JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

November 2024

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 either swollen with vacuolated cytoplasm (degeneration) or shrunken with hypereosinophilic cytoplasm and karyolytic or pyknotic nuclei (necrosis), and often contain basophilic, 4-8 µm 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 there are mildly increased numbers of neutrophils and lymphocytes.

 

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

 

ETIOLOGIC DIAGNOSIS: Adenoviral hepatitis

 

CAUSE: Canine adenovirus type 1 (CAdV-1 or CAV-1)

 

CONDITION: Infectious canine hepatitis (ICH)

 

GENERAL DISCUSSION:

• Adenoviruses are ubiquitous non-enveloped dsDNA viruses that affect a wide range of mammals, avians, and reptiles
  1. Adenoviruses tend to be species specific, but may infect closely related species
• Adenoviruses most often infect endothelial cells in addition to specific epithelial cells throughout the body (e.g., hepatocytes) and are classically associated with enteritis, hepatitis, and/or respiratory disease
  1. Adenoviral upper respiratory infections and/or pneumonia seen in many species (P-V20, P-V21)
  2. Adenoviral enteritis is seen in many species, including humans, cattle, swine, horses, sheep, cervids, camelids dogs, Spanish ibex, inland bearded dragons, and various avians (D-V32)
  3. Adenoviral hepatitis is noted in canines, avians, and various reptiles (D-V20)
  4. Most infectious are asymptomatic; adenoviral disease is often associated with young and/or immunosuppressed (e.g., SCID foals, pups with canine morbillivirus/canine distemper)
• CAdV-1 causes viral hepatitis and endothelial damage (with subsequent hemorrhage) in dogs and other canids as well as bears (Uridae) and skunks and otters (Mustelidae)
  1. Widespread vaccination has made ICH rare in many parts of the world
  2. Canine adenoviruses have also been associated with retinal dysplasia (infection during development) and tubulointerstitial nephritis

 

PATHOGENESIS:

• CAdV-1 causes cytolysis in endothelial cells, epithelial cells of the liver and kidney, and mesothelial cells of all organ systems
  1. Most non-hepatic lesions are due to endothelial damage
• Transmitted by contact with contaminated fomites, nasal and conjunctival secretions, feces, or urine
• Inhalation or ingestion -> Regional virus replication (Inside local oral/pharyngeal mucosa macrophages and then to tonsils causing tonsilitis) -> Viremia (or systemic spread inside macrophages) -> Infect endothelial cells (causes lysis and necrotizing vasculitis) -> Infect epithelial cells (esp. liver and kidney, but also spleen and lung) -> Centrilobular hepatocellular necrosis
  1. Hepatic centrilobular necrosis may be secondary to endothelial injury and local hypoxia rather than a particular viral tropism
  2. Endothelial cell injury -> Vasculitis -> Widespread petechiae and ecchymotic hemorrhage and edema (increased vascular permeability) and can result in disseminated intravascular coagulation (DIC)
     • Widespread endothelial damage -> Initiation of clotting cascade -> Accelerated consumption and exhaustion of clotting factors
  3. Viremia is associated with leukopenia and fever; leukopenia may be due to viral replication within lymphocytes
  4. Viral receptors/targets: A virus capsid protein called fiber protein may serve as an attachment protein that binds to target cell receptors such as coxsackievirus-adenovirus (in intestine) or integrin receptor
• Virus can persist in the kidney and be shed in urine for several months
• With increasing neutralizing antibody titer, some dogs may develop a type III hypersensitivity reaction -> Immune complex glomerulonephritis, corneal edema (“blue eye”), and/or anterior uveitis
• Surviving animals have little to no residual hepatic lesions due to rapid and complete hepatic regeneration as the reticulin framework remains intact

 

TYPICAL CLINICAL FINDINGS:

• Most cases have only mild febrile illness with pharyngitis and tonsillitis; severe cases may have vomiting, high fever, melena, abdominal pain, and/or nonspecific nervous signs
  1. Death usually sporadic and rare in dogs >2 years of age
• Mucous membranes (e.g. gums) may have petechiae and be pale and occasionally jaundiced/icteric
•  Clinical pathology
  1. CBC: Early: Neutropenia, lymphopenia, and thrombocytopenia; Later: Neutrophilia and lymphocytosis
  2. Chemistry: Elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST)
  3. Clotting: Prolonged BT, APTT, and TT and increased FDP’s with DIC
• Corneal edema and anterior uveitis usually occur between 14 and 21 days after dogs begin clinical recovery

 

TYPICAL GROSS FINDINGS:

• Widespread petechial and ecchymotic hemorrhages ("paintbrush lesions") on mucous membranes and serosal surfaces +/- fluid effusion
• Liver: Hepatomegaly; friable liver with an enhanced lobular pattern (due to of the centrilobular hepatic necrosis); fibrin strands may be present on the surface
• Gallbladder: Wall thickened by edema and hemorrhage

Superficial lymph nodes, tonsils: Enlargement with edema and redness due to congestion and hemorrhage

• Inconsistent lesions in other organs:
  1. Hemorrhagic infarcts in renal cortex
  2. Foci of hemorrhage in the lung, brain (esp. midbrain brain stem and cerebellum), kidneys, and the metaphysis of the long bones
• Diffuse clouding of the eye from corneal edema causes unilateral or bilateral “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 hepatocytes as well as lymphoreticular cells/macrophages throughout the body
• Liver:
  1. Coalescing centrilobular (periacinar) zonal necrosis (resembles hepatotoxic lesion); INIBs in Kupffer cells, hepatocytes, endothelial cells, and biliary epithelium
  2. Margin of necrosis is usually sharp; apoptosis of hepatocytes and fatty change is common; sinusoids dilated and filled with blood
  3. Mild leukocyte presence predominately associated with necrotic tissue (neutrophils predominate)
  4. Reticulin framework remains intact (complete recovery possible)
• Gallbladder: Cholecystitis with inflammatory cell infiltrates, hemorrhage, and marked subserosal edema
• Lesions in other organs:
  1. Kidney: INIB in glomerular epithelium and occasional renal tubules; focal interstitial nephritis occurs commonly but is not functionally significant; Later: 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
  2. Lung: May see hemorrhage, fibrin, and edema in alveoli and INIB in alveolar capillary endothelium and bronchial epithelium; mononuclear interstitial inflammation
  3. Brain: Focal hemorrhage with secondary demyelination
  4. Lymphoid organs: Congestion with neutrophilic and mononuclear cell infiltrates; lymphoid follicles have central necrotic foci
  5. Eye: During acute disease, subclinical nonsuppurative uveitis may be present (with endothelial INIBs); Later: Type III hypersensitivity with anterior uveitis, endothelial damage, and corneal edema

 

ULTRASTRUCTURAL FINDINGS:

 

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: INIBs may be visible cytologically in infected cells (e.g., hepatocytes)
• Fluorescent antibody test, virus isolation, immunohistochemistry, transmission electron microscopy, PCR

 

DIFFERENTIAL DIAGNOSIS:

Centrilobular necrosis:

• Toxins
  1. Mebendazole toxicity: Diffuse, massive necrosis
  2. Acetaminophen toxicity: Diffuse, submassive necrosis
  3. Idiosyncratic drug reactions (submassive to massive necrosis): examples include trimethoprim-sulfonamide, zonisamide
  4. Xylitol (centrilobular to massive necrosis)
  5. Carprofen (diffuse and massive necrosis)
  6. Anticonvulsants: primidone, phenytoin, phenobarbital, cause chronic hepatic disease and cirrhosis (bridging portal fibrosis, biliary hyperplasia) in dogs
  7. 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:

Select Adenoviruses from 5 genera and 1 proposed genera:

• Mastadenovirus
  1. Canine adenovirus type 1 (this entity): Infectious canine hepatitis
     • Recent report of fatal natural infection in 2 maned wolf pups with hepatitis, spleno- and lymphadenomegaly, and multifocal hemorrhages and INIBs in various organs (Pereira, J Comp Pathol. 2021)
  2. Canine adenovirus type 2 (P-V21): Produces bronchointerstitial pneumonia with necrotizing bronchiolitis; and is part of the Canine Infectious Respiratory Disease Complex clinical disease is usually a consequence of immunosuppression (P-V21)
  3. Bovine (BAdV): 
     • Associated with respiratory (part of Bovine Respiratory Disease Complex), keratoconjunctivitis, and enteric disease, primarily in calves; many strains (bovine mastadenoviruses A-C; bovine adenovirus 1, 3 and 10)
     • Enteritis: Multifocal to diffuse ischemic necrosis in forestomaches and/or intestine +/- pseudodiphtheritic membrane; Peyer’s patch necrosis and INIBs in endothelium
  4. Equine: Equine adenovirus types 1 and 2: Mild upper repository tract disease except in SCID Arabian foals where adenoviral infection leads to severe bronchiolitis and atelectasis (equine mastadenovirus A and B); EAdV-2 may be associated with gastrointestinal tract disease/diarrhea
  5. Porcine: Associated with encephalitis and potentially enteritis with diarrhea (porcine mastadenoviruses A-C; porcine adenoviruses 1-5)
  6. Sheep: Ovine mastadenoviruses A and B (includes ovine adenoviruses 1-5, bovine adenovirus 2 and goat adenovirus 2) associated with occasional enteritis or chronic enzootic pneumonia (P-V20)
  7. Lab animal
     • Mouse:
       • Murine Adenovirus-1 (MAdV-1) infects cells of the monocyte–macrophages, endothelial cells, respiratory epithelium, adrenal cortical cells, and renal distal tubular cells; there is marked mouse strain differences in susceptibility (e.g. C57BL/6, DBA/2, SJL, SWR susceptible; BALB/c resistant); severe infections include focal hemorrhagic enteritis, hepatitis with Reye’s-like syndrome (hepatoencephalopathy and fatty degeneration of viscera), and hemorrhagic encephalomyelitis
       • MAdV-2: Enterotropic; usually no clinical signs, but may see with runting, hemorrhage, and necrosis in multiple organs
       • MAdV-1 or MAdV-2 also seen incidentally in rats and hamsters
     • Guinea pig: Guinea pig adenovirus (GPAdV) leading to necrotizing bronchitis and bronchiolitis
  8. Pinnipeds: California sea lion adenovirus-1 (CSLAdV-1) results in multifocal necrotizing hepatitis with hepatocyte INIBs; also keratitis/uveitis and necrotizing enteritis
  9. Non-human primates: Mild to moderately severe respiratory and enteric disease as well as keratitis/conjunctivitis
• Atadenovirus
  1. Bovine: Some serotypes of BAdV are classified here
  2. Cervids: Odocoileus adenovirus 1 (OdAdV-1): Affects Mule deer (Odocoileus hemionus) most severely, but also other species of deer, results in 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
  3. Snakes and lizards: Subclinical or produces hepatitis, esophagitis, enteritis, splenitis and encephalopathy (lizard atadenovirus A, snake atadenovirus A)
  4. Chickens, ducks, geese: Egg drop syndrome (duck atadenovirus A; duck adenovirus 1)
  5. Goats and sheep: Mild to no clinical disease (ovine atadenovirus D; goat adenovirus 1 and ovine adenovirus 7)
• Aviadenovirus
  1. 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)
  2. Quail bronchitis virus (fowl aviadenovirus A)
  3. Turkey aviadenovirus B (turkey adenovirus 2 (TAdV2))
• Siadenovirus:                                                                                                                                                                                           
  1. Frog siadenovirus A
  2. Raptor siadenovirus A 
  3. Turkey siadenovirus A (TAdV3)
     • Hemorrhagic enteritis (turkeys)
     • Marble spleen disease (H-V08, pheasants)
     • Avian adenovirus splenomegaly (broilers) 
  4. Psittacine adenovirus 2
  5. Budgerigar adenovirus 1
  6. Gouldian finch adenovirus 1
  7. Sulawesi tortoise adenovirus 1 (STAdv-1)
• Ichtadenovirus  
  1. Sturgeon ichtadenovirus A
• Testadenovirus (proposed adenovirus genus)
  1. Proposed genus to include Lacertilian (lizard) and testudinoid adenoviruses; adenoviral hepatitis has been documented in bearded dragons

 

REFERENCES:

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