JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
October 2021
D-T01

Signalment (JPC #1617774):  A pig

HISTORY:  This animal was non-confinement raised and died acutely.

HISTOPATHOLOGIC DESCRIPTION:  Liver:  Affecting 60% of hepatic lobules, there is submassive necrosis characterized by disruption and loss of centrilobular and midzonal hepatic cords with replacement by abundant necrotic debris and hemorrhage.  Remaining hepatocytes are individualized, shrunken, and hypereosinophilic with pyknotic, karyorrhectic, or karyolytic nuclei (single cell death), and are admixed with moderate hemorrhage, fibrin, edema, and few neutrophils.  Adjacent to areas of necrosis, few hepatocytes are swollen with clear, vacuolated cytoplasm (degenerate) admixed with few lymphocytes, plasma cells, rare neutrophils, and eosinophils.  Centrilobular sinusoids are diffusely markedly congested.  Multifocally within portal areas, there is a mild to moderate infiltrate of the previously described inflammatory cells, expansion by eosinophilic homogenous fluid (edema), and mildly dilated lymphatics.

MORPHOLOGIC DIAGNOSIS: 

1. Liver:  Necrosis, acute, centrilobular to midzonal (submassive), diffuse, with multifocal hemorrhage and congestion, breed unspecified, porcine.
2. Liver: Hepatitis, portal, lymphoplasmacytic, mild to moderate, chronic.

ETIOLOGIC DIAGNOSIS:  Toxic hepatic necrosis

CAUSE:  Xanthium strumarium

CONDITION:  Cocklebur intoxication

GENERAL DISCUSSION:

• Xanthium cause fatal hepatic necrosis most often in pigs and less commonly in cattle and sheep
• The toxin is carboxyatractyloside, a diterpenoid glycoside which targets the liver, especially the centrilobular hepatocytes
• Other diterpenoid glycosides include: other atractylosides, parquin, carboxyparquin and wedeloside
• X. strumarium is the most common species; there are three varieties with worldwide distribution
• Toxin concentration is highest in the seeds and cotyledon (seedling stage), which is when the plant is most palatable

PATHOGENESIS:

• Carboxyatractyloside inhibits oxidative phosphorylation by binding to ADP/ATP carrier 1 (AAC1) > inhibits the exchange of ATP from mitochondria with ADP in the cytosol > decreased ATP > mitochondrial damage > pore leakage > release of cytochrome-c > apoptosis OR necrosis with massive mitochondrial damage, ion pump failure, lipid peroxidation, and glutathione depletion

TYPICAL CLINICAL FINDINGS:

• Clinical signs appear abruptly within hours of ingestion
• Depression, nausea, weakness, ataxia, anorexia, hypersensitivity, opisthotonos, convulsions, acute death
• Swine: Ascites and marked hypoglycemia
• Elevated hepatocellular leakage enzymes: SDH, AST, ALT

TYPICAL GROSS FINDINGS:

• Accentuated hepatic centrilobular pattern and submassive necrosis
• Gastroenteritis with thickening of mucosa
• Subepicardial and subserosal hemorrhages
• Ascites with fibrin strands on hepatic and visceral surfaces
• Gallbladder edema in swine
• May have burs in stomach, rumen

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Severe centrilobular to massive hepatic necrosis
• Necrosis of renal proximal convoluted tubule epithelium
• Chronic hepatitis may occur after recovery
• Cattle: white matter astrocytes with abundant eosinophilic or vacuolated cytoplasm and pyknotic nuclei (Botha, J Vet Diagn Invest. 2014)

DIFFERENTIAL DIAGNOSIS

Microscopic:

• Iron toxicity (iron dextran): Usually neonatal swine; centrilobular to massive hepatic necrosis; can cause iron-catalyzed lipid peroxidation in hepatocytes and skeletal muscle
• Vitamin E/selenium deficiency (hepatosis dietetica, D-M10): Massive, multifocal hepatic necrosis and stromal collapse; cardiomyocyte degeneration and necrosis; fibrinoid necrosis of arterioles; steatitis
• Gossypol toxicosis (cottonseed, D-T02): Submassive hepatic necrosis; mid-zonal fatty change; also myocardial degeneration and necrosis
• Cresol toxicosis (coal-tar pitch/clay pigeon): Centrilobular to massive hepatic necrosis, with jaundice and ascites

COMPARATIVE PATHOLOGY:

Toxic plant causes of centrilobular necrosis in animals:

Plant Family	Species Affected	Toxic Principle	Characteristic Injury	Miscellaneous
Compositae    Xanthium spp.	Cattle, pigs	Carboxyatractyloside	Centrilobular necrosis	Hypoglycemia and ascites occur in acute intoxication in pigs.
Myoporaceae    Myoporum spp.	Sheep, cattle, horses, pigs	Furanosesquiterpenoid oils (ngaione)	Usually centrilobular to variable zonal necrosis	Sheep also develop pulmonary injury.
Leguminosae    Cassia spp.	Cattle	Unknown	Centrilobular necrosis	Myocardial and skeletal muscle injuries predominate in Cassia occidentalis intoxication.
Ulmaceae    Trema aspera Trema tomentosa	Cattle, sheep, goats	Trematoxin (glycoside)	Centrilobular necrosis	Neuromuscular toxins also. Usually acute disease.
Solanaceae   Cestrum parqui,         C. laevigatum     (not C. diurnum)	Cattle, sheep	Saponins	Centrilobular necrosis	Gallbladder edema and hemorrhage. Usually acute disease.
Asteraceae    Tetradymia        glabrata   Wedelia glauca	Sheep   Ox, swine, goat, horse	Tetradymol   Wedelocide (atractyloside)	Centrilobular necrosis	Photosensitization is common.   (Giannitti, Vet Pathol. 2013)
Cycadales    Zamiaceae    Cycadaceae    Stangeriaceae	Cattle, sheep, goats, dogs	Methylazoxymethanol	Centrilobular necrosis, megalocytosis, cholestasis	Toxin split from nontoxic glycoside. Neurotoxins also present. Chronic ingestion causes paralysis in cattle.
Fabaceae    Indigofera    linnaei	Cattle, dogs	Indospicine	Centrilobular necrosis	Dogs can be intoxicated by eating meat from horses ingesting Indigofera.
Cyanophyceae (blue-green algae)    Microcystis   Aphanizomenon	Cattle, sheep, horses, goats, dogs	Microcystins and others	Centrilobular to massive necrosis	Blue-green algae are not considered to be plants but cyanobacteria. Multiple toxins are present and can cause death by neuromuscular injury

Table adapted from Pathologic Basis of Veterinary Disease, 6^th ed., 2017, Web Table 8-1 Common Hepatotoxic Plants of Veterinary Importance

REFERENCES:

1. Botha CJ, Lessing D, Rosemann M, van Wilpe E, Williams JH. Analytical confirmation of Xanthium strumarium poisoning in cattle. J Vet Diagn Invest. 2014:26(5):640-645.
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: Web Table 8-1.
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. St. Louis, MO: Elsevier Ltd; 2016:116, 331.
4. Giannitti F, Margineda CA, Cid MS, et al. Fatal Wedelia glauca intoxication in calves following natural exposure. Vet Pathol. 2013;50(3):530-533.
5. Sebastian MM. Plants. In: Gupta RC, ed. Veterinary Toxicology, pp. 1121-1122. New York, NY: Elsevier; 2007:1121-1122.

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