What Are Autoimmune Polyglandular Syndromes?

[dropcap]A[/dropcap]utoimmune polyglandular syndromes (APS) are rare clusterings of two or more endocrine and non-endocrine autoimmune disorders in the same affected person.

Polyglandular is somewhat of a misnomer since many of the manifestations of the diseases do not concern endocrine glands.¹

Endocrine autoimmune disorders involve the abnormal production of autoantibodies that target and destroy the body’s own endocrine tissues, causing loss of essential hormone production by the targeted glands. Endocrine glands include the pituitary, thyroid, adrenal, parathyroid, islets of Langerhans (pancreas), testes in males, and ovaries in females.

First degree relatives (siblings of same parents, parents, children) have an increased incidence of latent, meaning not apparent, autoimmune pathology.²

Q: How many autoimmune polyglandular syndromes are described?

A: Three syndromes have been identified and they are all inherited: APS type-1, APS type-2, and APS type-3.

• APS type-1 is a genetic mutation inherited in an autosomal recessive manner. A child with APS type-1 has inherited two mutated copies of a gene called the AIRE (autoimmune regulator) gene, which is on the long arm of 21st chromosome present in each cell.³ The parents, called carriers, are unaffected since they each have only a single copy of the AIRE mutated gene. Humans have a total of 23 pairs of chromosomes that contain genes inherited from each parent. Mutations in the genes cause disease.

Diagnosis criteria for autoimmune polyglandular syndrome type-1 includes these three disorders:

1. Chronic candida infection (CMC), which usually develops first, typically attacks skin, but very commonly also nails, mouth, vagina, esophagus and intestine. CMC in APS type-1 patients is usually mild, and in most cases, it is chronic. It is found in 73–100 % of APS type-1 patients. 
2. Hypoparathyroidism, causing loss of parathyroid function (hypoparathyreosis) is found in 76–93 % of APS type-1 patients.
3. Autommune Addison’s disease, also called autoimmune adrenalitis, is found in 72-100 % of APS type-1 patients. Still many of them die for unrecognized or late diagnosed autoimmune Addison’s disease, so regular follow-up for children in suspicion of APS type-1 (with CMC or/and hypoparathyroidism) is necessary.⁴

Other assocated disorders that may develop, but are not required for diagnosis, include: vitiligo, premature menopause, pernicious anemia, parathyroid gland failure, alopecia, and celiac disease. Thyroid disease rarely occurs.⁵

• APS type-2 is linked to the inheritance of HLA antigens on chromosome 6 and appears to be autosomal dominant with incomplete penetrance. This suggests the contribution of environmental factors, such as bacterial and viral infections, medications, psychological factors, etc.⁶ It does not have an identified mutation of the AIRE gene.

Diagnosis criteria for  autoimmune polyglandular syndrome type-2 includes these two disorders:

1. Autommune Addison’s disease combined with
2. Autoimmune thyroid disease (thyroid atrophy, hypertrophic goiter related to Hashimoto’s thyroiditis, Graves’ disease, asymptomatic autoimmune thyroiditis)⁶ and/or type I diabetes mellitus.  The conditions may occur in any order.

Polyglandular autoimmune syndrome type-2  is also known as Schmidt’s syndrome when adrenalitis (adrenal insufficiency) is associated with thyroiditis and Carpenter’s syndrome for adrenal insufficiency with hypoparathyreosis (impaired function of parathyroid glands).

Other disorders that may develop, but are not required for diagnosis, include:  type 1 diabetes (50%), frequently gonadal failure or vitiligos, also celiac disease, autoimmune hepatitis, alopecia, pernicious anemia, and myasthenia gravis.⁷ Decades may arise between the onset of one disease and the onset of the second in the same patient.⁸

Therapy of APS type-2 consists of hormone replacement therapy for each separate condition, except that treatment for adrenal insufficiency must be given before thyroid therapy is started when the conditions occur together.⁹ Thyroxin replacement may induce life-threatening adrenal failure in a patient with untreated Addison’s disease. Thus, in case of doubt hydrocortisone should be given before the thyroxine administration is started.¹⁰

• APS type-3  has a strong genetic background. Diagnosis criteria for autoimmune polyglandular syndrome type-3 involves these conditions:

1.  Autoimmune thyroiditis that occurs with another organ-specific autoimmune disease, but not with autoimmune Addison’s disease, and
2. Other autoimmune diseases can include diabetes mellitus, pernicious anemia, vitiligo, alopecia, myasthenia gravis, celiac disease, and Sjögren’s syndrome. The most common APS type-3 combination is autoimmune disease of thyroid gland and pernicious anemia.¹¹

Who is Affected in the General Population?

• APS type-1 is usually apparent in childhood with the incidence of 1 in100,000 persons. It is more common among Finns (1 in 25,000), Sardinians (1 in 14,000), and Iranian Jews (1 in 6,500 to 1 in 9,000). The age of onset is usually early childhood, but new symptoms can develop throughout life. It affects both sexes equally.
• APS type-2 has a peak onset in middle age, although the first signs usually develop between 20–30 years of age. Its prevalence is 1 in 20,000 persons. It is three times more frequent among women than men.¹²
• APS type-3 is most frequent among middle-aged women.⁷[/box]

What Is Autoimmune Polyglandular Syndrome In Celiac Disease and/or Gluten Sensitivity?

Sources:

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10. Lipowsky C, Schorl-Schweikardt BA, Kehl O, Brändle M. 19-year-old patient with adrenal cortex insufficiency–only the tip of the iceberg. Polyendocrine autoimmune syndrome type II (Schmidt syndrome). Praxis (Bern 1994). 2008 Jan 23;97(2):77-81. [↩]
11. http://autoimmune.pathology.jhmi.edu/diseases.cfm?systemID=3&DiseaseID=68 [↩]
12. Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Neth J Med. 2009 Dec;67(11):376-87. [↩]