|Year : 2018 | Volume
| Issue : 3 | Page : 282-286
Noninvasive predictors of hepatic fibrosis in patients with chronic hepatitis C virus in comparison with liver biopsy
Ayman N Menessy1, Nancy A Ahmed1, Nagwa I Abdallah2, Salah S Arif3
1 Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Mansoura Insurance Hospital, Mansoura, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||18-Jun-2017|
|Date of Acceptance||17-Jul-2017|
|Date of Web Publication||07-Jan-2019|
Dr. Nancy A Ahmed
Department of Internal Medicine, Mansoura
Source of Support: None, Conflict of Interest: None
Background Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy can help plan therapy. However, biopsy is an invasive procedure with occasional complications and poor patient acceptance.
Aim The aim of this work was to compare noninvasive and invasive methods for evaluation of fibrosis in patients with chronic hepatitis C.
Patients and methods This cross-sectional study was carried out at the Liver Unit of Mansoura University Hospital and Mansoura Health Insurance Hospital. The study was conducted on 100 patients with chronic active hepatitis. Biochemical and virological studies were performed in addition to abdominal ultrasonography and liver biopsy in all patients. Moreover, analyses of serum fibronectin (FN), AST-to-platelet ratio index (APRI), and alanine aminotransferase/aspartate aminotransferase (AST/ALT) ratio were performed.
Results We found that FN has the highest sensitivity and specificity, and the independent variables related to fibrosis were FN, APRI, and AST/ALT ratio.
Conclusion The biochemical tests including APRI, AST/ALT ratio, and particularly FN could be valuable noninvasive predictors for assessment of liver fibrosis in patients with chronic hepatitis C infection.
Keywords: biopsy, fibronectin, hepatitis C virus, liver
|How to cite this article:|
Menessy AN, Ahmed NA, Abdallah NI, Arif SS. Noninvasive predictors of hepatic fibrosis in patients with chronic hepatitis C virus in comparison with liver biopsy. Benha Med J 2018;35:282-6
|How to cite this URL:|
Menessy AN, Ahmed NA, Abdallah NI, Arif SS. Noninvasive predictors of hepatic fibrosis in patients with chronic hepatitis C virus in comparison with liver biopsy. Benha Med J [serial online] 2018 [cited 2020 Feb 26];35:282-6. Available from: http://www.bmfj.eg.net/text.asp?2018/35/3/282/249412
| Introduction|| |
Hepatitis C virus (HCV) infection is a major health problem in Egypt, where its seroprevalence is 10- to 20-folds higher than that in the USA. Egypt has the highest prevalence of HCV worldwide, ranging from 6% to more than 40% across regions and demographic groups. At present, liver biopsy (LB) is considered the ‘gold standard’ to evaluate the grade of liver fibrosis . Liver fibrosis is the main predictor of the progression of chronic hepatitis C (CHC), and its assessment by LB can help plan therapy . However, biopsy is an invasive procedure with occasional complications and poor patient acceptance . Diagnosis of HCV infection is based on the presence of both anti-HCV antibodies, detected by enzyme immunoassays, and HCV-RNA, detected by molecular assays. HCV-RNA testing is essential for the management of HCV therapy . Advanced liver fibrosis results in cirrhosis that can in turn lead to liver failure, portal hypertension, and hepatocellular carcinoma. Fibrosis develops with different spatial patterns and is a consequence of various prevalent mechanisms according to the diverse causes of parenchymal damage. Early detection of fibrosis would allow for initiation of antifibrotic therapies capable of halting and even reversing this process .
Pain is the most common complication of percutaneous LB, occurring in up to 84% of patients, including those with relatively mild discomfort . The most important complication of LB is bleeding, which when severe occurs intraperitoneally . A number of other complications have been reported after LB, which include pneumothorax, hemothorax, perforation of any of several viscous organs, bile peritonitis, infection, hemobilia, and neuralgia . There are some contraindications in using biopsy as absolute − severe coagulopathy, infection of the hepatic bed, and extrahepatic biliary obstruction − and relative − ascites, morbid obesity, possible vascular lesions, amyloidosis, and hydatid disease. Of similar importance to adequate specimen size is the necessity that a pathologist experienced in liver disease interpret the biopsy, ideally in partnership with the clinician who performed the biopsy and/or who is caring for the patient . In the absence of this interaction, diagnostic errors by nonspecialist pathologists have been reported in more than 25% of patients evaluated at an academic center . Complex scoring systems, such as the Knodell scoring system, and its revised form, the Ishak scoring system, have been devised for grading and staging of chronic viral hepatitis, as shown in the following table :
Several noninvasive tests have become available for clinicians to assess liver fibrosis and determine the best course of management for their patients, especially those with CHC . Serum markers of liver fibrosis offer an attractive, cost-effective alternative to LB for both patients and clinicians. In addition to being substantially less invasive, there are practically no complications, little or no sampling errors, and small observer-related variability. Moreover, measurements may be performed repeatedly, thus allowing for a dynamic monitoring of fibrosis . Fibronectin (FN) is a glycoprotein produced from hepatocytes, Kupffer cells, and endothelial cells. Circulating FN represents a viable marker for the presence of significant and advanced liver fibrosis in patients with CHC. FN was identified as a 90 kDa protein and quantified in sera of individuals with CHC using enzyme linked immunosorbent assay . FN is one of the molecules produced by hepatic stellate cells. It is also part of the extracellular matrix, so it is important for the assembly of a collagen matrix in vitro. Its continuous presence also supports matrix integrity, both in vitro and in vivo. It further regulates cell proliferation and cell cycle progression . FN has been related to liver fibrosis and subsequent development of portal hypertension in chronic liver disease . Interpretation of serum aminotransferase levels, coagulation parameters, and platelet counts has been used in clinical practice to determine whether cirrhosis is compensated or decompensated. Several studies have also evaluated the accuracy of combinations (or ratios) of these measures .
| Patients and methods|| |
The present study was cross-sectional in nature.
This study was carried out at the Liver Unit of Mansoura University Hospital and Mansoura Health Insurance Hospital.
Sample and sampling technique
A total of 100 adult patients with chronic active hepatitis were included in the study. The inclusion criteria included the following: age from 18 to 60 years, positive anti-HCV and HCV-RNA, patients with LB-proven chronic hepatitis, and HBs-Ag negative. Exclusion criteria were aged younger than 18 and older than 60 years, coinfection with hepatitis B virus, active alcohol consumption or features of alcoholic disease in the LB, hepatitis B surface antigen positive, pre-existing psychiatric condition, pregnancy or breast feeding, and comorbidities. All patients were subjected to thorough history taking and complete clinical examination. Laboratory investigations included the following: complete blood count (white blood cells, hemoglobin, and platelets), bleeding time, alanine aminotransferase (ALT) (U/l), aspartate aminotransferase (AST) (U/l), serum bilirubin (mg/dl), serum albumin (g/dl), alkaline phosphatase (U/l), international normalized ratio, viral markers including HCV antibody and HCV-RNA (IU/m1), and hepatitis B surface antigen, AST/ALT ratio (AAR), AST-to-platelet ratio index (APRI), antinuclear antibody titer, smooth muscle antibody, antimitochondrial antibody, and liver–kidney microsomal antibodies, thyroid-stimulating hormone level, α-fetoprotein (ng/dl), pregnancy test for females in childbearing period, and serum FN (ng/ml), which was detected as follows: samples and standards were added and incubated in plates at 37°C for 90 min, with no wash. Biotinylated antibodies were added and the plates were incubated at 37°C for 60 min and washed three times with 0.01 M TBS. ABC working solution was added and then again the plates were incubated at 37°C for 30 min after washing five times with 0.01 M TBS. TMB color-developing agent was added, and the plates were incubated at 37°C in dark for 20–25 min. TMB stop solution was added, and the plated were analyzed (Boster Biological Technology Co., Pleasanton, California, USA). Abdominal ultrasound was performed for all cases. LB was performed by a highly qualified specialist in a well-equipped place under complete aseptic conditions. The biopsy samples were examined by a pathologist unaware of the laboratory results. Needle LB specimens (n=100) were taken from all patients and, biopsies were processed for diagnostic purposes. They were fixed in 10% neutral, buffered formalin solution, embedded in paraffin, cut into 4 µm thick slice, and routinely stained with hematoxylin and eosin for analysis. The biopsies were pathologically classified according to Metavir staging system into different stages of fibrosis and cirrhosis from F0 to F4.
Data collection and ethical considerations
In the period between April 2012 and May 2014, the study was carried out on 100 adult patients with chronic active hepatitis; of them, 53 (53%) were males and 47 (47%) were females. Informed written consent to participate in the study was obtained from each patient.
Descriptive statistics were calculated for the anthropometric measurements and laboratory data in the form of mean±SD, median and interquartile range, and frequency [n (%)], using one of the following tests: Student’s t-test, analysis of variance, and Mann–Whitney U-test. The sensitivity and specificity of FN, APRI, AST/ALTs ratio, and serum albumin to diagnose fibrosis were examined at different cutoff points using receiver operating characteristic (ROC) curve analysis to determine the best cutoff point as well as the diagnostic power of each test. A P value less than 0.05 was considered statistically significant. P value less than 0.0001 was considered highly significant in all analyses.
| Results|| |
[Table 1] shows the stages of fibrosis in studied cases according to Metavir.
As shown in [Table 2], there is no significant difference in serum albumin level in the different stages of liver fibrosis.
As shown in [Table 3], serum bilirubin level is significantly increased with the progress of the degree of hepatic fibrosis.
As shown in [Table 4], the increase in the degree of fibrosis is significantiy associated with decrease in platelet count.
As shown in [Table 5], AST is increased significantly with the increase in the stages of fibrosis.
|Table 5 Aspartate aminotransferase level in different stages of fibrosis|
Click here to view
As shown in [Table 6], there is no significant changes in ALT level with the progress of the degree of liver fibrosis.
As shown in [Table 7], AST/ALT ratio is significantly increased with the increase in degree of fibrosis from F0 to F4.
|Table 7 Alanine aminotransferase/aspartate aminotransferase ratio in different stages of fibrosis|
Click here to view
As shown in [Table 8], the progress of the stages of fibrosis from F0 to F4 is associated with significant increase in APRI.
|Table 8 Aspartate aminotransferase-to-platelet ratio index in different stages of fibrosis|
Click here to view
As shown in [Table 9], there is significant increase in serum level of FN with the increase in stages of liver fibrosis from F0 to F4.
| Discussion|| |
The gold standard for detecting liver fibrosis remains percutaneous LB. However, the procedure is limited by its invasive nature, expense, morbidity, intraobserver and interobserver variability, and sampling errors . Fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. Blood-based biomarkers offer a number of advantages over the traditional standard of fibrosis assessment of LB, including safety, cost savings, and widespread accessibility . According to Metavir scoring system, AST was increased (P<0.001), as shown in [Table 5]. These results were in agreement with Ahmed et al.  who reported that AST was significantly increased with the progress of fibrosis stages. With the progress in the stages of fibrosis, platelet count was decreased (P 0.01), as shown in [Table 4]. Snyder et al.  reported that low platelet count was caused by a variety of diseases such as HCV. In the current study, the progress in the degree of fibrosis is associated with the increase in AAR (AST/ALT ratio), as shown in [Table 7]. Yu Hsieh et al.  reported that the AAR scores increased significantly as fibrosis advanced. The level of APRI was increased significantly with the progression of liver fibrosis stages, as shown in [Table 8] (P<0.001). Similar results were obtained by Ahmed et al.  who reported that APRI was significantly increased with progression of fibrosis stages. Similar results were obtained by Yilmaz et al.  who reported that APRI was significantly associated with fibrosis scores in patients with CHC. In the current study, serum level of FN was increased with the progress of the degree of fibrosis, as shown in [Table 9] (P<0.001). Similar results were obtained by Mosa et al. . In the current study, the level of serum bilirubin was significantly increased within the progress of fibrosis stages (P<0.001), as shown in [Table 3]. This result was in agreement with Ahmed et al.  who reported that serum bilirubin was significantly increased with the progress in stages of fibrosis. According to the stages of fibrosis (Metavir scoring system), the level of serum albumin was not significantly affected with the change in degrees of fibrosis (P=0.85), as shown in [Table 2]. This result was in agreement with Saudy et al. . Using ROC curves, the patients were examined to assess and compare the diagnostic accuracy of blood markers such as FN, APRI, AST/ALT ratio, and serum albumin in patients with liver fibrosis. In the current study, as shown in [Table 10], ROC curves of biomarkers were used for discriminating patients with CHC with no liver fibrosis (F0) from those with liver fibrosis (F1–F4). Using cutoff value of 16, 0.13, 1.087, and less than 4.25 and the area under the curve of 83.3, 79.6, 61.7, and 51.1 for FN, APRI, AST/ALT ratio, and albumin, respectively, the sensitivity of FN, APRI, AAR, and albumin were 80.7, 80.7, 55.7, and 47.7%, respectively; specificity of FN, APRI, AAR, and albumin were 77, 77, 42, and 58.3, respectively; positive predictive value for serum FN, APRI, AAR, and albumin was 94.6, 94.6, 90.7, and 89.4, respectively; and negative predictive value for FN, APRI, AAR, and serum albumin was 32, 32, 15.2, and 13.2, respectively.
|Table 10 Sensitivity and specificity of different laboratory parameters in detection of fibrosis|
Click here to view
| Conclusion|| |
FN has a better accuracy than APRI, AST/ALT ratio, and albumin in the ability to predict fibrosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Okasha H, Abdalla MN, Ramadan NN, El-Nabwey W. Non-invasive evaluation of hepatic fibrosis in patients with hepatitis C using elastography. Egypt J Intern Med 2012; 24:79–82. [Full text]
Ziol M, Luca AH, Kettaneh A, Christidis C, Mal F, Kazemi F et al.
Non-invasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005; 41:48–54.
Forns X, Ampurdanès S, Llovet JM, Aponte J, Quint L, Bauer EM et al.
Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002; 36:986–1992.
Chevaliez S, Pawlotsky JM. Diagnosis and management of chronic viral hepatitis antigens, antibodies and viral genomes. Best Pract Res Clin Gastroenterol 2008; 22:1031–1048.
Yilmaz Y, Yonal O, Kurt R, Bayrak M, Aktas B, Ozdogan O. Non-invasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio index (APRI): usefulness in patients with chronic liver disease. Hepat Mon 2011; 11:103–107.
Eisenberg E, Konopniki M, Veitsman E, Kramskay R, Gaitini D, Baruch Y. Prevalence and characteristics of pain induced by percutaneous liver biopsy. Anesth Analg 2003; 96:1392–1396.
Huang JF, Hsieh MY, Dai CY, Hou NJ, Lee LP, Lin ZY et al.
The incidence and risks of liver biopsy in non-cirrhotic patients: An evaluation of 3806 biopsies. Gut 2007; 56:736–737.
Kalambokis G, Manousou P, Vibhakorn S, Marelli L, Cholongitas E, Senzolo M et al.
Transjugular liver biopsy − indications, adequacy, quality of specimens, and complications − a systematic review. J Hepatol 2007; 47:284–294.
Bellest L, Eschwege V, Poupon R, Chazouilleres O, Robert A. Amodified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology 2007; 46:528–534.
Bejarano PA, Koehler A, Sherman KE. Second opinion pathology in liver biopsy interpretation. Am J Gastroenterol 2001; 96:3158–3164.
Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy by the American Association for the Study of Liver Diseases. Hepatology 2009; 49:1017–1044.
Kotlyar D, Blonski W, Rustgi V. Non-invasive monitoring of hepatitis C fibrosis progression. Clin Liver Dis 2008; 12:557–571.
Zhou K, Lu LG. Assessment of fibrosis in chronic liver diseases. J Dig Dis 2009 10:7–14.
Attallah AM, Abdallah SO, Attallah AA, Omran MM, Farid K, Nasif WA et al.
Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients. Ann Hepatol 2013; 47:44–53.
Kawelke N, Vasel M, Sens C, von Au A, Dooley S, Nakchbandi IA. Fibronectin protects from excessive liver fibrosis by modulating the availability of and responsiveness of stellate cells to active TGF-β. J Cell Biol 2011; 178:167–178.
Mosa TE, Khayyal AA, Saad A, Abo-Zeid MM. Evaluation of serum fibronectin and interleukin-10 in Egyptian patients with combined viral hepatitis C and schistosomiasis. J Genet Eng Biotechnol 2007; 5:1–8.
Zarski JP, Sturm N, Guechot J. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study. J Hepatol 2012; 56:55.
Gumusay O, Ozenirler S, Atak A. Diagnostic potential of serum direct markers and non-invasive fibrosis models in patients with chronic hepatitis B. Hepatol Res 2013; 43:228–237.
Adam LA. Biomarkers of liver fibrosis. J Gastroenterol Hepatol 2011; 20:802–809.
Ahmad W, Ijaz B, Javed FT, Gull S, Kausar H, Sarwar MT et al.
A comparison of four fibrosis indexes in chronic HCV: Development of new fibrosis-cirrhosis index (FCI). BMC Gastroenterol 2011; 11:44.
Snyder N, Gajula L, Xiao SY, Grady J, Luxon B, Lau DT. APRI: an easy and validated predictor of hepatic fibrosis in chronic hepatitis C. J Clin Gastroenterol 2006; 40:535–542.
Yu Hsieh Y, Yi Tung S, Lin L, Lee K, Heng Shen C, Liang Wei K et al.
FibroQ: an easy and useful non-invasive test for predicting liver fibrosis in patients with chronic viral hepatitis. Chang Gung Med J 2009; 32:614–622.
Saudy N, Elghannam DM, Farag R, Abd El-Maksoud M, El-Hussiny MA, Mohamed EM et al.
Study of some fibrosis indices in genotype 4 HCV infected Egyptian patients. Life Sci J 2012; 9:972–984.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]