Progression Of Liver Fibrosis Research Articles

Successful therapy with tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) does not guarantee amelioration of liver damage assessing by transient elastography. A retrospective - prospective multicenter study

BackgroundPreventing disease progression and viral suppression are the main goals of antiviral therapy in chronic hepatitis B (CHB). Liver stiffness measurement (LSM) by transient elastography is a reliable non-invasive method to assess liver fibrosis in patients with CHB. Our aim was to explore factors that may affect changes in LSMs during long term tenofovir (TDF) monotherapy in a well characterized cohort of patients with compensated CHB.MethodsWe analyzed serial LSMs in 103 adult patients with CHB who were on TDF monotherapy and had at least three LSMs over a period of 90 months.ResultsTwenty-five (24%) patients had advanced fibrosis at baseline. A significant decline in mean LSM between baseline and last visit (8.7 ± 6.2 kPa vs. 6.7 ± 3.3, p = 10− 3) was observed. Twenty-four (23%) patients had progression of liver fibrosis with mean increase in liver stiffness of 2.8 kPa (range: 0.2–10.2 kPa). Multivariate analysis showed that BMI ≥ 25 (OR, 0.014; 95% CI, 0.001–0.157; p = 0.001) and advanced fibrosis (OR, 5.169; 95% CI, 1.240–21.540; p = 0.024) were independently associated with a fibrosis regression of > 30% of liver stiffness compared to baseline value.ConclusionsIn CHB patients TDF monotherapy resulted in liver fibrosis regression, especially in patients with advanced fibrosis. Despite the successful antiviral effect of TDF, 1 out of 4 patients had liver fibrosis progression. Obesity and advanced fibrosis at baseline were independently associated with significant liver fibrosis regression.

Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-β-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently invitro and invivo. HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

StarD5 levels of expression correlate with onset and progression of steatosis and liver fibrosis.

Insufficient expression of steroidogenic acute regulatory-related lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. The ablation of StarD5 was analyzed in mice on a normal or Western diet (WD) to determine its importance in hepatic lipid accumulation and fibrosis compared with wild-type (WT) mice. Rescue experiments in StarD5-/- mice and hepatocytes were performed. In addition to increased hepatic triglyceride (TG)-cholesterol levels, global StarD5-/- mice fed a normal diet displayed reduced plasma triglycerides and liver very low-density lipoprotein (VLDL) secretion as compared with WT counterparts. Insulin levels and homeostatic model assessment for insulin resistance (HOMA-IR) scoring were elevated, demonstrating developing insulin resistance (IR). WD-fed StarD5-/- mice upregulated WW domain containing transcription regulator 1 (TAZ or WWTR1) expression with accelerated liver fibrosis when compared with WD-fed WT mice. Suppression of oxysterol 7α-hydroxylase (CYP7B1) coupled with chronic accumulation of toxic oxysterol levels correlated with presentation of fibrosis. "Hepatocyte-selective" StarD5 overexpression in StarD5-/- mice restored expression, reduced hepatic triglycerides, and improved HOMA-IR. Observations in two additional mouse and one human metabolic dysfunction-associated steatotic liver disease (MASLD) model were supportive. The downregulation of StarD5 with hepatic lipid excess is a previously unappreciated physiological function appearing to promote lipid storage for future needs. Conversely, lingering downregulation of StarD5 with prolonged lipid-cholesterol excess accelerates fatty liver's transition to fibrosis; mediated via dysregulation in the oxysterol signaling pathway.NEW & NOTEWORTHY We have found that deletion of the cholesterol transport protein StarD5 in mice leads to an increase in insulin resistance and lipid accumulation due to the upregulation of lipid synthesis and decrease VLDL secretion from the liver. In addition, deletion of StarD5 increased fibrosis when mice were fed a Western diet. This represents a novel pathway of fibrosis development in the liver.

Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients.

Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients. We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR. In the post-SVR group, the microbial β-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients. In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.

Dietary inflammatory index in relation to the progression of hepatic steatosis and liver fibrosis: evaluation by elastography/Fibroscan

One of the proposed mechanisms by which nutrition influences the progression of hepatic steatosis to fibrosis is inflammation. The study investigated how the inflammatory potential of the diet affects the risk of liver damage in patients with nonalcoholic fatty liver disease (NAFLD), a condition where fat accumulates in the liver. This cross-sectional study included 170 outpatients with newly diagnosed NAFLD. This study used a device called Fibroscan® to measure the degree of liver fibrosis, which is the scarring of the liver tissue due to chronic inflammation. The study also used a tool called the Dietary Inflammatory Index (DII) to measure the inflammatory potential of the diet based on the intake of different foods and nutrients. In the findings of the study, patients with more severe fat accumulation in the liver (hepatic steatosis) had higher DII scores, meaning they had more inflammatory diets. The study also found that higher DII scores were associated with higher weight and body mass index (BMI). One standard deviation (SD) increase in DII scores was associated with a 0.29 kilopascal (95% CI: 0.10–0.44; P-value 0.001) increase in the mean liver stiffness, an indicator of liver fibrosis. The study concluded that patients with higher DII scores had a higher risk of developing liver fibrosis than those with lower DII scores, even after adjusting for confounding factors (odds ratio: 5.89; P-value: 0.001). The study suggested that eating less inflammatory foods may help prevent or slow down the progression of hepatic steatosis and liver in patients with NAFLD.

MicroRNA-122: assessment of diagnostic significance in HDV infection

Aim: To evaluate the diagnostic significance of the relationship between the level of microRNA-122 expression and liver fibrosis during HDV infection.Materials and methods. The expression of microRNA-122 was determined in 203 blood samples. Blood sampling was done from 53 patients with chronic viral hepatitis D, 49 patients with liver cirrhosis of HDV etiology, and 69 patients with newly diagnosed HBs antigenemia. The control group consisted of practically healthy individuals (n=32).Results. In patients with negative RNA HDV levels, the level of microRNA-122 in the blood serum was significantly higher than in samples with positive RNA HDV levels (14.0±2.8 2^-ΔΔCt and 1.6±0.17 2^-ΔΔCt) (p ˂ 0.005). Meanwhile, in healthy individuals, the expression of microRNA-122 was statistically significantly lower – 1.3±0.03 2^-ΔΔCt (p ˂ 0.005). Undetectable levels of HDV RNA in the serum were accompanied by a high HBV viral load and a significantly higher level of microRNA-122, which was 8.7 times higher than in the group of HDV RNA-positive patients (p<0.005). In patients with liver fibrosis F1, the expression of microRNA-122 was higher than in patients with liver fibrosis F2, F3, F4 (p = 0.0001). The lowest levels of microRNA-122 were observed in liver fibrosis F4. Conclusion. The expression level of microRNA-122 in blood serum during HDV infection decreases as liver fibrosis progresses. The development of cirrhosis is accompanied by a 3.7-fold drop in the level of microRNA-122 compared to the group of patients with chronic hepatitis D. MicroRNA-122 can be used in laboratory monitoring of patients with various stages of HDV infection as an indicator of the activity of the process, assessing the severity of liver damage and the rate of progression of liver fibrosis.> ˂ 0.005). In patients with liver fibrosis F1, the expression of microRNA-122 was higher than in patients with liver fibrosis F2, F3, F4 (p = 0.0001). The lowest levels of microRNA-122 were observed in liver fibrosis F4.Conclusion. The expression level of microRNA-122 in blood serum during HDV infection decreases as liver fibrosis progresses. The development of cirrhosis is accompanied by a 3.7-fold drop in the level of microRNA-122 compared to the group of patients with chronic hepatitis D. MicroRNA-122 can be used in laboratory monitoring of patients with various stages of HDV infection as an indicator of the activity of the process, assessing the severity of liver damage and the rate of progression of liver fibrosis.

Diverse potential of secretome from natural killer cells and monocyte-derived macrophages in activating stellate cells.

Chronic liver diseases, such as non-alcoholic steatohepatitis (NASH)-induced cirrhosis, are characterized by an increasing accumulation of stressed, damaged, or dying hepatocytes. Hepatocyte damage triggers the activation of resident immune cells, such as Kupffer cells (KC), as well as the recruitment of immune cells from the circulation toward areas of inflammation. After infiltration, monocytes differentiate into monocyte-derived macrophages (MoMF) which are functionally distinct from resident KC. We herein aim to compare the in vitro signatures of polarized macrophages and activated hepatic stellate cells (HSC) with ex vivo-derived disease signatures from human NASH. Furthermore, to shed more light on HSC activation and liver fibrosis progression, we investigate the effects of the secretome from primary human monocytes, macrophages, and NK cells on HSC activation. Interleukin (IL)-4 and IL-13 treatment induced transforming growth factor beta 1 (TGF-β1) secretion by macrophages. However, the supernatant transfer did not induce HSC activation. Interestingly, PMA-activated macrophages showed strong induction of the fibrosis response genes COL10A1 and CTGF, while the supernatant of IL-4/IL-13-treated monocytes induced the upregulation of COL3A1 in HSC. The supernatant of PMA-activated NK cells had the strongest effect on COL10A1 induction in HSC, while IL-15-stimulated NK cells reduced the expression of COL1A1 and CTGF. These data indicate that other factors, aside from the well-known cytokines and chemokines, might potentially be stronger contributors to the activation of HSCs and induction of a fibrotic response, indicating a more diverse and complex role of monocytes, macrophages, and NK cells in liver fibrosis progression.

Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression.

Metabolic dysfunction-associated steatohepatitis (MASH) - previously described as nonalcoholic steatohepatitis (NASH) - is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.

Crosstalk of lysyl oxidase-like 1 and lysyl oxidase prolongs their half-lives and regulates liver fibrosis through Notch signal.

Lysyl oxidase (LOX) family members (LOX and LOXL1 to 4) are crucial copper-dependent enzymes responsible for cross-linking collagen and elastin. Previous studies have revealed that LOX and LOXL1 are the most dramatically dysregulated LOX isoforms during liver fibrosis. However, the crosstalk between them and the underlying mechanisms involved in the profibrotic behaviors of HSCs, as well as the progression of liver fibrosis, remain unclear. pCol9GFP-HS4,5Tg mice, Loxl1fl/flGfapCre mice, human HSC line, and primary HSCs were enrolled to study the dysregulation pattern, profibrotic roles, and the potential mechanisms of LOX and LOXL1 interaction involved in the myofibroblast-like transition of HSCs and liver fibrogenesis. LOX and LOXL1 were synergistically upregulated during liver fibrogenesis, irrespective of etiology, together orchestrating the profibrotic behaviors of HSCs. LOX and LOXL1 coregulated in HSCs, whereas LOXL1 dominated in the coregulation loop. Interestingly, the interaction between LOXL1 and LOX prolonged their half-lives, specifically enhancing the Notch signal-mediated myofibroblast-like transition of HSCs. Selective disruption of Loxl1 in Gfap+ HSCs deactivated the Notch signal, inhibited HSC activation, and relieved carbon tetrachloride-induced liver fibrosis. Our current study confirmed the synergistic roles and the underlying mechanisms of LOXL1 and LOX crosstalk in the profibrotic behaviors of HSCs and liver fibrosis progression, providing experimental evidence for further clear mechanism-based anti-LOXL1 strategy development in the therapy of liver fibrosis.

Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease.

Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver and hepatic steatosis, which can progress to critical conditions, including Metabolic dysfunction-associated Steatohepatitis (MASH), liver fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Galectin-3, a member of the galectin family of proteins, has been involved in cascades that are responsible for the pathogenesis and progression of liver fibrosis in MAFLD. This review summarizes the present understanding of the role of galectin-3 in the severity of MAFLD and its associated liver fibrosis. The article assesses the underlying role of galectin-3-mediated fibrogenesis, including the triggering of hepatic stellate cells, the regulation of extracellular degradation, and the modulation of immune reactions and responses. It also highlights the assessments of the potential diagnostic and therapeutic implications of galectin-3 in liver fibrosis during MAFLD. Overall, this review provides insights into the multifaceted interaction between galectin-3 and liver fibrosis in MAFLD, which could lead to the development of novel strategies for diagnosis and treatment of this prevalent liver disease.

18F]AlF-ND-bisFAPI PET imaging of fibroblast activation protein as a biomarker to monitor the progression of liver fibrosis.

Hepatic fibrosis is a progressive disease, which is reversible in the early stages. The current monitoring methods have notable limitations that pose a challenge to early detection. In this study, we evaluated the utility of [18F]AlF-ND-bisFAPI positron emission tomography imaging of fibroblast activation protein (FAP) to monitor the progression of liver fibrosis. Two mouse models of liver fibrosis were established by bile duct ligation and carbon tetrachloride administration, respectively. Positron emission tomography imaging was performed with the FAP-specific radiotracer [18F]AlF-ND-bisFAPI for the evaluation of rat HSCs and mouse models of fibrosis and combined with histopathology, immunohistochemical staining, and immunoblotting to elucidate the relationships among radioactivity uptake, FAP levels, and liver fibrosis progression. Furthermore, [18F]AlF-ND-bisFAPI autoradiography was performed to assess tracer binding in liver sections from patients with varying degrees of liver fibrosis. Cell experiments demonstrated that [18F]AlF-ND-bisFAPI uptake was specific in activated HSCs. Compared with control mice, [18F]AlF-ND-bisFAPI uptake in livers increased in the early stages of fibrosis and increased significantly further with disease progression. Immunohistochemistry and western blot analyses demonstrated that FAP expression increased with fibrosis severity. In accordance with the findings in animal models, ex vivo autoradiography on human fibrotic liver sections showed that radioactivity increased as fibrosis progressed from mild to severe. [18F]AlF-ND-bisFAPI positron emission tomography imaging is a promising noninvasive method for monitoring the progression of liver fibrosis.

Indicators of cellular immunity and lymphocyte metabolism in children with type 1 autoimmune hepatitis at different stages of liver fibrosis

Autoimmune hepatitis (AIH) is a progressive hepatocellular inflammation of unknown etiology, accompanied by the process of liver fibrosis. Damage in the liver is associated with the formation of highly reactive molecules that contain unpaired electrons (free radicals), which in turn induce lipid peroxidation, leading to the development of mitochondrial dysfunction. Mitochondrial DAMPs released from damaged hepatocyte mitochondria (with mtDNA as the main active component) directly activate hepatic stellate cells and cause liver scarring. Assessing cellular metabolism can be done by examining the activity of succinate dehydrogenase (SDH), a key enzyme involved in both the tricarboxylic acid cycle and OXPHOS. Aim. to examine indicators of cellular immunity and succinate dehydrogenase activity in lymphocyte populations at different stages of liver fibrosis in children with type I AIH.. Materials and methods. During hospitalization, 69 children with AIH type I, aged 12 to 18 years, Me=15.5 [12.8;16.9], were examined. 62 healthy children made up the comparison group. The stage of liver fibrosis was assessed using the FibroScan F502. The subpopulation composition of lymphocytes and the activity of succinate dehydrogenase in them were assessed using flow cytometry. The following lymphocyte populations were evaluated: T-lymphocytes, activated T-cells, B-lymphocytes, NK cells, CD16/56+CD3+ lymphocytes, cytotoxic T-lymphocytes, T-helpers, including small populations: activated T-helpers, regulatory T-cells, Th17 lymphocytes. Statistica 10.0 (USA) program was used for statistical data processing. Results. The study included 47 girls and 22 boys. Children with AIH were on standard therapy with glucocorticosteroids for 2.6 [1.1;5.4] years. In 53 children, AIH occurred in combination with gastroduodenitis (76.8% of observations), in 12 children – with gastroesophageal reflux disease (17% of observations). 7 children had comorbid autoimmune diseases or a combination of them: 5 patients had autoimmune thyroiditis (7% of cases), 2 children had vitiligo (3% of cases), as well as type 1 diabetes mellitus, juvenile rheumatoid arthritis and celiac disease in one case (1.5%), 3 children (5% of cases) had multiple autoimmune syndrome. In children with AIH, an increase in the relative content of T cells and T helper cells was detected. The relative number of NK cells and B cells was reduced in all stages of AF relative to the comparison group. A significant increase in the absolute number of Thact and Tregs was obtained at all stages of fibrosis relative to the comparison group, while the relative number of Thact (% CD4+) was significantly higher only at stages F0, F3 and F4, and the relative number of Tregs (% CD4+) was significantly higher only at stages F0 and F4. The proportion of Th17 lymphocytes (% CD4+) was significantly reduced relative to the comparison group at stages F0 and F2. From the F0 to F3 stage, the relative number of B cells decreased, and then significantly increased by the F4 stage. The proportion of T helper cells, Tregs and Thact in most patients was higher than the comparison group, however, no significant differences were found between different stages. The proportion of Th17 lymphocytes increased with increasing stage of liver fibrosis, the maximum values were detected at stage F4. A study of SDH revealed a significant decrease in the activity of this enzyme in all populations of lymphocytes. The greatest decrease in activity was detected in double negative CD3+CD4-CD8- cells by 18.5% and NK cells by 17.5% relative to the comparison group. In the populations of Th17 and Treg lymphocytes, SDH activity was significantly lower in the state of exacerbation of the disease, relative to in the state of remission. Analysis of SDH activity indicators depending on the stage of liver fibrosis revealed a nonlinear relationship: in the populations of T-helpers, T-cytotoxic and Thact – an increase to stage F2-3, and then a decrease to stage F4. SDH activity in the population of Th17 lymphocytes increased maximally at the F1 stage and subsequently decreased to the F4 stage. With increasing stage of liver fibrosis, SDH activity significantly increased in the Treg population, but did not reach normative values. Children with autoimmune hepatitis need clinical observation and strict monitoring of the development of the disease. Conclusion. The subpopulation composition of peripheral blood lymphocytes and the activity of succinate dehydrogenase in lymphocyte populations objectively reflect the severity of the patient’s condition at the time of examination and can be used for additional laboratory assessment of the progression of liver fibrosis. The identified signs of mitochondrial dysfunction justify the use of correction of metabolic disorders as a therapy that improves the basic treatment of patients with type 1 AIH.

Hepatocyte CEBPA restricts the progression of liver fibrosis

Hepatocyte CEBPA restricts the progression of liver fibrosis

Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study

ObjectivePatients with haemophilia and HIV who acquire hepatitis C virus (HCV) after receiving contaminated blood products can experience accelerated progression of liver fibrosis and a poor prognosis, making liver disease...

The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality.Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

Efficacy of human placenta hydrolyzate in the treatment of patients with metabolic associated fatty liver disease at the stage of fibrosis (pilot study)

Background. Despite active research, drug treatment options for metabolic associated fatty liver disease (MAFLD) are limited, and there are no currently approved drugs for patients with MAFLD. Treatment of patients at risk of developing non-alcoholic steatohepatitis and progressive liver fibrosis (LF) is of particular relevance, since they determine the clinical outcomes of the disease.
 Aim. To evaluate the clinical efficacy of complex polypeptide drug (CPD), human placenta hydrolyzate, containing low molecular weight regulatory peptides, amino acids, vitamins, macro- and microelements in patients with MAFLD at the LF stage.
 Materials and methods. A single-center, placebo-controlled pilot study. Patients with MAFLD at LF stage 1≤F≤3 according to METAVIR were included (n=10, of which 8 were women, median age was 55 years old). Patients were randomized into 2 groups: 5 people received CPD therapy for 12 weeks (intravenous infusion of 6 ml 2 times a week); another 5 people initially received placebo x 2 times a week (12 weeks), with transfer to the open phase for CPD therapy in the same regimen. The dynamics laboratory and instrumental data was assessed, as well as determine the presence of fibrosis by non-invasive tests – measurement of liver stiffness by transient elastography and use of serum biomarker (SM) by FibroTest and detection of steatosis with controlled attenuation parameter for transient elastography and SM by SteatoTest. The quality of life of patients was assessed using questionnaire SF-36 and well-being via Visual Analogue Scale. Statistical processing of the material was carried out using the methods of nonparametric analysis, using the Statistica 13.3 software.
 Results. Patients in the CPD group compared with the baseline data and with the placebo group showed a statistically significant improvement: 1) transaminases (ALT, AST), lipid profile indicators (cholesterol), ferritin; 2) indicators of LF, based on a decrease in liver stiffness by transient elastography and SM of Fibrotest, as well as the degree of steatosis based on controlled attenuation parameter and SM of Steatotest; 3) in well-being and quality of life (according to testing: SF-36 physical, mental well-being and general condition of the VAS). CPD was well tolerated, no side effects were noted.
 Conclusion. In patients with MAFLD during CPD therapy, a decrease in the level of liver enzymes was noted, as well as in LF and liver steatosis according to noninvasive methods. Randomized controlled trials are required to confirm these findings.

Glucagon-like peptide 1 receptor agonists in the treatment of patients with type 2 diabetes and metabolically-associated steatosic liver disease. Review

In recent years, the prevalence of metabolically‑associated steatosis of the liver (MASLD) in patients with type 2 diabetes mellitus (T2DM) has been increasing significantly. Therefore, there is an urgent need to study new strategies for the treatment of this pathology, in particular, to prevent the progression of liver steatosis and fibrosis and to reduce the mortality associated with liver diseases. A systematic review and meta‑analysis of randomized controlled trials was recently conducted to assess the efficacy and safety of glucagon‑like peptide‑1 receptor agonists (GLP‑1RAs) in the treatment of hepatic steatosis and fibrosis in patients with T2DM s and MASLD. A total of eight trials were included in the review, involving a total of 468 participants with T2DM and MASLD. Analysis of the primary results showed that administration of GLP‑1RAs in patients with T2DM and MASLD significantly reduced the content of intrahepatic fat, subcutaneous adipose tissue, and visceral adipose tissue. Analysis of secondary outcomes showed that GLP‑1RAs caused significant reductions in alanine aminotransferase, aspartate aminotransferase, body weight, body mass index, waist circumference, fasting blood glucose and HbA1c, HoMA‑IR insulin resistance index, total cholesterol and triglycerides compared with the control schemes of treatment. The main adverse events associated with GLP‑1RAs included mild to moderate gastrointestinal discomfort and hypoglycemia, which resolved within several weeks. GLP‑1 RAs have a positive effect in patients with T2DM and MASLD and have a positive effect on inflammatory markers, contribute to reducing of weight, waist circumference, and insulin resistance index. Therefore, GLP‑1RAs can be considered as a potential treatment strategy for patients with type 2 diabetes and MASLD, if there are no contraindications. Further studies are needed to clearly understand the effect of GLP‑1RAs on the course of MASLD and the potential mechanisms by which they exert a therapeutic effect and prevent its progression.

SIRT1 activation ameliorates rhesus monkey liver fibrosis by inhibiting the TGF-β/smad signaling pathway

TGF-β/Smad signaling pathway plays an important role in the pathogenesis and progression of liver fibrosis. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+) dependent enzyme and responsible for deacetylating the proteins. Increasing numbers of reports have shown that the molecular mechanism of SIRT1 as an effective therapeutic target for liver fibrosis but the transformation is not very clear. In the present study, liver fibrotic tissues were screened by staining with Masson, hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) for histopathological observation from the liver biopsy of seventy-seven rhesus monkey, which fixed with 4% paraformaldehyde (PFA) after treatment with high-fat diet (HFD) for two years. And the liver function was further determined by serum biochemical tests. The mRNA levels and protein expression of rat hepatic stellate (HSC-T6) cells were determined after treatment with Resveratrol (RSV) and Nicotinamide (NAM), respectively. The results showed that with the increasing of hepatic fibrosis in rhesus monkeys, the liver function impaired, and the transforming growth factor-β1 (TGF-β1), p-Smad3 (p-Smad3) and alpha-smooth muscle actin (α-SMA) was up-regulated, while SIRT1 and Smad7 were down-regulated. Moreover, when stimulated the HSC-T6 with RSV to activate SIRT1 for 6, 12, and 24 h, the results showed that RSV promoted the expression of smad7, while the expression of TGF-β1, p-Smad3 and α-SMA were inhibited. In contrast, when the cells stimulated with NAM to inhibit SIRT1 for 6, 12, and 24 h, the Smad7 expression was decreased, while TGF-β1, p-Smad3, and α-SMA expressions were increased. These results indicate that SIRT1 acts as an important protective factor for liver fibrosis, which may be attributed to inhibiting the signaling pathway of TGF-β/Smad in hepatic fibrosis of the rhesus monkey.

Mesenchymal stem cells alleviate mouse liver fibrosis by inhibiting pathogenic function of intrahepatic B cells.

The immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them a promising therapeutic approach for liver fibrosis (LF). Here, we postulated that MSCs could potentially suppress the pro-fibrotic activity of intrahepatic B cells, thereby inhibiting LF progression. Administration of MSCs significantly ameliorated LF as indicated by reduced myofibroblast activation, collagen deposition, and inflammation. The treatment efficacy of MSCs can be attributed to decreased infiltration, activation, and pro-inflammatory cytokine production of intrahepatic B cells. Single-cell RNA sequencing revealed a distinct intrahepatic B cell atlas, and a subtype of naive B cells (B-II) was identified, which were markedly abundant in fibrotic liver, displaying mature features with elevated expression of several proliferative and inflammatory genes. Transcriptional profiling of total B cells revealed that intrahepatic B cells displayed activation, proliferation, and pro-inflammatory gene profile during LF. Fibrosis was attenuated in mice ablated with B cells (μMT) or in vivo treatment with anti-CD20. Moreover, fibrosis was recapitulated in μMT after adoptive transfer of B cells, which in turn could be rescued by MSC injection, validating the pathogenic function of B cells and the efficacy of MSCs on B cell-promoted LF progression. Mechanistically, MSCs could inhibit the proliferation and cytokine production of intrahepatic B cells through exosomes, regulating the Mitogen-activated protein kinase and Nuclear factor kappa B signaling pathways. Intrahepatic B cells serve as a target of MSCs, play an important role in the process of MSC-induced amelioration of LF, and may provide new clues for revealing the novel mechanisms of MSC action.

CCL20 and CD8A as potential diagnostic biomarkers for HBV-induced liver fibrosis in chronic hepatitis B

BackgroundThe main cause of the liver fibrosis (LF) remains hepatitis B virus (HBV) infection, especially in China. Histologically, liver fibrosis still occurs progressively in chronic hepatitis B (CHB) patients, even if HBV-DNA is negative or undetectable. The diagnosis of LF is beneficial to control the development of it, also it may promote the reversal of LF. Although liver biopsy is the gold standard of diagnosis in LF at present, it isa traumatic diagnosis. There are no diagnostic biomarkers as yet for the condition. It is badly in need of biomarkers clinically, which is simple to test, minimally invasive, highly specific, and sensitive. Early detection of HBV-LF development is crucial in the prevention, treatment, and prognosis prediction of HBV-LF. Cytokines are closely associated with both immune regulation and inflammation in the progression of hepatitis B virus associated-liver fibrosis (HBV-LF). In this bioinformatic study, we not only analyzed the relationship between HBV-LF and immune infiltration, but also identified key genes to uncover new therapeutic targets. ObjectivesTo find potential biomarkers for liver fibrosis in the development of chronic hepatic B patients. Materials and methodsWe obtained two sets of data including CHB/healthy control and CHB/HBV-LF from the Integrated Gene Expression (GEO) database to select for differential expression analysis. Protein-protein interaction (PPI) network was also generated, while key genes and important gene modules involved in the occurrence and development of HBV-LF were identified. These key genes were analyzed by functional enrichment analysis, module analysis, and survival analysis. Furthermore, the relationship between these two diseases and immune infiltration was explored. ResultsAmong the identified genes, 150 were individually associated with CHB and healthy control in the differential gene expression (DGE) analysis. While 14 with CHB and HBV-LF. It was also analyzed in the Robust rank aggregation (RRA) analysis, 34 differential genes were further identified by Cytohubba. Among 34 differential genes, two core genes were determined: CCL20 and CD8A. CCL20 was able to predict CHB positivity (area under the receiver operating characteristic curve [AUC-ROC] = 0.883, 95% confidence interval [CI] 0.786–0.963), while HBV-LF positivity ([AUC-ROC] = 0.687, 95% confidence interval [CI] 0.592–0.779). And CD8A was able to predict CHB positivity ([AUC-ROC] = 0.960, 95% confidence interval [CI] 0.915–0.992), while HBV-LF positivity ([AUC-ROC] = 0.773, 95% confidence interval [CI] 0.680–0.856). Relationship between CCL20 gene expression and LF grades was P < 0.05, as well as CD8A. ConclusionCCL20 and CD8A were found to be potential biomarkers and therapeutic targets for HBV-LF. It is instructive for research on the progression of LF in HBV patients, suppression of chronic inflammation, and development of molecularly targeted-therapy for HBV-LF.