PROGRESSIVE NECROSIS AFTER HEPATECTOMY AND THE PATHOPHYSIOLOGY OF LIVER-FAILURE AFTER MASSIVE RESECTION

Background. Mortality after hepatectomy in rats increases markedly bey ond the classic 2/3 resection from which complete recovery is the rule . Because an extremely small hepatocyte population can theoretically s ustain life, we hypothesize that lethal liver failure after subtotal r esection could be due to progressive injury occurring in the remnant l iver. The obligatory increase in portal blood through the small remnan t may be central to the pathogenesis because of sinusoidal injury and Kupffer's cell activation. To test this hypothesis an experimental stu dy in rats was undertaken to characterize liver cell injury after leth al (85%) and nonlethal (70%) hepatectomy. Methods. One hundred thirty Wistar rats were divided into three groups: control group (sham laparo tomy, n = 30), 70[5] hepatectomy group (n = 50), and 85% hepatectomy g roup (n = 50). Five rats in each group were killed for blood and liver collections from 15 minutes to day 14 after hepatectomy. Survival, hi stologic characteristics, serum activities of aspartate (AST) and alan ine (ALT) aminotransferases and arginase were determined; serum level of tumor necrosis factor-alpha (TNF-alpha) and plasma level of prostag landin E(2) (PGE(2)) were measured by enzyme-linked immunosorbent assa y. Results. Whatever the extent of resection, hepatic injury, as demon strated by increased serum levels of arginase, ALT, and AST, was obser ved. The kinetics of arginase release after hepatectomy mimicked quite well those of AST and ALT, representing a reliable maker of hepatocyt e injury. A significantly higher, more prolonged blood release of enzy mes was observed after 85% hepatectomy than after 70% hepatectomy. Bec ause of a very short half-life the rise in arginase several hours afte r hepatectomy seems to indicate ongoing liver damage distinct from the surgical injury. Significant elevations of TNF-alpha were detected th at were much more severe after 85% hepatectomy. PGE(2) levels that inc reased significantly after 70% resection remained depressed after 8% h epatectomy. Light microscopy demonstrated extensive patchy necrosis af ter 85% hepatectomy. Conclusions. A pattern of progressive necrosis of the remnant liver was identified with Kupffer's cell dysfunction. We hypothesize that failure of down-regulation of TNF-alpha production by PGE(2) could contribute to the pathophysiology of liver injury in the remnant after massive hepatectomy. These events may be initiated in p art by the dramatic increase of portal flow through a too small remain ing liver, and a pathologic mechanism may be amenable to pharmacologic manipulation.