JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2548607): 3-month-old mixed breed beef heifer
HISTORY: This heifer was one of several calves and cows that were acutely ill. Several died in the last four months. This calf died enroute to the laboratory. A bottle of monosodium methanearsonate herbicide with a pinhole leak had been dripping into a meal supplement in a storage shed.
HISTOPATHOLOGIC DESCRIPTION: Rumen: Diffusely there is a lack of normal ruminal papillar architecture with blunting, collapse and loss of papillae. The mucosal epithelium is eroded, ulcerated, and multifocally separated from the underlying lamina propria and replaced by eosinophilic cellular and karyorrhectic debris (necrosis), keratin debris, eosinophilic fibrillar fibrin, hemorrhage, edema, numerous viable and degenerate neutrophils and fewer lymphocytes and plasma cells, and few small colonies of coccobacilli. Multifocally within the lamina propria, most severely underlying areas of ulceration, there is necrotic debris, viable and degenerate neutrophils, edema and fibrin. Edema and neutrophils extend transmurally through all layers of the rumen to the serosa..
MORPHOLOGIC DIAGNOSIS: Rumen: Rumenitis, necrohemorrhagic and neutrophilic, acute, diffuse, severe, with transmural congestion and edema, mixed breed, bovine.
ETIOLOGIC DIAGNOSIS: Rumenal arsenic toxicosis
CAUSE: Organic arsenic (trivalent)
- Poisoning usually occurs by accidental exposure to herbicides and pesticides via ingestion or percutaneous absorption
- Sources include insecticides, herbicides, wood preservatives, smelter exhaust, feed additives and injectable arsenicals
- Arsenicals are classified as organic or inorganic, and each has a trivalent and a pentavalent form
- Toxicity from most to least toxic > inorganic As3+ (arsenite) > inorganic As5+ (arsenate) > trivalent organics > pentavalent organics
- Inorganics and trivalent organics > affects the gastrointestinal tract and capillaries
- Pentavalent organics > neurological syndrome
- As5+ is reduced to the more toxic As3+ within the rumen
- Indestructible and remain permanently in the environment
- Partially methylated in liver and kidney; rapidly excreted in urine, feces, bile, milk, saliva, and sweat; excretion is rapid and complete within a few days
- May cross placental and blood-brain barriers in small amounts
- Trivalent arsenicals (As3+) inhibit cellular respiration by binding to sulfhydryl compounds (the main mechanism of action), especially lipoic acid and alpha-keto oxidases (tricarboxylic acid cycle), and inactivation of them, which decreases metabolic activity
- Tissues of high oxidative energy and/or rapidly dividing cells such as intestinal epithelium, kidney, liver, skin, brain and lung are most affected
- Arsenites (As3+) affects capillary integrity by decreasing differential expression of extracellular matrix proteins
- The lesions in arsenical poisoning are often associated with vascular injury: Capillary dilation is followed by transudation of plasma into the gastrointestinal tract, resulting in submucosal congestion and edema, followed by diarrhea, electrolyte loss, mucosal necrosis and possible death
- Chronic, low-level exposure > disruption of the extracellular matrix of small arteries in the heart and lung
- Inorganic aresenates (As5+) > substitution for phosphate in oxidative phosphorylation > uncoupling of oxidative phosphorylation > increased body temperature and cellular energy deficit
- Pentavalent (As5+) organic arsenicals (poultry and swine feed additives) act by an unknown mechanism to produce demyelination and eventual axonal degeneration, possibly by inhibiting the vitamins B1 and B6
TYPICAL CLINICAL FINDINGS:
- Inorganic As3+, inorganic As5+ and organic trivalent arsenicals (As3+)
- Peracute: Sudden death within minutes to hours
- Acute: Vomiting, intense colic, weakness, staggering, ataxia, recumbency, severe watery diarrhea, rumen and gastrointestinal atony, shock, collapse and death
- Subacute: Depression, anorexia, incoordination, +/- hemorrhagic and diffuse diarrhea
- Chronic: Fatigue, dyspnea; intense thirst, rough dry haircoat, brick-red mucous membranes, and enlarged joints
- When gastroenteritis is the predominant lesion, the case fatality rate approaches 100%
- Multi-day high dose or chronic organic pentavalent arsenical exposure > incoordination and blindness
- Increased PCV and BUN, proteinuria and renal tubular casts
TYPICAL GROSS FINDINGS:
- Gastrointestinal mucosal congestion (“rose-red inflammation”), prominent submucosal edema, epithelial necrosis, massive accumulation of fluids in a dilated atonic intestine (epithelium peels away easily); abomasum is most severely affected acutely and chronic
- Edema of gastric rugae of abomasum in cattle; also may lead to hemorrhage, necrosis, and ulceration
- Typhlocolitis in ruminants: Arsenic and other heavy metals associated with hemorrhagic typhlocolitis as well as dysentery
- Peracute: No lesions to minimal gastrointestinal irritation
- Subacute: Pale swollen kidneys, pale soft liver; petechiae of the intestinal serosa and mucosa Chronic dermatitis when applied to the skin
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Acute toxicity (vascular injury)
- Gastric and intestinal mucosal and submucosal congestion, edema, hemorrhage and ulceration
- Multifocal hepatic and renal proximal tubular necrosis
- Chronic toxicity: Glomerular capillary dilatation results in decreased blood flow and renal ischemia and/or proteinuria and tubular necrosis, both resulting in tubular fibrosis; fatty change in heart, liver and kidney
- Organic pentavalent arsenicals: Moderate, diffuse, cerebral edema and petechiae; demyelination and degeneration of peripheral nerves
- One case report with the only histologic lesion being lymphoid necrosis of the mesenteric lymph nodes and GALT; recent research demonstrates trivalent arsenic’s lethality on neoplastic and normal lymphocytes
ADDITIONAL DIAGNOSTIC TESTS:
- Detection of chemical residues in tissues or body fluids
- Acute exposure: Urine, vomitus, feces, milk, liver, intestine and kidney
- Chronic exposure: Skin, hair, and nervous tissue (organic arsenicals)
- Analysis of suspected baits, feed, plants or soil
DIFFERENTIAL DIAGNOSIS (for clinical signs):
- Acute inorganic poisoning (differential diagnosis for gastroenteritis and central nervous system signs):
- Lead toxicosis: Central nervous sytem signs predominate; gastrointestinal involvement is inconsistent
- Malignant catarrhal fever (bovine gammaherpesvirus): Ocular and buccal lesions will be present
- Mucosal disease (bovine pestivirus): Buccal and nasal mucosa lesions will be present
- Mercury toxicity in pigs and cattle: Central nervous system and gastrointestinal signs, edematous kidneys; laminar cortical necrosis in cattle
- Plants: Brackens and mustards
- Salmonellosis: Button ulcers; paratyphoid nodules; culture
- Chronic inorganic arsenical poisoning (diarrhea and weight loss):
- Parasitism: Ostertagiasis, trichostrongylosis and oesophagostomiasis
- Organic arsenical poisoning (afebrile nervous system disease)
- Organic mercury poisoning
- Salt poisoning
- Industrial organophosphate contamination of swine feed
- Selenium toxicosis of swine feed: Focal symmetrical encephalomalacia
- Humans are most susceptible to inorganic arsenicals followed by dogs, rats and mice
- In rats and mice, high exposure can lead to urothelial hyperplasia, which is a preneoplastic change (high exposures is a known human carcinogen, which includes tumors of the urinary bladder, skin and lungs)
- Administration of sodium arsenite (As3+) in drinking water increases the rate of cutaneous carcinoma development in SENCAR mice
- Organic arsenical poisoning in pigs is predominately neurologic
- In swine, organoarsenical phenylarsonic acid derivatives are used as feed additives
- Arsanilic acid causes mild edema in white matter of central nervous sytem with marked Wallerian degeneration of the optic and peripheral nerves
- 3-nitro causes Wallerian degeneration in dorsal proprioceptive and spinocerebellar tracts of the cervical spinal cord, and lateral and ventral funiculi of the caudal spinal cord
- Arnold LL, Suzuki S, Yokohira M, Kakiuchi-Kiyota S, Pennington KL, Cohen SM. Time course of urothelial changes in rats and mice orally administered arsenite. Toxicol Pathol. 2014;42(5):855-862.
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- Haschek WA, Rousseaux CG, Wallig MA. Gastrointestinal tract. In: Haschek WA, Rousseaux CG, Wallig MA, eds. Fundamentals of Toxicologic Pathology. 2nd ed. San Diego, CA: Academic Press; 2010:180.
- Hays AM, Lantz RC, Rodgers LS, et al. Arsenic-induced decreases in the vascular matrix. Toxicol Pathol. 2008;36(6):805-817.
- Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer"s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:571.
- Miller AD, Zachary JF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2017:854.
- Neiger R, Nelson N, Miskimins D, Caster J, Caster L. Bovine arsenic toxicosis. J Vet Diagn Invest. 2004;16(5):436-438.
- Palmieri MA, Molinari BL. Effect of sodium arsenite on mouse skin carcinogenesis. Toxicol Pathol. 2015;43(5):704-714.
- Uzal FA, Platter BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer"s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:51, 52, 57, 100, 114.
- Valentine BA, Rumbeiha WK, Hensley TS, Halse RR. Arsenic and metaldehyde toxicosis in a beef herd. J Vet Diagn Invest. 2007;19(2):212-215.
- Waalkes MP, Ward JM, Liu J, Divan BA. Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. Toxicol Appl Pharmacol. 2003;186(1):7-17.