Multiple endocrinopathies of autoimmune nature

In clinical practice, the greatest difficulties for diagnosis are endocrine diseases with symptoms of impaired functions of several endocrine glands. In most cases, clinical features of this kind are manifested in hypothalamic-pituitary disorders. However, endocrine syndromes are known, but little has been studied, in which the functions of several peripheral endocrine glands are primarily disturbed. The most common cause of this pathology is autoimmune lesions or tumors of two or more peripheral endocrine organs.

[1], [2], [3], [4], [5], [6], [7]

Forms

Currently, there are two main immune-endocrine syndromes of types I and II.

[8], [9], [10]

Autoimmune polyglandular syndrome type I

Autoimmune polyglandular syndrome type I (APGSI) is characterized by a classical triad: adrenal insufficiency in combination with mucocutaneous candidiasis and hypoparathyroidism. The disease is of a family nature, but usually affects one generation, most siblings. It appears more often in childhood and is known as juvenile familial polyendocrinopathy. The cause of the disease is unclear. An autosomal recessive type of inheritance is possible.

The first manifestation of autoimmune polyglandular syndrome I is usually chronic mucocutaneous candidiasis, most often in combination with hypoparathyroidism; later there are signs of adrenal insufficiency. Sometimes there are decades between the first and subsequent symptoms of the disease in the same patient. The classic triad of the disease is often accompanied by the pathology of other organs and systems. About 2/3 of patients with autoimmune polyglandular syndrome I suffer from alopecia, about 1/3 - malabsorption syndrome, gonadal insufficiency; less often they have chronic active hepatitis, thyroid disease, pernicious anemia, and about 4% develop insulin-dependent diabetes mellitus.

Patients often have antiadrenal and antiparatyroid antibodies. Many of them have hypersensitivity to any agent, part - hypersensitivity selectively to fungi, with candidiasis rarely seen in patients with autoimmune polyglandular syndrome I, which developed in the adult period. In adults, he often accompanies immunological disorders caused by thymoma. In patients with autoimmune polyglandular syndrome I, changes in T-lymphocytes are also described.

Treatment of adrenal insufficiency and hypoparathyroidism is described in the relevant chapters. Candidiasis therapy is successfully performed with ketoconazole, but rehabilitation takes at least 1 year. However, the withdrawal of the drug and even a reduction in the dose of ketoconazole often lead to a recurrence of candidiasis.

[11]

Autoimmune polyglandular syndrome type II

Autoimmune polyglandular syndrome II type is the most frequent variant of autoimmune polyglandular syndrome, it is characterized by the defeat of 2 or more endocrine organs with the development of adrenal insufficiency, hyper- or primary hypothyroidism, insulin-dependent diabetes mellitus, primary hypogonadism, myasthenia and steatorrhea. These manifestations are often accompanied by vitiligo, alopecia, pernicious anemia. The causes of an autoimmune polyglandular syndrome of type II are unknown.

However, in these diseases, certain immunogenetic and immunological manifestations related to the pathogenesis of the main components of the disease are always detected. Obviously, its triggering mechanism is the anomalous expression of antigens in the HLA system on the cellular membranes of the endocrine glands. The conditional HLA predisposition to autoimmune polyglandular syndrome is realized under the influence of some external factors.

All diseases encountered in combination with autoimmune polyglandular syndrome type II are mainly associated with the histocompatibility antigen HLA-B8. The heritability of the disease is often associated with the transition from generation to generation of the common haplotype HLA-AI, B8. Even in patients with symptoms of impaired function of 1-2 glands of internal secretion, organ-specific antibodies can be detected in the blood, including antigens of those organs that are involved in the pathological process, but its clinical manifestations are not revealed.

When microscopic examination of these organs, massive lymphoid infiltration with the formation of lymphoid follicles is revealed. There is a significant replacement of the parenchyma of the organ with a lymphoid tissue followed by fibrosis and organ atrophy. Approximately 3-5% of cases in the thyroid gland develops not an autoimmune thyroiditis, but another autoimmune pathology: Graves' disease with a clinical picture of thyrotoxicosis and a characteristic pathology in the thyroid gland with minor lymphoid infiltration. In the blood of these patients, thyroid-stimulating antibodies are detected.

The most frequent variant of autoimmune polyglandular syndrome of type II is Schmidt's syndrome, in which the adrenal gland and thyroid gland are affected by an autoimmune process; while it develops an  autoimmune thyroiditis. The main clinical manifestations of the syndrome are the symptoms of chronic adrenal insufficiency and hypothyroidism, although in some cases the function of the gland is not disturbed, especially in the early stages of the disease. 

Hypothyroidism  in these patients can be hidden. In 30% of patients, the syndrome is combined with insulin-dependent diabetes mellitus, 38% have antibodies to the thyroid gland microsomes, 11% have thyroglobulin, 7% have islet cells, and 17% have steroid-producing cells. The antibodies listed can be found in relatives of patients and in the absence of clinical manifestations of the disease. They can also detect antiparietal antibodies.

Autoimmune polyglandular syndrome II is often accompanied by atrophy of the optic nerves, lipodystrophy, autoimmune thrombocytopenic purpura, idiopathic diabetes insipidus with autoantibodies to vasopressin producing cells, multiple endocrine tumors syndrome, hypophysitis, pseudolymphoma, isolated ACTH deficiency, pituitary gland tumors.

[12], [13], [14], [15]

Diagnostics of the multiple endocrinopathies of autoimmune nature

For the diagnosis of disease, particularly in patients with lesions only single endocrine organ, such as the adrenal, should determine the content of T ₄  and TSH in the blood glucose level on an empty stomach; pay attention to the presence of signs of pernicious anemia, gonadal insufficiency and other endocrine symptoms.

Screening in families with patients with autoimmune polyglandular syndrome type II is conducted among its members aged 20 to 60 years every 3-5 years; They are examined for signs of disease. Furthermore, they have fasting glucose determined, antibodies to islet cell cytoplasm, the content of T ₄  and TSH in blood, excretion rate in urine 17-keto and 17-hydroxycorticosteroids in basal conditions and conditions of the sample with ACTH.

[16], [17], [18]

Treatment of the multiple endocrinopathies of autoimmune nature

Treatment of the syndrome is complex, it reduces to the treatment of its constituent diseases. Its methods are described in the relevant chapters. It should be noted that adrenal insufficiency therapy with corticosteroids may be accompanied by an improvement in functional disorders caused by autoimmune thyroiditis. These features of the course of combined autoimmune diseases of endocrine organs allow differentiating, for example, Schmidt's syndrome from Addison's disease with a secondary decrease in thyroid function. It is interesting to note that in a number of cases of Addison's disease of tuberculous etiology in the thyroid gland develops lymphomatous thyroiditis, and, conversely, in the Hashimoto's goiter, the adrenal glands are rarely affected by an autoimmune process.

It should also be remembered that reducing the need for insulin in patients with insulin-dependent diabetes mellitus may be the first manifestation of the presence of adrenal insufficiency before the appearance of electrolyte disorders and the appearance of hyperpigmentation. Diabetes mellitus in autoimmune polyglandular syndrome II often requires immunotherapy. However, side effects are also possible. Thus, cyclosporine causes nephrotoxicosis, hepatotoxicosis, decreased hemoglobin, hirsutism, gingival hypertrophy, development of lymphomas. Antilymphocytic globulin causes anaphylaxis, fever, skin rashes, transient, light thrombocytopenia, etc. Cytotoxic drugs and azathiaprin help inhibit myelopoiesis, the development of malignant neoplasms.

Syndromes of polyglandular insufficiency include a combination of pseudohypoparathyroidism and isolated deficiency of TGT, the cause of which is unclear; this association is obviously of genetic origin. Another combination of diseases (sugar and diabetes insipidus, optic nerve atrophy) is considered as a genetic anomaly with autosomalessive inheritance. Polyglandular insufficiency can develop with hemochromatosis, when iron deposition is observed only in the pancreas, liver, skin, as in the classical hemochromatosis, but also in the parenchymal cells of the thyroid and parathyroid glands, the pituitary gland and the adrenal glands.

"Bronze" diabetes, often observed in hemochromatosis, is caused not only by the deposition of iron in the skin, but also by concomitant hypocorticism. To the loss of the function of many endocrine glands can cause damage to the pituitary gland, adrenal glands, thyroid gland and other endocrine organs with giant cell granulomatosis of unclear etiology (non-tuberculous, non-serous, non-syphilitic). It most often develops in women 45-60 years old. It is impossible to exclude the autoimmune nature of the process, since the lymphoid elements are a constant component of the granulomas.