THE ROLE OF CAPILLARIZATION IN HEPATIC-FAILURE - STUDIES IN CARBON TETRACHLORIDE-INDUCED CIRRHOSIS

During the cirrhotic process, the hepatic microvascular phenotype is transformed from sinusoids (discontinuous capillaries) into continuous capillaries. This transformation has been termed capillarization. Many hepatic functions depend on the rapid, bidirectional exchange of macromolecules between plasma and hepatocytes. To determine whether capillarization contributes to hepatic failure in cirrhosis, we decided to study the plasma clearance (I-125) and hepatocyte uptake (electron microscopy) of three tracers in normal and cirrhotic rats. The tracers chosen were a hemeundecapeptide with peroxidatic activity (fluid-phase pinocytosis), asialofetuin (receptor-mediated endocytosis of a medium size protein) and ferritin (receptor-mediated endocytosis of a large size protein). The results demonstrate a decreased hepatocyte uptake of hemeundecapeptide; a significant delay in plasma clearance of asialofetuin; and a minor delay in plasma clearance of ferritin, but a striking trapping of ferritin in the cirrhotic capillary basement membrane. The delayed plasma clearance in cirrhosis cannot be ascribed to a decreased number of surface receptors because, in isolated hepatocytes, the number of molecules bound per cell was equivalent in normal and cirrhotic livers. These findings support the concept of capillarization, with the formation of continuous diffusion and filtration barriers between plasma and hepatocytes, representing a significant hindrance to the bidirectional macromolecular exchange normally taking place between these two compartments. Furthermore, at least in the case of ferritin, the capillary basement membrane of cirrhotic livers seems to be the major filtration barrier. This hindrance to hepatocyte uptake, and presumably also to secretion, may be the cause (or at least a major determinant) of the hepatic failure characteristic of cirrhosis.