Stereological Estimation and Zonal Distribution of the Hepatotoxic Effects of Doxorubicin on the Female Albino Rat (Rattus Norvegicus)

Abstract

Background: Doxorubicin is an anti-neoplastic agent widely indicated for a variety of cancers. One of its adverse effects is hepatotoxicity which presents with hepatocyte necrosis, sinusoidal dilation, and fibrosis. However, there remains a dearth in the quantification and zonal distribution of this damage. Methods: Twenty-three adult female Wister albino rats were placed into baseline, control, and experimental group receiving 2.5mg/kg bodyweight Doxorubicin intra-peritoneally thrice weekly for 3-weeks. Rats were sacrificed on days 0, 7, 14 and 21 and livers harvested for processing. Masson’s Trichrome was used in staining 7 µm thick sections. Images were taken and analyzed via STEPanizer, and data entered into SPSS for analysis. Results: Rats treated with Doxorubicin had increased liver to body weight ratios from 5.00% at baseline to 6.15%, 6.69% and 7.56% on days 7, 14 and 21 (p=0.090). There was a decrease in hepatocyte densities from 51.88/mm2 to 48.61/mm2, 46.65/mm2 and 42.24/mm2 on day 7, 14 and 21 (p=0.779). Collagen fiber deposition increased from 0.12±0.06 cm3 to 0.47±0.55 cm3, 1.64±0.11 cm3 and 1.88±0.24 cm3 on days 7, 14 and 21 (p=0.009). Deposition was greatest periportally and least pericentrally. Volume of sinusoidal spaces increased from 5.46±0.50 cm3 to 5.49±0.15 cm3, 5.53±0.24 cm3 and 5.50±0.17 cm3 on days 7, 14 and 21 respectively (p=0.827).  Sinusoids were larger pericentrally than periportally. Conclusion: Doxorubicin administration is associated with an increase in volume density of fibrotic tissue and sinusoidal spaces but decrease in hepatocytes. The quantitative changes presented may facilitate histopathological grading of Doxorubicin-induced hepatotoxicity.