A Case of Canine Hepatitis with Hepatocellular Attack by Non-Neoplastic Perforin-Laden Lymphocytes

Abstract

The etiology of canine chronic hepatitis (CH) is unknown, although an autoimmune background has been suggested in some cases of canine CH. An 11 y old spayed female Norwich Terrier showed a marked elevation of liver enzymes with hyperbilirubinemia, regenerative anemia, and thrombocytopenia. A bacterial culture of the surgically excised liver tissue and bile was negative. The histological features of the liver biopsy resembled those of human autoimmune hepatitis except for a paucity of intralesional plasma cells. It was established through immunohistochemistry that CD3-positive perforin-containing T lymphocytes had actively infiltrated the patient's liver causing hepatocellular apoptosis, implying an autoimmune attack on hepatocytes. The patient's general condition improved, with normalization of platelet and serum total bilirubin levels, after immunosuppressive therapy with prednisolone and cyclosporine, whereas liver enzymes did not reach the reference interval. The dog died 11 months after the initiation of immunosuppressive therapy. These pathological findings may be one aspect of autoimmune mediation in canine CH.

Keywords: autoimmune hepatitis; canine chronic hepatitis; hepatocellular apoptosis; immunohistochemistry; immunosuppressive therapy; perforin-containing T lymphocytes.

Figure 1

Chronological change in blood biochemistry values. The timings of vaccination and immunosuppressant (prednisolone and cyclosporine) administration are also shown. Biochemical data were converted to multiples of the upper RI (× URI). * RI varied due to a change in the methodology. The values indicated by white diamonds represent measurements exceeding the detection limit. Alanine aminotransferase, ALT; aspartate transaminase, AST; alkaline phosphatase, ALP; gamma-glutamyl transpeptidase, GGT; serum total bilirubin, T-Bil; C-reactive protein, CRP.

Figure 2

Gross appearance of the liver. The liver lobes have rounded edges, multiple nodules, and a rough capsular surface. The tip of the left lateral liver lobe was ligated for biopsy (arrowhead). The gallbladder was slightly dilated (arrow).

Figure 3

Histopathological findings from a dog with suspected immune-mediated hepatitis. (A): Individual necrosis (apoptosis) of hepatocytes (arrows), sinusoidal infiltration of small lymphocytes (black arrowheads), disruption of hepatic cords by small lymphocytes (emperipolesis, yellow arrowheads), and irregularly aligned hepatic cords are present. H&E stain. Bar = 50 μm. (B): The limiting plate is disrupted by lymphocytic infiltration and hepatocellular necrosis/apoptosis (interface hepatitis, arrows). H&E stain. Bar = 50 μm.

Figure 4

Histochemical findings for a dog with suspected immune-mediated hepatitis. (A): Numerous (Thornburg grade 5) intracytoplasmic copper granules are present in the hepatocytes of the control dog afflicted with copper-storage hepatopathy. Victoria blue method. Bar = 50 μm. (B): Small numbers (Thornburg grade 1) of intracytoplasmic copper granules are present in the hepatocytes (arrowheads) of the index case. Victoria blue method. Bar = 50 μm.

Figure 5

Immunohistochemical (IHC) findings for a dog with suspected immune-mediated hepatitis. (A): CD3-immunopositive lymphocytes are sparse in the liver of the control healthy dog. IHC. Bar = 50 μm. (B): CD3-immunopositive lymphocytes are numerous in the liver of the index dog. IHC. Bar = 50 μm. (C): Lymphocytes containing perforin-immunoreactive granules (arrowheads) in the cytoplasm surround an apoptotic hepatocyte (arrow). IHC. Bar = 25 μm.