Potential Role of ADAMTS13 in the Progression of Alcoholic Hepatitis

Author(s): Masahito Uemura , Yoshihiro Fujimura , Tomomi Matsuyama , Masanori Matsumoto , Masatoshi Ishikawa , Hiromichi Ishizashi , Seiji Kato , Tatsuhiro Tsujimoto , Masao Fujimoto , Hitoshi Yoshiji , Chie Morioka , Hiroshi Fukui .

Journal Name: Current Drug Abuse Reviews

Volume 1 , Issue 2 , 2008

Abstract:

Alcoholic hepatitis (AH) is a potentially life-threatening complication of alcohol abuse. The severe form of AH, severe alcoholic hepatitis (SAH), is characterized by multiorgan failure (MOF) with manifestations of acute hepatic failure and is associated with high morbidity and mortality. However, the pathogenesis of SAH in addition to AH remains to be elucidated. Recent advances showed that ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) is closely related to thrombotic thrombocytopenic purpura, a multiorgan disorder. Decreased activity of plasma ADAMTS13 (ADAMTS13:AC) leads to the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and subsequent platelet clumping and/or thrombi under high shear stress, resulting in microcirculatory disturbances. Immunological studies and in situ hybridization have indicated that ADAMTS13 is produced exclusively in hepatic stellate cells (HSCs). Plasma ADAMTS13:AC was extremely low in fatal SAH cases, and enhanced ULVWFM production with deficient ADAMTS13:AC may contribute to the progression of MOF through microcirculatory disturbances in SAH and AH. Considering that ADAMTS13 is synthesized in HSCs and its substrate, UL-VWFM, is produced in transformed vascular endothelial cells, the imbalance between ADAMTS13:AC and VWF:Ag in AH patients might also involve sinusoidal microcirculatory disturbances and subsequent liver injury. It will be necessary to clarify the mechanism of the decrease in plasma ADAMTS13:AC in association with pro-inflammatory cytokinemia, an ADAMTS13 inhibitor and the production of ADAMTS13 in HSCs. The determination of ADAMTS13:AC and its substrate will give us new insights into the pathophysiology of acute alcoholic liver injury and help to elucidate additional therapeutic strategies for this disease.

Keywords: ADAMTS13 activity, alcoholic hepatitis, severe alcoholic hepatitis, von Willebrand factor, unusually large von Willebrand factor multimer, microcirculatory disturbance, multiorgan failure

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Article Details

VOLUME: 1
ISSUE: 2
Year: 2008
Page: [188 - 196]
Pages: 9
DOI: 10.2174/1874473710801020188
Price: $58

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