Primary chronic adrenocortical insufficiency, also known as Addison's disease, results from significant destruction of both adrenal glands, leading to insufficient secretion of glucocorticoids and mineralocorticoids. Secondary adrenocortical insufficiency arises due to hypothalamic or pituitary dysfunction, leaving mineralocorticoid secretion unaffected.
Etiology
Infections
Adrenal tuberculosis is a common cause and is often associated with tuberculosis lesions in other organs such as the lungs, kidneys, or intestines. The adrenal glands are replaced by epithelioid granulomas and caseous necrotic lesions, which later undergo fibrosis, often accompanied by adrenal calcification. The pathological process of adrenal fungal infections is similar to that of adrenal tuberculosis. In the advanced stages of AIDS, adrenocortical insufficiency may occur, often presenting asymptomatically, although some patients have notable clinical manifestations. Necrotizing adrenalitis is frequently associated with cytomegalovirus infection. Severe infections, such as meningococcal meningitis, can cause acute adrenal insufficiency. Severe sepsis, especially in children, can lead to adrenal hemorrhage accompanied by functional insufficiency.
Autoimmune Adrenalitis
Adrenal glands demonstrate bilateral cortical destruction with fibrosis, infiltration of lymphocytes, plasma cells, and monocytes, while the medulla remains unaffected. Most patients have detectable anti-adrenal autoantibodies in their blood. Nearly half of these patients also suffer from other organ-specific autoimmune diseases, a condition termed autoimmune polyendocrine syndrome (APS), which is more common in females. Isolated autoimmune adrenalitis, unassociated with other endocrine disorders, is more prevalent in males.
APS type I primarily affects children and is characterized by adrenal insufficiency, hypoparathyroidism, mucocutaneous candidiasis, and ovarian insufficiency. It follows an autosomal recessive inheritance pattern.
APS type II more commonly affects adults and primarily presents with adrenal insufficiency, autoimmune thyroid diseases, and type 1 diabetes, typically showing dominant inheritance.
Less Common Causes
Malignant metastases, lymphoma, leukemia infiltration, amyloidosis, bilateral adrenalectomy, radiation damage, long-term use of adrenal enzyme inhibitors such as metyrapone, aminoglutethimide, or ketoconazole, cytotoxic drugs like mitotane (o,p’-DDD), and vascular embolism represent less frequent etiologies of the condition.
Adrenoleukodystrophy is a congenital hereditary disorder of long-chain fatty acid metabolism, characterized by impaired β-oxidation of fatty acids. It primarily affects neural tissue and steroid hormone-secreting cells, leading to both adrenal insufficiency and hypogonadism, along with neurological complications.
Clinical Manifestations
The most characteristic feature is generalized hyperpigmentation of the skin, which is most pronounced in exposed areas, regions subject to friction, areolas, and scars. Mucosal pigmentation is apparent on the gums, tongue, and buccal mucosa, a result of elevated ACTH and melanocyte-stimulating hormone secretion from the pituitary. Additional symptoms include:
Neurological and Psychiatric Symptoms
Patients may exhibit fatigue, apathy, and easy fatigability. In severe cases, somnolence, confusion, and mental disorders may occur.
Gastrointestinal Symptoms
Reduced appetite, a craving for salt, low gastric acid secretion, and indigestion are common. Nausea, vomiting, and diarrhea may indicate worsening disease severity.
Cardiovascular Symptoms
Hypotension, reduced heart size, and muffled heart sounds are frequent findings. Symptoms may include dizziness, blurred vision, and orthostatic syncope.
Metabolic Disturbances
Impaired gluconeogenesis may result in hypoglycemia.
Renal Symptoms
Impaired ability to excrete a water load may cause dilutional hyponatremia after large fluid intake. Increased antidiuretic hormone release, resulting from glucocorticoid deficiency and reduced blood volume, also contributes to hyponatremia.
Reproductive System Symptoms
Females may experience reduced or absent axillary and pubic hair and irregular or absent menstruation, though mild cases may still permit fertility. Men often have decreased libido or sexual dysfunction.
Reduced Stress Response
Resistance to infections, trauma, and other stressors is diminished.
Coexisting Tuberculosis
Patients with active tuberculosis lesions may present with low-grade fever, diaphoresis, profound weakness, and significant weight loss.
Adrenal Crisis
An adrenal crisis represents an acute exacerbation of the disease. It is often triggered by stressors such as infections, trauma, surgery, childbirth, exhaustion, heavy sweating, vomiting, diarrhea, dehydration, or abrupt discontinuation of glucocorticoid therapy. Clinical manifestations include nausea, vomiting, abdominal pain or diarrhea, severe dehydration, hypotension, tachycardia, a weak and thready pulse, mental confusion, and psychosis. Patients may also exhibit high fever, hypoglycemia, and hyponatremia, with potassium levels either decreased or elevated. Without prompt medical intervention, the crisis may progress to shock, coma, or death.
Laboratory Examinations
Blood Biochemistry
Hyponatremia and hyperkalemia may be present. In cases of severe dehydration, hyponatremia may not be evident. Hyperkalemia is generally mild; if it is pronounced, renal insufficiency or other underlying causes should be suspected. A small number of patients may exhibit mild to moderate hypercalcemia due to the role of glucocorticoids in promoting calcium excretion through the kidneys and intestines. The presence of hypocalcemia along with hyperphosphatemia suggests coexisting hypoparathyroidism. Significant dehydration may result in azotemia. Fasting hypoglycemia may occur, and glucose tolerance tests typically show a flattened curve.
Complete Blood Count
Normocytic normochromic anemia is typically observed, and a few patients may have associated pernicious anemia. White blood cell differentiation frequently shows neutropenia, relative lymphocytosis, and a marked increase in eosinophils.
Hormonal Tests
Baseline Levels of Blood and Urinary Cortisol, and Urinary 17-Hydroxycorticosteroids
These levels are often reduced but may occasionally approach normal values.
Plasma ACTH Measurement
Plasma ACTH levels are significantly elevated, exceeding 55 pmol/L and often ranging from 88 to 440 pmol/L (normal levels are below 18 pmol/L). In secondary adrenocortical insufficiency, ACTH concentrations are reduced.
Measurements of Aldosterone and Renin
In primary adrenocortical insufficiency, blood aldosterone levels may be below normal or at the lower end of the normal spectrum, while plasma renin activity increases. In secondary adrenocortical insufficiency, both plasma renin activity and aldosterone levels remain within the normal range.
ACTH Stimulation Test
Blood cortisol levels are measured before and at 30 and 60 minutes after intravenous injection of 250 μg synthetic ACTH (1–24). A peak serum cortisol level of less than 500 nmol/L following stimulation is indicative of adrenocortical insufficiency. For patients with severe symptoms or suspected adrenal insufficiency, a combined test involving the co-administration of dexamethasone and ACTH, along with pre- and post-injection plasma cortisol measurements, may serve dual purposes of diagnosis and treatment initiation.
Imaging Studies
Patients with tuberculosis may show adrenal enlargement and calcifications on X-ray, CT, or MRI scans. Other infections, hemorrhages, and metastatic lesions may also appear as adrenal enlargement on CT scans. However, in autoimmune-related cases, the adrenal glands typically do not show enlargement.
Diagnosis and Differential Diagnosis
This condition requires differentiation from other chronic wasting conditions. The ACTH stimulation test holds the highest diagnostic value. In this disease, adrenal reserve function is impaired, whereas in other conditions, ACTH stimulation results in a significant increase in blood and urinary corticosteroids (in some cases, continuous stimulation for 2–3 days may be required).
In emergency settings, adrenal crisis should be suspected under the following circumstances:
- Severe circulatory collapse occurs despite an underlying illness that is not severe.
- Dehydration, shock, and exhaustion are present.
- Hypoglycemia of uncertain origin occurs.
- Unexplained vomiting is evident.
- Physical examination reveals hyperpigmentation, vitiligo, sparse body hair, or underdeveloped genitalia.
Treatment
Basic Management
Patients should be made aware of the chronic nature of the disease and the necessity of lifelong adrenal hormone replacement therapy.
Glucocorticoid Replacement Therapy
The appropriate maintenance dose is determined based on factors such as height, weight, sex, age, and physical activity level. Administration mimics the physiological diurnal rhythm of hormone secretion, with two-thirds of the total daily dose taken in the morning upon awakening and the remaining one-third taken by 4 p.m. For most adults, initial daily doses include hydrocortisone at 20–30 mg or cortisone acetate at 25–37.5 mg, which can later be gradually reduced to hydrocortisone at 15–20 mg or an equivalent dose of cortisone acetate. The dosage may need to be increased in the presence of fever or other complications.
Sodium and Mineralocorticoid Supplementation
Sufficient salt intake should be ensured, with a minimum daily consumption of 8–10 grams. Additional salt intake may be necessary during heavy sweating or diarrhea. Most patients achieve satisfactory outcomes with hydrocortisone supplementation and adequate salt intake alone. For patients who continue to experience symptoms such as dizziness, fatigue, or low blood pressure, mineralocorticoid therapy may be required. These patients may take fludrocortisone orally at a dose of 0.05–0.1 mg once daily in the morning at 8 a.m. If side effects such as edema, hypertension, or hypokalemia occur, the dose should be reduced.
Etiological Treatment
For patients with active tuberculosis, antituberculosis therapy should be administered promptly. Replacement doses of adrenal corticosteroids do not interfere with tuberculosis control. In cases of autoimmune-related disease, other endocrine insufficiencies should be screened for and treated accordingly if identified.
Treatment of Adrenal Crisis
Adrenal crisis constitutes a medical emergency and requires immediate intervention.
Fluid Replacement
Patients in adrenal crisis typically have fluid deficits amounting to about one-fifth of their extracellular fluid volume. Normal saline should be administered rapidly in the first one to two days, with a daily volume of 2,000–3,000 mL. For patients whose primary deficiency is glucocorticoids and whose dehydration is not severe, the volume of saline can be appropriately reduced. Glucose solutions should be supplemented to prevent hypoglycemia.
Glucocorticoids
Hydrocortisone should be administered immediately via intravenous injection at a dose of 100 mg to bring serum cortisol levels to those seen during severe physiological stress in healthy individuals. Subsequently, every six hours, an additional 100 mg of hydrocortisone should be added to the intravenous fluids for infusion. On the second and third days, the total daily dose may be reduced to 300 mg, divided into intravenous infusions. As the patient's condition improves, the dosage can be further reduced to 200 mg per day and then to 100 mg per day. Once emesis ceases and the patient is able to tolerate oral intake, the medication may be transitioned to oral administration.
Management of Infections and Other Triggers
Underlying infections and other precipitating factors should be treated aggressively.
Treatment during Surgery or Other Stressful Events
During periods of severe stress, the total daily dose of hydrocortisone should be approximately 300 mg or higher. Most surgical stressors are transient, and the dosage can typically be tapered back to maintenance levels over a few days. For milder and shorter stress events, a daily dose of 100 mg of hydrocortisone may be sufficient, with subsequent reductions as deemed appropriate.