Autoimmune polyglandular syndromes E31.0

Autoimmune polyglandular syndromes/polyglandular autoimmune syndromes (APS/PAS) are multifactorial diseases with at least two coexisting autoimmune-mediated endocrinopathies. APS show a great heterogeneity of syndromes and manifest sequentially with a long time interval between the occurrence of the first and the second autoimmune glandular disease. APS occur together with several non-endocrine autoimmune diseases. In most endocrine APS diseases, the autoimmune process causes an irreversible loss of function, while chronic autoimmune reactions can simultaneously alter physiological processes in the affected tissue and lead to altered organ function. The rare juvenile APS type I is inherited monogenetically, while several susceptibility gene polymorphisms are known for the more common (polygenic) adult types. Screening for polyglandular autoimmunity in patients with monoglandular autoimmune disease and/or first-degree relatives of patients with PAS is important for a timely diagnosis at an early stage. The most common adult PAS type is the combination of type 1 diabetes with autoimmune thyroid disease (Kahaly GJ et al. 2018).

In principle, 3 forms of autoimmune polyendocrine syndromes can be distinguished:

• APS-1: APS-1, which manifests in childhood and is very rare, is inherited autosomal recessively and is caused by mutations in the so-called "autoimmune regulator" (AIRE) gene. Affected individuals suffer from chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency (Addison's disease). In addition, ectodermal dystrophies of the nails and tooth enamel, alopecia, vitiligo and other autoimmune diseases (ovarian insufficiency, autoimmune gastritis and hepatitis) may occur.
• APS-2: APS-2 is significantly more common. The syndrome is polygenic and occurs in children and adults (Bouça B et al. 2022).
• APS-2 is much more common among patients with polyglandular autoimmunity. The prevalence of APS-2 is estimated at 15 to 45 cases per million inhabitants. According to a more recent understanding, APS-2 is not defined by Addison's disease alone, but is characterized by the joint occurrence of various autoimmune diseases. APS-2 includes the combination of Addison's disease with type 1 diabetes mellitus, thyroid dysfunction (Hashimoto's thyroiditis or Graves' disease) and other autoimmunological diseases (ovarian insufficiency, autoimmune gastritis, coeliac disease, vitiligo, alopecia).
• Few patients with APS-2 suffer from isolated adrenocortical insufficiency. In a larger comparative study, signs of an additional autoimmune disease were found in > 80% of patients after 10 years. In a Swedish study of Addison's disease patients, 42% had one, 14% two and 4% three additional associated autoimmune diseases. Thyroid dysfunction (especially Hashimoto's chronic lymphocytic thyroiditis), type 1 diabetes and autoimmune gastritis were most frequently associated. In most cohorts, premature ovarian failure is found in more than 5% of affected women. In contrast to APS-1, APS-2 affects women 1.6 to 3 times more frequently than men. The associated autoimmunopathies usually manifest themselves at the beginning of the second or third decade of life, but can develop with a clear downward trend into the sixth decade of life
• APS type 3 (MAS-3): is a rarer variant of an autoimmune polyendocrine syndrome. It shows the following components: autoimmune thyreopathy, diabetes mellitus type 1, Sjögren's syndrome, atrophic gastritis and pernicious anemia, vitiligo, myasthenia gravis, autoimmune nephritis, ITP, SLE, MCTD, Sharp syndrome (Betterle C et al. 2023; Bouça B et al. 2022).

The pathogenesis of polyglandular syndromes has not yet been clarified. A loss of immune tolerance is probably the pathophysiological basis of most of the disease components. One indication of this are circulating autoantibodies, which most APS patients exhibit and which are directed against various tissues such as the adrenal glands, gonads and liver. Autoantibodies can be divided into two groups: On the one hand, enzymes of the cytochrome P450 system act as antigens, which are found in a number of autoimmune diseases and viral diseases. Furthermore, enzymes of neurotransmitter synthesis have been identified. The former include 17a-hydroxylase (CYPc17), 21-hydroxylase (CYPc21) and side chain cleavage enzyme (CYPscc) and cytochrome P450 1A2 (CYP1A2), while aromatic L-amino acid decarboxylase (AADC), tryptophan hydroxylase (TPH), tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD) belong to the second group. Antibodies against the TSH receptor (TRAK) and against TPO are found in particular in patients with autoimmune thyreopathies. The risk of developing diabetes mellitus has been associated with high titers of anti-ICA, anti-GAD, anti-IA2 and anti-insulin antibodies. Antibodies against TPH are frequently found in intestinal dysfunction, anti-CYPscc and anti-CYPc17 in gonadal insufficiency, anti-CYPc21, anti-CYPscc and anti-CYPc17 in adrenocortical insufficiency, anti-TH in alopecia areata and anti-CYP1A2 and anti-CYP2A6 antibodies in hepatitis.

The associated autoimmune diseases can occur before, together or after the diagnosis of Addison's disease. In particular, thyroid dysfunction, vitiligo and diabetes mellitus can manifest themselves before adrenal insufficiency.

The clinical constellation means that people with one of these diseases are at risk of developing hypocortisolism in the course of the disease. Accordingly, clinical suspicion should be high if corresponding symptoms occur (e.g. greatly reduced insulin requirement and frequent hypoglycaemia in diabetes) and prompt clarification should be sought.

1. Betterle C et al. (2023) Type 3 autoimmune polyglandular syndrome (APS-3) or type 3 multiple autoimmune syndrome (MAS-3): an expanding galaxy. J Endocrinol Invest 46:643-665.
2. Bouça B et al. (2022) Clinical characteristics of polyglandular autoimmune syndromes in pediatric age: an observational study. J Pediatr Endocrinol Metab 35:477-480.
3. Clemente MG et al. (1997) Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1997; 82: 1353-1361.
4. Kahaly GJ et al (2018) Polyglandular autoimmune syndromes. J Endocrinol Invest 41:91-98.