JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
August 2021
D-B17

 

Signalment (JPC #2370239):  Holstein cow

 

HISTORY:  This cow presented with acute icterus, tachycardia, hemoglobinuria, and fever.

 

HISTOPATHOLOGIC DESCRIPTION:  Liver, two (or three) sections:  Approximately 5% of the hepatic parenchyma contains multifocal random areas of necrosis characterized either by hepatocytes with retained architecture and loss of differential staining (coagulative necrosis) or loss of architecture and replacement with eosinophilic and karyorrhectic debris (lytic necrosis) admixed with viable and necrotic neutrophils, fewer eosinophils, macrophages, lymphocytes, plasma cells, hemorrhage, fibrin, and edema, as well as several distinct, round to oval, clear foci up to 2mm in diameter that contain flocculent, eosinophilic material (emphysema).  Blood vessels in the areas of necrosis have neutrophils transmigrating the vessel walls which disrupt and obscure the vessel wall (vascular necrosis).  Along the periphery of the necrotic foci are multifocal colonies of 1x7um bacilli.  The hepatic cords adjacent to the areas of necrosis are disorganized and contain several individualized hepatocytes that are shrunken with hypereosinophilic cytoplasm and pyknotic nuclei (single cell death), and the neighboring sinusoids are moderately expanded by fibrin and cellular debris.  Portal areas contain aggregates of neutrophils with fewer eosinophils, macrophages, and lymphocytes.  One (two) section(s) of liver is diffusely autolytic and contains multifocal to coalescing foci of emphysema.   

 

MORPHOLOGIC DIAGNOSIS:  Liver:  Hepatitis, necrosuppurative, random and multifocal, acute, severe, with colonies of bacilli, Holstein, bovine.

 

ETIOLOGIC DIAGNOSIS:  Clostridial hepatitis

 

CAUSE:  Clostridium haemolyticum

 

CONDITION:  Bacillary hemoglobinuria (BH)

 

SYNONYMS:  Red water disease, Infectious icterohemoglobinuria  

 

GENERAL DISCUSSION: 

• C. hemolyticum is a gram-positive, spore forming, anaerobic bacillus measuring 1 x 7 um and is commonly found in soil of areas with poorly drained pastures and alkaline pH
• BH is an acute, highly fatal, endemic disease of cattle and sheep most often tied to liver fluke migration (Fasciola hepatica); often seasonal (Summer, early Autumn)
  • Occurs primarily where Fasciola hepatica is abundant
• Other causes of hepatic ischemia allowing sporulation of haemolyticum and therefore BH include: hepatic necrosis due to Fusobacterium necrophrum secondary to rumenitis, liver damage secondary to Cysticercus tenuicollis, incidental vascular disorders such as telangectasia, and other causes of reduced liver perfusion
• C. haemolyticum produces a single major toxin, hemolytic beta toxin (phospholipase C), that causes massive intravascular hemolysis and cellular necrosis through destruction of hepatocyte and erythrocyte cell membranes
• Previously classified as Clostridium novyi type D
• Mortality rates 90-95%, death results from anoxia

 

PATHOGENESIS:

• Spores ingested with contaminated feed/soil > hematogenous spread to the liver > phagocytized by Kupffer cells and remain latent > liver damage (e.g. fluke migration through liver and in intrahepatic veins) > thrombosis, ischemia, infarction within hepatic parenchyma > decreased oxygen tension > germination of spores > production of exotoxin hemolytic beta toxin (phospholipase C) > hepatocellular necrosis > vascular damage > toxemia > intravascular hemolysis
• Phospolipase C hydrolyzes phosphatidylcholine into phosphocholine and a diglyceride, inducing hemolysis, hepatocyte and endothelial cell damage, platelet aggregation, and increased vascular permeability
• Local injury is cell lysis (acute coagulative necrosis) of hepatocytes (necrotizing hepatitis), whereas systemic injury is lysis of erythrocytes in the vascular system

 

TYPICAL CLINICAL FINDINGS:

• Most commonly, dead cattle without clinical signs
• Intravascular hemolysis with anemia and hemoglobinuria
  • Hemolysis is not a feature in all cases
• In peracute disease: fever, lethargy, anorexia, decreased production, hematochezia, tachycardia, tachypnea, abdominal pain, brisket edema

 

TYPICAL GROSS FINDINGS:

• Large (often single) distinct, well demarcated foci of hepatic necrosis surrounded by an intensely hyperemic zone
• “Port wine” urine in bladder
• Kidneys: petechiae and hemoglobin-stained kidneys, speckled red/brown by hemoglobin
• Subepicardial, subendocardial, and subpleural petechiae and ecchymoses
• Severe pulmonary congestion and edema
• Severe, dry, fibrinohemorrhagic peritonitis (some cases)
• Hemoglobin-tinged abdominal, thoracic, and pericardial transudates
• Blood clots in abomasum and/or large intestine
• Variable degree of icterus
• Lesions are larger than those of black disease and usually single

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Hepatic necrosis, often focally extensive and in a single location
  • Thrombosis of hepatic venules (more common) and portal vein branches with infarction – secondary to necrosis
• Thrombi in hepatic venules, intestines, and other abdominal organs (secondary to exotoxin induced necrosis)
• Kidney: Acute necrosis of the proximal and distal convoluted tubules
• Spleen: Sinusoidal congestion and multifocal necrosis
• Bacilli present singly or in short chains and have distinctive bulging subterminal spores
• +/- evidence of trematode migration (fluke pigment)

 

ADDITIONAL DIAGNOSTIC TESTS:

• Culture from area of hepatic necrosis
• Fluorescent antibody test on impression smears

 

	Plasma color	Urine clears on centrifugation	Urine clears with NH4SO4	RBC’s in urine
Myoglobinuria	Clear	No	No	No
Hemoglobinuria	Pink	No	Yes	No
Hematuria	Clear	Yes	na	Yes

 

 

DIFFERENTIAL DIAGNOSIS:

• Black disease (Clostridium novyi, usually type B), also known as infectious necrotic hepatitis, occurs mostly in sheep and cattle, occasionally in horses and pigs; however, pathogenesis very similar to bacillary hemoglobinuria
  • Hepatic necrosis (immature fluke migration) > decreased oxygen tension > germination of dormant spores > toxin production
  • Produces alpha toxin (related to toxins produced by difficile and C. sordelli) and beta toxin (phospholipase C, a lecithinase, the necrotizing and hemolytic toxin)
  • The subcutis of dead animals is dark colored / black secondary to venous congestion (hence the name)
  • The liver may show both the hemorrhagic lesions of acute fascioliasis as well as circular yellow-white areas of necrosis surrounded by hyperemia
  • Bacteria often at leading margin of lesion admixed with infiltrating neutrophils
  • Hepatic lesions are smaller than those of bacillary hemoglobinuria and usually multiple
• Acute leptospirosis causes intravascular hemolytic anemia and hemoglobinuria
• Hypophosphatemic hemolytic anemia (postparturient hemoglobinuria): This is common in dairy cows 3 to 8 weeks following parturition; erythrocytes require phosphorus for the synthesis of ATP (Embden-Meyerhof pathway), which is essential for membrane function and integrity
• Babesia bovis (Texas or red water fever): Fever, intravascular hemolysis, hemoglobinuria; intracytoplasmic paired pyriform protozoa
• Hemolytic anemia associated with Brassica sp. (rape or kale): Anemia results from dimethyl disulfide produced by ruminal bacteria from plant breakdown.
• Bracken fern (enzootic hematuria): Hemorrhagic cystitis; neoplasia in chronic cases
• Other bacteria: perfringens, E. coli
• Oxidants: Acetaminophen, copper, onions, propylene glycol, red maple, phenothiazine
• Immune mediated: Autoimmune hemolytic anemia (horses, cattle)

 

COMPARATIVE PATHOLOGY:

• Experimentally induced disease in rabbits

 

References:

1. Constable PD, Hinchcliff KW, Done SH, Grunberg W, eds. Veterinary Medicine, A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats. 11th ed. St. Louis, MO: Elsevier; 2017:635-637.
2. Navarro MA, Durtra F, Briano C, et al. Pathology of naturally occurring bacillary hemoglobinura in cattle. Vet Pathol. 2017; 54(3): 457-466.
3. Navarro MA, Uzal FA. Pathobiology and diagnosis of clostridial hepatitis in animals. J Vet Diagn Invest. 2020; 32(2): 192-202.
4. Smith GW. Bacillary hemoglobinura (“red water”). In: Smith BP, ed. Large Animal Internal Medicine. 5th ed. St. Louis, MO: Elsevier Mosby; 2015:850-851.
5. 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. St. Louis, MO: Elsevier; 2016:316-317.
6. Zachary JF. Mechanisms of microbial infections. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:167.

 

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