Addison’s Disease: Causes

Pathogenesis (disease development)

The causes of primary adrenocortical insufficiency (primary NNR insufficiency) are diverse:

• Genetic causes (frequency: very rare):
  • Adrenoleukodystrophy (synonyms: X-ALD; Addison-Schilder syndrome) – X-linked recessive disorder leading to a defect in steroid hormone synthesis with accumulation of overlong-chain fatty acids in the NNR and CNS; consequently, neurological deficits and dementia develop with onset in childhood.
  • Familial glucocorticoid deficiency (isiolated cortisol deficiency with normal aldosterone concentrations; e.g., due toACTH receptor defect (→ lack of responsiveness of ACTH to NNR).
  • Hemochromatosis (iron storage disease) – genetic disease with autosomal recessive inheritance with increased deposition of iron as a result of increased iron concentration in the blood with tissue damage.
  • Primary cortisol resistance, due to absent or defective glucocorticoid receptors at the target tissue (→ secondary hypersecretion of: ACTH, cortisol, androgens and mineralocorticoids).
• Autoimmune destruction of the NNR (75% of cases).
• Infections (10-25% of cases; see below).
• Vascular (vascular-related) causes (see below).
• Malignancies (tumor diseases; metastases in the NNR).

Patients become symptomatic only when there is tissue loss (= destruction of the hormone-producing cells of the adrenal cortex, NNR) of more than 90% of both NNR. The disease is often associated with endocrinological diseases such as diabetes mellitus type 1 and autoimmune thyroid diseases (polyglandular autoimmune syndrome type 1 or 2). Stressful events, such as trauma, burns, sepsis (blood poisoning), and surgery, often trigger acute NNR insufficiency (Addisonian crisis) based on chronic NNR insufficiency (= lack of stress response) or ischemia (reduced blood flow) to the NNR (= primary acute NNR insufficiency).

Etiology (causes)

Biographic factors

• S. u. Pathogenesis

Disease-related causes

Blood-forming organs – immune system (D50-D90).

• Antiphospholipid syndrome (APS; antiphospholipid antibody syndrome); autoimmune disease; predominantly affects women (gynecotropia); characterized by the following triad:
  • Venous and/or arterial thrombosis (blood clot (thrombus) in a blood vessel).
  • Thrombocytopenia (lack of platelets (thrombocytes) in the blood).
  • Recurrent spontaneous abortions (occurrence of three or more consecutive spontaneous abortions before 20 weeks’ gestation/pregnancy).
• Sarcoidosis – granulomatous inflammation; inflammatory multisystem disease, the cause of which is still unclear.Often the lungs and hilar lymph nodes are almost always affected (up to 95% of cases).
• Thrombocytopenia (decreased number of platelets).

Endocrine, nutritional, and metabolic diseases (E00-E90).

• Adrenoleukodystrophy (see below “Genetic causes”).
• Amyloidosis – extracellular (“outside the cell”) deposits of amyloids (degradation-resistant proteins) that can lead to cardiomyopathy (heart muscle disease), neuropathy (peripheral nervous system disease), and hepatomegaly (liver enlargement), among other conditions.
• Autoimmune adrenalitis – infection of the adrenal gland triggered by an autoimmune event, resulting in atrophy.
• Familial adrenal insufficiency
• Familial glucocorticoid deficiency (see below “Genetic causes”).
• Hemochromatosis (see below “Genetic Causes”).
• Primary cortisol resistance (see below “Genetic causes”).

Infectious and parasitic diseases (A00-B99) [approximately 10-25% of cases].

• Cytomegalovirus infection (CMV).
• Histoplasmosis – fungal disease caused by Histoplasma capsulatum.
• HIV infection
• Coccidioidomycosis – fungal disease caused by Coccidioides immitis.
• Cryptococcosis – fungal disease caused by Cryptococcus neoformans.
• Tuberculosis (consumption)
• Waterhouse-Friderichsen syndrome (synonyms: adrenal apoplexy; suprarenal apoplexy) – acute failure of the adrenal glands due to massive bacterial infections (e.g., meningococcus, Haemophilus influenzae, or pneumococcus).

Cardiovascular system (I00-I99).

• Bilateral thrombosis of the adrenal vein
• Bilateral hemorrhage/infarction as in Waterhouse-Friderichsen syndrome (synonyms: Adrenal apoplexy; suprarenal apoplexy; acute failure of the adrenal glands due to massive bacterial infection and is a special form of consumptive coagulopathy), obstetric
• Adrenal hemorrhage under anticoagulants.
• Adrenal infarction

Musculoskeletal system and connective tissue (M00-M99)

• Lupus erythematosus – group of autoimmune diseases in which the formation of autoantibodies occurs. It belongs to the collagenoses

Neoplasms – tumor diseases (C00-D48).

• Hodgkin’s disease – malignant neoplasm (malignant neoplasm) of the lymphatic system, which is classified as malignant lymphoma.
• Non-Hodgkin’s lymphoma (NHL; all malignant (malignant) diseases of the lymphatic system except Hodgkin’s lymphoma).
• Tumor metastases (in bronchial, colon, and breast carcinoma/lung, colon, and breast cancer)

Operations

• Bilateral adrenalectomy (bilateral surgical removal of the adrenal gland).

Medications

• Aminogluthimide (antiestrogen)
• Anticoagulants (drug used to inhibit blood clotting).
• Etomidate (narcotic)
• Abrupt discontinuation of glucocorticoids (e.g., cortisone).
• Ketoconazole (antifungal drug; drug against fungal diseases).
• Mitotane (o,p’-DDD; adrenostatic; drug that inhibits the production of the hormone cortisol in the adrenal glands).
• Rifampicin (bactericidal antibiotic from the group of ansamycins (rifamycins)/tuberculostatics).
• Suramin (antiprotozoal; drug for the treatment of parasitic infectious diseases).