Serum Fucosylated Haptoglobin as a Novel Diagnostic Biomarker for Predicting Hepatocyte Ballooning and Nonalcoholic Steatohepatitis

Yoshihiro Kamada; Maaya Akita; Yuri Takeda; Shin Yamada; Hideki Fujii; Yoshiyuki Sawai; Yoshinori Doi; Hitomi Asazawa; Kotarosumitomo Nakayama; Kayo Mizutani; Hironobu Fujii; Takayuki Yakushijin; Masanori Miyazaki; Hisao Ezaki; Naoki Hiramatsu; Yuichi Yoshida; Shinichi Kiso; Yasuharu Imai; Norifumi Kawada; Tetsuo Takehara; Eiji Miyoshi

doi:10.1371/journal.pone.0066328

Serum Fucosylated Haptoglobin as a Novel Diagnostic Biomarker for Predicting Hepatocyte Ballooning and Nonalcoholic Steatohepatitis

PLoS One. 2013 Jun 21;8(6):e66328. doi: 10.1371/journal.pone.0066328. Print 2013.

Affiliation

¹ Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan ; Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem around the world. NAFLD patients with nonalcoholic steatohepatitis (NASH) can develop cirrhosis and hepatocellular carcinoma. The ability to distinguish NASH from simple steatosis would be of great clinical significance. Ballooning hepatocytes are characteristic of typical pathological NASH; here, the polarized secretion of proteins is disrupted due to destruction of the cytoskeleton. We previously reported that fucosylated glycoproteins are secreted into bile, but not into sera in normal liver. Therefore, we hypothesized that the fucosylation-based sorting machinery would be disrupted in ballooning hepatocytes, and serum fucosylated glycoproteins would increase in NASH patients. To confirm our hypothesis, we evaluated serum fucosylated haptoglobin (Fuc-Hpt) levels in biopsy-proven NAFLD patients (n = 126) using a lectin-antibody ELISA kit. Fuc-Hpt levels were significantly increased in NASH patients compared with non-NASH (NAFLD patients without NASH) patients. Interestingly, Fuc-Hpt levels showed a significant stepwise increase with increasing hepatocyte ballooning scores. Multiple logistic regression analysis showed that Fuc-Hpt levels were independent and significant determinants of the presence of ballooning hepatocytes. Moreover, Fuc-Hpt levels were useful in monitoring liver fibrosis staging. Next, to investigate the significance of serum Fuc-Hpt in a larger population, we measured Fuc-Hpt levels in ultrasound-diagnosed NAFLD subjects (n = 870) who received a medical health checkup. To evaluate NAFLD disease severity, we used the FIB-4 index (based on age, serum AST and ALT levels, and platelet counts). Fuc-Hpt levels increased stepwise with increasing FIB-4 index.

Conclusion: Measurement of serum Fuc-Hpt levels can distinguish NASH from non-NASH patients, and predict the presence of ballooning hepatocytes in NAFLD patients with sufficient accuracy. These results support the potential usefulness of measuring Fuc-Hpt levels in clinical practice.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age Factors
Aged
Biomarkers / blood
Female
Haptoglobins / metabolism*
Hepatocytes / metabolism*
Hepatocytes / pathology
Humans
Male
Middle Aged
Non-alcoholic Fatty Liver Disease* / blood
Non-alcoholic Fatty Liver Disease* / diagnosis
Non-alcoholic Fatty Liver Disease* / pathology

Substances

Biomarkers
HP protein, human
Haptoglobins

Grants and funding

This study was supported by a Grant-in-Aid for Scientific Research (A), No. 21249038 and (C), No. 24590972 from the Japan Society for the Promotion of Science, and by the Global COE Program of Osaka University funded by Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.