JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

October 2024

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 mild lymphoplasmacytic cholangiohepatitis, polypay-cross, ovine.

 

ETIOLOGIC DIAGNOSIS: Mycotoxic hepatic fibrosis

 

CAUSE: Sporidesmin intoxication

 

CONDITION: Facial eczema

 

GENERAL DISCUSSION: 

• Sporidesmin is a polyphagus saprophyte produced by the fungus Pithomyces chartarum and is found most often on moist dead ryegrass (among other grasses) in warm weather
• Most of the toxin is concentrated on the fungal spores (conidia); toxicity of the pasture is related to the density of these spores
• Serious cause of loss of sheep and, to a lesser extent, cattle and goats in New Zealand, Australia, South Africa, and South America; also reported in camelids
• Toxin is reported to bind to zinc atoms of some metalloproteins (De Las Heras, Vet Pathol, 2022)
• Ingestion of toxin produces chronic liver damage and severe hepatogenous photosensitivity (Type 3); skin lesions predominate on the head (i.e. “facial eczema”)
• Sporidesmin, in conjunction with ingestion of Tribulus terrestris, (from the Zygophyllaceae family) causes Geeldikkop which is histologically distinct photosensitization caused by steroidal sapogenins that damage or obstruct bile ducts
• Photosensitization (type 3) occurs in unpigmented skin where not covered by a heavy wool or hair layer and is exposed to the sun

• 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:

• Sporidesmin is absorbed in the small intestine
• Unconjugated sporidesmin is not directly hepatotoxic, but when it concentrates in bile it may initiate oxidative injury likely mediated by the production a hydroxyl radical> disrupts canalicular membranes and microvilli, irritation and necrosis of biliary epithelium (intra and extrahepatic biliary ducts), portal mesenchymal tissue, and adjacent blood vessels > progressive obliterative cholangitis > bile flow disruption and 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:

• Acutely, within a few hours, erythema and edema of unpigmented skin, most commonly the eyelids, pinnae, muzzle, face, coronary bands, and back; followed by epidermal blisters, ulceration, exudation, necrosis, and sloughing of skin 
• Icterus
• Elevated GGT, AAT, and bilirubin (De Las Heras, Vet Pathol, 2022)

 

TYPICAL GROSS FINDINGS: 

• Early, liver is swollen, finely mottled, and yellow-green discolored (bile stasis); later, liver is contracted and tough 
• Left lobe of liver usually most severely affected, may undergo atrophy and fibrosis
  1. Most ventral in ruminants, longer bile ducts compared to other lobes
• Extrahepatic duct thickened and prominent 
• Congestion and distended gall bladder; bile may be normal quality of with mucin (white)
• Chronic: Hepatic fibrosis, with exaggerated acinar pattern, and pale atrophic parenchyma surrounding occluded bile ducts (“biliary infarcts”); liver is firm and on cut section intrahepatic ducts are prominent with narrow lumens. May see large nodules of regeneration 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Liver

• Acute necrotizing cholangitis or cholangiohepatitis with minimal inflammation (lymphocytic and histiocytic); biliary epithelium undergoes necrosis

• Disorganization of hepatic cell organelles and triglyceride accumulation

• Prominent small caliber bile ducts dilated by bile with periductal edema
• Hepatic arteries and portal vein have eccentric intimal thickening (De Las Heras, Vet Pathol, 2022)
• In severe cases, coagulative necrosis of blood vessel walls in the portal triads 
• Chronic: Bile duct fibrosis, portal tract fibrosis, chronic cholangitis 
• Inspissated bile or "bile plugs" 

Skin

• Lytic to coagulative necrosis of the epidermis and possibly hair follicles, adnexal glands, and superficial dermis
• Subepidermal vesicles and bullae 
• Endothelial cells of the superficial, middle, and deep dermal vessels are swollen and necrotic, with fibrinoid degeneration and thrombosis resulting in edema and infarction

 

DIFFERENTIAL DIAGNOSIS:

• 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

• 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. 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; 2016: 269, 285, 335-336.
2. De Las Heras M, Lacasta D, Reséndiz RA, et al. Chronic pithomycotoxicosis associated with obstructive rhinopathy in sheep. Vet Pathol. 2022;59(6):950-959. 
3. Van Wettere AJ, Brown DL. Hepatobiliary System and Exocrine. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:505, 512.e1, 520.e1, 522-523,  

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