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AUTREV-01447; No of Pages 5
Autoimmunity Reviews xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev
Review
Autoimmune polyendocrine syndromes
Maurizio Cutolo ⁎,1
Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova Italy, Viale Benedetto XV, 6, 16132 Genova Italy
a r t i c l e
i n f o
Article history:
Received 16 July 2013
Accepted 27 July 2013
Available online xxxx
Keywords:
Autoimmune polyendocrine syndromes (APS)
Neuroendocrine immunology (NEI)
a b s t r a c t
Autoimmune polyendocrine syndromes (APS), also called polyglandular autoimmune syndromes (PGAS), are a
heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organs, although non-endocrine organs can be affected.
The two major autoimmune polyendocrine syndromes, (type1–type2/APS-1 and APS-2), both have Addison's
disease as a prominent component. Further autoimmune polyendocrine syndromes include APS3 and APS4.
The major autoimmune polyendocrine syndromes have a strong genetic component with the type 2 syndrome
occurring in multiple generations and the type I syndrome in siblings.
It is well recognized that more than 20 years may elapse between the onset on one endocrinopathy and the diagnosis of the next, for example, almost 40–50% of subjects with Addison's disease will develop an associated
endocrinopathy.
The discovery of the polyendocrine autoimmune syndromes offered the possibility to understand autoimmune
disorders with particular interest for type 1A diabetes and the neuroendocrine immunology (NEI) is further contributing to understand the links.
© 2013 Elsevier B.V. All rights reserved.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Autoimmune polyendocrine syndrome type 1 (APS-1) . . . . . . . . .
2.1.
Pathogenetic factors
. . . . . . . . . . . . . . . . . . . . .
2.2.
Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Diagnosis and treatment
. . . . . . . . . . . . . . . . . . .
3.
Autoimmune polyendocrine syndrome type 2 (APS-2, Schmidt's syndrome)
3.1.
Pathogenetic factors
. . . . . . . . . . . . . . . . . . . . .
3.2.
Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Diagnosis and treatment
. . . . . . . . . . . . . . . . . . .
3.4.
Other polyendocrine syndromes . . . . . . . . . . . . . . . .
4.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
The term autoimmune polyendocrine syndromes (APS) comprise
several and different conditions in which, however, not all patients
necessarily have multiple endocrine disorders, and many have
⁎ Tel.: +39 010 353 7994, +39 335 23 36 21 (mobile); fax: +39 010 353 8885.
E-mail address: mcutolo@unige.it.
1
Secretary: +39 010 353 8885.
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nonendocrine autoimmune diseases [1]. Interestingly, it is likely that
the involved tissues and organs do not share any specific molecule but
rather have different molecules that may more or less likely act as targets when the immune system fails to maintain self-tolerance to a variety of molecules.
The two major autoimmune polyendocrine syndromes, (autoimmune polyendocrine syndromes type1–type2/APS-1 and APS-2), both
have Addison's disease as a prominent component, but exist also APS-3
and APS-4.
1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.autrev.2013.07.006
Please cite this article as: Cutolo M, Autoimmune polyendocrine syndromes, Autoimmun Rev (2013), http://dx.doi.org/10.1016/
j.autrev.2013.07.006
2
M. Cutolo / Autoimmunity Reviews xxx (2013) xxx–xxx
The major autoimmune polyendocrine syndromes have a strong genetic component with the type 2 syndrome occurring in multiple generations and the type I syndrome in siblings [2].
In addition, patients with APS-1 and APS-2 develop multiple diseases over time and approximately one out of seven relatives of them
have an undiagnosed autoimmune disorder (most often hypothyroidism for the type 2 syndrome) [3].
For practical reasons the major pathological conditions associated
with both APS-1 and APS-2 are listed in Table 1.
2. Autoimmune polyendocrine syndrome type 1 (APS-1)
2.1. Pathogenetic factors
The APS-1 syndrome is almost always inherited in an autosomal recessive manner linked to mutation of the AIRE gene (AIRE: Autoimmune Regulator gene) on chromosome 21 [4,5].
In autoimmune disorders including Addison's disease, patients without the APS-1 syndrome, do not show AIRE mutations suggesting that
the gene alterations are not involved in these more common diseases.
In contrast, there is evidence that in rare diseases with abnormal
T cell development (i.e. T-B-SCID or Omenn syndrome) there are abnormal thymocyte epithelial interaction and deficient thymic AIRE and lack
of expression of AIRE dependent “peripheral” molecules such as insulin
[6].
It has been hypothesized that mutations of the AIRE gene (i.e. APS-1
syndrome) cause loss of peripheral antigen expression in the thymus
and probably decreased deletion of autoreactive T lymphocytes that target such peripheral antigens [7].
Patients with APS-1 express autoantibodies reacting with different
autoantigens, and particular patterns of autoantibodies are associated
with the syndrome [8]. The presence of anti-adrenal autoantibodies
(i.e. 21-hydroxylase) is strongly associated with the development of
Addison's disease.
In addition, anti-GAD autoantibodies of patients with the APS I syndrome differ from anti-GAD autoantibodies of typical patients with type
1 diabetes in terms of being able to react with GAD on Western blots and
inhibit enzymatic activity. Patients expressing multiple anti-islet autoantibodies are at higher risk for progression to diabetes.
Table 1
Major pathological conditions associated with both APS-1 and APS-2.
Major pathological conditions
associated with autoimmune
polyendocrine syndrome type 1
Addison's disease
Alopecia
Asplenism
Autoimmune bronchiolitis
Autoimmune thyroiditis
Chronic active hepatitis
Dental enamel and nail dystrophy
Major pathological conditions
associated with autoimmune
polyendocrine syndrome type 2
Alopecia
Myasthenia gravis
Autoimmune thyroiditis
Idiopathic heart block
Ectodermal dysplasia
Graves' disease
Hypogonadism
IgA deficiency
Keratitis
Malabsorption syndrome
Pernicious anemia
Pure red cell aplasia
Type 1 DM (18%)
Vitiligo
Graves' disease
Hypogonadism
Stiff-man syndrome
Parkinson’s disease
IgA deficiency
Serositis
Celiac disease, dermatitis herpetiformis
Pernicious anemia
Idiopathic thrombocytopenia
Hypophysitis
Type 1 DM (50%)
Vitiligo
APS-1 patients express additional autoantibodies consistent with
widespread loss of tolerance to multiple self antigens [8].
Recently 100% of patients with APS-1 have been found to express autoantibodies reacting with interferon-omega and the great majority express autoantibodies reacting with interferon alpha [9].
2.2. Onset
The onset of the disease is usually in infancy. Chronic mucocutaneous candidiasis is often the first condition detected, later complicated
by the development of adrenal insufficiency. Interestingly, the etiology
of the mucocutaneous candidiasis in the absence of systemic candidiasis
in the APS-1 syndrome has been related to anti-cytokine autoantibodies
(anti-IL17A, IL17F and IL22) related to Th17 T cells and depressed production of IL17F and IL22 by peripheral blood mononuclear cells
through increased IL17 with decreased IL22 also reported [10,11].
The most frequent pathological conditions related to the APS-1 autoimmune polyendocrine syndrome include Addison's disease, hypoparathyroidism and mucocutaneous candidiasis. This condition is also
termed as APECED autoimmune polyendocrinopathy-candidiasisectodermal dystrophy [12,13] (Table 1).
Other APS-1 associated diseases include autoimmune hepatitis, primary hypothyroidism, a malabsorption syndrome, vitiligo, pernicious
anemia, type 1 diabetes, alopecia, primary hypogonadism, cutaneous
abnormalities, pulmonary disease, ovarian failure, pericarditis, cerebellar degeneration, encephalopathy, asplenia, esophageal cancer,
polyneuropathy, pure red cell aplasia and others [14,15].
2.3. Diagnosis and treatment
The diagnosis of APS-1 is usually made with two or three of the following conditions: mucocutaneous candidiasis, hypoparathyroidism
and/or adrenal insufficiency (or autoantibodies against CYP450c21, 21
hydroxylase) [16].
Since the different components of disease develop over years to decades, surveillance is mandatory for other associated autoimmune disorders. Especially under the age of 30 years surveillance is suggested if
more than one of the following conditions is identified: chronic or recurring mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, chronic gastrointestinal disease characterized by obstipation,
diarrhea or steatorrhea, vitiligo, alopecia, keratoconjunctivitis or
urticaria-like erythema [17].
Consideration for AIRE gene mutational analysis should be
entertained (if possible) in the presence of those associations. Usually,
sudden hypercalcemia in hypoparathyroid individuals may signal the
beginning of adrenal insufficiency [18]. Symptoms of diarrhea, malabsorption with failure to thrive in children and/or obstipation may be
identified. These symptoms may be due to the underlying endocrine
disease (e.g. diarrhea with the hypocalcemia of hypoparathyroidism)
or may be a manifestation of a new disorder.
Treatment of course, will in part depend upon the autoimmune disorder identified and aggressive therapy of oral candidiasis is indicated in
order to prevent the late complication of epithelial carcinoma [19].
Recently, the presence of cardiac failure in APS-1 has been successfully cured with calcium, calcitriol and hydrocortisone supplementation, since hypocalcemia and hypocortisol state are curable causes of
myocardial dysfunction and subsequent congestive cardiac failure [20].
3. Autoimmune polyendocrine syndrome type 2
(APS-2, Schmidt's syndrome)
3.1. Pathogenetic factors
Differently from APS-1, genetic abnormalities underlie disease susceptibility for autoimmune polyendocrine syndrome type 2 (APS-2) and consist primarily of alleles of genes within the major histocompatibility
Please cite this article as: Cutolo M, Autoimmune polyendocrine syndromes, Autoimmun Rev (2013), http://dx.doi.org/10.1016/
j.autrev.2013.07.006
M. Cutolo / Autoimmunity Reviews xxx (2013) xxx–xxx
complex [21]. The primary association of APS-2, similar to many autoimmune conditions appears to be with class II HLA alleles (immune response genes) and in particular with DQ2 and DQ8.
Therefore, APS-2 is has been found strongly associated with
human leukocyte (HLA) haplotypes with DR3/DQ2 (DQ2:DQA1*0501,
DQB1*0201) and DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302) and with
DRB1*0404 [22–24]. In multiplex Addison's disease families, 95% of
DR3 haplotypes have HLA-B8 compared to approximately 50% of control U.S. DR3 haplotypes.
Several of the diseases of the type 2 syndrome are associated with
HLA antigens HLA-DR3 or HLA-DR4 [22,25]. Primary adrenal insufficiency in type 2, but not in type 1 APS, is strongly associated with both HLADR3 and HLA-DR4 [25].
The association of HLA markers with disease can correlate with inheritance of a common HLA-haplotype within families, but haplotypes
with DR3 are often introduced into the family by more than one relative.
Other HLA-B8 and DR3 associated illnesses include selective
IgA deficiency, juvenile dermatomyositis, and dermatitis herpetiformis,
alopecia, scleroderma, autoimmune thrombocytopenia purpura,
hypophysitis, metaphyseal osteopenia, serositis and premature
ovarian failure (16%) [26,27].
Even though signs and symptoms of disease may be absent, patients
with multiple disorders should be screened every few years with measurement of anti-islet antibodies, 21-hydroxylase autoantibodies and
transglutaminase autoantibodies, a sensitive thyrotropin assay, and
measurement of serum B12 levels [28,29].
Several autoantibodies are both disease specific (i.e. antiacetylcholine receptor antibodies in myasthenia gravis and antiTSH receptor antibodies in Graves' disease) and causal [30]. Other
autoantibodies such as anti-thyroid autoantibodies including antithyroid peroxidase, formerly termed anti-microsomal, and antithyroglobulin are as frequent among patients and relatives as to
be of little predictive value.
Similarly, many individuals may show antibodies to parietal
cells, H+/K+ adenosine triphosphatase of the stomach and intrinsic
factor, but the autoantibodies may not correlate well with abnormal gastric acid secretion or development of pernicious anemia
[31–33].
Further autoantibodies associated with the type 2 syndrome
include anti-melanocytic, anti-adrenal and anti-gonadal autoantibodies [34,35].
Finally, antibodies to specific receptors are characteristic of given
disorders for example anti-acetylcholine receptor antibodies of myasthenia gravis, and oocyte sperm receptor autoantibodies associated
with oophoritis.
3.2. Onset
It is recognized that more than 20 years may elapse between the
onset on one endocrinopathy and the diagnosis of the next, for example,
almost 40–50% of subjects with Addison's disease will develop an associated endocrinopathy.
However, a distinction must be made for subjects with isolated thyroid disease who have no family history of polyglandular syndrome
type 2, since relatively frequent in the general population. As matter
of fact, individuals have a relatively low probability of developing additional autoimmune disorders in comparison with individuals with rare
autoimmune disorders such as Addison's disease or myasthenia gravis.
Interestingly, initiating factors for the type 2 syndrome and its
component illnesses are not completely established except for celiac
disease (wheat protein gliadin), the insulin autoimmune syndrome
(i.e. methimizole), myasthenia gravis, type 1A diabetes (rarely congenital rubella), Graves' disease (rarely anti-CD52 monoclonal treating patients with multiple sclerosis) and hypothyroidism (interferon therapy
associated with thyroid autoimmunity and diabetes) [36–39].
3
3.3. Diagnosis and treatment
APS-2 is the most common autoimmune polyendocrine syndrome
and includes Addison's disease, Graves' disease (thyrotoxicosis), primary
hypothyroidism, primary hypogonadism, hypopituitarism, IgA deficiency, insulin-dependent or type 1A diabetes mellitus (IDDM), Parkinson's
disease, myasthenia gravis, celiac disease, vitiligo, serositis, stiff-man
syndrome, alopecia, pernicious, and autoimmune thyroiditis [1,21,27].
Generally, individuals with a single autoimmune disease are at increased risk for the development of a second disease compared to the
general population and often patient individuals with APS-2 syndrome
will develop autoimmunity sequentially over a period of many years.
In addition, patients often will not have polyglandular failure at the
onset of clinical symptoms of the initial autoimmune disease, conversely, the possible development of sequential autoimmune diseases should
be expected after a polyglandular disease.
Interestingly, controversy exists regarding the screening tests that
should be employed and the frequency of testing performed when
expecting an autoimmune diseases. For example, in patients affected
by type 1diabetes, the routine screening for thyroid disease with biochemical assays should be performed (i.e. TSH assay) [40].
Again, the screening for celiac disease within the APS-2 patients is
controversial, since the disease is expected in the diabetic population
and many of these patients are asymptomatic at the time of the diagnosis [41]. Increased concentrations of transglutaminase autoantibodies
are associated with a positive celiac biopsy [42].
Data on anti-pituitary autoimmunity have recently identified: IgG4
hypophysitis, anti-Pit1 combined pituitary deficiencies and recognition
of predictive pituitary antibody staining pattern [43]. In order to finalize
the diagnosis of APS-2, once a second autoimmune disease is identified,
a further extensive screening is suggested with the intention to identify
the further disease at an early stage.
Therefore, the screening for autoantibodies associated with diabetes
(i.e. IA-2, insulin and GAD), thyroid disease (i.e. TG and/or TPO),
Addison's disease (21-hydroxylase), celiac disease (transglutaminase)
and autoimmune hepatitis (cytochrome P450 enzymes) may discover
an associated autoimmune disease not yet clinically evident.
Treatment of the APS-2 syndrome is obviously related to the specific
disease manifestation with a some further suggestions [1,21,27].
3.4. Other polyendocrine syndromes
The third type of autoimmune polyendocrine syndromes (APS type 3)
involves the same disorder of endocrine glands as type 2 but usually
without any defect of adrenal cortex. If the autoimmune endocrine
gland disorder does not fulfill the criteria of APS 1–3, the disease may
be categorized as autoimmune polyendocrine syndrome type 4 [44]. Further syndromes are reported in the following Table 2.
4. Conclusions
The discovery of the polyendocrine autoimmune syndromes offered
the possibility to understand autoimmune disorders with particular interest for type 1A diabetes [52]. As matter of fact the early evidence that
type 1A diabetes should be considered as an autoimmune disorder
came from its association with spontaneous Addison's disease [53]. On
the other side, the first demonstration of cytoplasmic islet cell autoantibodies occurred in patients with polyendocrine autoimmunity [54].
Moreover, the relationships observed between the different polyendocrine autoimmune disorders suggest that as the disease pathogenesis is understood and antigen-specific therapies are developed, the
improved knowledge of pathogenesis and improvements in therapy
will be applicable to several autoimmune diseases.
The science of neuroendocrine immunology (NEI) is approaching
systematically from long time the intriguing relationships that characterize the polyendocrine autoimmune syndromes [55–57].
Please cite this article as: Cutolo M, Autoimmune polyendocrine syndromes, Autoimmun Rev (2013), http://dx.doi.org/10.1016/
j.autrev.2013.07.006
4
M. Cutolo / Autoimmunity Reviews xxx (2013) xxx–xxx
Table 2
Other polyendocrine syndromes.
Other polyendocrine syndromes
IPEX (Immune Dysfunction Polyendocrinopathy X-linked)
The IPEX syndrome is a very rare disorder that presents in neonates with fatal autoimmunity and has multiple different names reflecting endocrinopathy, allergic
manifestations, intestinal destruction and immune dysregulation [45].
Thymic tumor diseases
Thymomas and thymic hyperplasia are associated with a series of autoimmune
diseases and the most common are myasthenia gravis and red cell aplasia. In
addition, Graves' disease, type 1 diabetes, and Addison's disease may also be
associated with thymic tumors [46].
POEMS syndrome
POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin
changes) patients usually are characterized by a sensory motor polyneuropathy,
diabetes mellitus (50%), primary gonadal failure (70%), and a plasma cell dyscrasia
with sclerotic bony lesions [47].
Insulin autoimmune syndrome (Hirata syndrome)
The insulin autoimmune syndrome, associated with Graves' disease and
methimazole therapy (or other sulfhydryl containing medications) is of particular
interest due to a remarkably strong association with a specific HLA haplotype
(DR4-positive individuals with DRB1*0406) [48].
Adult Combined Pituitary Hormone Deficiency (CPHD)
Very rare disease. The pituitary-specific transcription factor Pit-1/GHF1 regulates
the expression of PRL, GH, and TSH beta genes through binding to specific regions of
the promoters of these genes. Mutations of the Pit-1 gene have been shown to be
responsible for a syndrome of combined pituitary hormone deficiency (CPHD), including complete GH and PRL deficiencies and central hypothyroidism [49].
Kearns–Sayre syndrome
From the first description by Kearns and Sayre in 1958, this syndrome, a complex
mitochondrial encephalomyopathy, has been diagnosed in several hundred
patients [50].
DIDMOAD syndrome (also termed Wolfram syndromes 1 and 2)
Wolfram syndrome 1 (WS1) is an autosomal recessive disorder characterized by
diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DI DM OA D
syndrome) associated with other variable clinical manifestations. The causative
gene for WS1 (WFS1) encoding wolframin maps to chromosome 4p16.1. Recently,
another causative gene, CISD2, has been identified in patients with a type of Wolfram
syndrome (WS2) resulting in early optic atrophy, diabetes mellitus, deafness, decreased lifespan, but not diabetes insipidus [51].
Take-home messages
• Autoimmune polyendocrine syndromes (APS—types 1/2/3/4) include
several and different conditions in which, however, not all patients
necessarily have multiple endocrine disorders, and many have
nonendocrine autoimmune diseases.
• The most frequent pathological conditions related to the APS-1 autoimmune polyendocrine syndrome include Addison's disease, hypoparathyroidism and mucocutaneous candidiasis.
• APS-2 is the most common autoimmune polyendocrine syndrome
and includes Addison's disease, Graves' disease (thyrotoxicosis), primary hypothyroidism, primary hypogonadism, hypopituitarism, IgA
deficiency, insulin-dependent or type 1A diabetes mellitus (IDDM),
Parkinson's disease, myasthenia gravis, celiac disease, vitiligo,
serositis, stiff-man syndrome, alopecia, pernicious, and autoimmune
thyroiditis.
• The science of neuroendocrine immunology (NEI) is investigating
from long time the complex relationships between immune system
and polyendocrine syndromes.
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