Definition of the disease. Causes of the disease
Adrenal insufficiency, or hypocorticism, is a severe endocrine disorder characterized by insufficient production of hormones by the adrenal cortex. It develops gradually over many months or even years, deteriorating health, masquerading as chronic fatigue syndrome and other serious illnesses, significantly complicating its diagnosis.
The adrenal glands are endocrine glands. Their inner (medullary) part produces adrenaline hormone, which mobilizes all the body’s defense mechanisms. The outer part of the adrenal glands – the cortex – produces corticosteroids:
• Cortisol – regulates energy reserves in the body (glucose, proteins, fats), helps the body cope with stress and infections, provides strength and energy;
• Aldosterone – controls the balance of water, potassium, and sodium in the body, necessary for the proper functioning of the heart, kidneys, and other organs, maintains normal blood pressure;
• Androgens – influence sexual development, libido, metabolism, mood, memory, thinking (ability to concentrate and maintain attention, achieve goals, tendency to conflicts and irritability), determine body structure, muscle strength, and bone density.
Depending on the level of involvement, primary insufficiency (Addison’s disease), in which the adrenal gland itself is affected, as well as secondary and tertiary, in which the control of adrenal function through the pituitary and hypothalamus is impaired, are distinguished.
Causes of primary adrenal insufficiency:
- Developmental disorders of the adrenal glands:
• Congenital adrenal hypoplasia (underdevelopment) – a rare genetic condition that occurs in boys; manifests as primary adrenal insufficiency and secondary hypogonadism – disruption of sexual development;
• ACTH resistance syndrome – receptor insensitivity to ACTH; manifested by at least three diseases: familial glucocorticoid deficiency of the first and second types, as well as Ogilvie syndrome. - Destruction of the adrenal glands (destruction):
• Autoimmune destruction of the adrenal cortex – accounts for 85% of all cases of destruction; often combined with damage to other endocrine glands and non-endocrine organs (autoimmune polyglandular syndromes);
• Bacterial, viral, and fungal infections – tuberculosis, blastomycosis, histoplasmosis, meningococcal infection, HIV infection, syphilis, sepsis;
• Hemorrhage into the adrenal glands;
• Metastatic involvement of the adrenal glands – more common in lung cancer and breast cancer;
• Complications after adrenal gland removal due to Cushing’s disease and other conditions, as well as the use of various medications: anticoagulants, adrenal steroidogenesis blockers (aminoglutethimide, mitotane, ketoconazole), barbiturates, spironolactone;
• Amyloidosis – a condition in which amyloid (a complex protein-polysaccharide complex) is deposited in tissues; leads to atrophy, sclerosis, and insufficiency of various organs, including the adrenal glands;
• Hemochromatosis – a genetic disease accompanied by iron metabolism disorder, which accumulates in excess in the liver, heart, pancreas, and pituitary gland;
• Adrenoleukodystrophy – a rare genetic disease caused by a mutation in the ALD gene; leads to adrenal insufficiency, hypogonadism (sexual development disorder), and progressive demyelination of white matter in the brain and spinal cord. - Steroidogenesis disorders (steroid formation disorders):
• Disorders of cholesterol biosynthesis – Smith-Lemli-Opitz syndrome;
• Congenital adrenal cortex dysfunction;
• Mitochondrial diseases .
Causes of secondary and tertiary adrenal insufficiency: - Congenital secondary hypocorticism.
- Destruction of hypothalamic-pituitary structures:
• Pituitary and hypothalamic tumors – craniopharyngiomas, germinomas, etc.;
• Head trauma;
• Infiltrative-granulomatous processes in the area of the pituitary gland (syphilis, sarcoidosis) or infectious damage;
• Surgeries, such as pituitary tumor removal;
• Head irradiation (pituitary and hypothalamus);
• Vascular diseases – aneurysm of the carotid artery, hemorrhage into the pituitary gland. - Complications due to prolonged treatment of various diseases with glucocorticoids and their abrupt withdrawal
Hypocorticism can develop at any age. Primary insufficiency is detected annually in approximately 4 cases per 100 thousand population.
The most common cause of acute adrenal cortex insufficiency in newborns is hemorrhage into the adrenal glands due to hypoxia or sepsis. In cases of adrenal gland developmental disorders, all forms of steroidogenesis disorders, and pseudoaldosteronism, symptoms of the disease appear shortly after birth. They are associated with salt loss, i.e., a lack of mineralocorticoids. In this case, newborns experience uncontrollable vomiting, rapid weight loss, dehydration, which can lead to vascular collapse – a sudden drop in blood pressure .
In the neonatal period and in early childhood, various forms of congenital adrenal cortex dysfunction in children of both sexes and congenital adrenal hypoplasia in boys occupy the first place among the causes of hypocorticism. In older children, as well as in adults, the most common causes are autoimmune polyglandular syndrome and adrenoleukodystrophy. With age, the proportion of autoimmune, infectious, and metastatic adrenal gland damage increases .
In older children, the main trigger for adrenal insufficiency is adrenal gland destruction. Symptoms appear with significant destruction of glandular tissue (only after destruction of more than 90% of all cells) and are practically indistinguishable from manifestations of the disease in adults.
Symptoms of adrenal insufficiency
Some symptoms of insufficiency are masked by chronic fatigue syndrome: unexplained fatigue, lack of alertness in the morning. A person starts to tolerate physical exertion worse, feeling better when lying down. Asthenia is accompanied by irritability, impatience, and memory problems.
Due to regulatory disruption and increased melanin synthesis, hyperpigmentation occurs—areas of the skin and mucous membranes darken. This occurs in areas of skin friction, skin folds, in postoperative scars, around the areolas of the breasts, anal opening, and on the oral mucosa.
- The functioning of the gastrointestinal tract is disrupted: appetite decreases to the point of complete absence, nausea, vomiting, and abdominal pain occur. Decreased body weight is associated with worsened appetite, intestinal absorption disorders, and dehydration.
- Decreased blood pressure is accompanied by dizziness and fainting. In people with hypertension, blood pressure may be normal or elevated.
- Hypoglycemia – low blood glucose levels – is accompanied by hunger, muscle weakness, sweating, and pre-fainting conditions. It is more common when a person is hungry, i.e., on an empty stomach.
- In women with adrenal androgen deficiency, libido decreases, and hair growth in the armpit becomes sparse.
- Reduced glucocorticoid production negatively affects the immune system, so patients experience reduced immunity and high susceptibility to infectious diseases.
- Symptoms of secondary and tertiary hypocorticism differ from primary with the absence of hyperpigmentation (as ACTH levels are always low) and symptoms of salt loss (as there is no mineralocorticoid deficiency).
- In stressful situations, acute infections, or surgeries, the body’s need for adrenal cortex hormones significantly increases, so in such cases, the condition can deteriorate significantly due to decompensation of adrenal insufficiency—a life-threatening condition where the body’s adaptation mechanisms are exhausted. Attention is drawn to unusually rapid fatigue and excessive tiredness, dizziness, very low blood pressure, craving for salty foods, poor appetite, nausea, vomiting, diarrhea, abdominal pain, muscle weakness, unexplained weight loss, and mood swings.
Pathogenesis of adrenal insufficiency
As a result of processes that destroy the adrenal cortex, the formation of glucocorticoids, mineralocorticoids, and androgens is disrupted, gradually leading to hormone deficiency and the appearance of disease symptoms.
Glucocorticoids and mineralocorticoids participate in protein, carbohydrate, fat, and water-electrolyte metabolism. Therefore, their deficiency disrupts these processes and decreases arterial pressure.
Cortisol is involved in carbohydrate metabolism and acts as an antagonist to insulin. With its deficiency, glycogen production in the liver decreases, as well as glucose synthesis. Peripheral tissues become more sensitive to insulin, leading to decreased blood glucose levels and the development of hypoglycemia.
Aldosterone deficiency – a natural mineralocorticoid – causes severe cardiovascular disorders due to decreased reabsorption of Na+ in the kidneys. This leads to decreased blood volume and arterial pressure, sometimes progressing to shock. Elevated potassium levels disrupt heart rhythm and lead to myopathies, diseases characterized by muscle weakness. Reduced Na+ reabsorption in the intestines results in a cascade of digestive symptoms, such as abdominal pain and impaired absorption.
Deficiency of adrenal androgens intensifies the breakdown of complex substances in the body and increases the level of residual nitrogen.
In primary hypocorticism, due to low cortisol levels, the level of corticotropin-releasing hormone, ACTH, and other derivatives of proopiomelanocortin increases, affecting the pituitary gland’s function. Elevated levels of ACTH, alpha-MSH, and gamma-MSH (melanocyte-stimulating hormone), acting on melanocortin receptors of melanocytes (pigment cells), enhance melanin production, resulting in darkening of the skin and mucous membranes.
Differences between central forms of hypocorticism and primary:
- Absence of mineralocorticoid deficiency, as the regulation of aldosterone production is controlled by the renin-angiotensin system, which regulates arterial pressure, and is only minimally dependent on ACTH.
- Absence of hyperpigmentation due to decreased levels of ACTH and other derivatives of proopiomelanocortin.
Classification and stages of development of adrenal insufficiency:
Depending on the level of involvement of the hypothalamic-pituitary-adrenal system, three types of adrenal insufficiency are distinguished:
- Primary: associated with damage to the adrenal cortex.
- Secondary: caused by decreased production of ACTH by the pituitary gland.
- Tertiary: associated with impaired production of corticotropin-releasing hormone or other factors that stimulate ACTH synthesis.
Two types of adrenal insufficiency are identified based on the clinical course:
- Acute insufficiency: develops rapidly, for example, in cases of bilateral adrenal hemorrhage in sepsis, severe trauma, hemorrhagic shock, fulminant liver failure, or the terminal stage of chronic liver failure.
- Chronic insufficiency: Addisonian crisis is a complication of the chronic course of the disease.
Depending on the effectiveness of treatment, chronic adrenal insufficiency is divided into three phases: decompensation, subcompensation, and compensation.
In substitution hormone therapy for primary chronic hypocorticism, the treating physician adjusts the dose of glucocorticoids to compensate for the deficient hormones, ensuring that hormone levels remain strictly within the normal range – neither lower nor higher.
If medications completely compensate for the deficiency and do not result in hormone excess in the body, the patient feels much better. This indicates that the disease is not cured once and for all since it is chronic but is in the compensation phase.
During stress or acute illnesses, i.e., in situations of increased need for glucocorticoids, the selected dose may not be sufficient. Since there are no reliable laboratory criteria for the effectiveness of treatment, the treating physician usually advises the patient to monitor their blood pressure, pay special attention to their well-being, and the presence of symptoms such as weakness, unexplained fatigue, nausea, dizziness, low blood pressure, fainting, and abdominal pain. The appearance of these symptoms may indicate the transition of the disease from the compensation phase to the subcompensation phase (mild, just beginning hormone deficiency) or decompensation phase (severe glucocorticoid deficiency), which is dangerous due to the development of an Addisonian crisis.
Complications of adrenal insufficiency:
If the diagnosis is not made in a timely manner and treatment is not initiated, a person with chronic hypocorticism may develop an Addisonian crisis, which can manifest itself in a stressful situation.
An Addisonian crisis is a life-threatening condition that develops due to a rapid or sharp decrease in the functional reserves of the adrenal cortex, leading to decreased production of glucocorticoids and mineralocorticoids.
The first symptoms of the crisis and acute insufficiency in general are nausea, vomiting, diarrhea, abdominal pain, low blood pressure, severe weakness, dizziness, fainting, and seizures. Dehydration and shock develop rapidly, leading to disruption of vital functions of the cardiovascular, respiratory, and nervous systems.
There are no specific symptoms of acute insufficiency. It can mimic other diseases:
- Gastrointestinal infection.
- Acute surgical abdominal conditions (abdominal pain).
- Acute cardiovascular insufficiency (arterial hypotension, collapse, tachycardia).
- Central nervous system involvement (seizures, meningeal syndrome, focal neurological symptoms, delirium, hallucinations, altered consciousness).
Salt-losing crises can develop in patients already diagnosed with adrenal insufficiency despite treatment with glucocorticoids and mineralocorticoids. This occurs when there is any acute condition (injury, infection, myocardial infarction, etc.), emotional stress, surgery, or the use of medications that accelerate cortisol metabolism (L-thyroxine, barbiturates). It is necessary to increase the dose of glucocorticoids in such situations; failure to do so may lead to the development of a crisis.
Patients should regularly take adequate doses of glucocorticoid and mineralocorticoid medications as prescribed by their doctor and independently increase their dosages during any stressful situations. If there is a deterioration in well-being, it is essential to call emergency medical services and switch to intramuscular or intravenous administration of glucocorticoids in a hospital setting.
Diagnosis of adrenal insufficiency involves:
- Clinical assessment of symptoms and medical history.
- Evaluation of adrenal cortex function and other endocrine gland status.
- Measurement of sodium, potassium, glucose levels in the blood, as well as aldosterone and renin levels in plasma.
- Determination of hormone levels: Elevated ACTH levels and low cortisol levels in blood and urine indicate adrenal insufficiency.
- Utilization of stimulating tests for a more accurate assessment of adrenal cortex function.
- For primary insufficiency, a short-acting ACTH stimulation test is recommended.
- Diagnosis of adrenal tuberculosis includes examination for the presence of tuberculosis lesions or calcifications in the adrenal glands, conducted by a pulmonologist.
- Detection of organ-specific autoantibodies in the blood serum indicates autoimmune adrenal damage.
- Secondary insufficiency requires ophthalmological examination and MRI of the brain to exclude tumors in the pituitary or hypothalamus.
Treatment of adrenal insufficiency
Treatment of adrenal insufficiency is crucial and aims to address the underlying cause of adrenal damage while replacing deficient hormones and electrolytes.
- For tuberculosis of the adrenal glands, antitubercular drugs are prescribed by a pulmonologist.
- In medication-induced adrenal insufficiency, the dosage of the causative medication is reduced.
- Tumors in the pituitary or hypothalamus causing adrenal insufficiency may require surgical intervention, radiation therapy, or a combination of both. However, surgery alone does not address the hormonal deficiency, necessitating hormone replacement therapy.
- Endocrinologists specialize in adrenal disorders, and patients should prepare questions before appointments to better understand their condition and treatment options.
- Cortisol replacement therapy typically involves medications such as hydrocortisone (Cortef), cortisone acetate, and prednisolone. Fludrocortisone (Florinef) may be used to replace aldosterone. These medications act for 6-12 hours, requiring multiple daily doses as prescribed by a physician. Hydrocortisone should generally be avoided before bedtime to prevent insomnia.
- It’s crucial to take medications at specific times each day to prevent dangerous lapses. If a dose is missed, it should be taken as soon as possible, or the next dose may be doubled.
- During certain situations like illness, stress, or surgery, hydrocortisone dosage may need to be temporarily increased by 2-3 times, gradually tapering back to the usual dose over 1-3 days.
- The effectiveness of hormone replacement therapy is assessed by the resolution of symptoms such as weakness, fatigue, nausea, and low blood pressure. There are no definitive laboratory criteria for confirming the efficacy of treatment.