Anna F. Sheptulina

Fatigue/weakness in chronic liver diseases is a clinically significant symptom that goes beyond subjective discomfort and requires separate clinical assessment. Available data indicate that fatigue/weakness affects quality of life, daily activities, and prognosis, while more pronounced fatigue/weakness at baseline is independently associated with a higher risk of adverse clinical events in patients with liver fibrosis and cirrhosis. The relevance of this problem is determined by the high prevalence of the symptom, its multifactorial nature, its frequent combination with sleep disorders, depressive symptoms, and reduced physical activity, as well as the need for an interdisciplinary approach to the management of such patients in real clinical practice. The present manuscript is a descriptive review. Literature selection was carried out taking into account scientific significance, relevance, and correspondence to the topic of the review. The review included 62 publications for the period 1977–2026, including clinical guidelines, position papers, reviews, meta-analyses, and clinical studies. The authors consider terminological aspects, the clinical significance of fatigue/weakness, as well as approaches to its diagnosis and treatment. The algorithm for assessing and managing patients with fatigue/weakness is considered in detail and may serve as a roadmap for clinical actions for practicing physicians. Particular attention is paid to sleep disorders and depressive disorders in liver diseases, since these conditions may exacerbate fatigue/weakness, affect quality of life, and reduce adherence to treatment. The role of ademethionine is also highlighted, as it occupies a unique position in the treatment of fatigue/weakness in liver diseases owing to its pleiotropic action.

Aim: to evaluate, based on an analysis of preclinical and clinical data, the efficacy and safety of fixed combinations of glycyrrhizic acid with phospholipids or ursodeoxycholic acid for the treatment of non-alcoholic fatty liver disease. Key points. Glycyrrhizic acid exerts antisteatotic, anti-inflammatory, and antifibrotic effects through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), the inhibition of sterol regulatory element-binding protein 1c (SREBP-1c), nuclear factor κB (NF-κB), and the modulation of the farnesoid X receptor (FXR)/sirtuin-1 (SIRT1) pathway. The “glycyrrhizic acid + phospholipids” fixed-dose combination (IV for 14 days followed by PO for 10 weeks) is recommended to reduce steatosis and inflammation and to prevent fibrosis (strength of recommendation: B; level of evidence: 2). In clinical studies, a 2–3-month therapy with the drug led to the normalization of aminotransferase activity in the majority of patients, while a 12-month study demonstrated regression of advanced stages of liver fibrosis (F2–F4), up to the complete disappearance of signs of cirrhosis (F4) in all patients. The “glycyrrhizic acid + ursodeoxycholic acid” fixed combination (12 weeks; 15 mg/kg/day of ursodeoxycholic acid) is recommended for patients with non-alcoholic fatty liver disease and elevated aminotransferase levels to reduce inflammation (strength of recommendation: B; level of evidence: 2). Randomized clinical trials have shown more than a twofold reduction in aminotransferase activity, as well as improvements in quality of life. An analysis of more than 1.3 million prescriptions confirms a favorable safety profile for both combinations (overall incidence of adverse events: 0.01–1.4 %, predominantly mild gastrointestinal disturbances). Conclusion. Fixed-dose combinations of “glycyrrhizic acid + phospholipids” and “glycyrrhizic acid + ursodeoxycholic acid” are effective and safe pharmacotherapeutic options for the treatment of non-alcoholic fatty liver disease, exhibiting antisteatotic, anti-inflammatory, and antifibrotic effect as supported by data from randomized clinical trials and post-marketing surveillance in the Russian Federation.

These guidelines describe the management of follow-up monitoring for patients with chronic pancreatitis by a general practitioner and outline modern approaches to diagnosis, including clinical, laboratory, and imaging methods, treatment, and the prevention of complications. Using the follow-up care (examination, consultation) algorithm presented in these guidelines will enable physicians providing follow-up monitoring for patients with chronic pancreatitis to make informed clinical decisions. These guidelines are intended for general practitioners, family doctors, and for nursing staff working with these physicians, for paramedics performing the doctor functions of managing follow-up monitoring. These guidelines are also intended for healthcare executives and heads of primary care facilities.

The review discusses the clinical significance of hyperammonemia and hyperammonihistia (tissue ammonia accumulation) in non-alcoholic (metabolic dysfunction-associated) fatty liver disease. Elevated blood and tissue ammonia levels can be observed already at pre-cirrhotic stages (in 40–78% of patients) and are not only a consequence but also a factor of disease progression, making it an independent pathogenetic target. Hyperammonemia exacerbates hepatocellular injury (through impairment of autophagy and epigenetic suppression of enzymes of the ornithine cycle), contributes to the development of sarcopenia, fatigue, cognitive and other neuropsychiatric impairments, and worsens the course of comorbid conditions. Key non-pharmacological approaches include the Mediterranean diet with adequate protein intake and regular physical activity combining aerobic and resistance exercise. From a pathogenetic pharmacotherapy perspective, the use of L-ornithine L-aspartate (LOLA) is justified, as it activates the urea cycle in the liver and the glutamine pathway in skeletal muscle. By reducing intracellular ammonia concentrations, LOLA helps alleviate mitochondrial dysfunction, restore autophagic processes, and slow the activation of hepatic stellate cells, which may in turn slow down the progression of steatosis, inflammation, and fibrosis. Course administration of LOLA at doses of 9–12 g per day for at least 12 weeks has been shown to reduce ammonia levels, decrease steatosis, improve cognitive function, enhance exercise tolerance, and improve patients’ quality of life. The experts emphasize that the decision to initiate therapy may be based on clinical manifestations (hepatogenic weakness, cognitive impairment, sarcopenia), even in the absence of routine monitoring of blood ammonia levels. The review was conducted in a narrative fashion without the use of systematic methodology. A targeted search of Russianand English-language publications was carried out using PubMed, eLIBRARY.RU, the Cochrane Library, and other databases.

Aim: to present the results of an interdisciplinary international expert council on addressing the challenges of managing patients with non-alcoholic (metabolic dysfunction-associated) fatty liver disease in connection with the creation of a new nomenclature, the definition of diagnostic criteria, and the development of approaches to the diagnosis and treatment of fatty liver disease. Key points. The key role of metabolic dysfunction in non-alcoholic (metabolic dysfunction-associated) fatty liver disease has been proven. Therefore, in the nomenclature, non-alcoholic fatty liver disease (NAFLD) has been replaced by metabolic dysfunction-associated fatty liver disease, and non-alcoholic steatohepatitis has been replaced by metabolic dysfunction-associated steatohepatitis. It is noted that, according to research, the prevalence of fatty liver disease in Russia is high: one-third of patients seeking primary care have this diagnosis. The results of a study of two incretin mimetics, semaglutide and tirzepatide, are presented, along with an opinion on their rational combination with ursodeoxycholic acid. The comorbidity of fatty liver disease with cardiovascular, endocrine, and oncological diseases, chronic kidney disease, and other conditions is discussed. Conclusion. The expert council included leading specialists: gastroenterologists-hepatologists, cardiologists, internists, and endocrinologists. There were confirmed that treatment for fatty liver disease should be comprehensive and integrated into the overall concept of metabolic health. Algorithms for diagnosis and personalized treatment of fatty liver disease have to be developed for the Russian medical community.

Cardiometabolic risk factors (CMRFs) are not only diagnostic criteria for metabolic dysfunction-associated steatotic liver disease (MASLD), but also important prognostic factors affecting the course and outcome of the disease. Real-world data on the prevalence and combination of CMRFs in large, unselected cohorts of patients with MASLD remain scarce. Objective. To study the profile of cardiometabolic risk factors in patients with metabolic dysfunction-associated steatotic liver disease in real-world settings. Materials and methods. A multicenter cross-sectional study with a retrospective component was conducted. The MASLD diagnosis was based on evidence of liver steatosis on ultrasound (US) and the presence of at least one CMRF. Anthropometric parameters, CMRFs, blood test results, abdominal ultrasound, and liver elastography data were recorded in all patients. Based on the data collected, the Fatty Liver Index (FLI) and the liver fibrosis index (Fibrosis-4 Index; FIB-4) were calculated. Results. Of the 2260 included patients, 785 patients were diagnosed with MASLD (34.7%; 58.8% females; median age: 56 [45–66] years). The most common CMRFs were overweight/obesity (n=677/785; 86.2%) and waist circumference above the reference values (n=631/785; 80.3%). In total, 6.7% of patients had only 1 CMRF. Among patients with ≥5 CMRFs, males predominated (p=0.003). The number of CMRFs correlated with patient age (ρ=0.499, p<0.001), the FLI index (ρ=0.352, p<0.001), and the FIB-4 index (ρ=0.278, p<0.001). Conclusion. Most patients with metabolic dysfunction-associated steatotic liver disease have several cardiometabolic risk factors strongly associated with changes in the liver. It highlights the need for a comprehensive assessment of metabolic status to optimize risk stratification and individualized patient management.

This review examines the role of programmed cell death in the pathogenesis of obesity and associated conditions. It provides the comprehensive examination of the key mechanisms of apoptosis and NETosis in the context of the pathogenesis of obesity and associated metabolic diseases, particularly type 2 diabetes mellitus, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD). One of the key consequences of excessive adipose tissue accumulation in obesity is chronic low-grade inflammation. The development of a proinflammatory state, the resulting cellular stress, and mitochondrial dysfunction contribute to the activation of signaling pathways that trigger programmed cell death. Apoptosis of adipocytes, cardiomyocytes, endothelial cells, pancreatic β-cells, and hepatocytes is mediated by an imbalance of proand antiapoptotic proteins of the Bcl-2 family and caspase activation and is implicated in the development of MASLD, type 2 diabetes mellitus, diabetic cardiomyopathy, and endothelial dysfunction. Studies of potentially protective molecules (apelin-13, agomelatine) and triggers are described. NETosis plays a key role in maintaining inflammation, endothelial dysfunction, and the development of thrombotic complications in obesity. Increased activity of NETosis markers, myeloperoxidase and neutrophil elastase, correlates with the severity of obesity, MASLD, and microvascular complications, while their inhibition restores endothelial function in preclinical models. Thus, key molecular factors and signaling pathways of apoptosis and NETosis are significant components in the pathogenesis of obesity and associated diseases. Studying the mechanisms of programmed cell death is a promising area in the context of the search for potential therapeutic targets for these diseases.

Objective . The purpose of this study was to establish the features of body composition and their association with functional activity in patients with arterial hypertension (HTN) and metabolic dysfunction-associated steatotic liver disease (MASLD). Design and methods . The study included 133 patients of both sexes with HTN grade I-II and MAFLD. The average age of the study participants was 48,0 ± 7,99 years, including 58 women (46,6 %). All patients underwent anthropometric measurements, evaluation of muscle strength and function, as well as instrumental examinations. Quantitative determination of body composition (fat, fat-free, and bone mass) was performed using dual-energy X-ray absorptiometry. The short form of the International Physical Activity Questionnaire (IPAQ) was used to assess physical activity. Statistical analysis of the data was performed using the SPSS 27.0 statistical software package (IBM, USA). The differences between the indicators were considered significant at p < 0,05. Results . Patients with HTN and MASLD had modified body composition with excessive fat tissue accumulation together with decreased muscle mass. Significant correlations were established between the increased fat mass, decreased muscle mass, muscle strength and disturbed muscle function, indicating a higher probability of the sarcopenic obesity in this category of patients. Conclusion . Assessment of body composition, as well as early interventions aimed at increasing muscle mass and improving its structure and function, are key aspects in planning a set of medical prevention measures for patients with HTN and MASLD.

Fatigue is a common systemic symptom of nonalcoholic fatty liver disease (NAFLD), negatively impacting quality of life and treatment adherence. Muscle dysfunction may contribute to its pathogenesis, but ultrasound characteristics of skeletal muscles in NAFLD have not been well studied. Objective: to assess the associations between ultrasound features of thigh soft tissues, muscle strength, and fatigue in NAFLD patients. Material and methods. This single-center study included 154 individuals with NAFLD (median age, 56 years; 59.1% women). All participants underwent ultrasound assessment of the quadriceps femoris, measurement of muscle strength using handgrip dynamometry and the five-times sit-to-stand test (5TSTS), and fatigue assessment with the Fatigue Assessment Scale (FAS). Clinically significant fatigue (CSF) was defined as FAS ≥22. Results. CSF was identified in 36.4% of participants and was associated with greater thigh subcutaneous fat thickness (ρ=0.202; p=0.003), lower relative handgrip strength (ρ=–0.187; p=0.032), longer 5TSTS duration (ρ=0.269; p=0.002), and smaller area and width of the rectus femoris (p<0.05 for all). In logistic regression, thigh subcutaneous fat thickness was the only independent predictor of CSF (p=0.009). The area under the ROC curve for subcutaneous fat thickness was 0.646 (p=0.008). Conclusion. Fatigue in NAFLD is linked to structural and functional muscle alterations. Thigh ultrasound may serve as a non-invasive method for detecting muscle dysfunction and stratifying CSF risk in clinical and research settings.

The investigation of the gut microbiome (GM)—its composition, metabolites, and effects on human physiology—along with the development of targeted therapeutic and preventive interventions, has become a major focus of contemporary biomedical research. Central to this field are GM biobanks, which implement standardized methods for the preservation and long-term storage of microbiome samples. Objective. To analyze current literature on the establishment of human GM biobanks for research and therapeutic purposes and to formulate methodological recommendations for GM biobanking. Key points. Research on the GM is closely linked to biobanking activities worldwide. Systematic collection and storage of biological material ensure high-quality, sufficient samples and support the creation of extensive clinical data repositories. These resources enable comprehensive assessment of the functional and pathogenetic roles of the GM in health and disease. Personalized use of probiotics and autoprobiotics, the development of artificial microbiota, and targeted microbiome modulation—all essential for regulating physiological functions—are possible only through well-structured biobanks. Therapeutic GM biobanks are designed to process, store, and provide access to biological materials used for microbiome modulation. Their infrastructure must comply with general biobanking standards and specific biosafety requirements for working with microorganisms. Protocols for sample preparation, storage, and use differ between research and therapeutic settings. Conclusion. GM biobanking is a critical tool for both research and clinical practice. Standardized biobanking practices provide a solid foundation for advancing GM research, developing innovative therapies, and accelerating translation into personalized medicine.