Polyglandular insufficiency syndromes

Syndromes of polyglandular insufficiency (autoimmune polyglandular syndromes, syndromes of polyendocrine deficiencies) are characterized by competitive disruption of the function of several endocrine glands. Etiology in most cases. Symptoms are determined by a combination of endocrine deficiencies, which can constitute any one of the three known types of pathology. The diagnosis is based on the results of hormonal studies and the determination of antibody levels against the endocrine glands involved in the pathological process. Treatment involves the replacement of a lost or deficient hormone.

[1], [2], [3], [4], [5]

Causes of the polyglandular insufficiency syndrome

The cause of development of endocrine deficiencies can be infections, infarctions or tumors that cause partial or complete destruction of the endocrine gland. Nevertheless, the triggering mechanism of polyglandular insufficiency is an autoimmune reaction leading to the development of autoimmune inflammation,  lymphocytic infiltration  and partial or complete destruction of the endocrine gland. Involvement in the pathological autoimmune process of one endocrine gland is almost always followed by the involvement of other glands, leading to the development of multiple endocrine deficiencies. Three models of emerging autoimmune disorders are described.

Type I

The onset usually occurs in childhood (especially often in the period from 3 to 5 years) or in adults under the age of 35 years. Hypoparathyroidism is the most frequent endocrine pathology (79%), followed by adrenal insufficiency (72%). Development of gonadal insufficiency occurs after the onset of puberty in 60% of women and about 15% of men. Chronic candidiasis of the skin and mucous membranes is a characteristic pathology. There may be malabsorption associated with a deficiency of cholecystokinin; other etiological factors include interstitial lymphangiectasia, IgA deficiency, excessive bacterial growth. Although 2/3 patients have antibodies to pancreatic glutamic acid decarboxylase, the development of type 1 diabetes is not common. Ectodermal diseases can also occur (for example, hypoplasia of tooth enamel, sclerosis of the tympanic membrane, tubulointerstitial pathology, keratoconjunctivitis). I type can develop as a hereditary syndrome, usually transmitted by an autosomal recessive type.

[6], [7], [8]

II type (Schmidt's syndrome)

Multiple endocrine deficiencies usually develop in adulthood, with a peak at 30 years. In women, this pathology is 2 times more common. At the same time, the cortical layer of the adrenal glands and often the thyroid gland and pancreatic islet cells, whose pathology is the cause of the development of type 1 diabetes, are always involved in the pathological process. Antibodies against target organs, especially against adrenocorticotropic hormones of cytochrome P450, are often detected. There may be a deficit of both mineralocorticoid and glucocorticoid functions. The destruction of the endocrine glands mostly develops as a result of cell-mediated autoimmune reactions, either as a result of a decrease in T-cell suppressor function, or as a result of the development of other types of T-cell mediated lesions. A characteristic feature is a decrease in systemic T-cell-mediated immunity, which is manifested by negative results of intradermal tests for standard antigens. In relatives of the 1st degree of kinship, the reactivity is also reduced, by about 30%, with normal endocrine function.

Some patients have thyroid-stimulating antibodies, and initially there are clinical symptoms of hyperthyroidism.

Theoretically, specific HLA types may have increased sensitivity to certain viruses, which can induce an autoimmune reaction. Pathology is usually inherited in an autosomal dominant type, with variable expressiveness.

Ill type

Ill type is characterized by endocrine disorders developing in adults, especially in middle-aged women. At the same time, the cortical layer of the adrenal glands is not involved in pathology, but at least 2 pathologies develop from the following: thyroid function deficiency, type 1 diabetes, pernicious anemia, vitiligo and alopecia. Heritability can follow an autosomal dominant type, with partial penetrance.

Symptoms of the polyglandular insufficiency syndrome

Clinical manifestations of the syndrome of polyendocrine deficiencies in patients consist of the sum of the symptoms of individual endocrine diseases. With these syndromes there are no specific clinical signs, as with individual endocrine pathology. Therefore, in patients with established any one endocrine disease after a certain period should be necessarily screened (clinical examination and laboratory diagnosis) and the presence of additional endocrine deficiencies. Relatives of patients with this pathology should be aware of the diagnosis, and they are strongly recommended to undergo a screening medical examination as prescribed by the doctor. Measurement of antibody levels to glutamic acid decarboxylase can help in establishing the degree of risk of developing pathology.

Diagnostics of the polyglandular insufficiency syndrome

The diagnosis is made clinically and is confirmed when there is a laboratory deficiency of hormone levels. Measuring the level of autoantibodies to the endocrine gland tissue involved in the pathological process can help differentiate the autoimmune endocrine syndrome from other causes of intraorganic pathology (eg, adrenal hypofunction of tuberculosis etiology, not autoimmune hypothyroidism).

The syndrome of polyendocrine deficiencies may indicate a pathology of the hypothalamic-pituitary zone. In almost all cases, increased levels of triple hormones in the pituitary gland in the plasma indicate the peripheral nature of the developing defect; nevertheless, sometimes hypothalamic-pituitary insufficiency develops as part of type II syndrome of polyendocrine deficiency.

Patients at risk without clinical manifestations of the syndrome should be tested for autoantibodies, since these antibodies can circulate for a long time in the blood without causing any endocrine pathology.

[9], [10]

Treatment of the polyglandular insufficiency syndrome

The treatment of various endocrine pathologies developing in certain endocrine organs was discussed in the relevant chapters of this manual. The presence in the clinical picture of signs of multi-organ endocrine pathology can complicate treatment.

Chronic candidiasis of the skin and mucous membranes usually requires prolonged antifungal therapy. If immunosuppressive doses of cyclosporine are administered to the patient in the early stages of development of endocrine disorders (within the first few weeks or months), treatment success can be achieved.

IPEX syndrome

IPEX (immune disorders, polyendocrinopathy, enteropathy, syndrome linked to the X chromosome) is a syndrome inherited in an autosomal recessive type and characterized by a pronounced immune autoaggression.

Without treatment IPEX syndrome usually ends fatal in the first year after diagnosis. Enteropathy leads to diarrhea. Immunosuppressive therapy and bone marrow transplantation can prolong life, but completely syndrome is incurable.

POEMS - syndrome

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes, Crow-Fukase syndrome) is not an autoimmune syndrome of polyendocrine deficiency.

The reason for POEMS-syndrome development is probably the circulating immunoglobulins produced by pathological clusters of plasma cells. Patients may develop hepatomegaly, lymphadenopathy, hypogonadism, type 2 diabetes mellitus, primary hypothyroidism, hyperparathyroidism, adrenal insufficiency and an increase in the formation of monoclonal IgA and IgG in myeloma and skin pathology (eg, skin hyperpigmentation, skin thickening, hirsutism, angiomas, hypertrichosis) . Patients may have swelling, ascites, pleural effusions, edema of the nipple and fever. Patients with this syndrome may also have elevated levels of circulating cytokines (IL1p, IL6), vascular endothelial growth factor and tumor necrosis factor a.

Treatment consists in carrying out autologous transplantation of hematopoietic stem cells with the subsequent appointment of chemotherapy and radiotherapy. The five-year survival rate for this pathology is about 60%.