Ann Lab Med.  2018 Jul;38(4):331-337. 10.3343/alm.2018.38.4.331.

Usefulness of Enhanced Liver Fibrosis, Glycosylation Isomer of Mac-2 Binding Protein, Galectin-3, and Soluble Suppression of Tumorigenicity 2 for Assessing Liver Fibrosis in Chronic Liver Diseases

• Moon HW
• Park M
• Hur M
• Kim H
• Choe WH
• Yun YM

• KMID: 2408072
• DOI: http://doi.org/10.3343/alm.2018.38.4.331

Abstract

BACKGROUND
Liver biopsies have been partially replaced by noninvasive methods for assessing liver fibrosis. We explored the usefulness of four novel biomarkers, enhanced liver fibrosis (ELF), glycosylation isomer of Mac-2 binding protein (M2BPGi), galectin-3, and soluble suppression of tumorigenicity 2 (sST2), in association with liver fibrosis.
METHODS
ELF, M2BPGi, galectin-3, and sST2 were assayed in 173 patients with chronic liver diseases. The results were analyzed according to fibrosis grade (F0/1, F2, and F3/4) by transient elastography (TE).
RESULTS
ELF, M2BPGi, galectin-3, and sST2 values differed significantly according to TE grade; ELF and M2BPGi values were higher in F2 and F3/4 than in F0/1 (P≤0.001, all), sST2 values were higher in F3/4 than in F0/1 and F2 (P < 0.05), and galectin-3 values were higher in F3/4 than in F0/1 (P=0.0036). ELF and M2BPGi showed good TE fibrosis detection performance (area under the curves [AUC], 0.841 and 0.833 for ≥F2; and 0.837 and 0.808 for ≥F3). The sensitivity and specificity for predicting TE grade F≥2 were 84.1% and 76.7% for ELF and 63.6% and 91.5% for M2BPGi.
CONCLUSIONS
This is the first study to compare the liver fibrosis assessment of four novel biomarkers: ELF, M2BPGi, galectin-3, and sST2. The biomarkers varied significantly according to TE grade, and each biomarker showed a different trend. ELF and M2BPGi seem to have comparable good performance for detecting liver fibrosis.

Keyword

Liver fibrosis; Biomarker; ELF; M2BPGi; Galectin-3; sST2

MeSH Terms

Biomarkers
Biopsy
Carrier Proteins*
Elasticity Imaging Techniques
Fibrosis
Galectin 3*
Glycosylation*
Humans
Liver Cirrhosis*
Liver Diseases*
Liver*
Sensitivity and Specificity
Biomarkers
Carrier Proteins
Galectin 3

Figure

• 

  Fig. 1 Comparison of the receiver operating characteristics curves for predicting transient elastography grade F≥2 (A) and F≥3 (B).Abbreviations: TE, transient elastography; ELF, enhanced liver fibrosis; M2BPGi, Mac-2-binding protein glycosylation isomer; sST2, soluble suppression of tumorigenicity 2.

Reference

1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008; 134:1655–1669. PMID: 18471545.

2. Kim JH, Kim MN, Han KH, Kim SU. Clinical application of transient elastography in patients with chronic viral hepatitis receiving antiviral treatment. Liver Int. 2015; 35:1103–1115. PMID: 24976523.

3. Lok AS. Hepatitis B: liver fibrosis and hepatocellular carcinoma. Gastroenterol Clin Biol. 2009; 33:911–915. PMID: 19577871.

4. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999; 341:1256–1263. PMID: 10528035.

5. Kim SU, Kim BK, Han KH. Clinical application of liver stiffness measurement using transient elastography: a surgical perspective. Digestion. 2013; 88:258–265. PMID: 24335341.

6. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001; 344:495–500. PMID: 11172192.

7. Rousselet MC, Michalak S, Dupré F, Croué A, Bedossa P, Saint-André JP, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology. 2005; 41:257–264. PMID: 15660389.

8. Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol. 2011; 54:650–659. PMID: 21146892.

9. Kim MN, Kim SU, Kim BK, Park JY, Kim DY, Ahn SH, et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology. 2015; 61:1851–1859. PMID: 25643638.

10. Friedrich-Rust M, Poynard T, Castera L. Critical comparison of elastography methods to assess chronic liver disease. Nat Rev Gastroenterol Hepatol. 2016; 13:402–411. PMID: 27273167.

11. Castéra L, Sebastiani G, Le Bail B, de Lédinghen V, Couzigou P, Alberti A. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol. 2010; 52:191–198. PMID: 20006397.

12. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T, et al. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001; 357:1069–1075. PMID: 11297957.

13. Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013; 3:1065. PMID: 23323209.

14. Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, et al. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol. 2015; 50:776–784. PMID: 25326152.

15. Yamasaki K, Tateyama M, Abiru S, Komori A, Nagaoka S, Saeki A, et al. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology. 2014; 60:1563–1570. PMID: 25042054.

16. Ito K, Kuno A, Ikehara Y, Sugiyama M, Saito H, Aoki Y, et al. LecT-Hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients. Hepatology. 2012; 56:1448–1456. PMID: 22535703.

17. Wettersten N. Biomarkers for heart failure: an update for practitioners of internal medicine. Am J Med. 2016; 129:560–567. PMID: 26844635.

18. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013; 128:e240–e327. PMID: 23741058.

19. Henderson NC. The regulation of inflammation by galectin-3. Immunol Rev. 2009; 230:160–171. PMID: 19594635.

20. Hsieh WC, Mackinnon AC, Lu WY, Jung J, Boulter L, Henderson NC, et al. Galectin-3 regulates hepatic progenitor cell expansion during liver injury. Gut. 2015; 64:312–321. PMID: 24837171.

21. Mueller T. The Presage(®) ST2 Assay: analytical considerations and clinical applications for a high-sensitivity assay for measurement of soluble ST2. Expert Rev Mol Diagn. 2013; 13:13–30. PMID: 23256700.

22. Hur M, Kim H, Kim HJ, Yang HS, Magrini L, Marino R, et al. Soluble ST2 has a prognostic role in patients with suspected sepsis. Ann Lab Med. 2015; 35:570–577. PMID: 26354344.

23. Kim H, Hur M, Moon HW, Yun YM. GREAT Network. Multimarker approach using procalcitonin, presepsin, galectin-3, and soluble suppression of tumorigenicity 2 for the prediction of mortality in sepsis. Ann Intensive Care. 2017; 7:27. PMID: 28271449.

24. Pejnovic N, Jeftic I, Jovicic N, Arsenijevic N, Lukic ML. Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis. World J Gastroenterol. 2016; 22:9706–9717. PMID: 27956794.

25. Kamath PS, Kim WR. Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology. 2007; 45:797–805. PMID: 17326206.

26. Murray KF, Carithers RL Jr. AASLD. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology. 2005; 41:1407–1432. PMID: 15880505.

27. Lichtinghagen R, Pietsch D, Bantel H, Manns MP, Brand K, Bahr MJ. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol. 2013; 59:236–242. PMID: 23523583.

28. McHugh ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012; 22:276–282. PMID: 23092060.

29. Weinstein MC, Fineberg HV. Clinical decision analysis. Philadelphia: WB Saunders;1980.

30. Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, et al. Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C. J Viral Hepat. 2011; 18:23–31. PMID: 20196799.

31. Kim BK, Kim HS, Park JY, Kim DY, Ahn SH, Chon CY, et al. Prospective validation of ELF test in comparison with Fibroscan and FibroTest to predict liver fibrosis in Asian subjects with chronic hepatitis B. PLoS One. 2012; 7:e41964. PMID: 22848675.

32. National Institute for Health and Care Excellence. Non-alcoholic fatty liver disease (NAFLD): assessment and management. NICE guideline [NG49]. 2016; 7.

33. Tapper EB. Use of liver imaging and biopsy in clinical practice. N Engl J Med. 2017; 377:756–768. PMID: 28834467.