Serum hyaluronan and hyaluronidase: very early markers of toxic liver injury

Background: Dimethylnitrosamine (DMN), a potent hepatotoxin, administered to rats, provides a convenient model for toxic liver injury. Indicators of early liver injury are important clinically, for surveillance, for screening new drugs that are potentially hepatotoxic and for identifying drugs that protect against liver injury. Both cirrhosis and wound healing culminate in deposition of fibrous connective tissue and scarring. Increased hyaluronan (HA) occurs in the earliest stage of wound healing. Hyaluronidase.. the enzyme that degrades hyaluronan, is also elevated whenever rapid turnover of hyaluronan occurs. We test the hypothesis that elevated levels of circulating hyaluronan and hyaluronidase could provide indicators of very early liver damage. Methods: Dimethylnitrosamine was administered to adult male albino rats by intraperitoneal injections for 7 consecutive days. Results: Increased serum hyaluronan levels observed on day 2 reached a maximum on day 4. Hyaluronidase was elevated on the first day and reached a maximum on day 2 that was 30-times control levels. Hyaluronan-specific staining in liver sections was maximal on day 7, Occurring predominantly in portal triads and in sinusoidal spaces. Individual hepatocytes were slightly enlarged and contained intracellular hyaluronan, which was not evident in control sections. Though circulating hyaluronan levels had decreased after day 4, continued hyaluronan staining persisted in liver sections through day 21. Conventional indicators of liver injury, such as serum aminotransferase enzymes, did not reach a peak until day 7. Conventional gross and histopathological changes, including severe centrilobular congestion and hemorrhagic necrosis, were observed only after day 7. Both hyaluronan and hyaluronidase are indicators of very early liver damage in the dimethylnitrosamine-treated rat, occurring well before conventional indicators appear, or before overt histopathologic changes of liver damage can be seen. However, levels are increased only transiently, indicating that serial assays are necessary. Conclusions: Measures of circulating hyaluronidase activity may be used to assess liver damage. (C) 2004 Elsevier B.V. All rights reserved.