JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
November 2021
D-V19

 

Signalment (JPC #1154150):  Young dog

 

HISTORY:  None

 

HISTOPATHOLOGIC DESCRIPTION:  Liver:  There is lytic necrosis of 95% of centrilobular areas, occasionally extending into midzonal areas (submassive), characterized by disruption of hepatic cord architecture and loss of hepatocytes with replacement by abundant fibrin, hemorrhage, edema, and necrotic debris admixed with low numbers of neutrophils and lymphocytes.  Hepatocytes at the periphery of necrotic areas often are degenerate, characterized by cell swelling with vacuolated cytoplasm, or are necrotic, characterized by shrunken cells with hypereosinophilic cytoplasm and karyolytic or pyknotic nuclei, and often containing basophilic, 4-8 um diameter, round to oval, intranuclear viral inclusion bodies that are occasionally surrounded by a clear halo and marginate the chromatin.  Similar intranuclear inclusion bodies are frequently present in Kupffer cells.  Multifocally portal vasculature endothelium is hypertrophied and rarely contains the previously described intranuclear inclusions.  Multifocally within surrounding hepatic sinusoids are mildly increased numbers of neutrophils and lymphocytes. 

 

MORPHOLOGIC DIAGNOSIS:  Liver:  Hepatitis, necrotizing, centrilobular to midzonal (submassive), acute, diffuse, severe, with hemorrhage and basophilic intranuclear viral inclusion bodies, breed unspecified, canine.

 

ETIOLOGIC DIAGNOSIS:  Adenoviral hepatitis

 

CAUSE:  Canine adenovirus type 1 (CAV1)

 

CONDITION:  Infectious canine hepatitis (ICH)

 

GENERAL DISCUSSION:

• ICH is a highly contagious disease that affects members of the Canidae, Mustelidae, and Ursidae families
• Foxes do not have significant lesions
• Bears (to include, brown grizzly and sloth bears) have similar lesions to canids
• Recent report of natural infection in maned wolf puppies (Pereira, J Comp Pathol. 2021)
• Adenoviruses are non-enveloped dsDNA viruses surrounded by a capsid with 252 capsomers

 

PATHOGENESIS:

• The virus has a predilection for epithelial cells of the liver and kidney and endothelial and mesothelial cells of all organ systems; most non-hepatic lesions are due to endothelial damage
• Transmitted by contact with contaminated fomites, nasal and conjunctival secretions, feces, or possibly urine
• Oropharynx infection > initially replicates in the tonsils > tonsillitis > cervical lymph nodes > thoracic duct > blood (viremia 4-8 days with leukopenia) > dissemination to viscera and central nervous system
• Virus can persist in the kidney and be shed in urine for several months
• Virally induced endothelial damage > disseminated intravascular coagulation and hemorrhagic diathesis
• The exhaustion of clotting factors (DIC) is largely due to their accelerated consumption, as the widespread endothelial damage is a potent initiator of the clotting cascade
• Some dogs that recover from ICH develop immune complex glomerulonephritis, corneal edema, and/or anterior uveitis due to type 3 hypersensitivity reaction

 

TYPICAL CLINICAL FINDINGS:

• CAdV1 can cause severe generalized fatal disease (not always fatal) or can be asymptomatic
• Dogs <2 yrs may be febrile with mild pharyngitis or tonsillitis
• Dogs >2 years of age rarely die of disease
• Severe cases; vomiting, melena, abdominal pain, non specific nervous signs, petechia of gums
• Peracute form: sudden death
• Surviving animals do not appear to have residual hepatic lesions due to rapid hepatic regeneration
• Vomiting, diarrhea, fever, melena, abdominal pain, tonsillar enlargement, coughing, and cervical lymphadenomegaly are possible signs
• Early neutropenia, lymphopenia, and thrombocytopenia
• Neutrophilia and lymphocytosis during recovery
• Prolonged BT, APTT, and TT and increased FDP’s with DIC
• Elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST)
• Marked bilirubinuria, proteinuria (albumin) from renal damage
• Decreased or absent megakaryocytes in bone marrow during viremic stage
• Corneal edema and anterior uveitis usually occur between 14 and 21 days after dogs begin clinical recovery

 

TYPICAL GROSS FINDINGS:

• Hepatomegaly; liver turgid and friable with yellowish mottling; in dogs surviving the acute phase, livers appear small, firm, and nodular
• Ascites with abdominal distention
• Serosal petechial and ecchymotic hemorrhages ("paintbrush lesions")
• Superficial lymph nodes, tonsils: Edema and hemorrhage
• Gallbladder edema
• Fibrin strands on the hepatic capsule
• Hemorrhagic infarcts in renal cortex
• Hemorrhages in distal ends of long bones and ribs, in the lungs, rarely in the brain
• Diffuse clouding of the eye from corneal edema causes “blue eye” phenomenon

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Characteristic basophilic adenoviral intranuclear inclusion bodies (INIB) surrounded by a clear zone that separates them from the marginated chromatin in affected epithelial and endothelial cells
• Liver:
• Coalescing centrilobular necrosis (resembles hepatotoxic lesion); intranuclear basophilic inclusion bodies (INIB) in Kupffer cells, hepatocytes, endothelial cells, and biliary epithelium
• Reticulin framework remains intact (complete recovery possible)
• Sinusoids dilated and filled with blood
• Degenerate neutrophils with fewer mononuclear cells associated with necrotic foci; +/- mononuclear periportal inflammation
• Gallbladder: Marked subserosal edema
• Urinary system: Immune complex glomeruloneprhtis; intranuclear inclusion bodies in glomerular mesangial cells, glomerular capillary endothelium, and tubular epithelium; inclusions in the urothelium of urinary bladder; interstitial nephritis
• Lung: Hemorrhage, edema, and fibrin in alveoli; INIB in alveolar capillary endothelium and bronchial epithelium; mononuclear interstitial inflammation
• Eye: Granulomatous iridocyclitis; corneal edema; INIB only in acute stages
• Central nervous system: Hemorrhage in the Virchow-Robin space and in the pons, thalamus, midbrain, and medulla oblongata; perivascular cuffing; vasculitis; endothelial intranuclear inclusion bodies; minimal gliosis
• Histiocytic cells: In virtually any organ, particularly lymph nodes and splenic red pulp, may have intranuclear inclusion bodies.
• Lymphoid organs: Congestion with neutrophilic and mononuclear cell infiltrates; lymphoid follicles have central necrotic foci
• Widespread intravascular fibrin thrombi

 

ULTRASTRUCTURAL FINDINGS:

• Virions arranged in paracrystalline array

 

ADDITIONAL DIAGNOSTIC TESTS:

• Fluorescent antibody test, virus isolation, immunohistochemistry, transmission electron microscopy, PCR

 

DIFFERENTIAL DIAGNOSIS:

• Centrilobular necrosis:
• Toxins
• Mebendazole toxicity: Diffuse, massive necrosis
• Acetaminophen toxicity: Diffuse, submassive necrosis
• Idiosyncratic drug reactions (submassive to massive necrosis): examples include trimethoprim-sulfonamide, zonisamde
• Xylitol (centrilobular to massive necrosis)
• Carprofen (diffuse and massive necrosis)
• Anticonvulsants: primidone, phenytoin, phenobarbital, cause chronic hepatic disease and cirrhosis (bridging portal fibrosis, biliary hyperplasia) in dogs
• Acute aflatoxicosis: Diffuse centrilobular to submassive necrosis with vacuolar change, lipid type
• Chronic passive congestion
• Canine herpesvirus 1 (CaHV-1): Multifocal, random hepatic necrosis with eosinophilic, typically smaller intranuclear inclusion bodies

 

COMPARATIVE PATHOLOGY:

Adenoviruses, Five genera:

• Mastadenovirus
  • Canine adenovirus type 1 (this entity): Infectious canine hepatitis
  • Canine adenovirus type 2 (P-V21): Produces bronchointerstitial pneumonia with necrotizing bronchiolitis; clinical disease is usually a consequence of immunosuppression
  • Bovine: Associated with respiratory and enteric disease in calves but not considered the primary pathogen in either syndrome (bovine mastadenoviruses A-C; bovine adenovirus 1, 3 and 10)
  • Equine adenovirus types 1 and 2: Mild respiratory disease except in SCID Arabian foals where adenoviral infection leads to severe bronchiolitis and atelectasis (equine mastadenovirus A and B)
  • Porcine: Associated with encephalitis and diarrhea (porcine mastadenoviruses A-C; porcine adenoviruses 1-5)
  • Guinea pig: Adenoviral pneumonitis (Guinea pig adenovirus (GPAdV))
  • Non-human primates: Mild to moderately severe respiratory and enteric disease as well as keratitis/conjunctivitis
  • Sheep (P-V20): Ovine mastadenoviruses A and B (includes ovine adenoviruses 1-5, bovine adenovirus 2 and goat adenovirus 2)
• Atadenovirus
  • Wildlife: Cervine adenovirus (Odocoileus hemionus deer adenovirus 1 (OdAdV-1) – proposed to be cervid atadenovirus A; cervid adenovirus 1) causes Adenovirus Hemorrhagic Disease of Deer present in Oregon and California; in deer it produces pulmonary edema and erosions, ulcerations, hemorrhage or abscesses in the oral cavity (similar to Bluetongue virus and Epizootic Hemorrhagic Disease (orbiviruses)) with widespread vasculitis and endothelial intranuclear inclusions
  • Snakes and lizards: Subclinical or produces hepatitis, esophagitis, enteritis, splenitis and encephalopathy (lizard atadenovirus A, snake atadenovirus A)
  • Chickens, ducks, geese: Egg drop syndrome (duck atadenovirus A; duck adenovirus 1)
  • Goats and sheep: Mild to no clinical disease (ovine atadenovirus D; goat adenovirus 1 and ovine adenovirus 7)
• Aviadenovirus
  • Chickens:
    • Inclusion body hepatitis (D-V20; fowl aviadenovirus D and E; fowl adenovirus 2 (FAdV2), FAdV8, FAdV11))
    • Hepatitis-hydropericardium syndrome virus (fowl aviadenovirus C; FAdV4)
    • Gizzard erosion (fowl aviadenovirus A; FAdV1)
  • Quail bronchitis virus (fowl aviadenovirus A)
  • Turkey aviadenovirus B (turkey adenovirus 2 (TAdV2))
• Siadenovirus:                                                                                                                     
  • Frog siadenovirus A
  • Raptor siadenovirus A
  • Turkey siadenovirus A (TAdV3)
    • Hemorrhagic enteritis (turkeys)
    • Marble spleen disease (H-V08, pheasants)
    • Avian adenovirus splenomegaly (broilers)
  • Psittacine adenovirus 2
  • Budgerigar adenovirus 1
  • Gouldian finch adenovirus 1
  • Sulawesi tortoise adenovirus 1
• Ichtadenovirus (proposed 6^th adenovirus genus)
  • Sturgeon ichtadenovirus A

 

REFERENCES:

1. Cianciolo RE, Mohr FC. Urinary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 2. 6th ed. Louis MO: Elsevier Ltd; 2016:410.
2. 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. Louis MO: Elsevier Ltd; 2016:310-312.
3. Fitzgerald SD, Hess M, Smyth JA, Pierson FW, Reed WM, Jack SW. Adenovirus infections. In: Swayne DE, ed. Diseases of Poultry. 13th ed. Ames, IA: John Wiley & Sons, Inc; 2013: 289-331.
4. Greene CE. Infectious canine hepatitis and canine acidophil cell hepatitis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. St Louis, MO: Saunders Elsevier; 2012:42-47.
5. Keel MK, Terio KA, McAloose D, Canidae, Ursidae and Ailuridae. Pathology of Wildlife and Zoo Animals. San Diego, CA:Elsevier. 2018. 239.
6. Pereira FM, de Oliveira AR, Melo ES, et. al. Naturally Acquired Infectious Canine Hepatitis in Two Captive Maned Wolf (Chrysocyon brachyurus) Puppies. J Comp Pathol. 2021;186:62-68.
7. Wachtman L, Mansfield K. Viral Diseases of Nonhuman Primates. In: Abee, ed. Nonhuman Primates in Biomedical Research: Diseases. Volume 2. San Diego, CA: Elsevier Inc; 2012:27-30.
8. Wilcock, BP, Njaa BL. Special Senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 1. 6th ed. Louis MO: Elsevier Ltd; 2016:452-453.
9. Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:207.

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