Pathology in Practice

Laura E. Rice 1Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843.

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Rodolfo Madrigal 2Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843.

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Allen Roussel 2Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843.

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Raquel Rech 1Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843.

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History

A 5-month-old 172-kg (378-lb) female Brahman-cross calf was evaluated after a sudden onset of ataxia and possible blindness. The calf's dam was also reported to have developed acute blindness 2 days prior to the onset of clinical signs in the calf. However, the cow had escaped its holding pen, and its clinical status was not known.

Clinical and Gross Findings

At the evaluation, the calf was laterally recumbent and unresponsive. On physical examination of the calf, the menace reflex was absent bilaterally, and the cranial nerve and patellar reflexes were bilaterally hyporeflexive. The calf was treated with thiamine (10 mg/kg [4.5 mg/lb], IV, once); however, the calf's condition continued to decline. Several hours after the thiamine injection, the calf developed seizures that were unresponsive to diazepam (0.5 mg/kg [0.23 mg/lb], IV, once). Given the poor prognosis, the owners elected euthanasia and the animal was submitted for necropsy. Grossly, the liver was mildly enlarged and had a diffuse enhanced zonal pattern (Figure 1). This zonal pattern in the liver was accentuated after fixation in neutral-buffered 10% formalin. The only other gross finding at necropsy was mild flattening of the cerebral gyri, suggestive of cerebral edema.

Figure 1—
Figure 1—

Photograph of the liver from a 5-month-old female calf that died after a sudden onset of neurologic signs. In a cut section, notice that the fresh liver has a diffusely enhanced zonal pattern. Inset—Following fixation, a cross section of the liver is provided to highlight the enhanced lobular pattern of the liver tissue.

Citation: Journal of the American Veterinary Medical Association 255, 7; 10.2460/javma.255.7.801

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page

Histopathologic Findings

The enhanced zonal pattern seen grossly in the liver corresponded to centrilobular (periacinar) areas of hepatocellular necrosis with hemorrhage surrounded by hepatocellular vacuolar degeneration (Figure 2). Areas of necrosis affected 45% to 55% of the liver parenchyma and contained small numbers of neutrophils and macrophages (Figure 3). Multifocally, the areas of necrosis extended into and affected the midzonal hepatocytes. The remaining hepatocytes within the midzonal and periportal zones were multifocally swollen and contained variably sized, clear, distinct cytoplasmic vacuoles (vacuolar degeneration with lipid). Single hepatocytes immediately adjacent to the centrilobular zone were occasionally shrunken and angular with hypereosinophilic cytoplasm and pyknotic nuclei (single cell necrosis). Additionally, scattered throughout the evaluated sections of cerebrum, there were pairs of astrocytes that had swollen, vesiculate nuclei (Alzheimer type II astrocytes). This suggested that the calf's neurologic signs were attributable to hepatic encephalopathy.

Figure 2—
Figure 2—

Photomicrograph of a section of the liver from the calf in Figure 1. There is diffuse, acute, centrilobular hepatocellular necrosis with hemorrhage. H&E stain; bar = 200 μm.

Citation: Journal of the American Veterinary Medical Association 255, 7; 10.2460/javma.255.7.801

Figure 3—
Figure 3—

Higher-magnification view of the liver section in Figure 2. The areas of centrilobular hepatocellular necrosis (asterisk) contain karyorrhectic debris and are infiltrated by few neutrophils and macrophages. These areas of centrilobular hepatocellular necrosis are also surrounded by hepatocytes with lipid vacuolar degeneration (arrow). H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 255, 7; 10.2460/javma.255.7.801

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: severe, acute diffuse, centrilobular to submassive hepatocellular necrosis with hemorrhage.

Case summary: suspected Xanthium hepatotoxicosis in a calf.

Comments

Upon receiving the report from the pathologist, the clinician called the owner, who then reported that the calf and its dam had both been confined in a pen where 3-inch-tall cocklebur plants (Xanthium sp) were growing. The gross and histologic findings in the case described in the present report, coupled with the identification of Xanthium sp in the enclosure where the cow and calf were kept, were consistent with hepatocellular toxicosis caused by ingestion of Xanthium plants. Xanthium strumarium and Xanthium spinosum have a near cosmopolitan distribution and are the 2 species of Xanthium found within the United States. Xanthium strumarium grows throughout the United States and Canada, and X spinosum is also found throughout the United States with the exception of the upper Midwest region. Several other species are more geographically localized, including Xanthium orientale in Europe and the Middle East, Xanthium cavanillesii in Brazil and South Africa, and Xanthium pungens in Australia. Xanthium spp are adapted to a variety of clay, loam, and sandy soils and are distributed throughout warmer parts of the world as weeds of disturbed sites and damp soils.1

Xanthium seeds and seedlings are considered to be hepatotoxic.2 Seedlings with 2 leaves contain a high concentration of the toxin carboxyatractyloside (CAT), and the toxin concentration in Xanthium spp decreases as the seedlings lose their cotyledons and develop 4 leaves.3 The seeds contain the highest concentration of CAT; however, the spiny bur surrounding the seeds may deter their consumption.4 Intoxications following ingestion of cocklebur plants are most common after rain during periods of warmer weather in the spring and summer, conditions that encourage germination of the seeds. Cattle, swine, horses, chickens, and sheep are susceptible to cocklebur toxicosis, especially after feedstuffs (eg, grains and hay) become contaminated with burs or seedlings.1,2,5 Occasionally, humans can also be affected by Xanthium toxicosis, and this risk may be heightened in areas of food scarcity.6

Carboxyatractyloside is a diterpene glycoside that competitively inhibits the adenosine nucleoside carrier, ADP translocase, on the cytosolic side of mitochondrial membranes.1,4 The inability of the mitochondria to bring in ADP from the cytosol eventually leads to an inhibition of oxidative phosphorylation and a decrease in available ATP for cellular processes. The eventual depletion of ATP within cells ultimately results in cell death via apoptosis or necrosis and subsequent development of lesions similar to those observed in the calf of the present report. The toxic effect of CAT is all or nothing and is not cumulative, and some animals may develop apparent tolerance.1,5 The toxin CAT also acts as a plant growth inhibitor, ensuring development of dense stands of Xanthium spp with little competition from other plants in the area.1

The toxic dose of fresh green Xanthium sprouts for pigs and calves is reported to be 1% of an animal's body weight (10 g/kg [0.16 oz/lb]), while the toxic dose of the burs in calves is reported to be 0.14% to 0.2% (1.4 to 2.0 g/kg [0.022 to 0.032 oz/lb]) of an animal's body weight.1 Clinical signs develop in calves within 12 hours after seedling ingestion and include excess salivation, tremors, ataxia, clonic and tonic seizures, signs of depression, anorexia, vomiting, opisthotonus, paddling, coma, and death.4 Hyperexcitablility and blindness have also been reported, and these signs are likely secondary to hepatic encephalopathy.7 The onset of neurologic signs has also been considered attributable to the hypoglycemic effect of CAT caused by the uncoupling of oxidative phosphorylation.8 In experimental intoxications of sheep and cattle from Brazil, neuromuscular signs, including myoclonus, bruxism, opisthotonus, blindness, and seizures, were reported to be the most consistent clinical signs caused by CAT.9,10 Death may occur in a few hours after ingestion of CAT; however, the disease course may take as long as 2 to 3 days. Affected animals may have high serum activities of γ-glutamyltransferase (indicative of cholestasis) and alanine aminotransaminase (indicative of hepatocellular damage).1 Treatment for animals with Xanthium toxicosis is generally supportive because there is no specific treatment to counteract the action of the toxin that leads to depletion of ATP in cells.

In cattle with cocklebur toxicosis, necropsy findings include hepatomegaly with lobular accentuation, renal congestion, ascites, and gastrointestinal petechiae.1,4,6–10 Occasionally, burs or intact sprouts may be found within the rumen contents. Histologically, the most distinctive lesion is severe, diffuse centrilobular hepatocellular necrosis. In the white matter of cattle experimentally fed X cavanillesii,11 astrocytes with swollen cytoplasm and a pyknotic nucleus have been detected, whereas neuronal degeneration and cerebral edema are inconsistent findings.8 Diagnosis of Xanthium toxicosis is generally made by identification of the plants in the affected animal's environment coupled with appropriate clinical signs and gross and histologic lesions. Diagnosis may be aided by use of thin-layer chromatography on rumen contents or urine, or liquid chromatography–high-resolution mass spectrometry on rumen contents or liver to detect the CAT toxin.4,8 Carboxyatractyloside concentrations of 100 to 200 ppm in the rumen contents and 0.1 ppm in urine samples detected by thin-layer chromatography have been reported for intoxicated calves.1,4,8 Prevention of Xanthium toxicosis is limited to inhibiting animals from having access to the plants or destroying the plants with herbicides. The differential diagnoses to consider in cases of acute hepatocellular necrosis in cattle caused by Xanthium toxicosis include water contamination with blue-green algae (cyanobacteria), exposure to aflatoxins, or ingestion of alsike clover (Trifolium hybridum), among other causes.

The case described in the present report has highlighted the importance of communication between pathologists and clinicians to determine a final diagnosis in large animal cases in which toxin exposure may be involved. The clinician or owner ideally would walk the field or analyze the feed to aid in discovery of the toxic insult to the animals; once identified, the source of the toxin can be removed to prevent other herd animals from being affected. As illustrated by this case, although the gross appearance of livers with acute, zonal hepatic necrosis mimics the appearance of chronic passive congestion, the cut section of livers with acute necrosis would be soft and should be described as having an enhanced lobular pattern.

References

  • 1. Burrows GE, Tyrl RJ. Chapter 13: Asteraceae martinov. In: Burrows GE, Tyrl RJ, eds. Toxic plants of North America. 2nd ed. Ames, Iowa: Wiley-Blackwell, 2013;221225.

    • Search Google Scholar
    • Export Citation
  • 2. Cullens JM, Stalker MJ. Chapter 2: Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's pathology of domestic animals. Vol 2. 6th ed. St Louis: Elsevier, 2016;331.

    • Search Google Scholar
    • Export Citation
  • 3. Kellerman TS, Coetzer JAW, Naude TW, et al. Chapter 1: Liver. In: Kellerman TS, Coetzer JAW, Naude TW, et al, eds. Plant poisonings and mycotoxicosis of livestock in Southern Africa. 2nd ed. Oxford, England: Oxford University Press, 2005;1718.

    • Search Google Scholar
    • Export Citation
  • 4. Witte ST, Osweiler GD, Stahr HM, et al. Cocklebur toxicosis in cattle associated with the consumption of mature Xanthium strumarium. J Vet Diagn Invest 1990;2:263267.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Mendez MC, dos Santos RC, Riet-Correa F. Intoxication by Xanthium cavanillesii in cattle and sheep in southern Brazil. Vet Hum Toxicol 1998;40:144147.

    • Search Google Scholar
    • Export Citation
  • 6. Gurley ES, Rahman M, Hossain MJ, et al. Fatal outbreak from consuming Xanthium strumarium seedlings during time of food scarcity in northeastern Bangladesh. PLoS One 2010;5:e9756.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Driemeier D, Irigoyen LF, Loretti AP, et al. Spontaneous intoxication of Xanthium cavanillesii (Asteraceae) fruits in cattle in Rio Grande do Sul. Pesqui Vet Bras 1999;19:1218.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Botha CJ, Lessing D, Rösemann M, et al. Analytical confirmation of Xanthium strumarium poisoning in cattle. J Vet Diagn Invest 2014;26:640645.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Colodel EM, Driemeier D, Pilati C. Experimental poisoning by Xanthium cavanillesii (Asteraceae) fruits in cattle. Pesqui Vet Bras 2000;20:3138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Loretti AP, Bezerra PS, Ilha MRS, et al. Experimental poisoning by Xanthium cavanillesii (Asteraceae) fruits in sheep. Pesqui Vet Bras 1999;19:7178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Wouters ATB, Wouters F, Boabaid FM, et al. Brain lesions associated with acute toxic hepatopathy in cattle. J Vet Diagn Invest 2017;29:287292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Photograph of the liver from a 5-month-old female calf that died after a sudden onset of neurologic signs. In a cut section, notice that the fresh liver has a diffusely enhanced zonal pattern. Inset—Following fixation, a cross section of the liver is provided to highlight the enhanced lobular pattern of the liver tissue.

  • Figure 2—

    Photomicrograph of a section of the liver from the calf in Figure 1. There is diffuse, acute, centrilobular hepatocellular necrosis with hemorrhage. H&E stain; bar = 200 μm.

  • Figure 3—

    Higher-magnification view of the liver section in Figure 2. The areas of centrilobular hepatocellular necrosis (asterisk) contain karyorrhectic debris and are infiltrated by few neutrophils and macrophages. These areas of centrilobular hepatocellular necrosis are also surrounded by hepatocytes with lipid vacuolar degeneration (arrow). H&E stain; bar = 100 μm.

  • 1. Burrows GE, Tyrl RJ. Chapter 13: Asteraceae martinov. In: Burrows GE, Tyrl RJ, eds. Toxic plants of North America. 2nd ed. Ames, Iowa: Wiley-Blackwell, 2013;221225.

    • Search Google Scholar
    • Export Citation
  • 2. Cullens JM, Stalker MJ. Chapter 2: Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's pathology of domestic animals. Vol 2. 6th ed. St Louis: Elsevier, 2016;331.

    • Search Google Scholar
    • Export Citation
  • 3. Kellerman TS, Coetzer JAW, Naude TW, et al. Chapter 1: Liver. In: Kellerman TS, Coetzer JAW, Naude TW, et al, eds. Plant poisonings and mycotoxicosis of livestock in Southern Africa. 2nd ed. Oxford, England: Oxford University Press, 2005;1718.

    • Search Google Scholar
    • Export Citation
  • 4. Witte ST, Osweiler GD, Stahr HM, et al. Cocklebur toxicosis in cattle associated with the consumption of mature Xanthium strumarium. J Vet Diagn Invest 1990;2:263267.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Mendez MC, dos Santos RC, Riet-Correa F. Intoxication by Xanthium cavanillesii in cattle and sheep in southern Brazil. Vet Hum Toxicol 1998;40:144147.

    • Search Google Scholar
    • Export Citation
  • 6. Gurley ES, Rahman M, Hossain MJ, et al. Fatal outbreak from consuming Xanthium strumarium seedlings during time of food scarcity in northeastern Bangladesh. PLoS One 2010;5:e9756.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Driemeier D, Irigoyen LF, Loretti AP, et al. Spontaneous intoxication of Xanthium cavanillesii (Asteraceae) fruits in cattle in Rio Grande do Sul. Pesqui Vet Bras 1999;19:1218.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Botha CJ, Lessing D, Rösemann M, et al. Analytical confirmation of Xanthium strumarium poisoning in cattle. J Vet Diagn Invest 2014;26:640645.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Colodel EM, Driemeier D, Pilati C. Experimental poisoning by Xanthium cavanillesii (Asteraceae) fruits in cattle. Pesqui Vet Bras 2000;20:3138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Loretti AP, Bezerra PS, Ilha MRS, et al. Experimental poisoning by Xanthium cavanillesii (Asteraceae) fruits in sheep. Pesqui Vet Bras 1999;19:7178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Wouters ATB, Wouters F, Boabaid FM, et al. Brain lesions associated with acute toxic hepatopathy in cattle. J Vet Diagn Invest 2017;29:287292.

    • Crossref
    • Search Google Scholar
    • Export Citation

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