Hepatic Injury Correlates With Apoptosis, Regeneration, and Nitric Oxide Synthase Expression in Canine Chronic Liver Disease

Abstract

Assessment of the clinical severity, pathogenesis, and prognosis of canine chronic liver disease poses significant challenges to clinicians and pathologists, relating in part to a lack of standardized terminology and assessment methods and also to a lack of understanding of the pathogenesis of chronic liver disease in the dog. This study graded the severity of necroinflammatory activity in chronic liver disease in dogs using a modification of Ishak's grading scheme for human chronic liver disease and examined the association of grade score with hepatocellular apoptosis, regeneration, nitric oxide synthase isoform expression, copper and iron accumulation, and indicators of oxidative stress. Formalin-fixed, paraffin-embedded hematoxylin and eosin (HE)-stained liver biopsies from 45 dogs with chronic liver disease and 55 healthy control dogs were graded for various morphologic components of liver injury and response. The cumulative score for grade of necroinflammatory activity was strongly and significantly correlated with immunoreactive labels for hepatocellular proliferation (Ki-67); apoptosis (cleaved caspase-3); inducible nitric oxide synthase (iNOS) in lobular, portal, and septal stromal cells; endothelial nitric oxide synthase (eNOS) in hepatocytes and lobular, portal, and septal stromal cells; and total stainable hepatic iron. A weaker significant correlation was found between grade and accumulation of hepatocellular copper. No significant correlation was found between grade and immunoreactivity for malondialdehyde-protein adducts. These results document a method for grading of the severity of necroinflammatory disease in canine liver biopsies and show an association with increased iNOS and eNOS expression.

ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs

“…During chelation treatment, antioxidant treatment, such as S‐adenosylmethionine (SAMe) and vitamin E, is recommended because Cu causes oxidative liver injury (Table ) …”

“…10 Based on limited information, a zinc dosage for CuCH has been extrapolated ( (Table 19). 113,286,[300][301][302][303][304][305][306][307][308][309][310][311][312] In some dogs with CuCH, severe lymphocytic hepatitis may reflect a concurrent primary process or reactive neoeptitope formation pro-…”

“…Necroinflammatory hepatic disease is associated with depletion of antioxidant defense mechanisms, 172,[303][304][305][306][307] justifying the use of cytoprotective agents with antioxidant properties (Table 19).…”

Diagnostic accuracy of Wright–Giemsa and rhodanine stain protocols for detection and semi‐quantitative grading of copper in canine liver aspirates

“…Primary causes include breed predispositions or specific genetic defects and have been demonstrated in Bedlington Terriers, Doberman Pinschers, Labrador Retrievers, Skye Terriers, West Highland White Terriers, and Dalmations . Secondary causes potentially include inflammation, cholestasis, or excessive dietary intake . The gold standard for determination of hepatic copper concentration is direct quantitation of hepatic copper content, reported on a dry weight basis .…”

“…[1][2][3][4][5][6] Secondary causes potentially include inflammation, cholestasis, or excessive dietary intake. 4,[7][8][9] The gold standard for determination of hepatic copper concentration is direct quantitation of hepatic copper content, reported on a dry weight basis. 8,10 Semiquantitative assessment using histologic sections stained with rubeanic acid or rhodanine and a grading system are also commonly used.…”