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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 14  |  Issue : 2  |  Page : 67-75

Serum hyaluronic acid as a noninvasive marker of hepatic fibrosis in chronic hepatitis c patients


1 Department of Tropical Medicine, Al-Azhar University for Girls, Cairo, Egypt
2 Department of Clinical Pathology, Al-Azhar University for Girls, Cairo, Egypt

Date of Submission17-Feb-2016
Date of Acceptance19-Apr-2016
Date of Web Publication21-Oct-2016

Correspondence Address:
Eman E Ahmed Ibrahem
Department of Tropical Medicine, AL-Azhar University for Girls, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-1693.192654

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  Abstract 

Background
Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis.
Aim of the work
The aim of this study was to evaluate the serum level of HA as a noninvasive marker of hepatic fibrosis in comparison with liver biopsy and indirect serum fibrosis markers such as AST/ALT ratio and aspartate transaminase to platelet ratio index (APRI) in chronic HCV patients.
Patients and methods
Our patients were classified into three groups: group 1 included 20 patients with mild hepatic fibrosis (F1 stage); group 2 included 20 patients with moderate hepatic fibrosis (F2 stage); and group 3 included 20 patients with marked hepatic fibrosis and cirrhosis (F3 and F4 stages). The control group included 20 normal volunteers. Serum HA level evaluation, liver function tests, and complete blood count were carried out for all groups, whereas liver biopsy was performed only for patients to determine the stage of liver fibrosis.
Results
There was a highly significant increase in serum HA level in group 2 and group 3 in comparison with the control group and a significant increase in group 1 in comparison with the control group. However, there was highly significant increase in group 3 in comparison with group 1 and group 2 and a significant increase in group 2 in comparison with group 1. The cutoff point for HA level was greater than 42.18 ng/l to discriminate between the patient and the control group, with a sensitivity of 91.7% and a specificity of 95.0% for HA. The cutoff point for HA level was greater than 81.68 ng/l to discriminate between group 1 (mild fibrosis) and group 2 (moderate fibrosis), with a sensitivity of 100% and a specificity of 70%. The cutoff point for HA level to discriminate between group 2 (moderate fibrosis) and group 3 (severe fibrosis and cirrhosis) was greater than 167.98 ng/l, with a sensitivity of 90% and specificity of 80%. There was a significant positive correlation between serum HA level and APRI.
Conclusion
HA is a promising reliable simple noninvasive marker for assessing liver fibrosis in HCV-infected patients with high sensitivity and specificity. There was a positive correlation between serum HA level with stages of hepatic fibrosis and APRI.

Keywords: hepatic fibrosis, hyaluronic acid, liver biopsy


How to cite this article:
Abd-Elghany SM, Ahmed Ibrahem EE, El-Sayed SZ, Mohammed S, Morsy AA. Serum hyaluronic acid as a noninvasive marker of hepatic fibrosis in chronic hepatitis c patients. Al-Azhar Assiut Med J 2016;14:67-75

How to cite this URL:
Abd-Elghany SM, Ahmed Ibrahem EE, El-Sayed SZ, Mohammed S, Morsy AA. Serum hyaluronic acid as a noninvasive marker of hepatic fibrosis in chronic hepatitis c patients. Al-Azhar Assiut Med J [serial online] 2016 [cited 2019 Sep 17];14:67-75. Available from: http://www.azmj.eg.net/text.asp?2016/14/2/67/192654


  Introduction Top


The WHO has declared hepatitis C as a global health problem, with ∼3% of the world’s population infected with hepatitis C virus (HCV). Egypt has one of the highest HCV prevalence in the world (15% of the ) [1].

The manifestations of chronic HCV range from an asymptomatic state to liver fibrosis, liver cirrhosis, and hepatocellular carcinoma [2].

Guidelines and recommendations indicate that staging of liver fibrosis is the most important parameter for the definition of prognosis and for the subsequent management of patients with chronic hepatitis C [3].

Liver fibrosis is defined as the buildup of excessive amount of extracellular matrix (ECM) in the liver parenchyma. During fibrosis, hepatic stellate cells play important roles in the control of ECM synthesis and degradation in fibrotic livers [4]. The ECM remodeling markers include several glycoproteins (hyaluronan, laminin, fibronectin, etc.) [5].

For the past 50 years, liver biopsy has been considered to be the gold standard for staging of liver fibrosis [6]. There is a risk for complications arising from liver biopsy, and they can vary from mild symptoms, such as mild abdominal pain, to severe hemorrhage and injury to the biliary system [7].

The lack of accurate, reproducible, and easily applied methods for assessment of hepatic fibrosis has been the major limitation for both clinical management and research in liver diseases [8].

Indirect markers include molecules released into the blood due to liver inflammation, molecules synthesized or excreted by the liver, and markers of processes commonly disrupted due to liver function impairment [9].

Among these, the majority of reports and studies are on hyaluronic acid (HA), type IV collagen (PIIINP), metalloproteinases, inhibitors of metalloproteinases, and transforming growth factor-β [10].

HA is a high molecular weight, nonsulfated, linear chain glycosaminoglycan also known as mucopolysaccharide. This molecule is present in extracellular, pericellular, and intracellular spaces [11]. Generally, in comparison with other serum markers such as PIIINP and various types of collagen, HA has a more significant efficacy to predict cirrhosis [12]. The applicability of serum HA levels to estimate liver necroinflammatory injuries has also been approved in other studies [13].


  Patients and methods Top


This case–control study was conducted on 60 patients with chronic HCV infection attending Al-Kaherh Al-Fatimia Hospital from October 2014 to April 2015 and 20 normal volunteers. Oral consent from all patients after explanation and written consent from ethics committee of Al-Azhar Faculty of medicine girls.

Inclusion criteria

Patients with chronic HCV infection confirmed by the presence of positive HCV-Ab and HCV-RNA on the basis of PCR were included in the study. Patients with compensated liver disease according to clinical examination, abdominal ultrasonography, and laboratory investigations were included.

Exclusion criteria

Patients with other causes of hepatic fibrosis, such as alcoholic liver disease, bilharziasis, and HCV infection, were excluded. Patients with hepatocellular carcinoma or other solid tumor, decompensated liver cirrhosis, nonalcoholic fatty liver, history of interferon therapy, and other conditions in which HA may be elevated, such as autoimmune diseases (e.g. rheumatoid arthritis and systemic lupus) or diabetes mellitus were excluded from the study.

Patients were selected and divided according to the stage of fibrosis by means of liver biopsy into three groups: group 1 included 20 patients with mild hepatic fibrosis (F1 stage); group 2 included 20 patients with moderate hepatic fibrosis (F2 stage); and group 3 included 20 patients with marked hepatic fibrosis and cirrhosis (F3 and F4 stages). The control group included 20 age and sex matched normal volunteers. They were negative for hepatitis B surface antigen, HCV-Ab, and bilharzial antibody, with normal physical and clinical examination, normal liver function tests, and normal abdominal ultrasonography.

After explaining the purpose of the study, oral consent was obtained from all groups for participation in the study.

All patients and controls were subjected to the following: complete history taking and clinical examination, complete blood picture and erythrocyte sedimentation rate, and liver function tests, including serum bilirubin, alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, serum albumin, and prothrombin time and concentration. Hepatitis seromarkers, hepatitis B surface antigen, and hepatitis C virus antibody were measured using the enzyme-linked immunosorbent assay (ELISA) technique (Abbott laboratories, USA) and PCR for HCV in patient groups. α-Fetoprotein was evaluated using ELISA, manufactured by Siemens Health Care Diagnostic Product. The reference range was less than 5 ng/ml. Bilharzial antibody was evaluated using shistosomiasis fumouze kit, manufactured by Fumouze Diagnostics Division, 1921 Hurd Drive Irding, Texas. Antinuclear antibody was evaluated by means of immunofluorescence to exclude autoimmune disease.

Serum hyaluronic acid

Serum HA was evaluated using HA ELISA kit manufactured by Glory Science Co. Ltd (Del Rio, Texas, USA).

Principle of the assay

This assay uses the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for HA was precoated onto a microplate, and standards and samples were pipetted into the wells. After washing away any unbound substance, an enzyme-linked polyclonal antibody specific for HA was added to the wells. Thereafter, the microplate was washed to remove any unbound antibody–enzyme reagent, and TMB substrate solution was added, following which the TMB substrate became blue on reaction with enzyme horseradish peroxidase enzyme. The reaction was terminated by the addition of a stop solution and the color change was measured spectrophotometrically at a wavelength of 450 nm.

Calculation of results

The concentration of HA in the samples was then determined by comparing the optical density of the samples with the standard curve.

Liver biopsy for the patient groups to determine stage of liver fibrosis

Biopsy specimens were stained with hematoxylin–eosin and silver. Grading and staging were carried out for clinical and pathological evaluation of cases using the METAVIR scoring system for grading the activity of inflammation and for staging of fibrosis.

METAVIR scoring system is composed of a two-letter and two-number coding system.

A: histological activity (A0: no activity, A1: mild activity, A2: moderate activity, and A3: severe activity), according to piecemeal and lobular necrosis.

F: fibrosis (F0: no fibrosis, F1: portal fibrosis without septa, F2: portal fibrosis with rare septa, F3: numerous septa without cirrhosis, and F4: cirrhosis).

Indirect fibrosis markers were calculated in the patient groups only as follows:

  1. AST/ALT ratio (AAR) [14].
  2. Aspartate transaminase to platelet ratio index (APRI) [15].


It was calculated as follows:



Statistical methods

Statistical presentation and analysis of the present study was carried out using mean, SD, χ2, linear correlation coefficient, and analysis of variance tests with SPSS, V17, produced by IBM (SPSS Inc., Chicago, Illinois, USA).

  1. Descriptive statistics: mean and SD were calculated to measure the central tendency and dispersion of quantitative data.
  2. Analytic statistics: comparison of groups was made using the Kruskal–Wallis test for comparison of nonparametric data between more than two groups. The coefficient was calculated to determine the association between two variables. The level of significance was considered at a P value less than 0.05 and nonsignificance at a P value more than 0.05.



  Results Top


This study included 60 patients with chronic hepatitis C proved by the presence of HCV-Ab and HCV-RNA by means of PCR, with compensated liver disease according to clinical examination, ultrasonography, and laboratory investigations, and 20 normal volunteers as controls. [Table 1] shows the results of serum HA in the studied groups. As regards HA, mean±SD was 74.47±51.76, 146.98±48.80, 280.06±88.72, and 25.83±10.70 in group 1, group 2, group 3, and the control group, respectively. [Table 2] shows comparison of serum HA among the studied groups. There was a highly significant increase in serum HA level in group 2 and group 3 in comparison with the control group, and in group 3 compared with group 1 and group 2. However, there was a significant increase in group 1 in comparison with the control group and in group 2 in comparison with group 1 ([Figure 1]). [Table 3] shows results of fibrosis markers AAR and APRI in the patient groups, and [Table 4] shows comparison of AAR and APRI among the patient groups. As regards AAR, mean±SD was 0.86±0.33, 0.96±0.26, and 0.98±0.33 in group 1, group 2, and group 3, respectively. There was no significant difference in AAR among patient groups ([Figure 2]). As regards APRI, mean±SD was 0.36±0.20, 0.71±0.44, and 1.12±0.65 in group 1, group 2, and group 3, respectively. There was a highly significant increase in APRI in group 3 in comparison with group 1 and a significant increase in group 2 in comparison with group 1 ([Figure 3]). Moreover, there was a significant positive correlation between serum HA level and APRI in the patient groups ([Figure 4]). [Table 5] shows results of α-fetoprotein (AFP) in the studied groups. As regards AFP, mean±SD was 3.11±1.19, 5.88±1.58, 13.90±2.17, and 1.06±0.15 in group 1, group 2, group 3, and the control group, respectively. [Table 6] shows comparison of AFP among the studied groups. There was a highly significant increase in serum AFP level in group 3 in comparison with the control group, group 1, and group 2, whereas there was no significant difference between groups 1 and 2 and the control group and between group 1 and group 2 ([Figure 5]). Moreover, there was a significant positive correlation between serum HA level and AFP in the patient group ([Figure 6]). As regards the cutoff point of serum HA level, it was more than 42.18 ng/l to discriminate between the patient group (fibrosis) and the control group (normal), with a sensitivity of 91.7%, specificity of 95.0%, positive predictive value (PPV) of 98.2%, negative predictive value (NPV) of 79.2%, and accuracy of 95.2% ([Table 7] and [Figure 7]). However, the cutoff point for HA level was more than 81.68 ng/l to discriminate between group 1 (mild fibrosis) and group 2 (moderate fibrosis), with a sensitivity of 100%, specificity of 70%, NPV of 100%, PPV of 76.9%, and 82.5% accuracy ([Table 8] and [Figure 8]). The cutoff point for HA level to discriminate between group 2 (moderate fibrosis) and group 3 (severe fibrosis and cirrhosis) was more than 167.98 ng/l; the sensitivity was 90% and the specificity was 80%, with 88.9% for NPV, 81.8% for PPV, and 89.7% accuracy ([Table 9] and [Figure 9]).
Table 1: Results of serum HA in the studied groups

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Table 2: Comparison of serum HA among the studied groups

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Figure 1: Comparison of serum HA level among the studied groups. HA, hyaluronic acid.

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Table 3: Results of fibrosis markers (AAR) and (APRI) in the patient groups

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Table 4: Comparison of AAR and APRI among the patient groups

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Figure 2: Comparison of AAR (AST/ALT) among the patient groups. AAR, AST/ALT ratio; ALT, alanine transaminase; AST, aspartate aminotransferase.

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Figure 3: Comparison of APRI among the patient groups. APRI, aspartate transaminase to platelet ratio index.

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Figure 4: Correlation between serum HA level and APRI in the patients group. APRI, aspartate transaminase to platelet ratio index; HA, hyaluronic acid.

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Table 5: Results of AFP in the studied groups

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Table 6: Comparison of AFP among the studied groups

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Figure 5: Comparison of AFP among the studied groups. AFP, α-fetoprotein.

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Figure 6: Correlation between serum HA level and α fetoprotein level in the patients group. HA, hyaluronic acid.

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Table 7: Cutoff point, sensitivity, specificity, PPV, NPV, and accuracy of HA (between all patients groups and the control group)

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Figure 7: ROC curve of HA between the patient group and the control group. HA, hyaluronic acid; ROC, receiver operating characteristic.

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Table 8: Cutoff point, sensitivity, specificity, PPV, NPV, accuracy of HA (between group 1 and group 2)

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Figure 8: ROC curve of HA between group 1 and group 2. HA, hyaluronic acid; ROC, receiver operating characteristic.

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Table 9: Cutoff point, sensitivity, specificity, PPV, NPV, accuracy of HA (between group 2 and group 3)

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Figure 9: ROC curve of HA between group 2 and group 3. HA, hyaluronic acid; ROC, receiver operating characteristic.

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There was a significant positive correlation between serum HA level and APRI in the patient group.

There was a significant positive correlation between serum HA level and AFP level in the patient group.


  Discussion Top


Noninvasive methods to measure the severity of liver injury and fibrosis are clinically important in Egypt where advanced liver disease from HCV is common and access to liver biopsy is limited; in addition, reliability of the biopsy to detect and measure hepatic pathology is not ideal [16].

Many noninvasive markers (NIMs) for assessing liver fibrosis have been developed, and they are frequently used in clinical practice. They have been validated in different studies, and some were found to be highly accurate in the assessment of liver fibrosis compared with liver biopsies, which have always been used as the standard reference method for evaluating the accuracy of noninvasive methods [17].

HA serum levels correlate with the histological stages of liver fibrosis in HCV monoinfected patients, and HA alone has shown very good diagnostic accuracy as a noninvasive assessment of fibrosis and cirrhosis [18].

This study aimed to evaluate the serum level of HA in the assessment of liver fibrosis in the different stages in comparison with liver biopsy and indirect serum fibrosis markers such as AAR and APRI in chronic HCV patients.

In our study, there was a highly significant increase in serum HA level in group 2 and group 3 in comparison with the control group, and in group 3 compared with group 1 and group 2. However, there was a significant increase in group 1 in comparison with the control group, and in group 2 in comparison with group 1. These results are in agreement with those of Resino et al. [18], who found that serum HA levels increase gradually with the hepatic fibrosis stage. However, HA is better than other simple noninvasive indexes using parameters easily available in routine clinical practice only for diagnosing cirrhosis.

Elevated serum levels of HA in chronic liver disease reflect both increased synthesis by hepatic stellate cells and reduced clearance as a result of endothelial cell dysfunction associated with advanced liver disease [19].

Khan et al. [20] found that serum HA is a useful NIM of liver fibrosis. There is a strong positive correlation between serum HA levels and degree of liver fibrosis. The concentration of serum HA rises according to progression of liver fibrosis, and levels are highest in patients with liver cirrhosis.

In a study conducted by Younis et al. [21] on 80 patients with chronic HCV of different stages of liver fibrosis (patients from F1 to F4), they found that the increase in serum levels of YKL-40 and HA was correlated to the progression of liver fibrosis.

As regards AAR in the patient groups in our study, there was no significant difference in AAR among patient groups, and this finding is in agreement with those of Reedy et al. [22], who observed that AAR failed to predict cirrhosis accurately in HCV patients.

In contrast, Sheth et al. [23] observed that an AAR up to 1 had 100% PPV for the presence of cirrhosis in chronic HCV patients; Park et al. [24] also reported that AAR more than one had very high specificity (82–100%) for prediction of cirrhosis.

As regards AST/platelet count (APRI) in our study, there was a highly significant increase in APRI in group 3 in comparison with group 1 and a significant increase in group 3 in comparison with group 2. Moreover, there was a significant increase in APRI in group 2 in comparison with group 1, and our results are in agreement with those of Khairy et al. [25], who proved that APRI was a significant predictor of fibrosis in their study. These results are in accordance with studies showing APRI score as a significant predictor of fibrosis [26],[27].

Berg et al. [28] and Wai et al. [15] found that APRI increased parallel to increase in the stage of fibrosis, and the cutoff less than 0.5 was used for the diagnosis of mild or significant fibrosis and cutoff greater than 0.5 for prediction of cirrhosis. As regards the correlation study between HA and laboratory parameter, there was a significant negative correlation between serum HA level and serum albumin, red blood cells count, hemoglobin level, platelet count, and prothrombin concentration. However, there was a significant positive correlation between serum HA level and ALT, AST, total bilirubin level, AFP, APRI, and PCR.

As regards AFP, there was a highly significant increase in serum AFP level in group 3 in comparison with the control group, group 1, and group 2, whereas there was no significant difference between group 2 and group 1 and between groups 1 and 2 and the control group. This result is in agreement with that of Khairy et al. [25], who proved that the severity of hepatic fibrosis was associated with a significant elevation in serum AFP level. Moreover, Tamura et al. [29] found that the elevated serum AFP level was associated with chronic HCV and was observed more in cirrhotic patients.

This result is in agreement with many studies that found that higher serum AFP levels were significantly correlated with advanced fibrosis/cirrhosis in chronic HCV [30],[31].

As regards the cutoff point of serum HA level, we found that the cutoff point of HA level was greater than 42.18 ng/l to discriminate between the patient group (fibrosis) and the control group (normal); the sensitivity of the HA was 91.7% and the specificity was 95.0%, with 98.2% for PPV, 79.2% for NPV, and 95.2% accuracy. Yilmaz et al. [32] found that serum HA level greater than 64.7 ng/l had 100% specificity for diagnosing chronic hepatitis.

However, the cutoff point for HA level was greater than 81.68 ng/l to discriminate between group 1 (mild fibrosis) and group 2 (moderate fibrosis), with a sensitivity of 100%, specificity of 70%, NPV of 100%, PPV of 76.9%, and accuracy of 82.5%. Yilmaz et al. [32] found that a cutoff value of 63 ng/l for HA had 100% specificity for diagnosing fibrosis score more than 1 in chronic hepatitis (P<0.001). However, Geramizadeh et al. [33] found that HA at level less than 113 ng/l could predict mild fibrosis with NPV of 89% and PPV of 94%.

The cutoff point for HA level to discriminate between group 2 (moderate fibrosis) and group 3 (severe fibrosis and cirrhosis) was greater than 167.98 ng/l, with a sensitivity of 90%, specificity of 80%, NPV of 88.9%, PPV of 81.8%, and accuracy of 89.7%. This is in agreement with the study by Geramizadeh et al. [33], who found that HA at level greater than 181.9 ng/l could predict severe fibrosis and cirrhosis with NPV of 100% and PPV of 78%.


  Conclusion Top


From this study we concluded that HA is a promising reliable simple NIM for assessing liver fibrosis in HCV-infected patients. HA has better diagnostic value with high sensitivity and specificity in differentiation between stages of liver fibrosis. The optimal cutoff of HA to differentiate between the patient and the control group in this study was more than 42.18 ng/l, with 91.7% sensitivity and 95.0% specificity. The optimal cutoff of HA to differentiate between mild fibrosis and moderate fibrosis in this study was more than 81.68 ng/l, with 100% sensitivity and 70% specificity. The optimal cutoff of HA to differentiate between cirrhosis patients from moderate fibrosis in this study was more than 167.98 ng/l, with 90% sensitivity and 80% specificity.

Recommendations

HA can be used to determine the stage of fibrosis when liver biopsy is contraindicated. HA in combination with APRI and other NIMs can be used in routine investigation to predict the degree of fibrosis, especially cirrhosis, instead of invasive liver biopsy. The possible role of HA in the development of liver fibrosis suggests the use of antagonist as a target therapy in amelioration of disease progression. Further studies are needed on a large group of patients to validate the result of this study and to show the possible use of HA levels as a follow-up of HCV therapy instead of invasive methods. Further studies are required to determine the significance and other potential diagnostic uses of HA in neoplastic liver disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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[PUBMED]  Medknow Journal  


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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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