From the mid-1950s, it was observed that liver injury by a variety of toxins greatly sensitized the host to the effects of administered lipopolysaccharide. In the nutritional cirrhosis of choline deficiency, and in acute toxic injury as well, the need for the presence of enteric endotoxin was demonstrated. The universality of this association was striking for almost all agents associated with liver injury. In addition, the presence of endotoxemia in human liver disease was documented in the 1970s, when the hypothesis was first proposed, and correlated with the severity of the disease. Despite imposing evidence of the critical role of enteric endotoxin in liver injury, it did not excite much interest in investigators until the 1980s. With the ability to study effects of alcohol in newer delivery systems, and an increased understanding of the role of Kupffer cells in the process, the original hypothesis has been accepted. This historical review details the progress of this novel concept of disease initiation and suggests future directions to bring potential therapies to the bedside.

The concept that relates intestinal bacteria and their toxins as a common pathway of liver injury by toxic agents has interested investigators for a long period. Recently, a number of studies in experimental animals and in patients with liver disease support this contention, and are reviewed. Evidence is presented to suggest that: (a) function of the sinusoidal cells is critical to integrity of the hepatocyte; (b) damage to these lining cells by several agents may be the initial injury leading to decreased ability of the liver to detoxify endotoxin (LPS); (c) following this primary injury to Kupffer and endothelial cells, LPS causes damage at amounts which are ordinarily innocuous and may represent a final pathway of liver necrosis; (d) "spillover" of LPS may lead to systemic manifestations of liver disease, and (e) modification of endotoxin toxicity or absorption may protect against several acute and chronic liver injuries.

The Anti-Toxic Function of the Liver ". . . If by means of a ligature placed on the portal vein the blood is compelled to deviate from the liver, poisonous symptoms appear consisting of fever and nephritis.

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