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

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.ConclusionMeasurement 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.

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…Yu et al [42] performed a serum protein fingerprint analysis, utilising the SELDI-TOF-MS technique combined with bioinformatic approaches and discovered that haemoglobin subunit alpha was significantly up-regulated in NAFLD group. It has been proposed that the relationship between serum haemoglobin and NAFLD may be partially modulated by haptoglobin (Hpt), an α2-glycoprotein acute phase protein produced in response to an inflammatory insult [44] . Serum haemoglobin levels may be a marker of hepatic steatosis but not of severity of NAFLD in obese patients.…”

“…A recent study by Kamada et al [44] has shed a light into the role of acute phase protein and progression of NAFLD. Kamada et al [44] utilised lectin antibody enzymelinked immunosorbent assay (ELISA) and demonstrated that serum fucosylated haptoglobin (Fuc-Hpt) underwent a stepwise increased with increasing hepatocyte ballooning scores in biopsy-proven NAFLD patients (AUROC ranging from 0.724 to 0.759).…”

“…Kamada et al [44] utilised lectin antibody enzymelinked immunosorbent assay (ELISA) and demonstrated that serum fucosylated haptoglobin (Fuc-Hpt) underwent a stepwise increased with increasing hepatocyte ballooning scores in biopsy-proven NAFLD patients (AUROC ranging from 0.724 to 0.759). Fucosylated alpha-fetoproteins have been previously shown to be more selectively secreted into bile [45] .…”

“…Fucosylated alpha-fetoproteins have been previously shown to be more selectively secreted into bile [45] . Kamada et al [44] hypothesised that an increase in ballooning hepatocytes could lead to the disruption of the fucosylation-based machinery and subsequently an increased secretion of Fuc-Hpt into the serum.…”

“…Increased de novo lipogenesis might play a role in NAFLD pathogenesis [27] Uric Acid Sirota et al [33] 2013 Association of increased serum uric acid level and severity of NAFLD Mitochondrial oxidative damage could contribute to hepatic steatosis Acute phase protein hs-CRP Yoneda et al [39] 2007 Increased hs-CRP serum level in advanced NASH Acute phase proteins may have an immediate role in hepatocytes injuries predictive markers Serum levels of acute phase proteins do not necessary reflect the severity of disease NAFLD progression has a more complex underlying protein mechanism Haemoglobin Yu et al [42] 2012 Association of elevated serum haemoglobin levels and prevalence of NAFLD Fuc-Hpt Kamada et al [44] 2013…”