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. CONCLUSION: 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.

Increased von Willebrand factor over decreased ADAMTS13 activity may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis.

BACKGROUND: Severe alcoholic hepatitis (SAH) in addition to alcoholic hepatitis (AH) is a life-threatening complication of alcohol abuse, and its pathogenesis remains unclear. The deficiency of ADAMTS13 results in an increase of the plasma unusually large von Willebrand factor multimer (UL-VWFM) and finally causes microcirculatory disturbance and multiorgan failure. We investigated the relationship of ADAMTS13 and von Willebrand factor antigen (VWF:Ag) with the clinical features of AH and SAH. METHODS: The plasma levels of ADAMTS13 activity, VWF:Ag, and UL-VWFM were determined in 24 patients with AH, 5 with SAH, and 10 with alcoholic liver cirrhosis (LC). RESULTS: The ADAMTS13 activity was significantly lower in SAH (mean 24%), AH (62%), and LC (76%) than in the healthy subjects (102%, n=62). The VWF:Ag levels were higher in SAH (806%), AH (405%), and LC (514%) than in the healthy subjects (100%), resulting in a higher ratio of VWF:Ag to ADAMTS13 activity in SAH (102.2), AH (8.9), and LC (8.6) compared with the healthy subjects (1.0). In 3 nonsurvivors with SAH and multiorgan failure, the protease activity markedly decreased (from 4.5 to 16%), and VWF:Ag remarkably increased (from 560 to 1,202%), resulting in an extremely high ratio of VWF:Ag to the activity (from 35.0 to 240.4). At the recovery stage in the survivors with SAH and AH, the protease activity increased and the VWF:Ag decreased, whereas in a nonsurvivor with SAH, the activity remained extremely low and the VWF:Ag was still high. Unusually large von Willebrand factor multimer was detected in 80.0% of SAH and 55.6% of AH. Multivariate analysis showed that the serum albumin and platelet count independently correlated with VWF:Ag. CONCLUSION: The enhanced production of UL-VWFM over deficient activity of ADAMTS13 may, in part, contribute to not only the progression of liver injury but also the development of multiorgan failure through microcirculatory disturbance in SAH in addition to AH. The imbalance between the plasma ADAMTS13 activity and VWF:Ag could be a useful prognostic marker in AH.