JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-T11

 

Signalment (# V51791): Cow, age not specified.

 

HISTORY: While on pasture, this cow suddenly became febrile, developed hemorrhage from several body openings and subsequently died.

 

HISTOPATHOLOGIC DESCRIPTION: Urinary bladder: Focally extensively expanding the lamina propria and elevating the overlying urothelium is a proliferation of fibroblasts surrounded by mature collagen fibers and numerous small caliber blood vessels. Focally there is a vague, nodular area of hemorrhage admixed with moderate numbers of lymphocytes, fewer macrophages and rare plasma cells, which also expand the submucosal connective tissue. There is congestion and increased clear space with dilated lymphatics (edema), and frequently urothelial cells contain a large, intracytoplasmic clear vacuole (hydropic degeneration). Multifocally, the tunica adventitia is expanded by few perivascular lymphocytes, plasma cells and macrophages.

 

MORPHOLOGIC DIAGNOSIS: Urinary bladder: Cystitis, hemorrhagic and lymphoplasmacytic, focally extensive, moderate, with fibrosis, breed not specified, bovine.

 

ETIOLOGIC DIAGNOSIS: Toxic cystitis

 

CAUSE: Chronic bracken fern toxicity 

 

CONDITION: Enzootic hematuria

 

GENERAL DISCUSSION:  

• Bracken fern (Pteridium aquilinum) is found worldwide in humid grassland areas, particularly in South America, Great Britain, and the Pacific Northwest of North America; rock fern (Cheilanthes sieberi) is implicated in disease outbreaks in Australia
• It contains several toxins, including ptaquiloside, quercetin (carcinogenic), thiaminase and other antithiamine factors, and a hemolysin.
• It is most toxic when actively growing (green); fronds and rhizomes are toxic, as is hay containing the fern; intoxications are often associated with droughts or an excess of lush pasture with insufficient roughage; toxic content can vary considerably by geographic location  
• Adult cattle (Molossi et al, 2021, J Vet Diagn Invest.) and horses are most susceptible, sheep are relatively resistant (they are less likely to eat the plant), and pigs are only occasionally affected
• Associated with persistent hematuria and anemia, and associated with hemorrhages or neoplasms in lower urinary tract
• Intoxication is cumulative, and chronic ingestion associated with disease; acute disease may not be evident
• Potential human health risk; toxic principal is eliminated in milk, and ingestion of products from bracken fern-fed cows increases the risk of digestive tract tumors in man  

 

PATHOGENESIS:

Acute toxicity

• Thiaminase > Thiamine deficiency: Horses most susceptible, pigs to a lesser extent; develop neurologic and cardiac manifestations; horses and sheep develop polioencephalomalacia
• Ruminants: Direct inhibition of a pluripotent stem cell > aplastic pancytopenia > thrombocytopenia followed by leukopenia and neutropenia > hemorrhage and neutropenic septicemia

Chronic toxicity

• Enzootic hematuria is seen in cattle and sheep and is characterized by persistent hematuria and anemia associated with neoplasms or hemorrhage in the lower urinary tract associated with chronic ingestion of bracken fern 
  • In >90% of cases, the hematuria originates from tumors of the urinary bladder
  • Cattle fed low levels of bracken fern develop microscopic, followed by macroscopic, hematuria
• The principal toxic agent in both acute and chronic disease is considered to be ptaquiloside, forms DNA adducts (binds to DNA) leading to point mutations in the genome
• Carcinogens found in bracken fern include ptaquiloside, quercetin, shikimic acid, prunasin and aquilide A; these carcinogens can act synergistically with papillomavirus to transform papillomas associated with the virus into carcinomas
  • Strong associated between Bovine papillomaviruses and the development of neoplasia in cattle exposed to bracken fern
    • Urinary bladder neoplasia – BPV-1 and BPV-2
    • Gastrointestinal carcinomas – BPV-1 and 4
• Cyclin D1 is dysregulated in all benign and malignant tumors; malignant tumors have p53 mutations

 

TYPICAL CLINICAL FINDINGS:

• Ruminants: The dominant clinical features of the acute disease are hemorrhage (secondary to thrombocytopenia), bacteremia and fever (secondary to granulocytopenia); clinical polioencephalomalacia is also reported with acute toxicity in sheep
• All exposed animals will have elevated pyruvate within the blood
• Monogastrics: Inappetence, weight loss, bradycardia and arrhythmias, nervous system signs (incoordination, tremors) which progress to clonic spasm, opisthotonos, and death
• In chronic cases, affected cattle exhibit persistent hematuria (often secondary to urinary bladder neoplasia) and anemia   
• Death is due to intractable hemorrhage and/or overwhelming bacteremia/ septicemia; adult cattle may also show an enteric form with depression, anorexia, enteritis, and hemorrhage from the nostrils, gastrointestinal, and urogenital tracts, accompanied by rapid onset pyrexia before death 
• Low morbidity, high mortality as hematologic damage is well advanced before signs develop  

 

TYPICAL GROSS FINDINGS:  

• Petechial, ecchymotic or suffusive hemorrhages are consistently present in the urinary system (renal calyces, renal pelvis, ureters, and urinary bladder) in both chronic and acute cases
• Bone marrow may appear watery, pink, and soft
  • Several types of epithelial and mesenchymal neoplasms may develop in the urinary tract (urothelial cell, squamous cell, carcinoma, papilloma, adenoma, hemangioma, hemangiosarcoma, leiomyosarcoma, fibroma and fibrosarcoma) 
• Usually on the ventral and lateral walls of the bladder; occasionally tumors will develop in the renal pelvis and ureter
  • Multiple tumors of more than one type may be present
  • In >50% of affected cattle, mixed epithelial-mesenchymal neoplasms develop
  • Papillomas, fibromas and hemangiomas with carcinomas are the most common types
  • Epithelial neoplasms may metastasize to lungs or lymph nodes
• Malignant neoplasms of the esophagus and forestomachs, ordinarily rare in ruminants, are relatively common in several localities within the bracken fern geographic range (squamous cell carcinomas with papillomas are common)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Acutely, there may be hemorrhage and infarcts in various tissues, caused by embolic clumps of bacteria (especially, liver, kidney and myocardium)  
• The bone marrow consists mostly of fat with small foci of hematopoietic tissue
• Chronic urinary bladder lesions include cystitis, hemorrhage, ectasia and engorgement of submucosal capillaries, nodular hemangiomatous lesions, epithelial proliferation, desquamation, and/or metaplasia, and infiltration of columns of epithelial cells into the submucosa (Brunn nests)
• Various types of urinary and/or intestinal neoplasia including transitional and squamous cell carcinomas, papillomas, adenomas, hemangiomas, hemangiosarcomas, leiomyosarcomas, fibromas, and fibrosarcomas
  • In high-grade urothelial carcinomas that demonstrate muscle invasion, there is a decrease in the immunohistochemical staining of uroplakin III 
• In Great Britain, there is progressive retinal degeneration in sheep known as “bright blindness”; affected sheep exhibit pupillary dilation and bilateral, central tapetal hyperreflectivity, resulting from progressive depletion of all retinal layers which begins in the outer photoreceptor layers  

 

DIFFERENTIAL DIAGNOSIS:

Causes of hematuria/hemoglobinuria in cattle:

• Trichlorethylene-extracted soybean meal: Lesions similar to acute bracken fern poisoning; differentiate on basis of history
• Sweet clover: Hematomas in the absence of fever (vitamin K antagonist)
• Crotalaria spp.: Similar hemorrhagic lesions but also hepatic fibrosis, gall bladder distension, abomasal/duodenal edema
• Babesiosis (B. bovis or B. bigemina): Intravascular hemolysis, hemoglobinuria, organisms in erythrocytes
• Bacillary hemoglobinuria (“Nevada Red Water”): Clostridium haemolyticum; C. novyi, type D
• Leptospirosis: Less extensive hemorrhages; organisms demonstrable with silver stains
• Copper toxicity: Acute tubular necrosis; hemolysis due to inhibition of erythrocyte enzymes in Embden-Meyerhof pathway, which results in ATP depletion and erythrocyte lysis
• Onion toxicity: Oxidative hemolytic anemia

 

COMPARATIVE PATHOLOGY:

• Horses: Polioencephalomalacia (laminar cerebral necrosis) with thiamine deficiency; ingestion of horsetail (Equisetum spp.) similar effect as bracken fern; typically die from the thiaminase and antithiamine factor-induced CNS effects before hematologic disturbances become life threatening
• Sheep: Polioencephalomalacia (laminar cerebral necrosis) with thiamine deficiency; in Great Britain, progressive retinal degeneration known as “bright blindness”
• Rats: Experimental treatment with bracken fern develop preneoplastic hyperplasia or neoplasia of the urinary bladder mucosa; acutely, rats may also develop polioencephalomalacia
• Carnivores: Thiamine deficiency causes periventricular necrosis
• Pigs: Bracken fern causes reticulocytopenia, elevated blood pyruvate, depression of growth rate and myocardial injury (experimental)
• Severe hemorrhagic cystitis is also associated with cantharidin toxicity (horses) or cyclophosphamide therapy (dogs)
• Farmed Sika deer: Intestinal adenocarcinoma in an inbred herd grazing on a pasture with bracken fern.

 

References:

1. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:312-314.
2. Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:461-462.
3. Howerth EW, Nemeth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:152.
4. Molossi FA, de Cecco BS, Pohl CB, Borges RB, Sonne L, Pavarini SP, Driemeier D. Causes of death in beef cattle in southern Brazil. J Vet Diagn Invest. 2021;33(4):677-683.
5. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:765-766.
6. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:471.

 

 

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