THE SIGNIFICANCE OF SAROCOPENIA IN LIVER CIRRHOSIS

ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-11 714 ЖИГАР ЦИРРОЗЛАРИДА САРОКПЕНИЯНИНГ AХАМИЯТИ Холиқова Д.С. Андижон давлат тиббиёт институти, Андижон, Ўзбекистон Мақолада жигар циррозларида саркопениянинг учраши, учраш частотаси ва унинг турли ривожланиш йўллари ифодаланган. Турли этиологияли жигар циррозларида саркопения ривожланиши тўғрисидаги жаҳон адабиётида келтирилган маълумотлар тахлили келтирилган. Унга кўра саркопениянинг ривожланиш механизмлари комплекс ва полиэтиологик бўлиб, улардан энг ахамиятлиси, миостатин, рапамицин 1 комплекси, убиквитин-протеасома йўли, инсулинга ўхшаш ўсиш омили-1, интерлейкин-6, алкоголни суиистеъмол қилиш каби ҳолатлар иштирок этиши кўрсатилган. Калит сўзлар: жигар циррози, сарокпения, миостатин, интерлейкин-6. ЗНАЧЕНИЕ САРОКОПЕНИИ ПРИ ЦИРРОЗЕ ПЕЧЕНИ Холикова Д.С. Андижанский Государственный Медицинский Институт, Андижан, Узбекистан В статье рассматриваются встречаемость, частота саркопении при циррозе печени и различные пути её развития. Проанализированы данные мировой литературы о развитии саркопении при циррозе печени различной этиологии. Установлено, что механизмы развития саркопении сложны и полиэтиологичны, важнейшими из которых являются участие миостатина, рапамицинового комплекса 1, убиквитин-протеасомного пути, инсулиноподобного фактора роста 1, интерлейкина-6 и злоупотребление алкоголем .Ключевые слова: цирроз печени, саркопения, миостатин, интерлейкин-6. THE SIGNIFICANCE OF SAROCOPENIA IN LIVER CIRRHOSIS Kholikova D.S. Andijan State Medical Institute, Andijan, Uzbekistan The article describes the occurrence, frequency of sarcopenia in liver cirrhosis, and its various development pathways. The data presented in the world literature on the development of sarcopenia in liver cirrhosis of various etiologies are analyzed. According to it, the mechanisms of sarcopenia development are complex and polyetiological, the most important of which are the involvement of myostatin, rapamycin complex 1, ubiquitin-proteasome pathway, insulin-like growth factor-1, interleukin-6, and alcohol abuse. Key words: liver cirrhosis, sarcopenia, myostatine, interleukin-6. The term sarcopenia was first coined in 1989 by Irwin Rosenberg in the American Journal of Clinical Nutrition in an article titled “Epidemiological and Methodological Issues in the Study of Nutritional Status in the Elderly—A Brief Review” [34]. Over the years, numerous observational studies and meta-analyses have been published on sarcopenia and its study. However, the mechanisms of sarcopenia development in a number of conditions associated with it, particularly in chronic diseases, including liver cirrhosis (LC), remain poorly understood [18]. Sarcopenia is a syndrome characterized by a decrease in muscle mass, strength, and/or function [8]. ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-11 715 The presentation “MELD - Sarcopenia” published in the Journal of the American College of Gastroenterology in 2015 was an important impetus for its worldwide study. In this presentation, the authors showed that sarcopenia is an important predictor of early death in patients with liver disease and those awaiting organ transplantation. The etiology of liver disease is important in the development of sarcopenia. There are a number of factors that can accelerate its development. These include alcohol abuse (because it contributes to the breakdown of skeletal muscle proteins), cholestasis (which contributes to the malabsorption of fat and vitamin D in primary biliary tract diseases). Pathological factors such as chronic inflammation, insulin resistance, and physical activity limitation are also common to sarcopenia and non-alcoholic liver diseases [10]. Tandon P. and Nishikawa et al. reported that sarcopenia has a prevalence of 30–70% in patients with chronic kidney disease, depending on the diagnostic criteria used. A previous study by this author showed that the incidence of sarcopenia detected by computed tomography was related to the severity of chronic kidney disease as assessed by the Child-Pugh score[39]. Sarcopenia and CVD have been strongly associated with poor diet and hormonal imbalances in patients with advanced disease. A recent meta-analysis of 22 studies including nearly 7,000 patients with cirrhosis found that the overall risk of developing sarcopenia in patients with cirrhosis was 37.5% [40]. As mentioned above, this study also found an association between sarcopenia and higher Child-Pugh scores. More than half of the patients in this study had sarcopenia in class C. In addition, the study showed that sarcopenia is an independent risk factor for mortality in patients with CVD [48]. Muscle protein turnover is controlled by several major molecular pathways, including the target of rapamycin 1 complex (mTORC1, a complex that functions as a sensor of nutrients, energy, and redox processes and regulates protein synthesis), the mechanoreceptor signaling cascade, satellite cell signaling, and the ubiquitin-proteasome pathway (UPS). mTORC1 is a key serine/threonine protein kinase that is activated by many factors, including amino acids, growth factors such as insulin-like growth factor-1 (IGF-1), energy status, and mechanical stress [17]. This process ultimately leads to the phosphorylation of two major effectors, eIF4E-binding protein 1 (4EBP1, a negative regulator of mRNA translation and a substrate for mechanistic target of rapamycin (mTOR)) and protein S6 kinase 1 (p70S6K1). In addition, companion cells play a key role in the growth, repair, and regeneration of muscle fibers and are regulated by a number of growth factors, including interleukin-6 (IL-6), IL-1, and myostatin [22, 23]. Several factors contribute to muscle protein breakdown, including inflammation, decreased activity, mitochondrial dysfunction, and myostatin. Myostatin is thought to inhibit muscle protein synthesis by inhibiting the PI3K/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTORC1 pathway and its downstream effectors [19, 23, 45]. In addition, myostatin has been suggested to activate the AMPK, which promotes increased muscle protein breakdown, resulting in negative protein balance [19]. At the same time, Akt activation and inhibition of the Forkhead box O (FOXO - a family of transcription factors involved in various cell functions, including survival, metabolism, cell cycle control, and DNA repair) transcription factor can prevent the activation of ubiquitin ligases, muscle RING finger-1 (MuRF-1 - a specific ubiquitin ligase that controls atrophy processes in transverse muscles) and muscle atrophy (MAFbx) [37]. Muscle protein in the body is in a constant state of flux, with both synthesis and degradation occurring simultaneously [5]. This pattern of muscle protein turnover is driven by a number of ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-11 716 environmental stimuli, including protein intake and physical activity [3]. These changes can lead to a net protein imbalance, with muscle loss, i.e., protein breakdown, occurring when protein synthesis exceeds protein synthesis. When protein synthesis exceeds protein breakdown, muscle growth occurs [5]. Although protein intake alone is sufficient to maintain muscle mass in young, healthy individuals, combining it with exercise synergistically increases muscle synthesis [2]. It is hypothesized that patients with chronic liver disease have impaired muscle protein turnover, which contributes to the development of sarcopenia. Indeed, early studies of muscle protein turnover in patients with CKD have shown that protein synthesis is reduced compared to healthy controls using arteriovenous (AV) balance and whole body condition monitoring [41]. However, previous studies of whole body protein breakdown (WbPB) have yielded conflicting results. Various studies have shown that muscle protein breakdown is increased, decreased, or even unchanged in patients with CKD [41, 42]. These findings may be due to a number of factors, including differences in the tests performed, the age of the patients, the severity of the disease, and its etiology [10]. However, it is known that sarcopenia is associated with an age-related phenomenon of muscle “anabolic resistance,” which is a reduced response of muscle protein synthesis to amino acid intake or exercise compared to younger individuals [6]. Muscle anabolic resistance has also been observed in patients with CKD in other studies [47]. The lack of such studies is probably due to the concern about performing muscle biopsy in this group of patients due to the high risk of platelet dysfunction, coagulopathy, and thrombocytopenia. However, it has recently been shown that muscle biopsies are safe in patients with Child-Pugh class A CKD [46]. This may provide a better understanding of the dysregulation of protein turnover that underlies muscle loss in patients with chronic liver disease. Hyperammonemia, a common pathological condition in patients with CKD, is a consequence of hepatocellular dysfunction, portosystemic shunting, and impaired ureagenesis, which in turn leads to increased ammonia concentrations in skeletal muscle [27]. It has been suggested that in chronic liver disease, ammonia uptake by skeletal muscle may be enhanced as a protective mechanism to prevent neurotoxicity [32]. Although the specific mechanism by which ammonia is absorbed is still unknown, the expression of its transporters, as well as Rh B (Rhbg) and Rh C glycoproteins (Rhcg), may also be important (66). Such ammonia accumulation is not without consequences and may lead to sarcopenia, which in turn leads to a decrease in muscle mass, which is necessary to prevent hyperammonemia [11, 32, 33]. In patients with CKD, similar to the ISR-like decrease in mTORC1 signaling observed in response to intracellular amino acid deprivation, GCN2 activation and increased eIF2a phosphorylation are observed [46]. However, hyperammonemia induces a state of cellular stress that disrupts ISR by preventing ATF4 mRNA expression. This failure to induce ATF4 mRNA expression may lead to further reductions in muscle protein synthesis and increased autophagy due to the cessation of ISR and the inability to return to normal levels of protein synthesis [14, 30]. The changes in adaptive ISR in patients with CKD have been described above, indicating that a second pathway is activated in response to increased ammonia concentrations. This second signaling pathway is mediated by SLC7A5 (SLC7A5 family member 7 member 5)/LAT1 (large neutral amino acid transporter 1), which is increased in patients with CKD. SLC7A5/LAT1 acts as an amino acid exchanger and increases L-leucine uptake [14, 46]. It is thought that increased L-leucine concentrations are used to ISSN: 2582-4686 SJIF 2021-3.261,SJIF 20222.889, 2024-6.875 ResearchBib IF: 9.948 / 2024 VOLUME-5, ISSUE-11 717 utilize this amino acid for acetyl-CoA formation in mitochondria and increase energy output. Under normal conditions, leucine transport relies on its transport by the glutamine exchange member SLC38A2. However, in hyperammonemia, glutamine is mainly used for ammonia detoxification [14, 16]. Taken together, the activation of ISR in patients with CKD leads to impaired mTORC1 signaling and increased autophagy, which may contribute to the development of sarcopenia [14, 30]. In addition, both alcohol abuse and chronic liver disease are considered to be important in the development of sarcopenia associated with it [9]. Therefore, it is often difficult to distinguish between chronic liver disease and the specific effects of alcohol on it. Ethanol can be metabolized not only in the liver and brain, but also in part in skeletal muscle [32]. Alcohol-induced liver disease is often accompanied by a decrease in skeletal muscle mass, as well as significant changes in protein turnover, and ethanol acts by inhibiting mTORC1 stimulation [36]. Excessive alcohol consumption is also associated with an increase in myostatin, which is thought to play a mediating role in impaired muscle protein synthesis [24]. However, markers of CKD remain unchanged in animal models of alcoholic liver disease and are reduced in humans. It has been shown that their autophagy may cause an increase in the breakdown of muscle proteins [40]. Similar to hyperammonemia, ethanol has been found to contribute to a decrease in muscle protein synthesis due to mitochondrial dysfunction, resulting in the formation of CFS and activation of autophagy [4]. In turn, muscle protein synthesis may be impaired due to the aforementioned reduction in ATF generation and mRNA translation [9]. In addition, some endocrine disorders, including low serum testosterone, are important in the pathogenesis of sarcopenia in chronic liver disease [35]. Low testosterone levels may be due to alterations in the hypothalamic-pituitary-gonadal axis in male patients with JC [41]. This has been shown to lead to decreased testosterone production and increased activity of aromatase, the enzyme responsible for its conversion to estradiol, as observed in older men and in rats with portocaval anastomosis [12]. Rats with portocaval anastomosis have low testosterone levels and a reduced growth rate due to reduced food intake and efficiency (where efficiency is measured as body weight gain per gram of food consumed). Inhibition of aromatase in this model resulted in increased testosterone and improved body weight along with increased food intake and efficiency [12]. However, it is advisable to continue research in this area in patients with CHD to confirm the findings. The above data confirm the complexity of the mechanism of development of sarcopenia in JTs, the involvement of a large number of factors. But a number of aspects of the problem have not been studied in depth, and it is necessary to continue research in this direction. In particular, the occurrence of sarcopenia in JTs of different etiologies, some of its specific development mechanisms have not been studied, besides, its course in rural, urban and district conditions has not been evaluated. ФОЙДАЛАНИЛГАН АДАБИЁТЛАР. 1. Allen SL, Quinlan JI, Dhaliwal A, Armstrong MJ, Elsharkawy AM, Greig CA, et al. Sarcopenia in chronic liver disease: mechanisms and countermeasures. Am J Physiol Gastrointest Liver Physiol. 2021;320(3):G241–G257. PMID: 33236953 https://doi.org/10.1152/ajpgi.00373.2020. 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