CHANGES IN THE CYTOKINE AND LIPID TRANSPORT SYSTEM IN PATIENTS WITH VIRAL HEPATITIS C AND VARIOUS DERMATOLOGICAL MANIFESTATIONS

ABSTRACT

The aim of the study was to study the state of the cytokine and lipid transport systems in patients with viral hepatitis with dermatological manifestations. The total number of 62 patients with chronic viral hepatitis with dermatological manifestations were examined. The parameters of cytokine and lipid transport systems in the blood were studied. It was revealed a high level of pro-inflammatory (TNF-a and IL-6) and a low level of anti-inflammatory (IL-10) cytokines, which were accompanied by an increase in the amount of total cholesterol, triglycerides and low-density lipoproteins in patients with viral hepatitis with manifestations of a dermatological nature.

The article presents data from a study of cytokine and lipid transport systems in patients suffering from viral hepatitis C and various dermatological diseases. According to the data obtained, in all 62 patients the content of circulating immune complexes increased by 1.7 times, TNF-a by 81%, IL-6 by 2.8 times, while IL-10 levels were significantly lower by 47% in compared with data from the control group, while in the lipid transport system the patients had dyslipidemia, characterized by an increase in the content of total cholesterol, triglycerides and low-density lipoproteins. The formation of atherogenic dyslipidemia in patients with viral hepatitis C and dermatological manifestations is associated with a high viral load, which is associated with a decrease in apolipoprotein A1 and Apo-B.

АННОТАЦИЯ

Цель исследования — изучить состояние систем транспорта цитокинов и липидов у больных вирусными гепатитами с дерматологическими проявлениями. Всего обследовано 62 больных хроническими вирусными гепатитами с дерматологическими проявлениями. Изучены параметры систем транспорта цитокинов и липидов в крови. Выявлен высокий уровень провоспалительных (ФНО-а и ИЛ-6) и низкий уровень противовоспалительных (ИЛ-10) цитокинов, которые сопровождались увеличением количества общего холестерина, триглицеридов и низким уровнем -липопротеиды плотности у больных вирусными гепатитами с проявлениями дерматологического характера.

В статье представлены данные исследования систем транспорта цитокинов и липидов у больных вирусным гепатитом С и различными дерматологическими заболеваниями. Согласно полученным данным, у всех 62 больных содержание циркулирующих иммунных комплексов увеличилось в 1,7 раза, ФНО-а - на 81%, ИЛ-6 - в 2,8 раза, при этом уровни ИЛ-10 были достоверно ниже на 47% по сравнению с данными. от контрольной группы, тогда как в липидтранспортной системе у больных наблюдалась дислипидемия, характеризующаяся увеличением содержания общего холестерина, триглицеридов и липопротеидов низкой плотности. Формирование атерогенной дислипидемии у больных вирусным гепатитом С и дерматологическими проявлениями связано с высокой вирусной нагрузкой, что связано со снижением аполипопротеина А1 и Аро-В.

Keywords: cytokine system, lipid transport system, viral hepatitis, skin rashes.

Ключевые слова: цитокиновая система, система транспорта липидов, вирусный гепатит, кожные высыпания.

INTRODUCTION

The hepatitis virus infects more than 150 million people worldwide. In most cases, viral hepatitis becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. At the same time, viral infection affects cholesterol homeostasis, and at the molecular level, each stage of the life cycle of the virus is closely related to lipid metabolism. It should be noted that the infection caused by the hepatitis virus is traditionally characterized by long-term persistence of the pathogen in the human body and many years of asymptomatic course [1,9]. Meanwhile, the pathological processes occurring in the liver, according to the opinion, sooner or later lead to a violation of its functions, one of which is participation in fat metabolism [3,4,10]. Research by Fadeenko G.D. (2003) [4]; and by Iino S. (2000) [5] proved that the hepatitis virus itself is able to change cell genes, including those are responsible for lipid metabolism, in particular, for cholesterol homeostasis. It is worth noting that patients infected with genotype 3 viruses are more prone to severe steatosis, suggesting that specific viral sequences are responsible for lipid accumulation in the liver. Although several mechanisms have been proposed to explain viral steatosis, no experimental model clearly reproduces the phenotype observed in humans [2].

More than twenty-five years of research have identified the molecular mechanisms of the link between HCV and lipid metabolism. The advent of an infectious system capable of supporting strong amplification of viral hepatitis in cell culture (HCVcc) has expanded our understanding of the role of lipids at every stage of the virus life cycle. Lipid metabolism is deeply involved in the molecular mechanisms of the infectious cycle of viral hepatitis [2,7,8]. While viral hepatitis is a lipoprotein that uses lipid-related factors to enter, viral replication is associated with profound changes in intracellular membrane architecture and viral assembly, and secretion occurs in the microenvironment of the endoplasmic reticulum (ER) and lipid droplets that occlude the secretion pathway. very low-density lipoproteins (VLDL). In addition, the lipid composition of viral hepatitis virions indicates that more than half of all viral hepatitis lipids are composed of cholesterol esters, which resembles the lipid content of VLDL and low-density lipoprotein (LDL) [7,11]. At the same time, the initial attachment of viral hepatitis particles to hepatocytes is mediated by the binding of the virion to heparan sulfate proteoglycans. It has recently been shown that the hepatitis virus virion mainly uses the syndecan-1 heparan sulfate proteoglycan to initiate entering into human hepatocytes. It initiates its life cycle by binding to glycosaminoglycans (GAGs) [13]. Then the lipoprotein component of the viral particle interacts with the LDL receptor [10]. Lipoprotein lipase has been shown to modulate hepatitis virus entering into hepatocytes [13]. Consistent with the role of fatty acid synthesis in promoting hepatitis virus replication, exogenous addition of saturated and monounsaturated fatty acids has been shown to increase genotype 1b replicon replication. However, polyunsaturated fatty acids (PUFAs) are inhibitory. This inhibition has been shown to result from PUFA peroxidation, which can be blocked by vitamin E [12,13,14].

As you know, the main function of the skin is to prevent fluid loss. The fluid loss barrier is located in the intercellular lipids (primarily sterols, fatty acids and sphingolipids) of the stratum corneum. The epidermis is a very active site for lipid synthesis, and when the permeability barrier is broken down by topical solvents or detergents, there is a marked stimulation of sterol, fatty acid, and sphingolipid synthesis. When the defect in barrier function is artificially corrected by occlusion with a water vapor impermeable membrane, as a result an increase in epidermal lipid synthesis is prevented, suggesting that water flow may be a regulating factor. The activity of the key enzyme that limits the rate of cholesterol synthesis, HMG-CoA reductase, increases after destroying the barrier [6].

Based on the foregoing, the unique interaction between the hepatitis virus and lipid metabolism makes it possible to study in depth the role of lipids at all stages of the infectious cycle of the virus, especially in dermatological manifestations [6,15,18,19]. Importantly, further research on the interaction between hepatitis virus and lipid metabolism in dermatological manifestations also has the potential to help better understand the role of certain lipids in cellular metabolism.

AIM: The aim of the study was to study the state of the cytokine and lipid transport systems in patients with viral hepatitis with dermatological manifestations.

MATERIAL AND RESEARCH METHODS

The total number of 62 patients with chronic viral hepatitis with dermatological manifestations were examined. The studies were carried out in strict accordance with the requirements of biomedical ethics in accordance with the Geneva Convention on Human Rights (1997) and the Helsinki Declaration of the World Medical Association (2000) based on the permission of the local ethical committee. In the group with chronic hepatitis by sex, the patients were distributed as follows: men — 58%, women 42%, the average age of patients was 35.6±10.7 years. All patients received written voluntary informed consent to participate in the study. Inclusion criteria: verified diagnosis of chronic viral hepatitis B and C detected by polymerase chain reaction (PCR) using a test system, patients who did not receive antiviral therapy. Exclusion criteria: patients under 18 years of age with concomitant viral hepatitis D or other diseases that cause liver damage, HIV infection, history of pulmonary tuberculosis, autoimmune, oncological diseases, as well as pregnant women. In order to determine the control values of the healthy studied parameters of the hemostasis system, 16 practically individuals aged 25 to 45 years were examined, who gave informed consent to the examination, did not differ from patients in gender and age, who, according to the anamnesis, did not have the results of biochemical and serological studies of viral infections. hepatitis and other liver diseases. The work used instrumental studies: ultrasound examination of the abdominal organs, clinical and laboratory methods. The indicators of glycemia, lipid spectrum (total cholesterol (CH), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), very low-density lipoprotein (VLDL), triglycerides (TG)), apolipoprotein A (ApoA1) and B (ApoV). The studies were carried out by enzyme immunoassay using reagents and equipment from HUMAN. The coefficient of atherogenicity was determined by the formula: (HDL-C)/HDL. The content of cytokines in the blood serum (IL-6, IL-10 and TNF) was determined by enzyme immunoassay using kits from Vector-Best (Russia).

Statistical processing of the obtained results was carried out using the applied analysis package of the spreadsheet editor Microsoft Excel 2002. The average sample and the error of the mean (M ± m) were calculated. The significance of differences for dependent and independent samples between the two means was assessed by Student's f-test. Differences in the compared indicators were taken as reliable results at p < 0.05.

RESEARCH RESULTS AND DISCUSSION.

As is known, in violation of the barrier function of the skin on the background of chronic viral pathology of the liver, there is a possibility of developing autoimmune diseases. This condition may be one of the reasons for insufficient delivery of lipids by the liver and an imbalance in their content in the blood. Due to impaired synthesis and delivery of lipids to various organs and tissues, in particular the skin, the pathogenetic mechanisms of skin permeability are disrupted, manifested both in transepidermal water loss (TEWL) and in skin susceptibility to infection, inflammation and contact sensitization {Eberting CL, Coman G, Blickenstaff N., 2014; Kovaleva Yu.S., Vedler A.A., Kozhevnikova P.E., 2019].

It should be noted that lipids affect all the main links in the protection of the epidermis and dermis: they strengthen the mechanical strength of the stratum corneum and dermis, stabilize chemical and physical protection, including preventing the penetration of foreign substances and microorganisms into the dermis, and also reduce the transepidermal loss of water and electrolytes. , reduce the damaging effect of UV and increase antimicrobial protection [Khlebnikova A.N., Petrunin D.D., Molochkov A.V., 2015; Petrova S.Yu., Albanova V.I., 2022].

As is known, the lipid matrix of the stratum corneum consists of ceramides, cholesterol and fatty acids and is a unique lamellar structure that helps reduce transepidermal skin moisture loss and prevents the penetration of foreign substances into the skin. In turn, keratinocytes synthesize lipids of the stratum corneum, in particular 7-dehydrocholesterol, which increases protection from ultraviolet rays, reduces DNA damage, reduces the process of apoptosis, increases cell survival and reduces erythema.

In healthy skin, disruption of skin barriers initiates a sequence of events that rapidly lead to the return of lipids to the stratum corneum and restoration of its barrier function. Meanwhile, in viral intoxication, the skin barrier increases the synthesis of cholesterol and fatty acids in the epidermis to prevent transepidermal water outflow, otherwise the restoration of the barrier function is delayed. As is known, the depletion or disruption of essential lipids in the stratum corneum, which can be caused by various factors, is considered one of the etiological factors that cause dryness and disruption of the skin barrier. As a result, the skin loses water and becomes dry, chapped, and cracked, allowing allergens, toxins, and microorganisms to enter, which can cause skin inflammation and irritation. Inflammation, in turn, can cause further damage to barrier function, completing a vicious cycle. It can also lead to other skin conditions such as severe dryness, itching and scratching which can further lead to secondary skin infections. Conversely, over the past three decades, numerous data have shown that patients with certain skin diseases, such as psoriasis, atopic dermatitis (AD), ichthyosis and xerosis, have a marked depletion of stratum corneum lipids. The secretion of pro-inflammatory cytokines also aggravates skin diseases. Therefore, depletion or disruption of any class of lipids (cholesterol, fatty acids, sphingomyelin, ceramides) results in impaired skin barrier function. Based on the foregoing, one of the objectives of our study was to analyze the cytokine composition of blood in patients with viral hepatitis with dermatological manifestations.

As is known, keratinocytes have the ability to produce interleukin-1. Interleukin-1, produced by keratinocytes, is called the epidermal thymocyte-activating factor. Keratinocytes are capable of phagocytosis and the production of immunoregulatory factors, primarily interleukins 1 and 8, which suggests their involvement in specific immunity reactions. Interleukin-1 and TNF stimulate the division of fibroblasts, the production of cytotoxic oxygen species by macrophages, and the degranulation of neutrophilic leukocytes. This mediator also has an effect on fibroblasts: it enhances their growth, stimulates the production of collagenase, inhibits the transcription of collagen genes and the synthesis of collagen by fibroblasts.

The numerical data of table № 1 indicate that immunological disorders in patients with viral hepatitis with manifestations of a dermatological nature are more pronounced, compared with the immunological parameters of the control group.

Table 1.

Indicators of circulating immune complexes and blood cytokines in patients with viral hepatitis with manifestations of a dermatological nature

Note: *- reliability of differences P<0.05 relative to the indicators of the comparison group

Thus, the content of circulating immune complexes in patients with viral hepatitis with dermatological manifestations increased by 1.7 times compared to the control group, TNF-a by 81%, IL-6 by 2.8 times, while IL- 10 were significantly less by 47% compared to the data of the control group.

As is known, free cholesterol and its esters are mainly components of epidermal lipids. Free cholesterol is formed during the breakdown of cell membranes of the stratum corneum. It is of great physiological importance, because. due to its hydrophilic OH group, it has densitic properties. Most of the functions of the stratum corneum are determined by its barrier properties. Preservation of moisture, its flow from the inner layers of cells to the outer layers in a temperate climate is one of the manifestations of this function. In addition, the lipid-poor barrier, in particular the stratum corneum of the skin, is not an immunologically inert substance; haptens can penetrate into it and interact with the antibodies of the stratum corneum.

The study of the state of lipid metabolism in 62 patients with viral hepatitis with manifestations of a dermatological nature gave the following results (table № 2). As shown the date in table № 2, in the blood serum of patients with viral hepatitis with manifestations of a dermatological nature, dyslipidemia is observed, which is expressed in a significant increase in total cholesterol (p <0.01), low-density lipoproteins (p <0.001) and triglycerides (p <0.001) and triglycerides (p <0.01). An increase in the level of total cholesterol was noted in 33 (53%) patients, a decrease in 9 (14%), and was within normal limits in 20 (33%). The amount of triglycerides above these healthy people was in 38 (61%) patients, within normal values - in 15 (24%), reduced - in 9 (15%). The level of low-density lipoproteins (LDL) was high in 46 (74%) patients, low - in 7 (11%), corresponded to normal values - in 9 (15%).

Table 2.

Indicators of lipid metabolism in patients with viral hepatitis with dermatological manifestations

Note: *- reliability of differences P<0.05 relative to the indicators of the comparison group

It should be noted that low-density lipoproteins (LDL) contain a large amount of cholesterol and are carriers of cholesterol, triglycerides, carotenoids, and fat-soluble vitamins. It is likely that high serum LDL levels may be involved in the induction of the innate immune response. Another plausible mechanism by which LDL can prevent chronic HCV infection is direct competition with attachment and penetration of virus through membrane surface liporeceptors on hepatocytes, mainly RLDL. Finally, gene polymorphisms of cholesterol metabolism may be an important factor in altering cholesterol and LDL levels, which may also influence the immunoregulatory effect of cholesterol.

CONCLUSIONS.

1. In the peripheral blood a high level of pro-inflammatory (TNF-a and IL-6) and low - anti-inflammatory (IL-10) cytokines, which were accompanied by an increase in the amount of total cholesterol, triglycerides and low-density lipoproteins in the blood of patients with viral hepatitis with dermatological manifestations.

2. The formation of atherogenic dyslipidemia in patients with viral hepatitis with dermatological manifestations is associated with a high viral load, which is associated with a decrease in apolipoprotein A1 and Apo-B.

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