The essence in brief:
Adrenal insufficiency can be categorized as primary, secondary, or tertiary, depending on its underlying cause.
Primary adrenal insufficiency involves decreased production of corticosteroids, including cortisol and often aldosterone, from the adrenal gland. It is commonly due to genetic factors in childhood and autoimmune processes in adulthood.
Secondary adrenal insufficiency results from reduced stimulation of the adrenal glands by ACTH from the pituitary gland.
Tertiary adrenal insufficiency occurs when the pituitary fails to release sufficient ACTH due to inadequate stimulation by CRH.
Prolonged use of corticosteroids at dosages above a certain threshold can suppress the pituitary-adrenal hormone axis and cause secondary or tertiary adrenal insufficiency.
Corticosteroid treatment, used for various conditions, must be tapered gradually to allow the adrenal gland’s feedback loop to recover.
Symptoms of adrenal insufficiency are nonspecific and may include fatigue, nausea, weight loss, low blood pressure, salt cravings, and skin pigmentation changes.
Stress or illness can precipitate an adrenal crisis in individuals with adrenal insufficiency.
Primary adrenal insufficiency is characterized by reduced production of corticosteroids, resulting in low sodium and often high potassium levels.
Laboratory tests include assessing basal cortisol and aldosterone levels, ACTH, and renin levels.
A ACTH test is performed if primary adrenal insufficiency is suspected, with cortisol levels below 18 µg/dL after 30 or 60 minutes indicating insufficiency.
DHEA levels can help differentiate adrenal insufficiency in some cases, with low levels suggesting a likelihood of the condition.
Secondary or tertiary adrenal insufficiency is assessed by checking basal ACTH levels and conducting a CRH test, where ACTH and cortisol responses are evaluated.
The gold standard for excluding secondary adrenal insufficiency is the insulin hypoglycemia test, which measures ACTH and cortisol responses to insulin-induced hypoglycemia.
Treatment for adrenal insufficiency typically involves the use of hydrocortisone.
The hydrocortisone dose needs to be adjusted to account for the body’s circadian rhythm, with higher doses in the morning.
Individualized dosing based on patient history and clinical symptoms is crucial, as laboratory values are not always reliable for dose adjustments.
The evening dose of hydrocortisone should not be skipped to prevent nighttime cortisol deficiency.
For patients with mineralocorticoid deficiency, fludrocortisone may also be prescribed to maintain electrolyte balance.
In the event of an adrenal crisis, immediate administration of high-dose corticosteroids is necessary, preferably intravenously, followed by a continuous infusion.
Patients should carry an emergency card outlining crisis management and perioperative care.
Proper preparation for travel, where parenteral administration may not be feasible, is important for patients with adrenal insufficiency.
In primary adrenal insufficiency, there is a reduced production of corticosteroids from the adrenal gland. Apart from cortisol, the mineralocorticoid aldosterone is often inadequately released.
In childhood, a genetic cause is often present, while in adolescence and adulthood, the cause of adrenal insufficiency is typically an autoimmune process.
Secondary adrenal insufficiency results from reduced stimulation of the adrenal glands by ACTH from the pituitary gland (see pituitary insufficiency). If the pituitary fails to release sufficient ACTH due to inadequate stimulation by CRH, it constitutes tertiary adrenal insufficiency.
Another common cause of secondary/tertiary adrenal insufficiency is the suppression of the pituitary-adrenal hormone axis due to prolonged administration of corticosteroids in dosages above the so-called Cushing threshold. Corticosteroids vary in potency, and their equivalent doses can be found in the following table.
Corticosteroid treatment is used, for example, in rheumatic diseases or during pituitary surgeries. The feedback loop requires some time to recover and stimulate the adrenal gland to produce cortisol again. Corticosteroid treatment should be gradually reduced to allow the feedback loop to recover. A practical approach is to halve the corticosteroid dose each week. To assess recovery, a CRH test can be performed at lower doses, such as 10 mg of hydrocortisone or 2.5 mg of prednisolone, without taking the morning dose of corticosteroid. Corticosteroid treatment continues until the results are available. If the feedback loop is intact, corticosteroid therapy can then be discontinued.
When corticosteroids are given at high doses for a short period (less than one week), tapering off is not necessary.
Symptoms:
The clinical symptoms of adrenal insufficiency in both children and adults are nonspecific, often leading to delayed diagnosis and the risk of an adrenal crisis.
Typical symptoms include:
Fatigue
Decreased performance
Nausea and vomiting
Abdominal and muscle pain
Weight loss
Hypoglycemia (low blood sugar)
Low blood pressure (hypotension) with dizziness and tachycardia
Increased craving for salt
Enhanced skin pigmentation in mucous membranes, palm lines, and areas not exposed to the sun
In newborns, additional clinical signs include cholestasis and jaundice, and affected children experience developmental delays.
During stressful situations or illnesses with fever, adrenal insufficiency can lead to an adrenal crisis.
Laboratory Tests:
A reduced sodium level is a typical laboratory finding in primary adrenal insufficiency. When sodium is low, adrenal insufficiency should always be considered. Approximately 50% of patients with adrenal insufficiency have elevated potassium levels. Basal cortisol and aldosterone levels are inappropriately low, accompanied by significantly elevated ACTH (greater than twice the upper reference value) and increased renin levels. Due to circadian rhythms, hormone levels should be measured in the morning between eight and nine. If these laboratory results raise suspicion of primary adrenal insufficiency, an ACTH test is performed. Cortisol levels below 18 µg/dL (500 nanomol/L) after 30 or 60 minutes indicate adrenal insufficiency.
The production of DHEA is also dependent on ACTH. A normal DHEA level makes adrenal insufficiency unlikely. Women with DHEA deficiency may experience reduced drive, loss of libido, dry skin, and dry mucous membranes.
If basal ACTH is low, there is suspicion of secondary or tertiary adrenal insufficiency. To further investigate, a CRH test is conducted.
During the CRH test, 100 µg of CRH (Corticotropin-Releasing Hormone) is injected intravenously. Blood samples are taken at time 0, 30, and 60, measuring ACTH and cortisol. Cortisol should increase by at least 7.2 µg/L, and ACTH should rise by at least 50% from the baseline value. If this increase occurs, insufficiency of the corticotropin axis is ruled out.
The gold standard for excluding secondary adrenal insufficiency is an insulin hypoglycemia test. In addition to assessing ACTH and cortisol production, this test can also evaluate the adequate production of growth hormone.
Test Procedure: The patient must be fasting, and a venous access must be established. For emergencies, 40% glucose solution (2 x 20 ml) should be readily available. Blood samples are taken at time 0, measuring blood sugar, ACTH, and cortisol.
Then, 0.1 IU/kg of insulin is administered. In obese patients with suspected insulin resistance, the doctor may administer a slightly higher dose, such as 0.15-0.2 IU/kg. Regular blood sugar checks are performed approximately 25 minutes after insulin administration. If hypoglycemia occurs (blood sugar <40 mg/dL) or if blood sugar drops to half the baseline value, blood is drawn to measure ACTH and cortisol (Between minute 25 and 35). Normally, blood sugar levels rise again due to counterregulation. If blood sugar levels do not rise, glucose is administered to induce an increase.
Secondary or tertiary adrenal insufficiency is ruled out if cortisol levels rise to 18-20 µg/dL or increase by >50% from the baseline value. Plasma ACTH should rise to >150 pg/mL.
The normal hydrocortisone requirement is approximately 10 mg of hydrocortisone per day. However, at such a low substitution therapy dosage, there is a risk of an adrenal crisis during stressful situations. Therefore, the hydrocortisone dose must be increased. Additionally, the hydrocortisone dose should be adjusted to the circadian rhythm of the body’s needs. Cortisol demand is highest in the morning hours. A typical adjustment schedule would be:
Hydrocortisone: 15-10-5 mg/day
The dose must be individually tailored to the patient. Adjustments should be based on patient history and clinical symptoms, as laboratory values are not suitable for this purpose. The evening dose should not be omitted because the half-life of hydrocortisone is too short. Patients who skip the evening dose may experience unnoticed cortisol deficiency during the night, leading to poor sleep quality. Waking up in the morning can be stressful, and there is an increased risk of a morning adrenal crisis.
Hydrocortisone is also available in extended-release form, allowing for a single dose of 20 mg. However, the extended-release form is associated with significantly higher costs.
Every patient with adrenal insufficiency should carry an emergency card that outlines the management of an adrenal crisis and perioperative care.
If adrenal insufficiency also affects the mineralocorticoid aldosterone, additional substitution with fludrocortisone at a dose of ½-2 milligrams in the morning is necessary. The dose of fludrocortisone is adjusted to maintain normal levels of sodium, potassium, and renin.
In unclear emergency situations, such as unconsciousness, the immediate administration of a high-dose corticosteroid is necessary. If the patient responds positively, it can be assumed that an adrenal crisis occurred. Preferably, corticosteroids should be given parenterally as an IV bolus or short infusion (100 mg of hydrocortisone). Subsequently, a continuous infusion of 100-300 mg over 24 hours, depending on the clinical situation, should be administered. If hydrocortisone is not available, any other corticosteroid can be used. If parenteral administration is not possible, a suppository can be administered (e.g., prednisolone 100 mg). Patients should be equipped accordingly before traveling if parenteral administration is not feasible.
Reference: Bornstein SR et al.: www.endocrine.org/guidelines-and-clinical-practice/clinical-practiceguidelines/primary-adrenal-insufficiency