Autoimmune polyendocrine syndrome overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]
Overview
Autoimmune polyendocrine syndrome (APS) are a group of autoimmune disorders against multiple (poly) endocrine organs, although non endocrine organs may be affected. On the basis of organ involvement, autoimmune polyendocrine syndrome (APS) can be classified into APS type 1, APS type 2 and APS type 3. In APS there is loss of self tolerance or defective T cell regulation and the immune system attacks various endocrine and nonendocrine organs throughout the body. APS is seen in genetically susceptible individuals, when exposed to certain environmental triggers (such as infection) leads to autoimmunity. Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404. There are no established risk factors for autoimmune polyendocrine syndrome. However, patients with single autoimmune disorder are at an increased risk of having another autoimmune disorder. The most common symptoms of APS-1 include mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. The most common symptoms of APS-2 include Addison's disease with autoimmune thyroiditis or diabetes mellitus type 1. The most common symptoms of APS 3 include autoimmune thyroiditis, diabetes mellitus type 1, pernicious anemia and/or with involvement of a nonendocrine organ. The diagnosis of autoimmune polyendocrine syndrome (APS) is made on the basis of presence of organ-specific antibodies (serological measurement) followed by functional testing. Medical therapy for autoimmune polyendocrine syndrome (APS) depends upon the subtype and the organ system involved. In APS the focus is to treat the presenting disorder.
Historical Perspective
In 19th century physicians first focussed their attention on constellation of symptoms associated with autoimmune polyendocrine syndrome. In 1855, Thomas Addison identified patients with Addison's disease who also appeared to have coexisting pernicious anemia. In 1956, Roitt and Doniach found that patients with Hashimoto's thyroiditis had circulating autoantibodies reacting with thyroid gland. In 1980, Neufeld and Blizzard first developed the classification for polyglandular failure and in 1982 categorised autoimmune polyendocrine syndrome into type 1 and type 2.
Classification
On the basis of organ involvement, autoimmune polyendocrine syndrome (APS) can be classified into APS type 1, APS type 2 and APS type 3. APS type 1 commonly presents with mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. APS type 2 commonly presents with Addison's disease, autoimmune thyroiditis and diabetes mellitus type 1. APS type 3 commonly presents with autoimmune thyroiditis, diabetes mellitus type 1 and pernicious anemia.
Pathophysiology
Autoimmune polyendocrine syndrome (APS) is a group of autoimmune disorders against multiple (poly) endocrine organs, although non endocrine organs may be affected. Autoimmune polyendocrine syndrome is also known as polyglandular autoimmune syndrome and polyendocrine autoimmune syndrome. In autoimmune polyendocrine syndrome there is loss of self tolerance or defective T cell regulation and the immune system attacks various endocrine and nonendocrine organs throughout the body. APS is seen in genetically susceptible individuals who when exposed to certain environmental triggers (such as infection) leads to autoimmunity. The involvement of endocrine glands can be simultaneous or sequential. The autoimmune reaction can either be humoral or cell mediated which may lead to partial or complete destruction of the tissue involved. The common endocrine glands involved are parathyroids, adrenals, thyroid, and pancreas. However any other non endocrine gland/tissue of the body may be involved.
Causes
Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404.
Differentiating Autoimmune Polyendocrine Syndrome from Other Diseases
Autoimmune polyendocrine syndrome (APS) must be differentiated from other similar conditions which lead to multiple endocrine disorders such as thymoma, Kearns–Sayre syndrome, POEMS syndrome, and Wolfram syndrome. APS should also be differentiated among its subtypes such as APS type 1, type 2 and type 3.
Epidemiology and Demographics
Autoimmune polyendocrine syndrome (APS) is a group of rare autoimmune disorders. APS type 2 is the most commonly seen autoimmune polyendocrine syndrome. The incidence of APS type 2 is estimated to be 1-2 per 100,000 individuals worldwide. The prevalence of APS type 2 is estimated to be 1-4 per 100,000 individuals worldwide. Most cases of APS type 1 and type 2 are symptomatic by early thirties, while APS type 3 is generally seen in 40-60 years of age. APS usually affects individuals of the caucasian race. In APS type 1, type 2 and type 3 females are more commonly affected than men.
Risk Factors
There are no established risk factors for autoimmune polyendocrine syndrome. However, patients with single autoimmune disorder are at an increased risk of having another autoimmune disorder. Any autoimmune endocrine disorder such as Addison's disease, type 1 diabetes mellitus, autoimmune thyroiditis, hypogonadism (usually autoimmune oophoritis), vitiligo, pernicious anemia, chronic atrophic gastritis, chronic active hepatitis may put the patient at an increased risk of autoimmune polyendocrine syndrome.
Screening
Screening is an important aspect in the early diagnosis and management of autoimmune polyendocrine syndrome (APS). The onset of APS is often with a single endocrine disorder and the subsequent involvement of other endocrine/non-endocrine organs may take up to years or decades. In patients of APS, high clinical suspicion should be maintained for presence of other autoimmune disorders. Once a patient has been diagnosed with a single autoimmune endocrine disorder, screening should be done for presence of other auto-antibodies such as 21- hydroxylase or 17-hydroxylase.
Natural History, Complications, and Prognosis
If left untreated, patients with autoimmune polyendocrine syndrome (APS) may progress to involve other endocrine and nonendocrine organs. APS can be a life threatening condition if vital hormone producing organs of the body are involved such as adrenal glands, thyroid, parathyroid glands. The complications of APS depend upon the subtype and organ system involved. Common complications of APS include those arising from hypoparathyroidism, Addison's disease and autoimmune thyroiditis. The prognosis of APS is variable and depends upon the duration and severity of endocrine/non-endocrine organ involved. Patients of APS with endocrine involvement generally require lifelong hormone replacement therapy.
Diagnosis
Diagnostic study of choice
The diagnosis of autoimmune polyendocrine syndrome (APS) is made on the basis of presence of organ-specific antibodies (serological measurement) followed by functional testing. Few examples of organ specific antibodies include autoantibodies against 21-hydroxylase, 17-hydroxylase, GAD, islet cells, thyroglobulin, thyroid peroxidase, intrinsic factor and tyrosinase. Genetic analysis may be done in suspected patients of APS for AIRE or FOXP3 gene mutation. Patients presenting with a single endocrine pathology should always be considered for other endocrine organ dysfunction. Patients with autoimmune endocrine disorder are always at a risk of developing autoimmune conditions of other endocrine organs.
History and Symptoms
A detailed history may be helpful in the early diagnosis of the autoimmune polyendocrine syndrome (APS). Autoimmune polyendocrine syndrome patients generally have an early onset. In such cases, history from the caregivers may be obtained. An important aspect involves obtaining family history about the presence of APS in family members since APS can be transmitted in genetic mode. Patients with the autoimmune polyendocrine syndrome (APS) have varied symptoms depending on the subtype. The most common presentation of APS-1 include mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. The most common presentation of APS-2 include Addison's disease with autoimmune thyroiditis or diabetes mellitus type 1. The most common presentation of APS 3 include autoimmune thyroiditis, diabetes mellitus type 1, pernicious anemia and/or with involvement of a nonendocrine organ.
Physical Examination
The physical examination findings in autoimmune polyendocrine syndrome (APS) depend upon the subtype and the organ system involved. APS may present as hypotension, bradycardia, tetany, dry skin, coarse hair, and muscle weakness depending upon the organ affected such as adrenals, thyroid or pancreatic islet cells. Patients of APS usually appear fatigued and dehydrated.
Laboratory Findings
Laboratory findings suggestive with the diagnosis of autoimmune polyendocrine syndrome (APS) include testing for the presence of autoantibodies (serology) followed by functional testing. Patients are tested for autoantibodies such as antibodies against 21-hydroxylase, 17-hydroxylase, glutamic acid decarboxylase (GAD), islet cell, thyroid peroxidase (TPO), TSH receptor and thyroid-stimulating immunoglobulins (TSI). Other tests include thyroid function test, adrenal function test, electrolytes, blood glucose, complete blood count (CBC) and vitamin B12.
Electrocardiogram
An ECG may be helpful in the diagnosis of autoimmune polyendocrine syndrome (APS) associated hypoparathyroidism which may present with cardiac dysfunction due to hypocalcemia. EKG findings suggestive of cardiac dysfunction due to hypoparathyroidism include prolongation of QT interval.
X-ray
There are no x-ray findings associated with autoimmune polyendocrine syndrome.
CT scan
A CT scan may be helpful in the diagnosis of autoimmune polyendocrine syndrome (APS) associated hypoparathyroidism and Addison's disease. Hypoparathyroidism on CT may present with increased volumetric bone mineral density (vBMD) of both cortical and trabecular bones. Addison's disease on CT scan may present with small adrenal remnants bilaterally (suggestive of autoimmune adrenalitis) or as atrophied adrenal glands.
MRI
Brain MRI may be helpful in the diagnosis of autoimmune polyendocrine syndrome associated hypopituitarism and hypogonadism. Findings on MRI suggestive of hypopituitarism may include decreased size of the pituitary gland and empty sella may also be noticed in some cases.
Other Imaging Findings
24-hour iodine-123 uptake may be helpful in the diagnosis of autoimmune thyroiditis associated with autoimmune polyendocrine syndrome (APS). Autoimmune thyroiditis can be seen in any subtype of APS but is more commonly seen in type 3 and type 2. Patients of APS with autoimmune thyroiditis present with decreased uptake of iodine-123, which can help in differentiating hypothyroidism seen in autoimmune thyroiditis from other causes.
Other Diagnostic Studies
Other diagnostic studies for autoimmune polyendocrine syndrome (APS) include endoscopy with biopsy of upper GI tract. Patients of APS may develop atrophic gastritis or celiac disease from autoantibodies against parietal cells or tissue transglutaminase. In patients with positive autoantibodies, endoscopy with biopsy may be helpful in the early diagnosis of atrophic gastritis or celiac disease.
Treatment
Medical Therapy
Medical therapy for autoimmune polyendocrine syndrome (APS) depends upon the subtype and the organ system involved. In APS, the focus is to treat the presenting disorder which can either be mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency or autoimmune thyroiditis. The goal of treatment is to correct hormone deficiencies, prevent complications, and reduce morbidity. Treatment includes monitoring of glandular functions for early detection of glandular failure, lifelong hormone replacement therapy for established glandular failure, and familial screening.
Surgery
Surgical intervention is not recommended for the management of autoimmune polyendocrine syndrome.
Primary Prevention
Effective measures for the primary prevention of autoimmune polyendocrine syndrome (APS) include patient education and screening. Autoimmune polyendocrine syndrome may be inherited in autosomal recessive (APS type 1), autosomal dominant (APS type 2) or X linked fashion (APS type 3) and therefore educating the relatives about the importance of a positive family history is necessary. In addition, screening should be done for first degree relatives of patients (parents, siblings or children) with APS for the presence of autoantibodies.
Secondary Prevention
Effective measures for the secondary prevention of autoimmune polyendocrine syndrome (APS) include patient education and periodic screening. In APS the time interval between involvement of one endocrine organ to other endocrine/nonendocrine organ may take years. Thus, patient should be informed about signs and symptoms of commonly associated conditions/disorders with APS. In addition, periodic screening at an interval of 6-12 months should be done to detect the presence of any autoantibody such as antibodies against 21-hydroxylase or islet cells.