Chronic alcohol abuse is the leading cause of progressive liver disease in Western countries. The more advanced stages of alcoholic liver disease (ALD) are associated with both hepatic infiltration and activation of leukocytes, findings that strongly support the assumption that the unspecific immune system may play an important role in the pathogenesis of ALD. Besides other factors such as changes associated with the metabolism of ethanol and genetic susceptibility, strong evidence has accumulated during the last two decades that bacterial toxins of intestinal origin (namely endotoxins) can be considered to be important inducers of hepatic damage after chronic alcohol abuse. In alcoholics, elevated plasma levels of endotoxin were shown to occur already at early stages of ALD. In patients chronically abusing alcohol, this increase was found to be paralleled by both bacterial overgrowth of the small intestine and increased permeability to macromolecules. Several studies revealed a close correlation between the plasma endotoxin concentration and several laboratory markers of ALD, both of which improved after alcohol withdrawal. The reduction of bacterial toxin concentration in the intestine by oral administration of broad spectrum antibiotics resulted nearly in the prevention of ALD in alcohol feeding studies
with rodents. In comparable studies, feeding with lactobacilli, which do not produce endotoxins, ameliorated the severity of ALD considerably. With respect to the pathomechanism of ALD development, pro-inflammatory cytokines
such as tumour-necrosis factor α (TNF-α) and interleukin (IL) 8, which are produced after endotoxin stimulation of hepatic macrophages (Kupffer cells), were shown to be of crucial importance for the development of ALD. Especially
TNF-α and reactive oxygen species (ROS) formed by hepatic phagocytes are important mediators of hepatic damage in ALD. This fact became clear in studies with rodents that were made deficient for genes either for the TNF-α receptor or NADPH oxidase (a key enzyme of ROS synthesis), as, in contrast to wild-type animals, these animals did not develop ALD after prolonged ethanol feeding.
In humans, in parallel to the early occurring endotoxaemia, several endotoxin-binding humoral factors are elevated after chronic alcohol abuse. These factors are either a result of specific stimulation of lymphocytes by endotoxin (IgA) or
of other origin such as lipopolysaccharide-binding protein (LBP) and bactericidal/permeability-increasing protein (BPI). The increase of these proteins and soluble CD14 is thought to contribute to an amelioration of the inflamma-
tory immune response caused by endotoxaemia.