JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-M17

 

Signalment (JPC #2384572):  Female spayed Doberman pinscher

 

HISTORY:  This dog presented with anorexia, icterus, and elevated ALT, ALP and total bilirubin.

 

SLIDE A:

HISTOPATHOLOGIC DESCIPTION: Liver:  Markedly expanding portal areas and bridging adjacent portal areas are numerous macrophages, lymphocytes, neutrophils, fewer plasma cells, fibroblasts, scant to moderate amounts of variably mature collagen (fibrosis), and increased biliary profiles (biliary ductular reaction).  Multifocally, inflammatory cells disrupt the limiting plate, extend into the adjacent periportal parenchyma, and separate, surround, or 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 are multifocal areas of bridging inflammation from the central vein to adjacent portal areas.  Diffusely, lobules are decreased in size evidenced by decreased distance between portal areas.  Hepatocytes often contain yellow-brown, intracytoplasmic pigment (copper, lipofuscin, or hemosiderin).  The capsule is undulant with multifocal loss of subcapsular hepatocytes and infiltration of lymphocytes, plasma cells, neutrophils, and macrophages admixed with hemorrhage, fibrin, and edema.  There are multifocal dilated lymphatics (edema), and scattered macrophages that contain golden brown cytoplasmic globules (hemosiderin). 

 

SLIDE B: Rhodanine:  Liver:  Diffusely, macrophages and hepatocytes, predominantly periportal but also midzonal and centrilobular, contain abundant red-brown, granular to globular pigment (copper).

 

MORPHOLOGIC DIAGNOSIS:  Liver:  Hepatitis, portal and periportal, histiocytic, lymphoplasmacytic, and neutrophilic, chronic, diffuse, moderate, with hepatocellular degeneration and necrosis, and abundant hepatocellular and histiocytic intracytoplasmic copper, Doberman pinscher, canine.

 

CONDITION: Canine Chronic Hepatitis

 

SYNONYMS:  Canine chronic-active hepatitis, chronic progressive hepatitis

 

GENERAL DISCUSSION

• In dogs, chronic hepatitis (CH) is a relatively common, long term (≥6 months), necroinflammatory disease
• Etiology is most often idiopathic; may develop following chronic bile duct obstruction, infections with hepatotropic diseases, familial or hereditary metabolic diseases, or may be toxin-induced, drug-induced, or possibly autoimmune in origin
  • Copper-associated hepatitis is the most recognized cause of chronic hepatitis
• Initial acute liver damage will not progress to fibrosis or cirrhosis unless inflammation and damage are protracted

 

PATHOGENESIS 

In dogs:

• Poorly understood
• There is a strong association between severity of the liver injury and the inflammation and nitric oxide synthase (NOS) isoform expression
• In Doberman pinschers:
  • Elevated concentrations of copper have been reported in many but not all individuals with chronic hepatitis; impaired copper excretion may play a role in the pathogenesis based on decreased mRNA expression associated with the proteins metallothionein, ATP7A, ATP7B, and ceruloplasmin
  • MHC-II-associated autoantigens have been suggested as possible targets for T-cell-mediated immune attack
• In Doberman pinschers and English Springer spaniels: Highly polymorphic DLA genes may also be involved in susceptibility to hepatitis
• In English cocker spaniels, alpha-1-antitrypsin deficiency may play a role
• 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

 

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: 

• Rubeanic acid and rhodanine histochemical stains to detect copper in hepatocytes
• Quantitative copper analysis - fresh or formalin-fixed tissues

 

DIFFERENTIAL DIAGNOSIS: 

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:
  • Primary: Hereditary copper storage disease in Bedlington terriers (see D-T05) – mutation of the COMMD1 gene (copper metabolism MURR1 domain protein 1) is associated with decreased copper excretion in hepatocytes > hepatocellular lysosomal copper accumulation
    • Centrilobular copper accumulation and necrosis
    • No cholestasis
    • Copper concentrations > 2000ppm
    • Micronodular regeneration
    • Elevated glucose
  • Secondary: Secondary copper storage disease: altered biliary excretion of copper due to hepatic inflammation, fibrosis and/or cholestasis (suggested pathogenesis)
    • Periportal copper accumulation and necrosis
    • Cholestasis
    • Copper 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 spaniels, Skye terrier, Labrador retriever, Dalmatian, standard poodle, English springer spaniel
  • Drug-associated
    • Anticonvulsants (primidone, phenytoin, phenobarbital); bridging portal fibrosis, biliary hyperplasia, nodular regeneration, mild inflammatory cell infiltrates
    • Dethylcarbamazine/oxibendazole combination (hookworm, roundworm treatment)
    • Milbolerone
    • Methotrexate
    • CCNU
    • Ketonconazole (dogs and cats)
    • Megesterol acetate
    • Griseofulvin (cats)
  • Autoimmunity – possible cause; reported in humans
  • Hemosiderosis/hemochromatosis (D-M20): 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

 

COMPARATIVE PATHOLOGY:

• 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
• Primary hereditary copper storage disease similar to Bedlington terriers seen in Long-Evans cinnamon rats, toxic milk mice, and humans (Wilson’s disease)

 

REFERENCES: 

1. Brown DL, Van Wettere AJ, Cullen JM. Hepatobiliary system and exocrine pancreas. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:420, 429, 459-460.
2. Charles JA, Cullen JM, Desmet VJ, Twedt DC, van den Ingh T, Van Winkle T. Morphological classification of parenchymal disorders of the canine and feline liver. In: WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Disease. Philadelphia, PA: Saunders Elsevier; 2006:94-99.
3. Cullen JM, Stalker MJ. Liver and Biliary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:301-305,329.
4. Gill RM, Kakar S. Liver and gallbladder. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran’s Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier; 2021:837-838.
5. Webb, CB. Canine inflammatory/infectious hepatic disease. In: Ettinger SJ, Feldman EC, Cote, E, eds. Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat. Vol. 2. 8th ed. St. Louis, MO: Elsevier; 2017:1630-1631.

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