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Postmortem Hepatocyte Vacuolation in Cynomolgus Monkeys

In safety studies, distinguishing subtle drug-associated tissue changes from spontaneous or incidental changes and postmortem or tissue processing induced artifactual changes is critical but often very challenging. A number of factors have been associated with the formation of non-drug-induced changes in tissues. These include the time between death, necropsy, and fixation as well as external factors (e.g., ambient temperature, humidity, light intensity, and trauma) and internal factors (e.g., physical or nutritional status and body temperature) (Trowell, 1946; Nunley et al., 1972; Splitter and McGavin, 1974; Sykes et al., 1976; Micozzi, 1986; Farnell, 1991; Kimura and Abe, 1994; Li et al., 2003). In the liver, it has been reported that anoxia and high intrahepatic blood pressure are two critical factors in the formation of postmortem hepatocytic vacuolation in rats and it was shown that the vacuoles were formed by intracytoplasmic influx of plasma secondary to sinusoidal congestion (Sykes et al., 1976; Li et al., 2003). We recently observed hepatocytic vacuolation similar to that reported in rats in a cynomolgus monkey model of extracorporeal blood circulation (ECC). In the required procedures for this model, each animal underwent anesthesia, surgical placement of catheters and cannulae, and heparinization to achieve activated clot time (ACT) 2–3 times baseline followed by 2 hours of ECC. Following the 2-hour ECC, protamine was administered to reverse the anticoagulation by heparin. When heparin effects were reversed, test material or placebo was administered and each animal was observed for an additional 6 hours while remaining under anesthesia. At the end of the 6-hour observation period, each animal was euthanized under deep anesthesia via exsanguination, perfused by gravity flow with physiological saline followed by 10% neutral buffered formalin and necropsied. Tissues were collected and preserved in 10% neutral buffered formalin, routinely processed to paraffin, then sectioned and stained with hematoxylin and eosin. Microscopically, the liver from each animal had diffuse hepatocellular vacuolation that was characterized by the presence of small, multivesicular intracellular vacuoles. This vacuolation, commonly associated with lipid metabolism, varied