Potential role of enhanced cytokinemia and plasma inhibitor on the decreased activity of plasma ADAMTS13 in patients with alcoholic hepatitis: relationship to endotoxemia.
BACKGROUND
Deficiency of ADAMTS13 (adisintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) results in an increase in unusually large von Willebrand factor multimer (UL-VWFM) of the plasma and finally causes microcirculatory disturbance. Our previous study demonstrated that the imbalance of increased UL-VWFM over decreased ADAMTS13 activity may contribute to the development of multiorgan failure in patients with alcoholic hepatitis (AH). The aim of this study was to explore the potential mechanism to reduce the activity of plasma ADAMTS13.


METHODS
Plasma cytokine levels including interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha), plasma endotoxin concentration, and the plasma inhibitor against ADAMTS13 were determined together with ADAMTS13 activity, VWF antigen (VWF:Ag), and UL-VWFM in 24 patients with AH and 5 patients with severe alcoholic hepatitis (SAH).


RESULTS
The concentrations of IL-6, IL-8, and TNF-alpha on admission were significantly higher in patients with SAH than in those with AH and controls. The ADAMTS13 activity concomitantly decreased, and the VWF:Ag progressively elevated with increasing concentrations of these cytokines from normal range to over 100 pg/ml. Plasma endotoxin concentration was markedly higher in patients with SAH (mean 52.3 pg/ml) and AH (21.7 pg/ml) than in controls (7.9 pg/ml). The endotoxin concentration inversely correlated with ADAMTS13 activity and was higher in patients with UL-VWFM than those without. The inhibitor was detected in 4 patients with SAH (0.9 to 2.1 BU/ml) and 6 patients with AH (0.5 to 1.6 BU/ml). Patients with the inhibitor showed lower functional liver capacity, higher endotoxin concentration, and marked inflammatory signs than those without. At the recovery stage, the ADAMTS13 activity increased to normal range, the VWF:Ag decreased, and the UL-VWFM disappeared with the decrease in the concentrations of cytokines and endotoxin, and the disappearance of the inhibitor.


CONCLUSIONS
Decreased ADAMTS13 activity and increased VWF:Ag could be induced not only by pro-inflammatory cytokinemia, but also by its inhibitor, both of which may be closely related to enhanced endotoxemia in patients with AH and SAH.
Ishikawa
Masatoshi
M
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Uemura
Masahito
M
Matsuyama
Tomomi
T
Matsumoto
Masanori
M
Ishizashi
Hiromichi
H
Kato
Seiji
S
Morioka
Chie
C
Fujimoto
Masao
M
Kojima
Hideyuki
H
Yoshiji
Hitoshi
H
Tsujimoto
Tatsuhiro
T
Takimura
Chikara
C
Fujimura
Yoshihiro
Y
Fukui
Hiroshi
H
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000097:blood*; D000071120:ADAMTS13 Protein; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000097:blood*; D004731:Endotoxins / Q000097:blood*; D004791:Enzyme Inhibitors / Q000097:blood*; D005260:Female; D006519:Hepatitis, Alcoholic / Q000097:blood*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014841:von Willebrand Factor / Q000032:analysis
D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human