Clinical and Pathological Features, and the Mechanism of Development in Severe Alcoholic Hepatitis, Especially in Comparison with Acute Type Fulminant Hepatitis

Increased von Willebrand Factor Over Decreased ADAMTS13 Activity May Contribute to the Development of Liver Disturbance and Multiorgan Failure in Patients With Alcoholic Hepatitis

“…These findings of enhanced production of UL-VWFM over deficient activity of ADAMTS13 may contribute to not only the development of multiorgan failure, but also the progression of the liver injury through microcirculatory disturbance in AH. Our results may give an additional mechanism to explain multiorgan failure together with liver disturbance particu- larly in the patients with SAH, although various factors including endotoxemia due to hepatic reticuloendothelial dysfunction and increased intestinal permeability, and subsequent proinflammatory cytokinemia have been implicated (Fukui et al, 1991;Ishii et al, 1993;Mookerjee et al, 2003).…”

“…Alternatively, regarding the reason for the decreased ADAMTS13 activity, we could speculate the following: the direct inhibition of the protease activity by ethanol itself, consumption of the protease due to a large amount of UL-VWFM, presence of inhibitor against the protease, which is detected in the majority of patients with ''idiopathic'' TTP (Matsumoto et al, 2004), and inflammatory cytokines such as IL-6, which inhibit the action of ADAMTS13 (Bernardo et al, 2004). The plasma cytokines including TNFa, IL-8, and IL-6 are remarkably high especially in SAH (Fujimoto et al, 2000;Ishii et al, 1993;Mookerjee et al, 2003), indicating that enhanced inflammatory cytokinemia may be one of the most important candidates to cause extremely low activity of the plasma ADAMTS13 and increased production of VWF in SAH.…”

“…S EVERE ALCOHOLIC HEPATITIS (SAH) in addition to alcoholic hepatitis (AH) is a potentially life-threatening complication of alcohol abuse, and frequently results in multiorgan failure with manifestations of acute hepatic failure, which is associated with high morbidity and mortality (Ishii et al, 1993;Maddrey et al, 1978;Mookerjee et al, 2003). Regarding the pathogenesis of SAH including AH, endotoxemia due to hepatic reticuloendothelial dysfunction and increased intestinal permeability may trigger the enhancement of proinflammatory cytokines, which may lead to systemic inflammatory response syndrome, together with microcirculatory disturbance and systemic hemodynamic derangements, resulting in development of multiorgan failure (Fukui et al, 1991;Ishii et al, 1993;Mookerjee et al, 2003).…”

“…Regarding the pathogenesis of SAH including AH, endotoxemia due to hepatic reticuloendothelial dysfunction and increased intestinal permeability may trigger the enhancement of proinflammatory cytokines, which may lead to systemic inflammatory response syndrome, together with microcirculatory disturbance and systemic hemodynamic derangements, resulting in development of multiorgan failure (Fukui et al, 1991;Ishii et al, 1993;Mookerjee et al, 2003).…”

Crucial Role of ADAMTS13 Related to Endotoxemia and Subsequent Cytokinemia in the Progression of Alcoholic Hepatitis

“…VWF:Ag was significantly correlated with nine clinical variables, including functional liver capacity, anemia, inflammation signs, and platelet counts (Matsuyama et al, 2007;Uemura et al, 2008b). The factors associated with decreased ADAMTS13:AC and increased VWF:Ag, reduced functional liver capacity, augmented inflammation, and thrombocytopenia are consistent with the clinical characteristics that frequently appear in AH and SAH (Fujimoto et al, 1999;Haber et al, 2003;Ishii et al, 1993;Maddrey et al, 1978;McClain et al, 1999;Mookerjee et al, 2003). Remarkably, the imbalance between the ADAMTS13:AC and VWF:Ag levels might provide another mechanism for thrombocytopenia that usually occurs in AH even in the absence of signs of apparent disseminated intravascular coagulation (DIC).…”