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

Background and Aims: There is an unmet need for new bi-omarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-alpha-inhibitor heavy chain 4 (ITIH4) is an abun-dant, liver-produced protein, and its synthesis may be al-tered in liver diseases. We investigated whether ITIH4 plas-ma 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 plas-ma concentration of ITIH4 was almost doubled in PBC [409 mu g/mL (95% CI: 388-431)] and 35% higher in PSC [308 mu g/mL, (95% CI: 296-319)] compared with HCs [226 mu g/ 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 mu g/mL (95% CI: 364-425)] vs. 460 mu g/mL (95% CI: 421-498); p=0.02]. Four weeks of UDCA treatment had no effect (p=0.19). In-creased ITIH4 immunohistochemical staining was seen in a liver biopsy from a PBC patient. ITIH4 levels in AIH [224 mu g/mL (95% CI: 208-241)] and HCs were similar (p=0.8). ITIH4 levels were lower in AH [199 mu g/mL (95% CI: 175- 223)] and CHC [202 mu g/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. Citation of this article: Laursen TL, Bossen L, Pihl R, Tr-oldborg A, Sandahl TD, Hansen AG, et al. Highly Increased Levels of Inter-alpha-inhibitor Heavy Chain 4 (ITIH4) in Autoim-mune Cholestatic Liver Diseases. J Clin Transl Hepatol 2022. doi: 10.14218/JCTH.2021.00515.