JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
October 2021
D-T07

Signalment (JPC# 1803025):  9-year-old spayed German shorthair pointer

HISTORY:  Initially in apparent good health.  A stool sample was positive for hookworms and whipworms.  Telmintic dewormer (Pitman-Moore) was dispensed.  The second deworming was started 2 weeks later.  On the third day of treatment the dog became incoordinated and would not eat.  The dog became depressed and icteric and died 4 hrs later.

LABORATORY RESULTS:

Glucose         74 mg/dl                                 T. bilirubin     12.3 mg/dl (0.0-0.3 normal)

BUN               5.1 mg/dl                                Alk phos        471 IU/L (20-50 normal)

Creatinine     0.7 mg/dl                                ALT                 2,200 IU/L (20-80 normal)

Total protein  7.4 mg/dl                                WBC               11.2 x10³/ul

Albumin         3.4 mg/dl                                Hematocrit     57.9%

HISTOPATHOLOGIC DESCRIPTION:  Liver:  There is diffuse, massive, marked stromal collapse of hepatic parenchyma characterized by loss of hepatocytes, loss of sinusoidal architecture, and close apposition of portal triads. Hepatic parenchyma is replaced by diffuse hemorrhage, fibrin, edema, scattered necrotic cellular debris, many hemosiderin-laden macrophages, and rare hematoidin.  This hemorrhage surrounds and separates few remaining individualized hepatocytes that are shrunken and hypereosinophilic with pyknotic nuclei (single cell death).  Multifocally within portal areas there are low numbers of lymphocytes, plasma cells, macrophages, and rare neutrophils.  Bile duct epithelial cells are swollen, often markedly, with vacuolated cytoplasm (degenerate) or are shrunken with pyknotic nuclei (single cell death).  Lymphatic vessels are ectatic and collagen is separated by increased clear space (edema).

MORPHOLOGIC DIAGNOSIS:  Liver:  Necrosis and hemorrhage, massive, acute, diffuse, severe, with stromal collapse and bile duct epithelial degeneration and single cell death, German shorthair pointer, canine.

ETIOLOGIC DIAGNOSIS:  Toxic hepatic necrosis

CAUSE:  Mebendazole toxicity

GENERAL DISCUSSION:

• Mebendazole is a broad-spectrum benzimidazole anthelmintic that, at therapeutic doses, can occasionally cause acute, diffuse, centrilobular to massive hepatic necrosis in the dog
• Benzimidazole drugs bind with parasite tubulin and prevent microtubule assembly, which affects many cell functions; mebendazole also inhibits glucose uptake by nematodes and cestodes

PATHOGENESIS:

• The exact mechanism of hepatic injury is unknown
• Thought to be an idiosyncratic drug reaction, especially since experimental studies in dogs fail to reproduce the hepatotoxic effects of mebendazole with high or repeated doses

TYPICAL CLINICAL FINDINGS:

• History of exposure: signs of hepatic failure appear within two weeks of mebendazole administration
• Anorexia, vomiting, icterus, bloody diarrhea, PU/PD
• Elevated ALT and alkaline phosphatase; hyperbilirubinemia

TYPICAL GROSS FINDINGS:

• Icterus
• Liver : Multifocal to coalescing, irregular, slightly depressed, dark red, firm areas

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Diffuse centrilobular to massive necrosis and hemorrhage with stromal collapse
• Fatty change of periportal hepatocytes, mild portal fibrosis, and hyperplasia of small bile ducts
• Moderate fibrosis around central veins; Kupffer cells in periportal and necrotic areas often filled with brown granular pigment (hemosiderin)

DIFFERENTIAL DIAGNOSIS:

• Other causes of massive hepatic necrosis in dogs: Aflatoxin, microcystin (blue-green algae), subcutaneous injection of intranasal bordatella vaccine, Amanita mushrooms, trimethoprim-sulfonamides, zonisamide
• Hepatotoxins that may cause acute reactions (necrosis and inflammation) in dogs (within 2 weeks): Sodium thiacetarsamide, diethylcarbamazine acetaminophen, methoxyflurane, mebendazole, halothane, diethylcarbamazine/oxibendazole, carprofen, xylitol
• Hepatotoxins that may cause chronic reactions (fibrosis, cirrhosis) in dogs (weeks to months): Primidone, phenytoin, phenobarbital, glucocorticoids, trimethoprim/sulfadiazine (destructive cholangitis), mibolerone, ketaconazole, methotrexate, aflatoxin

COMPARATIVE PATHOLOGY:

• In cats, diazepam, acetaminophen, methimazole, glipizide and ketoconazole have been implicated as causes of hepatocellular necrosis
• In humans, mebendazole can cause granulomatous hepatitis

REFERENCES:

1. Brown DL, Van Wettere AJV, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:451-452.
2. 2.     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 Ltd; 2016:329.
3. Polzin DJ, Stowe CM, O'Leary TP, Stevens JB, Hardy RM. Acute hepatic necrosis associated with the administration of mebendazole to dogs. J Am Vet Med Assoc. 1981;179(10):1013-1016.
4. Sebastian MM. Role of pathology in diagnosis. In: Gupta RC, ed. Veterinary Toxicology Basic and Clinical Principles. New York, NY: Academic Press; 2007:1102.

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