Causes and pathogenesis of generalized lipodystrophy

The cause of the syndrome of generalized lipodystrophy is unknown. Various adverse factors (infection, traumatic brain injury, surgery, pregnancy and childbirth, various stressful situations) can serve as impetus to the development of the disease. In some cases, the cause of the disease can not be established. There are cases of both congenital and acquired syndrome of generalized lipodystrophy. The disease occurs mainly in women and is manifested in most cases up to 40 years.

Most researchers adhere to the "central" theory of the origin of the syndrome of generalized lipodystrophy. This theory is convincingly demonstrated by the results of a series of scientific studies conducted in 1963-1972. LH Louis et al. These authors isolated from the urine of patients suffering from generalized lipodystrophy syndrome, a protein that, when systematically administered to experimental animals, gave them a clinical picture of the disease, and once administered to a person, hypertriglyceridemia, hyperglycemia and hyperinsulinemia. According to the authors, this substance has a pronounced fat-mobilizing effect and has a pituitary origin. The isolated and purified this substance was studied by the method of isoelectric focusing. It was found that it is not identical to any of the known hormones of the pituitary gland, although it possesses physicochemical properties similar to this group of protein hormones. In subsequent years, these studies found the same substance in the urine of some diabetic patients, 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, diabetic patients and patients with the syndrome of generalized lipodystrophy was not carried out, therefore at the present time it cannot be stated that its excessive content in the body leads to the development of the syndrome of generalized lipodystrophy. The amino acid sequence of this peptide also remains unexplored. Studies conducted at our institute together with Yu. M. Keda showed that the plasma of patients with generalized lipodystrophy syndrome actually has an elevated lipolytic activity, which speaks in favor of the presence in the blood of these patients of a factor with fat-mobilizing properties.

It is suggested that the increase in the syndrome of generalized secretion lipodystrophy growth hormone. However, most researchers found normal levels of GH in the plasma of patients. The study of pituitary reserves of growth hormone in patients with generalized lipodystrophy syndrome, conducted at the Institute of Experimental Endocrinology, did not reveal any deviations from the norm in one of the examined women. Therefore, we believe that a quantitative violation of the secretion of growth hormone is not involved in the pathogenesis of the syndrome of generalized lipodystrophy. At the same time, the issue of secretion of growth hormone with altered biological properties, as well as the issue of disturbance of GH metabolism, remains open. It is known that there is a fragment of a human growth hormone molecule, which has a pronounced fat-mobilizing activity, but is completely devoid of growth-stimulating effect.

Recent evidence suggests that the main symptoms of generalized lipodystrophy can be triggered when used in the clinic to treat a-protease inhibitors. So, Sagg A. Et al. Showed that the use of these drugs in patients with AIDS develops lipodystrophy, hyperinsulinism and carbohydrate metabolism, ie, 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 genesis of generalized lipodystrophy. The lack of deposition of subcutaneous fat may be due, in their opinion, to an enzymatic defect — a congenital absence of triglyceride receptors on adipocytes, and possibly other causes. It seems that both these theories are not mutually exclusive. Most likely, the syndrome of generalized lipodystrophy is heterogeneous, since any reason that causes adipocyte inability to deposit neutral fats automatically leads to lipoatrophy, hyperlipidemia, and compensatory chronic endogenous hyperinsulinemia with the subsequent development of a cascade of hormonal and metabolic reactions that form a clinical disease of the disease.

Pathogenesis of generalized lipodystrophy

Little is known about the pathogenesis of generalized lipodystrophy syndrome. For reasons not yet known, the body loses its ability to accumulate neutral fats in fat depots, as a result of which generalized lipoatrophy and significant hyperlipidemia develop. At the same time, lipids, apparently, cease to be an energy substrate, their utilization slows down significantly, and the only way to eliminate the liver and the gastrointestinal tract. There are prerequisites for the development of fatty liver. To restore the deposition of neutral fats in adipocytes, hyperinsulinemia occurs a second time. However, this reaction as a compensatory reaction is unable to normalize the functional activity of adipose tissue. As a result, the cardinal signs of the syndrome of generalized lipodystrophy - lipodystrophy and hyperlipidemia - remain, and the joined hyperinsulinemia from the compensatory mechanism turns into its opposite, contributing to the acceleration and increase in lipid synthesis in the liver. The condition is aggravated by the addition of insulin resistance with the subsequent occurrence of insulin-resistant hyperglycemia.

Chronic endogenous hyperinsulinemia in the syndrome of generalized lipodystrophy has, apparently, a complex origin. As shown by studies conducted in individuals with moderate impaired carbohydrate tolerance, hyperinsulinemia develops in them not only because of excessive production of insulin by pancreatic beta cells, but also as a result of metabolic disorders of this hormone. Normally, 50-70% of insulin is destroyed in the liver. The decrease in the functional activity of the liver tissue in the syndrome of generalized lipodystrophy due to its fatty degeneration leads to a decrease in the extraction of insulin by hepatocytes and an increase in its content in peripheral blood. As it is known, a certain part of insulin degradation is receptor-conditioned, and insulin receptors, apparently, can be a reservoir of the hormone contained in plasma. Consequently, a slight 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 allowed us to partially explain the development of a number of clinical signs in generalized lipodystrophy syndrome. For example, hypertrophy of skeletal muscles, moderate prognathism, visceromegaly, resumption of growth in a number of patients in adulthood, excessive development of subcutaneous fat, where it can still be deposited (in the face and neck area in about half of our patients), can be explained as noted above, the presence of chronic endogenous hyperinsulinemia. Insulin has a pronounced anabolic and some growth activity. In addition, there are suggestions about the possible effect of an excess of insulin circulating in the blood on specific tissue receptors of insulin-like growth factors that have a chemical structure similar to insulin. Experimental data on the cross-interaction of insulin and insulin-like growth factors with specific receptors of each other were obtained.

In this regard, interesting are our observations regarding the relationship between hyperinsulinemia and the functional state of the ovaries, as well as hyperinsulinemia and prolactin secretion. Conducted overseas clinical studies have found a direct correlation 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 showing the ability of insulin to stimulate the secretion of androgens by ovarian stromal and human thecal tissue.

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

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

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

Pathology of generalized lipodystrophy

When conducting a morphological study of adipocytes in patients with generalized lipodystrophy syndrome, immature fat cells were found at the sites of lipoatrophy. When these cells were transplanted to healthy people, the transplanted adipocytes matured and began to function normally, forming adipose tissue. The syndrome of generalized lipodystrophy is marked by hypertrophy and hyperplasia of the endocrine glands and internal organs, true hypertrophy of the skeletal muscles, thickening of the articular cartilage, capsules and ligaments.

[5], [6], [7]