2021 No. 6

Research and development of new drugs for nonalcoholic steatohepatitis: An unmet need in clinical practice

Yining HE, Junping SHI

2021, 37(6): 1241-1244. DOI: 10.3969/j.issn.1001-5256.2021.06.001

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With the effective control of viral hepatitis around the world, nonalcoholic steatohepatitis (NASH) will become the main cause of liver transplantation in the next ten years. There is a huge number of NASH patients, but currently no drug has been approved by authorities, which represents a large unmet need in clinical practice. The complex pathogenesis of NASH, heterogeneity of this disease, difficulties in diagnosis, and selection of treatment endpoints have brought great challenges to the research and development of new drugs.

Interpretation of clinical trial guidelines for nonalcoholic steatohepatitis

Huiying RAO, Lai WEI

2021, 37(6): 1245-1248. DOI: 10.3969/j.issn.1001-5256.2021.06.002

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In December 2019, National Medical Products Administration of China issued Guidelines for Clinical Trials of Drugs for Treatment of Nonalcoholic Steatohepatitis (Interim), which mainly targeted at adult patients with nonalcoholic steatohepatitis with significant liver fibrosis and compensated liver cirrhosis (F2-F4). This article introduces related considerations from the aspects of clinical trial endpoint, overall clinical trial design, specific research and development stages, and safety. With reference to related guidelines of the United States and the European Union, this article attempts to explore the association between clinical trial and clinical practice.

Evaluation of clinical endpoints in new drug research and development for nonalcoholic steatohepatitis

Xiaofei TONG, Yameng SUN, Hong YOU

2021, 37(6): 1249-1253. DOI: 10.3969/j.issn.1001-5256.2021.06.003

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Nonalcoholic steatohepatitis (NASH) has gradually become a common cause of liver cirrhosis, hepatocellular carcinoma, and liver-related deaths, and currently no effective therapeutic drugs have been approved for the treatment of NASH. Therefore, there is an urgent need for effective new drugs to improve clinical endpoints and reduce disease burden. The development and progression of NASH are closely associated with metabolism and have strong heterogeneity, and it takes a long time to observe its clinical outcome. These characteristics bring challenges to the research and development of new drugs for NASH. In the process of drug research and development, the selection of treatment endpoints is crucial to the evaluation of drug efficacy, and the basic principle of endpoint selection is whether it can reflect clinical outcome and predict clinical benefit. This article summarizes and discusses the selection of treatment endpoints at different stages of the research and development of new drugs for NASH.

Key factors in the research and development of new drugs for nonalcoholic steatohepatitis

Zhaoyang GUO, Fajuan RUI, Jie LI

2021, 37(6): 1254-1258. DOI: 10.3969/j.issn.1001-5256.2021.06.004

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Nonalcoholic fatty liver disease (NAFLD) has become the most important chronic liver disease in China and a major cause of liver transplantation in developed countries in Europe and America. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis (NASH) is highly likely to progress to end-stage liver disease including liver cirrhosis and liver cancer, resulting in an increase in liver-related mortality. However, there are still no therapeutic drugs for NASH at present, and many new drugs are under development in ongoing clinical trials. The research and development of new drugs for NASH require the selection of an appropriate target population and treatment outcomes depending on anti-metabolic, anti-inflammatory or anti-fibrotic effect. This article summarizes and reviews several key factors in the research and development of new drugs for NASH.

Prospects of marketed hypoglycemic drugs in treatment of nonalcoholic fatty liver disease

Xin GAO

2021, 37(6): 1259-1261. DOI: 10.3969/j.issn.1001-5256.2021.06.005

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Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome in the liver and is closely associated with glucose and lipid metabolism disorders, and they interact as both cause and effect of each other, with insulin resistance as the common pathogenesis. About three quarters of patients with obesity and type 2 diabetes mellitus have NAFLD, and current guidelines recommend reducing metabolic risk factors and treating metabolic syndrome as the primary treatment goals for patients with NAFLD. Although there are no approved drugs for the treatment of NASH at present, the hypoglycemic drugs on the market can bring varying degrees of benefits to NAFLD patients while lowering blood glucose. This article reviews the prospects of three types of hypoglycemic drugs on the market (thiazolidinediones, GLP-1 receptor agonists, and SGLT-2 inhibitors) in the treatment of NAFLD.

Current status and perspectives of fibroblast growth factor 21 in nonalcoholic fatty liver disease

Leigang JIN, Leiluo GENG, Aimin XU

2021, 37(6): 1262-1267. DOI: 10.3969/j.issn.1001-5256.2021.06.006

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Fibroblast growth factor 21 (FGF21) is a peptide hormone predominantly secreted by the liver and plays a crucial role in maintaining whole-body energy metabolism and regulating insulin sensitivity. A large number of clinical studies have demonstrated that serum FGF21 levels are increased in obese patients with non-alcoholic fatty liver disease (NAFLD), and high circulating FGF21 is a sensitive biomarker for predicting the onset and progression of NAFLD. Injection of exogenous FGF21 can effectively alleviate pathological process in both animal models and NAFLD patients. This review aims to describe the molecular mechanism underlying the hepatoprotective effects of FGF21; to summarize the current data and challenges of the clinical trials on FGF21 analogs and receptor agonists in the treatment of NAFLD and nonalcoholic steatohepatitis (NASH); and to speculate the future directions of FGF21 as a diagnosis and treatment for NAFLD.

Current status of the research on low-level viremia in chronic hepatitis B patients receiving nucleos(t)ide analogues

Fengming LU, Bo FENG, Sujun ZHENG, Suzhen JIANG, Ruifeng YANG, Junliang FU, Dong JI, Shuangsuo DANG, Xiaobo LU, Hongsong CHEN, Xinyue CHEN, Hong REN, Zhiliang GAO, Yuemin NAN, Xiaoyuan XU, Junqi NIU, Wenhong ZHANG, Hui ZHUANG

2021, 37(6): 1268-1274. DOI: 10.3969/j.issn.1001-5256.2021.06.007

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Nucleos(t)ide analogues (NAs), which are widely used as the first-line anti-hepatitis B virus (HBV) drugs in clinical practice, can effectively inhibit the replication of HBV DNA, significantly slow down disease progression in chronic hepatitis B (CHB) patients, and reduce the development of end-stage liver diseases such as liver failure and liver cancer. However, for some CHB patients receiving first-line NAs for 48 weeks or longer, serum HBV DNA is still persistently or intermittently higher than the lower detection of limit of sensitive nucleic acid detection reagents. After discussion by the authors, low-level viremia (LLV) is defined as follows: persistent LLV refers to the condition in which CHB patients, who receive entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate for ≥48 weeks, have positive for HBV DNA are positive by two consecutive detections with sensitive quantitative PCR, with an interval of 3-6 months, but < 2000 IU/ml; intermittent LLV refers to serum HBV DNA are positive intermittently by at least three consecutive detections, with an interval of 3-6 months, but HBV DNA < 2000 IU/ml. For the diagnosis of LLV, the issues of poor compliance and drug-resistant mutations should be excluded. LLV might be associated with the increased risk of progression to liver fibrosis, or hepatocellular carcinoma in patients with liver cirrhosis under NA treatment, but there are still controversies over whether the original treatment regimen with NAs should be changed after the onset of LLV. This article summarizes the incidence rate of LLV under NA treatment and the influence of LLV on prognosis and analyzes the possible mechanisms of the osnet of LLV, so as to provide a reference for the management of LLV in patients treated with NAs.

Antiviral therapy should be used selectively in the immune-tolerant phase of hepatitis B virus infection

Letian LI

2021, 37(6): 1275-1276. DOI: 10.3969/j.issn.1001-5256.2021.06.008

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Individualized treatment should be performed in the immune-tolerant phase of hepatitis B virus infection

Zixin CUI, Jiayun LI, Peiyao WEI, Yunru CHEN, Jianzhou LI, Feng YE

2021, 37(6): 1277-1277. DOI: 10.3969/j.issn.1001-5256.2021.06.009

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Antiviral therapy should be selected for patients in the immune-tolerant phase of chronic hepatitis B virus infection

Xinyue CHEN, Aixin SONG

2021, 37(6): 1278-1278. DOI: 10.3969/j.issn.1001-5256.2021.06.010

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Antiviral therapy is not recommended in immune-tolerant phase chronic hepatitis B patients without complications

Min QUAN, Huichun XING

2021, 37(6): 1279-1280. DOI: 10.3969/j.issn.1001-5256.2021.06.011

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How to determine the optimal treatment timing in chronic HBV infection patients with normal ALT and positive HBeAg?

Hong ZHAO, Wen XIE

2021, 37(6): 1281-1281. DOI: 10.3969/j.issn.1001-5256.2021.06.012

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Antiviral therapy for patients with chronic hepatitis B in the immune-tolerant phase: A systematic review

Yanlin LI, Yan WANG, Yingqiong ZHOU, Xueliang YANG, Na CHEN, Fangyao CHEN, Xiaojing LIU

2021, 37(6): 1282-1287. DOI: 10.3969/j.issn.1001-5256.2021.06.013

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Objective Objective To systematically evaluate the efficacy and safety of antiviral therapy in patients with chronic hepatitis B (CHB) in the immune-tolerant phase. Methods PubMed, Embase, Cochrane Library, CNKI, and Wanfang Data were searched for clinical trials of antiviral therapy for CHB patients in the immune-tolerant phase published up to September 2020. Related data were extracted after quality assessment for systematic review. HBV DNA clearance rate was the primary outcome. Results A total of 9 studies involving 821 patients were included. Eight studies reported HBV DNA clearance rate in the treatment group, among which 6 studies had an HBV DNA clearance rate of > 60%, which was significantly higher than that in the untreated patients (0%-29.1%), and the combination therapy group had a better clearance rate than the monotherapy group. However, virologic recurrence was more common in the long term. Eight studies reported HBeAg seroconversion, and only 2 studies of the treatment of children with interferon-α (IFN-α) reported a seroconversion rate of > 20% in the treatment group, which was higher than that in the untreated group. HBsAg clearance was observed in 2 studies of IFN-α treatment, while HBsAg seroconversion was not observed. One study reported the risk of liver cirrhosis and hepatocellular carcinoma (HCC) and showed that antiviral therapy could reduce the risk of liver cirrhosis and HCC in patients. The incidence rate of adverse events ranged from 4.1%-13.0% in the treatment with nucleos(t)ide analogues and reached 100% in the treatment with IFN-α, and serious adverse events were rare. Conclusion The majority of CHB patients in the immune-tolerant phase show satisfactory virologic response after antiviral therapy, but they tend to experience recurrence after drug withdrawal and have a low seroconversion rate. Antiviral therapy has good safety. Current evidence suggests that such patients can be dynamically observed if there is no clear evidence for disease progression.

Chinese expert opinion on frequency-doubled double pulse laser lithotripsy of biliary stones

Digestive Endoscopy Professional Committee of Chinese Endoscopist Association, Chinese Society of Digestive Endoscopy, National Clinical Research Center for Digestive Diseases (Shanghai)

2021, 37(6): 1288-1290. DOI: 10.3969/j.issn.1001-5256.2021.06.014

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Biliary calculi is one of the common digestive disorders. The major therapeutic options of biliary calculi include surgery and endoscopic intervention, but challenges still exist in the treatment of certain difficult stones. With the advantages of safety and high efficiency, frequency-doubled double pulse laser lithotripsy is considered an effective method to solve difficult stones. The frequency-doubled double pulse neodymium-doped yttrium aluminum garnet laser has been approved by the State Drug Administration for lithotripsy of biliary stones. However, there is no consensus on its indications, introduction methods and operating specifications yet. Therefore, on the basis of reference to literatures, the National Clinical Research Center for Digestive Diseases (Shanghai), Endoscopy Professional Committee of Chinese Endoscopist Association and Chinese Society of Digestive Endoscopy organized domestic experts in relevant fields to formulate this expert opinion after full discussion. This expert opinion may provide some guidance and references for the standard conduction of laser lithotripsy for biliary stones in China.

An excerpt of Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines (2021)

Linna YUAN, Hengbin NA, Wu LI

2021, 37(6): 1291-1294. DOI: 10.3969/j.issn.1001-5256.2021.06.015

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Effect of HBsAg on the production of interferon-α in peripheral blood plasmacytoid dendritic cells induced by the stimulator of interferon genes signaling pathway

Wanwei DU, Jian GENG, Yifan YANG, Xia WANG, Juanjuan FU, Xiucheng PAN

2021, 37(6): 1295-1298. DOI: 10.3969/j.issn.1001-5256.2021.06.016

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Objective To investigate the effect of HBsAg on the expression of interferon-α (IFN-α) in peripheral blood plasmacytoid dendritic cells (pDCs) induced by the stimulator of interferon genes (STING) signaling pathway activated by cyclic GMP-AMP (cGAMP). Method Peripheral venous blood was collected from healthy adults and the patients with chronic hepatitis B virus (HBV) infection who attended the outpatient service or were hospitalized in Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, from February to December 2016, and peripheral blood mononuclear cells (PBMCs) were isolated and extracted. After the STING agonist cGAMP was added to PBMCs, ELISA was used to measure the levels of IFN-α, interferon-β, and tumor necrosis factor-α in supernatant. PBMCs from healthy adults were pre-incubated with HBsAg and then stimulated by cGAMP, and supernatant was collected to measure IFN-α. The magnetic-activated cell sorting method was used to remove pDCs from PBMCs, and after culture with cGAMP, ELISA was used to measure the level of IFN-α in supernatant. PBMCs from healthy adults were stimulated by HBsAg and/or cGAMP, and then flow cytometry was used to measure the frequency of pDCs. The independent samples t-test was used for comparison of continuous data between two groups. Results PBMCs from the patients with chronic HBV infection stimulated by cGAMP in vitro had a significantly lower level of IFN-α than healthy controls (469.72±18.95 vs 599.90±84.06, t=4.868, P=0.001). PBMCs from healthy adults co-cultured with HBsAg and stimulated by cGAMP had a significantly lower level of IFN-α than those in the non-HBsAg group (448.5±52.0 vs 571.0±30.8, t=4.500, P=0.011). Compared with PBMCs containing pDCs, PBMCs without pDCs stimulated by cGAMP had a significant reduction in the level of IFN-α (164.50±40.73 vs 339.50±35.33, t=6.482, P=0.001). Compared with PBMCs from healthy adults stimulated by cGAMP, PBMCs pre-incubated with HBsAg and then stimulated by cGAMP had a significant reduction in the frequency of pDCs (0.12%±0.04% vs 0.24%±0.04%, t=5.176, P=0.014). Conclusion HBsAg can inhibit the expression of IFN-α induced by the STING pathway in pDCs activated by cGAMP.

Expression of HBcAg in hepatocytes and its association with the efficacy of antiviral therapy

Xihua FU, Xuan HUANG, Guojun SHEN, Haibo LOU, Yuqiao MAO

2021, 37(6): 1299-1303. DOI: 10.3969/j.issn.1001-5256.2021.06.017

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Objective To investigate the effect of the expression of HBcAg in hepatocytes on the serum level of HBcAb and seroconversion of HBeAg after antiviral therapy with nucleos(t)ide analogues (NUCs). Methods Serum samples and liver tissue paraffin sections were collected from 101 chronic hepatitis B (CHB) patients who received antiviral therapy with NUCs in Nanfang Hospital and Panyu Central Hospital from January 2015 to June 2018. ELISA was used to measure the serum level of HBcAb, and immunohistochemistry was used to measure the expression of HBcAg in the liver. The GEO database (GSE96851) was analyzed to obtain differentially expressed genes in the liver of patients with HBcAg-positive hepatitis. The two-independent-samples t test was used for comparison of continuous data between two groups; the multiple-independent-samples nonparametric Kruskal-Wallis H test was used for comparison of continuous data between multiple groups, and Dunnett method was used for further comparisons; the chi-square test was used for comparison of categorical data between groups. Results The expression pattern of HBcAg in hepatocytes was classified as absent expression, nuclear expression, cytoplasmic expression, and nuclear/cytoplasmic expression, and according to expression level, HBcAg expression was classified as grades Ⅰ, Ⅱ, Ⅲ, and Ⅳ expression. HBeAg seroconversion rates after 96 weeks of antiviral therapy were 5.88%, 16.67%, 22.73%, and 24.24%, respectively, in the patients with absent expression, nuclear expression, cytoplasmic expression, and nuclear/cytoplasmic expression (χ²=4.753, P=0.037), and HBeAg seroconversion rates after 96 weeks of antiviral therapy were 5.88%, 13.04%, 27.59%, and 26.67%, respectively, in the patients with grade Ⅰ, Ⅱ, Ⅲ, and Ⅳ expression (χ²=6.580, P=0.016). There were significant differences in the serum levels of HBcAb-IgM and total HBcAb between the patients with absent expression, nuclear expression, cytoplasmic expression, and nuclear/cytoplasmic expression of HBcAg (HBcAb-IgM: H=9.760, P=0.021; total HBcAb: H=21.46, P < 0.001), and there were also significant differences in the serum levels of HBcAb-IgM and total HBcAb between the patients with grade Ⅰ, Ⅱ, Ⅲ, and IV expression of HBcAg (HBcAb-IgM: H=18.80, P < 0.001; total HBcAb: H=26.03, P < 0.001). The analysis of differentially expressed genes in the liver showed that the expression of antibody-related genes was upregulated in the liver of patients with HBcAg-positive acute liver failure. Conclusion The expression pattern and level of HBcAg in the cytoplasm of hepatocytes are associated with serum HBcAb, and the measurement of HBcAg may help to predict the efficacy of antiviral therapy with NUCs.

Tolerance and pharmacokinetics of coblopasvir hydrochloride capsules in patients with hepatitis C virus infection

Jinfeng LOU, Hong ZHANG, Huan WANG, Jifeng SHI, Qiuhua WU, Yanhua DING, Junqi NIU, Xiaoxue ZHU

2021, 37(6): 1304-1308. DOI: 10.3969/j.issn.1001-5256.2021.06.018

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Objective To investigate the tolerance, pharmacokinetics, and antiviral activity of coblopasvir hydrochloride capsules in patients with hepatitis C. Methods A total of 36 patients with hepatitis C who were admitted to The First Hospital of Jilin University from November 2016 to January 2017 were enrolled as subjects, and four dose groups (30 mg, 60 mg, 90 mg, and 120 mg) and one placebo group were established. The subjects were administered once daily for 3 consecutive days; tolerance was evaluated on D2 and D6, and follow-up was performed on D8 and D10. The subjects were enrolled based on single dose escalation, and a multiple-dose study was conducted under the premise of good tolerance to single dose. Liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of coblopasvir hydrochloride in human body, and WinNonlin 6.4 software was used to calculate main pharmacokinetic parameters. HCV RNA load was used to evaluate antiviral activity at different time points; a one-way analysis of variance was used for comparison between multiple groups, and the LSD t-test was used for further comparison between two groups. Results After coblopasvir hydrochloride capsules were administered orally once a day at a dose of 30-120 mg, the plasma concentration and exposure of coblopasvir hydrochloride increased with the increase in dose. There were no significant differences in plasma concentration and exposure between multiple-dose administration and single-dose administration in a fasting state, without accumulation in human body. After the oral administration of coblopasvir hydrochloride capsules once a day, the subjects with HCV genotype 1b had a reduction in HCV RNA load since baseline, with the lowest level at 120 hours, and there was a significant difference in antiviral activity between different dose groups (F=14.621, P < 0.000 1), among which the 60 mg group had a significantly greater reduction than the 30 mg group (P=0.025), while there was no significant difference between the 60 mg group and the 90/120 mg group (P > 0.05). There was no significant difference in HCV RNA load between different groups of patients with HCV genotype 2a (P > 0.05). Of all 36 subjects, 20 reported 34 cases of treatment-emergent adverse events, among which 19 cases were associated with coblopasvir hydrochloride, and no significant adverse events or serious adverse events were observed. Conclusion Oral administration of coblopasvir hydrochloride capsules in a fasting state at a dose of 30-120 mg/d (for 3 consecutive days) has good safety and antiviral activity. Therefore, it has good application prospect in the treatment of HCV infection and provides a basis for dose selection in phrase 2 study.

Value of gamma-glutamyl transpeptidase/albumin ratio in the noninvasive diagnosis of liver fibrosis in patients with chronic hepatitis B virus infection

Feng HE, Yufeng GAO, Xiang WANG, Zhaoru ZHANG

2021, 37(6): 1309-1313. DOI: 10.3969/j.issn.1001-5256.2021.06.019

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Objective To investigate the value of gamma-glutamyl transpeptidase (GGT)/albumin (Alb) ratio in the noninvasive diagnosis of liver fibrosis degree in patients with chronic hepatitis B virus (HBV) infection. Methods A retrospective analysis was performed for the clinical data of 322 patients with chronic HBV infection who underwent liver biopsy in Chaohu Hospital of Anhui Medical University from January 2018 to March 2020, and according to liver fibrosis degree based on liver biopsy, the 322 patients were divided into S0-S1 group with 183 patients, S2 group with 68 patients, S3 group with 35 patients, and S4 group with 36 patients. The clinical indices of routine blood test, virology, and blood biochemistry were collected. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups; the chi-square test was used for comparison of categorical data. A Spearman rank correlation analysis was used to investigate the correlation of the three noninvasive models GGT/Alb ratio, aspartate aminotransferase-to-platelet ratio index (APRI) score, and fibrosis-4 (FIB-4) index with liver fibrosis degree. A receiver operating characteristic (ROC) curve was plotted for GGT/Alb ratio to evaluate its diagnostic value. Results With the aggravation of liver fibrosis degree, there were gradual reductions in Alb (F=7.351, P < 0.05), HBV DNA (χ²=2.820, P < 0.05), and platelet count (F=6.182, P < 0.05) and gradual increases in age (χ²=3.145, P < 0.05), GGT (χ²=6.149, P < 0.05), GGT/Alb ratio (χ²=7.064, P < 0.05), APRI score (χ²=9.022, P < 0.05), and FIB-4 index (χ²=8.254, P < 0.05). The Spearman rank correlation analysis showed that GGT/Alb ratio was positively correlated with liver fibrosis stage (r=0.396, P < 0.01), with a significantly higher correlation coefficient than APRI score (r=0.327, P < 0.001) and FIB-4 index (r=0.370, P < 0.001). The ROC curve analysis showed that in the patients with significant liver fibrosis, severe liver fibrosis, and liver cirrhosis, GGT/Alb ratio had similar areas under the ROC curve to APRI score and FIB-4 index (0.680/0.676/0.695 vs 0.692/0.698/0.728 and 0.659/0.661/0.684, all P > 0.05). At the optimal cut-off values of 0.435, 0.465, 0.465, respectively, GGT/Alb ratio had sensitivities of 69.1%, 66.2%, and 69.0%, respectively, and specificities of 65.4%, 65.9%, and 67.0%, respectively, in the diagnosis of significant liver fibrosis, severe liver fibrosis, and liver cirrhosis. Conclusion Like APRI score and FIB-4 index, GGT/Alb ratio is a simple and practical noninvasive model for the diagnosis of liver fibrosis and can provide a reference for the diagnosis of liver fibrosis degree in patients with chronic HBV infection.

Value of liver/spleen stiffness combined with serum adenosine deaminase in predicting severe esophageal varices in patients with hepatitis B cirrhosis

Qing XIE, Zeng LI, Zhen TANG, Jinqiang LI, Feng'e LIU

2021, 37(6): 1314-1318. DOI: 10.3969/j.issn.1001-5256.2021.06.020

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Objective To investigate the value of liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) based on FibroTouch (FT) transient elastography combined with serum adenosine deaminase (ADA) in predicting severe esophageal varices (EV) in patients with hepatitis B cirrhosis. Methods Related clinical data were collected from 120 patients with hepatitis B cirrhosis who attended Department of Infectious Diseases, Changsha First Hospital, from December 2017 to June 2020. FT was used to measure LSM and SSM, and related examinations were performed, including electronic gastroscopy and serum levels of ADA, hemoglobin, albumin, alanine aminotransferase, and aspartate aminotransferase and platelet count. The serum liver fibrosis markers aspartate aminotransferase-to-platelet ratio index (APRI), aspartate aminotransferase/alanine aminotransferase ratio (AAR), and fibrosis-4 (FIB-4) were calculated. According to the severity of EV under gastroscopy, the subjects were divided into severe EV group with 58 patients and non-severe EV (without EV or with mild-to-moderate EV) group with 62 patients. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The Spearman rank correlation test was used to investigate the correlation of LSM, SSM, and ADA with severe EV. The receiver operating characteristic (ROC) curve was used to analyze the efficacy of LSM, SSM, and ADA in the diagnosis of severe EV, and sensitivity and specificity were calculated. A multivariate binary logistic regression analysis was performed to calculate the area under the ROC curve (AUC) of the combined indicators, and the Z test was used for comparison of AUC. Results There were significant differences in LSM, SSM, and ADA between the two groups (all P < 0.05). LSM, SSM, and ADA were positively correlated with severe EV, with a correlation coefficient of 0.686, 0.743, and 0.723, respectively (all P < 0.05). The optimal cut-off value was 22.35 kPa for LSM, 45.25 kPa for SSM, and 34.50 U/L for ADA in predicting severe EV, with an AUC of 0.746, 0.802, and 0.791, respectively, a sensitivity of 82.8%, 75.9%, and 58.6%, respectively, and a specificity of 65.6%, 77.4%, and 90.2%, respectively. LSM+ADA, SSM+ADA, and LSM+SSM+ADA had an AUC of 0.826, 0.853, and 0.907, respectively, in predicting severe EV (all P < 0.05). Conclusion Liver/spleen stiffness combined with serum ADA has a good value in predicting severe EV, which can provide a preliminary diagnostic basis for severe EV in patients who refuse to undergo gastroscopy.

Value of red blood cell distribution width-to-platelet ratio, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio in predicting compensated liver cirrhosis in patients with chronic hepatitis C

Na YANG, Hua HE, Tianye ZHAO, Xuerong TAO, Yanhua WU, Jing JIANG

2021, 37(6): 1319-1325. DOI: 10.3969/j.issn.1001-5256.2021.06.021

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Objective To investigate the value of red blood cell distribution width-to-platelet ratio (RPR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in predicting chronic hepatitis C (CHC)-related compensated liver cirrhosis by comparing serological markers between CHC patients and patients with compensated hepatitis C cirrhosis. Methods The patients with CHC in two townships of Fuyu County were screened for liver cirrhosis and liver cancer from September to December in 2019 and 2020, respectively. General information was collected; HCV RNA quantification, liver function, and routine blood test results were measured; liver transient elastography and abdominal ultrasound were performed at the same time. RPR, PLR, NLR, fibrosis-4 (FIB-4), and aspartate aminotransferase-to-platelet ratio index (APRI) were calculated. The Mann-Whiney U test was used for comparison between groups. The chi-square test was used for comparison of categorical data between groups. The receiver operating characteristic (ROC) curve was plotted to determine the optimal cut-off values of RPR and PLR. A multivariate unconditional logistic regression analysis was used to investigate the risk factors for CHC-related liver cirrhosis. The linear regression trend test was used to investigate the changing trend of RPR, PLR, FIB-4, and APRI in hepatitis C patients with different fibrosis stages. Results A total of 968 CHC patients were enrolled, among whom 123 (12.7%) were diagnosed with compensated liver cirrhosis (liver cirrhosis group). Compared with the CHC group, the liver cirrhosis group had a significant increase in RPR and a significant reduction in PLR (P < 0.001). The multivariate logistic regression analysis showed that age > 60 years (odds ratio [OR]=1.79, 95% confidence interval [CI]: 1.12-2.86, P=0.015), albumin < 40 g/L (OR=10.40, 95% CI: 3.47-31.18, P < 0.001), RPR > 0.081 (OR=3.83, 95% CI: 2.19-6.69, P < 0.001), PLR < 91.11 (OR=2.25, 95% CI: 1.31-3.89, P=0.004), FIB-4 > 3.25 (OR=3.14, 95% CI: 1.74-5.67, P < 0.001), and APRI > 2 (OR=3.60, 95% CI: 1.10-11.78, P=0.035) were associated with the development of CHC-related compensated liver cirrhosis. With the aggravation of liver fibrosis, RPR, FIB-4, and APRI gradually increased and PLR gradually decreased (all P < 0.001). Conclusion RPR and PLR are associated with the development and fibrosis progression of CHC-related compensated liver cirrhosis. Elderly patients with CHC (age > 60 years) should be monitored for the changes in albumin and liver fibrosis indicators, and RPR and PLR should also be monitored regularly to identify liver cirrhosis in the early stage, give timely treatment, and reduce the incidence rate of liver cancer.

Rebleeding and prognosis of patients with liver cirrhosis and severe esophagogastric variceal bleeding

Yingying CAO, Tao HAN, Yu ZHANG, Fang LIU, Jing LIANG, Haixia YUAN, Jun LI, Huiling XIANG

2021, 37(6): 1326-1330. DOI: 10.3969/j.issn.1001-5256.2021.06.022

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Objective To investigate the risk factors for rebleeding within 5 years and the influencing factors for 5-year survival in patients with liver cirrhosis and severe esophagogastric variceal bleeding (EVB). Methods A retrospective analysis was performed for 129 patients with liver cirrhosis who attended Tianjin Third Central Hospital from May 2012 to May 2014 due to severe EVB for the first time, with a follow-up time of 5 years. Related clinical data were analyzed, including age, sex, cause of liver cirrhosis, presence or absence of infection at the first time of bleeding, liver stiffness measurement (LSM), splenic stiffness measurement (SSM), portal vein diameter, biochemical parameters, rebleeding time, and prognosis. Esophagogastric variceal rebleeding was defined as the primary endpoint and death was defined as the secondary endpoint. The t-test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups; a logistic regression analysis was used to investigate the independent risk factors for rebleeding, and a Cox regression analysis was used to analyze the predictive indicators for 5-year survival in EVB patients; the Kaplan-Meier curve was used to analyze the cumulative non-rebleeding rate. Results Among the 129 patients, 87(67.4%) experienced rebleeding during follow-up. There were significant differences between the rebleeding group and the non-rebleeding group in the proportion of patients with alcoholic cirrhosis (χ²=4.896, P=0.027), portal vein diameter (t=2.203, P=0.030), LSM(Z=-2.771, P=0.006), and SSM(t=2.678, P=0.010). The patients with alcoholic cirrhosis had a significantly higher mean number of times of bleeding than those with non-alcoholic cirrhosis (all P < 0.05). The multivariate logistic regression analysis showed that alcoholic cirrhosis (odds ratio [OR]=5.687, 95% confidence interval [CI]: 1.230-26.129, P=0.025), LSM(OR=1.039, 95% CI: 1.010-1.070, P=0.007), and SSM(OR=1.078, 95% CI: 1.028-1.129, P=0.001) were independent risk factors for rebleeding within 5 years after treatment in EVB patients. Among the 129 patients, 45 (34.9%) died. The univariate Cox regression analysis showed that there were significant differences between the death group and the survival group in age, times of bleeding, mean arterial pressure, portal vein diameter, aspartate aminotransferase, lymphocyte percentage, and presence or absence of infection at the first time of bleeding (all P < 0.05). Further multivariate analysis showed that 5-year survival rate was associated with portal vein diameter (OR=1.459, 95% CI: 1.056-2.014, P=0.022), age (OR=1.053, 95% CI: 1.006-1.103, P=0.026), times of bleeding (OR=1.286, 95% CI: 1.040-1.591, P=0.020), and presence or absence of infection at the first time of bleeding (OR=5.239, 95% CI: 1.750-15.641, P=0.003). Conclusion Alcoholic cirrhosis, LSM, and SSM are independent risk factors for rebleeding within 5 years in EVB patients, and age, times of bleeding, portal vein diameter, and presence or absence of infection at the first time of bleeding are associated with 5-year survival.

Value of transjugular intrahepatic portosystemic shunt in the prevention of esophageal variceal rebleeding in patients with portal vein thrombosis after splenectomy

Zhaopeng LI, Guangchuan WANG, Chunqing ZHANG

2021, 37(6): 1331-1335. DOI: 10.3969/j.issn.1001-5256.2021.06.023

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Objective To investigate the technical success rate and outcome of transjugular intrahepatic portosystemic shunt (TIPS) in preventing esophageal variceal rebleeding in patients with portal vein thrombosis (PVT) after splenectomy. Methods A retrospective analysis was performed for the clinical data of 46 patients with PVT after splenectomy who were admitted to Shandong Provincial Hospital from December 2009 to January 2017 and underwent TIPS to prevent esophageal variceal rebleeding. According to the success or failure of TIPS, the patients were divided into TIPS success group with 38 patients and TIPS failure group with 8 patients. The two groups were compared in terms of postoperative variceal rebleeding, stent dysfunction, hepatic encephalopathy (HE), and survival. The paired t-test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The Kaplan-Meier curve was used to analyze variceal rebleeding-free rate, stent patency rate, HE-free rate, and survival rate, and the log-rank test was used for comparison of cumulative rebleeding-free rate and cumulative survival rate. Results The technical success rate of TIPS was 82.6%. There were significant differences in 6-, 12-, and 24-month cumulative rebleeding-free rates between the TIPS success group and the TIPS failure group (94.3%/89.8%/89.8% vs 85.7%/85.7%/28.6%, χ²=4.563, P=0.033). In the TIPS success group, the 6-, 12-, and 24-month cumulative stent patency rates were 79.3%, 74.3%, and 69.0%, respectively, and the 6-, 12-, and 24-month cumulative HE-free rates after TIPS were 72.1%, 55.5%, and 55.5%, respectively. There were significant differences in 6-, 12-, and 24-month cumulative survival rates between the TIPS success group and the TIPS failure group (94.0%/94.0%/86.2% vs 71.4%/71.4%/71.4%, χ²=4.988, P=0.026). Conclusion TIPS is a safe and feasible method for preventing esophageal variceal rebleeding in patients with PVT after splenectomy, and TIPS combined with a percutaneous transhepatic approach may promote technical success.

Association between the alteration of serum N-glycan profile and the change of glycosyltransferase expression in liver tissue in patients with hepatitis B virus-related hepatocellular carcinoma

Xi CAO, Yanling SUN, Cuiying CHEN, Yiwei XIAO, Kuanhui XIANG, Xueen LIU, Hui ZHUANG

2021, 37(6): 1336-1341. DOI: 10.3969/j.issn.1001-5256.2021.06.024

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Objective To investigate the potential mechanism of serum N-glycan alterations in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by measuring serum N-glycan profile and comparing glycosyltransferase gene expression between HCC tissue and adjacent tissue. Methods The samples of HCC tissue, adjacent tissue, and normal liver tissue were collected from 34 patients with HBV-related HCC who were admitted to Chinese PLA General Hospital, and serum samples were also collected. Among these 34 patients, 8 were randomly selected and their serum samples were established as HCC experimental group, and the serum samples of 20 healthy adults were established as control group. DNA sequencer-aided fluorophore-assisted carbohydrate electrophoresis was used to analyze serum N-glycan profile in the HCC experimental group and the control group. Quantitative real-time PCR was used to measure the mRNA expression of 8 glycosyltransferase genes (FUT3, FUT4, FUT6, FUT7, FUT8, Gn-TIII, Gn-TIVa, and Gn-TV) in the HCC tissue and adjacent tissue of 34 patients with HBV-related HCC, and Western blot was used to measure the expression of corresponding proteins. The independent samples t-test was used for comparison of continuous data between two groups. Results Compared with the control group, the HCC experimental group had a significant increase in the abundance of N-glycan peak9 (NA3Fb) in serum(t=-2.514, P < 0.05). There were significant differences in the mRNA expression of FUT8, Gn-TIVa, and Gn-TV between HCC tissue and adjacent tissue, and the mRNA and protein expression levels of FUT8 and Gn-TV in HCC tissue were significantly higher than those in adjacent tissue (FUT8 mRNA: 1.50±0.34 vs 0.65±0.11, t=-2.354, P=0.022; Gn-TV mRNA: 3.57±0.64 vs 1.33±0.16, t=-3.384, P=0.001; FUT8 protein: 0.70±0.11 vs 0.083±0.017, t=9.555, P=0.001; Gn-TV protein: 1.33±0.19 vs 0.60±0.15, t=5.097, P=0.007). The mRNA expression level of Gn-TIVa in HCC tissue was significantly higher than that in adjacent tissue (2.90±0.47 vs 1.68±0.19, t=-2.403, P=0.019), but there was no significant difference in the protein expression level of Gn-TIVa between HCC tissue and adjacent tissue (0.52±0.24 vs 0.24±0.11, t=1.833, P=0.141). The changes of glycosyltransferase gene expression in HCC tissue were consistent with the alteration of serum N-glycan profile. Conclusion Serum N-glycan alterations in patients with HBV-related HCC may be closely associated with the upregulated expression of the glycosyltransferase genes FUT8, Gn-TIVa, and Gn-TV in HCC tissue.

Expression and clinical significance of forkhead box A2 and forkhead box J2 in hepatocellular carcinoma

Xiaoke RAN, Xinju CHEN, Yunxia ZHAO, Xin ZHANG, He YANG, Yiyao SUN, Xiaoqi CHEN

2021, 37(6): 1342-1347. DOI: 10.3969/j.issn.1001-5256.2021.06.025

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Objective To investigate the expression levels of forkhead box A2 (FOXA2) and forkhead box J2 (FOXJ2) in hepatocellular carcinoma (HCC) tissue and the association of FOXA2 and FOXJ2 with HCC. Methods Clinical data and pathological tissue samples were collected from 54 patients with pathologically confirmed HCC in The First Affiliated Hospital of Henan University of Traditional Chinese Medicine from January 2014 to July 2019. The immunohistochemical SP method was used to measure the protein expression levels of FOXA2 and FOXJ2 in HCC tissue, and their association with HCC-related clinicopathological features and patient prognosis was analyzed. The chi-square test and the adjusted chi-square test were used for comparison of categorical data; a Spearman correlation analysis was performed to investigate the correlation between the expression of FOXA2 and FOXJ2; the Kaplan-Meier method was used for survival analysis; Image-Pro Plus was used to perform the semi-quantitative analysis of the expression of FOXA2 and FOXJ2; the Wilcoxon rank-sum test was used for comparison between groups. Results The positive rates of the protein expression of FOXA2 and FOXJ2 in HCC tissue were 70.37% (38/54) and 75.92% (41/54), respectively, and there was a significant positive correlation between the expression levels of FOXA2 and FOXJ2 (r_s=0.648, P < 0.001). In both negative and positive groups, the expression level of FOXA2 was associated with tumor diameter, degree of tumor differentiation, number of tumors, and alpha-fetoprotein (χ²=5.440, 4.113, 4.352, and 3.865, P=0.020, 0.043, 0.037, and 0.049), and the expression level of FOXJ2 was associated with the degree of tumor differentiation (χ²=9.267, P=0.002). The group with positive expression of FOXA2 and FOXJ2 had a significantly higher cumulative survival rate than the group with negative expression of FOXA2 and FOXJ2 (P < 0.01). Conclusion The expression levels of FOXA2 and FOXJ2 are associated with the development, progression, and prognosis of HCC, and they have a synergistic effect in the development and progression of HCC.

Role and mechanism of Lycium barbarum polysaccharide combined with aerobic exercise in improving nonalcoholic steatohepatitis in rats

Jiamin MA, Lulu GAO, Mengwei ZHANG, Qinghan GAO, Xiujuan TAO, Yanna FAN, Jianjun YANG

2021, 37(6): 1348-1353. DOI: 10.3969/j.issn.1001-5256.2021.06.026

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Objective To investigate the protective effect of Lycium barbarum polysaccharide (LBP) combined with aerobic exercise (AE) on the liver of rats with nonalcoholic steatohepatitis (NASH) induced by high-fat diet based on the p38 mitogen-activated protein kinase (p38 MAPK)-nuclear factor-κB (NF-κB) pathway. Methods After 1 week of adaptive feeding, 45 Sprague-Dawley rats, aged 8 weeks, were randomly divided into control group (10 rats fed with normal diet) and high-fat group (35 rats fed with high-fat diet). At the end of week 28, the high-fat group was randomly divided into model group, LBP group, AE group, and LBP+AE group, with 8 rats in each group, and intervention was performed for 10 weeks. At the end of the experiment, fasting blood glucose was measure for all rats, and serum samples, liver tissue, and visceral fat were collected. Biochemical kits were used to measure the serum levels of triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), and aspartate aminotransferase (AST); ELISA kits were used to measure the serum levels of fasting insulin (FINS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1); quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of Toll-like receptor 4 (TLR4), p38 MAPK, and NF-κB in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the control group, the model group had significant increases in TG, TC, AST, ALT, FINS, and homeostasis model assessment of insulin resistance (HOMA-IR) (all P < 0.05), a tendency of increases in the serum levels of the inflammatory factors MCP-1, TNF-α, and IL-6 (all P < 0.05), and significant increases in the mRNA and protein expression levels of TLR4, p38 MAPK, and NF-κB in liver tissue (all P < 0.05). Compared with the model group, each intervention group had significant reductions in TG, TC, AST, ALT, FINS, and HOMA-IR (all P < 0.05), a tendency of reductions in the serum levels of the inflammatory factors MCP-1, TNF-α, and IL-6 (all P < 0.05), and significant reductions in the mRNA and protein expression levels of TLR4, p38 MAPK, and NF-κB (all P < 0.05). Compared with LBP group, the LBP+AE group had significant reductions in TG, ALT, FINS, HOMA-IR, MCP-1, the mRNA expression level of TLR4, protein expression levels of p38 MAPK and NF-κB(all P < 0.05). Compared with Ae group, the LBP+ AE group had significant reductions in FINS, HOMA-IR, IL-6, MCP-1, the mRNA expression level of TLR4 (all P < 0.05). Conclusion LBP combined with AE may improve inflammation in NASH rats by regulating the p38 MAPK/NF-κB pathway.

KCNJ11 rs5210 polymorphism and genetic susceptibility to nonalcoholic fatty liver disease and coronary artery disease

Yanyan XU, Zhenzhen ZHAO, Shousheng LIU, Huan SONG, Yongning XIN

2021, 37(6): 1354-1359. DOI: 10.3969/j.issn.1001-5256.2021.06.027

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Objective To investigate the association of KCNJ11 rs5210 single nucleotide polymorphism with nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population in Qingdao, China. Methods A total of 246 patients with NAFLD who attended Qingdao Municipal Hospital from December 2018 to September 2019 were enrolled as NAFLD group, 201 patients with CAD were enrolled as CAD group, and 116 patients with NAFLD and CAD were enrolled as NAFLD+CAD group; 342 healthy individuals were enrolled as control group. Fasting venous blood samples were collected for biochemical analysis. Whole blood genomic DNA was extracted, and PCR was used to determine KCNJ11 rs5210 genotype. The chi-square test was used to analyze whether the distribution of KCNJ11 rs5210 gene frequencies met the Hardy-Weinberg equilibrium, in order to determine whether the tested samples could represent the population. The chi-square test was used to analyze the differences in sex and genotype/allele frequency between groups. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the Bonferroni method was used for further comparison between two groups. The unconditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval. Results Three genotypes (AA, GA, and GG) of KCNJ11 rs5210 were found by gene sequencing. There were no significant differences in rs5210 allele frequency and genotype distribution between the control group, the NAFLD group, the CAD group, and the NAFLD+CAD group (all P > 0.05), and there were still no significant differences after adjustment for sex, age, and body mass index (BMI) (all P > 0.05). For all subjects, the subjects with AA genotype had a higher level of alkaline phosphatase than those with GA genotype (P=0.048); in the NAFLD group, the patients with GA genotype had significantly higher BMI and total bilirubin than those with AA genotype (P=0.042 and 0.002). The unconditional logistic regression analysis showed that elevated BMI was associated with the risk of NAFLD (OR=1.35, P < 0.01), while decreased high-density lipoprotein (HDL) might indicate an increase in the risk of NAFLD (OR=0.33, P < 0.01); elevated fasting plasma glucose and decreased HDL might indicate an increase in the risk of CAD (OR=1.51 and 0.11, both P < 0.01) and NAFLD with CAD (OR=1.46 and 0.06, both P < 0.01). Conclusion There is no significant association between KCNJ11 rs5210 polymorphism and the risk of NAFLD and CAD in the Chinese Han population in Qingdao.

A functional analysis of differentially expressed microRNAs involved in liver injury in mice with autoimmune hepatitis induced by concanavalin A

Jianheng HAO, Zhencheng LI, Ying LIU, Yiwen HOU, Yan GAO, Yuchuan MIAO, Yang LIU, Huiqin HAO

2021, 37(6): 1360-1367. DOI: 10.3969/j.issn.1001-5256.2021.06.028

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Objective To investigate the changes and potential effects of differentially expressed microRNAs (miRNAs) in the development and progression of liver injury in a mouse model of autoimmune hepatitis (AIH) induced by concanavalin A (ConA). Methods Eight healthy male specific pathogen-free C57BL/6 mice were randomly divided into model group and control group, with four mice in each group. The mice in the model group were given tail vein injection of ConA 15 mg/kg, and those in the control group were given an equal volume of normal saline. All mice were sacrificed after 8 hours of modeling, Total RNA in liver tissue was extracted, gene microarray was used to screen out differentially expressed miRNAs, and target prediction and function analysis were performed for upregulated and downregulated miRNAs. The independent samples t-test was used for comparison of differentially expressed miRNAs between two groups. Results The principal component analysis showed that the inter-group difference of the data extracted by gene microarray met the conditions for further analysis. Compared with the control group, the model group had 31 upregulated miRNAs and 18 downregulated miRNAs in mouse liver, which had a regulatory relationship with 959 target genes (601 upregulated genes and 358 downregulated genes). GO analysis showed that in the model group, the target genes of the upregulated miRNAs mainly had the molecular functions such as "DNA binding" (P=1.47×10^-6), participated in the biological processes such as "transcription, DNA-templated" (P=2.36×10^-7), and were mainly enriched in the cellular components such as "neuronal cell body" (P=5.99×10^-6), while the target genes of the downregulated miRNAs had the molecular functions such as "RNA polymerase Ⅱ proximal promoter sequence-specific DNA binding" (P=2.49×10^-6), participated in the biological processes such as "regulation of transcription, DNA-templated" (P=1.64×10^-11), and were mainly enriched in the cellular components such as "nucleoplasm" (P=4.30×10^-10). KEGG pathway enrichment analysis showed that the target genes of the upregulated miRNAs were mainly enriched in "Endocytosis" (P=0.000 4), while the target genes of the downregulated miRNAs were mainly enriched in the "Hippo signaling pathway" (P=0.004), and the above functional analysis results were statistically significant (P < 0.05). Conclusion There are differentially expressed miRNAs in the pathogenesis of AIH, and these differentially expressed miRNAs can provide new targets for the clinical treatment of AIH.

Effect of Cordyceps polysaccharides on hepatocyte apoptosis induced by tumor necrosis factor-α

Jianan ZHAO, Jinghua PENG, Ping LIU, Yiyang HU

2021, 37(6): 1368-1372. DOI: 10.3969/j.issn.1001-5256.2021.06.029

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Objective To investigate the effect of Cordyceps polysaccharides on hepatocyte apoptosis and its mechanism of action. Methods Normal human L02 hepatocytes without any drug treatment was established as normal group. The L02 hepatocytes were treated with different concentrations of tumor necrosis factor-α (TNF-α) (5, 10, 20, and 40 ng/ml) for 24 hours to screen out the modeling conditions for the model of hepatocyte apoptosis, which were established as model group. According to the experimental design, L02 hepatocytes pretreated with three different concentrations of Cordyceps polysaccharides (50, 100, and 200 μg/ml) for 12 hours, with or without TNF-α treatment for 24 hours at the selected concentration, were established as experimental group. Related samples were collected for analysis. CCK8 assay was used to measure cell proliferation; Annexin V/PI double staining was used to measure the number of apoptotic hepatocytes; RT-PCR was used to measure the mRNA expression of cell apoptosis genes (Bax, caspase-3, caspase-8, caspase-9, and death receptor Fas); Western blotting was used to measure the protein expression of cleaved-caspase-3 and cleaved-caspase-8. A one-way analysis of variance or the Kruskal-Wallis H test was used for comparison of continuous data between multiple groups, and the least significant difference t-test or the Dunnett-t test was used for further comparison between two groups. Results CCK8 assay showed that compared with the normal group, the L02 hepatocytes induced by 40 ng/ml TNF-α for 24 hours had a significant reduction in proliferation (73.54%±14.19% vs 100.00%±23.61%, P < 0.01), and compared with the model group under the premise that Cordyceps polysaccharides had no obvious cytotoxicity to hepatocytes at the three concentrations, the 50, 100, and 200 μg/ml experimental groups had a significant increase in cell proliferation (108.10%±9.05%/114.30%±8.79%/117.70%±9.66% vs 93.02%±7.21%, all P < 0.01). Annexin V/PI double staining showed that compared with the normal group, the model group had a significant increase in the number of apoptotic cells (11.57%±1.41% vs 7.71%±1.20%, P < 0.05), and compared with the model group, the 50, 100, and 200 μg/ml experimental groups had a significant reduction in the number of apoptotic cells (15.16%±0.16%/13.28%±1.57%/16.91%±0.21% vs 18.91%±0.80%, all P < 0.05). RT-PCR and Western blotting showed that compared with the normal group, the L02 hepatocytes induced by 40 ng/ml TNF-α had significant increases in the mRNA expression of the apoptosis-related genes Bax, caspase-9, and death receptor Fas (all P < 0.05), as well as significant increases in the protein expression of the activated forms of cleaved-caspase-3 and cleaved-caspase-8 (P < 0.05). Compared with the model group, the 50 μg/ml experimental group had significant reductions in the mRNA expression of Bax, caspase-3, and caspase-9 and the protein expression of cleaved-caspase-8; the 100 μg/ml experimental group had significant reductions in the mRNA expression of Bax, caspase-3, caspase-8, Fas, and caspase-9 and the protein expression of cleaved-caspase-8; the 200 μg/ml experimental group had significant reductions in the mRNA expression of caspase-3, caspase-8, Fas, and caspase-9 and the protein expression of cleaved-caspase-3 and cleaved-caspase-8. The three concentrations of Cordyceps polysaccharides had a certain dose-effect trend. Conclusion Cordyceps polysaccharides can effectively inhibit the apoptosis of normal L02 hepatocytes induced by TNF-α.

Protective effect of resolvin D1 pretreatment in a rat model of hepatic ischemia-reperfusion injury and its mechanism

Yangyang WANG, Xueying PENG, Jie MENG, Boran AN, Wenjuan HE, Sucai LU, Yan CHEN, Liwen KONG, Chuan NIU, Cong LIU, Wei HUANG, Yingjian HOU

2021, 37(6): 1373-1378. DOI: 10.3969/j.issn.1001-5256.2021.06.030

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Objective To investigate the protective effect of resolvin D1 (RvD1) in a rat model of hepatic ischemia/reperfusion (IR) injury and its association with heme oxygenase-1 (HO-1). Methods A total of 36 Sprague-Dawley rats were randomly divided into sham-operation (sham)+phosphate-buffered saline (PBS) group, sham+high-dose RvD1 (10 μg/kg) group, IR+PBS group, IR+low-dose RvD1 (2 μg/kg) group, IR+middle-dose RvD1 (5 μg/kg) group, and IR+high-dose RvD1 (10 μg/kg) group, with 6 rats in each group. RvD1 were intraperitoneally injected at 1 hour before ischemia. A biochemical analyzer was used to measure the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST); ELISA was used to measure the plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); HE staining was used to observe the histological changes of the liver; Western blot was used to measure the change in HO-1 in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the IR+PBS group, the IR+middle-dose RvD1 group and the IR+high-dose RvD1 group had significant reductions in the levels of ALT, AST, and the inflammatory factors TNF-α, IL-6, and IL-8 (all P < 0.05), and there were no significant differences between the IR+middle-dose RvD1 group and the IR+high-dose RvD1 group (all P > 0.05). Western blot showed that compared with the IR+PBS group, the IR+middle-dose RvD1 group and the IR+high-dose RvD1 group had a significant increase in the protein expression of HO-1 in the liver (P < 0.05). HE staining showed that compared with the IR+PBS group, the IR+middle-dose RvD1 group and the IR+high-dose RvD1 group had cell swelling and disordered hepatic cords, without massive necrosis. Conclusion RvD1 exerts a protective effect against hepatic IR injury in rats by increasing the expression of HO-1 and reducing the levels of inflammatory factors (TNF-α, IL-6, and IL-8) and aminotransferases (ALT and AST).

Effect of fecal microbiota transplantation on intestinal flora in mice with acute-on-chronic liver failure

An GAO, Yujing XU, Shengwei LU, Wei SUN, Jianhe GAN

2021, 37(6): 1379-1385. DOI: 10.3969/j.issn.1001-5256.2021.06.031

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Objective To investigate the protective effect of fecal microbiota transplantation (FMT) on mice with acute-on-chronic liver failure (ACLF) and its effect on intestinal flora. Methods A total of 40 mice were randomly divided into control group (CON group), model group (MOD group), FMT group (feces of the mice in the CON group were used as fecal microbiota donor), and FMT model group (ANFMT group, with feces of the mice in the MOD group as fecal microbiota donor), with 10 mice in each group. All mice were observed in terms of body weight, death, liver histopathology, and changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and intestinal flora. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the SNK-q test was used for further comparison between two groups. Results Compared with the CON group, the MOD group had a significant reduction in body weight and significant increases in AST and ALT (all P < 0.05), as well as large patchy necrosis of hepatocytes, significant increases in Verrucomicrobia, Akkermansia, and Erysipelatoclostridium, and significant reductions in Dubosiella and Duncaniella (all P < 0.05). Compared with the CON group, the ANFMT group had a significant increase in AST (P < 0.05), hepatocyte swelling and mild ballooning degeneration, significant increases in Unclassified and Faecalibaculum, and significant reductions in Patescibacteria, Deferribacteres, Muribaculum, Candidatus_Saccharimonas, Rikenella, Odoribacter, Mucispirillum, and Lachnospiraceae_unclassified (all P < 0.05). Compared with the MOD group, the FMT group had significant reductions in AST and ALT (both P < 0.05), mild hepatocellular necrosis and marked ballooning degeneration, significant increases in Paramuribaculum and Bilophila, and significant reductions in Firmicutes, Rikenella, and Absiella (all P < 0.05). Conclusion Intestinal flora disturbance is observed in ACLF mice, and dysbacteriosis may lead to liver injury. FMT can alleviate liver inflammation in ACLF mice and thus exert a protective effect.

Value of modified objective Bedside Index for Severity in Acute Pancreatitis score in predicting the severity and prognosis of acute pancreatitis

Haoyou TANG, Sheng LIU, Chengjun HU, Lin MA, Jianshui LI

2021, 37(6): 1386-1391. DOI: 10.3969/j.issn.1001-5256.2021.06.032

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Objective To investigate the value of modified objective Bedside Index for Severity in Acute Pancreatitis (BISAP) score (MBISAP) in predicting the severity and prognosis of acute pancreatitis (AP). Methods A retrospective analysis was performed for the data of 313 patients with AP who were treated in Affiliated Hospital of North Sichuan Medical College from June 2018 to June 2020, and the subjective indicator of mental state in BISAP score was removed. According to the scoring criteria for Computed Tomography Severity Index (CTSI), the degree of pancreatic necrosis was classified as 4 grades (0%, 0%-30%, 30%-50%, and > 50%) and was assigned a score of 0-3 points, respectively, and MBISAP score was determined by adding the above points, with the highest score of 7 points. According to the receiver operating characteristic (ROC) curve, the 313 patients with pancreatitis were divided into low-level MBISAP group (MBISAP < 3) and high-level MBISAP group (MBISAP ≥3). The two groups were compared in terms of baseline data and clinical outcome. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. The area under the ROC curve (AUC) was used to analyze an compare the value of MBISAP score, BISAP score, and CTSI score in predicting the severity and prognosis of AP. Results There were significant differences between the two groups in age (Z=-5.480, P < 0.001), etiology (χ²=36.536, P < 0.001), length of hospital stay (Z=-6.038, P < 0.001), mortality rate (P < 0.001), peripancreatic infection (P < 0.001), multiple organ dysfunction syndrome (MODS) (P < 0.001), BISAP score (χ²=215.320, P < 0.001), and CTSI score (P < 0.001). Severity of AP, mortality rate, and incidence rates of peripancreatic infection and MODS tended to increase with the increase in MBISAP score (P < 0.001). In predicting severe AP, MBISAP score had an AUC of 0.898 (95% confidence interval [CI]: 0.859-0.929, P < 0.001), with a sensitivity of 71.43% and a specificity of 90.53%; at the optimal cut-off value of ≥3, MBISAP score was significantly better than BISAP score (AUC=0.868) and CTSI score (AUC=0.827) (both P < 0.05). In predicting the mortality of patients with AP, MBISAP score had an AUC of 0.925 (95% CI: 0.890-0.952, P < 0.001), with a sensitivity of 88.89% and a specificity of 82.89%; at the optimal cut-off value of ≥3, MBISAP score was similar to BISAP score (AUC=0.915) and CTSI score (AUC=0.879) (both P > 0.05). In predicting peripancreatic infection in AP, MBISAP score had an AUC of 0.842 (95% CI: 0.796-0.880, P < 0.001), with a sensitivity of 72.22% and a specificity of 84.07%; at the optimal cut-off value of > 2, MBISAP score was better than BISAP score (AUC=0.776) and was inferior to CTSI score (AUC=0.932) (both P < 0.05). In predicting MODS in patients with AP, MBISAP score had an AUC of 0.874 (95% CI: 0.832-0.909, P < 0.001), with a sensitivity of 76.19% and a specificity of 84.93%; at the optimal cut-off value of > 2, MBISAP score was similar to BISAP score (AUC=0.855) and CTSI score (AUC=0.829) (both P > 0.05). Conclusion MBISAP score is better than BISAP score in predicting the severity of AP patients and peripancreatic infection, and it also has a good value in predicting mortality and MODS in patients with AP. MBISAP score can evaluate the conditions of AP patients more accurately and objectively than BISAP score.

Effectiveness and safety of nanoknife ablation guided by real-time virtual sonography in treatment of locally advanced pancreatic cancer

Dongzhao SU, Xiaoyong LI, Yanjun CHEN, Jinyu YANG, Shengyang CHEN, Shuiquan HU, Hao TONG

2021, 37(6): 1392-1397. DOI: 10.3969/j.issn.1001-5256.2021.06.033

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Objective To investigate the effectiveness and safety of nanoknife ablation guided by real-time virtual sonography (RVS) in the treatment of locally advanced pancreatic cancer (LAPC). Methods A retrospective analysis was performed for the clinical data of 27 patients with LAPC who attended The Fifth Affiliated Hospital of Zhengzhou University from April 2018 to October 2019, and according to the treatment method, the patients were divided into combination group (12 patients treated with IRE combined with chemotherapy) and control group (15 patients treated with chemotherapy alone). The chemotherapy regimen was gemcitabine combined with tegafur, gimeracil and oteracil potassium for both groups. Adverse reactions and complications were observed for the combination group during the perioperative period, and the two groups were compared in terms of the changes in myocardial enzymes, blood amylase, and carbohydrate antigen 19-9 (CA19-9) before treatment and at different time points after treatment, as well as remission rate (RR) and disease control rate (DCR) at 3 months after treatment and survival status during follow-up. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups, and the Wilcoxon test was used for comparison within each group; the Fisher's exact test was used for comparison of categorical data between groups; the Kaplan-Meier method was used to analyze the survival status during follow-up. Results In the combination group, there were 12 cases of adverse reactions and mild complications during the perioperative period, i.e., 9 Clavien-Dindo grade Ⅰ cases and 3 grade Ⅱ cases. All patients in the combination group experienced a transient increase in myocardial enzymes, which returned to normal within 7 days, and there were no significant changes in creatine kinase and lactate dehydrogenase on day 7 after treatment (P > 0.05); 9 patients had a significant increase in blood amylase on day 1 after surgery, which significantly decreased on day 7 after surgery and basically returned to normal on day 14 after surgery, and there was no significant change in blood amylase on days 7、14, and 1 month after surgery (P > 0.05). Before treatment, the level of CA19-9 was higher than the normal value in both groups, and the combination group had a significant reduction in CA19-9 at 1, 2, and 3 months after treatment (all P < 0.05); in the control group, the level of CA19-9 firstly decreased for a short time and then increased, while there was no significant change in CA19-9 at 1, 2, and 3 months after treatment (all P > 0.05). At 3 months after treatment, the combination group had significantly higher RR and DCR than the control group (RR: 75.0% vs 26.7%, P=0.021; DCR: 91.6% vs 53.3%, P=0.043). During the median follow-up time of 13 months, compared with the control group, the combination group had significantly higher median progression-free survival time (10 months vs 5 months, P=0.014) and median overall survival time (18 months vs 10 months, P=0.034). Conclusion RVS-guided percutaneous nanoknife ablation has marked clinical effect and high safety in the treatment of LAPC and can be used as a new treatment option for patients who refuse or cannot tolerate laparotomy for ablation therapy.

Serum expression of angiopoietin-like protein 2 in pancreatic cancer patients with or without diabetes and its association with prognosis

Wen QIN, Taiwen CHEN, Haiping ZHENG, Xianing HUANG, Xiaodong ZHU

2021, 37(6): 1398-1403. DOI: 10.3969/j.issn.1001-5256.2021.06.034

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Objective To investigate the expression level of angiopoietin-like protein 2 (ANGPTL2) in pancreatic cancer patients with or without diabetes and the clinical value of ANGPTL2 as a prognostic marker in patients with pancreatic cancer. Methods Serum samples were collected from 125 pancreatic cancer patients who were treated in The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University Cancer Hospital, and Wuming Hospital of Guangxi Medical University from January 2015 to January 2018, among whom 64 had pancreatic cancer alone and 61 had pancreatic cancer and diabetes, and 66 individuals who underwent physical examination were enrolled as control group. ELISA was used to measure the serum level of ANGPTL2, and the association of the expression level of ANGPTL2 with clinical indices, survival, and prognosis was analyzed. A one-way analysis of variance was used for comparison of normally distributed continuous data between three groups, and the Bonferroni test was used for comparison between two groups. The independent-samples Kruskal-Wallis H test was used for comparison of continuous data with skewed distribution between three groups and the one-way ANOVA analysis was used for comparison between two groups. The chi-square test was used for comparison of categorical data between groups. Spearman correlation analysis was also performed to investigate correlation. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison of survival rate. The Cox risk model was used to perform univariate and multivariate analyses to determine independent risk factors for the prognosis of pancreatic cancer. Results The pancreatic cancer+diabetes group had a significantly higher serum concentration of ANGPTL2 than the pancreatic cancer group and the control group [7.79 (7.12-8.17) ng/ml vs 5.74 (5.08-6.40) ng/ml and 3.72 (3.25-4.16) ng/ml, χ²=126.367, P < 0.001]. Serum ANGPTL2 concentration was positively correlated with carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) (r=0.560 and 0.731, both P < 0.001). The univariate analysis showed that tumor size, distant organ metastasis, degree of tumor differentiation, CEA, ANGPTL2, and HbA1c were closely associated with the long-term survival of pancreatic cancer patients, and the multivariate analysis showed that tumor size (HR=2.657, P=0.005), distant organ metastasis (HR=5.000, P=0.014), degree of tumor differentiation (HR=2.466, P=0.004), CEA(HR=1.110, P < 0.001) and ANGPTL2(HR=1.901, P=0.001) were independent risk factors for the prognosis of pancreatic cancer patients. For all pancreatic cancer patients, the high ANGPTL2 expression group had a significantly lower 2-year survival rate than the low ANGPTL2 expression group (8.51% vs 25.81%, χ²=5.651, P=0.017). For the pancreatic cancer patients with diabetes, the high ANGPTL2 expression group had a significantly lower 2-year survival rate than the low ANGPTL2 expression group (2.20% vs 32.70%, χ²=24.895, P < 0.001). Conclusion ANGPTL2 can be used as an effective clinical index to evaluate the prognosis of pancreatic cancer patients, especially those with diabetes.

Expression and significance of L1 cell adhesion molecule and transforming growth factor-β1 in pancreatic cancer tissue

Wen QIN, Jianyu YANG, Taiwen CHEN, Haiping ZHENG, Xiaodong ZHU

2021, 37(6): 1404-1408. DOI: 10.3969/j.issn.1001-5256.2021.06.035

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Objective To investigate the expression of L1 cell adhesion molecule (L1CAM) and transforming growth factor-β1 (TGFβ1) in pancreatic cancer tissue and their association with the prognosis of pancreatic cancer. Methods Histological specimens were collected from 125 patients with pancreatic cancer who underwent surgical resection in The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University Cancer Hospital, and Wuming Hospital of Guangxi Medical University from January 2015 to January 2018. Immunohistochemistry was used to measure the expression of L1CAM and TGFβ1 in all specimens, and the association of the expression of L1CAM and TGFβ1 with clinical indices, survival, and prognosis was analyzed. The t-test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups; the Cox proportional-hazards regression model was used to investigate the influencing factors for the survival of patients with pancreatic cancer; the Kaplan-Meier survival analysis was used to evaluate the survival of patients with different expression levels of L1CAM and TGFβ1. Results The high protein expression rate of L1CAM in pancreatic cancer tissue was significantly higher than that in adjacent tissue (75.20% vs 20.00%, χ²=76.352, P < 0.001). The high protein expression rate of TGFβ1 in pancreatic cancer tissue was significantly higher than that in adjacent tissue (81.60% vs 23.20%, χ²=85.461, P < 0.001). The protein expression of L1CAM was positively correlated with that of TGFβ1 in pancreatic cancer (r=0.492, P < 0.001). The protein expression of L1CAM and TGFβ1 were associated with tumor size, degree of tumor differentiation, TNM stage, lymph node metastasis, intravascular tumor thrombus, and perineural invasion (all P < 0.05). The patients with high protein expression of L1CAM or TGFβ1 had a significantly lower overall survival rate than those with low expression (χ²=54.661 and 39.597, both P < 0.001). Conclusion L1CAM and TGFβ1 proteins are highly expressed in pancreatic cancer tissue and may be associated with poor prognosis by promoting lymphatic metastasis and hematogenous metastasis. L1CAM and TGFβ1 proteins play an important role in the development, progression, and metastasis of pancreatic cancer.

Clinical features of hyperthyroidism with severe jaundice: An analysis of seven cases

Xiaoqin ZHENG, Li LI, Hua JIN, Chunyan GOU, Xiaojun WANG

2021, 37(6): 1409-1412. DOI: 10.3969/j.issn.1001-5256.2021.06.036

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Stapfer type I duodenal perforation after endoscopic retrograde cholangiopancreatography: A clinical analysis of 4 cases

Yong ZHANG, Min WENG, SHENG HE, Yi HUANG, Shanhong TANG, Hongbin CHEN

2021, 37(6): 1413-1415. DOI: 10.3969/j.issn.1001-5256.2021.06.037

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A case of idiopathic portal hypertension in chronic hepatitis B

Fang ZHU, Zhenjiang ZHANG, Ling YUAN, Bing PEI

2021, 37(6): 1416-1418. DOI: 10.3969/j.issn.1001-5256.2021.06.038

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ABCB4 gene mutation-associated liver cirrhosis misdiagnosed as Wilson's disease: A case report

Lei HUA, Quan SUN, Wenbin XU, Long ZHANG, Gongqiang WANG

2021, 37(6): 1419-1420. DOI: 10.3969/j.issn.1001-5256.2021.06.039

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A case of congenital intrahepatic portosystemic venous shunt with hepatic encephalopathy in the elderly

Junjun ZHANG, Xin GAO, Ying WU, Yi CHENG, Weitian XU

2021, 37(6): 1421-1424. DOI: 10.3969/j.issn.1001-5256.2021.06.040

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A case of acute hemorrhagic necrotizing enteritis with hepatic portal venous gas

Yinni TONG, Jimin ZHENG, Shaohui SU, Jian ZHANG

2021, 37(6): 1425-1426. DOI: 10.3969/j.issn.1001-5256.2021.06.041

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Primary liver cancer with prostate metastasis: A case report

Huangbin ZHANG, Yehong YAN, Hao WAN, Jiansheng XIAO, Shitao ZHAO, Weiqiang ZENG

2021, 37(6): 1427-1428. DOI: 10.3969/j.issn.1001-5256.2021.06.042

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A case of primary hepatic neuroendocrine tumor

Jikang DU, Xiaoling ZHAO, Guibin YANG, Wu WEI, Hongfang TUO

2021, 37(6): 1429-1431. DOI: 10.3969/j.issn.1001-5256.2021.06.043

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Complete remission after comprehensive treatment of lung metastases following liver cancer surgery: A case report

Jiachao ZHANG, Zhensheng ZHANG, Pingping CHEN, Rong TANG, Yongchao ZENG, Qizhao LI

2021, 37(6): 1432-1434. DOI: 10.3969/j.issn.1001-5256.2021.06.044

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Role of the JAK/STAT/SOCS signaling pathway in hepatitis B virus-related liver diseases

Yujuan PENG, Jing YOU, Jing LI, Guangjun TANG

2021, 37(6): 1435-1439. DOI: 10.3969/j.issn.1001-5256.2021.06.045

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The JAK/STAT/SOCS signaling pathway can mediate a variety of cytokines involved in inflammation, tumor, and autoimmune diseases and it also plays an important role in hepatitis B virus (HBV) infection-related liver diseases. This article briefly reviews the structure and signal pathway regulation of JAK-STAT and SOCS and elaborates on their role in the development and progression of HBV-related chronic hepatitis B, liver cirrhosis, liver failure, and hepatocellular carcinoma. The final analysis shows that the JAK/STAT/SOCS signaling pathway is dysregulated in HBV-related liver disease and is involved in the development and progression of the disease, and it may even influence the treatment and prognosis of the disease.

Role of autophagy in liver fibrosis

Qianlan DAI, Shaoneng LIU

2021, 37(6): 1440-1444. DOI: 10.3969/j.issn.1001-5256.2021.06.046

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Autophagy refers to the process in which organelles and proteins in eukaryocytes are degraded in lysosomes and their degradation products are reused, and it plays an important role in cell proliferation, differentiation, and homeostasis. In recent years, the role of autophagy in liver fibrosis has attracted more and more attention, and intervention of autophagy may become a new method for the treatment of liver fibrosis. This article summarizes the process and function of autophagy and its role in liver fibrosis. These data reveal the complex mechanism of action of autophagy in liver fibrosis and point out the need to find more reliable and definite mechanisms and targets for autophagy intervention in the future, so as to provide new ways for the treatment of liver fibrosis.

Magnetic resonance imaging-proton density fat fraction: A potential surrogate endpoint for nonalcoholic steatohepatitis clinical trials

Ziming AN, Qin FENG

2021, 37(6): 1445-1448. DOI: 10.3969/j.issn.1001-5256.2021.06.047

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Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) is an imaging method that uses magnetic resonance technology to perform objective, quantitative, and noninvasive assessment of fat in the whole liver. This article mainly analyzes the correlation between MRI-PDFF value and the "gold index" nonalcoholic steatohepatitis (NASH) liver histological evaluation and explores its advantages and disadvantages as a noninvasive evaluation index for NASH clinical trials. Current studies have shown that MRI-PDFF, as an emerging noninvasive technique, is suitable for quantifying liver fat content and evaluating the degree of hepatic steatosis, but it cannot replace liver biopsy as a tool for the diagnosis of NASH. Meanwhile, the relative reduction in MRI-PDFF after drug intervention is not only highly correlated with the improvement of fat deposition, but also correlated with the improvement of inflammation and ballooning degeneration, and MRI-PDFF can predict the overall improvement of liver histology to a certain extent. Therefore, MRI-PDFF is considered a potential surrogate endpoint for NASH clinical trials.

Research advances in the clinical and basic research on Fuzheng Huayu prescription in treatment of chronic liver diseases

Xi GUAN, Wei LIU, Jiamei CHEN, Yongping MU, Ping LIU, Ying XU

2021, 37(6): 1449-1453. DOI: 10.3969/j.issn.1001-5256.2021.06.048

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Fuzheng Huayu prescription is developed by Shanghai University of Traditional Chinese Medicine and has the functions of promoting blood circulation, removing blood stasis, nourishing essence, and tonifying the liver, and it is an effective empirical prescription for the treatment of chronic liver diseases including chronic viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, liver cirrhosis, and liver cancer. This prescription has been used in clinical practice for many years and has a marked clinical effect in alleviating clinical symptoms and improving liver fibrosis and complications. In recent years, many scholars have conducted in-depth studies on the clinical effect and mechanism of action of Fuzheng Huayu prescription in the treatment of chronic liver diseases and achieved satisfactory results. This article summarizes related research findings in order to provide a reference for subsequent studies.

Mechanism of ferroptosis and its role in liver diseases

Feiyu ZHANG, ADILA·Yakepu, Jinming ZHAO, Yanhang GAO

2021, 37(6): 1454-1458. DOI: 10.3969/j.issn.1001-5256.2021.06.049

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Ferroptosis is a newly discovered regulatory cell death induced by the accumulation of iron-dependent lipid peroxides, with the morphological manifestations of decreased mitochondrial volume, increased mitochondrial membrane density, and reduction or disappearance of mitochondria. The mechanism of ferroptosis is mainly associated with disturbance of iron metabolism, imbalance of amino acid antioxidant system, and accumulation of lipid peroxides. Studies have shown that ferroptosis plays different roles in different liver diseases, and ferroptosis can participate in the progression of various liver inflammatory diseases and inhibit the formation of liver fibrosis, the development of hepatocellular carcinoma, and sorafenib resistance. This article summarizes the advances in the mechanism of ferroptosis and its role in liver diseases, so as to provide a reference for further research and treatment of liver diseases.

Research advances in clinical treatment of adult autoimmune hepatitis

Mingyue ZHANG, Lin HAN, Ying SUN, Zhengsheng ZOU

2021, 37(6): 1459-1465. DOI: 10.3969/j.issn.1001-5256.2021.06.050

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Autoimmune hepatitis (AIH) is an immune-mediated inflammatory injury of hepatocytes, which can develop into liver cirrhosis and end-stage liver disease. Timely immunosuppressive therapy can help patients achieve biochemical remission and even histological remission and thus improve prognosis. However, adverse drug reactions during treatment and recurrence after withdrawal are commonly seen, and therefore, standard therapy, dose reduction at the right time, and timely drug withdrawal are important for improving patients' prognosis. This article summarizes the advances in guidelines for the diagnosis and treatment of AIH and related studies in China and globally, so as to provide a reference for clinicians in the treatment of AIH.

Immune mechanism of biliary epithelial cell injury in the small intrahepatic bile ducts in primary biliary cholangitis

Yafei YANG, Zhihua DENG

2021, 37(6): 1466-1468. DOI: 10.3969/j.issn.1001-5256.2021.06.051

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Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by the combined effect of genetic and environmental factors and characterized by the apoptotic necrosis of biliary epithelial cells (BEC) in the small intrahepatic bile ducts. This article describes the effect of B cells, macrophages, natural killer cells, NKT, and T cells on the immune injury of BEC during PBC, so as to provide some guidance for the targeted immune therapy for PBC.

Research advances in the value of sarcopenia in the prognosis of patients after liver transplantation

Yuxuan LI, Wenya LIU

2021, 37(6): 1469-1472. DOI: 10.3969/j.issn.1001-5256.2021.06.052

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Sarcopenia is often observed in patients with end-stage liver disease such as advanced liver cancer. This complication is associated with mortality rate in the perioperative period of liver transplantation, and limited liver resources require traditional evaluation systems to further improve the survival rate of the transplant cohort. Summarization and evaluation of skeletal muscular pathology and diagnosis and treatment strategies show that as a body composition parameter that can effectively predict the survival of patients, skeletal muscle can help to optimize the sequence of transplantation cohorts and surgical benefits in combination with liver function assessment scale. The specific mechanism of related death remains unclear, the diagnostic indicators are gradually streamlined, and there is no treatment strategy that can reverse the mortality rate. Based on the existing literature, sarcopenia is one of the important parameters for determining candidates for liver transplantation.

Influence of hepatocellular carcinoma microenvironment on myeloid-derived suppressor cells

Xueyan LI, Changjun WANG

2021, 37(6): 1473-1476. DOI: 10.3969/j.issn.1001-5256.2021.06.053

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Myeloid-derived suppressor cells (MDSCs) are a group of immature bone marrow cells with an immunosuppressive effect, and they are abundant in tumor patients and can induce tumor cells to escape the killing of immune cells and thus promote the development, progression, and metastasis of tumor. In recent years, its role in hepatocellular carcinoma microenvironment has attracted more and more attention, but the mechanisms of its recruitment and differentiation in hepatocellular carcinoma microenvironment have not been clearly elucidated. This article mainly summarizes the mechanism of action of tumor cells and tumor stromal cells in hepatocellular carcinoma microenvironment (such as hepatic stellate cells, tumor-associated fibroblasts, and tumor-associated endothelial cells) in the recruitment and differentiation of MDSCs, and it is proposed to target MDSCs as an adjuvant therapy to enhance the potential value of immunotherapy for liver cancer.

Clinical features, diagnosis, and treatment of autoimmune pancreatitis

Kai XU, Chuanling WU, Fengjiao YIN, Wendeng LI, Wang HU, Chuchu LIU, Haijiu WANG, Zhixin WANG

2021, 37(6): 1477-1480. DOI: 10.3969/j.issn.1001-5256.2021.06.054

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Autoimmune pancreatitis (AIP) is an autoimmune-mediated abnormal chronic inflammatory disorder and is often misdiagnosed as pancreatic neoplastic lesions. With in-depth studies of this disease in recent years, it has been taken seriously by hepatobiliary physicians and surgeons. This article summarizes the clinical features, diagnostic criteria, and treatment methods for autoimmune pancreatitis at the present stage, so as to provide clinicians with diagnosis and treatment experience to reduce clinical misdiagnosis.

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