Adrenal Insufficiency – Causes, Symptoms, Treatment

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Adrenal insufficiency is a disorder that occurs when the adrenal glands don’t make enough of certain hormones. The adrenal glands are located just above the kidneys. Adrenal insufficiency can be primary, secondary, or tertiary. Primary adrenal insufficiency is often called Addison’s disease.

Adrenal insufficiency is a serious pathologic condition characterized by decreased production or action of glucocorticoids and/or mineralocorticoids and adrenal androgens. This life-threatening disorder may be classified as primary, secondary, or tertiary, resulting from diseases affecting the adrenal cortex, the anterior pituitary gland or the hypothalamus, respectively. The clinical manifestations of adrenal insufficiency include anorexia, abdominal pain, weakness, weight loss, fatigue, hypotension, salt craving, and hyperpigmentation of the skin in case of primary adrenal insufficiency.

Types of Adrenal Insufficiency 

There are three major types of adrenal insufficiency.

  • Primary adrenal insufficiency – is due to impairment of the adrenal glands.
    • 80% are due to an autoimmune disease called Addison’s disease or autoimmune adrenalitis.
    • One subtype is called idiopathic, meaning of unknown cause.
    • It can also be due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
    • Other causes include; Infections (TB, CMV, histoplasmosis, paracoccidioidomycosis), vascular (hemorrhage from sepsis, adrenal vein thrombosis, HIT), deposition disease (hemochromatosis, amyloidosis, sarcoidosis), drugs (azole antifungals, etomidate (even one dose), rifampin, anticonvulsants)
  • Secondary adrenal insufficiency – is caused by impairment of the pituitary gland or hypothalamus.[rx] Its principal causes include pituitary adenoma (which can suppress the production of adrenocorticotropic hormone (ACTH) and lead to adrenal deficiency unless the endogenous hormones are replaced); and Sheehan’s syndrome, which is associated with impairment of only the pituitary gland.
  • Tertiary adrenal insufficiency – is due to hypothalamic disease and a decrease in the release of corticotropin-releasing hormone (CRH).[rx] Causes can include brain tumors and sudden withdrawal from long-term exogenous steroid use (which is the most common cause overall).[rx]

Causes of Adrenal Insufficiency

Causes of Primary Adrenal Insufficiency

The etiology of primary adrenal insufficiency has changed over time. Prior to 1920, the most common cause of primary adrenal insufficiency was tuberculosis, while since 1950, the majority of cases (80-90%) have been ascribed to autoimmune adrenalitis, which can be isolated (40%) or in the context of an autoimmune polyendocrinopathy syndrome (60%).

  • Autoimmune adrenalitis (Addison’s disease) – This condition is characterized by the destruction of the adrenal cortex by cell-mediated immune mechanisms. Antibodies that react against steroid 21-hydroxylase are detected in approximately 90% of patients with autoimmune Addison’s disease, but only rarely in patients with other causes of adrenal insufficiency or normal subjects. Considerable progress has been made in identifying genetic factors that predispose to the development of autoimmune adrenal insufficiency. In addition to the major histocompatibility complex (MHC) haplotypes DR3-DQ2 and DR4-DQ8, other genetic factors, such as protein tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T lymphocyte antigen 4 (CTLA-4), and the major histocompatibility complex class II transactivator (CIITA) have been associated with this condition. Primary adrenal insufficiency may also present as part of autoimmune polyendocrinopathy syndromes. Patients with autoimmune polyendocrinopathy syndrome type 1 (APS1) or APECED (Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy) syndrome may present with chronic mucocutaneous candidiasis, adrenal insufficiency, hypoparathyroidism, hypoplasia of the dental enamel, and nail dystrophy, while type 1 Diabetes Mellitus (T1DM) or pernicious anemia, may develop later in life. Clinical manifestations of autoimmune polyendocrinopathy syndrome type 2 (APS2) include autoimmune adrenal insufficiency, autoimmune thyroid disease, and/or T1DM, whereas autoimmune polyendocrinopathy syndrome type 4 (APS4) is characterized by autoimmune adrenal insufficiency and one or more other autoimmune diseases, such as atrophic gastritis, hypogonadism, pernicious anemia, celiac disease, myasthenia gravis, vitiligo, alopecia, and hypophysitis, but without any autoimmune disorders of APS1 or APS2.
  • Adrenoleukodystrophy – This is an X-linked recessive disorder affecting 1 in 20.000 males (2). The molecular basis of this condition has been ascribed to mutations in the ABCD1 gene, which result in defective beta-oxidation of very-long-chain fatty acids (VLCFAs) within peroxisomes. The abnormally high concentrations of VLCFAs in affected organs, including the adrenal cortex, resulting in the clinical manifestations of this disorder, which include neurological impairment due to white-matter demyelination and primary adrenal insufficiency, with the latter presenting in infancy or childhood.
  • Hemorrhagic infarction – Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis may also lead to adrenal insufficiency. The diagnosis is usually made in critically ill patients in whom a computed tomography (CT) scan of the abdomen shows bilateral adrenal enlargement. Several coagulopathies and the heparin-induced thrombocytopenia syndrome have been associated with adrenal vein thrombosis and hemorrhage, while the primary antiphospholipid syndrome has been recognized as a major cause of adrenal hemorrhage. Adrenal hemorrhage has been mostly associated with meningococcemia (Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa infection.
  • Infectious adrenalitis – Many infectious agents may attack the adrenal gland and result in adrenal insufficiency, including tuberculosis (tuberculous adrenalitis), disseminated fungal infections, and HIV-associated infections, such as adrenalitis due to cytomegalovirus and mycobacterium avium complex.
  • Drug-induced adrenal insufficiency Drugs that may cause adrenal insufficiency by inhibiting cortisol biosynthesis, particularly in individuals with limited pituitary and/or adrenal reserve, include aminoglutethimide (antiepileptic), etomidate (anesthetic-sedative), ketoconazole (antimycotic), and metyrapone. Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, and rifampicin can also cause adrenal insufficiency in patients with limited pituitary or adrenal reserve, as well as those who are on replacement therapy with glucocorticoids. Furthermore, some of novel tyrosine kinase-targeting drugs (e.g. sunitinib) have been shown in animal studies to cause adrenal dysfunction and hemorrhage.

Causes of Primary Adrenal Insufficiency

Disease Pathogenetic Mechanism
Autoimmune adrenalitis
Isolated Associations with HLA-DR3-DQ2, HLADR4-DQ8, MICA, CTLA-4, PTPN22,
CIITA, CLEC16A, Vitamin D receptor
APS type 1 (APECED) AIRE gene mutations
APS type 2 Associations with HLA-DR3, HLA-DR4,
CTLA-4
APS type 4 Associations with HLA-DR3, CTLA-4
Infectious adrenalitis
Tuberculous adrenalitis Tuberculosis
AIDS HIV-1, cytomegalovirus
Fungal adrenalitis Histoplasmosis, cryptococcosis,
coccidiodomycosis
Syphilis Treponema pallidum
African Trypanosomiasis Trypanosoma brucei
Bilateral adrenal hemorrhage Meningococcal sepsis (Waterhouse-
Friderichsen syndrome), primary
antiphospholipid syndrome
Bilateral adrenal metastases Primarily lung, stomach, breast, and colon
cancer
Bilateral adrenal infiltration Primary adrenal lymphoma, amyloidosis,
hemochromatosis
Bilateral adrenalectomy Unresolved Cushing’s syndrome,
bilateral adrenal masses, bilateral pheochromocytoma
Drug-induced adrenal insufficiency
Anticoagulants (heparin, warfarin),
tyrosine kinase inhibitors (sunitinib)
Hemorrhage
Aminoglutethimide Inhibition of P450 aromatase (CYP19A1)
Trilostane Inhibition of 3β-hydroxysteroid
dehydrogenase type 2 (HSD3B2)
Ketoconazole, fluconazole, etomidate Inhibition of mitochondrial cytochrome
P450-dependent enzymes (e.g. CYP11A1,
CYP11B1)
Phenobarbital Induction of P450-cytochrome enzymes
(CYP2B1, CYP2B2), which enhance
cortisol metabolism
Phenytoin, rifampin, troglitazone Induction of P450-cytochrome enzymes
(primarily CYP3A4), which enhance
cortisol metabolism
Genetic disorders
Adrenoleukodystrophy or
adrenomyeloneuropathy
ABCD1 and ABCD2 gene mutations
Congenital adrenal hyperplasia
21-Hydroxylase deficiency CYP21A2 gene mutations
11β-Hydroxylase deficiency CYP11B1 gene mutations
3β-hydroxysteroid dehydrogenase
type 2 deficiency
HSD3B2 gene mutations
17α-Hydroxylase deficiency CYP17A1 gene mutations
P450 Oxidoreductase deficiency POR gene mutations
P450 side-chain cleavage deficiency CYP11A1 gene mutations
Congenital lipoid adrenal hyperplasia StAR gene mutations
Smith-Lemli-Opitz syndrome DHCR7 gene mutations
Adrenal hypoplasia congenital
X-linked NR0B1 gene mutations
Xp21 contiguous gene syndrome Deletion of the Duchenne muscular
dystrophy, glycerol kinase and NR0B1
genes
SF-1 linked NR5A1 gene mutations
IMAGe syndrome CDKN1C gene mutations
Kearns-Sayre syndrome Mitochondrial DNA deletions
Wolman’s disease LIPA gene mutations
Sitosterolaimia (also known as
phytosterolemia)
ABCG5 and ABCG8 gene mutations
Familial glucocorticoid deficiency
(FGD, or ACTH insensitivity syndromes)
Type 1 MC2R gene mutations
Type 2 MRAP gene mutations
Variant of FGD MCM4 gene mutations
FGC – Deficiency of mitochondrial ROS detoxification NNTTXNRD2GPX1PRDX3 gene mutations
Primary Generalized Glucocorticoid
Resistance or Chrousos syndrome
NR3C1 gene mutations
Sphingosine-1-phosphate lyase 1 deficiency SPGL1 gene mutations
Infantile Refsum disease PHYH, PEX7 gene mutations
Zellweger syndrome PEX1 and other PEX gene mutations
Triple A syndrome (Allgrove’s syndrome) AAAS gene mutations
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Causes of Secondary and Tertiary Adrenal Insufficiency

Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. The ACTH deficiency may be isolated or occur in association with other pituitary hormone deficits.

Tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with CRH secretion. The most common cause of tertiary adrenal insufficiency is chronic administration of synthetic glucocorticoids that suppress the hypothalamic-pituitary-adrenal (HPA) axis (50).

Causes of Secondary Adrenal Insufficiency.

Disease Pathogenetic Mechanism
Space occupying lesions or trauma
Pituitary tumors (adenomas, cysts,
craniopharyngiomas, ependymomas,
meningiomas, rarely carcinomas) or
trauma (pituitary stalk lesions)
Decreased ACTH secretion
Pituitary surgery or irradiation for pituitary
tumors, tumors outside the HPA axis or
leukemia
Decreased ACTH secretion
Infections or Infiltrative processes
(lymphocytic hypophysitis,
hemochromatosis, tuberculosis, meningitis,
sarcoidosis, actinomycosis, histiocytosis X,
Wegener’s granulomatosis)
Decreased ACTH secretion
Pituitary apoplexy Decreased ACTH secretion
Sheehan’s syndrome (peripartum pituitary
apoplexy and necrosis)
Decreased ACTH secretion
Genetic disorders
Transcription factors involved in pituitary
development
HESX homeobox 1 HESX1 gene mutations
Orthodentical homeobox 2 OTX2 gene mutations
LIM homeobox 4 LHX4 gene mutations
PROP paired-like homeobox 1 PROP1 gene mutations
SRY (sex-determining region Y) – box 3 SOX3 gene mutations
T-box 19 TBX19 gene mutations
Congenital Proopiomelanocortin (POMC)
deficiency
POMC gene mutations
Prader-Willi Syndrome (PWS) Deletion or silencing of genes in the
imprinting center for PWS

Causes of Tertiary Adrenal Insufficiency.

Disease Pathogenetic Mechanism
Space occupying lesions or trauma
Hypothalamic tumors
(craniopharyngiomas or metastasis from
lung, breast cancer)
Decreased CRH secretion
Hypothalamic surgery or irradiation for
central nervous system or nasopharyngeal
tumors
Decreased CRH secretion
Infections or Infiltrative processes
(lymphocytic hypophysitis,
hemochromatosis, tuberculosis, meningitis,
sarcoidosis, actinomycosis, histiocytosis X,
Wegener’s granulomatosis)
Decreased CRH secretion
Trauma, injury (fracture of the skull base) Decreased CRH secretion
Drug-induced adrenal insufficiency
Glucocorticoid therapy (systemic or topical) or endogenous glucocorticoid
hypersecretion (Cushing’s syndrome)
Decreased CRH and ACTH secretion
Mifepristone Tissue resistance to glucocorticoids
through impairment of glucocorticoid
signal transduction
Antipsychotics (chlorpromazine),
antidepressants (imipramine)
Inhibition of glucocorticoid-induced gene
transcription

Symptoms of Adrenal Insufficiency 

  • Signs and symptoms include hypoglycemia, dehydration, weight loss, and disorientation.
  • Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse, muscle aches, nausea, vomiting, and diarrhea.
  • These problems may develop gradually and insidiously. Addison’s disease can present with tanning of the skin that may be patchy or even all over the body.
  • Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa). Goiter and vitiligo may also be present.[rx] Eosinophilia may also occur.[rx]

Diagnosis of Adrenal Insufficiency

The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary and, hence, dependent or independent of ACTH deficiency, and detecting the cause of the disorder.

  • Basal morning serum cortisol concentrations – The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (06:00h – 08:00h), ranging between 10 – 20 mcg/dL (275 – 555 nmol/L) than at other times of the day. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency, while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. Simultaneous measurements of cortisol and ACTH concentrations confirm in most cases the diagnosis of primary adrenal insufficiency.
  • Morning salivary cortisol concentrations – Adrenal insufficiency is excluded when salivary cortisol concentration at 08:00his higher than 5.8 ng/mL (16 nmol/L), whereas the diagnosis, is more possible for values lower than 1.8 ng/mL (5 nmol/L).
  • Urinary free cortisol (UFC) – Basal urinary cortisol and 17-hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may below-normal in patients with partial adrenal insufficiency. Generally, baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency.
  • Basal plasma ACTH, renin, and aldosterone concentrations – Basal plasma ACTH concentration at 08:00h, when determined simultaneously with the measurement of basal serum cortisol concentration, may both confirm the diagnosis of adrenal insufficiency and establish the cause. The normal values of basal 08:00h plasma ACTH concentrations range between 20-52 pg/mL (4.5-12 pmol/L). In primary adrenal insufficiency, the 08:00h plasma ACTH concentration is elevated and is coupled with increased concentration or activity of plasma renin, low aldosterone concentrations, hyperkalemia and hyponatremia. In the cases of secondary or tertiary adrenal insufficiency, plasma ACTH concentrations are low or low normal, associated with normal values of plasma concentrations of renin and aldosterone.
  • Standard dose ACTH stimulation test – Adrenal insufficiency is usually diagnosed by the standard-dose ACTH test, which determines the ability of the adrenal glands to respond to 250 mcg intravenous or intramuscular administration of ACTH(1-24) by measurement of serum cortisol concentrations at 0, 30 and 60 min following stimulation. The test is defined as normal if peak cortisol concentration is higher than 18–20 mcg/dL (500–550 nmol/L), thereby excluding the diagnosis of primary adrenal insufficiency and almost all cases of secondary adrenal insufficiency. However, if secondary adrenal insufficiency is of recent onset, the adrenal glands will have not yet atrophied, and will still be capable of responding to ACTH stimulation normally. In these cases, a low-dose ACTH stimulation test or an insulin-induced hypoglycemia test may be required to confirm the diagnosis.
  • Low-Dose ACTH stimulation test This test theoretically provides a more sensitive index of adrenocortical responsiveness because it results in physiologic plasma ACTH concentrations. This test should be performed at 14:00h when the endogenous secretion of ACTH is at its lowest. The results might not be valid if it is performed at another time. At 14:00h, a blood sample is collected for the determination of basal cortisol concentrations. The low dose of ACTH(1-24) (500 nanograms ACTH(1-24)/1.73 m2 ) is then administered as an intravenous bolus. In normal subjects, this dose results in a peak plasma ACTH concentration about twice that of insulin-induced hypoglycemia. Subsequently, blood samples are collected at +10 min, +15 min, +20 min, +25 min, +30 min, +35 min, +40 min, and +45 min after stimulation for determination of serum cortisol concentrations. A value of 18 µg/dL (500 nmol/L) or more at any time during the test is indicative of normal adrenal function. The advantage of this test is that it can detect partial adrenal insufficiency that may be missed by the standard-dose test. The low-dose test is also preferred in patients with secondary or tertiary adrenal insufficiency.
  • Prolonged ACTH Stimulation Tests – Prolonged stimulation with exogenous administration of ACTH helps differentiate between primary and secondary or tertiary adrenal insufficiency. In secondary or tertiary adrenal insufficiency, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH, whereas in primary adrenal insufficiency, the adrenal glands are partially or completely destroyed and do not respond to ACTH. The prolonged ACTH test consists of the intravenous administration of 250 μg of ACTH as an infusion over eight hours (8-hour test) or over 24 hours on two (or three) consecutive days (two-day test), and the measurement of serum cortisol, and 24-hour urinary cortisol and 17-hydroxycorticoid (17-OHCS) concentrations before and after the infusion.
  • Insulin-induced hypoglycemia test – This test provides an alternative choice for confirmation of the diagnosis when secondary adrenal insufficiency is suspected. The insulin tolerance test helps in the investigation of the integrity of the HPA axis and has the ability to assess growth hormone reserve. Insulin, at a dose of 0.1-0.15 U/kg, is administered to induce hypoglycemia, and measurements of cortisol concentrations are determined at 30 min intervals for at least 120 min. This test is contraindicated in patients with cardiovascular disease or a history of seizures and requires a high degree of supervision.
  • Corticotropin-releasing hormone (CRH) test – This test is used to differentiate between secondary and tertiary adrenal insufficiency. It consists of intravenous administration of CRH (1 mcg/kg up to a maximum of 100 mcg) and determination of serum cortisol and plasma ACTH concentrations at 0, 15, 30, 45, 60, 90, and 120 min following stimulation. Patients with secondary adrenal insufficiency demonstrate little or no ACTH response, whereas patients with tertiary adrenal insufficiency show an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response.
  • Autoantibody screen – Adrenocortical antibodies or antibodies against 21-hydroxylase can be detected in more than 90% of patients with recent-onset autoimmune adrenalitis. Furthermore, antibodies that react against other enzymes involved in steroidogenesis and anti-steroid-producing cell antibodies are present in some patients.
  • Very long-chain fatty acids – To exclude adrenoleukodystrophy, plasma very-long-chain fatty acids should be determined in male patients with isolated Addison’s disease and negative autoantibodies.
  • Imaging – Patients without any associated autoimmune disease and negative autoantibody screen should undergo computed tomography (CT) scan of the adrenal glands. In cases of tuberculous adrenalitis, the CT scan shows initially hyperplasia of the adrenal glands and subsequently spotty calcifications during the late stages of the disease. Bilateral adrenal lymphoma, adrenal metastases or adrenal infiltration (sarcoidosis, amyloidosis, hemochromatosis) may also be detected by CT scan. If central adrenal insufficiency is suspected, a magnetic resonance imaging (MRI) scan of the hypothalamus and pituitary gland should be performed. This may detect any potential disease process, such as craniopharyngiomas, pituitary adenomas, meningiomas, metastases, and infiltration by Langerhans cell histiocytosis, sarcoidosis, or other granulomatous diseases. It should be noted that imaging is not required when adrenal cortex autoantibodies are detected.
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Treatment of Adrenal Insufficiency

Treatment of Chronic Primary Adrenal Insufficiency

1. Glucocorticoid replacement (one of the given regimens)

  • Hydrocortisone 15 to 25 mg orally in two or three divided doses (the largest dose is taken early in the  morning; typically 10 mg upon awakening in the morning, 5 mg early afternoon, 2.5 mg late afternoon), or
  • Prednisone 5 mg (2.5 to 7.5 mg) orally at bedtime, or
  • Dexamethasone 0.75 mg (0.25 to 0.75 mg) orally at bedtime
  • Monitor clinical symptoms and morning plasma ACTH as needed.

2. Mineralocorticoid replacement

  • Fludrocortisone 0.1 mg (range: 0.05 to 0.2 mg) orally. Hydrocortisone 20 mg and prednisone 50 mg provide a mineralocorticoid effect that is almost equivalent to 0.1 mg of fludrocortisone. Therefore, fludrocortisone replacement (if needed) must be decreased accordingly. Dexamethasone, however, lacks a mineralocorticoid effect and would require a full dose of fludrocortisone.
  • Liberal salt intake.
  • Monitor supine and standing blood pressure as well as pulse, edema, serum potassium, and plasma renin activity

3. Androgen replacement

  • Dehydroepiandrosterone (DHEA) initially 25 to 50 mg orally (only in women for psychological well-being, if needed, after optimal glucocorticoid and mineralocorticoid replacement).

4. Patient education

  • Educate the patient about the illness, how to manage stresses, and inject dexamethasone or other glucocorticoids intramuscularly or subcutaneously.

5. Emergency precautions

  • Patients should have a medical alert bracelet/necklace, an emergency medical information card on their phone or inside their wallet, and prefilled syringes containing 4 mg of dexamethasone 1 mL saline.

6. Treatment of minor febrile illness or stress

  • Increase glucocorticoid dose two to three times for the few days of illness. Do not change the mineralocorticoid dose (3×3 rule).
  • The patient should contact the clinician if the condition worsens or persists for more than three days.
  • No extra dose is required for most uncomplicated, outpatient dental procedures under local anesthesia.
  • Glucocorticoid supplement for surgical stress:
  • Minor: hydrocortisone 25 mg IV (or equivalent) on the day of the procedure
  • Moderate: hydrocortisone 50 to 75 mg IV (or equivalent) on day of surgery and postoperative day 1
  • Major: hydrocortisone 100 to 150 mg IV (or equivalent) in two or three divided doses on the day of surgery and postoperative days 1 and 2

7. Emergency treatment of severe stress or trauma

  • Each patient should have an injectable as well as vials of sterile 0.9% normal saline and syringes.

Treatment of Adrenal Crisis

Measures to stabilize the patient

  • Intravenous access with one or two large-gauge needles
  • Laboratory analysis, including serum electrolytes, glucose, and routine measurement of plasma cortisol and ACTH.
  • Infusion of 2 to 3 liters of isotonic saline or 5% dextrose in isotonic saline as urgently as possible. Periodic hemodynamic monitoring and measurement of serum electrolytes.
  • Give hydrocortisone (100 mg intravenous bolus), followed by 50 mg intravenously every 6 hours (or 200 mg/24 hours as a continuous intravenous infusion for the first 24 hours). If hydrocortisone is unavailable, alternatives include prednisolone, prednisone, and dexamethasone.
  • Correct any ongoing electrolyte abnormalities. Hyponatremia is often corrected by cortisol and volume repletion.

Subacute measures after stabilization of the patient

  • Intravenous isotonic saline infusion at a slower rate for the next 24 to 48 hours.
  • Diagnosis and treatment of possible infectious precipitating causes of the adrenal crisis.
  • If the patient does not have known adrenal insufficiency, a short ACTH stimulation test should establish the diagnosis and determine its type and cause.
  • 4. Tapering of parenteral glucocorticoid over 1 to 3 days to the oral glucocorticoid maintenance dose, if there are no ongoing contraindications.
  • Initiating mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily after stopping the saline infusion.

Treatment By specific condition

Adrenal insufficiency is one of the most life-threatening disorders. Treatment should be administered to the patients as soon as the diagnosis is established, or even sooner if an adrenal crisis occurs.

  • Treatment of Chronic Adrenal Insufficiency – One of the most important aspects of the management of chronic primary adrenal insufficiency is patient and family education. Patients should understand the reason for life-long replacement therapy, the need to increase the dose of glucocorticoid during minor or major stress, and to inject hydrocortisone, methylprednisolone, or dexamethasone in emergencies.
  • Emergency precautions – Patients should wear a medical alert (Medic 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 and should be educated about how and when to administer them.
  • Glucocorticoid replacement therapy – Patients with adrenal insufficiency should be treated with hydrocortisone, the natural glucocorticoid, or cortisone acetate if hydrocortisone is not available. The hydrocortisone daily dose is 10-12 mg per meter square body surface area and can be administered in two to three divided doses with one-half to two-thirds of the total daily dose being given in the morning. Small reductions of bone mineral density (BMD) probably due to higher than recommended doses, as well as impaired quality of life were observed in patients treated with hydrocortisone. A longer-acting synthetic glucocorticoid, such as prednisone, prednisolone, or dexamethasone, should be avoided because their longer duration of action may produce manifestations of chronic glucocorticoid excess, such as loss of lean body mass and bone density, and gain of visceral fat. Recently, preparations of hydrocortisone that lead to both delayed and sustained release of this compound have been developed and are under clinical investigation. These formulations maintain stable cortisol concentrations during 24 hours and physiologic circadian rhythmicity with the cortisol peak occurring during the early morning after oral intake of the preparation at bedtime. Furthermore, a novel once-daily (OD) dual-release hydrocortisone tablet has been developed to maintain more physiologic circadian-based serum cortisol concentrations. Compared to the conventional treatment, the OD dual-release hydrocortisone improved glucose metabolism, cardiovascular risk factors, and quality of life. Regardless of the type of formulation used, glucocorticoid replacement should be monitored clinically, evaluating weight gain/loss, arterial blood pressure, annualized growth velocity, and presence of Cushing features.
  • Glucocorticoid replacement during minor illness or surgery – During minor illness or surgical procedures, glucocorticoids should be given at a dosage up to three times the usual maintenance dosage for up to three days. Depending on the nature and severity of the illness, additional treatment may be required.
  • Glucocorticoid replacement during major illness or surgery – During major illness or surgery, high doses of glucocorticoid analogs (10 times the daily production rate) are required to avoid an adrenal crisis. A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone eliminates the possibility of glucocorticoid deficiency. This dose can be halved on the second postoperative day, and the maintenance dose can be resumed on the third postoperative day.
  • Mineralocorticoid replacement therapy – Mineralocorticoid replacement therapy is required to prevent intravascular volume depletion, hyponatremia, and hyperkalemia. For these purposes, fludrocortisone (9-alpha-fluorohydrocortisone) in a dose of 0.05 – 0.2 mg daily should be taken in the morning. The dose of fludrocortisone is titrated individually based on the findings of clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma renin activity. Patients receiving prednisone or dexamethasone may require higher doses of fludrocortisone to lower their plasma renin activity to the upper normal range, while patients receiving hydrocortisone, which has some mineralocorticoid activity, may require lower doses. The mineralocorticoid dose may have to be increased in the summer, particularly if patients are exposed to temperatures above 29ºC (85ºF). If patients receiving mineralocorticoid replacement develop hypertension, the dose of fludrocortisone should be reduced accordingly. In case of uncontrolled blood pressure, patients should be encouraged to continue fludrocortisone and initiate antihypertensive therapy, such as angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or dihydropyridine calcium blockers.
  • Androgen replacement – In women, the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Treatment with DHEA enhances mood and general well-being both in adult patients and in children and adolescents with adrenal insufficiency. A single oral morning dose of DHEA of 25-50 mg may be sufficient to maintain normal serum androgen concentrations in premenopausal women with primary adrenal insufficiency, who present with decreased libido, anxiety, depression, and low energy levels. If symptoms are still present during a period of 6 months, patients are advised to discontinue DHEA replacement. Naturally, women should be encouraged to report any side effects of androgen therapy. Finally, DHEA replacement should be monitored by determining serum DHEA concentrations in the morning before the patient receives her daily DHEA dose.
  • Treatment of adrenal crisis – The aim of initial management in an adrenal crisis is to treat hypotension, hyponatremia, and hyperkalemia, and to reverse glucocorticoid deficiency. Treatment should be started with immediate administration of 100 mg hydrocortisone i.v. and rapid rehydration with normal saline infusion under continuous cardiac monitoring, followed by 100–200 mg hydrocortisone in glucose 5% per 24-hour continuous iv infusion; alternatively, hydrocortisone could be administered iv or im at a dose of 50-100 mg every 6 hours depending on body surface area and age. With daily hydrocortisone doses of 50 mg or more, mineralocorticoids in patients with primary adrenal insufficiency can be discontinued or reduced because this dose is equivalent to 0.1 mg fludrocortisone. Once the patient’s condition is stable and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose. Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement therapy.
  • Treatment of chronic secondary and tertiary adrenal insufficiency – In chronic secondary or tertiary adrenal insufficiency, glucocorticoid replacement is similar to that in primary adrenal insufficiency, however, measurement of plasma ACTH concentrations cannot be used to titrate the optimal glucocorticoid dose. Mineralocorticoid replacement is rarely required, while replacement of other anterior pituitary deficits might be necessary.
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References

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