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Background <p>Advanced liver fibrosis in cases of metabolic dysfunction-associated steatotic liver disease (MASLD) leads to cirrhosis and hepatocellular carcinoma. The current gold standard for liver fibrosis is invasive liver biopsy. Therefore, a less invasive biomarker that accurately reflects the stage of liver fibrosis is highly desirable.</p> Methods <p>This study enrolled 269 patients with liver biopsy-proven MASLD. Patients were divided into three groups (F0/1 (<i>n</i> = 41/85), F2 (<i>n</i> = 47), and F3/4 (<i>n</i> = 72/24)) according to fibrosis stage. We performed serum <i>N</i>-glycomics and identified glycan biomarker for fibrosis stage. Moreover, we explored the carrier proteins and developed a sandwich ELISA to measure <i>N</i>-glycosylation changes of carrier protein.</p> Results <p>Comprehensive <i>N</i>-glycomic analysis revealed significant changes in the expression of A2F bisect and its precursors as fibrosis progressed. The sum of neutral <i>N</i>-glycans carrying bisecting GlcNAc and core Fuc (neutral sum) had a better diagnostic performance to evaluate advanced liver fibrosis (AUC = 0.804) than conventional parameters (FIB4 index, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), and serum level of Mac-2-binding protein glycol isomer&#xa0;(M2BPGi). The combination of the neutral sum and FIB4 index enhanced diagnostic performance (AUC = 0.840). IgM, IgA, and complement C3 were identified as carrier proteins with A2F bisect <i>N</i>-glycan. A sandwich ELISA based on <i>N</i>-glycans carrying bisecting GlcNAc and IgA showed similar diagnostic performance than the neutral sum.</p> Conclusions <p>A2F bisect <i>N</i>-glycan and its precursors are promising candidate biomarkers for advanced fibrosis in MASLD patients. Analysis of these glycan alterations on IgA may have the potential to serve as a novel ELISA diagnostic tool for MASLD in routine clinical practice.</p> Clinical trial number <p>UMIN000030720.</p>

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Elevated A2F bisect N-glycans of serum IgA reflect progression of liver fibrosis in patients with MASLD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月24日

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  • Hisatoshi Hanamatsu,
  • Goki Suda,
  • Masatsugu Ohara,
  • Koji Ogawa,
  • Nobuharu Tamaki,
  • Hayato Hikita,
  • Hiroaki Haga,
  • Shinya Maekawa,
  • Masaya Sugiyama,
  • Tatsuhiko Kakisaka,
  • Masato Nakai,
  • Takuya Sho,
  • Nobuaki Miura,
  • Masayuki Kurosaki,
  • Yasuhiro Asahina,
  • Akinobu Taketomi,
  • Yoshiyuki Ueno,
  • Tetsuo Takehara,
  • Takashi Nishikaze,
  • Jun-ichi Furukawa,
  • Naoya Sakamoto

摘要

Background

Advanced liver fibrosis in cases of metabolic dysfunction-associated steatotic liver disease (MASLD) leads to cirrhosis and hepatocellular carcinoma. The current gold standard for liver fibrosis is invasive liver biopsy. Therefore, a less invasive biomarker that accurately reflects the stage of liver fibrosis is highly desirable.

Methods

This study enrolled 269 patients with liver biopsy-proven MASLD. Patients were divided into three groups (F0/1 (n = 41/85), F2 (n = 47), and F3/4 (n = 72/24)) according to fibrosis stage. We performed serum N-glycomics and identified glycan biomarker for fibrosis stage. Moreover, we explored the carrier proteins and developed a sandwich ELISA to measure N-glycosylation changes of carrier protein.

Results

Comprehensive N-glycomic analysis revealed significant changes in the expression of A2F bisect and its precursors as fibrosis progressed. The sum of neutral N-glycans carrying bisecting GlcNAc and core Fuc (neutral sum) had a better diagnostic performance to evaluate advanced liver fibrosis (AUC = 0.804) than conventional parameters (FIB4 index, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), and serum level of Mac-2-binding protein glycol isomer (M2BPGi). The combination of the neutral sum and FIB4 index enhanced diagnostic performance (AUC = 0.840). IgM, IgA, and complement C3 were identified as carrier proteins with A2F bisect N-glycan. A sandwich ELISA based on N-glycans carrying bisecting GlcNAc and IgA showed similar diagnostic performance than the neutral sum.

Conclusions

A2F bisect N-glycan and its precursors are promising candidate biomarkers for advanced fibrosis in MASLD patients. Analysis of these glycan alterations on IgA may have the potential to serve as a novel ELISA diagnostic tool for MASLD in routine clinical practice.

Clinical trial number

UMIN000030720.