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Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases
Accepted Manuscript Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases
Xiude Fan, Huan Deng, Xiqiang Wang, Siqi Fu, Zitong Liu, Jiao Sang, Xiaoge Zhang, Na Li, Qunying Han, Zhengwen Liu PII: DOI: Reference:
S0009-8981(18)30160-8 doi:10.1016/j.cca.2018.04.002 CCA 15136
To appear in:
Clinica Chimica Acta
Received date: Revised date: Accepted date:
17 January 2018 31 March 2018 2 April 2018
Please cite this article as: Xiude Fan, Huan Deng, Xiqiang Wang, Siqi Fu, Zitong Liu, Jiao Sang, Xiaoge Zhang, Na Li, Qunying Han, Zhengwen Liu , Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Cca(2017), doi:10.1016/j.cca.2018.04.002
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ACCEPTED MANUSCRIPT Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases
Xiude Fan a , Huan Deng a , Xiqiang Wang b, Siqi Fu a,c, Zitong Liu
a,c
, Jiao Sang a ,
a
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Xiaoge Zhang a , Na Li a , Qunying Han a , Zhengwen Liu a,*
Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong
Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University,
Xi’an , Shaanxi, People’s Republic of China
Xi’an Medical University, Xi’an, 710021, Shaanxi, People’s Republic of China
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c
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b
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University, Xi’an, 710061, Shaanxi, People’s Republic of China
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* Correspondence to: Zhengwen Liu, M.D., Ph.D. Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West
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Road, Xi’an, 710061, Shaanxi Province, the People’s Republic of China. E-mail:
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[email protected]
Funding information: National Natural Science Foundation of China (Grant no.
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81371798).
ACCEPTED MANUSCRIPT Abstract
Background Red blood cell distribution width (RDW) has been indicated to be an inflammatory indicator in a variety of diseases. However, no consistent conclusions regarding it’s
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relevance to hepatitis B virus (HBV) -related liver diseases have been made. This meta-analysis was conducted to assess the significance of RDW in HBV-related liver
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diseases.
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Methods
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A comprehensive literature review was conducted using PubMed, Embase, and China National Knowledge Infrastructure (CNKI) through August 20, 2017 to identify
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studies that reported the association between RDW and HBV-related liver diseases. The standard mean difference (SMD) and corresponding 95% confidence interval (CI)
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were used to assess the associations. Results
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Twenty-four studies met the eligibility criteria were included in the meta-analysis. These studies included 3272 HBV-infected patients and 2209 healthy controls.
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Chronic hepatitis B (CHB) patients had significantly increased RDW levels compared with healthy controls (SMD =1.399, 95% CI 0.971-1.827, p < 0.001]. Moreover, acute on chronic liver failure (ACLF) patients (SMD = 1.309, 95% CI 0.775-1.843, p < 0.001) and cirrhotic patients (SMD = 0.948, 95% CI 0.715-1.180, p < 0.001) had significantly elevated RDW levels compared with CHB patients. However, no statistical significance was obtained in RDW levels between cirrhosis and ACLF (SMD = 0.167, 95% CI -0.382 -0.716, p = 0.051). Conclusion RDW values were elevated in HBV-related liver diseases and correlated with the disease severity, suggesting that RDW levels may differantiate CHB from healthy
ACCEPTED MANUSCRIPT controls and ACLF and cirrhosis from CHB but they appear to have no distinguishing characteristic between ACLF and cirrhosis.
Keywords: red blood cell distribution width (RDW); hepatitis B virus; liver diseases;
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meta-analysis.
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1. Introduction
Chronic hepatitis B virus (HBV) infection, a leading cause of chronic liver disease, affects approximately 240 million people worldwide [1,2]. About 25 percent
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of chronic hepatitis B (CHB) patients may progress to primary liver cancer or
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cirrhosis and eventually to liver failure [1]. Early cirrhosis is reversible, but a large
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number of CHB patients progress into decompensated cirrhosis with various
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complications which are major causes of mortality in most region worldwide [3]. Therefore, monitoring and assessing the disease severity and progression of chronic
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HBV infection is important in clinical practice.
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Red blood cell distribution width (RDW, or RCDW) is an automated measure of the range of transformation of red blood cell (RBC) volume, which is recorded as part
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of a standard complete blood cell count. It is mainly used to identify the cause of anemias [4]. Recently, a series of studies have proved that RDW can serve as an
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independent predictor of prognosis or an inflammatory indicator in a variety of diseases such as lung cancer [5], pulmonary hypertension [6], peripheral artery disease [7,8], acute myocardial infarction [9] and acute infections [10]. In terms of liver disease, elevated RDW has been reported to be associated with different disease states in HBV-infected patients [11-16]. RDW levels increase with progressive liver inflammation and fibrosis. This routine laboratory parameter is expected to become a new simple marker for inflammation and fibrosis in patients with chronic HBV infection.
ACCEPTED MANUSCRIPT However, there are inconsistent conclusions regarding the relevance of RDW to HBV-related liver diseases. Therefore, this meta-analysis was conducted based on the existing published works to evaluate the significance of RDW levels in HBV- related
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liver diseases.
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2. Materials and methods
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2.1. Literature search
Two independently investigators (X.F. and X.W.) searched literatures describing
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the association between RDW value and different stages of chronic HBV infection,
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including CHB, acute on chronic liver failure (ACLF) or chronic severe hepatitis B (CSHB) and HBV-related cirrhosis (LC). The term "ACLF" is equivalent to the term
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"CSHB" in China and represents the fatal form of chronic hepatitis [17]. Study data
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were retrieved by searching of PubMed, Embase, and China National Knowledge Infrastructure (CNKI). In addition, recent review articles were checked for additional relevant studies. To identify observational studies, the following combinations of
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search terms were used: (“RDW” or “red blood cell distribution width” or "blood routine examination" ) and (“chronic viral hepatitis B” or “chronic hepatitis B” or “CHB” or “chronic severe hepatitis B” or “CSHB” or “acute on chronic liver failure” or “ACLF” or “liver fibrosis” or “liver cirrhosis” or “LC”). We restricted this search to observational studies involving humans that were published in English and Chinese language until August 20, 2017.
ACCEPTED MANUSCRIPT 2.2. Inclusion and exclusion criteria Any study that met all of the following criteria were included: case–control or cross-sectional studies; studies evaluating the association of RDW value with HBV-related liver diseases (CHB, ACLF or CSHB and hepatitis B related cirrhosis);
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studies with provision of the number of cases and controls and the means and standard
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deviations of RDW value. In addition, studies published in Chinese language must be
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on the Chinese Core Journals selection database.
Studies that met the following criteria were excluded: (1) review, letter, and
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meeting abstract; (2) duplicate publications; (3) unavailability of the original data; (4)
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studies with less than 30 HBV chronically infected patients.
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2.3. Data collection and quality assessment
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Two investigators (X.F. and X.W.) independently extracted the original data from all eligible papers. Disagreements between the two investigators were settled by consultation with the corresponding author (Z.L). If multiple updates of the same data
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were found, the most recent version was used for analysis. The data extracted included first author's name, year of report, location, age of participants, sex, number of cases and controls, RDW values, and diagnostic criteria.
2.4. Statistical analysis STATA 13 (Stata Corp.) was used to perform the meta-analysis in the present study. The standard mean difference (SMD) and corresponding 95% CI was utilized
ACCEPTED MANUSCRIPT to assess the associations. SMDs were pooled using a random-effects model to minimize the potential heterogeneity among studies. Heterogeneity among studies was mainly assessed using I2 statistic and Cochrane's Q statistic. An I2 value of >50% is suggestive of significant heterogeneity. For the Q statistic, P < 0.10 was considered
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statistically significant for heterogeneity. Due to the high heterogeneity existed in the
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studies of association of RDW level with CHB and the studies of comparison of
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HBV-related cirrhosis with CHB in RDW levels, meta-regressions were conducted to examine the impact of moderator variables, such as publication language, diagnostic
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criteria, case load and the number of control group. Sensitivity analysis was also
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performed by excluding each study at a time to evaluate whether one or more studies influenced the overall results. Publication bias was investigated using the Bgger's test
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and the Egger’s test. P < 0.05 was considered significant. These 2 tests were not
3. Results
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conducted when the included studies were <10.
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3.1. Literature search and study characteristics A total of 1215 studies were identified after an initial search from the PubMed, Embase and CNKI. After duplicates removal and further screening, 24 eligible studies [11,14-36] were selected for meta-analysis. Of the 24 eligible studies, 19 were published in Chinese and 5 in English language. There are 5481 subjects, including 2209 control subjects and 3272 HBV-infected patients (1769 cases of CHB, 256 cases of ACLF, and 1247 cases of cirrhosis). The mean age of the participants ranged from
ACCEPTED MANUSCRIPT 32 to 52 years and the percentage of male patients ranged from 54% to 100%. The data of mean age were missing in 7 of these studies [21,23-25,27,31,32]. The analyzed population was Chinese in almost all studies [11,15-36] except one study which analyzed population of Turks [14]. The flow chart of the search process is
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summarised in Fig. 1. The detailed characteristics of the eligible studies are presented
3.2. Association of RDW levels with CHB
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in Table 1.
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There are 22 studies [11,15-35] reporting the association of RDW level with
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CHB. Data from these studies were analyzed in a random-effects model to compare the RDW levels between CHB patients and healthy controls (Table 1). CHB patients
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had significantly higher levels of serum RDW than controls (SMD = 1.399; 95% CI 0.971-1.827, p < 0.001, Supplementary Fig. 1). Significant heterogeneity was found
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among these studies (I2 = 96.6%, p < 0.001). A meta-regression was performed to explore potential sources of heterogeneity. The publication language, diagnostic
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criteria, case load and the number of controls, which might be potential sources of heterogeneity, were all tested by the meta regression method. In meta regression analyses, publication language, diagnostic criteria and case load had no moderating effects, except for the number of controls (p = 0.007; Table 2). Sensitivity analyses showed that the corresponding pooled RDW levels in CHB varied from 1.270 (0.874-1.666) with exclusion of Xie et al [21] to 1.460 (1.022-1.898) with exclusion of Yang et al [26] (Supplementary Table 1), and no single study significantly changed
ACCEPTED MANUSCRIPT the results. Each single study did not statistically change the pooled RDW levels estimate, indicating the reliability of the results. According to the Begg’s funnel plots and Egger’s test, no evidence of publication bias was found (p = 0.864 and p = 0.096,
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3.3. Comparison of RDW levels between ACLF and CHB
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respectively).
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Eight studies [17,18,22,23,26,31,34,35] were selected with a pooled sample size of 678 subjects including 256 ACLF patients and 422 CHB patients (Table 1).
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Random-effects meta-analysis demonstrated that patients with ACLF had
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significantly higher RDW levels than CHB patients (SMD = 1.309; 95% CI 0.775-1.843, p < 0.001, Supplementary Fig. 2) with significant heterogeneity among
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these studies (I2 = 88.9%, p < 0.001). Sensitivity analyses showed that the
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corresponding pooled RDW level in ACLF varied from 0.985 (0.685-1.284) with exclusion of Wu et al [18] to 1.458 (0.900-2.016) with exclusion of Wang et al [34] (Supplementary Table 2). Due to the limited number of studies, we did not perform
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analysis to evaluate publication bias.
3.4. Comparison of RDW levels between HBV-related cirrhosis and CHB There are 18 studies [11,14-16,18,19,21,23-27,29,30,33-36] reporting the association of RDW level with HBV-related cirrhosis relative to CHB. I2 test indicated that the heterogeneity is significant (p < 0.001, I2 = 85.40%). Therefore, the random-effects model was applied to perform meta-analysis. The results showed that
ACCEPTED MANUSCRIPT RDW level in cirrhosis was higher than that in CHB (SMD = 0.948; 95% CI 0.715-1.180, p < 0.001; Supplementary Fig. 3). Meta-regression analyses revealed that diagnostic criteria had moderating effects on the outcomes of the meta-analysis (p = 0.005; Table 2). Sensitivity analyses showed that no single study significantly
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changed the results (Supplementary Table 3). The results of Begg’s (p = 0.031) and
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Egger’s (p = 0.724) test in the present meta-analysis indicated the possibility of
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publication bias. Because of this, a sensitivity analysis using the trim and fill method was performed. The pooled analysis merging the eligible studies continued to show
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that RDW level in cirrhosis was higher than that in CHB (SMD = 1.873; 95% CI
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1.436-2.444, p < 0.001).
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3.5. Comparison of RDW levels between HBV-related cirrhosis and ACLF
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Meta-analysis on 6 studies [18,22,23,26,34,35] by combining studies investigating RDW levels in cirrhosis and ACLF was also performed. Random-effects meta-analysis demonstrated that no statistical significance was obtained between
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cirrhosis and ACLF in RDW levels (SMD = 0.167, 95% CI -0.382-0.716, p = 0.051, Supplementary Fig. 4). Given the limited number of studies, neither subgroup analyses nor publication bias were performed.
4. Discussion In the analysis of 24 controlled observational studies, CHB patients had higher RDW levels than normal controls. Furthermore, the RDW levels were significantly
ACCEPTED MANUSCRIPT elevated in ACLF patients and cirrhosis patients compared with CHB patient. However, no significant difference in RDW levels between ACLF patients and cirrhosis patients was observed. RDW, a parameter routinely reported as part of the complete blood count in
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laboratories, is a measure of the range of variation of red blood cell volume and
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reflects the variability in circulating RBC size. RDW test results are mainly used to
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determine the possible causes of the anemia [37]. Normally, RBCs are a moderate size of about 6-8 μm in diameter. Higher values indicate greater variability in RBC
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size. Significant variation of RDW may be caused by a variety of abnormalities
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[4,38-42], including inflammation, oxidative stress, erythrocyte fragmentation, poor nutritional status, and abnormality of erythropoietin function. These disorders and
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anemia are common in patients with chronic liver disease and correlate with the
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severity of the liver disease. Thus, elevated RDW values may associate with the severity of the liver disease. However, the exact mechanisms underlying the association between RDW values and the severity of HBV-related liver diseases are
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largely unclear. It was reported that inflammation might contribute to elevated RDW values by not only impairing erythrocyte maturation but also causing immature erythrocytes to enter the blood flow [43]. It is plausible that inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 might inhibit iron metabolism and the production of erythropoietin, resulting in synthesis disorders or abnormal activity of erythropoietin [44,45]. Oxidative stress is common in liver disease with the characteristic of impairment of balance between oxidants and
ACCEPTED MANUSCRIPT antioxidant defenses. Moreover, oxidative stress has a profound influence on erythrocyte homeostasis and survival, and low serum antioxidant concentrations have been shown to be related to increased RDW levels [46,47]. Therefore, oxidative stress may be another mechanism that leads to increased RDW levels in liver disease.
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Additionally, poor nutritional status such as iron deficiency, vitamin B12 or folate
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deficiency during liver disease can also lead to ineffective RBC production, leading to
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elevated RDW levels [48].
In the comparison of RDW levels between CHB and controls, the number of
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controls ranged from 30 to 285 and the small sample size of studies may contribute to
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the heterogeneity. Subsequent meta-regression analysis showed that the number of control might be one of the potential sources of heterogeneity. In the majority of
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included studies, CHB, ACLF and cirrhosis patients were diagnosed according to
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different versions of guidelines of prevention and treatment for chronic hepatitis B established by the Chinese Medical Association [49-52], and there are also several studies which did not provide a clear diagnostic criteria. The diagnostic guidelines
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released by the Chinese Medical Association had a chronological order and minor difference in clinical diagnostic details. Although these minor difference in clinical diagnostic details have no effect on the diagnosis of the patients, meta-regression analysis showed that different diagnostic criteria might be one of the potential sources of heterogeneity in the comparison of RDW levels between cirrhosis and CHB. It should also be noted that two studies included in the analyses were reported by the same first author [30,33] but they were conducted in different patient populations
ACCEPTED MANUSCRIPT [30,33]. Sensitivity analysis was performed to evaluate the impact of each single study on the results of the meta-analysis. The results showed that no individual study could significantly change the pooled SMD, suggesting that the results of this meta-analysis are stable.
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The present study has some limitations. First, CHB, ACLF and cirrhosis were
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diagnosed according to different guidelines in the included studies, which might be
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one of the potential sources of heterogeneity. Second, the number of cases and controls in certain studies was relatively small, even with the exclusion of studies with
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less than 30 CHB patients. Third, in almost all studies the analyzed population was
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Chinese and only one study was Turk. Fourth, the present study only included studies that evaluated the association of RDW value with HBV-related liver diseases.
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Recently, a series of studies regarding hepatitis C virus (HCV)-related liver diseases
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[53], nonalcohol fatty liver disease (NAFLD) [54] or primary biliary cirrhosis (PBC) [55] have been published. One study performed a diagnostic tests in 152 patients with native liver and 70 patients with transplanted liver, and found that RDW values had a
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strong correlation with the degree of fibrosis but not the degree of inflammation in native liver [56]. RDW values and RDW/platelet ratio (RPR) were revealed to be a predictor of the degree of fibrosis in patients with chronic hepatitis C [53]. In a following study, RDW levels in 619 NAFLD patients and 1637 healthy persons were investigated and suggested that RDW values was significantly increased in NAFLD patients [57]. These findings were consistent with the results of our meta-analysis irrespective of difference in the etiologies of liver disease. However, the study in PBC
ACCEPTED MANUSCRIPT detected no significant difference in terms of RDW and RPR levels between PBC histological stages [55]. Thus, more studies with larger sample sizes in various ethnic populations are needed to define the association between RDW values and liver
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diseases of different etiologies.
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5. Conclusion
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We demonstrated that RDW values were elevated and associated with the severity of liver disease in patients with chronic HBV infection. However, the results
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should be interpreted with caution, due to the significant clinical and statistical
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heterogeneity among included studies. In addition, RDW levels appear to have no distinguishing quality between ACLF and cirrhosis associated with HBV infection.
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Therefore, clinical data including other laboratory parameters and auxiliary
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examinations are needed to achieve a definite evaluation, especially in the
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circumstance between ACLF and cirrhosis.
Acknowledgement
The study was supported by National Natural Science Foundation of China.
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and treatment for chronic hepatitis B. Zhonghua Gan Zang Bing Za Zhi (Chin J
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Hepatol). 2005;13:881-891.
[51] Chinese Society of Hepatology, Chinese Society of Infectious Diseases, Chinese
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Medical Association. The guideline of prevention and treatment for chronic
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hepatitis B: a 2010 update. Zhonghua Gan Zang Bing Za Zhi (Chin J Hepatol). 2011; 19:13-24.
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[52] Chinese Society of Hepatology, Chinese Medical Association; Chinese Society
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of Infectious Diseases, Chinese Medical Association The guideline of prevention and treatment for chronic hepatitis B: a 2015 update. Zhonghua Gan Zang Bing Za Zhi (Chin J Hepatol). 2015;23:888-905.
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[53] Karagöz E, Tanoğlu A, Ülçay A, Erdem H, Turhan V, Kara M, et al. Mean platelet volume and red cell distribution width to platelet ratio for predicting the severity of hepatic fibrosis in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol. 2016; 28:744-748. [54] Giorgio V, Mosca A, Alterio A, Alisi A, Grieco A, Nobili V, et al. Elevated Hemoglobin Level Is Associated With Advanced Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease. J Pediatr Gastroenterol Nutr. 2017; 65:150-155.
ACCEPTED MANUSCRIPT [55] Tahtaci M, Yurekli OT, Bolat AD, Balci S, Akin FE, Buyukasik NS, et al. Increased mean platelet volume is related to histologic severity of primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2015; 27:1382-1385. [56] Taefi A, Huang CC, Kolli K, Ebrahimi S, Patel M. Red cell distribution width to
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platelet ratio, a useful indicator of liver fibrosis in chronic hepatitis patients.
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Hepatol Int. 2015; 9:454-460.
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[57] Yang W, Huang H, Wang Y, Yu X, Yang Z. High red blood cell distribution width is closely associated with nonalcoholic fatty liver disease. Eur J
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Gastroenterol Hepatol. 2014; 26:174-178.
ACCEPTED MANUSCRIPT Fig. legends
Fig. 1 Fowchart of the literature selection process.
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Supplementary Fig. 1 Mean differences in red blood cell distribution width (RDW)
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values between chronic hepatitis B (CHB) patients and health controls.
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Supplementary Fig. 2 Mean differences in red blood cell distribution width (RDW) values between hepatitis B virus (HBV)-related acute on chronic liver failure (ACLF)
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patients and chronic hepatitis B (CHB) patients.
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Supplementary Fig. 3 Mean differences in red blood cell distribution width (RDW) values between hepatitis B virus (HBV)-related cirrhosis patients and chronic
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hepatitis B (CHB) patients.
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Supplementary Fig. 4 Mean differences in red blood cell distribution width (RDW) values between hepatitis B virus (HBV)-related acute on chronic liver failure (ACLF)
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patients and HBV-related cirrhosis patients.
ACCEPTED MANUSCRIPT Table 1 Characteristics of included studies on association between RDW levels and hepatitis B virus-related liver diseases. Autho
Y
Co
Investi
Ag
%
No.
Diagno
Control
r
ea
untr
gation
e
M
of
stic
Me
S
r
y
s year
(y
al
partic
criteria
an
D
ear
e
ipant
Pathol
0.1
0.
2
0.1
0.0
1
0.1
0.0
ogic
36
01
8
63
35
1
76
36
0
5
Lan
2
Chi
2015-
F[11]
0
na
2016
47
N
Me
Cirrhosis SD
an
73
725
3
J[35]
0
na
2017
32
60
250
1
Versio
12.
0.
5
15.
n
03
57
0
52
2015*
0
0
NA
NA
N
N
15.
2.9
1
17.
3.4
A
A
12
00
5
29
00
2
0
Hao
2
Chi
2014-
S[36]
0
na
2015
52
60
329
NU
7
1
2
Chi
2010-
N
J[32]
0
na
2011
A
65
303
Versio
1
2
Chi
2014-
46.
76
H[33]
0
na
2015
5
.5
Chi
2012-
L[34]
0
na
2014
1
H[30]
0 1 5
32
Chi
2012-
na
2013
Gong
2
Chi
J[31]
0
na
2014
60
190
.5
AC C
6
227
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1
2
51
S
N
an
D
1
N
N
N
3
A
A
A
66
N
87
A
.8
436
127
1
13.
0.
7
17.
0
36
3
2.4
3
18.
2.
3
10
0
61
35
0
0
0
1
N
N
N
7
A
A
A
0
7
1
13.
0.7
1
N
N
N
N
N
N
4
22
90
6
A
A
A
A
A
A
2010*
0
0
0
0
Versio
12.
0.
1
13.
1.6
6
14.
2.0
3
N
N
N
n 2010
95
83
2
47
20
9
49
50
5
A
A
A
*
0
0
3
0
Versio
16.
0.
3
16.
0.1
6
16.
0.2
2
16.
0.
2
n
32
68
0
68
20
0
71
50
0
73
32
0
2010*
0
0
0
0
Versio
12.
0.
2
15.
2.8
1
17.
3.0
2
N
N
N
n
95
78
1
12
90
5
13
70
2
A
A
A
2010*
0
0
2
0
2
0
Versio
0.1
0.
4
0.1
0.0
4
N
N
N
0.1
0.
4
n
21
00
5
40
15
2
A
A
A
62
02
0
ED
Lv
Wang
Me
75
6
6
N
06
n
MA
Yan
2
90
0
7
Lv
0
2.7
RI
2015-
SC
Chi
SD
an
7 2
Me
ACLF
s
1
Chen
N
PT
s)
CHB
2005*
3
0
0
0
4
5
5
5 Karag
2
Tur
2010-
oz[14]
0
key
2013
27
91
229
Pathol
NA
ogic
N
N
11.
0.8
1
12.
1.3
4
N
N
N
A
A
83
90
8
57
20
1
A
A
A
8
0
6
16.
2.4
6
N
N
N
1
0
4 Huang
2
Chi
2011-
50
66
171
Versio
12.
0.
4
13.
1.0
ACCEPTED MANUSCRIPT R[15]
0
na
2013
1
n
75
70
1
29
90
9
2005*
0
0
10
1
A
A
A
Pathol
0.1
0.
5
0.1
0.0
5
0.5
3.2
7
N
N
N
ogic
27
00
9
58
33
7
53
80
4
A
A
A
0
07 0
4 Liu
2
Chi
2010-
S[29]
0
na
2011
45
54
190
1
6
4 2
Chi
2009-
L[28]
0
na
2012
40
66
139
1
Versio
13.
1.
5
14.
1.4
4
N
N
N
N
N
N
n
69
25
0
23
70
0
A
A
A
A
A
A
2000*
0
0
Versio
12.
1.
6
13.
n
20
10
6
40
2005*
0
0
Versio
13.
1.
4
16.
2.4
6
N
N
n
03
33
8
37
30
1
A
A
2000*
6
NA
12.
0
2
Chi
2010-
Z[16]
0
na
2011
43
54
364
1
Lou
2
Chi
2010-
Y[17]
0
na
2011
44
75
123
1 2 2
Chi
J[27]
0
na
2011
N
64
A
.4
250
2008-
R[26]
0
na
2010
43
73
Yang
2
Chi
L[25]
0
na
NA
X[23]
0 0 9
AC C
0 2
N
Chi
59
391
NA
na
N
55
A
.4
Chen
2
Chi
2007-
N
M[24]
0
na
2008
A
64
278
516
0
N
N
N
00
2
A
A
A
N
18.
3.
4
A
30
11
6
6
0
3
30 0
5
6
1
15.
1.2
4
17.
2.0
2
N
N
N
00
3
20
00
4
A
A
A
20
0
0
0
0
13.
1.
5
14.
1.5
3
17.
2.9
8
16.
1.
1
n 2000
87
22
0
03
90
1
53
90
9
73
91
8
*
0
0
0
0
NA
12.
0.
1
15.
1.3
6
17.
2.4
3
N
N
N
80
60
5
70
00
1
40
00
9
A
A
A
0
0
0
0
Versio
14.
7.
3
15.
7.3
5
28.
8.2
2
21.
8.
3
n 2005
83
45
0
14
40
9
63
10
8
79
04
7
*
0
0
0
0
Versio
12.
0.
2
15.
1.8
6
N
N
N
N
N
N
n
50
62
5
65
50
5
A
A
A
A
A
A
2000*
0
0
8
0
Versio
13.
3.
1
14.
2.5
3
16.
5
3
18
3.
5
n 2000
00
00
0
00
00
0
60
00
0
*
0
0
0
0
Versio
12.
0.
1
15.
Versio
A
1
Yang
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1 1
282
1
0
ED
Chi
3.4
50
2 2
0.
16.
00
3
50
1
Yang
0
MA
Wu
NU
3
0
2.3
SC
Hu
RI
3
PT
Zhang
0
0
0
0
0
0
9 Wang
2
Chi
2002-
T[22]
0
na
2006
35
10
300
0
0
0
0
0
8 Xie
2
Chi
2004
N
55
340
1.2
4
17.
2.6
2
N
N
N
ACCEPTED MANUSCRIPT R[21]
0
na
A
0
n
40
50
5
40
00
7
2000*
0
0
6
0
Versio
13.
1.
1
14.
1.7
6
n
20
20
0
20
00
2000*
0
0
0
0
NA
12.
1.
3
16.
90
40
0
00
0
0
13.
1.
8
15.
20
40
6
80
0
0
40
00
7
A
A
A
N
N
N
N
N
N
5
A
A
A
A
A
A
1.8
3
19.
2.1
2
N
N
N
00
0
50
00
8
A
A
A
0
6 Fang
2
Chi
2004-
Y[20]
0
na
2005
41
62
230
.6
0 5 2
Chi
1998-
L[19]
0
na
2000
38
71
192
0
0
0
Wu
1
Chi
S[18]
9
na
1997
42.
N
6
A
306
NA
0
1.6
2.1
6
22.
1.
1
00
2
20
90
5
0
0
00
6 9
70 0
SC
9
19.
RI
0
PT
Tan
7
RDW, red blood cell distribution width; CHB, chronic hepatitis B; ACLF, acute on chronic liver failure; *Di fferent versions of guidelines
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of prevention and treatment for chroni c hepatitis B established by the Chinese Medical Association[49-52], which had no effect on the disease diagnosis including CHB, cirrhosis and ACLF in spite of some minor modifications. Hematology analyzers used in included studies, Sysmex XS-1000i[35], Sysmex XS-2100[17,30,32,34,36], Sysmex XN-1000[33], Sysmex XE-5000[29,31], Sysmex SF-3000[22],
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Sysmex XS-800i[27,28], Sysmex K-1000[19,26], Sysmex NE-1500[18], AC-920EO+[25], Abbott Cell-Dyn Sapphire[14], Abbott Cell-Dyn1700[24], Beckman Coulter MD-II[21], Beckman Coulter LH750[11,20,23]. Two studies[15,16] didn ’ t provided the
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information of hematology analyzer.
ACCEPTED MANUSCRIPT Table 2 Regression analysis for the association of RDW levels in HBV-related liver diseases (CHB and cirrhosis).
Concomitant variable
Regression coefficient
T-value
P-value
95%CI
Association of RDW levels with CHB Single logistic regression model 0.400
0.610
NS
-0.886--1.694
Diagnostic criteria
-0.210
-1.530
NS
-0.490-0.061
Number of control
0.005
1.700
NS
-0.001-0.012
Case load
-0.005
-0.740
NS
-0.196--0.008
Publication language
0.360
0.630
NS
-0.754--1.476
Diagnostic criteria
-0.160
-1.250
NS
-0.412-0.092
Number of control
0.009
2.690
0.007
0.002-0.016
Case load
-0.015
-2.010
0.045
-0.030-0.000
0.320
NS
-0.517-0.719
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Publication language
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Publication language
0.100
Diagnostic criteria
-0.182
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Comparison of RDW levels between cirrhosis and CHB
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Multiple logistic regression models
-3.500
0.000
-0.284--0.080
Number of control
-0.003
-1.280
NS
-0.008-0.001
Case load
-0.002
-1.030
NS
-0.006-0.002
0.036
0.130
NS
-0.500-0.572
-0.019
-2.780
0.005
-0.330--0.057
0.000
0.270
NS
-0.005-0.007
0.000
0.000
NS
-0.004-0.004
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Single logistic regression model
Publication language Number of control Case load
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Diagnostic criteria
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Multiple logistic regression models
RDW, red blood cell distribution width; CHB, chronic hepatitis B; HBV, hepatitis B virus; SM D, Standardized
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mean difference.
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ACCEPTED MANUSCRIPT
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Fig. 1
ACCEPTED MANUSCRIPT Highlights Red blood cell distribution width (RDW) has been indicated to be an inflammatory indicator The significance of RDW in hepatitis B virus (HBV)-related liver diseases was assessed RDW was elevated in HBV-related liver diseases and correlated with the disease severity
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RDW appears to have no distinguishing quality between acute on chronic liver failure and
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cirrhosis
Xiude Fan, Huan Deng, Xiqiang Wang, Siqi Fu, Zitong Liu, Jiao Sang, Xiaoge Zhang, Na Li, Qunying Han, Zhengwen Liu PII: DOI: Reference:
S0009-8981(18)30160-8 doi:10.1016/j.cca.2018.04.002 CCA 15136
To appear in:
Clinica Chimica Acta
Received date: Revised date: Accepted date:
17 January 2018 31 March 2018 2 April 2018
Please cite this article as: Xiude Fan, Huan Deng, Xiqiang Wang, Siqi Fu, Zitong Liu, Jiao Sang, Xiaoge Zhang, Na Li, Qunying Han, Zhengwen Liu , Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Cca(2017), doi:10.1016/j.cca.2018.04.002
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ACCEPTED MANUSCRIPT Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases
Xiude Fan a , Huan Deng a , Xiqiang Wang b, Siqi Fu a,c, Zitong Liu
a,c
, Jiao Sang a ,
a
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Xiaoge Zhang a , Na Li a , Qunying Han a , Zhengwen Liu a,*
Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong
Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University,
Xi’an , Shaanxi, People’s Republic of China
Xi’an Medical University, Xi’an, 710021, Shaanxi, People’s Republic of China
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c
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b
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University, Xi’an, 710061, Shaanxi, People’s Republic of China
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* Correspondence to: Zhengwen Liu, M.D., Ph.D. Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West
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Road, Xi’an, 710061, Shaanxi Province, the People’s Republic of China. E-mail:
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[email protected]
Funding information: National Natural Science Foundation of China (Grant no.
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81371798).
ACCEPTED MANUSCRIPT Abstract
Background Red blood cell distribution width (RDW) has been indicated to be an inflammatory indicator in a variety of diseases. However, no consistent conclusions regarding it’s
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relevance to hepatitis B virus (HBV) -related liver diseases have been made. This meta-analysis was conducted to assess the significance of RDW in HBV-related liver
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diseases.
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Methods
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A comprehensive literature review was conducted using PubMed, Embase, and China National Knowledge Infrastructure (CNKI) through August 20, 2017 to identify
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studies that reported the association between RDW and HBV-related liver diseases. The standard mean difference (SMD) and corresponding 95% confidence interval (CI)
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were used to assess the associations. Results
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Twenty-four studies met the eligibility criteria were included in the meta-analysis. These studies included 3272 HBV-infected patients and 2209 healthy controls.
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Chronic hepatitis B (CHB) patients had significantly increased RDW levels compared with healthy controls (SMD =1.399, 95% CI 0.971-1.827, p < 0.001]. Moreover, acute on chronic liver failure (ACLF) patients (SMD = 1.309, 95% CI 0.775-1.843, p < 0.001) and cirrhotic patients (SMD = 0.948, 95% CI 0.715-1.180, p < 0.001) had significantly elevated RDW levels compared with CHB patients. However, no statistical significance was obtained in RDW levels between cirrhosis and ACLF (SMD = 0.167, 95% CI -0.382 -0.716, p = 0.051). Conclusion RDW values were elevated in HBV-related liver diseases and correlated with the disease severity, suggesting that RDW levels may differantiate CHB from healthy
ACCEPTED MANUSCRIPT controls and ACLF and cirrhosis from CHB but they appear to have no distinguishing characteristic between ACLF and cirrhosis.
Keywords: red blood cell distribution width (RDW); hepatitis B virus; liver diseases;
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meta-analysis.
ACCEPTED MANUSCRIPT
1. Introduction
Chronic hepatitis B virus (HBV) infection, a leading cause of chronic liver disease, affects approximately 240 million people worldwide [1,2]. About 25 percent
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of chronic hepatitis B (CHB) patients may progress to primary liver cancer or
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cirrhosis and eventually to liver failure [1]. Early cirrhosis is reversible, but a large
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number of CHB patients progress into decompensated cirrhosis with various
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complications which are major causes of mortality in most region worldwide [3]. Therefore, monitoring and assessing the disease severity and progression of chronic
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HBV infection is important in clinical practice.
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Red blood cell distribution width (RDW, or RCDW) is an automated measure of the range of transformation of red blood cell (RBC) volume, which is recorded as part
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of a standard complete blood cell count. It is mainly used to identify the cause of anemias [4]. Recently, a series of studies have proved that RDW can serve as an
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independent predictor of prognosis or an inflammatory indicator in a variety of diseases such as lung cancer [5], pulmonary hypertension [6], peripheral artery disease [7,8], acute myocardial infarction [9] and acute infections [10]. In terms of liver disease, elevated RDW has been reported to be associated with different disease states in HBV-infected patients [11-16]. RDW levels increase with progressive liver inflammation and fibrosis. This routine laboratory parameter is expected to become a new simple marker for inflammation and fibrosis in patients with chronic HBV infection.
ACCEPTED MANUSCRIPT However, there are inconsistent conclusions regarding the relevance of RDW to HBV-related liver diseases. Therefore, this meta-analysis was conducted based on the existing published works to evaluate the significance of RDW levels in HBV- related
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liver diseases.
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2. Materials and methods
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2.1. Literature search
Two independently investigators (X.F. and X.W.) searched literatures describing
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the association between RDW value and different stages of chronic HBV infection,
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including CHB, acute on chronic liver failure (ACLF) or chronic severe hepatitis B (CSHB) and HBV-related cirrhosis (LC). The term "ACLF" is equivalent to the term
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"CSHB" in China and represents the fatal form of chronic hepatitis [17]. Study data
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were retrieved by searching of PubMed, Embase, and China National Knowledge Infrastructure (CNKI). In addition, recent review articles were checked for additional relevant studies. To identify observational studies, the following combinations of
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search terms were used: (“RDW” or “red blood cell distribution width” or "blood routine examination" ) and (“chronic viral hepatitis B” or “chronic hepatitis B” or “CHB” or “chronic severe hepatitis B” or “CSHB” or “acute on chronic liver failure” or “ACLF” or “liver fibrosis” or “liver cirrhosis” or “LC”). We restricted this search to observational studies involving humans that were published in English and Chinese language until August 20, 2017.
ACCEPTED MANUSCRIPT 2.2. Inclusion and exclusion criteria Any study that met all of the following criteria were included: case–control or cross-sectional studies; studies evaluating the association of RDW value with HBV-related liver diseases (CHB, ACLF or CSHB and hepatitis B related cirrhosis);
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studies with provision of the number of cases and controls and the means and standard
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deviations of RDW value. In addition, studies published in Chinese language must be
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on the Chinese Core Journals selection database.
Studies that met the following criteria were excluded: (1) review, letter, and
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meeting abstract; (2) duplicate publications; (3) unavailability of the original data; (4)
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studies with less than 30 HBV chronically infected patients.
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2.3. Data collection and quality assessment
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Two investigators (X.F. and X.W.) independently extracted the original data from all eligible papers. Disagreements between the two investigators were settled by consultation with the corresponding author (Z.L). If multiple updates of the same data
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were found, the most recent version was used for analysis. The data extracted included first author's name, year of report, location, age of participants, sex, number of cases and controls, RDW values, and diagnostic criteria.
2.4. Statistical analysis STATA 13 (Stata Corp.) was used to perform the meta-analysis in the present study. The standard mean difference (SMD) and corresponding 95% CI was utilized
ACCEPTED MANUSCRIPT to assess the associations. SMDs were pooled using a random-effects model to minimize the potential heterogeneity among studies. Heterogeneity among studies was mainly assessed using I2 statistic and Cochrane's Q statistic. An I2 value of >50% is suggestive of significant heterogeneity. For the Q statistic, P < 0.10 was considered
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statistically significant for heterogeneity. Due to the high heterogeneity existed in the
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studies of association of RDW level with CHB and the studies of comparison of
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HBV-related cirrhosis with CHB in RDW levels, meta-regressions were conducted to examine the impact of moderator variables, such as publication language, diagnostic
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criteria, case load and the number of control group. Sensitivity analysis was also
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performed by excluding each study at a time to evaluate whether one or more studies influenced the overall results. Publication bias was investigated using the Bgger's test
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and the Egger’s test. P < 0.05 was considered significant. These 2 tests were not
3. Results
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conducted when the included studies were <10.
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3.1. Literature search and study characteristics A total of 1215 studies were identified after an initial search from the PubMed, Embase and CNKI. After duplicates removal and further screening, 24 eligible studies [11,14-36] were selected for meta-analysis. Of the 24 eligible studies, 19 were published in Chinese and 5 in English language. There are 5481 subjects, including 2209 control subjects and 3272 HBV-infected patients (1769 cases of CHB, 256 cases of ACLF, and 1247 cases of cirrhosis). The mean age of the participants ranged from
ACCEPTED MANUSCRIPT 32 to 52 years and the percentage of male patients ranged from 54% to 100%. The data of mean age were missing in 7 of these studies [21,23-25,27,31,32]. The analyzed population was Chinese in almost all studies [11,15-36] except one study which analyzed population of Turks [14]. The flow chart of the search process is
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summarised in Fig. 1. The detailed characteristics of the eligible studies are presented
3.2. Association of RDW levels with CHB
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in Table 1.
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There are 22 studies [11,15-35] reporting the association of RDW level with
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CHB. Data from these studies were analyzed in a random-effects model to compare the RDW levels between CHB patients and healthy controls (Table 1). CHB patients
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had significantly higher levels of serum RDW than controls (SMD = 1.399; 95% CI 0.971-1.827, p < 0.001, Supplementary Fig. 1). Significant heterogeneity was found
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among these studies (I2 = 96.6%, p < 0.001). A meta-regression was performed to explore potential sources of heterogeneity. The publication language, diagnostic
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criteria, case load and the number of controls, which might be potential sources of heterogeneity, were all tested by the meta regression method. In meta regression analyses, publication language, diagnostic criteria and case load had no moderating effects, except for the number of controls (p = 0.007; Table 2). Sensitivity analyses showed that the corresponding pooled RDW levels in CHB varied from 1.270 (0.874-1.666) with exclusion of Xie et al [21] to 1.460 (1.022-1.898) with exclusion of Yang et al [26] (Supplementary Table 1), and no single study significantly changed
ACCEPTED MANUSCRIPT the results. Each single study did not statistically change the pooled RDW levels estimate, indicating the reliability of the results. According to the Begg’s funnel plots and Egger’s test, no evidence of publication bias was found (p = 0.864 and p = 0.096,
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3.3. Comparison of RDW levels between ACLF and CHB
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respectively).
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Eight studies [17,18,22,23,26,31,34,35] were selected with a pooled sample size of 678 subjects including 256 ACLF patients and 422 CHB patients (Table 1).
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Random-effects meta-analysis demonstrated that patients with ACLF had
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significantly higher RDW levels than CHB patients (SMD = 1.309; 95% CI 0.775-1.843, p < 0.001, Supplementary Fig. 2) with significant heterogeneity among
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these studies (I2 = 88.9%, p < 0.001). Sensitivity analyses showed that the
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corresponding pooled RDW level in ACLF varied from 0.985 (0.685-1.284) with exclusion of Wu et al [18] to 1.458 (0.900-2.016) with exclusion of Wang et al [34] (Supplementary Table 2). Due to the limited number of studies, we did not perform
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analysis to evaluate publication bias.
3.4. Comparison of RDW levels between HBV-related cirrhosis and CHB There are 18 studies [11,14-16,18,19,21,23-27,29,30,33-36] reporting the association of RDW level with HBV-related cirrhosis relative to CHB. I2 test indicated that the heterogeneity is significant (p < 0.001, I2 = 85.40%). Therefore, the random-effects model was applied to perform meta-analysis. The results showed that
ACCEPTED MANUSCRIPT RDW level in cirrhosis was higher than that in CHB (SMD = 0.948; 95% CI 0.715-1.180, p < 0.001; Supplementary Fig. 3). Meta-regression analyses revealed that diagnostic criteria had moderating effects on the outcomes of the meta-analysis (p = 0.005; Table 2). Sensitivity analyses showed that no single study significantly
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changed the results (Supplementary Table 3). The results of Begg’s (p = 0.031) and
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Egger’s (p = 0.724) test in the present meta-analysis indicated the possibility of
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publication bias. Because of this, a sensitivity analysis using the trim and fill method was performed. The pooled analysis merging the eligible studies continued to show
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that RDW level in cirrhosis was higher than that in CHB (SMD = 1.873; 95% CI
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1.436-2.444, p < 0.001).
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3.5. Comparison of RDW levels between HBV-related cirrhosis and ACLF
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Meta-analysis on 6 studies [18,22,23,26,34,35] by combining studies investigating RDW levels in cirrhosis and ACLF was also performed. Random-effects meta-analysis demonstrated that no statistical significance was obtained between
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cirrhosis and ACLF in RDW levels (SMD = 0.167, 95% CI -0.382-0.716, p = 0.051, Supplementary Fig. 4). Given the limited number of studies, neither subgroup analyses nor publication bias were performed.
4. Discussion In the analysis of 24 controlled observational studies, CHB patients had higher RDW levels than normal controls. Furthermore, the RDW levels were significantly
ACCEPTED MANUSCRIPT elevated in ACLF patients and cirrhosis patients compared with CHB patient. However, no significant difference in RDW levels between ACLF patients and cirrhosis patients was observed. RDW, a parameter routinely reported as part of the complete blood count in
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laboratories, is a measure of the range of variation of red blood cell volume and
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reflects the variability in circulating RBC size. RDW test results are mainly used to
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determine the possible causes of the anemia [37]. Normally, RBCs are a moderate size of about 6-8 μm in diameter. Higher values indicate greater variability in RBC
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size. Significant variation of RDW may be caused by a variety of abnormalities
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[4,38-42], including inflammation, oxidative stress, erythrocyte fragmentation, poor nutritional status, and abnormality of erythropoietin function. These disorders and
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anemia are common in patients with chronic liver disease and correlate with the
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severity of the liver disease. Thus, elevated RDW values may associate with the severity of the liver disease. However, the exact mechanisms underlying the association between RDW values and the severity of HBV-related liver diseases are
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largely unclear. It was reported that inflammation might contribute to elevated RDW values by not only impairing erythrocyte maturation but also causing immature erythrocytes to enter the blood flow [43]. It is plausible that inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 might inhibit iron metabolism and the production of erythropoietin, resulting in synthesis disorders or abnormal activity of erythropoietin [44,45]. Oxidative stress is common in liver disease with the characteristic of impairment of balance between oxidants and
ACCEPTED MANUSCRIPT antioxidant defenses. Moreover, oxidative stress has a profound influence on erythrocyte homeostasis and survival, and low serum antioxidant concentrations have been shown to be related to increased RDW levels [46,47]. Therefore, oxidative stress may be another mechanism that leads to increased RDW levels in liver disease.
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Additionally, poor nutritional status such as iron deficiency, vitamin B12 or folate
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deficiency during liver disease can also lead to ineffective RBC production, leading to
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elevated RDW levels [48].
In the comparison of RDW levels between CHB and controls, the number of
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controls ranged from 30 to 285 and the small sample size of studies may contribute to
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the heterogeneity. Subsequent meta-regression analysis showed that the number of control might be one of the potential sources of heterogeneity. In the majority of
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included studies, CHB, ACLF and cirrhosis patients were diagnosed according to
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different versions of guidelines of prevention and treatment for chronic hepatitis B established by the Chinese Medical Association [49-52], and there are also several studies which did not provide a clear diagnostic criteria. The diagnostic guidelines
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released by the Chinese Medical Association had a chronological order and minor difference in clinical diagnostic details. Although these minor difference in clinical diagnostic details have no effect on the diagnosis of the patients, meta-regression analysis showed that different diagnostic criteria might be one of the potential sources of heterogeneity in the comparison of RDW levels between cirrhosis and CHB. It should also be noted that two studies included in the analyses were reported by the same first author [30,33] but they were conducted in different patient populations
ACCEPTED MANUSCRIPT [30,33]. Sensitivity analysis was performed to evaluate the impact of each single study on the results of the meta-analysis. The results showed that no individual study could significantly change the pooled SMD, suggesting that the results of this meta-analysis are stable.
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The present study has some limitations. First, CHB, ACLF and cirrhosis were
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diagnosed according to different guidelines in the included studies, which might be
SC
one of the potential sources of heterogeneity. Second, the number of cases and controls in certain studies was relatively small, even with the exclusion of studies with
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less than 30 CHB patients. Third, in almost all studies the analyzed population was
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Chinese and only one study was Turk. Fourth, the present study only included studies that evaluated the association of RDW value with HBV-related liver diseases.
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Recently, a series of studies regarding hepatitis C virus (HCV)-related liver diseases
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[53], nonalcohol fatty liver disease (NAFLD) [54] or primary biliary cirrhosis (PBC) [55] have been published. One study performed a diagnostic tests in 152 patients with native liver and 70 patients with transplanted liver, and found that RDW values had a
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strong correlation with the degree of fibrosis but not the degree of inflammation in native liver [56]. RDW values and RDW/platelet ratio (RPR) were revealed to be a predictor of the degree of fibrosis in patients with chronic hepatitis C [53]. In a following study, RDW levels in 619 NAFLD patients and 1637 healthy persons were investigated and suggested that RDW values was significantly increased in NAFLD patients [57]. These findings were consistent with the results of our meta-analysis irrespective of difference in the etiologies of liver disease. However, the study in PBC
ACCEPTED MANUSCRIPT detected no significant difference in terms of RDW and RPR levels between PBC histological stages [55]. Thus, more studies with larger sample sizes in various ethnic populations are needed to define the association between RDW values and liver
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diseases of different etiologies.
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5. Conclusion
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We demonstrated that RDW values were elevated and associated with the severity of liver disease in patients with chronic HBV infection. However, the results
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should be interpreted with caution, due to the significant clinical and statistical
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heterogeneity among included studies. In addition, RDW levels appear to have no distinguishing quality between ACLF and cirrhosis associated with HBV infection.
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Therefore, clinical data including other laboratory parameters and auxiliary
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examinations are needed to achieve a definite evaluation, especially in the
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circumstance between ACLF and cirrhosis.
Acknowledgement
The study was supported by National Natural Science Foundation of China.
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Gastroenterol Hepatol. 2014; 26:174-178.
ACCEPTED MANUSCRIPT Fig. legends
Fig. 1 Fowchart of the literature selection process.
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Supplementary Fig. 1 Mean differences in red blood cell distribution width (RDW)
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values between chronic hepatitis B (CHB) patients and health controls.
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Supplementary Fig. 2 Mean differences in red blood cell distribution width (RDW) values between hepatitis B virus (HBV)-related acute on chronic liver failure (ACLF)
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patients and chronic hepatitis B (CHB) patients.
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Supplementary Fig. 3 Mean differences in red blood cell distribution width (RDW) values between hepatitis B virus (HBV)-related cirrhosis patients and chronic
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hepatitis B (CHB) patients.
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Supplementary Fig. 4 Mean differences in red blood cell distribution width (RDW) values between hepatitis B virus (HBV)-related acute on chronic liver failure (ACLF)
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patients and HBV-related cirrhosis patients.
ACCEPTED MANUSCRIPT Table 1 Characteristics of included studies on association between RDW levels and hepatitis B virus-related liver diseases. Autho
Y
Co
Investi
Ag
%
No.
Diagno
Control
r
ea
untr
gation
e
M
of
stic
Me
S
r
y
s year
(y
al
partic
criteria
an
D
ear
e
ipant
Pathol
0.1
0.
2
0.1
0.0
1
0.1
0.0
ogic
36
01
8
63
35
1
76
36
0
5
Lan
2
Chi
2015-
F[11]
0
na
2016
47
N
Me
Cirrhosis SD
an
73
725
3
J[35]
0
na
2017
32
60
250
1
Versio
12.
0.
5
15.
n
03
57
0
52
2015*
0
0
NA
NA
N
N
15.
2.9
1
17.
3.4
A
A
12
00
5
29
00
2
0
Hao
2
Chi
2014-
S[36]
0
na
2015
52
60
329
NU
7
1
2
Chi
2010-
N
J[32]
0
na
2011
A
65
303
Versio
1
2
Chi
2014-
46.
76
H[33]
0
na
2015
5
.5
Chi
2012-
L[34]
0
na
2014
1
H[30]
0 1 5
32
Chi
2012-
na
2013
Gong
2
Chi
J[31]
0
na
2014
60
190
.5
AC C
6
227
EP T
1
2
51
S
N
an
D
1
N
N
N
3
A
A
A
66
N
87
A
.8
436
127
1
13.
0.
7
17.
0
36
3
2.4
3
18.
2.
3
10
0
61
35
0
0
0
1
N
N
N
7
A
A
A
0
7
1
13.
0.7
1
N
N
N
N
N
N
4
22
90
6
A
A
A
A
A
A
2010*
0
0
0
0
Versio
12.
0.
1
13.
1.6
6
14.
2.0
3
N
N
N
n 2010
95
83
2
47
20
9
49
50
5
A
A
A
*
0
0
3
0
Versio
16.
0.
3
16.
0.1
6
16.
0.2
2
16.
0.
2
n
32
68
0
68
20
0
71
50
0
73
32
0
2010*
0
0
0
0
Versio
12.
0.
2
15.
2.8
1
17.
3.0
2
N
N
N
n
95
78
1
12
90
5
13
70
2
A
A
A
2010*
0
0
2
0
2
0
Versio
0.1
0.
4
0.1
0.0
4
N
N
N
0.1
0.
4
n
21
00
5
40
15
2
A
A
A
62
02
0
ED
Lv
Wang
Me
75
6
6
N
06
n
MA
Yan
2
90
0
7
Lv
0
2.7
RI
2015-
SC
Chi
SD
an
7 2
Me
ACLF
s
1
Chen
N
PT
s)
CHB
2005*
3
0
0
0
4
5
5
5 Karag
2
Tur
2010-
oz[14]
0
key
2013
27
91
229
Pathol
NA
ogic
N
N
11.
0.8
1
12.
1.3
4
N
N
N
A
A
83
90
8
57
20
1
A
A
A
8
0
6
16.
2.4
6
N
N
N
1
0
4 Huang
2
Chi
2011-
50
66
171
Versio
12.
0.
4
13.
1.0
ACCEPTED MANUSCRIPT R[15]
0
na
2013
1
n
75
70
1
29
90
9
2005*
0
0
10
1
A
A
A
Pathol
0.1
0.
5
0.1
0.0
5
0.5
3.2
7
N
N
N
ogic
27
00
9
58
33
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2011
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ACCEPTED MANUSCRIPT R[21]
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5
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PT
Tan
7
RDW, red blood cell distribution width; CHB, chronic hepatitis B; ACLF, acute on chronic liver failure; *Di fferent versions of guidelines
NU
of prevention and treatment for chroni c hepatitis B established by the Chinese Medical Association[49-52], which had no effect on the disease diagnosis including CHB, cirrhosis and ACLF in spite of some minor modifications. Hematology analyzers used in included studies, Sysmex XS-1000i[35], Sysmex XS-2100[17,30,32,34,36], Sysmex XN-1000[33], Sysmex XE-5000[29,31], Sysmex SF-3000[22],
MA
Sysmex XS-800i[27,28], Sysmex K-1000[19,26], Sysmex NE-1500[18], AC-920EO+[25], Abbott Cell-Dyn Sapphire[14], Abbott Cell-Dyn1700[24], Beckman Coulter MD-II[21], Beckman Coulter LH750[11,20,23]. Two studies[15,16] didn ’ t provided the
AC C
EP T
ED
information of hematology analyzer.
ACCEPTED MANUSCRIPT Table 2 Regression analysis for the association of RDW levels in HBV-related liver diseases (CHB and cirrhosis).
Concomitant variable
Regression coefficient
T-value
P-value
95%CI
Association of RDW levels with CHB Single logistic regression model 0.400
0.610
NS
-0.886--1.694
Diagnostic criteria
-0.210
-1.530
NS
-0.490-0.061
Number of control
0.005
1.700
NS
-0.001-0.012
Case load
-0.005
-0.740
NS
-0.196--0.008
Publication language
0.360
0.630
NS
-0.754--1.476
Diagnostic criteria
-0.160
-1.250
NS
-0.412-0.092
Number of control
0.009
2.690
0.007
0.002-0.016
Case load
-0.015
-2.010
0.045
-0.030-0.000
0.320
NS
-0.517-0.719
PT
Publication language
SC
Publication language
0.100
Diagnostic criteria
-0.182
NU
Comparison of RDW levels between cirrhosis and CHB
RI
Multiple logistic regression models
-3.500
0.000
-0.284--0.080
Number of control
-0.003
-1.280
NS
-0.008-0.001
Case load
-0.002
-1.030
NS
-0.006-0.002
0.036
0.130
NS
-0.500-0.572
-0.019
-2.780
0.005
-0.330--0.057
0.000
0.270
NS
-0.005-0.007
0.000
0.000
NS
-0.004-0.004
MA
Single logistic regression model
Publication language Number of control Case load
EP T
Diagnostic criteria
ED
Multiple logistic regression models
RDW, red blood cell distribution width; CHB, chronic hepatitis B; HBV, hepatitis B virus; SM D, Standardized
AC C
mean difference.
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
AC C
EP T
ED
Fig. 1
ACCEPTED MANUSCRIPT Highlights Red blood cell distribution width (RDW) has been indicated to be an inflammatory indicator The significance of RDW in hepatitis B virus (HBV)-related liver diseases was assessed RDW was elevated in HBV-related liver diseases and correlated with the disease severity
PT
RDW appears to have no distinguishing quality between acute on chronic liver failure and
AC C
EP T
ED
MA
NU
SC
RI
cirrhosis