Endotoxin-induced liver necrosis and intravascular coagulation in rats enhanced by portacaval collateral circulation.

Abstract

SUMMARY The effects of intravenously administered endotoxin on the hepatic and systemic circulation as well as on the coagulation system were evaluated in normal rats (n = 26), in rats with experimental portal hypertension (n = 15), and in rats with portacaval anastomosis (n = 22). Endotoxin (15 mg/kg) in the normal rat leads to a prompt increase of transaminase activity and to a hyperdynamic circulation with a consequent increase in the total hepatic blood flow. In a later phase (6 h postoperatively) the hepatic artery dilated with a consequent hepatic arterial hyperperfusion. The coagulation system was affected with signs of consumption coagulopathy.In the rats with portal hypertension and portacaval collaterals as well as in those with portacaval anastomosis, the endotoxin injection resulted in acute liver necrosis within 12 to 15 hours. The hepatic artery became overdilated with a cardiac output fraction of 25 % (normal 5-5 %). Blood extravasates and thrombi, rich in fibrin, were detected in the liver. It is suggested that this exaggeration of the endotoxin effect was due to an impaired clearance function of the reticuloendothelial system, probably as consequence of portacaval collateral circulation. It is concluded that endotoxins (1) damage the liver even in a normal organism; (2) are potent to induce acute liver necrosis, if the reticuloendothelial system is altered; (3) have to be taken into consideration as contribution to the pathogenesis of acute as well as chronic liver diseases.Endotoxaemia is of increasing interest in the pathogenesis of acute hepatic failure and its complications. It is proposed that endotoxins coming from the intestine are insufficiently cleared from the portal venous system because of an impairment of the reticuloendothelial system. Endotoxins may then be responsible for both the intravascular coagulation and renal failure which are part of the picture of acute liver failure (Wilkinson, Gazzard, Arroyo, Moodie, and Williams, 1974). Gans, Mori, Lindsey, Kaster, Richter, Quinlan, Dineen, and Tan (1971) discussed these problems in connexion with their experiments concerning the anhepatic dog and suggested from the results that bacteria from the intestine or their products, no longer adequately eliminated by the liver reticuloendothelial system, are contributing significantly toward the pathogenesis of hepatic failure.

Pulmonary Hypertension in Patients With Congenital Portosystemic Venous Shunt: A Previously Unrecognized Association

“…[30][31][32][33] In particular, the 5-HT transporter expression increased in lung tissue specimens, and the pulmonary arteries from patients with IPAH and 5-HT markedly enhanced the growth of cultured pulmonary arterial smooth muscle cells. 34,35 As a result, these vasocontracting substances, especially 5-HT, may, therefore, play an important role in the advancement of PAH, and additional affirmative studies are needed.…”

Pathophysiology of hypotension in patients with fulminant hepatic failure.

“…In favour of this mechanism was the correlation found between unexplained hypotension and the severity of the hepatic necrosis as assessed by the prothrombin time. One such vasoactive compound, endotoxin, has been demonstrated in the serum of 64% of patients with fulminant hepatic failure (Wilkinson et al, 1974), and injection of endotoxin experimentally leads to the opening up of peripheral arteriovenous shunts (Liehr et al, 1975). In this respect it is of interest that intrapulmonary shunts of up to 39% of the cardiac output have been demonstrated in patients with fulminant hepatic failure with a corresponding increase in peripheral vasodilatation (Trewby et al, 1976).…”

The Role of the False Neurotransmitter Octopamine in the Hypotension of Fulminant Hepatic Failure

“…In addition, endotoxaemia, which in an earlier study (Wilkinson, Arroyo, Gazzard, Moodie & Williams, 1974) was found in 64% of patients with fulminant hepatic failure, may exacerbate the fall in peripheral resistance. Experimental injection of endotoxin leads to vasodilatation, and the opening of peripheral arteriovenous shunts (Liehr, Grun, Thiel, Brunswig & Rasenack, 1975), and in this respect it is noteworthy that we have recently demonstrated intrapulmonary shunts of up to 39% of the cardiac output in patients with fulminant hepatic failure with a corresponding increase in peripheral shunting as assessed by the arteriovenous oxygen content difference (Trewby, Williams, Williams & Reid, 1976). If central vasomotor depression were combined with peripheral arteriovenous shunting then a considerable fall in blood pressure would be expected.…”