eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease
Polyglandular Autoimmune Syndrome, Type II
Updated: Oct 2, 2008
Introduction
Background
Polyglandular autoimmune syndrome type II (PGA-II) is the most common of the immunoendocrinopathy syndromes. It is characterized by the obligatory occurrence of autoimmune Addison's disease in combination with thyroid autoimmune diseases and/or type 1 diabetes mellitus (also known as insulin-dependent diabetes mellitus, or IDDM). Primary hypogonadism, myasthenia gravis, and celiac disease also are commonly observed in this syndrome.
The definition of the syndrome depends on the fact that if one of the component disorders is present, an associated disorder occurs more commonly than in the general population. The most frequent clinical combination association is Addison's disease and Hashimoto's thyroiditis, while the least frequent clinical combination is Addison's disease, Graves disease, and type 1 diabetes mellitus. The complete triglandular syndrome is sometimes referred to as Carpenter's syndrome.
PGA-II occurs primarily in adulthood, usually around the third and fourth decades of life. Middle-aged women have shown an increased prevalence of PGA-II. It is associated with HLA-DR3 and/or HLA-DR4 haplotypes, and the pattern of inheritance is autosomal dominant with variable expressivity.1
Two other related autoimmune endocrinopathies exist, namely type I and type III. The former is rare and presents in childhood. It usually consists of mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (presenting in that order). PGA-I usually is inherited in an autosomal recessive pattern, with variable inheritance; it has no HLA association and, unlike PGA-II, has an equal sex incidence. Type 1 diabetes mellitus is rare in children with PGA-I.
Type III, although ill defined, is the co-occurrence of autoimmune thyroid disease with 2 other autoimmune disorders, including diabetes mellitus type 1, pernicious anemia, or a nonendocrine, organ-specific autoimmune disorder in the absence of Addison disease.2
Pathophysiology
The pathogenesis of polyglandular autoimmune syndrome type II (PGA-II) is poorly understood.3,4 The following steps have been postulated:
- Some degree of genetic susceptibility must exist in the individual.5
- The individual is then exposed to the autoimmune trigger, which could be an environmental or intrinsic factor. The trigger mimics the molecular structure of a self-antigen. An alternative explanation is that a breakdown in normal immunologic tolerogenesis occurs.
- Next, a subclinical phase of active production of organ-specific autoantibodies occurs.
- This phase is followed by autoimmune activity in the respective organ, in which there is progressive glandular destruction. The individual is still asymptomatic.
- Overt clinical disease subsequently develops when extensive organ damage, caused by the aforementioned autoimmune activity, has occurred. Evidence of this autoimmune phenomenon that may be responsible for this syndrome is based on whether the affected organs demonstrate a chronic inflammatory infiltrate composed of lymphocytes (mainly).
Some of the component diseases are associated with immune-response genes encoded by the class II HLA complex.1 The syndrome is replete with autoantibodies reacting to target tissue-specific antigens.
Frequency
United States
Approximately 14-20 people per million population are affected by polyglandular autoimmune syndrome type II. Observations have revealed, however, that the disease is much more prevalent if subclinical forms are included.
Mortality/Morbidity
To date, the mortality and morbidity rates of polyglandular autoimmune syndrome type II (PGA-II) have not been clinically estimated. The mortality and morbidity of PGA-II are believed to equal the mortality and morbidity of the individual component disorders.
Sex
The female-to-male ratio of polyglandular autoimmune syndrome type II is 3-4:1.6
Age
Polyglandular autoimmune syndrome type II occurs in the third or fourth decade of life.
Clinical
History
Polyglandular autoimmune syndrome type II (PGA-II) consists of Addison's disease plus either an autoimmune thyroid disease or type 1 diabetes mellitus associated with hypogonadism, pernicious anemia, celiac disease, and recent primary biliary cirrhosis.7 The clinical features consist of a constellation of the individual endocrinopathies.
- Type 1 diabetes mellitus - Some of these clinical features closely mimic those of primary adrenal insufficiency.
- Symptoms - Polyuria, polydipsia, polyphagia, unexplained weight loss, intermittent blurred vision, and lethargy (may present initially with diabetic ketoacidosis and coma)
- Signs - Depend on the severity; consist of poor skin turgor, orthostasis, and hypotension
- Hashimoto's thyroiditis (chronic lymphocytic thyroiditis)
- Symptoms - Usually nonspecific and include cold intolerance, fatigue, somnolence, poor memory, constipation, menorrhagia, myalgias, and hoarseness
- Signs - Slow tendon reflexes, bradycardia, facial and periorbital edema, dry skin and nonpitting edema, carpal tunnel syndromes, deafness, and pericardial or pleural effusions
- Graves disease
- Symptoms - Heat intolerance, weight loss, weakness, palpitations, oligomenorrhea, and anxiety
- Signs - Brisk tendon reflexes, fine tremor, proximal weakness, stare and eyelid lag, exophthalmos, atrial fibrillation, and sinus tachycardia
- Addison's disease (primary adrenal insufficiency)
- Symptoms - Anorexia, nausea, vomiting, weight loss, weakness, and fatigue
- Signs - Chronic hyperpigmentation of creases and scars, as well as orthostatic hypotension
- Celiac disease - Weight loss, steatorrhea, bloating, cramping, and malnutrition
- Pernicious anemia - Pallor, jaundice, ataxia, glossitis, impaired cognition, impaired vibratory and position sense, and impaired cognition
- Other disorders associated with PGA-II include the following:
- Hypogonadism (usually autoimmune oophoritis) and hypopituitarism
- Idiopathic thrombocytopenic purpura
- Myasthenia gravis
- Parkinson's disease
- Vitiligo
- Alopecia
- Seronegative arthritis
Physical
See History.
Causes
The etiology of polyglandular autoimmune syndrome type II (PGA-II) is very poorly understood.
- Some association has been seen between diabetes or hypothyroidism and congenital rubella infection.
- Immune stimulation by certain dietary proteins is a possible etiologic factor.
- Additional possibilities include genetic susceptibility and idiopathic immunopathologic dysfunction.
- Animal models have demonstrated that cytomegalovirus-infected mice may develop PGA-II with lymphocytic infiltration of the thyroid, liver, myocardium, adrenals, pancreatic islets, and salivary glands. At this time, however, no infectious agents or noticeable immunodeficiency states have been associated with human PGA-II.
More on Polyglandular Autoimmune Syndrome, Type II |
 Overview: Polyglandular Autoimmune Syndrome, Type II |
| Differential Diagnoses & Workup: Polyglandular Autoimmune Syndrome, Type II |
| Treatment & Medication: Polyglandular Autoimmune Syndrome, Type II |
| Follow-up: Polyglandular Autoimmune Syndrome, Type II |
| References |
| Further Reading |
| Next Page » |
References
Obermayer-Straub P, Manns MP. Autoimmune polyglandular syndromes. Baillieres Clin Gastroenterol. Jun 1998;12(2):293-315. [Medline].
Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. May 13 2004;350(20):2068-79. [Medline].
Baker JR Jr. Autoimmune endocrine disease. JAMA. Dec 10 1997;278(22):1931-7. [Medline].
Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg?. Clin Exp Immunol. Aug 2004;137(2):225-33. [Medline]. [Full Text].
Ramos-Lopez E, Lange B, Kahles H, et al. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II. BMC Med Genet. Jul 11 2008;9:65. [Medline]. [Full Text].
Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. May 2003;2(3):119-25. [Medline].
Borgaonkar MR, Morgan DG. Primary biliary cirrhosis and type II autoimmune polyglandular syndrome. Can J Gastroenterol. Nov 1999;13(9):767-70. [Medline].
de Graaff LC, Smit JW, Radder JK. Prevalence and clinical significance of organ-specific autoantibodies in type 1 diabetes mellitus. Neth J Med. Jul-Aug 2007;65(7):235-47. [Medline].
Förster G, Krummenauer F, Kühn I, et al. [Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation]. Dtsch Med Wochenschr. Dec 10 1999;124(49):1476-81. [Medline].
Bizzaro N. The predictive significance of autoantibodies in organ-specific autoimmune diseases. Clin Rev Allergy Immunol. Jun 2008;34(3):326-31. [Medline].
Rakel RE, ed. Conn's Current Therapy. Philadelphia, Pa: Saunders; 1999:630-54.
Eisenbarth G, Verge C. Immunoendocrinopathy syndromes. In: Wilson JD, ed. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: Saunders; 1998:1651-9.
Lachmann PJ, Rosen F. Autoimmune endocrine disease. In: Lachmann PJ, ed. Clinical Aspects of Immunology. 5th ed. Boston, Mass: Blackwell Scientific Pubs; 1993:2001-2.
Muir A, Katz D, McClaren N. Polyglandular failure syndromes. In: DeGroot LJ, ed. DeGroot's Endrocrinology. 3rd ed. Philadelphia, Pa: Saunders; 1995:3013-22.
Further Reading
Related eMedicine topics:
Addison Disease [Dermatology]
Addison Disease [Endocrinology]
Celiac Disease
Celiac Sprue
Graves Disease [Endocrinology]
Graves Disease [Pediatrics: General Medicine]
Hashimoto Thyroiditis
Keywords
type II polyglandular autoimmune syndrome, type II PGA, PGA syndrome type II, PGA-II syndrome, autoimmune disease, autoimmune diseases, autoimmune disorder, autoimmune disorders, polyglandular failure syndrome, Schmidt syndrome, immunoendocrinopathy syndromes, autoimmune thyroid disease, type 1 diabetes mellitus, insulin-dependent diabetes mellitus, IDDM, Carpenter's syndrome, Carpenter syndrome, Addison disease, Addison's disease, Graves disease, Grave's disease, Hashimoto disease, Hashimoto's disease, Hashimoto thyroiditis, Hashimoto's thyroiditis, celiac disease, celiac sprue
