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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 943-948

Noninvasive methods for fibrosis assessment in chronic hepatitis C virus infection


1 Internal Medicine Department, Faculty of Medicine, Menoufia University, Shebeen El Kom, Egypt
2 Internal Medicine at Ministry of Health, Shebeen El Kom, Egypt

Date of Submission21-Jan-2018
Date of Acceptance17-Mar-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Mohammed O Belal
El-Santa, Gharbia, 23717
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_19_18

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  Abstract 

Objective
The objective of this study is to compare several noninvasive methods of fibrosis assessment (platelet count, the aspartate aminotransferase/platelet ratio index, the Lok score, and the fibrosis-4 score) versus percutaneous liver biopsy (LB) in chronic hepatitis C virus infection.
Background
Noninvasive methods for assessment of hepatic fibrosis are increasingly needed. LB is an invasive procedure and includes a risk of complications, such as pain, pneumothorax, puncture of other viscera, and hemorrhage. In addition to the added cost, LB cannot be performed universally in all patients with impaired hemostasis of any origin.
Patients and methods
Our study included 500 patients with chronic hepatitis C virus infection in which LB and biological tests needed for calculating the scores (according to the classic formulas) were performed.
Results
There was a highly significant correlation between different stages of fibrosis and all studied markers of fibrosis (P < 0.001). Lok score at a cutoff value of 0.25 had 68.73% sensitivity and 55% specificity for diagnosis of liver fibrosis, fibrosis-4 score at a cutoff value of 1.26 had 55.9% sensitivity and 68.54% specificity, aspartate aminotransferase/platelet ratio index at a cutoff value of 0.66 had 50.0% sensitivity and 74.16% specificity, and platelet count at a cutoff value of 208 (103/mm3) had 67.7% sensitivity and 59.55% specificity for diagnosis of liver fibrosis.
Conclusion
All studied noninvasive markers of fibrosis are very good markers for detection of fibrosis.

Keywords: aspartate aminotransferase/platelet ratio index, fibrosis.4 score, hepatitis C virus, Lok score, markers of liver fibrosis


How to cite this article:
Abd El-Atty EA, El-Shayb ESI, Belal MO. Noninvasive methods for fibrosis assessment in chronic hepatitis C virus infection. Menoufia Med J 2019;32:943-8

How to cite this URL:
Abd El-Atty EA, El-Shayb ESI, Belal MO. Noninvasive methods for fibrosis assessment in chronic hepatitis C virus infection. Menoufia Med J [serial online] 2019 [cited 2019 Nov 12];32:943-8. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/943/268813




  Introduction Top


Worldwide, hepatitis C virus (HCV) is one of the major causes of chronic liver diseases, which include inflammation, fibrosis, and cirrhosis. Furthermore, HCV has been associated with increased morbidity and mortality [1].

Liver biopsy (LB) is an invasive procedure and includes a risk of complications, such as pain, pneumothorax, puncture of other viscera, and hemorrhage; however, it is still the gold standard for grading the severity of necroinflammation and staging the extent of liver fibrosis in patients with chronic HCV infection [2].

In addition to the added cost, LB cannot be performed universally in all patients with impaired hemostasis of any origin [3]. The procedure is known to underestimate liver fibrosis when small tissue samples are collected, and it is prone to intraobserver and interobserver variation [4].

In 2005, an Italian survey reported major discrepancies among hepatologists regarding when and how to take an LB from the same subgroup of patients with chronic hepatitis C (CHC) [5].

Considering these limitations, many studies have recently focused on the development of noninvasive markers as surrogates of LB [6].


  Patients and Methods Top


This retrospective cohort study was carried out on 500 patients having HCV RNA-positive CHC attending the outpatient clinics of Shebeen El-Kom Teaching Hospital. All selected patients were potential candidates for interferon therapy. This study was carried out at Clinical Pathology Department, Faculty of Medicine, and Shebeen El-Kom Teaching Hospital, Menoufia, from January 2014 to December 2014. Patients with the following criteria were excluded: patients with chronic hepatitis B infection, autoimmune hepatitis, decompensated liver disease, hepatocellular carcinoma, patients with history of previous antiviral therapy, and patients with absolute contraindication for LB.

All patients were subjected to thorough history taking and investigated for complete blood count, hepatitis markers (HCVAb and HBsAg), quantitative PCR for HCV RNA, serum α-feto protein (ng/dl), serum aspartate aminotransferase (AST) (IU/l), serum alanine aminotransferase (ALT) (IU/l), serum albumin (g/dl), serum bilirubin (mg/dl), prothrombin time (PT) (s), international normalized ratio (INR), and antinuclear antibodies. In the study, ultrasonography was done and LB was performed to assess the stage of fibrosis.

Serological tests for assessing fibrosis

We evaluated the following serological tests for the assessment of fibrosis:

  1. The platelet count
  2. Aspartate aminotransferase/platelet ratio index (APRI score) is calculated according to the following formula: APRI=[(AST/ULN)×100]/platelet count 109/l, where ULN is the upper limit of normal
  3. The Lok score was calculated according to the following formula: Log odds=−5.56-0.0089 × platelet count (103/mm 3)+1.26×(AST/ALT)+5.27 × INR


  4. Lok=[exp (log odds)]/[1 + exp (log odds)]

  5. The fibrosis-4 (FIB-4)=[age (years)×AST (IU/l)]/[platelet count (109/l)×ALT (IU/l)1/2].


The protocol for this study followed the ethical standards and was approved by the ethical committee of our institution, and all subjects gave informed consent to participate in this study.

Statistical analysis

The data were analyzed with the statistical package for the social sciences (SPSS) version 22.0 on IBM compatible computer (SPSS Inc., Chicago, Illinois, USA). All quantitative variables were presented as mean ± SD and range. Qualitative variables were presented as number of frequency and percentages. Comparisons between the groups were done by χ2-test when both variables were qualitative. Comparisons were done by t independent test when one variable is quantitative and other is qualitative. Sensitivity and specificity were calculated to evaluate the screening tests. Reciever operating characteristic (ROC) curve was used for evaluation of screening quantitative tests. A P value of less than 0.05 was considered statistically significant. Values of P value of 0.001 were taken as statistically highly significant.


  Results Top


In our study, male represented 71.20% and female represented 28.8% of the studied populations [Figure 1]. The mean of age is 40.53 ± 9.02 years [Table 1].
Figure 1: Sex of studied population (n = 500).

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Table 1: Demographic data of studied population (n=500)

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The LBs of studied population according to METAVIR scoring system showed F0 = 3.2%, F1 = 32.2%, F2 = 46.8%, F3 = 16.4%, and F4 = 1.4% of studied population [Figure 2].
Figure 2: Liver biopsy of studied population (n = 500).

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The study showed highly significant correlations between (age, albumin, AST, ALT, total bilirubin, INR, and PT%) of studied population and the degree of fibrosis in LB (P < 0.001), significant correlation with total bilirubin (P = 0.04), and no significant correlation regarding sex, creatinine, white blood cells (WBC), hemoglobin, and HCV-RNA [Table 2].
Table 2: Demographic data and laboratory investigations of studied population according to degree of fibrosis in liver biopsy (n=500)

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There were highly statistically significant correlations between different stages of fibrosis and all studied noninvasive markers of fibrosis (P < 0.001) [Table 3].
Table 3: Noninvasive markers of liver fibrosis of studied population according to degree of fibrosis in liver biopsy (n=500)

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Lok score had highly statistically significant correlations with age, albumin, AST, total bilirubin, WBC, platelet count, INR, PT, Child–Pugh score, and model for end-stage liver disease (MELD score) (P < 0.001) and no significant correlation with weight, creatinine, ALT, and HCV-RNA [Table 4].
Table 4: Correlations between studied scores and liver profile of studied population (n=500)

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FIB-4 score had highly statistically significant correlations with age, albumin, ALT, AST, total bilirubin, WBC, platelet count, INR, PT, Child–Pugh score, and MELD score (P < 0.001) and no significant correlation with creatinine, hemoglobin, and HCV-RNA [Table 4].

APRI score had highly statistically significant correlations with age, albumin, ALT, AST, total bilirubin, WBC, platelet count, INR, PT, HCV-RNA, Child–Pugh score, and MELD score (P < 0.001) and no significant correlation with creatinine and hemoglobin [Table 4].

Platelet count had highly statistically significant correlations with age, albumin, ALT, AST, total bilirubin, WBC, INR, PT, and MELD score (P < 0.001) and no significant correlation with weight, creatinine, hemoglobin, HCV-RNA, and Child–Pugh score [Table 5].
Table 5: Correlations between platelet count and liver profile of studied population (n=500)

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  Discussion Top


The gold standard tool in assessing the stage of liver fibrosis is the histological evaluation of an LB. However, the procedure carries moderate risk of complications, including bleeding and a small risk of death [7]. LB is a costly procedure, and difficult to be accepted by many patients; moreover, many patients may discourage antiviral therapy because their fear of LB [8].

Various noninvasive markers of liver fibrosis have been developed and are now interesting alternatives to LB to evaluate the severity of liver fibrosis in patients with CHC, but none of these tests met the expectations, and their superiority to standard clinical evaluation is still questionable [9].

Noninvasive tests for the assessment of the severity of hepatic fibrosis are gaining ever more ground among hepatologists, who have now been put in a difficult position of choosing which one to use, taking into account that, at this time more than 20 biochemical tests are available, not to mention elastographic methods [10].

This study aimed to assess the diagnostic accuracies of four laboratory scores in comparison with each other and with LB using categories and cutoff values for assessing the degree of liver fibrosis on 500 HCV RNA-positive naive patients with CHC proven by biopsy.

The study showed highly significant correlations between age, albumin, AST, ALT, total bilirubin, INR and PT% of the studied population and degree of fibrosis in LB and significant correlation with total bilirubin. This was in agreement with the results of El-Saeid et al. [9], whose laboratory tests showed highly significant difference in AST, ALT, ALP, albumin, and INR in severe and mild liver fibrosis groups compared with the control group (P < 0.001).

In the current study, there was a highly statistically significant decrease in platelet count with progression of fibrosis stage (P < 0.001). This result agreed with Attallah et al. [11] who reported that platelet count was correlated with the progression of fibrosis, and this may in part be owing to increased splenic sequestration and to low thrombopoietin levels. On the contrary, Erdogan et al. [12] found that platelet count had insignificant correlation with the stage of fibrosis. This is owing to different etiologies, as the latter study contains patients who are infected with HBV, whereas the patients of the current study are infected with HCV.

In our study, we found that the platelet count, was statistically significantly correlated with the severity of fibrosis (P < 0.0001). Moreover, a platelet count smaller than the cutoff value of 208.000/mm 3 proved to be a predictor of significant fibrosis, with a specificity of 59.55%, but with a low sensitivity of 67.70%, with positive predictive value (PPV) of 75.2%, negative predictive value (NPV) of 50.5%, and accuracy of 67.6% [Table 6].
Table 6: ROC curve of noninvasive markers of fibrosis of studied population

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A meta-analysis [1] from 2007 proved that for a cutoff value of 0.5, the APRI score had 81% sensitivity and 50% specificity for predicting significant fibrosis (F ≥ 2 metavir) and that for a cutoff value of 1, the sensitivity and specificity for predicting cirrhosis were 76 and 71%. In our study, for a cutoff value of 0.66, the APRI score had 50% sensitivity and 74.16% specificity for predicting significant fibrosis, with 77.8% PPV and 45.1% NPV.

The FIB-4 score was originally developed for HIV-HCV coinfection but was confirmed also for HCV infection, with performances similar to the Fibro test [13] for the diagnosis of severe fibrosis (F3 and F4), with Area under reciever operating characteristic. (AUROC) 0.85 (95% confidence interval: 0.82–0.89). For values lower than a cutoff of 1.45, FIB-4 excluded severe fibrosis with a good NPV (94.7%), with 74% sensitivity and 80% specificity. For values higher than a cutoff of 3.25, FIB-4 confirmed severe fibrosis with 82% PPV, 37.6% sensitivity, and 98% specificity. For predicting cirrhosis, FIB-4 had an AUROC of 0.91.

In our study, for a cutoff value of 1.26, the FIB-4 score had 55.90% sensitivity and 68.54% specificity in discriminating significant fibrosis with 76.3% PPV and 46.2% NPV [Table 6].

The Lok score was proposed by the group led by Ann Lok during the Halt-C trial [14]. According to the authors, for a cutoff value smaller than 0.2 to exclude cirrhosis, only 7.8% of patients had been wrongly classified (98% sensitivity, 53% specificity, 27% PPV, and 99% NPV), and for values higher than 0.5 to confirm cirrhosis, only 14.8% of patients had been wrongly classified (40% sensitivity, 99% specificity, 84% PPV, and 90% NPV).

In our study, for a cutoff value of 0.25, the Lok score had 68.63% sensitivity and 55.06% specificity for cirrhosis discrimination, with 73.4% PPV and 49.2% NPV [Table 6].


  Conclusion Top


These noninvasive tests and their cutoffs have accepted diagnostic accuracy and can be used alternatively to LB for identifying patients with significant fibrosis and cirrhosis through the different clinical stages of CHC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology 2007; 46:912–921.  Back to cited text no. 1
    
2.
Lewin M, Poujol-Robert A, Boëlle PY, Wendum D, Lasnier E, Viallon M, et al. Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C. Hepatology 2007; 46:658–665.  Back to cited text no. 2
    
3.
The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994; 20:15–20.  Back to cited text no. 3
    
4.
Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, et al. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol 2010; 16:966–972.  Back to cited text no. 4
    
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Şirli R, Ioan S, Bota S, Popescu A, Cornianu M. A comparative study of non-invasive methods for fibrosis assessment in chronic HCV infection. Hepat Mon 2010; 10:88–94.  Back to cited text no. 5
    
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Degos F, Perez P, Roche B, Mahmoudi A, Asselineau J, Voitot H, Bedossa P. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol 2010; 53:1013–1021.  Back to cited text no. 6
    
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Omran MM, Farid K, Emran TM, Attallah AA. Fibro-α score as a simple and useful non-invasive test for predicting significant liver fibrosis in chronic hepatitis C patients. Arab J Gastroenterol 2011; 12:74–79.  Back to cited text no. 7
    
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Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001; 344:495–500.  Back to cited text no. 8
    
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El-Saeid GK, El-Sharawy AA, Tahaa HE, Fathy WM, El-morsy Bedira Isis S. Assessment of laminin level and its comparison with five liver fibrosis indices in chronic hepatitis B and C patients. Menoufia Med J 2016; 29:354–359.  Back to cited text no. 9
    
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Gressner OA, Weiskirchen R, Gressner AM. Biomarkers of liver fibrosis: clinical translation of molecular pathogenesis or based on liver-dependent malfunction tests. Clin Chim Acta 2007; 381:107–113.  Back to cited text no. 10
    
11.
Attallah AM, El-Far M, Omran MM, Farid K, Albannan MS, El-Dosoky I. Non-invasive diagnosis of liver fibrosis and cirrhosis inchronic hepatitis C patients. J Clin Lab Anal 2013; 27:121–129.  Back to cited text no. 11
    
12.
Erdogan S, Dogan HO, Sezer S, Uysal S, Ozhamam E, Kayacetin S, et al. The diagnostic value of non-invasive tests for the evaluation of liver fibrosis in chronic hepatitis B patients. scand J Clin Lab Invest 2013; 73:300–308.  Back to cited text no. 12
    
13.
Vallet-Pichard V, Nalpas MB, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology 2007; 46:32–36.  Back to cited text no. 13
    
14.
Lok AS, Ghany MG, Goodman ZD, Wright EC, Everson GT, Sterling RK, et al. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort. Hepatology 2005; 42:282–292.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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