Type III Polyglandular Autoimmune Syndrome

Updated: Aug 28, 2014
  • Author: KoKo Aung, MD, MPH, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Overview

Background

Polyglandular autoimmune syndrome (PAS) is made up of a group of autoimmune disorders of the endocrine glands. [1] The syndrome results in failure of the glands to produce their hormones. Glandular abnormalities of the endocrine system tend to occur together; consequently, up to a quarter of patients with evidence of hypofunction in one gland have evidence of other endocrine diseases. Continue to consider other glandular hypofunction when evaluating patients with any type of endocrine hypofunction, because the risk of multiple glandular involvement is quite significant.

The concept of polyglandular failure is not new, having achieved recognition as early as in the 19th century. In 1853, Thomas Addison first described the clinical and pathological features of adrenocortical failure in patients who also appeared to have pernicious anemia (PA). In 1908, Claude and Gougerot suggested a common pathogenesis for these conditions in an article titled "Insufficance pluriglandulaire endocrinnienne." In 1926, Schmidt documented the association between adrenocortical failure and thyroiditis. Carpenter, in 1964, expanded the syndrome described by Schmidt to include insulin-dependent diabetes mellitus.

In 1980, Neufeld and Blizzard developed the first classification of polyglandular failure. [2] Neufeld and Blizzard's classification distinguishes 2 broad categories, PAS type I and PAS type II (PAS I and PAS II). An additional group, PAS type III (PAS III), was subsequently described. PAS III, in contrast to PAS I and II, does not involve the adrenal cortex. In PAS III, autoimmune thyroiditis occurs with another organ-specific autoimmune disease, but the syndrome cannot be classified as PAS I or II.

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

  • PAS IIIA - Autoimmune thyroiditis with immune-mediated diabetes (IMD) mellitus (also known as polyglandular autoimmune syndrome type 3 variant)
  • PAS IIIB - Autoimmune thyroiditis with PA
  • PAS IIIC - Autoimmune thyroiditis with vitiligo and/or alopecia and/or other organ-specific autoimmune disease

PAS III is associated with the following diseases:

Cases of PAS III associated with a different immunological or genetic disorders have been sporadically reported. The association of PAS III with common variable immunodeficiency (CVID) in a 24-year-old patient was described by Bahceci and colleagues. [3] This patient had PAS III due to the presence of autoimmune thyroiditis, hypergonadotropic hypogonadism, and growth hormone deficiency, without adrenal or parathyroid disease. Such coexistence of PAS III and CVID may be due to autoimmunity and the association of both conditions with human leukocyte antigen (HLA).

A rare case of PAS III in monozygotic twins, in which one of the twins also had autoimmune leukopenia, was also reported, [4] as was a case of PAS III with autoimmune leukopenia. [5] In addition, a case of PAS III complicated with autoimmune hepatitis was reported from Japan. [6] Another report from Japan described a 61-year-old woman with slowly progressive type 1 diabetes mellitus associated with chronic thyroiditis, pernicious anemia, and idiopathic thrombocytopenic purpura. [7] This patient had DQA1 0102, 0103 and DQB1 0602, 0601 that were considered as type 1 diabetes–protective HLA alleles. A case reported from Poland described acquired von Willebrand syndrome in a patient with severe primary hypothyroidism associated with myasthenia gravis in the course of PAS III. [8] PAS IIIC in 12-year-old boy with generalized vitiligo, alopecia universalis, and Hashimoto thyroiditis was recently reported from Turkey, and the patient was the youngest of previously reported cases. [9]

While it is rare, growth hormone deficiency may be a component of all PAS. It has been reported more often with PSA I and PSA II. Recently, an occurrence of growth hormone deficiency was reported in an 8-year-old child who has type 1 diabetes mellitus and received iodine I 131 ablation at age 5 years for hyperthyroidism, suggesting that it could also be a component of PAS III. [10] Ulcerative colitis and primary sclerosing cholangitis have also recently been reported as part of PSA III. [11] Association between PAS III and myasthenia gravis has been reported with both generalized myasthenia [12] and seronegative ocular myasthenia. [13] A complex case of PAS III, characterized by the association of Graves disease, autoimmune leukopenia, latent autoimmune diabetes of the adult (LADA), autoimmune gastritis, ulcerative colitis, Sjögren syndrome, and antiphospholipid syndrome has been recently reported. [14]

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Pathophysiology

Autoimmunity, environmental factors, and genetic factors are the 3 major factors that should be considered in the pathophysiology of PAS III.

Autoimmunity

Autoimmune disease affecting a single endocrine gland is frequently followed by impairment of other glands, resulting in multiple endocrine failure. The autoimmune pathogenesis of these disorders began to emerge in the mid-20th century. In 1956, Roitt and colleagues discovered circulating precipitating autoantibodies to thyroglobulin in patients with Hashimoto thyroiditis.

The identification of circulating organ-specific autoantibodies provided the earliest and strongest evidence for the autoimmune pathogenesis of polyglandular failure syndromes. Endocrine autoimmunities are associated with autoantibodies that react to specific antigens, whereas patients with collagen diseases synthesize immunoglobulins that recognize nonorgan-specific cellular targets, such as nucleoproteins and nucleic acids.

Cellular autoimmunity is also important in the pathogenesis of polyglandular failure syndromes. Histologic examination of the affected glands (eg, thyroid, parathyroid, ovaries, pancreatic islets, gastric mucosa) has demonstrated similar results, that is, mononuclear infiltrate composed mainly of lymphocytes, macrophages, natural killer (NK) cells, and plasma cells. The striking feature is the sparing of adjacent nontarget tissue. As the disease progresses, atrophy and fibrosis predominate.

Experimental animal models of PAS III have been described. In BioBreeding/Worcester (BB/W) rats, the frequency of chronic lymphocytic thyroiditis was remarkably increased in diabetic insulin-treated BB/W rats. [15]

Animal models have provided many of the insights into endocrine immunities. Polyglandular immunity, including gastritis, oophoritis, orchitis, and thyroiditis, could be induced in genetically susceptible mice by depleting T lymphocytes permanently or transiently. By using the model of neonatal thymectomy, it has been demonstrated that early interactions between the lymphoid system and target organs are important in the pathogenesis of autoimmunity. Furthermore, it also was demonstrated that CD4+ splenocytes from adult (but not neonatal mice) contain regulatory populations that can prevent the transfer of autoimmune endocrinopathies.

An autoimmune attack of a target organ often begins in individuals who have a genetic predisposition after an unknown precipitating event. The early process manifests by provoking autoantibody production, and it may arrest at this stage. Progressive disease is associated with secondary responses against antigens released by damaged tissue. Disease initially is detectable by observing minimal biochemical abnormalities such as elevation of trophic hormones. Organ function loss may plateau before the threshold of critical organ mass is reached, or it may progress to clinically overt disease. Early hormone replacement therapy may decelerate the destruction of surviving tissue; but, at the late stage, complete organ atrophy is inevitable.

Environmental factors

Some authorities postulate that environmental precipitators of autoimmunity might play a role in polyglandular autoimmunity. Viral infection may exaggerate the ongoing immune response and precipitate glandular failure, although no human epidemiological studies show infection triggering polyglandular autoimmunity.

The links between congenital rubella infection, type 1 diabetes mellitus, and hypothyroidism are well known. Reovirus type I infection in susceptible mice causes type 1 diabetes mellitus and growth failure.

International comparisons show a positive correlation between type 1 diabetes mellitus prevalence and ingestion of cow milk. Circulating autoantibodies against a peptide with homology to bovine serum albumin and human islet cell surface protein have been observed in patients with IMD.

Development of PAS III after interferon-alpha therapy for hepatitis C has been described, raising the possibility of interferon-enhanced major histocompatibility complex expression, which in turn initiated the onset of organo-specific autoantibodies and the clinical manifestations of autoimmune diseases.

Genetic factors

PAS III, as well as PAS II, is associated with HLA class II genes with apparently distinctive HLA alleles for each. The underlying non-HLA genes of PAS III remain to be further defined genetically. PAS III is often observed in individuals in the same family, suggesting that its inheritance could be an autosomal dominant trait with incomplete penetrance. [16, 17, 18]

HLA-DRB1*04/DQA1*0301/DQB1*0302 is the predominant HLA haplotype associated with susceptibility in IMD. Interestingly, the HLA-DQB1*0602 allele protects against IMD, even if the HLA-DQB1*0301 or DQB1*0302 susceptibility gene is present. HLA-DQB1*0301 is the HLA haplotype frequently associated with autoimmune thyroiditis. HLA-DRB1*13 is associated with vitiligo. Alopecia areata is strongly associated with DQB1*03 and DRB1*1104, which appear to be markers of general susceptibility to alopecia areata. In addition, the frequency of HLA-DRB1*0401 and DQB1*0301 is remarkably increased among patients with alopecia totalis and those with alopecia universalis, the most extensive form of the condition.

Multigenetic involvement in the development of the individual components of PAS III has been proved. For example, IMD is linked to several loci in non-HLA genomic regions. Furthermore, autoimmune thyroiditis also is polygenic.

Family and population studies showed that the PAS IIIA has a strong genetic background. Several gene variations present in both autoimmune thyroiditis and IMD have been identified by whole genome and candidate gene approaches. The most important susceptibility genes are human leucocyte antigen (chromosome 6), cytotoxic T-lymphocyte–associated antigen 4 (chromosome 2), protein tyrosine phosphatase nonreceptor type 22 (chromosome 1), forkhead box P3 (X chromosome), and the interleukin 2 receptor alpha/CD25 gene region (chromosome 10). [19]

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Epidemiology

Frequency

United States

The exact prevalence of PAS III in the United States is unknown.

International

The exact international prevalence of PAS III is unknown.

Mortality/Morbidity

The morbidity and mortality of PAS III is determined by the individual components of the syndrome.

Race

No racial or ethnic difference in frequency of PAS III has been reported.

Sex

PAS III is more common in females than in males.

Age

PAS III typically is observed in middle-aged women but can occur in persons of any age.

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