title: Potential role of ADAMTS13 in the progression of alcoholic hepatitis.
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 UL-VWFM 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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, 634-8522, Japan. muemura@naramed-u.ac.jp
authors.forename: Masahito
authors.initials: M
authors.lastname: Uemura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ishizashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kato
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Tsujimoto
authors.forename: Masao
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Chie
authors.initials: C
authors.lastname: Morioka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D051722:ADAM Proteins / Q000097:blood*; D000071120:ADAMTS13 Protein; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D006519:Hepatitis, Alcoholic / Q000097:blood* / Q000401:mortality; D006801:Humans; D008099:Liver / Q000098:blood supply; D017093:Liver Failure / Q000097:blood / Q000401:mortality; D008833:Microcirculation / Q000502:physiology; D009102:Multiple Organ Failure / Q000097:blood / Q000401:mortality; D010974:Platelet Aggregation / Q000502:physiology; D055503:Protein Multimerization; D013927:Thrombosis / Q000097:blood / Q000401:mortality; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D016207:Cytokines; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human