Primary adrenal insufficiency - also known under the eponym Addison’s disease - occurs when the adrenal glands situated on top of the kidneys produce inadequate amounts of glucocorticoid and mineralocorticoid hormones. Autoimmune destruction of the aforementioned glands is the most common cause of primary adrenal insufficiency in the developed countries, whereas tuberculosis is the second most frequent cause worldwide.
A plethora of autoimmune comorbidities can be associated with primary adrenal insufficiency – most notably Hashimoto’s disease, primary atrophic hypothyroidism, type I diabetes mellitus, as well as hypogonadism and primary ovarian failure. Their association can also be syndromic - main examples are type I or II polyglandular autoimmune syndrome.
In addition to those associations, autoimmune primary adrenal insufficiency has also been associated with vitiligo, parathyroidism, and pernicious anemia. If adrenal failure is caused by tuberculosis, then much less comorbidities are observed owing to the different disease mechanism.
Type I Polyglandular Autoimmune Syndrome
Type I polyglandular autoimmune syndrome is characterized by the occurrence of three major comorbid diseases: primary adrenal insufficiency of autoimmune origin, chronic candidiasis, and chronic hypoparathyroidism. In the medical literature, this combination of symptoms is also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or Candida endocrinopathy syndrome.
Type I polyglandular autoimmune syndrome has its onset in older children and adolescents, and shows a slight female predominance. The gene associated with this syndrome is AIRE (which stands for autoimmune regulator) found on chromosome 21, frequently encountered among Iranian Jews and Finns.
The other notable facet of this syndrome is its association with autoimmune disorders of the gastrointestinal tract (such as malabsorption syndromes, intestinal dysfunction, and chronic active hepatitis). The dermatologic components commonly found are vitiligo (loss of melanin skin pigment) and alopecia (hair loss).
Rare studies of adrenal glands from the autopsy of patients with type I polyglandular autoimmune syndrome showed adrenal atrophy with a concomitant lymphocytic infiltration. This type of autoimmune syndrome is also known to have the largest simultaneous combination of autoimmune antibodies and subsequent autoimmune diseases in a single individual.
Type II Polyglandular Autoimmune Syndrome
Type II polyglandular autoimmune syndrome (also known as Schmidt’s syndrome) is characterized by the presence of primary autoimmune adrenal insufficiency in association with autoimmune diseases of the thyroid gland and/or diabetes mellitus type 1. Comorbid diseases in this syndrome tend to develop in a specific order: diabetes generally develops before adrenal failure, while thyroid diseases develop before, together with, or after adrenal failure.
Schmidt’s syndrome is a rare condition that affects women two to four times more often as men. It can occur in both sexes and at any age, albeit it is most commonly observed in females between 20 and 40 years of age. Furthermore, it can also be seen in many generations of the same family via an autosomal dominant pattern of inheritance.
Thyroid disease is usually chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), although toxic diffuse goiter (Graves’ disease) may also develop. Thyroid microsomal or thyroglobulin autoantibodies are usually observed, while ultrasound examination of the thyroid gland reveals hypoechogenic pattern.
The Importance of Recognizing Comorbidities
Adequate recognition of endocrine and other comorbid disorders in patients with primary adrenal insufficiency has several clinical implications. First of all, both hypogonadism and hypopituitarism are common in polyglandular syndromes; therefore the clinical mimicry of polyglandular autoimmune syndrome to panhypopituitarism has been well established in the medical literature. The measurement of hypophyseal tropic hormones can clearly differentiate between those two entities.
Further, the likelihood of individuals with autoimmune adrenal insufficiency developing a second (or even third) endocrinopathy can be as high as 25%. This emphasizes the need for diligent search for the presence of other endocrinological dysfunctions – not only during the active phase of primary adrenal insufficiency, but essentially during the rest of patient’s life.
In addition, pernicious anemia and other systemic autoimmune disorders should be actively sought. The screening of family members can be also assumed relevant, as there is a role of HLA antigens (namely HLA B8-DW-DR3) in predisposing individuals to the polyglandular autoimmune syndrome.
Reviewed by Susha Cheriyedath, MSc