title: Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas Damgaard
authors.initials: TD
authors.lastname: Sandahl
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbaek
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Holger Jon
authors.initials: HJ
authors.lastname: Møller
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Støy
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karen Luise
authors.initials: KL
authors.lastname: Thomsen
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anders Kirch
authors.initials: AK
authors.lastname: Dige
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Agnholt
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hamilton-Dutoit
authors.affiliation: Department of Biomedicine, Medical Microbiology, and Immunology, Aarhus University, Aarhus C, Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D001706:Biopsy; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006519:Hepatitis, Alcoholic / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000276:immunology*; D008262:Macrophage Activation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000276:immunology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface