NEWSLETTER

POLYGLANDULAR AUTOIMMUNE SYNDROMES

Prof. Zaman Sheikh, Ali. Syed Imran. NIDE-DUHS

The term "Polyglandular Autoimmune Syndromes" (PAS) refers to a group of disorders in which two or more endocrine glands are hypo-functional or hyper- functional as a result of autoimmune dysfunction. Defects in T suppressor cell subsets occur which permits activation of cellular and humoral arms of the immune system. Connective tissue diseases, hematological & gastrointestinal autoimmune disorders are commonly associated with such syndromes. Association with sarcoidosis is also reported.

HISTORY:

Dating back to 1853, it was Thomas Addison who first described the association of pernicious anemia with adrenocortical failure, then Schmidt in 1926, described the association of thyroiditis and adrenocortical failure which was further expanded by Carpentar in 1964 to include Type 1 diabetes mellitus.

It was in 1980 that Neufeld distinguished the two major Polyglandular Autoimmune Syndromes and a third type was described subsequently.

CLASSIFICATION OF POLYGLANDULAR AUTOIMMUNE SYNDROMES:

Altogether three major types of PAS have been described.

PAS Type I

It is a rare pediatric disorder first described in 1946,2 & has sporadic, autosomal recessive inheritance having highest prevalence of 1/25000 in Finland. Also known as Whitaker or APECED (autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy) syndrome, involves a single gene defect3 and is believed to result from presence of chronic inflammatory infiltrate mainly composed of lymphocytes in affected organs and presence of antibodies in target tissue specific antigens. Defective immune response leads to chronic mucocutaneous candidiasis. The mechanisms are:

  1. Defective blast transformation.

  2. Macrophage migration inhibition.

  3. Lymphocyte toxicity.

PAS Type II

This disorder occurs in adulthood and commonly occurs between 20 to 30 years of age, 50% of cases are sporadic and 50% are familial. It is related to HLA-DR 3 and HLA-DR 4 and HLA-DR B1 haplotypes with autosomal dominant pattern of inheritance4 and is the most common form of all Polyglandular syndromes characterized by the presence of adrenocortical insufficiency with either thyroid disease or Type 1 Diabetes Mellitus.

Schmidt's syndrome, a subtype of PAS Type 11, is a combination of Addison's disease and hypothyroidism.

Association are with hypogonadism, celiac disease, vitiligo, alopecia, chronic autoimmune hepatitis, myasthenia gravis, Sjogren's syndrome, hypophysitis, chronic atrophic gastritis and rheumatoid arthritis.

PAS Type III

This also occurs in adulthood and in contrast to PAS I and II, it does not involve the adrenal cortex. It involves autoimmune thyroiditis occurring with other organ specific autoimmune disease. It is associated with HLA-DR 3 and decreased function of T suppressor cells is a consistent abnormality.

PAS III can be further classified into the following 3 subcategories:

  • PAS IIIA - Autoimmune thyroiditis with Immune-Mediated Diabetes mellitus Type 1 (IMD)
  • PAS IIIB - Autoimmune thyroiditis with pernicious anemia.
  • PAS IIIC - Autoimmune thyroiditis with vitiligo and/or alopecia and/or other organ-specific autoimmune diseases.

It is also associated with celiac disease, myasthenia gravis, Sjogren's syndrome, hypogonadism and gastric carcinoid tumour.

CLINICAL FEATURES AND PRESENTATIONS:

These disorders having multiple gland involvement have highly variable presentations but the typical scenarios are mentioned below:

PAS I

The 3 major components are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure, out of which two are essential in making a diagnosis. Usually candidiasis and hypoparathyroidism present by age of 5 years and adrenal insufficiency by 12 years and all manifestations by age of 15 years.

Candidiasis occurs first and about 75% of patients with PAS I develop recurrent monilial infections mostly in nail, oral and anal mucosa. Therefore, any young patient with moniliasis should be assessed for a possible state of T cell deficiency and PAS I.

Hypoparathyroidism occurs second and usually involves about 89% of cases and presents with typical features of hypocalcemia (tetany, seizures, leg cramps etc). 10 to 40% of patients are reported to have anti-parathyroid antibodies.

Addison's disease occurs in about 60% of cases and the typical symptoms include weakness, lethargy, anorexia and postural hypotension.

Type 1 Diabetes Mellitus occurs in 1 - 4% of cases,

Less common presentations are with gonadal failure, chronic active hepatitis, chronic atrophic gastritis and keratoconjunctivitis.

PAS II

The clinical features are a summation of all the features of individual components like:

Addison's disease occurs in 100% of cases and has symptoms of adrenocortical insufficiency as mentioned above.

Type 1 Diabetes Mellitus occurring in 61% of cases5 presents with classical symptoms of polyuria, polydipsia and polyphagia. Weight loss, lethargy and other complications may also be present.

Autoimmune thyroid disorders that occur are Graves disease and Hashimoto's thyroiditis and even atrophic thyroid is seen.

Chronic lymphocytic thyroiditis will lead to cold intolerance, fatigue, somnolence, poor memory, myalgias etc.

Graves disease occurring in 50% of cases has symptoms of heat intolerance, weight loss, weakness, oligomenorrheoa, anxiety etc.

Celiac disease occurring in 6.7% of cases6 presents with weight loss, steatorrhea, bloating, and malnutrition.

Pernicious anemia if present has symptoms of pallor, jaundice, dizziness, dyspnoea, glossitis etc.

Gonadal failure occurs in 5 - 50% of cases, mainly affecting females and presents as primary amenorrhea.

Other disorders like alopecia, myasthenia gravis, Sjogren's syndrome and rheumatoid arthritis are seen in less than 5% of cases.

PAS III

The symptoms are as follows:

Autoimmune thyroiditis causing goiter and all symptoms of hypothyroidism. Initially a transient increase in thyroid hormone levels may be seen

Type 1 Diabetes Mellitus with all the features already mentioned.

In addition there may be vitiligo, alopecia and neuro-psychiatric symptoms.

LAB INVESTIGATIONS:

A clinical history and examination that suggests evidence of more than one endocrine dysfunction prompts the use of following tests:

Serum endocrine autoantibody screen:

This helps verify the autoimmune etiology of the disease and is useful for screening family members who may develop disease in future. Usually antibodies to 21 hydroxylase, 17 hydroxylase, thyroid peroxidase and thyroid stimulating immunoglobulins, glutamic acid decarboxylase and islet cell antibodies are checked but their absence does not exclude the disease.

End Organ Function Tests:

They are:

  • Short Synacthen test to confirm the diagnosis of Addison's disease.
  • Serum FSH, LH and Testosterone (in males) and Estradiol (in females) levels.
  • Thyroid function tests.
  • Serum electrolytes to check mineralocorticoid activity.
  • Fungal skin scrapings for candidiasis
  • Complete blood count with MCV and Vit B 12 levels to look for pernicious anemia.
  • Serologic tests like anti-transglutinase (Ig A & Ig G) antibodies for workup of celiac disease.

Imaging studies:

CT scan abdomen to rule out other causes, e.g., adrenal hemorrhage or tuberculous calcification in cases of adrenocortical insufficiency.

Procedures:

Endoscopy may be required for work up of celiac disease.

MANAGEMENT:

The management should ideally be done at a tertiary care centre involving a team of specialists including endocrinologist, infectious disease specialist, dermatologist, haematologist and gastroenterologist. The treatment is directed at managing the components of disease and the mainstay is hormonal therapy along with drugs for other components.

Candidiasis is treated with fluconazole and ketokenazole, fluconazole is preferred because it does not inhibit steroidogenesis.

Hypoparathyroidism is treated with oral calcium and vitamin D supplementation.

Addison's Disease is treated mainly with hydrocortisone and for mineralocorticoid replacement, fludrocortisone may be required.

Thyroid replacement therapy if required should be preceded by correction of glucorticoid levels as Thyroid hormone therapy can precipitate adrenocortical insufficiency, because of increased metabolism.

Type I diabetes requires insulin therapy and adjustment in insulin dosages for correction of blood glucose levels, as in associated Addison's disease, there is tendency for hypoglycemia.

Pernicious anemia treated with cyanocobalamin replacement.

Celiac disease requires placing patients on gluten-free diet.

Finally it is emphasized that, although the patients with Polyglandular Autoimmune Endocrinopathies can participate in all activities of life but they should be aware of their disease status & must be advised to seek regular medical check up as the disease requires continuous monitoring and adjustments in drug therapy.

REFERENCES:

  1. Papadopolous KI, Hornblad Y, Liljebladh H, and Hallengren B.High frequency of endocrine autoimmunity in patients with sarcoidosis. Eur J. Endocrinol, 1996:134; (3),331-336.
  2. Hemker MO, Berkinblit GV, Anhalt GT, Yardley JH. Pernicious anemia and widespread absence of gastrointestinal endocrine cells in a patient with APS Type 1 and malabsorption.J. Clin. Endocrinol Met. 2006:91;(8),2833-2838.
  3. Davidson A, Diamond B.Autoimmune Diseases. (Review article) N. Engl. J. Med. 2001:345;340-350.
  4. Dittmar et al.Early onset of Polyglandular failure is associated with HLA-DRB 1. Eur J. Endocrinol, 2008;159:55-60.
  5. Dittmar M, Kahaly GJ.Polyglandular Autoimmune Syndromes, lmmunogenetics and long term followup. J. Clin. Endocrinol. Met. 2003;88(7),2983-2992.
  6. Bitterle C, Lazzarotto F, Spadaccino AC, Basso D, Plebani M, Pedini B,Chiarelli S. & Albergoni M. Celiac disease in North Italian patients with autoimmune Addison's disease. Eur. J. Endocrinol. 2006;154(2),275-279.
  7. Lazzarotto F, Basso D, Plebani M, Moscon A, Zanchetta R, Betterle C. Celiac disease and Type 1 Diabetes. Diabetes Care 26:248-249,2003.

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