased sweating. Newborns and children may also require higher fludrocortisone because MC sensitivity is lower.
In chronic secondary and tertiary AI GCs replacement is similar to that in primary AI; however, measurement of plasma ACTH concentrations cannot be used to titrate the optimal GC dose. Replacement of other anterior pituitary deficits may be also necessary, and changing doses of growth hormone and thyroxine may change requirements.
For patients with either primary AI or secondary AI the beneficial effects of adrenal androgen replacement therapy with 25 to 50 mg/day of DHEA have been reported. To date, the reported benefit is principally confined to female patients and includes improvement in sexual function and well-being.
In children with primary AI, HC in three or four divided doses (total starting daily dose of 8 mg/m2 body surface area) over synthetic, long-acting GCs (prednisolone, dexamethasone) is preferred. In case of documented aldosterone deficiency, treatment with fludrocortisone is suggested by a starting dosage, 100 mcg/d, while sodium chloride supplements are needed in the newborn period until the age of 12 months. Most experience has been gained from the treatment of children with CAH; however, since in this case under treatment is confirmed by hyperandrogenism higher GC therapy is usually given.
Novel therapies have been tried such as rituximab in newly diagnosed autoimmune primary AI patients and with depot teracacidin in established primary AI patients. The regenerative potential of adrenocortical stem cells combined with immunomodulatory treatment to stop the autoimmune destruction or adrenal transplantation or gene therapy in forms of monogenic PAI may be a useful option in the future.
For CIRCI with septic shock, it has been suggested to use i.v. HC < 400 mg/day for ≥ 3 days at full dose (rather than high-dose and short-course regimes) when they are not responsive to fluid and moderate-to high-dose vasopressor therapy (> 0.1 mcg/kg/min of norepinephrine or equivalent) as opposed to CSs in adult patients with sepsis without shock. In patients with early moderate to severe acute respiratory distress syndrome (ARDS) (PaO2/ FiO2 < 200 and within 14 days of onset) the use of i.v. methylprednisolone 1 mg/kg/day is suggested since GC treatment was associated with a significant reduction in markers of systemic inflammation (inflammatory cytokines and/or C-reactive protein levels), a reduction in the duration of mechanical ventilation by approximately 7 days, and probable reduction in hospital mortality by approximately 7% and 11%, respectively. In the case of late (> 6 days of onset) persistent ARDS the dose is increased to 2 mg/kg/day followed by slow tapering over 13 days. In hospitalized adults with community-acquired pneumonia a daily dose <400mg i.v. HC or equivalent has been suggested. GCs are also suggested in patients suffering from meningitis, cardiac arrest (methylprednisolone given during resuscitation or HC given for post-resuscitation shock), and cardiopulmonary bypass surgery (CPB) (250 mg i.v. of methylprednisolone at anesthesia induction and at onset of CPB) or dexamethasone (1 mg/kg perioperatively). Corticosteroids are not suggested for patients after major trauma or suffering from influenza. Nevertheless, it should be emphasized that this is a rapidly changing situation, and the use of corticosteroids in the ICU with severely ill patients remains controversial.
FOLLOW-UP
Patients with chronic AI should be followed-up closely by an endocrinologist or a healthcare provider with endocrine expertise at least annually (for infants every 3 to 4 months) to ensure the adequacy of their GC and MC (in primary AI) replacement dose (Table 10), to reduce the risk of AC crisis, providing necessary education to the patients, and to confirm that they have a prompt updated emergency pack with HC to treat an emergency. Clinical symptoms including body weight, postural blood pressure and energy levels should be used to monitor GC replacement in order to avoid signs of frank GC excess and adjust accordingly the dose of steroids. The ‘mapping’ of the dose has been suggested to assess the compliance, but also in cases with reduced quality of life where the detailed questioning for daily habits, working patterns, general feelings of energy, mental concentration, daytime somnolence, and dips in energy can help decide when tablets should be taken. Hormonal monitoring (serum or salivary cortisol ‘day-curves’) of GC replacement is not routinely recommended, but can be useful in specific situations where the clinical response cannot be reliably be used to adjust treatment or when malabsorption is suspected. In addition, the use of ACTH levels to assess GC replacement is not suggested since it leads to over-replacement.
Similarly, MC replacement should be monitored based on clinical assessment (postural hypotension by lying and standing blood pressure and pulse, salt craving, edema, blood electrolyte measurements) (Table 11). Reported well-being, electrolytes within the normal range and normal blood pressure without postural hypotension indicate adequate replacement, and the PRA should be targeted to the upper reference range. Licorice and grapefruit juice potentiate the MC effect of HC and should be avoided. Phenytoin increase fludrocortisone metabolism and higher doses are needed when it is co-administered. In pregnancy, only sodium and potassium can be reliably monitored in blood and urine for the adequacy of the replacement.
It is of note that in patients who develop hypertension while receiving fludrocortisone, the dose of fludrocortisones should be reduced and HC replacement should be adjusted; if blood pressure remains uncontrolled, anti-hypertensive treatment should be initiated without fludrocortisones discontinuation. First-line anti-hypertensive drugs to be selected are the angiotensin II receptor blockers or angiotensin-converting enzyme blockers to counterbalance the vasoconstrictive effects of elevated angiotensin II, second-line a dihydropyridine calcium blocker, while diuretics should be avoided and aldosterone receptor blockers are contraindicated.
Since AI might mask the presence of partial diabetes insipidus (DI), DI should be monitored after starting GC replacement or conversely, when DI has improved, patients have to be tested for AI.
With DHEA replacement, morning serum DHEA sulfate (DHEAS) levels should be measured before the intake of the daily dose aiming at the mid-normal range. An annual screening for autoimmune diseases (autoimmune thyroid disease, type 1 diabetes, premature ovarian failure, celiac disease, and autoimmune gastritis) should be included in patients with primary AI and no other obvious cause of adrenal failure.
Special populations, like pregnant females, should be followed-up for clinical symptoms and signs of GC over- and under-replacement (weight gain, fatigue, postural hypotension or hypertension, hyperglycemia), with at least one visit per trimester. In children, the monitoring of GC replacement includes clinical assessment such as growth velocity, body weight, blood pressure, and energy levels.
Genetic counselling may be useful in particular situations due to monogenic disorders.
Table 10.
Assessment of Glucocorticoid Replacement
| Under replacement | Lethargy, tiredness, nausea, poor appetite, weight loss, hyperpigmentation. Low serum cortisol level on cortisol day curve (useful for HC or cortisone replacement only) (specific cases only) |
| Over replacement | Cushingoid appearance, weight gain, insomnia, peripheral edema High 24-hour UFC, high serum cortisol on hydrocortisone day curve (useful for HC or cortisone replacement only) (specific cases only) Low bone mineral density |
UFC: Urinary Free Cortisol
Table 11.
Assessment of Mineralocorticoid Replacement
| Inadequate replacement | Postural hypotension, light-headedness High PRA (should be at the upper level of normal) |
| Over replacement | Hypertension, peripheral edema, hypokalemia |
PRA: Plasma Renin Activity
Patient Education
This is very crucial in the management of AI and for the prevention of adrenal crisis (AC). All patients and their relatives should be educated about their condition and the emergency measures they should take at home to prevent AC, particularly concerning GC adjustments in stressful events and AC prevention strategies including parenteral self- or lay-administration of emergency GCs particularly in situations of intercurrent illness, fever, and any type of stress. This information should be reinforced during the annual follow-up visits by the clinicians and if possible, through a structured patient education program. All patients should be equipped with a steroid emergency card and medical-alert identification to inform health personnel of the need for increased GC doses to avert or treat AC and the need of immediate parenteral steroid treatment in the event of an emergency. Every patient should be equipped with a GC injection kit for emergency use and be educated on how to use it (Table 12).
Table 12:
Information and Equipment for Patients with AI
| Steroid Sick Day Rules |
Sick day rule 2: need to inject a GC preparation i.m. or i.v. in case of severe illness, trauma, persistent vomiting, when fasting for a procedure (colonoscopy!), or during surgical intervention
|
| Steroid Emergency Pack |
|
| Medical-Alert bracelet or pendant and emergency steroid card |
|
| Follow up |
|
GCs: glucocorticoids; HC: hydrocortisone; i.m.: intramuscularly; i.v.: intravenously; HC: hydrocortisone; MCs: mineralocorticoids; sc: subcutaneously
PROGNOSIS
The mortality of patients with primary AI was increased in some studies and adrenal crisis (AC) was a significant cause of death, emphasizing the need to educate the patients with AI to prevent AC. Recent evidence suggests that the quality of life of patients with primary AI remains impaired despite the adequate replacement dose but seems to be related to the delay in diagnosis.
GUIDELINES
- Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364–89. [PMC free article: PMC4880116] [PubMed: 26760044]
- Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Nov;101(11):3888–3921. [PubMed: 27736313]
- Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers SC, Russell JA, Van den Berghe G. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017 Dec;45(12):2078–2088. [PubMed: 28938253]
- Pastores SM, Annane D, Rochwerg B. Corticosteroid Guideline Task Force of SCCM and ESICM. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2018 Jan;46(1):146–148. [PubMed: 29095205]
REFERENCES
- Nicolaides NC, Chrousos GP, Charmandari E. Adrenal Insufficiency. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000- 2017 Oct 14.
- J Yeo KT, Babic N, Hannoush ZC, Weiss RE. Endocrine Testing Protocols: Hypothalamic Pituitary Adrenal Axis. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000- 2017 May 17.
- Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. 1989;110(3):227. [PubMed: 2643380]
- Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab. 1985;14(4):947. [PubMed: 3002680]
- Alkataib AA, Cosma M, Elamin MB, et al. DHEA Treatment of Women J Clin Endo Metab. 2009;94:3676. [PubMed: 19773400]
- Diagnosis and Management of Adrenal Insufficiency - EndotextDiagnosis and Management of Adrenal Insufficiency - Endotext
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