This systematic review and meta-analysis aimed to compare the diagnostic performance of transient elastography (TE) and two-dimensional shear wave elastography (2D-SWE) for staging liver fibrosis in patients with chronic viral hepatitis (CVH).
Adipogenesis of adipocytes includes two stages: initiation and maturation. Growth hormone (GH) secretion is decreased in obese subjects and GH levels are inversely correlated with abdominal fat mass. The effects of growth hormone (GH) on lipids accumulation or maturation of adipocytes remains elusive.In the present study, effect of GH on lipid accumulation in vitro and in vivo was examined. cDNA microarray, quantitative real time-PCR (qPCR) and western blotting was used to analyze the expression of genes related to adipocyte lipid accumulation or degradation in pre- or mature 3T3-F442A adipocytes treated with GH and in epididymal adipose tissue of C57BL/6 mice administrated with GH. Level of adiponectin in supernatants of cultured F442A adipocytes was determined by enzyme-linked immune-sorbent assay.We found that in 3T3-F442A especially 6 days post initiation of adipogenesis, GH intervention resulted in decreased expression of adipocyte maturation regulators (C/EBPα, PPARγ) and prominent genes related to lipid synthesis such as FAS and FABP, while the expression of UCP1 was markedly enhanced. cDNA microarray analysis and qPCR showed that the expression of SOCS2 and Adipor2 was increased under GH-treatment in mature 3T3-F442A adipocytes. GH treatment increased the mRNA expression of adiponectin and UCP1 in mature adipocytes. The above results were confirmed by in vivo study.GH potentially negatively modulates the maturation and accumulation of lipid in adipocytes.
Despite proton pump inhibitors (PPIs) being generally safe, there are questions about their potential long-term complications. The present study aimed to investigate the association between PPI therapy and the incidence of hepatic steatosis and liver fibrosis in the outpatient population of the United States. The present study included 7,395 individuals aged ≥20 years who underwent hepatic vibration-controlled transient elastography (VCTE) examination. The data were obtained from the January 2017 to March 2020 pre-pandemic National Health and Nutrition Examination Survey. Among the 7,395 adults who were included (mean age, 50.59 years; 3,656 male), 9.8% were prescribed PPIs. Following multivariable adjustment, the use of PPIs was significantly associated with hepatic steatosis [odds ratio (OR), 1.25; 95% confidence interval (CI), 1.02-1.53]. Prolonged use of PPIs was found to increase the risk of developing hepatic steatosis over time (P=0.006). Sensitivity analyses using different definitions of hepatic steatosis, such as a controlled attenuation parameter ≥285 dB/m (OR, 1.19; CI, 1.01-1.40), non-alcoholic fatty liver disease (OR, 1.50; 95% CI, 1.16-1.93) and metabolic dysfunction-associated steatotic liver disease (OR, 1.26; 95% CI, 1.05-1.52), consistently demonstrated an association between PPI prescription and hepatic steatosis. The administration of PPI therapy was linked with hepatic steatosis in US adults, although no significant association was observed with liver stiffness, as determined by VCTE.
In the present study, the left anterior descending coronary arteries of mice under anesthesia were ligated, and the optimal surgical conditions for coronary artery ligation (CAL) in the establishment of a myocardial infarction (MI) mouse model were investigated. All mice that survived were sacrificed seven days subsequent to the successful surgery. Body weight, blood serum and heart tissues were obtained for further analysis or biochemical and histopathological examinations. The survival rate of the mice following the CAL procedure was 70%. The aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations in the serum of the experimental mice were significantly increased compared with those of the control mice, which reflected the enzyme release from the infarcted myocardial cells. Histopathological examination showed different degrees of MI in the heart tissues of the experimental mice. The results indicate that an MI model in mice may be successfully established using CAL under the surgical conditions utilized in the present study. These conditions were cost effective and the results may be replicated by laboratories that are less well-equipped.
Abstract Background Type 2 diabetes increases the risk of cirrhosis and liver cancer. Noninvasive and early assessment of liver fibrosis is essential. We aimed to develop a score to aid in the initial assessment of liver fibrosis in the diabetic population. Methods A fibrosis investigating navigator in diabetes (FIND) score was developed and validated in the NHANES dataset (2017–2020). Fibrosis was defined as a liver stiffness measurement (LSM) ≥8.0 kPa. The diagnostic accuracies of FIB‐4, NFS, LiverRisk, steatosis‐associated fibrosis estimator (SAFE) and metabolic dysfunction–associated fibrosis (MAF‐5) were compared. FIND was also externally validated in various liver diseases via biopsy as a reference in an Asian centre between 2016 and 2020. Finally, we examined the prognostic implications of the FIND index utilizing data from the UK Biobank cohort (2006–2010). Results The FIND score model yielded an AUROC of 0.781 for the prediction of an LSM ≥8 kPa in the validation set, which was consistently greater than that of other available models (all p < 0.05). In the whole NHANES dataset, the 85% sensitivity cut‐off of 0.16 corresponded to a NPV of 91.9%, whereas the 85% specificity cut‐off of 0.31 corresponded to a PPV of 50.6%. FIND displayed overall accuracies similar to those of the other models in staging fibrosis stages, with biopsy used as a reference. In the UK Biobank cohort, FIND >0.31 was associated with an increased risk of all‐cause and liver‐related mortality in the diabetic population in adjusted models (HR, 1.75; 95% CI, 1.62–1.89; HR, 23.59; 95% CI, 13.67–40.69). Conclusions In diabetes patients, the novel FIND score performs well in identifying subjects at risk of liver fibrosis and predicting all‐cause and liver‐related mortality.
ABSTRACT Background and Aims In chronic hepatitis B (CHB), an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes. Methods We conducted a retrospective cohort study to compare the risk of transitioning to immune active phase between inactive and indeterminate CHB and the incidence of hepatocellular carcinoma (HCC) and cirrhosis between untreated patients with indeterminate CHB (at baseline and throughout follow‐up) and those who received treatment, following standard AASLD 2018 guidance. Results The risk of transitioning to the immune active phase over 3, 5, and 10 years was 6.3%, 8.9%, and 14.2%, respectively, for inactive phase patients ( n = 104). For HBeAg‐negative indeterminate phase patients ( n = 194), the risk was significantly higher at 23.0%, 31.9%, and 38.2%, and for HBeAg‐positive indeterminate phase patients ( n = 140), it was 40.4%, 52.0%, and 55.0% ( p < 0.001). Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated indeterminate patients. Following IPTW adjustment, the Kaplan–Meier curve analysis indicates that the risk of HCC and cirrhosis among untreated patients ( n = 294) is higher than that among treated patients ( n = 76), ( p = 0.015 and 0.007, respectively). In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of HCC (aHR 0.128, 95% CI 0.031–0.522, p = 0.005) and cirrhosis (aHR 0.148, 95% CI 0.044–0.496, p = 0.002). Conclusion The indeterminate phase patients had a high‐risk transition to active phase, and antiviral therapy can reduce the incidence of developing HCC and cirrhosis.
Abstract Objective To investigate the inhibition of low dose radiation (LDR) on S180 sarcomas and its modulation of MMP-2 and TIMP-2 in mice. Methods S180 subcutaneously implanted tumor model mice were randomly divided into two groups: control (N) and low dose radiation (LDR) groups. N mice were sacrificed after 12 h, whereas LDR mice were sacrificed after 12 (LDR-12 h), 24 (LDR-24 h), 48 (LDR-48 h), and 72 (LDR-72 h) h. Thereafter, we measured the tumor volumes. Histopathology was performed, and P-V immunohistochemistry was applied to assess MMP-2 and TIMP-2 expression. Results Compared with the control group, the tumor growth was significantly inhibited in the LDR groups ( P < 0.05). MMP-2 expression was considerably reduced in LDR-24h ( P < 0.05) and LDR-48h ( P < 0.05), whereas the change of TIMP-2 was not obvious in the LDR groups ( P > 0.05) in contrast to that of the control group. Conclusion LDR can effectively suppress the growth of S180 implanted tumors by reducing MMP-2, which is associated with invasion and metastasis.
To the Editor: Liver cirrhosis (LC), the end-stage condition of chronic liver disease, results in >1,300,000 annual deaths worldwide. Meanwhile, the global incidence of decompensated cirrhosis is rising yearly.1 Following clinically significant portal hypertension (CSPH) in the late compensated stage of LC, as the disease progresses to the decompensated stage, ascites, gastroesophageal variceal bleeding, hepatic encephalopathy (HE), and other severe complications present. Nonselective beta-blockers (NSBBs) have currently served as the first-line therapy for primary and secondary prophylaxis of portal-hypertensive gastrointestinal bleeding, as recommended by practice guidelines.2 Moreover, recent recommendations have extended the use of NSBBs to compensate LC patients with CSPH.2 In addition to the hemodynamic effect of lowering the risk of variceal bleeding, NSBBs have recently been shown to exert non-hemodynamic effects through a reduction in intestinal mucosal permeability and intestinal bacterial translocation.3 Thereby, the incidence of non-bleeding cirrhotic complications, including spontaneous bacterial peritonitis (SBP), HE, and hepatocellular carcinoma (HCC), has significantly reduced, which may defer the progression to decompensation.3 However, few studies have discussed the important effects that may lead to the repurposing of NSBBs. In this paper, we summarized the pathophysiological basis of NSBBs in the progression of SBP, HE, HCC, ascites, and acute-on-chronic liver failure (ACLF). Furthermore, we briefly reviewed the effects of NSBBs based on high-quality evidence derived from randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large-scale observational studies, aiming to provide balanced insights to enrich the therapeutic strategy of LC. SBP is the most prevalent bacterial infection among patients with decompensated LC. NSBBs can effectively accelerate small intestinal transit and decrease intestinal bacterial translocation. They may also ameliorate portal hypertension (PHT)-induced mesenteric blood congestion, thus decreasing the incidence of SBP.3 A nationwide, population-based, retrospective study conducted in Denmark suggested that propranolol could substantially lower the risk of SBP in patients with decompensated cirrhosis.4 Moreover, two recent meta-analyses reported the effectiveness of NSBBs in preventing SBP in cirrhosis patients with ascites,5, 6 although one found a nonsignificant reduced incidence of SBP in the NSBB group5 (Table 1). 1. NSBBs versus non-NSBBs 2. Hemodynamic responders versus non-responders Propranolol: 80 mg/d Carvedilol: 18.8 mg/d Carvedilol: 12.5 mg/d Propranolol: 100 mg/d Carvedilol: 12.5 mg/d Carvedilol: 12.5 mg/d HCC is the third leading cause of cancer mortality globally. The incipient symptoms of HCC are usually latent and atypical. A screening program to improve prognosis through early diagnosis is essential as it may lead to curative therapeutic interventions for early stage HCC.12 The therapeutic potential of NSBBs on HCC can be explained by the following mechanisms. First, widespread pathological bacterial translocation in cirrhosis patients with PHT results in endothelial dysfunction and systemic inflammation; the latter is considered a key driver of the malignant transformation of hepatocytes. Second, the antiangiogenic properties of NSBBs may suppress catecholamine-driven cancer cell migration, as well as inhibit tumor angiogenesis, invasion, and proliferation, thus arresting tumor growth.12 From the clinical perspective, based on Cerner's Health Facts database, Wijarnpreecha et al. retrospectively analyzed 107,428 cirrhosis patients and reported that the use of either carvedilol or propranolol was associated with a significant reduction in HCC risk, regardless of cirrhosis severity and complications, while the use of NSBBs reduced the absolute risk of HCC by 25%–39%.13 Another retrospective study performed in large tertiary medical centers in Taiwan, China suggested that propranolol can effectively reduce the incidence of HCC in patients with alcoholic cirrhosis.12 However, recently published meta-analyses and RCTs draw mixed conclusions; the meta-analyses concluded that NSBBs were able to prevent HCC, whereas the RCTs did not support this conclusion7-9 (Table 1). HE is a neuropsychiatric disorder that develops in patients with end-stage chronic liver disease; it is usually caused by severely impaired liver function and/or a portosystemic shunt. Up to 80% of cirrhosis patients may suffer from HE during disease progression. In addition to hyperammonemia, systemic inflammation, intestinal barrier dysfunction, and alteration of intestinal microbiota have been implicated in HE development. An NSBB-related reduction in intestinal permeability and mitigation of inflammation may reduce the occurrence of HE.3, 14 Nevertheless, studies by Labenz and colleagues indicated that NSBBs may increase the risk of developing an HE episode. Specifically, they reported that NSBBs affect cognitive and memory function through an increase in the plasma concentration of ammonia. Therefore, NSBBs may be associated with the onset of subclinical HE and aggravation of overt HE in patients with decompensated LC.14 Clinical trials on the effect of NSBBs in preventing HE were also inconclusive; one RCT indicated that carvedilol may delay the first episode of HE, but two other RCTs did not confirm the significant preventive effect7, 8, 10 (Table 1). In addition to the aforementioned non-bleeding complications, a recent retrospective study nested in a large-scale prospective cohort of decompensated cirrhosis patients demonstrated that NSBB treatment was associated with improved ACLF in terms of chronic liver failure consortium (CLIF-C) ACLF scores and short-term mortality.15 It was hypothesized that the underlying mechanism was that the sustainable use of NSBBs can alleviate the severity of systemic inflammation, which is remarkably elevated in ACLF patients.11 However, to date, there has only been one published RCT addressing this issue, which revealed that carvedilol reduced the 28-day mortality and improved the ACLF grades for up to 2 weeks; of note, the actual incidence of ACLF in patients on NSBBs compared with that in patients on placebo remains unknown11 (Table 1). Further high-quality studies are needed to determine this. Ascites is the most common clinical manifestation of early decompensation of LC, with an annual incidence of 10% in compensated LC patients. Although NSBBs prevent ascites mainly via hemodynamic mechanisms by reducing portal pressure, recent evidence has indicated that non-hemodynamic mechanisms may also be involved. In this context, NSBBs have been reported to improve intestinal permeability and inhibit the release of pro-inflammatory cytokines to exert anti-inflammatory activities.16 Unfortunately, only non-randomized retrospective studies have reported that non-hemodynamic biomarkers of NSBBs are independent protective factors of further decompensation, including ascites.16, 17 Therefore, high-quality data addressing this important non-bleeding complication are expected in the future. In summary, NSBBs serve as a basic medication to decelerate the progression of LC in the compensated stage through the combination of hemodynamic and non-hemodynamic effects. For patients in the decompensated stage, NSBBs have the potential to prevent further decompensation and thereby improve the long-term prognosis.3 However, establishing a new indication of NSBBs based on non-hemodynamic effects requires two lines of further investigation. First, the underlying mechanisms of NSBBs in preventing decompensation events such as SBP, HCC, and HE remain unclear and require further investigation. Moreover, the improvements of non-hemodynamic effects have not been widely verified in clinical practice, especially in RCT studies. Nonsignificant and conflicting results were observed in real-world observations.14 Second, although some studies found that non-hemodynamic indicators were partly correlated with those of the hemodynamic response, non-hemodynamic benefits could be achieved by different types of NSBBs at various doses, as summarized in Table 1.16 Accordingly, the optimal dose and type of NSBB for optimal non-hemodynamic effects remains unknown, and a standardized prescription has not been established. To provide reliable and precisive treatment guidance, additional well-designed clinical trials, and prospective follow-up studies are highly warranted in the future to explore the effect of NSBBs in cirrhosis patients at different disease stages and with various complications. Yi Yang, Mingkai Li, and Xing Wang planned and designed the study. Yi Yang, Mingkai Li, Jinni Luo, Hongsheng Yu, and Xing Wang performed the literature review. Hong Tian and Xing Wang provided administrative and material support for the study, and critically reviewed the manuscript. All authors wrote the manuscript and approved this version of submitted manuscript. None. This study was supported by grants from the National Natural Science Foundation of China (No. 82070574). The authors declare no conflict of interest. All data relevant to the study have been included in the published paper. All data relevant to the study have been included in the published paper.
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