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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 2  |  Page : 354-359

Assessment of laminin level and its comparison with five liver fibrosis indices in chronic hepatitis B and C patients


1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, National Liver Institute, Menoufia University, Menoufia, Egypt

Date of Submission11-Jun-2014
Date of Acceptance02-Sep-2014
Date of Web Publication18-Oct-2016

Correspondence Address:
Isis S El-morsy Bedira
Department of Clinical Pathology, National Liver Institute, Menoufia University, 5 Taiseer Street, Shebein El kom, Menoufia Governorate, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.192419

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  Abstract 

Objective:
The aim of the study was to assess the serum level of laminin in patients with chronic hepatitis B and C and conduct a comparative study with laminin and five liver fibrosis indices in chronic hepatitis B and C patients.
Background:
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases – for example, viral hepatitis. Over the last decade, several noninvasive markers for assessing the stage of hepatic fibrosis have been developed. Some have been well validated and are comparable to liver biopsy.
Materials and methods:
This study was carried out at the Clinical Pathology Department, Faculty of Medicine, and National Liver Institute, Menoufia University, from June 2012 to December 2013. The study included 34 patients with mild liver fibrosis and 28 patients with severe liver fibrosis, in addition to 20 unrelated healthy adults with matched age and sex who served as controls. Serum laminin concentration was estimated by enzyme-linked immunosorbent assay and five liver fibrosis indices were calculated.
Results:
Serum laminin concentrations could discriminate between patients with liver fibrosis and healthy individuals and between patients with severe fibrosis and those with mild fibrosis with high accuracy compared with other fibrosis markers like aspartate aminotransferase-to-platelet ratio index, FIB4, Fibro Q, AAR, and AP.
Conclusion:
There is a positive correlation between laminin levels and degree of liver fibrosis with high accuracy compared with other fibrosis markers like aspartate aminotransferase-to-platelet ratio index, FIB4, Fibro Q, AAR, and AP, although in combination they show higher efficacy.

Keywords: chronic hepatitis C and B patients, laminin, liver fibrosis


How to cite this article:
El-Saeid GK, El-Sharawy AA, Tahaa HE, Fathy WM, El-morsy Bedira IS. Assessment of laminin level and its comparison with five liver fibrosis indices in chronic hepatitis B and C patients. Menoufia Med J 2016;29:354-9

How to cite this URL:
El-Saeid GK, El-Sharawy AA, Tahaa HE, Fathy WM, El-morsy Bedira IS. Assessment of laminin level and its comparison with five liver fibrosis indices in chronic hepatitis B and C patients. Menoufia Med J [serial online] 2016 [cited 2019 Nov 21];29:354-9. Available from: http://www.mmj.eg.net/text.asp?2016/29/2/354/192419


  Introduction Top


Chronic liver diseases constitute a major global health problem, causing ∼800 000 deaths per year worldwide. Liver fibrosis is the common pathologic process of all chronic liver diseases, regardless of the cause, which results from excessive accumulation of extracellular matrix [1].

For the past 50 years liver biopsy has been considered the gold standard for staging of liver fibrosis. This technique allows physicians to obtain diagnostic information not only on fibrosis but also on many other liver injury processes, such as inflammation, necrosis, steatosis, and hepatic deposits of iron or copper [2]. A liver biopsy is considered the gold standard for assessing the stage of hepatic fibrosis, but it has many limitations [3].

Direct and indirect markers may be used alone or – more commonly – in combination with each other to produce composite scores: examples of direct markers are hyaluronic acid, laminin, and connective tissue growth factor and an example of an indirect marker is the aspartate aminotransferase-to-platelet ratio index (APRI) [4]. The APRI had an acceptable accuracy for the assessment of liver fibrosis in patients with chronic hepatitis C [5].

Laminin is a major basement membrane-associated noncollagenous glycoprotein of extracellular matrix and is deposited in the space of Disse during capillarization. It comprises a large complex of three long polypeptide chains arranged across each other and held together by disulfide bonds. Laminin is easily detectable in serum and has been related to liver fibrosis [6].


  Materials and Methods Top


This was a case–control study that included 82 patients, 34 of them with mild liver fibrosis and 28 patients with severe liver fibrosis, in addition to 20 unrelated healthy adults with matched age and sex. This study was carried out at Clinical Pathology Department, Faculty of Medicine, and National Liver Institute, Menoufia University, from June 2012 to December 2013.

Exclusion criteria (excluded subjects)

Patients who received antiviral or immunomodulatory therapy, those with a history of excessive alcohol consumption, those treated with hepatotoxic drugs or having other chronic liver diseases (such as Wilson's disease, hemochromatosis, hepatocellular carcinoma), or with active intravenous drug abuse were excluded.

Inclusion criteria

Hepatitis B patients with positive HBsAg and hepatitis C patients with positive HCVAb were eligible for inclusion in the study. All patients had to have undergone liver biopsy to determine the stage of liver fibrosis.

All individuals were subjected to the following:

  1. Clinical assessment including full history and clinical examination;
  2. abdominal ultrasonography, computed tomography scanning, or liver biopsy when possible;
  3. laboratory investigations including complete blood count and liver function tests for hepatitis viral markers (HBsAg, HBsAb, HBcAb, HBeAg, and HCVAb);
  4. assessment of serum laminin level by enzyme-linked immunosorbent assay.


The Mann–Whitney U-test (nonparametric test): This is a test of significance used for comparison between two groups with not normally distributed quantitative variables.


  Results Top


Regarding age, there were highly significant differences between mild liver fibrosis patients (group 1), severe liver fibrosis patients (group 2), and controls (P<0.001). With regard to sex, there were no significant differences between the studied groups (P = 0.98) ([Table 1]).
Table 1: Comparison between the studied groups as regards age and sex

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There were 34 patients with mild liver fibrosis, representing 54.8% of patients, and 28 patients with severe liver fibrosis, representing 45.2%. The total number of patients with liver fibrosis was 62 ([Table 2]).
Table 2: Grades of fibrosis among the studied patients

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As regards liver function tests, higher levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and international normalized ratio (INR) were found in patients than in healthy controls (P<0.001). Total and direct bilirubin levels were not significantly higher in the mild liver fibrosis group compared with the control group (P = 0.2 and 0.44, respectively). However, all levels were significantly higher in the severe liver fibrosis group compared with the mild liver fibrosis group (P<0.001). The mean value of albumin was significantly lower among patients with severe liver fibrosis than among those with mild liver fibrosis (P<0.001), but there was no significant difference between the mild liver fibrosis group and the control group. The mean value of INR was significantly higher in the severe liver fibrosis group than in the mild liver fibrosis group. The mean value of INR was significantly higher in both groups than in the control group (P<0.001) ([Table 3]).
Table 3: Comparison between the three studied groups as regards liver functions

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The mean levels of APRI, FIB4, AP, and Fibro Q were significantly higher in group 2 than in group 1 and the levels of both groups were significantly higher than those of the control group (P<0.001). The mean level of AAR was not significantly higher in group 2 compared with group 1 (P = 0.27) but there was a significantly higher mean level in patients with severe liver fibrosis compared with the control group (P = 0.02) and a significantly higher mean level in group 1 compared with the control group (P = 0.05) ([Table 4]).
Table 4: Comparison between the three studied groups as regards the five fibrosis markers

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The mean level of laminin concentration was significantly higher in group 2 than in group 1 and both groups had significantly higher levels than the control group (P<0.001) ([Table 5]).
Table 5: Comparison between the three studied groups as regards laminin concentration

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The cutoff point of 40.5 ng/ml for laminin level selected for discrimination of patients with liver fibrosis from controls showed good accuracy of 97.6, with an area under the curve (AUC) of 0.97, sensitivity of 98.4%, specificity of 95%, positive predictive value (PPV) of 98.4%, and negative predictive value (NPV) of 95%. The AUC accuracy, sensitivity, specificity, PPV, and NPV of serum marker panels AP, AAR, FIB4, Fibro Q, and APRI were compared with those of serum laminin concentration and the results are presented in [Table 6].
Table 6: Comparison between laminin and the five fibrosis markers for differentiation between patients with liver fibrosis and controls

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The cutoff points for laminin level (58.77 ng/ml) for discrimination of patients with mild liver fibrosis from those with severe liver fibrosis showed good accuracy (93.5), with AUC of 0.99, sensitivity of 96.4%, specificity of 91.2%, PPV of 90%, and NPV of 96.9%. The AUC, accuracy, sensitivity, specificity, PPV, and NPV of serum marker panels AP, AAR, FIB4, Fibro Q, and APRI were compared with those of serum laminin concentration and the results are presented in [Table 7].
Table 7: Comparisons between laminin and the five fibrosis markers for differentiation between mild and severe fibrosis

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  Discussion Top


Noninvasive methods include serum tests and imaging techniques. In recent years, there has been growing interest in identifying and describing liver fibrosis using molecular serum markers. Serum markers offer a cost-effective alternative to liver biopsy for both patients and clinicians. In addition to being less invasive, there is a low risk of sampling error and small observer-related variability. Moreover, measurements may be taken repeatedly over time, allowing for ongoing monitoring of fibrosis.

This study revealed highly significant difference between mild liver fibrosis patients, severe liver fibrosis patients, and controls with regard to age (P<0.001), which was in agreement with the results of whose study showed significant statistical differences in age between patients with different fibrosis stages.

The present study revealed highly significant difference in AST, ALT, ALP, Alb, and INR in severe and mild liver fibrosis groups compared with the control group (P<0.001). This was in agreement with the results of Parsian et al. [8], whose laboratory tests showed that the serum levels of AST and ALT in patients were highly significantly higher than those of the control group (P<0.001), but the differences in INR were not significant (P = 0.28). These results were also in agreement with those of Alboraie et al.[7], who showed that there was a highly significant positive correlation between stage of fibrosis and bilirubin, AST, ALP, and g-glutamyl transpeptidase. There was no significant linear correlation between fibrosis stage and ALT. Our results were also in agreement with Aktug et al. [9], who found a positive correlation between fibrosis stage and AST and ALT.

In contrast, Sebastiani et al. [0] reported that elevation of noninvasive indirect serum markers of fibrosis, such as serum aminotransferases AST and ALT, in chronic hepatitis patients reflects alterations in hepatic function rather than in extracellular matrix metabolism. As several hepatitis C virus reports have described normal aminotransferase levels in about 25–30% of chronic hepatitis C patients, there may be a potential advantage in assessing serum direct fibrosis markers that do not involve transaminases.

In the current study there was a highly significant higher mean level of APRI, FIB4, AP, and Fibro Q in severe liver fibrosis compared with mild liver fibrosis and the levels of both groups were highly significantly higher than that of the control group (P<0.001), whereas the mean level of AAR was not significantly higher in severe liver fibrosis compared with mild liver fibrosis (P = 0.27). However, the mean level was significantly higher in severe liver fibrosis than in controls (P = 0.02); the level was also significantly higher in mild liver fibrosis patients than in controls (P = 0.05).

The obtained results are in agreement with those of who reported that the APRI had an acceptable accuracy for the assessment of liver fibrosis in patients with chronic hepatitis C, but not in those with chronic hepatitis B. Zhang et al. [1] assessed the diagnostic value of FIB4 in 212 chronic hepatitis B patients by comparing their results with histological features. The AUC of the receiver operating characteristic (ROC) (P) of FIB4 for significant fibrosis, extensive fibrosis, and cirrhosis were 0.733 (P<0.01), 0.746 (P<0.01), and 0.756 (P<0.01), respectively. They concluded that the FIB4 index is an accurate and inexpensive method for assessing liver fibrosis in chronic hepatitis and may reduce the need for liver biopsy.

In the present study the mean level of laminin concentration was significantly higher in severe liver fibrosis compared with mild liver fibrosis, and the level in both groups was significantly higher than the control mean level (P<0.001). This was in agreement with the results of Parsian et al. [8], in whose study the mean serum laminin (LN) and N terminal peptide of procollagen type III (PIIINP) concentrations in stages 2, 3, 4, 5, and 6 of liver fibrosis showed statistically significant differences compared with the healthy group. These findings suggest that patients with higher serum LN and PIIINP concentrations might have higher liver fibrosis stage and inflammation grade. Therefore, we can conclude that in the presence of liver damage the LN and PIIINP are poorly metabolized by the liver. Patients in early stage of liver fibrosis possibly metabolized LN and PIIINP better than those with advanced-stage liver fibrosis.

In the present study it was found that a cutoff point of 40.5 ng/ml for laminin level can discriminate patients with liver fibrosis from controls with good accuracy (97.6), with an AUC of 0.97, sensitivity of 98.4%, specificity of 95%, PPV of 98.4%, and NPV of 95% compared with fibrosis serum marker panels AP, AAR, FIB4, Fibro Q, and APRI. Further, the cutoff point of 58.77 ng/ml for laminin level for discriminating patients with mild liver fibrosis from those with severe liver fibrosis showed good accuracy of 93.5, with an AUC of 0.99, sensitivity of 96.4%, specificity of 91.2%, PPV of 90%, and NPV of 96.9% compared with other fibrosis serum marker panels AP, AAR, FIB4, Fibro Q, and APRI. This was in agreement with the results of Parsian et al. [8], whose cutoff point of 52.0 ng LN/ml for discrimination of patients with liver fibrosis from those without liver fibrosis showed a good AUC, accuracy, sensitivity, specificity, PPV, and NPV. Serum marker panels in selected cutoff points showed reasonably good AUC (AP: 0.632; AAR: 0.907; APRI: 0.818; FIB4: 0.754; and Fibro Q: 0.957) but lower than that of laminin level. In addition, in Parsian et al. [8], a cutoff point of 92.5 ng LN/ml for discrimination of patients with mild fibrosis from those with severe fibrosis showed an AUC of the ROC (P) of 0.879 (P = 0.005) and 0.911 (P = 0.002), respectively. It means that LN can discriminate between patients with mild fibrosis and those with severe fibrosis. But the AUC-ROC of serum panel markers for discrimination of severe liver fibrosis (stage ≥3) from mild liver fibrosis (stage < 2) revealed a different pattern as follows: AAR = 0.491 (0.947), AP = 0.518 (0.137), APRI = 0.268 (0.107), FIB4 = 0.232 (0.110), and Fibro Q = 0.491 (0.997). It seems only laminin performed better at differentiating between advanced fibrosis and mild fibrosis ([Figure 1],[Figure 2],[Figure 3],[Figure 4]).
Figure 1: The mean levels of the five liver fibrosis markers in the studied groups

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Figure 2: The mean levels of laminin concentration in the studied groups

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Figure 3: Receiver operating characteristic (ROC) curve of the five fibrosis markers and laminin concentration for differentiation of patient group and control group

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Figure 4: Receiver operating characteristic (ROC) curve of the five fibrosis markers for differentiation between mild and severe fibrosis

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  Conclusion Top


We conclude that there is a positive correlation between laminin levels and degree of liver fibrosis. Our findings suggest that measurement of serum laminin concentrations can differentiate between patients with liver fibrosis and healthy individuals and between severe fibrosis and mild fibrosis with high accuracy compared with other fibrosis markers such as APRI, FIB4, Fibro Q, AAR, and AP.

Conflicts of interest

There are no conflicts of interest.[11]

 
  References Top

1.
Liu T, Wang X, Karsdal MA, Leeming DJ, Genovese F. Molecular serum markers of liver fibrosis. Biomark Insights 2012; 7:105-17.  Back to cited text no. 1
    
2.
Sebastiani G, Vario A, Guido M, Alberti A. Non-invasive fibrosis biomarkers. Reduce but not substitute the need for liver biopsy. World J Gastroenterol 2006; 12:3682–3694.  Back to cited text no. 2
    
3.
Hind IF. Non-invasive biomarkers of liver fibrosis: an overview. Adv Hepatol 2014; 2014:1–15.  Back to cited text no. 3
    
4.
Vasilios P, Emmanuel T, Andrew KB. Non-invasive assessment of liver fibrosis. Ann Gastroenterol 2012; 25:218–231.  Back to cited text no. 4
    
5.
Yusuf Y, Oya Y, Ramazan K, Muharrem B, Bilge A, Osman O. Noninvasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio index (APRI). Hepat Mon 2011; 11:103–107.  Back to cited text no. 5
    
6.
Mosa TE, Abd El-Maksoud MD, Saad A, Abo-Zeid M. Clinical significance of serum laminin and INR ratio to diagnose fibrosis in patients with chronic active Hepatitis C. IJIB 2010; 9:1–31.  Back to cited text no. 6
    
7.
MA Alboraie, ME Afifi, Amany RA. Egy-score predicts severe hepatic fibrosis and cirrhosis in Egyptians with chronic liver diseases: a pilot study. Hepat Mon 2013; 13:e10810.  Back to cited text no. 7
    
8.
Parsian H, Mohammad N, Ali R, Mohammad H, Durdi Q. Comparison of five liver fibrosis indexes with serum levels of laminin and N terminal peptide of procollagen type III in chronic hepatitis patients. J Gastrointestinal Liver Dis 2011; 22:344–357.  Back to cited text no. 8
    
9.
Aktug DN, Kolgelier S, Ozcimen S, Gungor G, Sumer S, Saltuk DL, et al. Evaluation of the relation between hepatic fibrosis and basic laboratory parameters in patients with chronic hepatitis B fibrosis. Hepat Mon 2014; 14:e16975.  Back to cited text no. 9
    
10.
10Sebastiani G, Vario A, Guido M, Alberti A. Performance of noninvasive markers for liver fibrosis is reduced in chronic hepatitis C with normal transaminases. J Viral Hepat 2008; 15:212–218.  Back to cited text no. 10
    
11.
11Zhang YF, Shi H, Chen LB, Xu QH. Value of FIB-4 for the diagnosis of liver fibrosis in chronic hepatitis B. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2010; 24:215–217.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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



 

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