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 Gronbaek; Steffen Thiel

doi:10.14218/JCTH.2021.00515

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 Gronbaek, Steffen Thiel

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

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 language	English
Journal	Journal of clinical and translational hepatology
Volume	10
Issue	5
Pages (from-to)	796–802
Number of pages	7
ISSN	2225-0719
DOIs	https://doi.org/10.14218/JCTH.2021.00515
Publication status	Published - Oct 2022

Keywords

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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@article{49858c08785149f5b4a4bec9b387191c,

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

abstract = "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.",

keywords = "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",

author = "Laursen, \{Tea Lund\} and Lars Bossen and Rasmus Pihl and Anne Troldborg and Sandahl, \{Thomas Damgaard\} and Hansen, \{Annette Gudmann\} and Trine Folserass and Mette Vesterhus and Henning Gronbaek and Steffen Thiel",

year = "2022",

month = oct,

doi = "10.14218/JCTH.2021.00515",

language = "English",

volume = "10",

pages = "796–802",

journal = "Journal of clinical and translational hepatology",

issn = "2225-0719",

publisher = "Xia and He Publishing Inc.",

number = "5",

}

Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases. / Laursen, Tea Lund ; Bossen, Lars; Pihl, Rasmus et al.
In: Journal of clinical and translational hepatology, Vol. 10, No. 5, 10.2022, p. 796–802.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases

AU - Laursen, Tea Lund

AU - Bossen, Lars

AU - Pihl, Rasmus

AU - Troldborg, Anne

AU - Sandahl, Thomas Damgaard

AU - Hansen, Annette Gudmann

AU - Folserass, Trine

AU - Vesterhus, Mette

AU - Gronbaek, Henning

AU - Thiel, Steffen

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Primary biliary cholangitis

KW - Primary sclerosing cholangitis

KW - Autoim-mune hepatitis

KW - Ursodeoxycholic acid treatment

KW - Alcoholic hepatitis

KW - Chronic viral hepatitis

KW - MACROPHAGE ACTIVATION

KW - FIBROSIS

KW - SURVIVAL

KW - PATHWAY

KW - PROTEIN

KW - MODEL

KW - Autoimmune hepatitis

U2 - 10.14218/JCTH.2021.00515

DO - 10.14218/JCTH.2021.00515

M3 - Journal article

C2 - 36304505

SN - 2225-0719

VL - 10

SP - 796

EP - 802

JO - Journal of clinical and translational hepatology

JF - Journal of clinical and translational hepatology

IS - 5

ER -

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

Abstract

Keywords

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