JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
August 2018
D-B05

SIGNALMENT (JPC # 2548132): 6-day-old male crossbred lamb

HISTORY:  This lamb was weak

HISTOPATHOLOGIC DESCRIPTION: Liver: Affecting approximately 60% of the liver are multifocal to coalescing, random, 1-3 mm diameter circular areas of hepatic parenchyma that have retention of cellular detail and loss of differential staining (coagulative necrosis).  The foci are rimmed by eosinophilic and karyorrhectic debris, necrotic leukocytes, basophilic fragmented material (mineral), and numerous radiating colonies of 1 um wide basophilic, extracellular, filamentous bacilli.  Hepatic cords surrounding necrotic areas are frequently discontinuous with individualization of hepatocytes that are swollen and vacuolated (degeneration) or shrunken with a scant amount of hypereosinphilic cytoplasm and a pyknotic nucleus (necrosis).  Multifocally, sinusoids are dilated up to three times by blood (congestion).

MORPHOLOGIC DIAGNOSIS: Liver: Necrosis, coagulative, acute, multifocal-random, moderate with filamentous bacilli, etiology consistent with Fusobacterium necrophorum, crossbred sheep, ovine. 

CAUSE: Fusobacterium necrophorum

CONDITION: Hepatic necrobacillosis 

GENERAL DISCUSSION:  

• Gram-negative, pleomorphic, filamentous, obligate anaerobe that is a normal inhabitant of the alimentary tract, respiratory tract, and reproductive tract
• Opportunistic pathogen that is common in livestock, causing a variety of suppurative and necrotic infections (oral, pharynx/larynx, digital, mandible/maxilla, liver)
• Family Bacteroidaceae; four biovars; two with subspecies status:

• F. necrophorum, subsp. necrophorum (biotype A) - more virulent
• F. necrophorum, subsp. funduliforme (biotype B)

PATHOGENESIS: 

• Common predisposing factors include ruminal acidosis in feedlot cattle and omphalitis (navel ill) in calves and lambs
• Ruminal damage (ex. toxic rumenitis) or omphalitis > entry via portal circulation > initial localization in the liver > hepatocellular necrosis and hepatitis > hepatic abscess
• Hepatic abscess may obstruct the hepatic vein or caudal vena cava, causing hepatic passive congestion and portal hypertension
• Hepatic abscesses may rupture into the hepatic vein or caudal vena cava, causing fatal septic embolization of the lungs
• Virulence factors: Leukotoxin (leukocidin), hemolysin, and endotoxin production cause toxin-induced necrosis; also LPS and hemagglutinin
• Leukocidin is specifically toxic to ruminant neutrophils and reduces phagocytosis by activating neutrophils and inducing their apoptosis – cause of significant abscessation
• Commonly found in mixed synergistic infections where facultative pathogens lower oxygen tension (allowing growth of necrophorum), and F. necrophorum leukotoxin protects the other organism from phagocytosis

TYPICAL CLINICAL FINDINGS: 

• Often no clinical signs in adult cattle
• Acute cases: Fever, depression, anorexia, decreased milk production, abdominal pain
• Chronic cases: Anorexia, emaciation, diarrhea
• Leukocytosis and increased liver enzymes may occur, but are often not seen in chronic cases

TYPICAL GROSS FINDINGS: 

• Liver: most common lesion includes a multifocal dry, white-tan, 2-5 cm, sharply demarcated, slightly elevated, rounded areas of coagulative necrosis often surrounded by a zone of intense hyperemia
• Rumen: Superficial mucosal necrosis and ulceration of the anterior ventral sac and occasionally the pillars; scar formation

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Acute: Circumscribed, random areas of coagulative necrosis bordered by a zone of degenerate neutrophils and clusters of radiating, filamentous bacteria; outermost zone of hyperemia/hemorrhage with frequent vascular thrombosis of local vessels
• Subacute to chronic: Multifocal lytic necrosis with neutrophils, lymphocytes and macrophages, and gradual formation of a fibrous capsule

ADDITIONAL DIAGNOSTIC TESTS: 

• Culture, ELISA, PCR, fluorescence in-situ hybridization (FISH)

DIFFERENTIAL DIAGNOSIS: 

Sheep and cattle: Multifocal random hepatic necrosis (hepatocellular necrosis)

• Infectious necrotic hepatitis (black disease): Clostridium novyi; most commonly associated with migration tracts of Fasciola hepatica; necrotic lesions similar but often linear and a single large lesion with sharp delineation of pale necrotic liver surrounded by hyperemic zone; alpha and beta toxins
• Bacillary hemoglobinuria (red water): Clostridium hemolyticum; also associated with migration tracts of Fasciola hepatica; lesions similar to novyi; intravascular hemolysis with anemia and hemoglobinuria; beta toxin (phospholipase C) induce hepatocellular necrosis
• Trueperella pyogenes (often isolated with necrophorum); Campylobacter fetus (neonatal lambs), Staphylococcus and Streptococcus can also cause hepatic abscesses
• Mycotic hepatitis (Mucor sp., Rhizopus sp., Absidia sp.): Damage to ruminal mucosa (ruminal acidosis) allows ruminal microflora to enter the portal circulation
• Clostridium piliforme (Tyzzer’s Disease): Uncommon in sheep; rather than bacteria being within the necrotic area as is the case with necrophorum, C. piliformis is found in the normal hepatocytes at the edge of the necrosis
• Traumatic reticuloperitonitis: Direct implantation of bacteria via foreign-body penetration
• Rift Valley Fever: Mosquito transmitted zoonotic viral disease, family Bunyaviridae, genus Phlebovirus; hepatomegaly with pale 1 to 2 mm random foci of hepatocellular necrosis, centrilobular and midzonal; eosinophilic intranuclear inclusion bodies may be seen and fibrin deposition in sinusoids is common; more severe in young animals (calves, lambs)

COMPARATIVE PATHOLOGY: 

Other Diseases/Lesions Caused by F. necrophorum

• Cattle:
  • Oral necrobacillosis/necrotic stomatitis and laryngitis (Calf diphtheria): Acute necroulcerative inflammation of the pharyngeal and buccal mucosa; secondary infection, ex. infectious bovine rhinotracheitis (IBR) by bovine herpesvirus 1 or vesicular stomatitis virus
  • Necrotic stomatitis, enteritis, and granulocytopenia have been associated with necrophorum; affected calves have nonregenerative anemia, leukopenia, neutropenia and hypoproteinemia
  • Necrobacillary rumenitis: Secondary to ruminal acidosis
  • Necrobacillary metritis
  • Necrobacillosis of the foot: Mixed infection with necrophorum as the primary pathogen (also Bacteroides melaninofenicus)
  • Necrobacillary pododermatitis (Contagious foot rot): Mild, similar to benign foot rot in sheep; mixed infection involving necrophorum with Dichelobacter nodosus as the primary pathogen
  • Epidural/subdural abscess: secondary to vertebral body osteomyelitis
• Sheep:
  • Necrobacillary pododermatitis (Contagious foot rot): Mixed infection involving necrophorum with Dichelobacter nodosus as the primary pathogen
  • Benign (foot scald) and virulent forms (due to virulent nodosus with more proteases)
  • Necrobacillosis of the foot: Mixed infection with nodosus and F. necrophorum (also Trueperella pyogenes); similar to benign foot rot; abscesses common
  • Necrobacillary rumenitis: More aggressive infection than in cattle
  • Necrobacillary metritis/placentitis/late-term abortion
• Swine:
  • Oral necrobacillosis/necrotic stomatitis: Associated with the trauma of removing needle teeth; bullnose as a sequela
  • Necrotic rhinitis (Bullnose): secondary to trauma of the face, nasal, or oral cavities
  • Swine dysentery: Synergistic infection with Brachyspira hyodysenteriae and F. necrophorum, resembles salmonellosis
• Horse:
  • Necrotizing pododermatitis (Thrush): necrosis and suppuration of the frog
  • Proliferative pododermatitis (Canker): papillary epidermal hyperplasia, hyperkeratosis
• Nonhuman primates:
  • Noma:  A rapidly developing necrotizing stomatitis and gingivitis that may affect the underlying bone; F. necrophorum, Prevotella intermedia and Streptococcus spp. are frequent isolates; usually associated with immunosuppression
• Deer
  • F. varium commonly isolated from deer

References:

1. Brooks JW, Kumar A, Narayanan S, Myers S, Brown K, Nagaraja TG, Jayarao BM. Characterization of Fusobacterium isolates from the respiratory tract of white-tailed deer (Odocoileus virginianus). J Vet Diagn Invest. 2014 Mar;26(2):213-20.
2. Brown DL, Van Wettere AJV, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:442.
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. Philadelphia, PA: Elsevier Saunders; 2016:316.
4. Gelberg HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:347-348, 393.
5. Maudlin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th Philadelphia, PA: Elsevier Saunders; 2016: 643.
6. Kramer JA, Bielitzki J. Integumentary System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Diseases. 2nd ed. San Diego, CA: Academic Press; 2012: 572.
7. Kumar A, Anderson D, Raghavendra G, et al. Characterization of Fusobacterium necrophorum isolated from llama and alpaca.  J Vet Diagn Invest. 2013; 25(4):502-507.
8. Hargis AM, Myers S. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Mosby Elsevier; 2016: 1119, 1126.
9. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:17, 39, 41.
10. Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:175.

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