Introduction
Polyglandular deficiency syndromes manifest as a cluster of symptoms, including potentially fatal endocrine gland and gastrointestinal dysfunctions. Autoimmune illnesses develop when the body's antibodies and immune cells attack one or more antigens in its own tissues. Autoimmune polyglandular syndrome -1 is caused by alterations in the gene called autoimmune regulator (AIRE). HLA-DR/DQ genes also contribute to determining which of the component autoimmune diseases the patient develops. Autoimmune polyglandular syndrome -1 must be recognized from the unrelated but more prevalent autoimmune polyglandular syndrome -2, which is characterized by type 1 diabetes and autoimmune thyroid disorders.
What Are the Causes of Autoimmune Polyglandular Deficiency Syndromes?
The most common cause is autoimmune. The following are risk factors for the development of autoimmunity:
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Factors of genetic origin.
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Triggers in the environment.
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Drugs.
The AIRE gene mutation, which causes type 1, and specific human leukocyte antigen (HLA) subtypes, which play a role in the development of types 2 and 3, are both genetic factors.
Viral infections, nutritional variables, and others are examples of environmental triggers.
Immune checkpoint inhibitors are employed in the treatment of specific cancers and have been linked to autoimmune endocrine disorders such as type 1 diabetes mellitus, hypophysitis, thyroid dysfunction, and inadequate primary levels of the hormones in the body.
What Is the Pathophysiology of Polyglandular Deficiency Syndrome?
The most common cause is autoimmune. Risk factors for the emergence of autoantibodies against endocrine tissues, cell-mediated autoimmunity, or both are involved in the underlying autoimmune reaction, which causes inflammation, lymphocytic infiltration, and partial or total gland death. Although clinical signs are not usually contemporaneous, more than one endocrine gland is implicated. Non-endocrine tissues can also be damaged by the autoimmune reaction and the resulting immune system malfunction.
What Are the Types of Polyglandular Deficiency Syndrome?
In polyglandular deficiency syndrome, three forms of immunological failure have been described, most likely representing separate autoimmune disorders. Some experts merge types 2 and 3 into a single category. Type 2 diabetes affects roughly 1 in 1000 people, while type 1 affects about 1 in 100,000.
Type - 1 Polyglandular Deficiency Syndrome
The autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also known as type 1 polyglandular deficiency, typically manifests in childhood. It has an autosomal recessive inheritance pattern and is brought on by mutations in the AIRE gene. It is indicated by at least two of the following:
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Chronic mucocutaneous candidiasis.
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Addison disease.
The first clinical symptom, typically presenting in individuals under the age of five, is candidiasis (it is a fungal infection caused by Candida albicans). Next, hypoparathyroidism develops, typically in individuals under ten years old. Patients under 15 years old get inadequate levels of hormones in the body. At least until the patient reaches the age of roughly 40, accompanying endocrine and nonendocrine diseases.
Type - 2 Polyglandular Deficiency Syndrome
Schmidt syndrome, sometimes referred to as type 2 polyglandular deficiency, mostly affects adults; the peak incidence is at age 30. Women experience it three times as frequently as males. It demonstrates polygenic inheritance and is linked to specific HLA genotypes. The following are typical signs of it.
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Inadequate levels of the hormones in the body.
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Hyperthyroidism versus hypothyroidism.
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Glucose intolerance type 1 (autoimmune etiology).
Type - 3 Polyglandular Deficiency Syndrome
Failure of the glands of type 3 typically affects adults, notably middle-aged women. Additionally, it displays polygenic inheritance and is linked to specific human leukocyte antigen genotypes. It is distinguished by hypothyroidism. Type 3 excludes the involvement of the adrenal cortex.
What Are the Signs and Symptoms Associated With Polyglandular Deficiency Syndrome?
Patients with polyglandular deficiency syndromes exhibit a combination of the accompanying nonendocrine illnesses and distinct endocrine deficits. Deficiencies in such circumstances may not always develop at the same time and may take years to manifest; they also do not always happen in the same order.
Some of the symptoms associated with polyglandular deficiency syndromes (type - 1) are:
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Hypoparathyroidism.
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Type 1 diabetes mellitus with inadequate levels of hormones in the body.
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Hypothyroidism.
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Ovarian failure.
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Male Patients with affected testicles.
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Failure of the gastric parietal cell.
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Ectodermal dysplasia due to hepatitis.
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Keratopathy.
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Alopecia.
Some of the symptoms associated with polyglandular deficiency syndromes (type - 2) are:
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Diabetes mellitus type 1.
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Autoimmune thyroid disease.
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Inadequate levels of hormones in the body.
Some of the symptoms associated with polyglandular deficiency syndromes (type - 3) are:
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Diabetes mellitus type 1.
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Autoimmune thyroid disease.
How Is Polyglandular Deficiency Syndrome Diagnosed?
Polyglandular deficiency can be diagnosed by the following methods:
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Hormone level measurement.
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On occasion, autoantibody titers.
Polyglandular deficiency disorders are diagnosed clinically and by measuring low hormone levels. In addition, hypothalamic-pituitary dysfunction and coincidental endocrine dysfunction brought on by distinct sources might result in various endocrine deficits (for example - tuberculous hypoadrenalism and non-autoimmune hypothyroidism in the same patient).
Autoantibodies against type 1 interferons are linked to type 1 polyglandular deficiency, and their existence signals this condition, which can be diagnosed further via mutational analysis of the AIRE gene. Elevated pituitary tropic hormone levels, such as thyroid-stimulating hormone, indicate the hypothalamic-pituitary axis is intact and can be used to distinguish polyglandular deficiency disorders from other causes (even if some people with type 2 polyglandular deficiency syndrome have insufficient hypothalamic-pituitary axis).
Lifelong follow-up is advised because decades may pass before all indications develop; undiagnosed hypoparathyroidism or inadequate levels of the adrenal hormones in the body can be fatal.
What Are the Treatment Plans Associated With Polyglandular Deficiency Syndrome?
The recommended course of treatment for autoimmune polyglandular syndrome - 1 is immune suppression and modulation using drugs like glucocorticoids like Prednisone, Cyclosporin, calcineurin inhibitors (Tacrolimus and Sirolimus), Methotrexate, Mycophenolate mofetil, Rituximab, a CD20 inhibitor; these are particularly used for auto-immune hepatitis, enteropathy, tubulointerstitial nephritis.
The known hormonal deficiencies should be treated with hormone and vitamin replacement (Vitamin D, B12), and other deficiencies should be anticipated and checked for on a regular basis, especially in people who have circulating antibodies for thyroid antibodies (TPO, TG antibodies), antibodies for thyroid hormones (TPO, TG antibodies), and antibodies for calcium, phosphate, or parathyroid hormone levels that are indicated. In addition to rigorous clinical examination at intervals of 6 months to 1 year in afflicted patients, periodic evaluation of hemoglobin A1c, fasting glucose, and liver function via ALT (alanine transaminase) and AST (aspartate aminotransferase) should be performed.
According to current recommendations for treating the main components of autoimmune polyglandular syndrome -2 and 3, treatment of autoimmune polyglandular syndrome -2 should concentrate on replacing missing hormones. A patient with autoimmune polyglandular syndrome -2 or 3 has a higher chance of acquiring another autoimmune illness that affects a specific organ. Specific precautions are required particularly if vitiligo and pernicious anemia are common. A massive family history of autoimmune illnesses, particularly with an early debut, may point to a monogenic disease, maybe a "non-classical" autoimmune polyglandular syndrome -1.
Conclusion
The function of many endocrine glands may be impaired simultaneously or sequentially in polyglandular deficient disorders. Organs other than the endocrine system may also be impacted. The majority of cases are autoimmune; triggers are frequently unknown but may include viruses, dietary components, or medications. The afflicted glands help to distinguish polyglandular deficient disorders. Deficient hormones are replaced as part of the treatment. For the detection and treatment of autoimmune polyglandular syndrome-related disorders, better diagnostic methods, like genetic tests and autoantibody studies, have been developed over the previous ten years. Early diagnosis and personalized genomics may allow medical professionals to administer early immunomodulatory therapy to lessen the autoimmune process before irreversible organ damage occurs.
