Progressive necrosis after hepatectomy and the pathophysiology of liver failure after massive resection.

BACKGROUND: Mortality after hepatectomy in rats increases markedly beyond the classic 2/3 resection from which complete recovery is the rule. Because an extremely small hepatocyte population can theoretically sustain life, we hypothesize that lethal liver failure after subtotal resection could be due to progressive injury occurring in the remnant liver. The obligatory increase in portal blood through the small remnant may be central to the pathogenesis because of sinusoidal injury and Kupffer's cell activation. To test this hypothesis an experimental study in rats was undertaken to characterize liver cell injury after lethal (85%) and nonlethal (70%) hepatectomy.
METHODS: One hundred thirty Wistar rats were divided into three groups: control group (Sham laparotomy, n = 30), 70[5] hepatectomy group (n = 50), and 85% hepatectomy group (n = 50). Five rats in each group were killed for blood and liver collections from 15 minutes to day 14 after hepatectomy. Survival, histologic characteristics, serum activities of aspartate (AST) and alanine (ALT) aminotransferases and arginase were determined; serum level of tumor necrosis factor-alpha (TNF-alpha) and plasma level of prostaglandin E2 (PGE2) were measured by enzyme-linked immunosorbent assay.
RESULTS: Whatever the extent of resection, hepatic injury, as demonstrated by increased serum levels of arginase, ALT, and AST, was observed. The kinetics of arginase release after hepatectomy mimicked quite well those of AST and ALT, representing a reliable marker of hepatocyte injury. A significantly higher, more prolonged blood release of enzymes was observed after 85% hepatectomy than after 70% hepatectomy. Because of a very short half-life the rise in arginase several hours after hepatectomy seems to indicate ongoing liver damage distinct from the surgical injury. Significant elevations of TNF-alpha were detected that were much more severe after 85% hepatectomy. PGE2 levels that increased significantly after 70% resection remained depressed after 8% hepatectomy. Light microscopy demonstrated extensive patchy necrosis after 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 PGE2 could contribute to the pathophysiology of liver injury in the remnant after massive hepatectomy. These events may be initiated in part by the dramatic increase of portal flow through a too small remaining liver, and a pathologic mechanism may be amenable to pharmacologic manipulation.