Table of Content

31 January 2018, Volume 23 Issue 1

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Editorial & contention

The medical laboratory issues about recommendation on uniform cutoff values of “Normal” ALT in the ACG Guidelines

YU Qian, PAN Bai-shen

2018, 23(1):  1-4. 

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In the recent American clinical guidelines dealing with laboratory tests for evaluation of liver disease, the American College of Gastroenterology (ACG) recommends ALT upper reference limits of 33 U/L for males and 25 U/L for females respectively, and that individuals with ALT above these “normal” cutoffs should be further investigated. Considering the differences between laboratory assays measuring ALT in our country, the standardization of methods and the consistency of results can not be completely ensured. The uniform "normal" range of ALT recommended by the ACG guidelines is largely based on findings from foreign studies and may not be suitable to Chinese population. On the other hand, reference upper/lower limits should not simply be equated with clinical decision thresholds. However, due to improper application of the related concepts of the above medical laboratory issues, simply recommending the uniform reference range of the ALT may lead to overdiagnosis and unnecessary follow-up examinations.

Original Articles

Clinical characteristics and significance of plasma von Willebrand factor antigen level and VITRO score in Chinese patients with various hepatic diseases

ZHUANG Yan, WANG Xiao-lin, LIU Ke-hui, XU Yu-min, XIE Jin-dong, LIN Zhi-mei, WANG Hui, XIE Qing, GUO Qing

2018, 23(1):  14-17. 

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Objective To evaluate the diagnostic accuracy of von Willebrand factor antigen (vWF: Ag) and von Willebrand factor antigen/thrombocyte ratio (VITRO) score in different types of liver diseases in Chinese patients. Methods A total of 122 patients admitted from January 2017 to September 2017 were enrolled. Plasma vWF: Ag was tested in all patients, and VITRO score was calculated upon admission. All cases were divided into acute group (50 cases) and chronic group (72 cases), which were further classified into 5 subgroups, including acute liver injury subgroup (43 cases), acute/subacute liver failure subgroup (7 cases), chronic liver injury subgroup (21 cases), acute on chronic liver failure subgroup (12 cases) and liver cirrhosis subgroup (39 cases). Clinical significance and characteristics of plasm vWF:Ag level and VITRO score were determined using Mann-Whitney U test and receiver operating characteristic (Hayashi, #19) curve analysis. Results Demographic characteristic were similar in acute and chronic liver disease groups except age. Plasma vWF:Ag levels [205.30 (185.30~235.35) vs 172.30 (158.30~194.10), P<0.01] and VITRO scores [2.47 (1.57~3.90) vs 1.00 (0.82~1.21), P<0.01] were both significantly higher in chronic group than acute group. Plasma vWF-Ag levels [225.40 (211.20~237.45) vs 196.30 (190.30~210.30), P<0.05] and VITRO score [3.61 (2.92~4.69) vs 1.28 (0.89~1.71), P<0.01] were both higher in acute on chronic/chronic liver failure subgroup than acute/subacute liver failure subgroup. ROC curve analysis revealed that the area under curve (AUCs) for the diagnosis of chronic liver disease was 0.812 (95% CI: 0.734~0.890, P<0.01) for vWF: Ag and 0.891 (95% CI: 0.828~0.953, P<0.01) for VITRO score. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for chronic liver disease were 81.9%, 70.0%, 79.7%, 72.9%, 77.0% using a vWF: Ag cut-off value of 185%, and were 79.7%, 72.9%, 89.2%, 82.0%, 86.1% using a VITRO cut-off value of 1.35, respectively. The AUCs for the diagnosis of acute on chronic liver failure was 0.833 (95% CI: 0.610~1.000, P<0.05) for vWF: Ag and 0.940 (95% CI: 0.000~1.000, P<0.01) for VITRO score. The sensitivity, specificity, positive predictive, negative predictive value and diagnostic accuracy for acute on chronic liver failure were 100.0%, 75.0%, 70.0%, 100.0% and 84.2% using a vWF: Ag cut-off value of 215%, and were 100%, 91.7%, 87.5%, 100% and 94.7% using a VITRO cut-off value of 2.00, respectively.Conclusion Elevated vWF: Ag level and VITRO score are characteristic of chronic liver diseases in Chinese patients, especially in patients with liver failure. VITRO score is of greater diagnostic value than vWF: Ag level.

Expression of Treg and Th17 in HBV-related acute-on-chronic liver failure patients and their correlations with the mutations in HBV pre-C/BCP region

GAO Hai-bing, WANG Xiang-mei, LIU Bao-rong, PAN Chen, FANG Jian-kai, LIN Sheng-long, MA Hua-xi, CHEN Xiu-min, LIN Ming-hua, ZHENG Rui-dan

2018, 23(1):  18-21. 

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Objective To investigate the expression characteristics of peripheral T regulatory cell (Treg) and T help cell 17 (Th17) in patients with hepatitis B related acute-on-chronic liver failure (HBV-ACLF), and their correlation with HBV pre-C/BCP mutations.Methods Forty-one HBV-ACLF patients and 41 early ACLF patients were enrolled. Levels of serum interleukin (IL)-17, transforming growth factor (TGF)-β1, interferon (IFN)-γ, IL-1β and IL-21 were determined using enzyme-linked immuno sorbent assay (ELISA). Expression of Treg and Th17 were determined using flow cytometry. Sequencing for mutations of HBV pre-C/BCP region was performed. Results Levels of Treg, Th17, IL-17, TGF-β1, IFN-γ and IL-1β, A1762T/G1764A double mutations and G1896A mutation were significantly higher in HBV-ACLF patients than those in early HBV-ACLF patients (t' = 8.594, P<0.001; t = 4.609, P<0.001; t=2.316, P=0.023; t=2.939, P=0.004; t=8.094, P<0.001; t=5.429,P<0.001; χ²=4.038, P=0.044; χ²=6.032, P=0.01), respectively. There were no significant difference in the ratio of Treg/Th17 and IL-21 level between HBV-ACLF and early HBV-ACLF group (t=0.902, P=0.370; t=0.294, P=0.769). Treg and Th17 levels in patients with A1762T/G1764A double mutations or G1896A mutation were both significantly higher than those with no mutations (t=2.932, P=0.004; t=2.339, P=0.022; t=3.232, P=0.002; t'=2.990, P=0.004). There were no significant difference in the ratio of Treg/Th17 between mutation and non-mutation groups (t=0.030, P=0.976; t'=0.272, P=0.787). Conclusion Changes of Treg and Th17, A1762T/G1764A double mutations in HBV BCP region and G1896A mutation in pre-C region might play roles in pathogenesis of HBV-ACLF.

Combination of APRI, FIB-4 and Fibro Touch for predicting early liver fibrosis in chronic hepatitis B patients

YU Chong, LI Min, GU Yu-ling, GU Er-li

2018, 23(1):  22-25. 

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Objective To investigate the predictive value of aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the four factors (FIB-4) and Fibro Touch for early liver fibrosis in chronic hepatitis B (CHB) patients. Methods A total of 402 CHB patients were retrospectively analyzed, including 146 cases in non-liver fibrosis (S0-S1)group, 162 cases in obvious liver fibrosis (S2-S3) group and 94 cases in early cirrhosis (S4) group according to liver pathology. The correlation between APRI, FIB-4 and Fibro Touch combined detection and liver pathology was calculated. The early diagnostic value of noninvasive diagnostic models for liver fibrosis (≥ S2)was analyzed. Meanwhile, the receiver operator characteristic (ROC) curve was performed for the best predictive value, sensitivity and specificity. Results APRI, FIB-4 and Fibro Touch were strongly correlated with liver fibrosis stages (P<0.05), with Spearman correlation coefficients of 0.768, 0.712 and 0.865, respectively. Using multivariate logistic regression analysis, APRI, FIB-4 and Fibro Touch had a certain predictive value for liver fibrosis (P<0.05), with OR values of 1.996, 1.563 and 2.180, respectively. APRI, FIB-4, Fibro Touch were fitted in binary logistic regression with high fitting degree (χ²＝13.689, P＝0.126) for early warning of liver fibrosis : logit(P)＝-0.556+1.119*(APRI)+1.202*(FIB-4)+1.682*(Fibro Touch). In predicting liver fibrosis (≥S2), the combination of APRI, FIB-4 and Fibro Touch had the best predictive value, with the area under ROC curve of 0.928 and the maximum Youden index of 0.819. Meanwhile, Fibro Touch performed better than APRI and FIB-4, which was without any significant difference between APRI and FIB-4. The cutoff value of combination of APRI, FIB-4 and Fibro Touch was 18.14, with sensitivity of 89.6% and specificity of 92.3%.Conclusion Combination of APRI, FIB-4 and Fibro Touch could help predict early liver fibrosis in CHB patients.

Pathological features of liver inflammation and fibrosis in hepatitis B virus transgenic mice C57BL/6N-Tg(1.28HBV)/Vst

SUN Xin, HUANG Kai, ZHAO Zhi-min, LV Jing, PENG Yuan, TAO Yan-yan, LIU Cheng-hai

2018, 23(1):  26-30. 

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Objective To investigate the pathological features of liver inflammation and fibrosis in hepatitis B virus transgenic (HBV-Tg) mice C57BL/6N-Tg(1.28HBV)/Vst at different ages. Methods HBV-Tg mice at different ages (12, 24 and 36-week old) and wild-type C57BL/6 mice at week 36 were enrolled. Levels of serum hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were detected using enzyme-linked immunosorbent assay (ELISA). HBV DNA in serum was detected using reverse transcription polymerase chain reaction (RT-PCR). The in situ expression of HBsAg and HBcAg in liver tissue was detected using immunohistochemical staining. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels in serum were tested using reagent kit. Hydroxyproline (Hyp) level in liver tissue was measured by hydrochloric acid hydrolysis method. Hematoxylin eosin (HE), sirius red and reticular fiber staining were used to observe morphological changes and collagen deposition in liver tissue, and α-SMA immunohistochemical staining was used to observe activation of hepatic stellate cells. Results HBsAg and HBeAg were positive in serum and liver tissues, and serum HBV DNA was more than 1.0×10⁷ IU/mL in all HBV-Tg mice at different ages. Serum ALT and AST levels gradually increased as age increasing. Compared with that in wild type, ALP level in HBV-Tg mice at different weeks was significantly higher and peaked at week 12. Besides, hydroxyproline content, collagen deposition and activation of hepatic stellate cells in liver tissue of HBV-Tg mice were gradually increased. Liver tissue inflammation and fibrosis aggravated gradually increased, and peaked at week 36. Conclusion The liver performed spontaneous inflammation and fibrosis as age increasing in HBV-Tg mice. HBV-Tg mice might be more suitable for the establishment of chronic HBV persistent infection model and liver fibrosis model after HBV infection. It provides technical supports for further mechanism research, as well as development of novel anti-fibrosis and HBV drug.

Regulation of microRNA-21 for cisplatin resistance in Huh7 cells by PTEN and Wnt signaling pathways

LU Tian-fei, ZHONG Cheng-peng, GU Guang-xiang, HAO Jun, ZHANG Jian-jun , XU Ning

2018, 23(1):  31-36. 

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Objective To investigate the mechanism of microRNAs in mediating cisplatin resistance in hepatocellular carcinoma (HCC).Methods MicroRNA-21 (miR-21) level was determined in HCC patients after cisplatin chemotherapy. miR-21 mimics and miR-21 inhibitor were used to upregulate or downregulate miR-21 level in Huh-7 cells. Human dickkopf-1(DKK-1) and bpV (phen) were used as Wnt inhibitor and phosphate and tension homology deleted on chromsome ten (PTEN) inhibitor, respectively. Relative mRNA level and protein expression were detected by real-time polymerase chain reaction (RT-PCR) and western blot, respectively. Results The results showed that overexpression of miR-21 decreased cisplatin (5 and 10 μg/mL)-induced inhibition of cell proliferation in Huh7 cells. Both mRNA level and protein expression of Wnt4 were elevated remarkably when Huh7 cells were treated with miR-21 mimics. Moreover, inhibition of Wnt4 and cell proliferation by DKK-1 was reversed using overexpression of miR-21. In addition, miR-21 mimics increased both mRNA level and protein expression of PTEN, and overexpression of miR-21 increased cell proliferation rate which was inhibited using bpV (phen, 100 and 200 nmol/L) in Huh7 cells. Conclusion miR-21 was involved in regulating resistance to cisplatin in Huh7 cells by activating Wnt and PTEN signaling pathways.