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 uncoordinated 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, panlobular, 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, panlobular, acute, diffuse, severe, with stromal collapse and biliary epithelial degeneration and necrosis, German shorthair pointer, canine.

ETIOLOGIC DIAGNOSIS: Toxic hepatic necrosis

CAUSE: Mebendazole toxicity

GENERAL DISCUSSION:

Hepatic adverse drug reactions are referred to as drug-induced liver injury (DILI) and are classified as dose-related or idiosyncratic
1. DILI is the most common form of adverse drug reaction in humans; hepatotoxic drug reactions are also recognized in veterinary species (the true prevalence unknown)
2. Often results in acute hepatic disease (including acute liver failure), but may also present with chronic disease (including end-stage liver)
Idiosyncratic toxicants generally only affect a small minority of patients; most who take the drug are unaffected
Mebendazole is a broad-spectrum benzimidazole anthelmintic used in a variety of species that, at therapeutic doses, can occasionally cause acute, diffuse, centrilobular to panlobular/massive hepatic necrosis in dogs
1. Other idiosyncratic hepatic reactions include non-steroidal anti-inflammatory (NSAID) hepatoxicity in dogs (see D-10), diazepam hepatic injury in some cats, or trimethoprim-sulfonamide or zonisamide in dogs

PATHOGENESIS:

Drug-induced liver injury often involves hepatic metabolism (bioactivation) of compounds (liver injury is typically centrilobular); cats in general are more susceptible
1. One mechanism of DILI is altered bile acid homeostasis due to functional impairment of some hepatic bile acid transporters, which have been examined in vitro (Saran, Toxicol Pathol. 2023)
The mechanism of injury for many idiosyncratic toxicants is unknown
1. Hepatic injury be due to inherited differences in hepatic enzyme content/activity, atypical immune reactions to drug metabolites, and/or novel antigens created when drug metabolites bind to cellular proteins

TYPICAL CLINICAL FINDINGS:

Signs of acute liver failure:
1. Anorexia, vomiting, icterus, bloody diarrhea; PU/PD or may be accompanied by oliguria and biochemical indications of renal failure; photosensitization (in herbivores
2. Hepatic encephalopathy: Serious sign usually indicating eminent death
3. Clinical pathology: Elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP); hyperbilirubinemia; coagulopathy with hemorrhage is most likely to occur when there is acute liver necrosis, although it is not common in acute liver failure
Mebendazole: History of exposure; signs of hepatic failure appear within two weeks of mebendazole administration

TYPICAL GROSS FINDINGS:

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

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Different idiosyncratic agents may have different histological features, ranging from pure hepatocellular injury to pure biliary injury to a mixed pattern:
1. Submassive to panlobular hepatic necrosis and cholestatic hepatitis have been reported with trimethoprim-sulfonamide
2. Severe lobular to panlobular necrosis has been associated with diazepam in cats
Mebendazole:
1. Diffuse centrilobular to panlobular/massive necrosis and hemorrhage with stromal collapse
2. Fatty change of periportal hepatocytes, mild portal fibrosis, and hyperplasia of small bile ducts
3. Moderate fibrosis around central veins; Kupffer cells in periportal and necrotic areas often filled with brown granular pigment (hemosiderin)

DIFFERENTIAL DIAGNOSIS:

Other causes of panlobular/massive hepatic necrosis in dogs: Aflatoxin, microcystin (blue-green algae), subcutaneous injection of intranasal Bordatella vaccine, Amanita spp. 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:

Drug-induced liver injury has been associated with many drugs in many species:
1. Dogs: Amiodarone (antiarrhythmic agent) or primidone, phenytoin, and phenobarbital (anticonvulsants), ketoconazole (antifungal)
  - Phenobarbital causes proliferation of the hepatocellular smooth endoplasmic reticulum, leading to fine diffuse granularity (“ground-glass” cytoplasm); actual hepatotoxicity may be idiosyncratic; may lead to chronic hepatitis with bridging portal fibrosis, biliary hyperplasia, nodular regeneration, and mild inflammatory cell infiltrates
2. Cattle and cats: Stanozolol (anabolic steroid)
3. Cats: Methimazole, glipizide, aluminum phthalocyanine tetrasulfonate (photodynamic therapy agent), megestrol acetate and griseofulvin
4. Various species: Thiacetarsemide, methoxyflurane, halothane, oil of pennyroyal, intravenous injection of manganese chloride
5. Avians:
  - Penguins: Voriconazole or itraconazole (antifungal) toxicity
  - Penguins and American white pelicans: Fenbendazole toxicity
Other idiosyncratic toxicities include chloramphenicol, phenylbutazone, trimethoprim-sulfamethoxazole, and cephalosporins that may result in myelosuppression (thrombocytopenia, leukocytopenia, anemia) in dogs and cats and grapes or raisins (Vitis vinifera fruit) leading to acute renal failure and uremia in dogs

REFERENCES:

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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.
Saran C, Brouwer KLR. Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity. Toxicol Pathol. 2023;51(7-8):405-413.
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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