Causes and pathogenesis of generalized lipodystrophy

The cause of generalized lipodystrophy syndrome is unknown. The development of the disease can be triggered by various unfavorable factors (infection, craniocerebral trauma, surgery, pregnancy and childbirth, various types of stressful situations). In some cases, the cause of the disease cannot be determined. There are known cases of both congenital and acquired generalized lipodystrophy syndrome. The disease occurs mainly in women and manifests itself in most cases before the age of 40.

Most researchers adhere to the "central" theory of the origin of generalized lipodystrophy syndrome. This theory is convincingly supported by the results of a series of scientific studies conducted in 1963-1972 by L. H. Louis et al. These authors isolated a protein substance from the urine of patients suffering from generalized lipodystrophy syndrome, which, when systematically administered to experimental animals, caused a clinical picture of the disease, and when administered to humans once, it caused hypertriglyceridemia, hyperglycemia, and hyperinsulinemia. According to the authors, this substance has a pronounced fat-mobilizing effect and is of pituitary origin. The isolated and purified substance was studied using isoelectric focusing. It was found that it is not identical to any of the known pituitary hormones, although it has physicochemical properties similar to this group of protein hormones. In subsequent years, these studies found the same substance in the urine of some patients with diabetes mellitus, in the pituitary gland of dogs and sheep, and finally in the adenohypophysis of healthy people. Unfortunately, the quantitative determination of the described peptide in healthy people, patients with diabetes, and patients with generalized lipodystrophy syndrome has not been carried out, so at present it cannot be stated that its excessive content in the body leads to the development of generalized lipodystrophy syndrome. The amino acid sequence of this peptide also remains unstudied. Studies conducted at our institute jointly with Yu. M. Keda showed that the plasma of patients with generalized lipodystrophy syndrome does indeed have increased lipolytic activity, which speaks in favor of the presence of a factor with fat-mobilizing properties in the blood of these patients.

An assumption is made about the increase in the secretion of growth hormone in the syndrome of generalized lipodystrophy. However, most researchers have found a normal content of STH in the plasma of patients. A study of the pituitary reserves of growth hormone in patients with the syndrome of generalized lipodystrophy, conducted at the Institute of Experimental Endocrinology, did not reveal any deviations from the norm in any of the examined women. Therefore, we believe that a quantitative violation of the secretion of STH does not participate in the pathogenesis of the syndrome of generalized lipodystrophy. At the same time, the question of the secretion of growth hormone with altered biological properties, as well as the question of the violation of STH metabolism, remain open. It is known about the existence of a fragment of the human growth hormone molecule, which has a pronounced fat-mobilizing activity, but is completely devoid of a growth-stimulating effect.

Worthy of attention are recently obtained data that the main symptoms of generalized lipodystrophy can be caused by the use of a-protease inhibitors in clinical treatment. Thus, Sugg A. et al. showed that when using these drugs in AIDS patients, lipodystrophy, hyperinsulinism and carbohydrate metabolism disorders develop, i.e., a typical clinical picture of generalized lipodystrophy. The mechanisms of development of these symptoms have not yet been clarified.

A number of researchers prefer the "peripheral" theory of the genesis of generalized lipodystrophy. The absence of subcutaneous fat deposition may be associated, in their opinion, with an enzymatic defect - a congenital absence of triglyceride receptors on adipocytes, and possibly with other reasons. It seems that both of these theories are not mutually exclusive. Most likely, the syndrome of generalized lipodystrophy is heterogeneous, since any reason that causes the inability of adipocytes to deposit neutral fats automatically leads to the development of lipoatrophy, hyperlipidemia and compensatory chronic endogenous hyperinsulinemia with the subsequent development of a cascade of hormonal and metabolic reactions that form the clinical picture of the disease.

Pathogenesis of generalized lipodystrophy

Little is currently known about the pathogenesis of generalized lipodystrophy syndrome. For reasons unknown, the body loses the ability to accumulate neutral fats in fat depots, resulting in the development of generalized lipoatrophy and significant hyperlipidemia. In this case, lipids apparently cease to be an energy substrate, their utilization slows down significantly, and the liver and gastrointestinal tract become the only path of elimination. Prerequisites for the development of fatty liver dystrophy appear. Hyperinsulinemia occurs secondarily to restore the processes of neutral fat deposition in adipocytes. However, this reaction, as a compensatory reaction, is unable to normalize the functional activity of adipose tissue. As a result, the cardinal signs of generalized lipodystrophy syndrome - lipodystrophy and hyperlipidemia - remain, and the accompanying hyperinsulinemia turns from a compensatory mechanism into its opposite, contributing to the acceleration and increase of lipid synthesis in the liver. The condition is aggravated by the addition of insulin resistance with the subsequent development of insulin-resistant hyperglycemia.

Chronic endogenous hyperinsulinemia in generalized lipodystrophy syndrome appears to have a complex origin. As studies conducted in individuals with moderate carbohydrate intolerance show, hyperinsulinemia develops not only as a result of excessive insulin production by pancreatic beta cells, but also as a result of impaired metabolism of this hormone. Normally, 50-70% of insulin is destroyed in the liver. Reduced functional activity of liver tissue in generalized lipodystrophy syndrome due to its fatty degeneration leads to decreased insulin extraction by hepatocytes and increased insulin content in peripheral blood. As is known, a certain portion of insulin degradation is receptor-mediated, and insulin receptors can apparently be a reservoir of the hormone contained in plasma. Therefore, some decrease in the number of insulin receptors or their affinity for insulin, which occurs in generalized lipodystrophy syndrome, may also contribute to an increase in the concentration of the hormone in the blood.

Our observations have made it possible to partially explain the development of a number of clinical signs in generalized lipodystrophy syndrome. Thus, the hypertrophy of skeletal muscles, moderate prognathism, visceromegaly, growth regrowth in some patients in adulthood, excessive development of subcutaneous fat where it can still be deposited (in the face and neck area in approximately half of our patients), characteristic of this disease, can be explained, as noted above, by the presence of chronic endogenous hyperinsulinemia. Insulin has pronounced anabolic and some growth activity. In addition, there are assumptions about the possible effect of excess insulin circulating in the blood on specific tissue receptors of insulin-like growth factors, which have a chemical structure similar to insulin. Experimental data have been obtained on the cross-interaction of insulin and insulin-like growth factors with each other's specific receptors.

In this regard, our observations regarding the relationship between hyperinsulinemia and the functional state of the ovaries, as well as hyperinsulinemia and prolactin secretion, are of interest. Clinical studies conducted abroad have found a direct relationship between the level of testosterone and the insulin content in the blood of women with ovarian polycystic disease. At the same time, there are experimental data indicating the ability of insulin to stimulate the secretion of androgens by the ovarian stroma and thecal tissue in humans.

The works of E. I. Adashi and co-authors demonstrated the modeling role of insulin in relation to the sensitivity of the anterior pituitary gland to gonadotropin-releasing hormone. The same authors established a direct stimulating effect of insulin on lactotrophs and gonadotrophs of the adenohypophysis. There are also clinical data on the relationship between hypersecretion of prolactin and insulin. Thus, in women with moderate hyperprolactinemia, a reliable increase in the level of immunoreactive insulin after meals was detected. The presented data indicate a complex genesis of hypothalamic-pituitary-ovarian disorders in generalized lipodystrophy syndrome.

V. G. Baranov et al. consider generalized lipodystrophy syndrome to be a type of polycystic ovary syndrome. Noting the existing close connection between generalized lipodystrophy syndrome and the functional state of the ovaries, we cannot agree with this point of view. Polycystic ovary syndrome in generalized lipodystrophy syndrome is secondary and is apparently caused by hyperinsulinemia. The literature describes a number of syndromes of severe insulin resistance (which include generalized lipodystrophy syndrome), often accompanied by ovarian polycystic disease. The fact that hyperandrogenic ovarian dysfunction develops only in some patients with generalized lipodystrophy syndrome indicates the independence of generalized lipodystrophy syndrome as a nosological entity. The morphological study of the ovaries of patients with generalized lipodystrophy syndrome, operated on for ovarian hyperandrogenism, conducted by M. E. Bronstein, revealed in these patients pronounced stromal thecomatosis with characteristic morphological features that occur only in generalized lipodystrophy syndrome. Therefore, in our opinion, it would be correct not to consider generalized lipodystrophy syndrome as a variant of Stein-Leventhal syndrome, but, on the contrary, to consider hyperandrogenic ovarian dysfunction observed in generalized lipodystrophy syndrome as a specific form of ovarian polycystic disease.

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

Pathological anatomy of generalized lipodystrophy

During a morphological study of adipocytes in patients with generalized lipodystrophy syndrome, immature fat cells were found in the areas of lipoatrophy. When these cells were transplanted into healthy people, the transplanted adipocytes matured and began to function normally, forming adipose tissue. In generalized lipodystrophy syndrome, hypertrophy and hyperplasia of the endocrine glands and internal organs, true hypertrophy of skeletal muscles, thickening of articular cartilage, capsules and ligaments are observed.

[ 5 ], [ 6 ], [ 7 ]