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Abstract There is a scarcity of publications evaluating the performance of the national liver transplantation (LTx) program in Kazakhstan. Spanning from 2012 to 2023, it delves into historical trends in LTx surgeries, liver transplant centers, and the national cohort of patients awaiting LTx. Survival analysis for those awaiting LTx, using life tables and Kaplan–Meier, is complemented by time series analysis projecting developments until 2030. The overall per million population (pmp) LTx rate varied from 0.35 to 3.77, predominantly favoring living donor LTx. Liver transplant center rates ranged from 0.06 to 0.40. Of 474 LTx patients, 364 on the waiting list did not receive transplantation. The 30-day and 1-year survival rates on the waiting list were 87.0% and 68.0%, respectively. Viral hepatitis and cirrhosis prevalence steadily rose from 2015 to 2023, with projections indicating a persistent trend until 2030. Absent targeted interventions, stable pmp rates of LTx and liver transplant centers may exacerbate the backlog of unoperated patients. This study sheds light on critical aspects of the LTx landscape in Kazakhstan, emphasizing the urgency of strategic interventions to alleviate the burden on patients awaiting transplantation.

There is a scarcity of publications evaluating the performance of the national liver transplantation (LTx) program in Kazakhstan. Spanning from 2012 to 2023, it delves into historical trends in LTx surgeries, liver transplant centers, and the national cohort of patients awaiting LTx. Survival analysis for those awaiting LTx, using life tables and Kaplan–Meier, is complemented by time series analysis projecting developments until 2030. The overall per million population (pmp) LTx rate varied from 0.35 to 3.77, predominantly favoring living donor LTx. Liver transplant center rates ranged from 0.06 to 0.40. Of 474 LTx patients, 364 on the waiting list did not receive transplantation. The 30-day and 1-year survival rates on the waiting list were 87.0% and 68.0%, respectively. Viral hepatitis and cirrhosis prevalence steadily rose from 2015 to 2023, with projections indicating a persistent trend until 2030. Absent targeted interventions, stable pmp rates of LTx and liver transplant centers may exacerbate the backlog of unoperated patients. This study sheds light on critical aspects of the LTx landscape in Kazakhstan, emphasizing the urgency of strategic interventions to alleviate the burden on patients awaiting transplantation. [ABSTRACT FROM AUTHOR]

STING (stimulator of interferon genes) also known as transmembrane protein 173 (TMEM173) is a cytoplasmic DNA sensor which can be activated by the upstream cyclic dinucleotides (CDNs). This activation produces cytokines such as interferons and pro-inflammatory factors via the downstream IRF3 and NF-κB pathways, triggering an innate immune response and adaptive immunity to maintain homeostasis. STING is mainly expressed and activated in non-parenchymal cells, thus exerting a corresponding effect to maintain the homeostasis of the liver. In viral hepatitis, interferons and pro-inflammatory factors produced after STING activation initiate the immune response to inhibit virus replication and assembly. In the case of metabolic diseases of the liver, the activation of STING in kupffer cells and hepatic stellate cells leads to inflammation, the proliferation of connective tissue, and metabolic disorders in the hepatocytes, promoting the occurrence and development of the disease. In hepatocellular carcinoma, STING has two contradictory roles. When STING is activated in dendritic cells and macrophages, a large number of cytokines can be produced to initiate innate immune effects directly and to exert adaptive immunity through the recruitment and activation of T cells; however, aberrant activation of the STING pathway leads to a weakening of immune function and promotes oncogenesis and metastasis. Here, we summarize the interactions between STING and liver disease that have currently been identified and how to achieve therapeutic goals by modulating the activity of the STING pathway. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver.Aim: To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies.Methods: Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD.Results: Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties.Conclusions: CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual’s drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases. [ABSTRACT FROM AUTHOR]

PRINCIPLES: Computed tomography (CT) is inferior to the fibroscan and laboratory testing in the noninvasive diagnosis of liver fibrosis. On the other hand, CT is a frequently used diagnostic tool in modern medicine. The auxiliary finding of clinically occult liver fibrosis in CT scans could result in an earlier diagnosis. The aim of this study was to analyse quantifiable direct signs of liver remodelling in CT scans to depict liver fibrosis in a precirrhotic stage. METHODS: Retrospective review of 148 abdominal CT scans (80 liver cirrhosis, 35 precirrhotic fibrosis and 33 control patients). Fibrosis and cirrhosis were histologically proven. The diameters of the three main hepatic veins were measured 1–2 cm before their aperture into the inferior caval vein. The width of the caudate and the right hepatic lobe were divided, and measured horizontally at the level of the first bifurcation of the right portal vein in axial planes (caudate-right-lobe ratio). A combination of both (sum of liver vein diameters divided by the caudate-right lobe ratio) was defined as the ld/crl ratio. These metrics were analysed for the detection of liver fibrosis and cirrhosis. RESULTS: An ld/crl-r

Abstract: Ethnopharmacological relevance: Paris polyphylla var. yunnanensis as a traditional Chinese medicine has been used in the treatment of liver disease for thousands of years. Rhizoma paridis saponins (RPS), as the main active components of Paris polyphylla, have been used to treat liver injury. Anti-cirrhosis effect of Rhizoma paridis saponins (RPS) has not been known. Materials and methods: We analyzed diethylnitrosamine (DEN)-induced metabonomic changes in multiple biological matrices (plasma and urine) of rats by using 1H-NMR spectroscopy together with clinical biochemistry assessments, oxidative stress test and DNA fragmentation assay. Results: Mechanisms of RPS that participated in the inhibition of the fibrotic process included anti-oxidant, anti-apoptosis, and metabolic disturbance such as decreasing lipid oxidation, regulation of TCA cycle, carbohydrate, and amino acid metabolisms in DEN-induced liver tissues. Conclusions: Integrated NMR analysis of serum and urine samples, together with traditional clinical biochemical assays provided a holistic method for elucidating mechanisms of potential anti-fibrotic agent, RPS. [ABSTRACT FROM AUTHOR]

Background & Aims: Certain liver diseases have been associated with depletion of glutathione (GSH), the major antioxidant in the liver. A recent report about Gclch/h mice with a hepatocyte-specific ablation of Gclc (the gene encoding the catalytic subunit of the rate-limiting enzyme in GSH synthesis) has shown an essential role of GSH in hepatic function. Gclch/h mice develop severe steatosis and die of liver failure within one month, due to ∼95% depletion of hepatic GSH; mitochondria are the major affected organelles, displaying abnormal ultrastructure and impaired functioning. Methods: Gclch/h mice were fed with L-N-acetylcysteine (NAC; 10g/L) in drinking water, starting at postnatal day 18. Results: Gclch/h mice were rescued by use of NAC supplementation, and survived until adulthood. NAC replenished the mitochondrial GSH pool and attenuated mitochondrial damage, with accompanying diminished hepatic steatosis; however, abnormal liver biochemical tests, hepatocyte death, and hepatic oxidative stress persisted in the rescued mice. At 50days of age, the liver from rescued Gclch/h mice started to display characteristics of fibrosis and at age 120days, macronodular cirrhosis was observed. Immunohistostaining for liver-specific markers as well as the expression profile of hepatic cytokines indicated that the repopulation of hepatocytes in the cirrhotic nodules involved the expansion of oval cells. Conclusions: Replenishment of mitochondrial GSH and restoration of mitochondrial function by NAC prevents mortality caused by the loss of hepatocyte GSH de novo synthesis, allowing steatosis to progress to a chronic stage. Thus, with NAC supplementation, Gclch/h mice provide a model for the development of liver fibrosis and cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract: Background and aim: Immunomodulatory and protective properties have been identified for the keratinocyte growth factor (KGF). For hepatocytes, pro-proliferative and anti-apoptotic effects of this growth factor have been reported in vitro. This study was designed to characterize a putative role of KGF in observed histomorphological changes in both, human and experimental liver fibrosis. Methods: Liver fibrosis and cirrhosis was induced in rats by repetitive exposure to phenobarbitone and increasing doses of carbon tetrachloride. Human samples were obtained from patients undergoing surgery for partial hepatectomy or transplantation. Organ samples were scored for inflammation and morphological changes. Expression of KGF and its receptor (KGFR) mRNA was quantified by real-time RT-PCR. Protein expression and receptor phosphorylation was determined by Western blot analysis. In-situ hybridization and immunohistochemistry were utilized to determine distribution of KGF and KGFR in the liver. Results: Expression of KGF was significantly increased in damaged liver tissue in correlation to the degree of fibrosis, whereas expression of the receptor was up-regulated in early stages of liver fibrosis and down-regulated in cirrhotic organs. Protein expression of this growth factor and its receptor correlated with the alterations in mRNA. KGF expression was restricted to mesenchymal cells, whereas expression of KGFR was detected on hepatocytes only. Conclusion: The expression of KGF and KGFR is differentially and significantly regulated in damaged liver tissue. This growth factor might therefore not only contribute to morphological alterations but also regeneration of liver parenchyma most likely mediated by indirect mechanisms of action. [Copyright &y& Elsevier]

There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1–7) (Ang-(1–7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are induced by several immune factors, such as interferon-γ, and act as intracellular enzymes that catabolize essential amino acid tryptophan into kynurenine and other downstream metabolites, including kynurenic acid (KYNA), xanthurenic acid (XA) and so on. IDO and TDO work as a double-edge sword. On one hand, they exert the immunomodulatory effects, especially immunosuppressive effects on the microenvironment including infections, pregnancy, tumor cells escape and transplantation. TDO plays the major role under basal conditions, while IDO comes into play under different circumstances of immune activation, thus IDO has a wider spectrum of immune regulation. On the other hand, these enzymes also inhibit pathogens such as Chlamydia pneumoniae, Staphylococcus aureus, Toxoplasma gondii and so on. Moreover, IDO regulates metabolic health through shaping intestinal microbiota. Recently, these enzymes have attracted more and more attention in liver diseases. Several studies have indicated that IDO and TDO can modulate viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, liver cancer even liver transplantation. Targeting them or their antagonists may provide novel therapeutic treatments for liver diseases. In this review, we will discuss the exact roles that IDO and TDO play in diverse hepatic diseases., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3594). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver. Aim: To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies. Methods: Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD. Results: Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties. Conclusions: CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual's drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.