Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases

Tea Lund Laursen; Lars Bossen; Rasmus Pihl; Anne Troldborg; Thomas Damgaard Sandahl; Annette Gudmann Hansen; Trine Folserass; Mette Vesterhus; Henning Grønbæk; Steffen Thiel

doi:10.14218/JCTH.2021.00515

Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases

J Clin Transl Hepatol. 2022 Oct 28;10(5):796-802. doi: 10.14218/JCTH.2021.00515. Epub 2022 Mar 11.

Authors

Affiliations

¹ Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
² Department of Biomedicine, Aarhus University, Aarhus, Denmark.
³ Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.
⁴ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁵ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁶ Haraldsplass Deaconess Hospital, Bergen, Norway.
⁷ Department of Clinical Science, University of Bergen, Bergen, Norway.

Abstract

Background and aims: There is an unmet need for new biomarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-α-inhibitor heavy chain 4 (ITIH4) is an abundant, liver-produced protein, and its synthesis may be altered in liver diseases. We investigated whether ITIH4 plasma concentrations were affected in PBC and PSC patients.

Methods: We developed an immunoassay specific for ITIH4 and determined ITIH4 plasma concentrations in 66 PBC, 126 PSC, 92 autoimmune hepatitis (AIH), 67 chronic hepatitis C (CHC), 33 alcoholic hepatitis (AH) patients and 138 healthy controls (HCs). Hepatic ITIH4 expression was investigated by immunohistochemistry in PBC.

Results: The mean plasma concentration of ITIH4 was almost doubled in PBC [409 µg/mL (95% CI: 388-431)] and 35% higher in PSC [308 µg/mL, (95% CI: 296-319)] compared with HCs [226 µg/mL (95% CI: 221-231); p<0.001]. In PBC patients, ITIH4 correlated with IgM (rho=0.49, p<0.001). Responders to ursodeoxycholic acid treatment (UDCA) had lower levels of ITIH4 than incomplete responders [395 µg/mL (95% CI: 364-425)] vs. 460 µg/mL (95% CI: 421-498); p=0.02]. Four weeks of UDCA treatment had no effect (p=0.19). Increased ITIH4 immunohistochemical staining was seen in a liver biopsy from a PBC patient. ITIH4 levels in AIH [224 µg/mL (95% CI: 208-241)] and HCs were similar (p=0.8). ITIH4 levels were lower in AH [199 µg/mL (95% CI: 175-223)] and CHC [202 µg/mL (192-212)] patients than in HCs (p<0.05).

Conclusions: The plasma concentration of ITIH4 was highly elevated in patients with PBC and PSC, suggesting that ITIH4 should be further investigated as a biomarker in cholestatic liver disease.

Keywords: Alcoholic hepatitis; Autoimmune hepatitis; Chronic viral hepatitis; Primary biliary cholangitis; Primary sclerosing cholangitis; Ursodeoxycholic acid treatment.