LONG-TERM TOTAL PARENTERAL NUTRITION-INDUCED HEPATOBILIARY DYSFUNCTION IN A RABBIT MODEL

Background/Purpose: Currently, the reason for hepatobiliary dysfunctio n associated with long-term total parenteral nutrition (TPN) is much d ebated and still unclear. No agreement can be achieved about whether b acteriotoxins and sepsis, enteral starvation, consequences of abdomina l operations, or the TPN solution itself is the real cause for the dis ease. Animal models were criticized for their short period of TPN and their failure to demonstrate cholestasis and bile duct proliferation. The aim of this study was to establish an animal model for long-term T PN in which the same alterations of the hepatobiliary system as observ ed in humans could be produced. Methods: In this model, rabbits could be kept for the first time under continuous TPN for 4 weeks. Th ree se rial liver biopsy sections were taken operatively from each animal and biochemical analyses were performed four times. A control group of en terally fed rabbits underwent exactly the same procedure in respect to operations and handling, so that differences in macroscopical, bioche mical, and histological changes between both groups could be attribute d exclusively to TPN. Results: Only in the TPN group gallbladder diste nsion developed in all animals after 1 week. After 3 and 4 weeks, visc ous dark bile, sludge and stones, a slight rise in direct bilirubin, a nd a decline in plasma albumin and alkaline phosphatase was noted. In both groups liver biopsy results showed a similar degree of mild porta l inflammation and single-cell necrosis at equivalent time points. The se changes could be caused by antiseptics, antibiotics, anesthesia, an d operations. Although mild to moderate proliferative changes and no h ydropic degeneration developed in the control group during the same ti me, the TPN group generated marked proliferative and degenerative chan ges. We noted as early as 1 week after starting TPN a severe hydropic degeneration in 90% of the animals. Fibrosis and bile duct proliferati on increased from a slight degree after 1 week up to a moderate to sev ere degree after 3 and 4 weeks, respectively. Conclusions: The hepatob iliary alterations associated with TPN in children, which cannot be se parated clinically from consequences of multiple other factors, can al most identically be reproduced in our rabbit model as a clear conseque nce of TPN. Furthermore, the hydropic degeneration of the liver cells begins in zone 3 and is an early predominant feature of hepatobiliary dysfunction in rabbits and infants. It must be rated as a response to a direct cytotoxic effect on the liver cell. Copyright (C) 1998 by W.B . Saunders Company.