JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #2384572): Female spayed Doberman pinscher
HISTORY: This dog presented with anorexia, icterus and elevated ALT, ALP and total bilirubin.
HISTOPATHOLOGIC DESCIPTION: D-M17a: Liver: Markedly expanding portal areas and bridging adjacent portal triads are numerous macrophages, lymphocytes and neutrophils, with fewer plasma cells, and fibroblasts (fibrosis) as well as increased biliary profiles (biliary ductular reaction). Multifocally, inflammatory cells disrupt the limiting plate and extend into the adjacent periportal parenchyma and separate, surround, and replace hepatocytes that are often degenerate with swollen vacuolated cytoplasm or are necrotic with shrunken hypereosinophilic cytoplasm and karyolytic, pyknotic, or karyorrhectic nuclei (“piecemeal” necrosis). Central veins are indistinct and there is occasional degeneration and necrosis of centrilobular hepatocytes admixed with lymphocytes, neutrophils and macrophages, and there multifocal areas of bridging from the central vein to adjacent portal areas. Diffusely, lobules are decreased in size with decreased distance between portal areas. Remaining hepatocytes contain yellow-brown pigment (copper, lipofuscin or hemosiderin) scattered within the cytoplasm. The capsule is irregular with loss of subcapsular hepatocytes and infiltration of lymphocytes and plasma cells, neutrophils, and macrophages, hemorrhage, fibrin and edema. There are multifocal dilated lymphatics (edema), and scattered macrophages and hepatocytes that contain golden brown cytoplasmic globules (hemosiderin).
D-M17b: Rhodanine: Liver: Diffusely, macrophages and hepatocytes, predominantly periportal but also midzonal and centrilobular, contain abundant red globular pigment (copper).
MORPHOLOGIC DIAGNOSIS: Liver: Hepatitis, portal and periportal, histiocytic, lymphoplasmacytic and neutrophilic, chronic, diffuse, moderate, with hepatic degeneration and necrosis, cholestasis, and abundant hepatocellular and histiocytic intracytoplasmic copper, Doberman pinscher, canine.
CONDITION: Canine Chronic Hepatitis
SYNONYMS: Canine chronic-active hepatitis, chronic progressive hepatitis
- Chronic hepatitis (CH) is a relatively common diagnosis in dogs; a long term (≥6 months), necroinflammatory disease
- Etiology is most often idiopathic; various infectious etiologies and drug- and toxin-induced CH has been described
- May develop following chronic bile duct obstruction, infections with hepatotropic diseases, familial or hereditary metabolic diseases, or may be toxin, drug-induced, or possibly autoimmune in origin
- Initial acute liver damage will not progress to fibrosis or cirrhosis unless inflammation and damage are protracted
- Alpha-1-antitrypsin deficiency – suggested to play a role in English cocker spaniel
- Copper-associated hepatitis: most recognized cause of chronic hepatitis
- Primary: hereditary metabolic defect inhibits biliary excretion of copper; results in hepatocellular lysosomal copper accumulation; Bedlington terriers (see D-T05), Long-Evans cinnamon rats, toxic milk mice, humans (Wilson’s disease)
- Centrilobular copper accumulation and necrosis
- NO cholestasis
- Cu concentrations > 2000ppm
- Micronodular regeneration
- Elevated glucose
- Secondary copper storage disease: altered biliary excretion of cooper due to hepatic inflammation, fibrosis and/or cholestasis (suggested pathogenesis)
- Periportal copper accumulation and necrosis
- Cu concentrations < 2000ppm
- Macronodular regeneration
- Decreased glucose
- Other breeds of dogs reported to be at risk for copper-associated CH: West Highland white terrier, Doberman pinscher, American and English cocker spaniel, Skye terrier, Labrador retriever, Dalmatian, standard poodle, English springer spaniel
- Increased hepatic copper occurs in various breeds of dogs that develop acute hepatic necrosis, subacute hepatitis, chronic hepatitis and cirrhosis; however, cause and effect of increased hepatic copper is not clear
- Canine – poorly understood; however, one study of early chronic hepatitis in Dobermans (with noncirrhotic livers) indicates the fibrosis and inflammation begin around the central hepatic vein and eventually extend outward to the portal areas
- Canine studies:
- Metallothionein, a heavy metal binding protein, may have a protective role in dogs effected with chronic hepatitis, increasing hepatocellular growth, decreasing inflammation, and decreasing the level of fibrosis
- Strong association between severity of liver injury and inflammation and the expression of isoforms of nitric oxide synthase (iNOS and eNOS), hepatocellular proliferation (Ki-67), apoptosis (CC-3), total stainable iron, and a diffuse pattern of MDA adduct immunoreactivity, which is a marker of oxidative stress (but NOT associated with MDA adduct activity score)
TYPICAL CLINICAL FINDINGS
- Most often middle-aged, female dogs
- Early signs - nonspecific, may include anorexia, depression, weakness, fatigue, weight loss, vomiting
- As the disease progresses, polydipsia, polyuria, icterus, ascites, and signs of hepatic encephalopathy (e.g. disorientation, behavioral changes, circling, head pressing, seizures, coma)
- Bleeding may occur (including gingival bleeding, epistaxis, and melena) secondary to decreased hepatic production of clotting factors
- Clinical pathology
- Elevated ALT and ALP, hyperbilirubinemia, hypoproteinemia, (hypoalbuminemia), hypergammaglobulinemia, bilirubinuria; in advanced CH, liver enzyme activities can appear normal or below reference range
- Liver function tests - usually abnormal; possibly prolonged coagulation times
TYPICAL GROSS FINDINGS:
- Small liver with accentuated lobular pattern
- Severely affected livers are characterized by architectural distortion ranging from coarsely nodular texture to end stage liver
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Periportal interface hepatitis (“piecemeal necrosis”) which initially destroys the limiting plate of periportal hepatocytes, and may continue to erode into the hepatic parenchyma, expanding portal areas
- Hepatocellular apoptosis or necrosis, variable portal and periportal mononuclear or mixed inflammation, intrahepatic cholestasis, fibrosis of portal areas of variable extent and pattern, hepatocellular regeneration
ADDITIONAL DIAGNOSTIC TESTS:
- Chronic hepatitis - biopsy and histopathology
- Rubeanic acid and rhodanine histochemical stains to detect copper in hepatocytes
- Quantitative copper analysis - fresh or formalin-fixed tissues
Causes of chronic hepatitis in dogs:
- Idiopathic – often in West Highland white terriers
- Infectious agents
- Infectious canine hepatitis virus (Canine adenovirus type 1) – basophilic intranuclear inclusion bodies may be seen in the first ten days of infection
- Leptospira sp. infections –spiral bacteria, seen with Warthin-Starry stains
- Aflatoxin – chronic changes may be seen but severity of hepatic lesions can be variable, more often in ruminants; acute, fulminating liver necrosis seen in dogs
- Copper accumulation:
- Hereditary copper storage disease in Bedlington terriers – mutation of the COMMD1 gene (previously the MURR1 gene) is associated with decreased copper excretion in hepatocytes
- Copper associated hepatitis (mechanisms unknown) – Skye terrier, Dalmation, West Highland white terrier, Doberman pinscher, American and English cocker spaniels, English springer spaniel and Labrador retriever
- Anticonvulsants (primidone, phenytoin, phenobarbital); bridging portal fibrosis, biliary hyperplasia, nodular regeneration, mild inflammatory cell infiltrates
- Dethylcarbamazine/oxibendazole combination (hookworm, roundworm treatment)
- Ketonconazole (dogs and cats)
- Megesterol acetate
- Griseofulvin (cats)
- Autoimmunity – possible cause; reported in humans
- Hemosiderosis/hemochromatosis – Excessive accumulation of hepatocellular iron; periportal and perivenular bridging fibrosis with nodular regeneration
- Common in birds and lemurs, otherwise considered rare
- Cholangitis / chronic biliary obstruction: May see loss of bile ducts with pigment laden macrophages and mixed inflammation including neutrophils; fibrosis with chronicity; biliary hyperplasia; +/- histologic evidence of cholestasis; may be associated with chronic bacterial cholangitis/cholangiohepatitis
- Sheep – Copper toxicity: paroxysmal intravascular hemolysis and liver failure
- Kidneys are deep red-brown to black and urine is deep red, as a result of hemoglobinuria with oxidation to methemoglobin and concurrent icterus
- Feline – Copper-associated chronic hepatitis and cirrhosis (rare)
- Seen as end-stage livers in horses and ruminants, particularly cattle; assumed to be associated with ingestion of hepatotoxins (pyrrolizidine alkaloids) or consequence of prolonged administration of hepatotoxic therapeutics
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- Bexfield NH, Watson PJ, Aguirre-Hernandez J, et al. DLA class II alleles and haplotypes are associated with risk for and protection from chronic hepatitis in the English Springer Spaniel. PLoS ONE. 2012;7(8):e42584.
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- Kanemoto H, Ohno K, Sakai M, et al. Expression of fibrosis-related genes in canine chronic hepatitis. Vet Pathol. 2011;48(4):839-845.
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