Comparison of serum fibrosis biomarkers for diagnosing significant liver fibrosis in patients with chronic hepatitis B

Tsuji,Yuki; Namisaki,Tadashi; Kaji,Kosuke; Takaya,Hiroaki; Nakanishi,Keisuke; Sato,Shinya; Saikawa,Soichiro; Sawada,Yasuhiko; Kitagawa,Kou; Shimozato,Naotaka; Kawaratani,Hideto; Moriya,Kei; Noguchi,Ryuichi; Akahane,Takemi; Mitoro,Akira; Yoshiji,Hitoshi

doi:10.3892/etm.2020.8798

Comparison of serum fibrosis biomarkers for diagnosing significant liver fibrosis in patients with chronic hepatitis B

Authors:
- Yuki Tsuji
- Tadashi Namisaki
- Kosuke Kaji
- Hiroaki Takaya
- Keisuke Nakanishi
- Shinya Sato
- Soichiro Saikawa
- Yasuhiko Sawada
- Kou Kitagawa
- Naotaka Shimozato
- Hideto Kawaratani
- Kei Moriya
- Ryuichi Noguchi
- Takemi Akahane
- Akira Mitoro
- Hitoshi Yoshiji
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Affiliations: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634‑8522, Japan
Published online on: May 27, 2020 https://doi.org/10.3892/etm.2020.8798
Pages: 985-995
Copyright: © Tsuji et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chronic hepatitis B (CHB) virus continues to be a leading cause of morbidity and mortality worldwide. The diagnosis of liver fibrosis has a key role in selecting patients with CHB for antiviral treatment. However, serum biomarkers demonstrate limited diagnostic utility. The present study aimed to compare the performances of fibrosis biomarkers for diagnosing significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB and to identify the most appropriate biomarker for these patients. The current study included 96 antiviral‑naïve patients with CHB who underwent liver biopsy. METAVIR scoring system was used to assess liver fibrosis and necroinflammation. The diagnostic performances were evaluated of the platelet (PLT) count; the levels of hyaluronan, serum 7S domain of type 4 collagen, procollagen type III N‑terminal peptide, tissue inhibitor of metalloproteinases 1, Mac‑2 binding protein glycosylation isomer (M2BPGi) and N‑terminal type III collagen propeptide (Pro‑C3); the fibrosis index based on four factors; the aspartate aminotransferase‑to‑platelet ratio index; and enhanced liver fibrosis score for identifying significant liver fibrosis [≥fibrosis stage 2 (F2)]. All fibrosis biomarkers, except the Pro‑C3 level, correlated with the fibrosis stage. M2BPGi was better than other biomarkers for diagnosing ≥F2, with the highest area under the curve of 0.902. M2BPGi demonstrated a higher diagnostic accuracy for significant fibrosis than mild/severe fibrosis or cirrhosis. However, no significant correlation was observed between the M2BPGi level and fibrosis stage in patients with CHB having significant liver necroinflammation defined as ≥ necroinflammatory activity 2. The M2BPGi level and PLT count were exclusively correlated with the fibrosis stage in 73 patients without significant liver necroinflammation. M2BPGi demonstrated the highest diagnostic performance for significant fibrosis in patients having significant liver fibrosis with no significant liver necroinflammation. In conclusion, the M2BPGi level can accurately diagnose significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB.

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1	Okura Y, Namisaki T, Moriya K, Kitade M, Takeda K, Kaji K, Noguchi R, Nishimura N, Seki K, Kawaratani H, et al: Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis. Hepatol Res. 47:1317–1328. 2017.PubMed/NCBI View Article : Google Scholar
2	Saleh HA and Abu-Rashed AH: Liver biopsy remains the gold standard for evaluation of chronic hepatitis and fibrosis. J Gastrointestin Liver Dis. 16:425–426. 2007.PubMed/NCBI
3	Fujinaga Y, Namisaki T, Moriya K, Kitade M, Kawaratani H, Shimozato N, Kaji K, Takaya H, Sawada Y, Seki K, et al: Identification of clinical risk factors for histological progression of primary biliary cholangitis. Hepatol Res. 49:1015–1025. 2019.PubMed/NCBI View Article : Google Scholar
4	Venkatesh SK, Yin M, Takahashi N, Glockner JF, Talwalkar JA and Ehman RL: Non-invasive detection of liver fibrosis: MR imaging features vs. MR elastography. Abdom Imaging. 40:766–775. 2015.PubMed/NCBI View Article : Google Scholar
5	Mattos AZ and Mattos AA: Transient elastography vs. aspartate aminotransferase to platelet ratio index in hepatitis C: A meta-analysis. Ann Hepatol. 16:349–357. 2017.PubMed/NCBI View Article : Google Scholar
6	Yasui Y, Abe T, Kurosaki M, Matsunaga K, Higuchi M, Tamaki N, Watakabe K, Okada M, Wang W, Shimizu T, et al: Non-invasive liver fibrosis assessment correlates with collagen and elastic fiber quantity in patients with hepatitis C virus infection. Hepatol Res. 49:33–41. 2019.PubMed/NCBI View Article : Google Scholar
7	Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, Feng ZZ, Reddy KR and Schiff ER: Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 97:2614–2618. 2002.PubMed/NCBI View Article : Google Scholar
8	Baranova A, Lal P, Birerdinc A and Younossi ZM: Non-invasive markers for hepatic fibrosis. BMC Gastroenterol. 11(91)2011.PubMed/NCBI View Article : Google Scholar
9	Parikh P, Ryan JD and Tsochatzis EA: Fibrosis assessment in patients with chronic hepatitis B virus (HBV) infection. Ann Transl Med. 5(40)2017.PubMed/NCBI View Article : Google Scholar
10	Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH and Wong JB: Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 67:1560–1599. 2018.PubMed/NCBI View Article : Google Scholar
11	Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. JSH Guidelines for the management of hepatitis B virus infection. Hepatol Res. 44 (Suppl 1):S1–S58. 2014.PubMed/NCBI View Article : Google Scholar
12	Kim BK, Kim DY, Park JY, Ahn SH, Chon CY, Kim JK, Paik YH, Lee KS, Park YN and Han KH: Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus-infected patients. Liver Int. 30:546–553. 2010.PubMed/NCBI View Article : Google Scholar
13	Nishikawa H, Takata R, Enomoto H, Yoh K, Kishino K, Shimono Y, Iwata Y, Hasegawa K, Nakano C, Nishimura T, et al: Proposal of a predictive model for advanced fibrosis containing Wisteria floribunda agglutinin-positive Mac-2-binding protein in chronic hepatitis C. Hepatol Res. 47:E74–E84. 2017.PubMed/NCBI View Article : Google Scholar
14	Hansen JF, Juul Nielsen M, Nyström K, Leeming DJ, Lagging M, Norkrans G, Brehm Christensen P and Karsdal M: PRO-C3: A new and more precise collagen marker for liver fibrosis in patients with chronic hepatitis C. Scand J Gastroenterol. 53:83–87. 2018.PubMed/NCBI View Article : Google Scholar
15	Luo Y, Oseini A, Gagnon R, Charles ED, Sidik K, Vincent R, Collen R, Idowu M, Contos MJ, Mirshahi F, et al: An Evaluation of the collagen fragments related to fibrogenesis and fibrolysis in nonalcoholic steatohepatitis. Sci Rep. 8(12414)2018.PubMed/NCBI View Article : Google Scholar
16	Yoshiji H, Noguchi R and Fukui H: Combined effect of an ACE inhibitor, perindopril, and interferon on liver fibrosis markers in patients with chronic hepatitis C. J Gastroenterol. 40:215–216. 2005.PubMed/NCBI View Article : Google Scholar
17	Casals G, Fernández-Varo G, Melgar-Lesmes P, Marfà S, Reichenbach V, Morales-Ruiz M and Jiménez W: Factors involved in extracellular matrix turnover in human derived cardiomyocytes. Cell Physiol Biochem. 32:1125–1136. 2013.PubMed/NCBI View Article : Google Scholar
18	Saw S, Zhao H, Tan P, Saw B and Sethi S: Evaluation of the automated ADVIA centaur^® XP syphilis assay for serological testing. Diagn Microbiol Infect Dis. 88:7–11. 2017.PubMed/NCBI View Article : Google Scholar
19	Hogemann B, Voss B, Pott G, Rauterberg J and Gerlach U: 7 S collagen: A method for the measurement of serum concentrations in man. Clin Chim Acta. 144:1–10. 1984.PubMed/NCBI View Article : Google Scholar
20	Jekarl DW, Choi H, Lee S, Kwon JH, Lee SW, Yu H, Kim M, Kim Y, Sung PS and Yoon SK: Diagnosis of liver fibrosis with wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP) among chronic hepatitis B patients. Ann Lab Med. 38:348–354. 2018.PubMed/NCBI View Article : Google Scholar
21	Nielsen MJ, Nedergaard AF, Sun S, Veidal SS, Larsen L, Zheng Q, Suetta C, Henriksen K, Christiansen C, Karsdal MA and Leeming DJ: The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am J Transl Res. 5:303–315. 2013.PubMed/NCBI
22	Noguchi R, Kaji K, Namisaki T, Moriya K, Kitade M, Takeda K, Kawaratani H, Okura Y, Aihara Y, Furukawa M, et al: Serum angiotensin-converting enzyme level for evaluating significant fibrosis in chronic hepatitis B. World J Gastroenterol. 23:6705–6714. 2017.PubMed/NCBI View Article : Google Scholar
23	Treatment with ursodeoxycholic acid in clinical hepatology. Proceedings of a workshop. Goteborg, Sweden, 3-4 February 1994. Scand J Gastroenterol Suppl. 204:1–72. 1994.PubMed/NCBI
24	Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 20: 15-20, 1994.
25	Rossi E, Adams LA, Bulsara M and Jeffrey GP: Assessing liver fibrosis with serum marker models. Clin Biochem Rev. 28:3–10. 2007.PubMed/NCBI
26	Yamada N and Mizuta K: Advanced assessment of serum Mac-2 binding protein glycosylation isomer in patients with biliary atresia. J Gastroenterol. 54:204–205. 2019.PubMed/NCBI View Article : Google Scholar
27	Shirabe K, Bekki Y, Gantumur D, Araki K, Ishii N, Kuno A, Narimatsu H and Mizokami M: Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: More than a biomarker of liver fibrosis. J Gastroenterol. 53:819–826. 2018.PubMed/NCBI View Article : Google Scholar
28	Bekki Y, Yoshizumi T, Shimoda S, Itoh S, Harimoto N, Ikegami T, Kuno A, Narimatsu H, Shirabe K and Maehara Y: Hepatic stellate cells secreting WFA⁺ -M2BP: Its role in biological interactions with Kupffer cells. J Gastroenterol Hepatol. 32:1387–1393. 2017.PubMed/NCBI View Article : Google Scholar
29	Matsuura K, Aizawa N, Enomoto H, Nishiguchi S, Toyoda H, Kumada T, Iio E, Ito K, Ogawa S, Isogawa M, et al: Circulating let-7 levels in serum correlate with the severity of hepatic fibrosis in chronic hepatitis C. Open Forum Infect Dis. 5(ofy268)2018.PubMed/NCBI View Article : Google Scholar
30	Ishii A, Nishikawa H, Enomoto H, Iwata Y, Kishino K, Shimono Y, Hasegawa K, Nakano C, Takata R, Nishimura T, et al: Clinical implications of serum Wisteria floribunda agglutinin-positive Mac-2-binding protein in treatment-naive chronic hepatitis B. Hepatol Res. 47:204–215. 2017.PubMed/NCBI View Article : Google Scholar
31	Nishikawa H, Enomoto H, Iwata Y, Kishino K, Shimono Y, Hasegawa K, Nakano C, Takata R, Nishimura T, Yoh K, et al: Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein for patients with chronic hepatitis B and C: A comparative study. J Viral Hepat. 23:977–984. 2016.PubMed/NCBI View Article : Google Scholar
32	Miyaki E, Imamura M, Hiraga N, Murakami E, Kawaoka T, Tsuge M, et al: Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients. Hepatol Res. 2016;46(8):758-64.
33	Liu J, Hu HH, Lee MH, Korenaga M, Jen CL, Batrla-Utermann R, et al: Serum Levels of M2BPGi as Short-Term Predictors of Hepatocellular Carcinoma in Untreated Chronic Hepatitis B Patients. Sci Rep. 2017;7(1):14352.
34	Nishimura T, Iijima H, Nishikawa H, Kondo R, Yano H, Kage M, Aoki T, Nakano C, Yuri Y, Ishii N, et al: Liver fibrosis markers as assessed by ultrasound elastography and serum samples: A large comparative study in hepatitis virus B and C liver diseases. Hepatol Res. 49:721–730. 2019.PubMed/NCBI View Article : Google Scholar
35	Yasui Y, Kurosaki M, Komiyama Y, Takada H, Tamaki N, Watakabe K, Okada M, Wang W, Shimizu T, Kubota Y, et al: Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts early occurrence of hepatocellular carcinoma after sustained virologic response by direct-acting antivirals for hepatitis C virus. Hepatol Res. 48:1131–1139. 2018.PubMed/NCBI View Article : Google Scholar
36	Nakamura M, Kanda T, Jiang X, Haga Y, Takahashi K, Wu S, Yasui S, Nakamoto S and Yokosuka O: Serum microRNA-122 and Wisteria floribunda agglutinin-positive Mac-2 binding protein are useful tools for liquid biopsy of the patients with hepatitis B virus and advanced liver fibrosis. PLoS One. 12(e0177302)2017.PubMed/NCBI View Article : Google Scholar
37	Mak LY, Wong DK, Cheung KS, Seto WK, Lai CL and Yuen MF: Role of serum M2BPGi levels on diagnosing significant liver fibrosis and cirrhosis in treated patients with chronic hepatitis B virus infection. Clin Transl Gastroenterol. 9(163)2018.PubMed/NCBI View Article : Google Scholar