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Medical Specialties / Hepatology / Cirrhosis


Serum CHI3L1 as a Biomarker for Non-invasive Diagnosis of Liver Fibrosis

Abstract: Background. Liver fibrosis is the early pathological manifestation of various chronic liver diseases (including schistosomiasis, alcoholic, viral, nonalcoholic, fatty liver, etc.), which can progress to cirrhosis and even liver cancer. Out of the 7.7 billion world population, approximately 2 billion individuals have evidence of hepatitis B virus (HBV) infection; of these, 350 to 400 million suffer from chronic HBV infection, accounting for about 5% of the global population. The global prevalence of hepatitis C is 3%. These figures indicate that liver fibrosis is quite common. Methods. 98 patients with liver fibrosis were included in this study. The serum chitinase-3 Like Protein-1 (CHI3L1) level was measured by the double antibody Sandwich ELISA method. Results. Serum levels of CHI3L1 were significantly different between no-fibrosis and fibrosis groups (P < 0.01). There was a strong correlation between the levels of CHI3L1, elastometry, hyaluronan, CIV (P < 0.01) and age and sex, TBIL, DBIL, ALB, AST, ALT, GGT, ALP, PLT, LN, PIINP, FIB-4, and APRI (P < 0.05). The expression of CHI3L1 was different from fibrosis grades S1, S3, and S4 (P < 0.05, P < 0.001). The expression of CHI3L1 was significantly different between F1 and F4 (P < 0.05). Serum CHI3L1 expression level can be a valuable metric for diagnosing liver fibrosis, with an AUC value of 0.812. Out of the 98 patients who had undergone liver puncture, 79 patients (30.38%) had ALT ≤ 2ULN. Conclusions. The expression level of serum CHI3L1 was significantly higher in patients with liver fibrosis than that in patients without liver fibrosis. The expression levels of serum CHI3L1 were different in different grades of liver fibrosis and increased with the severity of liver fibrosis. Serum CHI3L1 can distinguish early stage (S1) of liver fibrosis from late stage (S3-4) of liver fibrosis. Serum CHI3L1 combined with HA is even more effective in the diagnosis of S2-4 hepatic fibrosis. The diagnostic efficacy of serum CHI3L1 in patients with ALT 2ULN was better than that of the other non-invasive diagnostic models. ... Read more

Farnesoid X Receptor as a Promising Therapeutic Target for Nonalcoholic Fatty Liver Disease (NAFLD) and the Current Development of Its Agonists

Abstract: Nonalcoholic fatty liver disease (NAFLD) comprises a group of clinical syndromes characterized by excessive fat deposition in liver cells. Owing to its increasing incidence, NAFLD has becomea pertinent global health problem as well as an important contributor to the fatality rate of liver and metabolic diseases. Farnesoid X receptor (FXR) has emerged as a new target in the treatment of NAFLD, and related drugs are being reported. This review provides an overview of the structure and function of FXR, along with its important regulatory roles in bile acid metabolism and lipid metabolism. The review also highlights the clinical application of FXR and the progress on basic research related to FXR modulators in NAFLD treatment. Identifying potent FXR modulators, structure-based virtual screening strategy, and the development of new drugs to regulate the allosteric pathway of FXR activity have become effective approaches for the study of novel ligand, which can expand the therapeutic applications of novel FXR agonists. Identification of potential FXR modulators may help elucidate the physiological effects of FXR and provide new opportunities for targeting FXR for metabolic diseases. ... Read more

Using Next-generation Sequencing to Identify Novel Exosomal miRNAs as Biomarkers for Significant Hepatic Fibrosis

Abstract: Objective: The aim of this study is to determine the role of serum exosomal miRNAs as potential non-invasive biomarkers for distinguishing no-or-mild fibrosis from significant fibrosis in patients with chronic hepatitis B (CHB). Methods: Next-generation sequencing was used to identify fibrosis-related serum exosomal miRNAs in 9 CHB patients. The candidate exosomal miRNAs were further validated by qRT-PCR in 282 CHB patients. Receiver operating characteristic curves were generated to assess the diagnostic performance of exosomal miRNAs and other non-invasive models. Results: Seventy-two miRNAs were differentially expressed in serum exosomes between patients with no-or-mild fibrosis and significant fibrosis. The expression of serum exosomal miR-92a-3p and miR-146a-5p progressively increased with the aggravation of liver fibrosis in the validation cohort. Multivariate analysis identified miR-92a-3p (P<0.001), miR-146a-5p (P<0.001), and liver stiffness measurement (LSM) (P=0.012) as independent predictors for significant fibrosis. The area under the receiver operating characteristic curve (AUROC) of exosomal miR-92a-3p (AUROC=0.88) was significantly higher than that of APRI (aspartate aminotransferase-to-platelet ratio index) (AUROC=0.72, P<0.001), FIB-4 (AUROC=0.71, P<0.001), and LSM (AUROC=0.80, P=0.022) for identifying significant fibrosis. Similarly, the AUROC of exosomal miR-146a-5p (AUROC=0.82) was also significantly better than that of APRI (AUROC=0.72, P=0.009), FIB-4 (AUROC=0.71, P=0.002), and comparable to LSM (AUROC=0.80, P=0.551) for discriminating significant fibrosis. Conclusion: Serum exosomal miR-92a-3p and miR-146a-5p are superior to APRI, FIB-4, and LSM for diagnosing significant fibrosis in CHB patients and offer a promising non-invasive alternative to liver biopsy. ... Read more

Role of Immune Dysfunction in Acute-on-Chronic Liver Failure: From Pathogenesis to Clinical Prognosis

Abstract: The progression of acute-on-chronic liver failure (ACLF) is associated with various factors, including inflammatory cells, cytokines, inflammatory mediators, and the gut microbiome. Acute insult activates immune cells which provokes cytokine and chemokine cascades and subsequently initiates hepatic damage, aggressive systemic inflammatory response syndrome (SIRS), and high mortality in patients with ACLF. Immune soluble components not only play a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh score, the model for end-stage liver disease (MELD) score, and sequential organ failure (SOF) score. Several immune soluble components lead to a better understanding of the pathophysiological basis of ACLF, and precise immune mechanisms offer therapeutic targets for ACLF. However, there are a number of specific issues that were not addressed unambiguously, such as whether dysfunctional immune soluble components are the cause or outcome of ACLF. Further evaluation and validation of emerging and relevant biomarkers will facilitate the formulation of a potential score which, either alone or in combination with existing scoring systems, will improve the clinical outcome prognostication and therapeutic efficacy of patients with ACLF. Extensive research is required to find out the mechanisms responsible for disease severity and high mortality in patients with ACLF. ... Read more

Serum HBV RNA Levels Predict Significant Liver Fibrosis in Patients with Chronic HBV Infection

Abstract: Background and Aim. Recently, several studies demonstrated that serum HBV RNA levels were associated with liver disease progression in patients with chronic hepatitis B virus (HBV) infection. This study aimed to determine whether serum HBV RNA levels were correlated with liver fibrosis. Methods. 319 treatment-naïve patients with chronic HBV infection were included. The correlation between serum HBV RNA levels and liver histological fibrosis stages was analyzed, and calculations of the area under the receiver operating curve (AUROC) were performed for serum HBV RNA. Results. Serum HBV RNA levels were an independent predictor for significant liver fibrosis both in HBeAg-positive patients (OR=0.514, p<0.001) and HBeAg-negative patients (OR=3.574, p<0.001). In 153 HBeAg-positive patients, HBV RNA had a better diagnostic performance than APRI and FIB-4 (AUROC of 0.77, 0.66, and 0.66 for HBV RNA, APRI, and FIB-4, respectively; p=0.045 for HBV RNA vs. APRI; p=0.043 for HBV RNA vs. FIB-4) for the diagnosis of significant liver fibrosis. In 166 HBeAg-negative patients, HBV RNA also had a better diagnostic performance than APRI and FIB-4 (AUROC of 0.78, 0.68, and 0.62 for HBV RNA, APRI, and FIB-4, respectively; p=0.036 for HBV RNA vs. APRI; p=0.003 for HBV RNA vs. FIB-4) for the diagnosis of significant liver fibrosis. Conclusion. Serum HBV RNA levels were a more accurate noninvasive test than APRI and FIB-4 for the diagnosis of significant liver fibrosis in treatment-naïve patients with chronic HBV infection. ... Read more

The Easy Liver Fibrosis Test (eLIFT) for Predicting Advanced Liver Fibrosis in Patients with Chronic Hepatitis B

Abstract: Objective. The easy liver fibrosis test (eLIFT) is a novel index to assess advanced liver fibrosis in chronic liver diseases. We aimed to investigate the diagnostic accuracy of eLIFT for advanced liver fibrosis in patients with chronic hepatitis B (CHB). Methods. A total of 294 CHB patients with liver biopsy were enrolled. The diagnostic accuracy of eLIFT for advanced liver fibrosis was evaluated and compared to aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 score (FIB-4), gamma-glutamyl transpeptidase-to-platelet ratio (GPR), and red cell distribution width-to-platelet ratio (RPR) by ROC curves. Results. The area under ROC curves (AUROCs) of eLIFT in predicting advanced fibrosis were 0.687 (95%CI 0.621 to 0.753), 0.714 (95%CI 0.631 to 0.798), and 0.633 (95%CI 0.522 to 0.744) in the entire cohort of CHB patients, HBeAg positive CHB patients, and HBeAg negative CHB patients, respectively. The optimal cut-off values of eLIFT for predicting advanced fibrosis in these three groups were 9.5. The eLIFT, as an easy-to-use scoring system, was comparable with APRI, FIB-4, GPR, and RPR in identifying advanced fibrosis in both HBeAg positive CHB and HBeAg negative CHB patients. Conclusions. eLIFT as a novel index can predict advanced liver fibrosis with a moderate sensitivity and accuracy in CHB patients. eLIFT, though having similar diagnostic values of advanced liver fibrosis compared to more complex existing tools such as APRI, FIB-4, GPR, and RPR in CHB patients, has the advantage of clarity of generation and ease of application and has the potential of being widely used by hepatologists. ... Read more

Genetic Association and Interaction of PD1 and TIM3 Polymorphisms in Susceptibility of Chronic Hepatitis B Virus Infection and Hepatocarcinogenesis

Abstract: The PD1 (rs2227982, rs41386349, rs6710479, rs7421861, and rs7565639) and TIM3 (rs11134551, rs11742259, rs246871, rs25855, and rs31223) polymorphisms were examined in 362 patients with chronic hepatitis B virus (HBV) infection, 91 HBV infection resolvers, and 158 healthy controls. Univariate logistic regression was carried out by SNPstats to detect the associations. Multifactor dimensionality reduction (MDR) analysis was performed to explore interactions between PD1 and TIM3 polymorphisms. Associations of polymorphisms with clinical disease were also evaluated. Compared with patients with chronic HBV infection and healthy controls, HBV infection resolvers had a lower frequency of PD1 rs41386349 allele A, higher frequency of PD1 rs6710479 allele C, and higher frequency of TIM3 rs246871 genotypes TC and TC + CC. A best MDR model composed of PD1 rs2227982, rs41386349, and rs7421861, and TIM3 rs11134551, rs11742259, rs246871, rs25855, and rs31223 was observed between patients with chronic HBV infection and HBV infection resolvers (maximum testing balance accuracy, 0.5803; maximum cross-validation consistency, 9/10; P = 0.0010). PD1 rs2227982, rs6710479, and rs7421861 were associated with a higher hepatocellular carcinoma risk. These findings suggest that PD1 rs41386349 and rs6710479 and TIM3 rs246871 and interactions between PD1 and TIM3 polymorphisms may affect the susceptibility of chronic HBV infection and PD1 rs2227982, rs6710479, and rs7421861 may implicate in hepatocarcinogenesis. ... Read more

Characteristics of Regulatory B Cells in Patients with Chronic Hepatitis B Virus Infection in Different Immune Phases

Abstract: Regulatory B cells (Bregs) are reported to play an important role in the immune responses to chronic hepatitis B virus (HBV) via Toll-like-receptors (TLRs) signaling. We aimed to investigate the characteristics of Bregs and the expressions of TLRs in Bregs in the peripheral blood of different immune phases of patients with chronic HBV infection. In this study, we determined the frequencies of Bregs and TLR9, TLR2, and TLR4 in peripheral blood using flow cytometry and determined the levels of IL-10 in serum with the Human Magnetic Cytokine/Chemokine Bead Panel. The results showed that the frequencies of CD19+ B cells and Bregs were elevated in patients with chronic HBV infection compared with healthy control (HC). The frequencies of Bregs were significantly increased in the immune active group compared with the immune tolerant group and HC group. Meanwhile, the frequencies of Bregs were higher in inactive carrier state group compared with HC group. The levels of serum IL-10 were elevated in the immune active group compared with immune tolerant, inactive carrier state and HC groups. Serum IL-10 levels were positively correlated with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the immune active group. Compared with HC group, the expression of TLR9 in Bregs reduced in chronic hepatitis B (CHB) patients. However, the expression of TLR2 in Bregs increased in CHB patients. There were no differences of the TLRs expressions in Bregs among various immune phases of chronic HBV infection. These data suggest that the frequencies of Bregs and levels of serum IL-10 were different in various immune phases in patients with chronic HBV infection. Bregs may play some important role in modulating the immune responses of chronic HBV infection. However, whether Bregs modulate immune responses via TLR signaling in chronic HBV infection remains ambiguous. ... Read more

The Independent Predictors of Liver Histological Changes in Chronic Hepatitis B Virus Infection Patients with Persistently High-normal or Low-normal Alanine Transaminase Levels

Abstract: Objective: To determine the independent predictors of significant liver histological changes (SLHC) defined as inflammatory grade ≥A2 and/or fibrosis stage ≥F2 using the METAVIR scoring system in chronic hepatitis B virus (HBV) infection patients with persistently normal ALT (PNALT) levels. Methods: We enrolled 392 chronic HBV infection patients with PNALT defined as normal ALT (≤40 IU/L) measured on at least three occasions at intervals of more than 2 months apart over a period of 12 or more months. Univariate and multiple analyses were performed to identify the independent predictors of SLHC in high-normal ALT (HNALT) (20<ALT≤40 IU/L) and low-normal ALT (LNALT) (ALT≤20 IU/L) groups, respectively. Results: Of 392 PNALT patients, 291 (74.2%) had HNALT and 101 (25.8%) had LNALT. The prevalence of SLHC in HNALT group is higher than that in LNALT group (36.4% vs. 19.8%, p=0.002). Of 291 HNALT patients, 106 (36.4%) had SLHC, and multivariate analysis showed that age (OR=1.059, 95%CI, 1.027-1.093, p<0.001), ALT (OR=1.018, 95%CI, 1.052-1.167, p<0.001), and gamma-glutamyl transpeptidase (GGT) (OR=1.012, 95%CI, 1.002-1.022, p=0.016) were independent predictors of SLHC. Of 101 LNALT patients, 20 (19.8%) had SLHC, and multivariate analysis showed that age (OR=1.121, 95%CI, 1.044-1.204, p=0.002) was the only independent predictor of SLHC. Conclusion: Age, ALT, and GGT were independent predictors of SLHC in HNALT patients, and age was the only independent predictor of SLHC in LNALT patients. These predictors might be used to screen SLHC, select candidates for liver biopsies, and guide proper antiviral therapy. ... Read more

Increase of Infiltrating Monocytes in the Livers of Patients with Chronic Liver Diseases

Abstract: Infiltrating monocytes have been demonstrated to contribute to tissue damage in experimental models of liver injury and fibrosis. However, less is known about monocyte infiltration in the livers of patients with chronic liver diseases (CLD). In the present study, we demonstrated that CD68+ hepatic macrophages and MAC387+ infiltrating monocytes were significantly increased in the livers of CLD patients with different etiologies as compared with normal liver tissue. In addition, CLD patients with higher inflammatory grading scores had more CD68+ macrophages and MAC387+ monocytes infiltration in their livers compared to those with lower scores. Significantly more MAC387+ infiltrating monocytes were found in the liver tissue of CLD patients with higher fibrotic staging scores compared to those with lower scores. Monocyte chemoattractant protein-1 (MCP-1) expression was significantly increased in the livers of CLD patients with different etiologies. MCP-1 staining scores were significantly positively associated with the numbers of MAC387+ infiltrating monocytes in CLD patients. Taken together, our results demonstrate that infiltrating monocytes may play a pathological role in exacerbating chronic liver inflammation and fibrosis in CLD. MCP-1 may be involved in the monocyte infiltration and progression of liver inflammation and fibrosis in CLD. ... Read more

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