Human liver regeneration in advanced cirrhosis is organized by the portal tree

Abstract

In advanced cirrhosis new hepatocytic nodules are generated by budding of ductules in areas of parenchymal extinction. However, the vascular alterations in the areas of parenchymal extinction, the blood supply and the structure of the new hepatocytic nodules have not been analyzed in detail. Explanted human cirrhotic livers of three different etiologies and two experimental rat models of cirrhosis were thoroughly examined. 3D reconstruction of the immunohistochemically stained serial sections and casting of human and experimental cirrhotic livers have been used to reveal the structural organization of the regenerative buds. In areas of parenchymal extinction the skeleton of the liver, the portal tree is preserved. The developing regenerative nodules are positioned along the portal tree and are directly supplied by terminal portal venules. The expanding nodules grow along the trunks of the portal vein. Casting of human and experimental cirrhotic livers by colored resin confirms that nodules are supplied by portal blood. The two other members of the portal triads become separated from the portal veins. As the structure of the hepatocyte nodules (centrally located portal vein branches, bile ducts at the periphery, hepatic veins and arteries in the connective tissue) impedes the restoration of normal liver structure, the basic architecture of hepatic tissue suffers permanent damage. We suggest that "budding" may initiate the second, irreversible stage of cirrhosis. Cirrhosis is the final common outcome of long lasting hepatic injury defined as the destruction of the normal liver architecture by scar tissue. In the late phase of cirrhosis stem cells-derived hepatocyte nodules appear along the branches of the portal vein suggesting an important role of this specially composed blood vessels (containing digestive end-products from the stomach and intestines) in liver regeneration. Our results contribute to a better understanding of this serious liver disease.