Association of hepatitis B e antigen and DNA viral load with severity of liver dysfunction and in-hospital outcomes in hepatitis B-related liver cirrhosis
Original Article

Association of hepatitis B e antigen and DNA viral load with severity of liver dysfunction and in-hospital outcomes in hepatitis B-related liver cirrhosis

Feifei Hou1*, Xingshun Qi1*#, Yongguo Zhang1, Eric M. Yoshida2, Nahum Mendez-Sanchez3, Frank Tacke4, Sien-Sing Yang5, Man-Fung Yuen6, Fernando Gomes Romeiro7, Andrea Mancuso8,9, Chun-Jen Liu10, Xintong Zhang1, Ran Wang1, Han Deng1, Jing Li1, Xiaoxi Wang1, Hongyu Li1, Xiaozhong Guo1#; Written on behalf of AME Liver Disease Cooperative Group

1Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China; 2Division of Gastroenterology, Vancouver General Hospital, Vancouver, Canada; 3Liver Research Unit, Medical Sur Clinic & Foundation, Mexico City, Mexico; 4Department of Gastroenterology, Metabolic Diseases and Intensive Care Medicine, University Hospital Aachen, Germany; 5Liver Unit, Cathay General Hospital and Medical Faculty, Fujen Catholic University, Taipei, Taiwan; 6Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; 7Botucatu Medical School, UNESP (Universidade Estadual Paulista), São Paulo State, Brazil, Brazil; 8Epatologia e Gastroenterologia, Ospedale Niguarda Ca’ Granda, Milano, Italy; 9Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina - Benfratelli, Piazzale Leotta 4, Palermo, Italy; 10Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine, Taiwan

Contributions: (I) Conception and design: X Qi; (II) Administrative support: X Guo; (III) Provision of study materials or patients: X Guo, H Li, X Qi; (IV) Collection and assembly of data: F Hou, X Zhang, R Wang, H Deng, J Li, X Wang; (V) Data analysis and interpretation: F Hou, X Qi, Y Zhang, EM Yoshida, N Mendez-Sanchez, F Tacke, SS Yang, MF Yuen, FG Romeiro, A Mancuso, CJ Liu, H Li, X Guo; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

*These authors contributed equally to this work.

#These authors contributed equally for the senior authorship.

Correspondence to: Prof. Xiaozhong Guo, MD. Department of Gastroenterology, General Hospital of Shenyang Military Area, No. 83 Wenhua Road, Shenyang 110840, China. Email: guo_xiao_zhong@126.com; Dr. Xingshun Qi, MD. Department of Gastroenterology, General Hospital of Shenyang Military Area, No. 83 Wenhua Road, Shenyang 110840, China. Email: xingshunqi@126.com.

Background: Hepatitis B virus (HBV) infection is a common cause of liver cirrhosis. Our study aimed to evaluate the clinical relevance of hepatitis B e antigen (HBeAg) and HBV DNA viral load in HBV-related liver cirrhosis.

Methods: All HBV-related cirrhosis patients consecutively admitted to our hospital between January 2012 and June 2014 were retrospectively reviewed. Clinical profiles were collected. HBV DNA viral load would be detectable, if HBV DNA viral load was >200 IU/mL.

Results: Overall, 428 patients were included. The prevalence of positive HBeAg was 11.9% (40/335). HBeAg-positive patients had significantly higher proportions of moderate-large ascites and Child-Pugh class B/C than HBeAg-negative patients. The in-hospital mortality was not significantly different between them. The prevalence of detectable HBV DNA viral load was 38.25% (109/285). Patients with detectable HBV DNA viral load had a significantly higher proportion of moderate-large ascites and higher Child-Pugh and model for end-stage liver disease (MELD) scores than patients with undetectable HBV DNA viral load. The in-hospital mortality was not significantly different between them. The prevalence of HBV DNA viral load >2,000 IU/mL was 31.9% (91/285). Patients with HBV DNA viral load >2,000 IU/mL had significantly higher proportions of moderate-large ascites and in-hospital death and higher Child-Pugh and MELD scores than patients with HBV DNA viral load <2,000 IU/mL. After adjusting Child-Pugh score, HBV DNA viral load >2,000 IU/mL was not significantly associated with in-hospital death (odds ratio =2.154, P=0.272).

Conclusions: In HBV-related cirrhosis, HBeAg and HBV DNA viral load were significantly associated with the severity of liver dysfunction, but not independently associated with in-hospital death.

Keywords: Liver cirrhosis; hepatitis B virus (HBV); survival; mortality; Child-Pugh


Received: 17 July 2017; Accepted: 12 September 2017; Published: 28 September 2017.

doi: 10.21037/amj.2017.09.10


Introduction

About 240 million people are infected with hepatitis B virus (HBV) worldwide (1). In patients with untreated chronic hepatitis B, the 5-year cumulative incidence of cirrhosis ranges from 8% to 20% (2). The 5-year mortality in patients with cirrhosis is 14–35% (3-7). Notably, 60% of cases with liver cirrhosis result from HBV infection in China (8).

Chronic HBV patients usually present either as positive or negative hepatitis B e antigen (HBeAg). Traditionally, the natural history of chronic HBV infection is usually divided into the immune tolerant phase, immune reactive HBeAg-positive phase, inactive HBV carrier state, HBeAg-negative chronic HBV infection phase, and HBsAg-negative phase (9-11). According to the updated guidelines, the natural history is defined as follows: HBeAg-positive chronic HBV infection, HBeAg-positive chronic hepatitis B, HBeAg-negative chronic HBV infection, HBeAg-negative chronic hepatitis B, and HBsAg-negative phase (2). HBV DNA viral load also plays an important role in the diagnosis and treatment of chronic HBV infection. As HBV continues to infect the liver, repeated inflammatory necrosis results in the regeneration and repair and activation of hepatic stellate cells. The abnormal deposition of extracellular matrix induces liver fibrosis and ultimately leads to liver cirrhosis (9,12). While the role of HBeAg status and HBV DNA viral levels for estimating the risk of individuals to progress to liver cirrhosis or hepatocellular carcinoma is well established in Asian and Caucasian cohorts (2), their clinical relevance as biomarkers in patients with HBV-related liver cirrhosis for complications and short-term mortality is unclear.

Herein, we conducted a retrospective monocentric study to evaluate the impact of HBeAg status and HBV DNA viral load on the clinical profiles and in-hospital mortality of patients with HBV-related liver cirrhosis.


Methods

Study design

All liver cirrhosis patients with chronic HBV infection who were consecutively admitted to our hospital between January 2012 and June 2014 were considered eligible for the study. All eligible patients were positive for HBsAg. The exclusion criteria were as follows: liver cancer or co-diagnosed with other malignant tumors; co-infection with hepatitis C virus or other chronic liver diseases; and a history of alcohol abuse. As our study endpoint was the in-hospital death, repeated admissions were included. The study protocol was approved by the Medical Ethical Committee of our hospital. The approval number was No. k[2015]39.

Laboratory tests

The following data were collected at the moment of the subjects’ admissions: age, sex, red blood cell count (RBC), hemoglobin (Hb), white blood cell count (WBC), platelet count (PLT), total bilirubin (TBIL), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), sodium (Na), kalium (K), international normalized ratio (INR), acute upper gastrointestinal bleeding (AUGIB), HBsAg, hepatitis B surface antibody (HBsAb), HBeAg, hepatitis B e antibody (HBeAb), hepatitis B core antibody (HBcAb), and HBV DNA viral load. Child-Pugh and model for end-stage liver disease (MELD) scores were calculated according to the results of laboratory tests and grades of ascites and hepatic encephalopathy (HE) (13,14). In-hospital death was recorded.

The serum HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb expression and quantification of HBV DNA viral load were detected by the electrochemiluminescence immunoassay with relevant reagents (Huake Co. Ltd., Shanghai, China) at the Department of Laboratory Medicine of our hospital. Detectable HBV DNA viral load was defined as HBV DNA viral load was more than 200 IU/mL (1 IU/mL=5 copies/mL) (15).

Definition and diagnosis

Chronic HBV infection is defined as hepatitis B surface antigen (HBsAg) positivity for more than 6 months. The clinical diagnosis of liver cirrhosis is made on the basis of clinical presentations, medical imaging examination, and laboratory abnormalities (16,17). Ascites is classified as three grades: (I) mild ascites only detectable by ultrasound; (II) moderate ascites with symmetrical distension of the abdomen; and (III) tense ascites (18,19). Hepatic encephalopathy (HE) manifests as impaired disturbance of consciousness, abnormal behavior, or coma (20).

Statistical analysis

Statistical analysis was performed using the SPSS statistics 17.0.0 software. Continuous data were expressed as mean ± standard deviation or median (range), and were compared by the non-parametric tests. Categorical data were expressed as frequency (percentage), and were compared by the Chi-square tests. The correlation analyses were performed by the Spearman rank test. Logistic regression analyses were performed to check the independent risk factor for in-hospital death. A two-sided P<0.05 was considered to be statistically significant.


Results

A total of 428 HBsAg-positive patients with liver cirrhosis were enrolled in this study. Among them, 284 (284/428, 66.4%) patients were male, and the median age was 53.91 years (range, 25.62–86.93 years). The proportion of positive HBsAg, positive HBeAb, and detectable HBV DNA viral load was 11.9% (40/335), 50.7% (170/335), and 38.25% (109/285), respectively. None (0/428) had positive HBsAb. The median HBV DNA viral load in 109 patients with detectable HBV DNA viral load was 94,000 IU/mL (range, 220–48,000,000 IU/mL). The in-hospital mortality was 3.7% (16/428). The patient characteristics were shown in Table 1. The causes of death were as follows: gastrointestinal bleeding (n=5), sudden death and pulmonary embolism (n=1), and liver failure with multiple organ failure (n=10).

Table 1
Table 1 Patient characteristics
Full table

Comparison between HBeAg-negative and HBeAg-positive patients

Compared with HBeAg-negative patients, HBeAg-positive patients had significantly higher HBV DNA viral load, ALT, AST, ALP, GGT, and Child-Pugh score, higher proportions of moderate-large ascites and Child-Pugh class B-C, and lower ALB (Table 2). The in-hospital mortality was not significantly different between HBeAg-negative and HBeAg-positive patients (3.7% vs. 2.5%, P=0.695). After adjusting the Child-Pugh score, the HBeAg status remained not associated with in-hospital death in a multivariate logistic regression analysis (odds ratio =0.494; 95% CI, 0.057–4.274; P=0.522).

Table 2
Table 2 Comparison between HBeAg-negative and HBeAg-positive hepatitis B virus liver cirrhosis patients
Full table

Comparison between patients with undetectable and detectable HBV DNA viral load

Compared with patients with undetectable HBV DNA viral load, patients with detectable HBV DNA viral load were significantly older and had significantly higher Hb, TBIL, ALT, AST, ALP, GGT, Cr, INR, Child-Pugh score, and MELD score, higher proportions of moderate-large ascites and Child-Pugh class B-C, lower ALB and Ca, and a lower proportion of AUGIB (Table 3). The in-hospital mortality was not significantly different between patients with undetectable and detectable HBV DNA viral load (2.3% vs. 6.4%, P=0.077). After adjusting the Child-Pugh score, detectable HBV DNA viral load remained not associated with in-hospital death in a multivariate logistic regression analysis (odds ratio =1.919; 95% CI, 0.486–7.578; P=0.353).

Table 3
Table 3 Comparison between patients with undetectable and detectable HBV DNA load
Full table

Comparison between patients with HBV DNA viral load <2,000 and >2,000 IU/Ml

Compared with patients with HBV DNA viral load <2,000 IU/mL, patients with HBV DNA viral load >2,000 IU/mL were significantly older and had significantly higher Hb, TBIL, ALT, AST, ALP, GGT, Cr, INR, Child-Pugh score, and MELD score, higher proportions of moderate-large ascites and Child-Pugh class B-C, lower ALB, Ca, and Na, and a lower proportion of AUGIB (Table 4). The in-hospital mortality was higher in patients with HBV DNA viral load >2,000 IU/mL than in those with HBV DNA viral load <2,000 IU/mL (7.7% vs. 2.1%, P=0.021). After adjusting the Child-Pugh score, HBV DNA viral load >2,000 IU/mL was not an independent risk factor for in-hospital death in a multivariate logistic regression analysis (odds ratio =2.154; 95% CI, 0.548–8.468; P=0.272).

Table 4
Table 4 Comparison between patients with serum HBV DNA load <2,000 and >2,000 IU/mL
Full table

Correlation analysis of HBV DNA viral load

In 109 patients with detectable HBV DNA, the HBV DNA viral load positively correlated with ALT, AST, ALP, BUN, INR, Child-Pugh score, and MELD score, and negatively correlated with RBC, Hb, ALB, and Ca (Table 5).

Table 5
Table 5 Correlation analysis of HBV DNA load in 109 patients with detectable HBV DNA load
Full table

Discussion

Major findings of our study were as follows: (I) the in-hospital mortality of cirrhotic patients with HBV DNA viral load >2,000 IU/mL was significantly elevated, but this association was compromised after adjusting the Child-Pugh score; (II) positive HBeAg, detectable HBV DNA viral load, and HBV DNA viral load >2,000 IU/mL were all related to the degree of liver and renal dysfunction, as indicated by biomarkers, such as TBIL, ALT, AST, ALP, GGT, Cr, and Child-Pugh and MELD scores; and (III) there was a significant correlation of HBV DNA viral load with worsening liver function laboratory/features.

Clinical practice guidelines on the management of chronic hepatitis B published by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) indicated that age was an important predictive factor for the progression of liver cirrhosis in chronic HBV infection patients (2,21-24). Chinese clinical practice guideline also suggested that the risk of liver cirrhosis in HBV patients would be increased with age and high serum HBV DNA viral load, especially in patients with age above 40 years. Additional studies reported that liver injury was more significant in chronic HBV patients with age above 46 years (25-27). Consistent with these findings, our patients with HBV-related liver cirrhosis had a median age of 53.91 years (range, 25.62–86.93 years).

HBeAg status, liver function, serum HBV DNA viral load, and liver histology are important factors in determining the severity of liver diseases (2,21,23,24). HBeAg is a significant marker of viral infectivity and persistence, and plays an important role in the natural history of chronic HBV (28). Traditionally, HBeAg seroconversion is defined as negative HBeAg and positive HBeAb with an associated reduction in HBV viral replication and a lower infectivity in the natural history of infection. In our study, the prevalence of HBeAg-negative patients was 88.1% (295/335) and the prevalence of HBeAb-positive patients was 57.3% (169/295) in HBeAg-negative patients. The data suggested that most of HBV-related cirrhotic patients had experienced HBeAg seroconversion. Our study found that HBeAg-negative patients with cirrhosis had significantly better liver function than HBeAg-positive patients, indicating that lack of HBeAg seroconversion (and subsequent high viremia) posed a particular risk for cirrhotic patients. However, some studies reported that HBeAg-negative patients with or without cirrhosis still could have experienced a high viral replication and/or risk of viral hepatitis exacerbation (25,29,30). Similarly, HBeAg-negative HBV patients with elevated ALT and active histological changes could experience faster progression to liver cirrhosis than HBeAg-positive HBV patients (31). The potential reasons included: (I) a longer duration of infection in HBeAg-negative patients than in HBeAg-positive patients; and (II) core promoter mutations that might increase the replication efficacy of HBV (32-35).

Some studies had reported that long-term antiviral therapy could improve the survival of patients with HBV-related liver cirrhosis (36-38), but few studies explored the impact of HBeAg status and HBV DNA viral load on the severity of liver dysfunction and in-hospital outcomes in HBV-related liver cirrhosis patients. Our study revealed higher likelihood of adverse outcomes in cirrhotic patients with HBV DNA viral load, thereby suggesting that antiviral treatment is urgently required in such patients. This is consistent with the recommendations from EASL guideline regarding management of HBV (2,22). Unfortunately, information regarding use of antiviral therapy was unavailable in our study. Accordingly, future studies should explore whether the initiation of antiviral therapy could improve the outcomes of HBV-related liver cirrhosis patients with HBV DNA viral load >2,000 IU/mL.

A lower proportion of AUGIB and higher Hb levels were observed in patients with HBV DNA viral load >2,000 IU/mL. Similarly, HBV DNA viral load negatively correlated with RBC and Hb. These findings suggested that patients with higher HBV DNA viral load might suffer from less bleeding events but had worse liver function. Indeed, the major cause of hospital admission in patients with HBV DNA viral load >2,000 IU/mL might be liver dysfunction; by contrast, the major cause of hospital admission in patients with HBV DNA viral load <2,000 IU/mL might be acute gastrointestinal bleeding.

Our study had some limitations. First, not all HBV patients had data available for HBeAg, HBeAb, and HBV DNA viral load. Second, the diagnosis of cirrhosis was not confirmed by liver histology. Third, this was a single-center observational study and we did not collect the long-term follow-up data. Fourth, we are unable to dissect a potential role of antiviral therapy. Some of patients with undetectable HBV DNA viral load might have been on nucleoside/nucleotide analogues.

In conclusion, HBeAg and HBV DNA viral load are factors associated with the severity of liver dysfunction in HBV-related liver cirrhosis patients. More importantly, the in-hospital mortality was significantly higher in such patients with HBV DNA viral load >2,000 IU/mL, but it was not an independent risk factor for death, after adjusting the Child-Pugh score.


Acknowledgements

Funding: Liaoning Provincial Startup Foundation for PhD (No. 201501023) for Dr. Y Zhang.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The study protocol was approved by the Medical Ethical Committee of our hospital. The approval number was No. k[2015]39.


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doi: 10.21037/amj.2017.09.10
Cite this article as: Hou F, Qi X, Zhang Y, Yoshida EM, Mendez-Sanchez N, Tacke F, Yang SS, Yuen MF, Romeiro FG, Mancuso A, Liu CJ, Zhang X, Wang R, Deng H, Li J, Wang X, Li H, Guo X; Written on behalf of AME Liver Disease Cooperative Group. Association of hepatitis B e antigen and DNA viral load with severity of liver dysfunction and in-hospital outcomes in hepatitis B-related liver cirrhosis. AME Med J 2017;2:145.

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