Guiyang Wang

Meta-analysis: clinicopathological and prognostic significance of cyclooxygenase-2 expression on oesophageal squamous cell carinoma

Background  Cyclooxygenase‐2 (COX‐2) is involved in oesophageal carcinogenesis, but the clinical and prognostic significance of COX‐2 expression in oesophageal squamous cell carcinoma (ESCC) remains controversial.

Gamma-glutamyl-transpeptidase to platelet ratio is not superior to APRI,FIB-4 and RPR for diagnosing liver fibrosis in CHB patients in China

The gamma-glutamyl transpeptidase to platelet ratio (GPR) is a novel index to estimate liver fibrosis in chronic hepatitis B (CHB). Few studies compared diagnostic accuracy of GPR with other non-invasive fibrosis tests based on blood parameters. We analyzed diagnostic values of GPR for detecting liver fibrosis and compared diagnostic performances of GPR with APRI (aspartate aminotransferase-to-platelet ratio index), FIB-4 (fibrosis index based on the four factors), NLR (neutrophil-to-lymphocyte ratio), AAR (aspartate aminotransferase/alanine aminotransferase ratio) and RPR (red cell distribution width-to-platelet ratio) in HBeAg positive CHB and HBeAg negative CHB. We found AUROCs of GPR in predicting significant liver fibrosis, advanced liver fibrosis and liver cirrhosis were 0.732 (95% CI 0.663 to 0.801), 0.788 (95% CI 0.729 to 0.847) and 0.753 (95% CI 0.692 to 0.814), respectively. Further comparisons showed the diagnostic performance of GPR was not significantly different with APRI, FIB-4 and RPR in identifying significant fibrosis, advanced fibrosis and cirrhosis, but it was significantly superior to AAR and NLR in both HBeAg positive CHB and HBeAg negative CHB. In conclusion, GPR does not show advantages than APRI, FIB-4 and RPR in identifying significant liver fibrosis, advanced liver fibrosis and liver cirrhosis in both HBeAg positive CHB and HBeAg negative CHB in China.

A scoring model for predicting prognosis of patients with severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease caused by the SFTS bunyavirus (SFTSV) with an estimated high case-fatality rate of 12.7% to 32.6%. Currently, the disease has been reported in mainland China, Japan, Korea, and the United States. At present, there is no specific antiviral therapy for SFTSV infection. Considering the higher mortality rate and rapid clinical progress of SFTS, supporting the appropriate treatment in time to SFTS patients is critical. Therefore, it is very important for clinicians to predict these SFTS cases who are more likely to have a poor prognosis or even more likely to decease. In the present study, we established a simple and feasible model for assessing the severity and predicting the prognosis of SFTS patients with high sensitivity and specificity. This model may aid the physicians to immediately initiate prompt treatment to block the rapid development of the illness and reduce the fatality of SFTS patients.

A novel predictive model using routinely clinical parameters to predict liver fibrosis in patients with chronic hepatitis B

Objectives Noninvasive models have been established for the assessment of liver fibrosis in patients with chronic hepatitis B(CHB). However, the predictive performance of these established models remains inconclusive. We aimed to develop a novel predictive model for liver fibrosis in CHB based on routinely clinical parameters. Results Platelets(PLT), the standard deviation of red blood cell distribution width(RDW-SD), alkaline phosphatase(ALP) and globulin were independent predictors of significant fibrosis by multivariable analysis. Based on these parameters, a new predictive model namely APRG(ALP/PLT/RDW-SD/globulin) was proposed. The areas under the receiver-operating characteristic curves(AUROCs) of APRG index in predicting significant fibrosis(≥F2), advanced fibrosis(≥F3) and liver cirrhosis(≥F4) were 0.757(95%CI 0.699 to 0.816), 0.763(95%CI 0.711 to 0.816) and 0.781(95%CI 0.728 to 0.835), respectively. The AUROCs of the APRG were significantly higher than that of aspartate transaminase(AST) to PLT ratio index(APRI), RDW to PLT ratio(RPR) and AST to alanine aminotransferase ratio(AAR) to predict significant fibrosis, advanced fibrosis and cirrhosis. The AUROCs of the APRG were also significantly higher than fibrosis-4 score (FIB-4) (0.723, 95%CI 0.663 to 0.783) for cirrhosis(P=0.034) and better than gamma-glutamyl transpeptidase(GGT) to PLT ratio(GPR) (0.657, 95%CI 0.590 to 0.724) for significant fibrosis(P=0.001). Materials and Methods 308 CHB patients who underwent liver biopsy were enrolled. The diagnostic values of the APRG for liver fibrosis with other noninvasive models were compared. Conclusions The APRG has a better diagnostic value than conventionally predictive models to assess liver fibrosis in CHB patients. The application of APRG may reduce the need for liver biopsy in CHB patients in clinical practice.OBJECTIVES Noninvasive models have been established for the assessment of liver fibrosis in patients with chronic hepatitis B(CHB). However, the predictive performance of these established models remains inconclusive. We aimed to develop a novel predictive model for liver fibrosis in CHB based on routinely clinical parameters. RESULTS Platelets(PLT), the standard deviation of red blood cell distribution width(RDW-SD), alkaline phosphatase(ALP) and globulin were independent predictors of significant fibrosis by multivariable analysis. Based on these parameters, a new predictive model namely APRG(ALP/PLT/RDW-SD/globulin) was proposed. The areas under the receiver-operating characteristic curves(AUROCs) of APRG index in predicting significant fibrosis(≥F2), advanced fibrosis(≥F3) and liver cirrhosis(≥F4) were 0.757(95%CI 0.699 to 0.816), 0.763(95%CI 0.711 to 0.816) and 0.781(95%CI 0.728 to 0.835), respectively. The AUROCs of the APRG were significantly higher than that of aspartate transaminase(AST) to PLT ratio index(APRI), RDW to PLT ratio(RPR) and AST to alanine aminotransferase ratio(AAR) to predict significant fibrosis, advanced fibrosis and cirrhosis. The AUROCs of the APRG were also significantly higher than fibrosis-4 score (FIB-4) (0.723, 95%CI 0.663 to 0.783) for cirrhosis(P=0.034) and better than gamma-glutamyl transpeptidase(GGT) to PLT ratio(GPR) (0.657, 95%CI 0.590 to 0.724) for significant fibrosis(P=0.001). MATERIALS AND METHODS 308 CHB patients who underwent liver biopsy were enrolled. The diagnostic values of the APRG for liver fibrosis with other noninvasive models were compared. CONCLUSIONS The APRG has a better diagnostic value than conventionally predictive models to assess liver fibrosis in CHB patients. The application of APRG may reduce the need for liver biopsy in CHB patients in clinical practice.

Association of serum gamma-glutamyl transferase with treatment outcome in chronic hepatitis B patients.

AIM To investigate the association of serum gamma-glutamyl transferase (GGT) levels with chronic hepatitis B infection and hepatitis B e antigen (HBeAg) seroconversion. METHODS A retrospective study was performed on clinical data collected from patients who had been positive for hepatitis B surface antigen for > 6 mo and who were antiviral-treatment naïve (n = 215) attending the Hepatitis Clinic at Nanjing Drum Tower Hospital between August 2010 and December 2013. Healthy individuals without liver disease (n = 83) were included as controls. Patients were categorized into four groups based on disease status as recommended by the European Association for the Study of the Liver: immune tolerance (IT; n = 47), HBeAg-positive hepatitis (EPH; n = 93), HBeAg-negative hepatitis (ENH; n = 20), and inactive carrier (IC; n = 55). Prediction of complete response (CR) based on serum GGT was also examined in EPH patients (n = 33) treated for 48 wk with nucleos(t)ide analogue (NA) therapy, including lamivudine plus adefovir combination therapy (n = 20) or entecavir monotherapy (n = 13). CR was defined as a serum hepatitis B virus DNA level < 500 copies/mL and HBeAg seroconversion by 48 wk of treatment. RESULTS Serum GGT levels were significantly increased in EPH and ENH patients relative to the IT, IC, and healthy control groups (P < 0.01 for all). However, no significant difference in serum GGT levels was found between the EPH and ENH groups. Baseline serum GGT levels were significantly higher in patients who achieved CR (7/33; 21.2%) compared to patients in the non-CR group (26/33; 78.8%; P = 0.011). In addition, the decline in serum GGT was greater in CR patients compared to non-CR patients after 24 wk and 48 wk of treatment (P = 0.012 and P = 0.008, respectively). The receiver operating characteristic curve yielded a sensitivity of 85.71% and a specificity of 61.54% at a threshold value of 0.89 times the upper limit of normal for baseline serum GGT in the prediction of CR following NA therapy. CONCLUSION Serum GGT is significantly elevated in EPH and ENH patients and is a potential biomarker for the prediction of HBeAg seroconversion following NA therapy.

Emodin Alleviates Liver Fibrosis of Mice by Reducing Infiltration of Gr1hi Monocytes

Emodin, as a major active component of Rheum palmatum L. and Polygonum cuspidatum, has been reported to have antifibrotic effect. However, the mechanism of emodin on antifibrotic effect for liver fibrosis was still obscure. In the present study, we aimed to investigate whether emodin can alleviate carbon tetrachloride- (CCl4-) induced liver fibrosis through reducing infiltration of Gr1hi monocytes. Liver fibrosis was induced by intraperitoneal CCl4 injection in mice. Mice in the emodin group received emodin treatment by gavage. Pretreatment with emodin significantly protected mice from liver inflammation and fibrosis revealed by the decreased elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as reduced hepatic necrosis and fibrosis by analysis of hematoxylin-eosin (HE) staining, Masson staining, α-smooth muscle actin (α-SMA), and collagen-I immunohistochemistry staining. Further, compared to CCl4 group, mice in the emodin group showed significantly less intrahepatic infiltration of Gr1hi monocytes. Moreover, emodin significantly inhibited hepatic expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), granulin (GRN), monocyte chemoattractant protein 1 (MCP-1), and chemokine ligand 7 (CCL7), which was in line with the decreased numbers of intrahepatic Gr1hi monocytes. In conclusion, emodin can alleviate the degree of liver fibrosis by reducing infiltration of Gr1hi monocytes. These results suggest that emodin is a promising candidate to prevent and treat liver fibrosis.

Non‐invasive fibrosis markers for chronic hepatitis B in sub‐Saharan Africa

To the editor, We read with great interest the article by Desalegn H et al.,1 in which they determined the potential diagnostic accuracy of aspartate aminotransferase to platelet ratio index (APRI), fibrosis4 score (FIB4) and gammaglutamyl transpeptidase to platelet ratio (GPR) in one of the largest chronic hepatitis B (CHB) cohorts in subSaharan Africa.1 They concluded that APRI, FIB4 and GPR were valuable for the diagnosis of liver fibrosis and cirrhosis in CHB patients in subSaharan Africa.1 However, the sensitivity for detecting fibrosis and cirrhosis was relatively low.1 These findings are interesting, because few studies have identified these noninvasive fibrosis biomarkers in subSaharan Africa. However, the results should be interpreted with cautions. Firstly, in this study transient elastography (TE) was used as a reference to define significant fibrosis and cirrhosis.1 Although TE has been widely evaluated in CHB patients, there is still lack of uniformly established standard to identify specific stages of liver fibrosis.2,3 In addition, several factors may affect the accuracy of TE. Indeed, the authors have excluded patients with ascites, overweight or obesity in this study, as fluid and adipose tissue may attenuate the elastic wave.1 However, other factors, such as sex (men tend to have higher liver stiffness than women), metabolic syndrome and experience of different operators may also influence the test results.3 Thus, a potential bias of liver fibrosis stages might exist in the study. Although, as the authors mentioned, sampling errors may lead to poor reproducibility for liver biopsies, liver histology remains the gold standard to determine liver fibrosis in clinical research.2,3 Secondly, the authors used 0.5 and 1.5 to distinguish F01 and F24,1.0 and 2.0 to differentiate F03 and F4 for APRI, 1.45 and 3.25 to distinguish F02 and F34 for FIB4.1 However, the above thresholds were developed from patients with chronic hepatitis C virus infection.4,5 These cutoff values have not been well validated among CHB patients. Thirdly, all the noninvasive fibrosis biomarkers in the study included platelets as a critical component.1 However, platelet count is pronouncedly influenced by various factors including chronic inflammatory diseases, haematological disorders and drug usage, which creates difficulty for further calculation of APRI, FIB4 and GPR, the biomarkers proposed in this study. In summary, further validation is essential for potential clinical application of these noninvasive biomarkers for liver fibrosis from CHB patients in subSaharan Africa.

Letter: is body-mass index really associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B?

relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 2014; 60: 87–97. 5. Manesis EK, Schina M, Le Gal F, et al. Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring. Antivir Ther 2007; 12: 381–8. 6. Ouzan D, P enaranda G, Joly H, Halfon P. Optimized HBsAg titer monitoring improves interferon therapy in patients with chronic hepatitis delta. J Hepatol 2013; 58: 1258–9. 7. Chen GY, Su TH, Kao JH. Successful treatment of chronic hepatitis B and D with pegylated-interferon plus entecavir. J Formos Med Assoc 2015; 114: 1140–1.

Letter: need to re-evaluate non-invasive markers for staging fibrosis in chronic delta hepatitis

SIRS, We read with great interest the article by Takyar et al. In this study, they evaluated the utility of serum fibrosis markers, including fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, aspartate aminotransferase ratio (AAR), age-platelet index (API), AST-toplatelet-ratioindex (APRI) and Hui score for staging liver fibrosis in hepatitis delta virus (HDV) infection and they also compared these non-invasive fibrosis biomarkers across hepatitis B virus (HBV), hepatitis C virus (HCV) and HDV infection. They found that serum fibrosis markers had lower performance accuracy in chronic HDV-infected patients compared to HBV and HCV patients. They also found that FIB-4 performed better than APRI in identifying advanced liver fibrosis (Ishak ≥ 4) and cirrhosis (Ishak = 6) in chronic HBV infection. We appreciated the efforts made by the authors to compare these non-invasive fibrosis biomarkers for staging fibrosis in HBV, HCV and HDV infection. However, several issues deserve further discussion. Firstly, most of the non-invasive fibrosis biomarkers in the study included platelets (four of five biomarkers) as the component. Nevertheless, platelets may also be affected by many factors such as infections, chronic inflammatory diseases, some haematological disorders and drug use. Therefore, when evaluating these noninvasive biomarkers that may affect the components of the non-invasive fibrosis biomarkers particular comorbidities need to be taken into consideration. However, the authors only excluded the patients with co-existing non-viral hepatitis liver diseases. The patients were not evaluated for the existence of comorbidities such as infections, chronic inflammatory diseases, haematological disorders or drug use, which might have affected the results. Secondly, in the study, chronic HBV infection was defined as presence of hepatitis B surface antigen (HBsAg) in serum at time of liver biopsy and positive staining for HBsAg or HBcAg in hepatocytes. However, according to current guidelines, 7 chronic HBV infection is defined as HBsAg seropositive status at 6 months or beyond. Thus, acute HBV infection might have been included in the study according to their criteria. Thirdly, FIB-4 performed the best across all chronic viral hepatitis cohorts in detecting advanced fibrosis and cirrhosis in the study by Takyar et al. However, FIB-4 is not recommended in WHO guidelines because it has been developed and validated for the detection of fibrosis stages ≥F3 but not cirrhosis. Instead, APRI is recommended as the most cost-effective non-invasive test to assess liver fibrosis in chronic HBV infection. Thus, the superiority of FIB-4 to assess liver fibrosis deserves further investigation. Finally, as the authors mentioned, only a relatively small number of patients with HDV infection (n = 62) were included in the study. Lack of a validation cohort was another weakness. Thus, large-scale research with well-defined inclusion and exclusion criteria is required to re-evaluate the utility of serum non-invasive fibrosis markers in patients with chronic viral hepatitis, especially in HDV infection. Furthermore, we believe that better results could be achieved using a combination of non-invasive fibrosis markers in HDV infection.

Deficient humoral responses and disrupted B-cell immunity are associated with fatal SFTSV infection

Severe Fever with Thrombocytopenia Syndrome (SFTS), an emerging infectious disease caused by a novel phlebovirus, is associated with high fatality. Therapeutic interventions are lacking and disease pathogenesis is yet to be fully elucidated. The anti-viral immune response has been reported, but humoral involvement in viral pathogenesis is poorly understood. Here we show defective serological responses to SFTSV is associated with disease fatality and a combination of B-cell and T-cell impairment contribute to disruption of anti-viral immunity. The serological profile in deceased patients is characterized by absence of specific IgG to viral nucleocapsid and glycoprotein due to failure of B-cell class switching. Expansion and impairment of antibody secretion is a signature of fatal SFTSV infection. Apoptosis of monocytes in the early stage of infection diminishes antigen-presentation by dendritic cells, impedes differentiation and function of T follicular helper cells, and contributes to failure of the virus-specific humoral response.SFTSV is a novel phlebovirus associated with high fatality, but understanding of pathogenesis is lacking. Here the authors show defective cellular immunity, deficient antibody production and defunct humoral immunity is associated with fatal infection in human cases of infection.