CORRELATION OF MORPHOLOGIC SUBTYPES OF LIVER CIRRHOSIS WITH EXCESS ALCOHOL INTAKE, HBV INFECTION, AGE AT DEATH, AND HEPATOCELLULAR CARCINOMA: A Study on 234 Autopsy Cases in Japan

ABSTRACTHepatitis B virus (HBV) infection is the leading cause of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study reveals a distinct mechanism underlying the regulation of HBV replication. HBV activates homeobox A10 (HoxA10) in human hepatocytes, leukocytes, peripheral blood mononuclear cells (PBMCs), HepG2-NTCP cells, leukocytes isolated from CHB patients, and HBV-associated HCC tissues. HoxA10 in turn represses HBV replication in human hepatocytes, HepG2-NTCP cells, and BALB/c mice. Interestingly, we show that during early HBV infection, p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were activated to facilitate HBV replication; however, during late HBV infection, HoxA10 was induced to attenuate HBV replication. Detailed studies reveal that HoxA10 binds to p38 MAPK, recruits SH2-containing protein tyrosine phosphatase 1 (SHP-1) to facilitate SHP-1 in catalyzing dephosphorylation of p38 MAPK/STAT3, and thereby attenuates p38 MAPK/STAT3 activation and HBV replication. Furthermore, HoxA10 binds to the HBV enhancer element I (EnhI)/X promoter, competes with STAT3 for binding of the promoter, and thereby represses HBV transcription. Taken together, these results show that HoxA10 attenuates HBV replication through repressing the p38 MAPK/STAT3 pathway by two approaches: HoxA10 interacts with p38 MAPK and recruits SHP-1 to repress HBV replication, and HoxA10 binds to the EnhI/X promoter and competes with STAT3 to attenuate HBV transcription. Thus, the function of HoxA10 is similar to the action of interferon (IFN) in terms of inhibition of HBV infection; however, the mechanism of HoxA10-mediated repression of HBV replication is different from the mechanism underlying IFN-induced inhibition of HBV infection.IMPORTANCETwo billion people have been infected with HBV worldwide; about 240 million infected patients developed chronic hepatitis B (CHB), and 650,000 die each year from liver cirrhosis (LC) or hepatocellular carcinoma (HCC). This work elucidates a mechanism underlying the control of HBV replication. HBV infection activates HoxA10, a regulator of cell differentiation and cancer progression, in human cells and patients with CHB and HCC. HoxA10 subsequently inhibits HBV replication in human tissue culture cells and mice. Additionally, HoxA10 interacts with p38 MAPK to repress the activation of p38 MAPK and STAT3 and recruits and facilitates SHP-1 to catalyze the dephosphorylation of p38 MAPK and STAT3. Moreover, HoxA10 competes with STAT3 for binding of the HBV X promoter to repress HBV transcription. Thus, this work reveals a negative regulatory mechanism underlying the control of HBV replication and provides new insights into the development of potential agents to control HBV infection.

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Studies on Mutual Relationship between Anti-HBx and sFas, IL-10 or IL-12 in Sera of Cases with Chronic Hepatitis B Infection

Infection International ◽

10.1515/ii-2017-0075 ◽

2014 ◽

Vol 3 (2) ◽

pp. 49-53

Author(s):

Ai-kun Ding ◽

Li-wei Guo ◽

Yong-kong Wang ◽

Wei Liu ◽

Cheng Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Sandwich Elisa ◽

Hbv Infection ◽

Mutual Relationship ◽

Chronic Hbv Infection ◽

Chronic Hbv

Abstract Objective To study the mutual relationship between anti-HBx and IL-10, IL-12 or soluble Fas (sFas) in sera of patients with chronic HBV infection and to explore the importance of anti-HBx detection as well as its role in the development of chronic HBV infection. Methods Total of 90 cases with chronic HBV infection were randomly selected, including 10 of asymptomatic carriers (ASC), 28 of chronic hepatitis B (CHB), 26 of liver cirrhosis (LC) and 26 patients of hepatocellular carcinoma (HCC). Their clinical data and blood samples were collected, and serum was prepared and stored at -73℃. Anti-HBx was detected with an indirect ELISA established in our earlier research, and levels of IL-10, IL-12 and Fas were determined with commercial double-antibody sandwich ELISA kits. The mutual relationship between anti-HBx and IL-10, IL-12 or sFas in serum were analyzed with the software SPSS 20.0. Results All levels of IL-10, IL-12 and sFas in peripheral blood showed a rising trend with development of chronic HBV infection. The levels of IL-10 in ASC, CHB, LC and HCC groups were 13.93 ± 14.40 ng/L, 39.38 ± 20.77 ng/L, 69.06 ± 46.37 ng/L and 62.82 ± 23.42 ng/L, respectively, levels of IL-12 in the 4 groups were 15.64 ± 23.04 ng/L, 68.50 ± 23.14 ng/L, 76.83 ± 12.82 ng/L and 83.74 ± 24.88 ng/L, respectively, and levels of sFas were 58.17 ± 77.42 ng/L, 179.88 ± 104.36 ng/L, 249.22 ± 107.80 ng/L and 252.98 ± 87.65 ng/L, respectively. Twenty-seven out of 90 patients showed a positive result for anti-HBx detection, including 1 in ASC, 4 in CHB, 12 in LC and 10 in HCC group. The levels of IL-10, IL-12 and sFas were higher in anti-HBx positive group than in negative group. Statistical analysis demonstrated significant differences of IL-10 and IL-12 between the two groups (P < 0.05), but the differences of sFas had no statistical significance (P = 0.094). Conclusions Anti-HBx antibody is not protective, and is closely related to IL-10, IL-12 and sFas. It may be an important serum indicator for aggravation from chronic hepatitis B to liver cirrhosis or hepatocellular carcinoma in patients with chronic HBV infection.

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Clinical, laboratory and coagulation system of blood feachers in patients with viral liver cirrhoses associated with virus hepatitis B, C and D

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2009-4(2)-33-38 ◽

2009 ◽

Vol 8 (4(2)) ◽

pp. 33-38

Author(s):

S. A. Bogushevich ◽

K. I. Chuikova

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis B ◽

Clinical Laboratory ◽

Hbv Infection ◽

Coagulation System ◽

Consumption Coagulopathy ◽

Virus Hepatitis

The research is devoted to study clinico-laboratory implications and indicators of coagulating system of blood at patiens with liver cirrhosis associated with virus hepatitises B, C and D. The group of 100 patients were analyzed. At patients combined the lesion of a liver viruses HCV and HBV met identical frequency with a HBV-infection (34%). The hepatocellular carcinoma is taped in 8% of cases. At 50 patients with a cirrhosis in subcompansation stage researches of coagulating system of blood have been carried out. According to the developed coagulogram consumption coagulopathy development became perceptible.

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Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.595699 ◽

2020 ◽

Vol 11 ◽

Author(s):

Qi Xia ◽

Zheyue Shu ◽

Ting Ye ◽

Min Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Feature Selection ◽

Liver Cirrhosis ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Hbv Infection ◽

Support Vector ◽

Chronic Hepatitis B Virus ◽

Healthy Control

As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is the fifth major cause of cancer-associated mortality worldwide. In 90% of cases, HCC develops in the context of liver cirrhosis and chronic hepatitis B virus (HBV) infection is an important etiology for cirrhosis and HCC, accounting for 53% of all HCC cases. To understand the underlying mechanisms of the dynamic chain reactions from normal to HBV infection, from HBV infection to liver cirrhosis, from liver cirrhosis to HCC, we analyzed the blood lncRNA expression profiles from 38 healthy control samples, 45 chronic hepatitis B patients, 46 liver cirrhosis patients, and 46 HCC patients. Advanced machine-learning methods including Monte Carlo feature selection, incremental feature selection (IFS), and support vector machine (SVM) were applied to discover the signature associated with HCC progression and construct the prediction model. One hundred seventy-one key HCC progression-associated lncRNAs were identified and their overall accuracy was 0.823 as evaluated with leave-one-out cross validation (LOOCV). The accuracies of the lncRNA signature for healthy control, chronic hepatitis B, liver cirrhosis, and HCC were 0.895, 0.711, 0.870, and 0.826, respectively. The 171-lncRNA signature is not only useful for early detection and intervention of HCC, but also helpful for understanding the multistage tumorigenic processes of HCC.

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Interrelationship between Alcohol Intake, Hepatitis C, Liver Cirrhosis, and Hepatocellular Carcinoma

Recent Developments in Alcoholism ◽

10.1007/0-306-47148-5_23 ◽

1998 ◽

pp. 457-469 ◽

Cited By ~ 13

Author(s):

Harumasa Yoshihara ◽

Katsuhisa Noda ◽

Takenobu Kamada

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis C ◽

Alcohol Intake

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Hepatitis B surface antigen-negative, but HBV DNA-positive patients in Bangladesh

Bangladesh Medical Research Council Bulletin ◽

10.3329/bmrcb.v38i3.14337 ◽

2013 ◽

Vol 38 (3) ◽

pp. 104-107 ◽

Cited By ~ 2

Author(s):

MA Mahtab ◽

SMF Akbar ◽

S Rahman

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis B ◽

Surface Antigen ◽

Healthy Subjects ◽

Hepatitis B Surface Antigen ◽

Hbv Dna ◽

Hbv Infection ◽

B Virus ◽

Control And Management

Hepatitis B surface antigen (HBsAg) is regarded as sole marker of hepatitis B virus (HBV) infection in Bangladesh and most other developing countries. However, some HBV-negative subjects may harbor HBV DNA and transfusion of their blood may cause HBV infection in recipients. HBV DNA was checked in 20 patients with cryptogenic liver cirrhosis, 10 patients with hepatocellular carcinoma without any known etiology, and 10 apparently healthy subjects with elevated levels of serum alanine aminotransferase (ALT). HBV DNA was detected in 8 of 20 patients with cryptogenic liver cirrhosis, 1 of 10 patients with hepatocellular carcinoma, and 2 of 10 apparent healthy subjects with elevated ALT. However, all of them were negative for HBsAg in the sera. This study indicates that some additional mechanisms should be developed for detection of HBsAg-negative HBV-infected subjects for efficient control and management of HBV infection in Bangladesh. DOI: http://dx.doi.org/10.3329/bmrcb.v38i3.14337 Bangladesh Med Res Counc Bull 2012; 38(3): 104-107 (December)

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Clinical Characteristics in Patients with Liver Cirrhosis Induced by HBV Infection and Combined with Mild Alcohol Intake

Infection International ◽

10.1515/ii-2017-0082 ◽

2014 ◽

Vol 3 (3) ◽

pp. 97-102

Author(s):

Ha-lida Xiaerfuhazi ◽

Hai-lin Ma ◽

Xiu-jiang Shi ◽

Xiao-tang Fan ◽

Xi-ernayi Abuduheilili ◽

...

Keyword(s):

Uric Acid ◽

Liver Cirrhosis ◽

Multivariate Regression ◽

Alcohol Intake ◽

White Cell Count ◽

Multivariate Regression Analysis ◽

Hbv Infection ◽

Excessive Alcohol ◽

Variant Analysis ◽

Medical University

Abstract Objective To investigate the differences of clinical and biochemical characteristics between patients with liver cirrhosis induced by HBV infection combined with and without mild alcohol intake. Methods Data of patients with liver cirrhosis who were hospitalized in the First Hospital Affiliated to Xinjiang Medical University were retrospectively analyzed. Patients were divided into three groups: patients with liver cirrhosis induced by HBV infection and combined with mild alcohol intake, patients with HBV-related cirrhosis, and patients with alcohol-related cirrhosis. Biochemical detections including liver function, fasting lipid profiles, lipoprotein, kidney function, glucose, uric acid and regular blood tests were carried out and results were compared among three groups. Data were analyzed through STATA software and co-variant analysis. Results Total of 2 350 patients with liver cirrhosis were included, 732 patients had cirrhosis induced by HBV infection combined with mild alcohol intake, 1 316 patients had HBV-related liver cirrhosis, 302 patients had alcohol-related cirrhosis. The highest mean level of white cell count, mean corpuscular volume, γ-glutamyltranspeptidase and uric acid were observed in HBV infection combined with mild alcohol intake group. Multivariate regression analysis revealed that HBV infection, excessive alcohol intake, male and age were risk factors for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. Conclusions HBV infection combined with mild alcoholic-related liver cirrhosis group showed the highest oxidative stress compared with alcoholic liver cirrhosis group, which suggested that mild alcohol intake may increase the incidence of liver cirrhosis in HBV infected patients and may not increase the incidence of HCC.

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