Hepatic Organelle Pathology in Dogs with Congenital Portosystemic Shunts

Diversion of portal blood in congenital portosystemic shunts (CPSS) results in liver atrophy and passage of toxins into the systemic circulation causing hepatic encephalopathy. In some dogs, there is indirect evidence for hepatic insufficiency, but histologic findings are equivocal. This study determined whether hepatocyte integrity in PSS is comprised at a subcellular level using analytical subcellular fractionation of liver biopsies. Six dogs with CPSS had hypoproteinemia (6/6), increased serum alkaline phosphatase (6/6) and alanine aminotransferase (4/6) activity, hypocholesterolemia (6/6), and decreased blood urea (2/6). Liver biopsy specimens had increased activities (mU/mg protein) of alkaline phosphatase (17.9 ± 10.1; controls 5.1 ± 5.3: P < 0.01), but not of other plasma membrane enzymes. There were increased activities of endoplasmic reticular (neutral α‐glucosidase: 1.67 ± 0.7; controls 0.86 ± 0.2: P < 0.01) and lysosomal enzymes (N‐acetyl‐β‐glucosaminidase: 12.6 ± 2.3; controls 6.24 ± 2.7: P < 0.01; α‐mannosi‐dase: 0.85 ± 0.5; controls 0.39 ± 0.3: P < 0.05). Subcellular fractionation on reorientating sucrose density gradients showed a high‐density peak of alkaline phosphatase suggestive of a specific increase in the biliary canalicular component of enzyme activity. Neutral α‐glucosidase was shifted to denser fractions, indicative of an increase in the proportion of rough‐to‐smooth endoplasmic reticulum and consistent with enhanced synthesis of membranous enzymes. There was also evidence for increased fragility of intracellular organelles, particularly lysosomes. In contrast, histology showed either no abnormalities or minor degenerative changes compatible with hepatic underperfusion. These findings indicate that CPSS may be associated with hepatocellular damage compatible with hepatic dysfunction and potentially overlooked by conventional morphologic criteria.