Read-Only Case Details Reviewed: Jan 2010

JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

October 2024

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 disorganization 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, micro-vacuolated cytoplasm (glycogen cahnge). Within portal areas there are few lymphocytes and plasma cells and rare eosinophils. Kupffer cells and hepatocytes often contain dark brown globular pigment (hemosiderin), and there is 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 sp.) contains gossypol, a yellow, pigmented, polycyclic lipophilic pigment that causes centrilobular hepatic necrosis, pulmonary congestion and edema, segmental necrosis of skeletal muscle (type 1 and 2), 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 and horses are most susceptible to toxic effects
1. Experimental toxicosis to calves and lambs when feed has <450 ppm (the level of free gossypol permitted in human and some animal foods).

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
Toxins are cumulative; clinical signs usually occur after weeks or months of exposure
Cardiac damage: Myocardial degeneration and necrosis causes cardiac conduction failure and congestive heart failure to develop; lesion similar to ionophore induced myocardial lesions
Reproductive damage: Gossypol inhibits steroid synthesis by testicular Leydig cells and reduces inhibin release from Sertoli cells (luteolytic), resulting in infertility
Death is due to congestive heart failure.

typical Clinical Signs:

Usually develop 1-3 months after cottonseed supplemented diet (>10% of diet) or fed on pasture containing cottonseed
Pot belly and dyspnea are the most common signs
Anorexia, lower feed efficiency, weakness, recumbency, exercise intolerance, cyanosis, seizures, and death
Marked elevation of hepatic leakage enzymes: SDH, AST, ALT

Typical Gross Findings:

Necrosis and congestion of liver
Cardiomegaly with thinning or compensatory dilated hypertrophy of ventricular walls, “flabby” myocardium
White to pale tan areas of myocardial necrosis (monophasic or polyphasic)
Hydrothorax, hydropericardium, hydroperitoneum
Edema of lungs, gallbladder, lymph nodes, and subcutis

Typical LIGHT Microscopic Findings:

Uniformly distributed centrilobular to submassive necrosis
Multifocal myocardial degeneration and necrosis (monophasic or polyphasic; myofiber hypertrophy
Segmental necrosis of skeletal muscle (both type 1 and type 2 muscle fibers)
- Cannot be distinguished from lesions of other toxic myopathies

Additional diagnosTIC TESTs:

Identification of toxic compound in stomach and liver

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 spp.) 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 spp. (poison peach) toxicosis:
        
        Centrilobular necrosis that appears identical to Cestrum and Xanthium poisoning
        
        Toxin is a glycoside, trematoxin
        
        Cestrum spp. 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

For Muscle Degeneration

Diaporthe toxica: Lupinosis in sheep
Water hemlock (Cicuta douglasii) toxicosis: Sheep,
Thermopsis montana toxicosis: Calves with false lupine
Ageratina (formerly Eupatorium spp.): White snakeroot toxicosis in horses and ruminants
Rayless goldenrod (Isocoma pluriflora) toxicosis: horses and ruminants
Selenium toxicosis: Pigs, cattle, sheep
Ionophore toxicosis: Horse, sheep, goat, cattle

COMPARATIVE PATHOLOGY:

Monogastrics and immature ruminants are most commonly affected
Ruminants more resistant because of detoxification in the rumen

Reported in dogs that ingested cottonseed bedding

References:

Cooper BJ, Valentine BA. Muscle and tendon. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th ed. St. Louis, MO: Elsevier; 2016:220.
Foster RA, Premanandan C. Male Reproductive System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1321.
Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 668.
Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 662.
Valentine BA. Skeletal Muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1009, 1029.