JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
October 2021
D-T02

Signalment (JPC #704742):  6-month-old Duroc pig.

History:  This pig received a standard ration, which contained 9% cottonseed meal for 50 days prior to death.  The cottonseed meal contained 0.25% gossypol.

HISTOPATHOLOGIC Description:  Liver:  Diffusely there is centrilobular to midzonal (submassive) necrosis characterized by disruption and loss of normal hepatic cord architecture. Hepatocytes in these areas are shrunken with hypereosinophilic cytoplasm and pyknotic or karryorhectic nuclei (single cell death) or are lost and replaced by abundant hemorrhage, fibrin, edema, and small amounts of cellular and karyorrhectic necrotic debris. Adjacent sinusoids are dilated up to 3x normal (congested) and filled with eosinophilic, beaded material (fibrin).  Occasional remaining hepatocytes are swollen with lacy, microvaculated cytoplasm (glycogen type degeneration).  Within portal areas there are few lymphocytes and plasma cells and rare eosinophils.  Kupffer cells and hepatocytes often contain dark brown globular pigment (hemosiderin), but there is also abundant acid hematin (artifact).

Morphologic Diagnosis:  Liver: Necrosis, centrilobular to midzonal (submassive), acute, diffuse, with moderate congestion and hemorrhage, Duroc, porcine.

Etiologic Diagnosis:  Toxic hepatic necrosis

Etiology:  Gossypol intoxication

General DISCUSION:

• Cottonseed (Gossypium ) contains gossypol, a polycyclic lipophilic pigment that causes centrilobular hepatic necrosis, pulmonary congestion and edema, segmental necrosis of skeletal muscle, and myocardial necrosis
• Gossypol concentration varies with plant variety and method used to extract oil
• Toxicity is attributed to the free form of pigment; the protein-bound form is non-toxic
• Gossypol is toxic to a wide variety of animals (predominately monogastrics); pigs are most susceptible to toxic effects

Pathogenesis:

• Liver damage: Gossypol inhibits glutathione-S-transferase which impairs hepatic metabolism of xenobiotics; damage caused by oxidative stress, formation of reactive oxygen species, and DNA damage or scission
• Toxins are cumulative; clinical signs usually occur after weeks or months of exposure
• Cardiac damage: Cardiac necrosis causes congestive heart failure to develop
• Reproductive damage: Gossypol inhibits steroid synthesis by testicular Leydig cells and exerts luteolytic action on the ovary, resulting in infertility

typical Clinical Signs:

• Usually develop 1-3 months after cottonseed supplemented diet
• Dyspnea is the most common sign
• Anorexia, lower feed efficiency, exercise intolerance, cyanosis, seizures, and death
• Marked elevation of hepatic leakage enzymes: SDH, AST, ALT
• Cattle and swine may have decreased hematocrit and hemoglobin with increased RBC fragility and prolonged clotting times

Typical Gross Findings:

• Necrosis and congestion of liver
• Cardiomegaly with thinning or compensatory hypertrophy of ventricular walls
• White to pale areas of myocardial necrosis
• Hydrothorax, hydropericardium, hydroperitoneum
• Edema of lungs, gallbladder, lymph nodes, and subcutis

Typical LIGHT Microscopic Findings:

• Uniformly distributed centrilobular to submassive necrosis
• Myocardial necrosis; myofiber hypertrophy
• Segmental necrosis of skeletal muscle (both type 1 and type 2 muscle fibers)
  • Cannot be distinguished from lesions of other toxic myopathies
• Midzonal fatty change may occur after 2-3 months on contaminated rations

Differential Diagnosis:

For centrilobular necrosis

• Coal-tar pitch or "clay pigeon" (cresol) poisoning:
  • Produces patchy centrilobular necrosis with central pooling of blood; less severe; no cardiac lesions
• Aflatoxicosis (chronic exposure to high dose rate) – D-T03:
  • Centrilobular hepatocytes replaced by inflammatory cells, fibroblasts and primitive vascular channels to centrilobular necrosis; hepatocellular steatosis
  • Absence of cardiac or pulmonary involvement
• Microcystin toxicosis - D-T11:
• Mycrocystin-LR produced by cyanobacteria (blue-green algae)
  • Centrilobular to massive necrosis with stromal collapse, perisinusoidal hemorrhage; phagolysosomes and bile pigments accumulate in hepatic cytoplasm; slight biliary proliferation and fibrosis
  • Renal tubular necrosis also often present
• Cycad (Cycas or Zamiaceae) toxicosis:
• Subtropical to tropical, palm-like plants (eg. Sago palm)
  • Seeds and young leaves are toxic – methylazoxymethanol
  • Centrilobular necrosis with megalocytosis, nuclear hyperchromasia, cholestasis, fatty change, and variable fibrosis
  • Acute renal tubular injury; chronic poisoning of cattle can cause Wallerian degeneration in upper spinocerebellar and lower corticospinal tracts caused by a neurotoxic amino acid, β-N-methylamino-L-alanine (BMAA)
• Compositae/Asteraceae toxicosis (various cockleburs) – D-T01:
  • Centrilobular necrosis with midzonal vacuolation
  • Toxic glycoside within the burrs and seedlings
• Trema (poison peach) toxicosis:
  • Centrilobular necrosis that appears identical to Cestrum and Xanthium poisoning
  • Toxin is a glycoside, trematoxin
• Cestrum toxicosis:
  • Marked centrilobular and midzonal coagulative necrosis and hemorrhage
  • South America, southern and central Africa, Australia
  • Toxin is an atractyloside
• Pyrrolizidine alkaloid toxicity – D-T04:
  • Acute centrilobular to massive necrosis occurs with large toxin exposure; megalocytosis

COMPARATIVE PATHOLOGY:

• Monogastrics, immature ruminants, and poultry are most commonly affected
• Ruminants more resistant because of detoxification in the rumen
• Chicken eggs develop pink egg whites on storage
• Reported in dogs that ingested cottonseed bedding

References:

1. Constable PD, Hinchcliff KW, Done SH, Grunberg W. Veterinary Medicine, A Textbook of the Diseases of Cattle, Sheep, Pigs, Goats and Horses. 11th ed. St. Louis, MO: Elsevier; 2017:2206-2207.
2. Cooper BJ, Valentine BA. Muscle and tendon. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th St. Louis, MO: Elsevier; 2016:220.
3. Cullen JM, Stalker MJ. Liver and Biliary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6^th St. Louis, MO: Elsevier; 2016:330-343.
4. Ensley SM, Osweiler GD. Toxic minerals, chemicals, plants, and gases. In: Karriker LA, Ramirez A, Schwartz KJ, Stevenson EW, eds. Diseases of Swine. 10^th Ames, IA: John Wiley & Sons; 2012:963-964.
5. Miller LM, Gal A. Cardiovascular system and lymphatic vessls. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier; 2017:593.
6. Nicholson, SS. Cottonseed toxicity. In: Gupta RC, ed. Veterinary Toxicology, Basic and Clinical Principles. 1st ed. New York, NY: Academia Press; 2007:926-928.
7. Valentine BA. Skeletal muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier; 2017:925,945.
8. Uzal FA, Puschner B, Tahara JM, Nordhausen RW. Gossypol toxicosis in a dog consequent to ingestion of cottonseed bedding. JVDI 2005; 17:626-629.

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