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

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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-α-inhibitor heavy chain 4 (ITIH4) is an abun-dant, 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.

Original languageEnglish
JournalJournal of clinical and translational hepatology
Pages (from-to)796–802
Number of pages7
Publication statusPublished - Oct 2022

    Research areas

  • Primary biliary cholangitis, Primary sclerosing cholangitis, Autoim-mune hepatitis, Ursodeoxycholic acid treatment, Alcoholic hepatitis, Chronic viral hepatitis, MACROPHAGE ACTIVATION, FIBROSIS, SURVIVAL, PATHWAY, PROTEIN, MODEL, Autoimmune hepatitis

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