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Background: The pathogenesis of alcoholic hepatitis (AH) remains unclear and the prognosis of severe alcoholic hepatitis (SAH) is very poor. Deficiency of von Willebrand factor (VWF)-cleaving protease (VWF-CP/ADAMTS13) results in an increase of the plasma unusually large VWF multimer and leads to platelet clumping, which causes microcirculatory disturbance and finally multiorgan failure. The aim of this study was to explore the potential role of ADAMTS13 on the development of liver disturbance and multiorgan failure in AH., Methods: The activity of plasma ADAMTS13 and its clinical correlation were determined in 14 patients with AH, 4 with SAH (Maddrey score, mean 62), and 10 with alcoholic liver cirrhosis (LC)., Results: The activity of the plasma ADAMTS13 significantly decreased in patients with AH (mean 59%, p < 0.001), SAH (17%, p < 0.001) and LC (76%, p < 0.02) as compared with the healthy subjects (102%, n = 60). The activity was markedly lower in SAH than in AH (p < 0.02) and LC (p < 0.02). In three nonsurvivors with SAH who had multiorgan failure, it was extremely low (4.5%, 5.0%, and 16.0%, respectively), but in a survivor with SAH it remained mild decrease (44%). In AH, the protease activity increased at the recovery stage (42% --> 75%, p < 0.05). In the univariate analysis, the activity correlated with 10 clinical variables including functional liver capacity, inflammation signs, renal function, and platelet count in patients with AH and SAH. Among these, multivariate analysis showed that serum total bilirubin and C-reactive protein independently correlated with the protease activity., Conclusion: The activity of plasma ADAMTS13 markedly decreased in SAH in addition to AH. The activity was closely related to hyperbilirubinemia and inflammation signs, and was extremely low in nonsurvivors with SAH and multiorgan failure. The marked decrease of plasma ADAMTS13 may, in part, contribute to not only the progression of liver disturbance in AH, but also the development of multiorgan failure in SAH through microcirculatory disturbance.

Background: Abstinence is a prerequisite for the treatment of alcoholic chronic pancreatitis, but there are patients who have repeated attacks because of their inability to abstain and the consequent congestive effects of the continued alcohol intake on pancreatic juice. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for acinar cells and causes them to secrete pancreatic juice of low viscosity., Methods: Twelve patients with alcoholic chronic pancreatitis, who were unable to abstain from drinking, were administered bromhexine hydrochloride for 6 months to assess its therapeutic efficacy., Results: Of 12 patients administered bromhexine, 8 (67%) reported symptomatic improvement, and all patients showed improvement in the levels of pancreatic enzymes. Pancreatic exocrine function also tended to improve, but no improvement of pancreatic endocrine function was detected. Although none of the pancreatic stones present in some patients disappeared, a protein plug present in one patient disappeared, accompanied by improvement in the irregular outline of the lumen of the main pancreatic duct., Conclusion: Bromhexine hydrochloride may be a new for the morbidity of chronic pancreatitis, in which there is increased viscosity of the pancreatic juice and formation of a protein plug.

Background: It is suggested that endotoxin and proinflammatory cytokines play an important role in the development and progression of alcoholic liver disease. Recently, a prostaglandin receptor subtype EP4 agonist with cytoprotective effect has been developed. We examined the efficacy of an EP4 agonist ONO-AE1-437 on tumor necrosis factor-alpha (TNF-alpha) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol-loaded rats., Methods: Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from control and acute ethanol-loaded rats (5 mg/g body weight of ethanol, intraperitoneally). After the preculture in the medium that containing 0, 0.1, 1, 10, or 100 nmol/liter of ONO-AE1-437, TNF-alpha secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr., Results: The amount of TNF-alpha secreted from alveolar macrophages was largest in both the control and the acute ethanol-loaded rats. Acute ethanol load enhances TNF-alpha secretion of splenic macrophages. The addition of ONO-AE1-437 significantly inhibited TNF-alpha secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol-loaded rats. Alveolar macrophages were less affected., Conclusions: An EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.

Background: It is suggested that endotoxin, proinflammatory cytokines, and lipopolysaccharide-binding protein (LBP) play an important role in the development of alcoholic liver disease. Our previous study showed that splenic macrophages were important for endotoxin uptake and excessive production of tumor necrosis factor (TNF) in rats given large amounts of alcohol. To determine the pathophysiological roles of macrophages in alcoholic liver disease, we examined the effect of ethanol on TNF-alpha secretion of rat Kupffer cells, alveolar macrophages, and peritoneal macrophages in the presence or absence of LBP., Methods: Kupffer cells, alveolar macrophages, and peritoneal macrophages were isolated from male Sprague Dawley rats. After the preculture in the medium containing 0, 10, 50, and 100 mmol/liter of ethanol, TNF-alpha secretion by these cells incubated with 100 ng/ml of endotoxin in the presence or absence of LBP (1% rat serum) was determined., Results: In the absence of LBP, an addition of ethanol to the medium suppressed TNF-alpha secretion of alveolar macrophages. Kupffer cells and peritoneal macrophages were less affected. Addition of LBP led to marked enhancement (7- to 24-fold) of TNF-alpha secretion of macrophages either with or without ethanol in the medium. Although ethanol tended to suppress TNF-alpha secretion of these cells, alveolar macrophages were less affected in the presence of LBP., Conclusions: Serum LBP enhances the secretion of TNF-alpha by macrophages. Alveolar macrophages may be important for excessive production of TNF-alpha in chronic alcoholics with endotoxemia.