JPC SYSTEMIC PATHOLOGY
Signalment (JPC #ML24078): 3-year old Hampshire ewe
HISTORY: This ewe was found dead, along with several others, on a pasture in South Dakota in June. Depression and emesis as well as photosensitization were noted in surviving sheep. Clinical pathology results were:
BUN 366 mg/dl (10-20 mg/dl)
SGOT 260 SF (0-150 IU/ml)
CPK 170 IU/l (<200 IU/l)
HISTOPATHOLOGIC DESCRIPTION: Kidney, cortex: Multifocally, up to 70% of tubules are ectatic, dilated up to 100 um in diameter, lined by attenuated epithelium, and contain variable amounts of proteinaceous material, few sloughed epithelial cells, eosinophilic cellular and karyorrhectic debris (necrosis), and, rarely, basophilic, anisotropic crystals (oxalate). Few tubules are lined by epithelial cells that are swollen with pale vacuolated cytoplasm (degeneration) or shrunken with hypereosinophilic cytoplasm and pyknotic nuclei (necrosis). Few glomeruli have hypertrophic parietal epithelium, and mild thickening of the basement membrane of Bowman’s capsule. There are multifocal aggregates of low numbers of lymphocytes and plasma cells scattered throughout the interstitium.
Liver: Diffusely, centrilobular hepatocytes are swollen and rounded with pale vacuolated cytoplasm (degeneration), which compress and distort sinusoids. Multifocally there is individual cell necrosis. Within the portal areas there are low numbers of lymphocytes and plasma cells.
- Kidney, cortex: Ectasia, tubular, multifocal, moderate, with tubular degeneration and necrosis, Hampshire, ovine
- Liver, hepatocytes: Degeneration and necrosis, centrilobular, mild-moderate.
ETIOLOGIC DIAGNOSIS: Algal hepatic and renal toxicosis
CAUSE: Blue-green algae toxin of Anabaena sp.
- Cyanobacteria (blue-green algae) are common in still fresh or brackish water in lakes, dams, stagnant rivers, ponds, watering holes, or lagoons
- Several genera are toxic; the most common are Microcystis, Anabaena, and Aphanozomenon; most well-documented cases have involved Microcystis aeruginosa
- Algal blooms occur predominantly in water with high nutrient content such as those with high concentrations of nitrogen and phosphate from fertilizer runoff and under conditions of hot, dry weather
- Wind or water movements cause piling of the algae against the shores of expanses of water and poisoning of animals that drink from it
- Toxins are liberated when the algae cells die or are damaged; this may occur spontaneously in water, after application of copper sulfate for algae control, or in the rumen or stomach after ingestion
- Some deaths are too sudden to be due to liver damage and are thought to be the result of a “fast-death factor”
- There are two main categories of toxins: neurotoxin and hepatotoxin
- The neurotoxins include: anatoxin-a, an alkaloid and potent post-synaptic depolarizing neuromuscular blocking agent; anatoxin-A(s), an organophosphorus compound and potent cholinesterase inhibitor; and saxitoxin and related paralytic shellfish toxins (sodium channel blockers)
- The hepatotoxins include: microcystin-LR, a potent cyclic heptapeptide protein phosphatase inhibitor, and cylindrospermopsin, an alkaloid
- Intoxication with microcystin-LR leads to disorganization of hepatocytic and endothelial cytoskeletal actin filaments, and disruption of their shape and integrity, leading to necrosis, apoptosis, and perisinusoidal hemorrhage; cytoskeletal changes are caused by inhibition of cytoplasmic protein phosphatase 1 and 2A and resultant rapid hyperphosphorylation of cytoskeletal proteins
- The distribution of necrosis is usually periacinar to massive, but varies within the individual liver and from case to case
- Rodent studies suggest that cytoskeletal damage also occurs in tubular epithelial cells and in cultured fibroblasts
TYPICAL CLINICAL FINDINGS:
- Sudden death within one to two hours after drinking contaminated water
- Rapidly progressing paralysis, acute prostration, and convulsions
- Cutaneous lesions characteristic of photosensitization may occur
TYPICAL GROSS FINDINGS:
- There may be no gross findings with sudden death or acute neurological disease
- Hepatotoxicosis results in icterus and a swollen, hemorrhagic and friable liver
- Cirrhotic livers are reported in chronic cases
- There is generalized petechiation and congestion
- There may be severe hemorrhagic gastroenteritis with bloody diarrhea
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Renal histopathologic findings in experimental rats include:
- Collapsed glomeruli with thickened basement membranes
- Dilated tubules filled with eosinophilic casts
- Hepatic histopathologic findings when sublethal doses are given to mice include:
- Centrilobular to massive hepatic necrosis
- Hepatomegaly and karyomegaly with parenchymal disarray
- Breakdown of sinusoidal endothelium
- Hemorrhage, and
- Eosinophilic cytoplasmic condensations, resembling Mallory bodies, around the outer nuclear membrane
- Pyrrolizidine alkaloids induce nuclear and cytoplasmic gigantism (megalocytosis) due to an anti-mitotic effect with continued nucleoprotein synthesis
- Phomopsin blocks the polymerization of tubulin (the major component of microtubules), resulting in defective microtubule formation; mitotic cells arrest in metaphase
- Aflatoxin B1 binds mitochondrial and nuclear DNA, inhibiting biosynthetic processes and respiration, m-RNA synthesis, and ribosomal protein synthesis leading to hepatocellular necrosis with a distribution dependent on animal species
- Ruminants are the primary species affected, but can affect all animals and birds
- Poisoning has been reported in horses, swine, dogs, and domestic poultry
- Also has been associated with mortalities in fish in brackish and marine water
- Recent report of intoxication in a dog from Nodulara spumigena
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- Khan SA, Wickstrom ML, Haschek WM, Schaeffer DJ, Ghosh S, Beasley VR. Microcystin-LR and kinetics of cytoskeletal reorganization in hepatocytes, kidney cells, and fibroblasts. Nat Toxins 1996;4:206-14.
- Milutinovic A, Zivin M, Zorc-Pleskovic R, Sedmak B, Suput D.font color=navy> Nephrotoxic effects of chronic administration of microcystins -LR and -YR. Toxicon 2003;42:281-288.
- Radostits OM, Gay CC, Hinchcliff KW, Constable PD. Veterinary Medicine: A textbook of the diseases of cattle, horses, sheep, pigs, and goats. 11th ed. St. Louis, MO; Elsevier Limited; 2017:101-103.
- Simola O, Wiberg M, Jokela J, et al. Pathologic Findings and Toxin Identification in Cyanobacterial (Nodularia spumigena) Intoxication in a Dog. Vet Pathol. 2012; 46(5):755-9..