Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study

Thomas Damgaard Sandahl; Henning Grønbaek; Holger Jon Møller; Sidsel Støy; Karen Luise Thomsen; Anders Kirch Dige; Jørgen Agnholt; Stephen Hamilton-Dutoit; Steffen Thiel; Hendrik Vilstrup

doi:10.1038/ajg.2014.262

Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study

Thomas Damgaard Sandahl, Henning Grønbaek, Holger Jon Møller, Sidsel Støy, Karen Luise Thomsen, Anders Kirch Dige, Jørgen Agnholt, Stephen Hamilton-Dutoit, Steffen Thiel, Hendrik Vilstrup

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

85 Citationer (Scopus)

Abstract

OBJECTIVES: Inflammatory activation of resident hepatic macrophages (Kupffer cells) by portal-derived lipopolysaccharide (LPS) has a primary role in animal models of alcoholic liver disease, but it has not been systematically or longitudinally studied in human alcoholic hepatitis (AH).

METHODS: We followed 50 patients with AH for 30 days. 26 patients with stable alcoholic cirrhosis and 20 healthy individuals were controls. We measured the plasma (P) concentrations of soluble CD163 (sCD163; a specific marker of inflammatory macrophage activation) and the expression of CD163 in liver tissue by immunohistochemistry and stereology of liver biopsies. We also measured the key components of the LPS pathway, P-LPS, sCD14, and LPS-binding protein (LBP), by enzyme-linked immunosorbent assay (ELISA). The 84-day mortality was registered.

RESULTS: At study entry, the sCD163 concentration was 10-fold higher than in the healthy controls and 30% higher than in the stable cirrhotics (P<0.002), and it correlated with the Glasgow Alcoholic Hepatitis, Model for End-stage Liver Disease, and Child-Pugh scores (r>0.35, P<0.02, all). The liver biopsies confirmed markedly increased CD163 staining (P<0.01). P-LPS, P-CD14, and P-LBP were increased to the same degree as sCD163. During the follow-up, the sCD163 and LPS pathway components all decreased by ∼25% (P<0.05) but remained higher than in both control groups. sCD163 was an independent predictor of the 84-day mortality.

CONCLUSIONS: The hepatic inflammation of human AH involves marked activation of hepatic macrophages, likely via the LPS pathway. Hepatic macrophages may thus present a target for biological therapy of AH.

Originalsprog	Engelsk
Tidsskrift	American Journal of Gastroenterology
Vol/bind	109
Nummer	11
Sider (fra-til)	1749-56
Antal sider	8
ISSN	0002-9270
DOI	https://doi.org/10.1038/ajg.2014.262
Status	Udgivet - nov. 2014

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10.1038/ajg.2014.262

Citationsformater

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title = "Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study",

abstract = "OBJECTIVES: Inflammatory activation of resident hepatic macrophages (Kupffer cells) by portal-derived lipopolysaccharide (LPS) has a primary role in animal models of alcoholic liver disease, but it has not been systematically or longitudinally studied in human alcoholic hepatitis (AH).METHODS: We followed 50 patients with AH for 30 days. 26 patients with stable alcoholic cirrhosis and 20 healthy individuals were controls. We measured the plasma (P) concentrations of soluble CD163 (sCD163; a specific marker of inflammatory macrophage activation) and the expression of CD163 in liver tissue by immunohistochemistry and stereology of liver biopsies. We also measured the key components of the LPS pathway, P-LPS, sCD14, and LPS-binding protein (LBP), by enzyme-linked immunosorbent assay (ELISA). The 84-day mortality was registered.RESULTS: At study entry, the sCD163 concentration was 10-fold higher than in the healthy controls and 30% higher than in the stable cirrhotics (P<0.002), and it correlated with the Glasgow Alcoholic Hepatitis, Model for End-stage Liver Disease, and Child-Pugh scores (r>0.35, P<0.02, all). The liver biopsies confirmed markedly increased CD163 staining (P<0.01). P-LPS, P-CD14, and P-LBP were increased to the same degree as sCD163. During the follow-up, the sCD163 and LPS pathway components all decreased by ∼25% (P<0.05) but remained higher than in both control groups. sCD163 was an independent predictor of the 84-day mortality.CONCLUSIONS: The hepatic inflammation of human AH involves marked activation of hepatic macrophages, likely via the LPS pathway. Hepatic macrophages may thus present a target for biological therapy of AH.",

keywords = "Antigens, CD, Antigens, Differentiation, Myelomonocytic, Biopsy, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Hepatitis, Alcoholic, Humans, Immunohistochemistry, Lipopolysaccharides, Macrophage Activation, Male, Middle Aged, Prospective Studies, Receptors, Cell Surface",

author = "Sandahl, {Thomas Damgaard} and Henning Gr{\o}nbaek and M{\o}ller, {Holger Jon} and Sidsel St{\o}y and Thomsen, {Karen Luise} and Dige, {Anders Kirch} and J{\o}rgen Agnholt and Stephen Hamilton-Dutoit and Steffen Thiel and Hendrik Vilstrup",

year = "2014",

month = nov,

doi = "10.1038/ajg.2014.262",

language = "English",

volume = "109",

pages = "1749--56",

journal = "American Journal of Gastroenterology",

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Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study. / Sandahl, Thomas Damgaard ; Grønbaek, Henning ; Møller, Holger Jon et al.
I: American Journal of Gastroenterology, Bind 109, Nr. 11, 11.2014, s. 1749-56.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis

T2 - a prospective cohort study

AU - Sandahl, Thomas Damgaard

AU - Grønbaek, Henning

AU - Møller, Holger Jon

AU - Støy, Sidsel

AU - Thomsen, Karen Luise

AU - Dige, Anders Kirch

AU - Agnholt, Jørgen

AU - Hamilton-Dutoit, Stephen

AU - Thiel, Steffen

AU - Vilstrup, Hendrik

PY - 2014/11

Y1 - 2014/11

N2 - OBJECTIVES: Inflammatory activation of resident hepatic macrophages (Kupffer cells) by portal-derived lipopolysaccharide (LPS) has a primary role in animal models of alcoholic liver disease, but it has not been systematically or longitudinally studied in human alcoholic hepatitis (AH).METHODS: We followed 50 patients with AH for 30 days. 26 patients with stable alcoholic cirrhosis and 20 healthy individuals were controls. We measured the plasma (P) concentrations of soluble CD163 (sCD163; a specific marker of inflammatory macrophage activation) and the expression of CD163 in liver tissue by immunohistochemistry and stereology of liver biopsies. We also measured the key components of the LPS pathway, P-LPS, sCD14, and LPS-binding protein (LBP), by enzyme-linked immunosorbent assay (ELISA). The 84-day mortality was registered.RESULTS: At study entry, the sCD163 concentration was 10-fold higher than in the healthy controls and 30% higher than in the stable cirrhotics (P<0.002), and it correlated with the Glasgow Alcoholic Hepatitis, Model for End-stage Liver Disease, and Child-Pugh scores (r>0.35, P<0.02, all). The liver biopsies confirmed markedly increased CD163 staining (P<0.01). P-LPS, P-CD14, and P-LBP were increased to the same degree as sCD163. During the follow-up, the sCD163 and LPS pathway components all decreased by ∼25% (P<0.05) but remained higher than in both control groups. sCD163 was an independent predictor of the 84-day mortality.CONCLUSIONS: The hepatic inflammation of human AH involves marked activation of hepatic macrophages, likely via the LPS pathway. Hepatic macrophages may thus present a target for biological therapy of AH.

AB - OBJECTIVES: Inflammatory activation of resident hepatic macrophages (Kupffer cells) by portal-derived lipopolysaccharide (LPS) has a primary role in animal models of alcoholic liver disease, but it has not been systematically or longitudinally studied in human alcoholic hepatitis (AH).METHODS: We followed 50 patients with AH for 30 days. 26 patients with stable alcoholic cirrhosis and 20 healthy individuals were controls. We measured the plasma (P) concentrations of soluble CD163 (sCD163; a specific marker of inflammatory macrophage activation) and the expression of CD163 in liver tissue by immunohistochemistry and stereology of liver biopsies. We also measured the key components of the LPS pathway, P-LPS, sCD14, and LPS-binding protein (LBP), by enzyme-linked immunosorbent assay (ELISA). The 84-day mortality was registered.RESULTS: At study entry, the sCD163 concentration was 10-fold higher than in the healthy controls and 30% higher than in the stable cirrhotics (P<0.002), and it correlated with the Glasgow Alcoholic Hepatitis, Model for End-stage Liver Disease, and Child-Pugh scores (r>0.35, P<0.02, all). The liver biopsies confirmed markedly increased CD163 staining (P<0.01). P-LPS, P-CD14, and P-LBP were increased to the same degree as sCD163. During the follow-up, the sCD163 and LPS pathway components all decreased by ∼25% (P<0.05) but remained higher than in both control groups. sCD163 was an independent predictor of the 84-day mortality.CONCLUSIONS: The hepatic inflammation of human AH involves marked activation of hepatic macrophages, likely via the LPS pathway. Hepatic macrophages may thus present a target for biological therapy of AH.

KW - Antigens, CD

KW - Antigens, Differentiation, Myelomonocytic

KW - Biopsy

KW - Case-Control Studies

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Flow Cytometry

KW - Hepatitis, Alcoholic

KW - Humans

KW - Immunohistochemistry

KW - Lipopolysaccharides

KW - Macrophage Activation

KW - Male

KW - Middle Aged

KW - Prospective Studies

KW - Receptors, Cell Surface

U2 - 10.1038/ajg.2014.262

DO - 10.1038/ajg.2014.262

M3 - Journal article

C2 - 25155228

SN - 0002-9270

VL - 109

SP - 1749

EP - 1756

JO - American Journal of Gastroenterology

JF - American Journal of Gastroenterology

IS - 11

ER -

Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study

Abstract

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