The Hope Center Blog

Case Study – Internal Medicine

Acute Hepatotoxicity

History

Lolly, a 9 year old female spayed Shih Tzu, was presented to the Hope Internal Medicine service for evaluation of inappetance, lethargy, and weight loss of about three days duration. About two weeks prior to presentation, Lolly ate a portion of a squirrel carcass found in the backyard; no other dietary indiscretion or exposure to toxins was known. On that evening, she developed retching and diarrhea. She was evaluated by her primary veterinarian the following day; blood work was performed which showed mildly elevated ALT (126U/L, range=12-118) and mild hyperglobulinemia (4.2 mg/dl, range = 1.6–3.6). A concurrent urinalysis showed isosthenuria, and fecal analysis was negative for parasites. She was treated symptomatically with metronidazole, and the diarrhea resolved.

About one week later, Lolly became inappetant, lethargic, polyuric, and polydipsic. On reevaluation, a biochemical profile showed continued hyperglobulinemia (4.8), markedly elevated ALT (out of range on the in-house analyzer), moderately elevated ALP (429U/L, range=23-212), mildly elevated GGT (16 U/L, range=0-7), and mild hyperbilirubinemia (1.4mg/dL, range=0-0.9). An abdominal ultrasound revealed splenomegaly with a 5 x 4 cm non-cavitated splenic mass. Based on these findings, she was referred to the Hope Center for further evaluation.

Presenting Findings and Initial Interventions

On presentation to our facility, a more complete biochemical profile revealed markedly progressive ALT elevation (2721) compared to six days earlier. In addition, a coagulation profile was performed; marked hypofibrinogenemia was noted (76mg/dl, range=90-255) with a normal PT and PTT.

The rapid progression and pattern of liver enzyme elevation is most consistent with an acute hepatic injury; hypofibrinogenemia suggests impairment of hepatic function. A fresh frozen plasma transfusion was administered, and exploratory laparotomy for splenectomy and liver biopsies was performed on the day of presentation to our facility. Initial therapy pending biopsy results included prednisone, Denamarin, metronidazole, vitamin E, and ursodiol.

Histopathological Assessment

Liver histopathology revealed hepatocellular necrosis predominantly in the region of the hepatic veins (zone 3) with microvesicular steatosis/lipidosis, with evidence of regeneration seen. These findings are hallmarks of toxins impacting mitochondrial function. Given the type and extent of hepatic injury, and the recent known ingestion of an animal carcass, intoxication by a bacterial putrefying toxin (such as Bacillus cereus) was suspected. The splenic histopathology revealed a benign lymphoid nodule with hemorrhage, likely secondary to underlying coagulopathy associated with impaired hepatic function.

Therapy and Progression

Based on the histopathological findings, prednisone was discontinued. Lolly remained hospitalized on intravenous fluids. Denamarin, metronidazole, vitamin E, and ursodiol were continued. She improved clinically and biochemically, and was discharged to the care of her owners 5 days after surgery (11 days after the initial insult); at that time, her ALT had improved (583).

However, two weeks later (25 days after the initial insult), Lolly again became inappetant and lethargic. Repeat biochemistry profile showed mild hyperbilirubinemia (1.7) and a massive increase in ALT (7029) and AST (1498) suggestive of ongoing hepatic injury. Repeat coagulation testing showed severe hypofibrinogenemia (<41mg/dl), consistent with hepatic synthetic failure. Fresh frozen plasma, followed by cryoprecipitate was administered to correct the hypofibrinogenemia. Cholestyramine was administered to promote elimination of persistent toxin, and levocarnitine was administered to improve metabolism of fatty acids in the face of microvesicular hepatic steatosis. Marked improvement in ALT and AST were seen within 4 days of initiating cholestyramine therapy; the hyperbilirubinemia and hypofibrinogenemia had resolved.

Graph4

ALT, AST and TBILI values during patient care

Outcome

70 days after the initial insult, only mild elevation of ALT (174) remained; all medications aside from ursodiol were discontinued by that time. On last recheck evaluation, 118 days after the initial insult, Lolly’s biochemical profile has completely normalized. Follow-up abdominal ultrasound revealed a small irregular liver with no evidence of portal hypertension or acquired portosystemic shunts detected.

Small_lolly-day-25-liver-2-2-15

Day 25

Small_lolly-day-117-liver-5-5-15

Day 117

Two ultrasonographic images of the left side of the liver, obtained 25 days post presumed toxin exposure (Left) and 117 days post toxin exposure (Right). On the left, the hepatic architecture and echogenicity are normal. On the right, there is rounding and subtle scalloping of the hepatic margins; the parenchyma is coarse and the architecture is distorted by indistinct nodules.

Discussion

This case demonstrates the importance of early histopathological evaluation in assessing acute hepatopathies. Based on the microscopic findings, we were able to determine the extent of hepatic necrosis, assess for evidence of hepatocellular regeneration, and find indications of the mechanism of action of the intoxicating principle.

In this case, patchy hepatocellular necrosis with evidence of a regenerative process indicated a fair prognosis for recovery. Presence of regeneration within the liver precludes the likelihood of a toxin affecting protein transcription. The distribution of the lesions and the presence of microvesicular steatosis suggested impaired mitochondrial function. These factors limited the field of possible heptotoxins, and allowed us to tailor specific therapeutic interventions.

Bacillus cereus is a ubiquitous spore-forming gram-positive bacteria; some strains has been implicated in foodborne illness in humans. This organism can produce a mitochondrial endotoxin, which can be detected in the feces following ingestion. We did not submit feces for endotoxin analysis, and therefore we cannot confirm our suspicions in this case. However, the history of ingestion of carcass immediately preceding onset of clinical signs is compelling.

Lolly2

Lolly feeling better at his recheck

The initial improvement in liver enzyme elevation, with subsequent recrudescence in a two week timeframe, suggested incomplete removal of the intoxicating principle. Recognizing this change prompted the use of cholestyramine. Cholestyramine is a bile acid sequestrant; it binds bile in the gastrointestinal tract, preventing enterohepatic recirculation. In humans, this drug is often used to limit bile acid diarrhea in certain forms of inflammatory bowel disease. The use of cholestyramine in the veterinary field has been limited; there are a few reports in the literature describing its use in dogs, mostly in a research setting. In this case, the dose of cholestyramine was extrapolated from human dosing protocols.

Lolly has completely recovered from acute fulminant hepatic failure with no residual evidence of dysfunction; her long term prognosis is excellent. This outcome could not have been achieved without the information gleaned from the liver biopsies and the histopathological assessment provided by highly skilled pathologists.

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BHurwitz

Brandi Hurwitz, DVM, DACVIM

Dr. Brandi Hurwitz grew up here in Montgomery County. She first entered the veterinary field in high school, working as a technician at a local general practice and volunteering at the Montgomery County Animal Shelter. Dr. Hurwitz attained her undergraduate degree in Anthropology at Tufts University in Medford, MA.

Dr. Hurwitz graduated from the Ross University School of Veterinary Medicine in 2003. After graduation, she completed a rotating internship at a specialty practice in Long Island, NY. Following her internship, Dr. Hurwitz pursued her residency training in small animal internal medicine at Cornell University in Ithaca, NY.

Dr. Hurwitz is board certified by the American College of Veterinary Internal Medicine. She has extensive experience in ultrasonography and endoscopy; she is also trained in minimally invasive endourologic techniques. Her special interests include hepatology, nephrology, immune-mediated diseases, and hematological diseases.

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