Bei Jia

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.

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.

Risk factors associated with fatality of severe fever with thrombocytopenia syndrome: a meta-analysis

Severe fever with thrombocytopenia syndrome is an emerging life-threatening infectious disease identified in 2009. Given high case-fatality rate among patients with severe fever with thrombocytopenia syndrome, identification of the risk factors at acute phase associated with fatality is crucial for treatment. Therefore, we aimed to meta-analytically evaluate risk factors of fatal clinical outcome of severe fever with thrombocytopenia syndrome. 238 fatal cases and 873 non-fatal cases from 12 studies were included in this meta-analysis. Elder age and high viral load were significantly associated with fatal clinical outcome. Further, severe fever with thrombocytopenia syndrome patients with fatal clinical outcome had significantly reduced level of albumin and platelet count, higher level of serum alanine aminotransferase, aspirate aminotransferase, lactic acid dehydrogenase and creatinine phosphokinase, and prolonged activated partial thromboplastin time, comparing with mild patients. These disturbed parameters function as predictors to warn fatal clinical outcome of the disease. Moreover, ribavirin has a minimal impact to alleviate disease progression of severe fever with thrombocytopenia syndrome. In conclusion, our finding demonstrates a panel of factors associated with fatality of SFTS disease, which have important implications during clinical practice.Severe fever with thrombocytopenia syndrome is an emerging life-threatening infectious disease identified in 2009. Given high case-fatality rate among patients with severe fever with thrombocytopenia syndrome, identification of the risk factors at acute phase associated with fatality is crucial for treatment. Therefore, we aimed to meta-analytically evaluate risk factors of fatal clinical outcome of severe fever with thrombocytopenia syndrome. 238 fatal cases and 873 non-fatal cases from 12 studies were included in this meta-analysis. Elder age and high viral load were significantly associated with fatal clinical outcome. Further, severe fever with thrombocytopenia syndrome patients with fatal clinical outcome had significantly reduced level of albumin and platelet count, higher level of serum alanine aminotransferase, aspirate aminotransferase, lactic acid dehydrogenase and creatinine phosphokinase, and prolonged activated partial thromboplastin time, comparing with mild patients. These disturbed parameters function as predictors to warn fatal clinical outcome of the disease. Moreover, ribavirin has a minimal impact to alleviate disease progression of severe fever with thrombocytopenia syndrome. In conclusion, our finding demonstrates a panel of factors associated with fatality of SFTS disease, which have important implications during clinical practice.

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.

A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B

Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma‐glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742‐0.839), 0.783 (95% CI: 0.717‐0.849) and 0.791 (95% CI: 0.716‐0.867) in the entire patients with CHB, HBeAg‐positive CHB patients and HBeAg‐negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg‐negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with GGT in HBeAg‐negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg‐positive CHB.

Characterization of clinical features and outcome for human-to-human transmitted severe fever with thrombocytopenia syndrome

Abstract Background: Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease identified in 2009. SFTS is mainly transmitted by contact with ticks or animals; however, sporadic reports suggested that SFTS could be transmitted among humans. Objectives: We aimed to comprehensively characterize clinical features and disease progression of SFTS acquired by human-to-human transmission. Study design: A retrospective study of 90 SFTS patients was performed in a tertiary hospital of Nanjing, China, from October 2010 to October 2016. Seven cases of secondary SFTS were identified based on their epidemic timeline. Their clinical presentations, dynamic laboratory results and clinical outcome were analyzed. Results: First, 20 out of 83 primary SFTS patients were deceased, leading to a case-fatality ratio of 24.1%, while all secondary patients survived, suggesting a superior clinical outcome for secondary infection. Moreover, clinical symptoms and laboratory tests in primary and secondary SFTS patients were analyzed, respectively. Secondary SFTS patients developed milder clinical manifestation in the absence of neurological disorder and multiple organ failure. Further, clinical laboratory tests revealed that secondary patients had less disturbed key laboratory parameters, compared to those in primary SFTS patients. During day 7–13 post illness onset, most of the clinical laboratory results of secondary patients went back to normal range. They also had significantly lower level of viral load than primary patients. Conclusions: Secondary SFTS acquired through human-to-human transmission leads to milder clinical representations and superior prognoses compared to primary SFTS, suggesting that the transmission route makes a difference in disease progression and clinical outcome of SFTS disease.