Journal List > Lab Med Online > v.9(3) > 1131944

TOOLS
Lee, Cho, Kim, Uh, and Youn: Evaluation of Noninvasive Liver Fibrosis Blood Markers in Patients with Chronic Hepatitis B and Hepatitis C
Original Article

Lab Med Online 2019;9(3):153-160.

Published online: 20 July 2019

DOI: https://doi.org/10.3343/lmo.2019.9.3.153

Evaluation of Noninvasive Liver Fibrosis Blood Markers in Patients with Chronic Hepatitis B and Hepatitis C

Jong-Han Lee, M.D., Jooyoung Cho, M.D., Juwon Kim, M.D., Young Uh, M.D., Kap Jun Youn, M.D.

Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea

Corresponding author: Jong-Han Lee, M.D., Ph.D. https://orcid.org/0000-0003-4036-8443 Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea Tel: +82-33-741-1594, Fax: +82-33-731-0506, E-mail: cello425@yonsei.ac.kr

Received 28 September 2018       Revised 9 November 2018       Accepted 13 December 2018

Copyright © 2019 The Korean Society for Laboratory Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Liver fibrosis evaluation is an important issue in chronic liver disease patients. We aimed to develop noninvasive liver fibrosis biomarkers based on transient elastography (TE, FibroScan®) through retrospective review of clinicopathological data.

Methods

We recruited 278 chronic hepatitis B patients who underwent Fibroscan and HBV DNA testing. A total of 115 HBeAg-positive and 159 HBeAg-negative chronic hepatitis B patients were analyzed. A total of 100 hepatitis C patients were analyzed. Successful fibroscan data, gamma-glutamyl transferase (GGT) to platelet ratio (GPR), platelet count, AST, ALT, international normalized ratio of prothrombin time, total cholesterol, triglycerides, bilirubin, mean platelet volume, AST to platelet ratio index, fibrosis index based on four factors (FIB-4), neutrophil to lymphocyte ratio (NLR), and NLR to platelet ratio were analyzed to determine the new noninvasive markers for assessing liver fibrosis.

Results

Elevated GPR (OR=9.1, P=0.011) and FIB-4 (OR=2.3, P=0.01) were associated with greater risk of liver fibrosis in chronic hepatitis B patients. FIB-4 (OR =6.04, P=0.005) was a risk factor for liver fibrosis in HBeAg-positive patients. FIB-4 (OR =2.371, P=0.015) and GPR (OR=33.78, P=0.003) were liver fibrosis risk factor in HBeAg-negative patients. In chronic hepatitis C patients, GGT (OR=1.033, P=0.002), triglyceride (OR=–0.990, P=0.038) and FIB-4 (OR=3.499, P=0.006) showed statistical significances. The AUCs were 0.816 in FIB-4 (P<0.001) and 0.849 in GPR (P<0.001).

Conclusions

FIB-4 and GPR may be useful blood markers for assessing liver fibrosis in chronic hepatitis B and hepatitis C patients. Further well-designed prospective study is required to validate these noninvasive blood markers in clinical practice.

Keywords: Liver fibrosis, Hepatitis B, Hepatitis C, Fibroscan, Noninvasive marker

References

1. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001; 344:495–500.
crossref
2. Coco B, Oliveri F, Maina AM, Ciccorossi P, Sacco R, Colombatto P, et al. Transient elastography: a new surrogate marker of liver fbrosis in-fuenced by major changes of transaminases. J Viral Hepat. 2007; 14:360–9.
3. Colombo S, Belloli L, Buonocore M, Jamoletti C, Zaccanelli M, Badia E, et al. True normal liver stiffness measurement (LSM) and its determinants. Hepatology. 2009; 50:741A–2A.
4. Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut. 2006; 55:403–8.
crossref
5. Friedrich–Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fbrosis: a metaanalysis. Gastroenterology. 2008; 134:960–74.
6. Kim SU, Choi GH, Han WK, Kim BK, Park JY, Kim DY, et al. What are ‘true normal'liver stiffness values using FibroScan?: a prospective study in healthy living liver and kidney donors in South Korea. Liver Int. 2010; 30:268–74.
7. Pinzani M, Vizzutti F, Arena U, Marra F. Technology Insight: noninvasive assessment of liver fbrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol. 2008; 5:95–106.
8. Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology. 2008; 47:380–4.
crossref
9. Sagir A, Erhardt A, Schmitt M, Häussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology. 2008; 47:592–5.
crossref
10. Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, De Lédinghen V, et al. Non‐invasive assessment of liver fbrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int. 2009; 29:242–7.
11. Lok AS and McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009; 50:661–2.
crossref
12. Kim SU, Seo YS, Cheong JY, Kim MY, Kim JK, Um SH, et al. Factors that affect the diagnostic accuracy of liver fbrosis measurement by Fibroscan in patients with chronic hepatitis B. Aliment Pharmacol Ther. 2010; 32:498–505.
13. Kim BK, Kim DY, Park JY, Ahn SH, Chon CY, Kim JK, et al. Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fbrosis and cirrhosis in hepatitis B virus-infected patients. Liver Int. 2010; 30:546–53.
14. Liu DP, Lu W, Zhang ZQ, Wang YB, Ding RR, Zhou XL, et al. Comparative evaluation of GPR versus APRI and FIB-4 in predicting different levels of liver fbrosis of chronic hepatitis B. J Viral Hepat. 2018; 25:581–9.
15. Lemoine M, Shimakawa Y, Nayagam S, Khalil M, Suso P, Lloyd J, et al. The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts signifcant liver fbrosis and cirrhosis in patients with chronic HBV infection in West Africa. Gut. 2016; 65:1369–76.
16. Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fbrosis: an updated metaanalysis. Hepatology. 2011; 53:726–36.
17. Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. FIB-4: an inexpensive and accurate marker of fbrosis in HCV infection. comparison with liver biopsy and fbrotest. Hepatology. 2007; 46:32–6.
18. Li J, Verhaar AP, Pan Q, de Knegt RJ, Peppelenbosch MP. Serum levels of caspase-cleaved cytokeratin 18 (CK18-Asp396) predict severity of liver disease in chronic hepatitis B. Clin Exp Gastroenterol. 2017; 10:203–9.
crossref
19. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, et al. Serum markers detect the presence of liver fbrosis: a cohort study. Gastroenterology. 2004; 127:1704–13.
20. Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S, et al. A serum “sweet-doughnut” protein facilitates fbrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013; 3:1065.
crossref
21. Nishikawa H, Takata R, Enomoto H, Yoh K, Kishino K, Shimono Y, et al. Proposal of a predictive model for advanced fbrosis containing Wisteria foribunda agglutinin-positive Mac-2-binding protein in chronic hepatitis C. Hepatol Res. 2017; 47:E74–84.
22. Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, et al. Association between Wisteria foribunda agglutinin-positive Mac-2 binding protein and the fbrosis stage of non-alcoholic fatty liver disease. J Gastroenterol. 2015; 50:776–84.
23. Umemura T, Joshita S, Sekiguchi T, Usami Y, Shibata S, Kimura T, et al. Serum Wisteria foribunda agglutinin-positive Mac-2-binding protein level predicts liver fbrosis and prognosis in primary biliary cirrhosis. Am J Gastroenterol. 2015; 110:857–64.
24. Nishikawa H, Enomoto H, Iwata Y, Hasegawa K, Nakano C, Takata R, et al. Clinical signifcance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level and high-sensitivity C-reactive protein concentration in autoimmune hepatitis. Hepatol Res. 2016; 46:613–21.
25. Yamada N, Sanada Y, Tashiro M, Hirata Y, Okada N, Ihara Y, et al. Serum Mac-2 binding protein glycosylation isomer predicts grade F4 liver fbrosis in patients with biliary atresia. J Gastroenterol. 2017; 52:245–52.

Fig. 1.
Box plot of gamma glutamyl transferase (GGT), platelet count, FIB-4 and GPR in chronic hepatitis B patients.
lmo-9-153f1.tif
Fig. 2.
Receiver operating characteristic (ROC) curve analysis of FIB-4 and GPR for the evaluation of liver fibrosis comparing transient elastography (fibroscan) results in chronic hepatitis B patients.
lmo-9-153f2.tif
Table 1.
Summary of calculated biomarkers for liver fibrosis expectation
Calculated biomarkers Calculation formula
APRI [100×AST (U/L)/ULN (40 (U/L) for male, 35 (U/L) for female/platelet count (109/L)]
FIB-4 age×AST (U/L)/platelet count×ALT1/2
GPR [100×GGT (U/L)/ULN (60 (U/L) for male, 40 (U/L) for female)/platelet count (109/L)]
NLR Neutrophil/lymphocyte
NLR to platelet count Neutrophil/lymphocyte/platelet count

Abbreviations: APRI, AST to platelet ratio index; ULN, upper limit of normal; FIB-4, fibrosis index based on four factors; GPR, GGT to platelet ratio; GGT, gamma-glutamyl transferase; NLR, neutrophil to lymphocyte ratio.

Table 2.
Levels of parameters according to different liver stiffness measurement levels measured by transient elastography
Scale of liver stiffness measurement (kPa) <5.3 kPa 5.3–<7.2 kPa 7.2–<9.4 kPa 9.4–<12.2 kPa ≥12.2 kPa
Number 60 54 38 34 92
Age 44±12.9 (20–81) 46.8±11.1 (19–73) 46.7±12 (25–78) 46.9±9.7 (29–66) 49.5±10.4 (15–81)
Gender ratio (Male/Female) 1.3 (34/26) 1.7 (34/20) 1.1 (20/18) 1.3 (19/15) 3 (69/23)
HBeAg (Positive/Negative) 0.3 (13/47) 0.6 (20/34) 0.5 (13/25) 0.9 (16/18) 1.4 (54/38)
Liver stiffness measurement (kPa) 4±0.69 (2.4–5.2) 6.03±0.54 (5.3–7.1) 8.14±0.67 (7.2–9.3) 10.72±0.87 (9.4–12) 24.92±12.82 (12.2–72)
Inter quartile range 0.57±0.25 (0.1–1.1) 0.76±0.33 (0.1–1.6) 1.06±0.4 (0.3–2) 1.31±0.58 (0.3–2.7) 2.74±1.73 (0–10.7)
Success rate (%) 93.4±11 (60–100) 96.6±7.6 (71–100) 97.5±8.14 (63–100) 98.6±4.3 (80–100) 96.6±7.6 (67–100)
Platelet (×109/L) 230.9±51.3 (128–358) 197.8±59.1 (66–321) 194.3±81.6 (62–547) 188.7±63 (77–339) 128.5±55.4 (44–395)
GGT (U/L) 28±26.4 (6–146) 38.6±32.7 (9–153) 58.4±82.3 (7–525) 71±49.6 (8–203) 114±115.4 (15–809)
Cholesterol (mg/dL) 180.6±30.1 (118–253) 177.2±35.4 (91–280) 172.9±37.3 (120–318) 174.2±28.4 (124–236) 159.7±32.6 (88–235)
AST (U/L) 30.3±32.6 (12–265) 33.6±19 (17–135) 58.1±50.1 (20–242) 57.4±40.9 (18–178) 147.1±283.8 (19–2255)
ALT (U/L) 40.4±93 (8–738) 40.7±36.8 (6–229) 81.1±96.4 (10–445) 69±71.9 (11–304) 198.2±473.5 (12–3690)
INR (sec) 1.01±0.06 (0.86–1.16) 1.02±0.06 (0.9–1.16) 1.06±0.12 (0.92–1.7) 1.05±0.05 (0.96–1.16) 1.16±0.19 (0.91–2.52)
Bilirubin (mg/dL) 0.74±0.33 (0.17–1.7) 0.83±0.42 (0.3–2.22) 0.74±0.35 (0.3–1.8) 0.69±0.33 (0.2–1.52) 1.45±2.11 (0.3–14.41)
HBVDNA (IU/mL) 2,501,759±9,852,121.6 (22–61,300,000) 7,517,113.8±29,539,919.9 (24–170,000,000) 16,979,600.8±45,423,067 (36–170,000,000) 11,900,288.5±40,473,294.1 (23–170,000,000) 9,871,502.5±20,958,659.1 (37–132,000,000)
Triglyceride (mg/dL) 104.3±53.2 (29–277) 99.3±49.8 (42–239) 84.8±37.8 (32–198) 93.7±29.7 (46–169) 94.3±43 (28–282)
MPV (fL) 7.918±0.748 (6.4–10) 7.989±0.715 (6.2–9.4) 8.113±0.767 (6.3–9.9) 8.147±0.827 (6.4–10.5) 8.762±0.882 (7–11.2)
Neutrophil (%) 55.9±8.5 (38.1–74.9) 53.3±8.2 (37.7–68.1) 52.5±8.7 (36.3–71.3) 50.9±10.6 (31.9–74.6) 52.3±10.5 (27.5–80.5)
Lymphocyte (%) 34±7.2 (18.6–49.8) 36±7.7 (19.6–50.6) 36.8±7.6 (19.8–52.8) 38.2±10.1 (16.8–56.8) 35.2±9.6 (11.8–59.5)
AST/ALT 1.04±0.42 (0.36–2.5) 1.04±0.47 (0.45–3.17) 1.02±0.65 (0.44–4) 1.08±0.59 (0.48–3.14) 1.14±0.72 (0.37–4.08)
APRI 0.37±0.398 (0.096–3.125) 0.498±0.394 (0.169–2.836) 0.913±0.902 (0.274–4.327) 0.873±0.624 (0.174–2.565) 3.348±7.101 (0.181–53.184)
FIB-4 1.063±0.573 (0.266–2.591) 1.539±1.019 (0.379–5.756) 2.022±1.807 (0.527–8.89) 2.023±1.127 (0.4–5.833) 4.657±3.961 (0.736–27.084)
GPR 0.251±0.266 (0.059–1.83) 0.43±0.485 (0.08–2.47) 0.689±0.889 (0.065–5.435) 0.821±0.655 (0.051–3.076) 1.878±2.225 (0.095–16.245)
NLR 1.778±0.665 (0.765–4.027) 1.604±0.604 (0.751–3.474) 1.549±0.633 (0.688–3.601) 1.534±0.841 (0.562–4.44) 1.716±0.954 (0.476–6.822)
NLR/platelet 0.008±0.004 (0.003–0.02) 0.009±0.006 (0.003–0.044) 0.009±0.005 (0.003–0.025) 0.01±0.009 (0.002–0.039) 0.016±0.012 (0.002–0.071)

Abbreviations: GGT, gamma-glutamyl transferase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio of prothrombin time; MPV, mean platelet volume; APRI, AST to platelet rati index; FIB-4, fibrosis index based on four factors; GPR, GGT to platelet ratio; NLR, neutrophil to lymphocyte ratio.

Table 3.
Diagnostic sensitivity, specificity, positive predictive value and negative predictive value of FIB-4 and GPR for liver fibrosis prediction
Parameters Sensitivity (%) Specificity (%) PPV (%) NPV (%) AUC P value
FIB-4 (cut-off: 1.571) 65.1 86.7 86.7 86.7 0.82 <0.001
GPR (cut-off: 0.299) 79.4 83.3 83.3 83.3 0.84 <0.001

Abbreviations: FIB-4, fibrosis index based on four factors; PPV, positive predictive value; NPV, negative predictive value; GPR, gamma-glutamyl transferase to platelet ratio; AUC, area under the curve.

Table 4.
Characteristics of baseline parameters according to HBeAg status
  HBeAg positive (N=115) HBeAg negative (N=159) P value
Age (yr) 45.4±11.9 48.3±10.9 0.037
Sex ratio (Male:Female) 1.7 (73:42) 1.7 (100:59) 0.921∗
Liver stiffness measurement (kPa) 14.751±11.156 10.757±10.683 0.003
AST (U/L) 95.8±142.3 63±193 0.124
ALT (U/L) 132.5±268 80.5±302.5 0.142
GGT (U/L) 68.3±58.2 63.7±94.2 0.644
Total Bilirubin (mg/dL) 0.9±0.55 1.05±1.63 0.344
Total Cholesterol (mg/dL) 170.5±30.8 172.1±35.4 0.696
Triglyceride (mg/dL) 94.5±41.9 97.4±47.5 0.605
Platelet count (×109/L) 174.1±73.6 186.4±70.1 0.163
Mean platelet volume (fL) 8.41±0.86 8.17±0.88 0.022
Prothrombin time, INR 1.09±0.12 1.07±0.16 0.265
HBV DNA (IU/mL) 21,028,204.8±41,665,244.9 591,105.9±3,276,928.3 <0.001
AST/ALT ratio 1.11±0.71 1.04±0.46 0.282
APRI 1.747±2.596 1.345±5.241 0.449
FIB-4 2.958±2.799 2.275±2.879 0.05
GPR 0.9±0.813 0.922±1.777 0.889
NLR 1.53±0.704 1.753±0.829 0.02
NLR/platelet count 0.011±0.008 0.012±0.01 0.309

∗ Pearson's chi-square test. Statistical significant P values were printed in bold.

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; INR, international normalized ratio of prothrombin time; APRI, AST to platelet ratio index; FIB-4, fibrosis index based on the four factors; GPR, GGT to platelet ratio; NLR, neutrophil to lymphocyte ratio.

Table 5.
Levels of parameters according to liver stiffness measurement in chronic HCV infected patients
  LSM<5.3 kPa (N=74) LSM≥5.3 kPa (N=26) P value
Genotype 1b/2a 37/37 17/9 0.176∗
Age (yr) 53 58 0.016
Male/Female 37/37 11/15 0.499∗
LSM (kPa) 4.05 10.3 <0.001
AST (U/L) 36 65 <0.001
ALT (U/L) 44.5 82 0.001
GGT (U/L) 27.5 83.5 <0.001
Bilirubin (mg/dL) 0.58 0.705 0.010
Cholesterol (mg/dL) 191.5 160.5 0.001
Triglyceride (mg/dL) 117.5 98 0.004
Platelet (×109/L) 237.5 173.5 <0.001
MPV (fL) 7.25 7.9 0.004
INR (sec) 0.985 1.025 0.005
HCV RNA 834,000 1,510,000 0.535
AST to ALT ratio 0.86 0.845 0.786
APRI 0.405 1.005 <0.001
FIB-4 1.245 2.78 <0.001
GPR 0.12 0.475 <0.001
NLR 1.755 1.45 0.210
NLR/platelet 0.007 0.008 0.049

∗ Pearson's chi-square test.

Abbreviations: GGT, gamma-glutamyl transferase; MPV, mean platelet volume; INR, international normalized ratio of prothrombin time; APRI, AST to platelet ratio index; FIB-4, fibrosis index based on four factors; GPR, GGT to platelet ratio; NLR, neutrophil to lymphocyte ratio.

TOOLS
Similar articles