SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
October 2021
D-T13 (NP)

Signalment (JPC# 1851823):  Eight-month-old castrated male polypay-cross lamb

HISTORY:  This lamb died during an outbreak of severe photosensitization.

HISTOPATHOLOGIC DESCRIPTION:  Liver:  Diffusely, portal areas are expanded by abundant fibrosis that extends between portal areas (portal bridging fibrosis), frequently surrounds, separates, and individualizes hepatic lobules, and contains numerous embedded variably-sized bile duct profiles (ductular reaction) admixed with few lymphocytes, plasma cells, and neutrophils.  Multifocally bile canaliculi are expanded by variably-sized accumulations of green-brown bile pigment (cholestasis). Hepatocytes in these areas of cholestasis and adjacent to fibrotic portal areas are often swollen with pale, vacuolated cytoplasm (degeneration), or are shrunken with hypereosinophilic cytoplasm and nuclear pyknosis, karyorrhexis, or karyolysis (single cell death).  There is also occasional loss of hepatic cord architecture with replacement by eosinophilic cellular and karyorrhectic debris, few neutrophils, macrophages, lymphocytes, and plasma cells (lytic necrosis).

MORPHOLOGIC DIAGNOSIS:  Liver:  Fibrosis, portal and bridging, diffuse, moderate, with ductular reaction, cholestasis, hepatocellular degeneration and necrosis, and minimal lymphoplasmacytic cholangiohepatitis, polypay-cross, ovine.

ETIOLOGIC DIAGNOSIS:  Mycotoxic hepatic fibrosis

CAUSE:  Sporidesmin intoxication

CONDITION:  Facial eczema

GENERAL DISCUSSION:

• Sporidesmin is produced by the fungus Pithomyces chartarum and is found most often on dead ryegrass that has become moistened in warm weather
• Serious cause of loss of sheep and, to a lesser extent, cattle in New Zealand, Australia, and South Africa; also reported in alpacas
• Ingestion of toxin produces chronic liver damage and severe hepatogenous photosensitivity; skin lesions predominate on the head (i.e. “facial eczema”)
• Sporidesmin, in conjunction with ingestion of Tribulus terrestris, causes Geeldikkop which is histologically distinct photosensitization caused by steroidal sapogenins that damage or obstruct bile ducts
• Zinc at 20-30 times normal daily intake prevents facial eczema; however, this dosage leaves little safety margin for zinc toxicosis
• Photosensitization (type 3) occurs in unpigmented skin where not covered by a heavy wool or hair layer
• There are three types of photosensitization:
  • Type 1 (Primary): Ingestion of preformed photodynamic toxins (eg. hypericin in St. John's Wort and certain drugs including phenothiazine and tetracycline)
  • Type 2 (Congenital porphyria, photosensitization due to defective pigment synthesis): Metabolic disorder/congenital enzyme deficiency causing abnormal heme synthesis with the resultant blood and tissue accumulation of photodynamic agents such as uroporphyrin I, coproporphyrin I and protoporphyrin III
  • Type 3 (hepatogenous photosensitization): Most common form; occurs in conjunction with cholestasis and is due to impaired capacity of the liver to excrete phytoporphyrins (previously referred to as phylloerythrin), a photodynamic agent which is a breakdown product of chlorophyll  which is normally excreted in bile via bilirubin transporters, resulting in increased blood levels and dermatitis; level of green feed consumption plays a role in severity of condition

PATHOGENESIS:

• Unconjugated sporidesmin is not directly hepatotoxic, but when it concentrates in bile > disrupts canalicular membranes and microvilli, irritation and necrosis of biliary epithelium, portal mesenchymal tissue, and adjacent blood vessels > progressive obliterative cholangitis > hepatic insufficiency > increased serum phylloerythrin
• Phylloerythrin absorbs specific wavelengths of UV or visible light known as the
• “action spectrum” > activation raises it to a metastable triplet state > reacts directly with biologic substrate or with molecular oxygen > reactive oxygen intermediates > damages to cell nucleus,  cell membrane, and cellular organelles

TYPICAL CLINICAL FINDINGS:

• Erythema and edema of unpigmented skin, most commonly the eyes, ears,
• muzzle, face, teats, vulva and perineum; epidermal exudation and ulceration
• Icterus

TYPICAL GROSS FINDINGS: 

• Early, liver is swollen and discolored (bile stasis); later, liver is contracted and tough
• Left lobe of liver usually most severely affected, may undergo atrophy and fibrosis
• Congestion and distended gall bladder
• Chronic: Hepatic fibrosis, with pale atrophic parenchyma surrounding occluded bile ducts (“biliary infarcts”)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Acute necrotizing cholangitis or cholangiohepatitis with minimal inflammation; biliary epithelium undergoes necrosis
• Small caliber bile ducts dilated by bile with periductal edema
• In severe cases, coagulative necrosis of blood vessel walls in the portal triads
• Chronic: Bile duct fibrosis, chronic cholangitis
• Inspissated bile or "bile plugs"

DIFFERENTIAL DIAGNOSIS:

• For hepatitis and hepatic fibrosis:
  • Geeldikkop:  Crystalline material (calcium salts of sapogenin) in the bile ducts and gall bladder; toxin is steroidal sapogenin; less extensive portal fibrosis
  • Plants:  Brassica rapa (turnip), Periconia sp., Microcystis sp. (blue-green algae), Panicum sp. (toxin is sapogenin), Lupines, Lantana, Phomopsin, Caltrops, Sacahuiste, coal oil bush, Alecrim, Ngaio, Crotalaria, ragwort, Phenosciadium
  • Chemicals:  Carbon tetrachloride, phenanthridium

• For photosensitization:
  • Inherited congenital photosensitivity in Corriedale and Southdown lambs
  • Type 3 (hepatogenous) (any condition resulting in cholestasis in green feed-consuming ruminants, most often plant toxins) and type 2 photosensitization (congenital enzyme defeciencies in cats and cattle)

References:

1. Brown DL, Van Wettere AJ, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6^th St. Louis MO: Elsevier; 2017:430, 450-451.
2. Collett MG. Bile duct lesions associated with turnip (Brassica rapa) photosensitization compared with those due to sporidesmin toxicosis in dairy cows. Vet Pathol. 2014;51(5):986-991.
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. Louis, MO: Elsevier; 2016:285, 335-336.
4. Hansen DE, McCoy RD, Hedstrom OR, Snyder SP, Ballerstedt PB. Photosensitization associated with exposure to Pithomyces chartarum in lambs. J Am Vet Med Assoc. 1994;204:1668-1671.
5. Radostits OM, Gay CC, Blood DC, Hinchcliff KW. Veterinary Medicine, A Textbook of the Diseases of Cattle, Sheep, Pigs, Goats and Horses. 11th ed. Louis, MO: Elsevier; 2017:652-654.

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