Abstract

Acetylcholinesterase (ACE) inhibitors are commonly used and generally safe for management of hypertension and congestive cardiac failure, but have been reported to produce idiosyncratic hepatotoxicity in humans.^1,2,4-9 The adverse effect (ADE) mechanism is unknown, but toxicity has occurred with both acute and chronic treatment.³ Diagnosis is usually presumptive by presentation, elimination of other causes of hepatic disease, and clinical recovery following drug discontinuation.^3,10,11 The presentation in humans is typically cholestatic, but other more inflammatory presentations have been reported that essentially mirrored the presentation of a 15-year-old Western lowland gorilla (Gorilla gorilla gorilla).² Vigilance to idiosyncratic hepatotoxicity as an infrequent ADE is important, since early identification shortens reaction time to provide appropriate treatment.^3,10 Long-term tracking should include reporting ADEs to the Great Ape Heart Project database (https://greatapeheartproject.org/projects/forms).

The 15-year-old gorilla was diagnosed with mild biventricular hypertrophy at a routine preventive health assessment. Enalapril^a (2.5 mg PO, SID) was initiated due to a history of progressive cardiac disease in this individual’s sire. Other than cardiac disease, clinically normal status was confirmed by first author during a preventive health assessment after 2 years of treatment.

An acute presentation after 3.5 years of enalapril treatment included anorexia, apparent gastrointestinal discomfort, and malaise which progressed over 5 days. Two anesthetic events were performed for assessment and supportive hydration. Physical examination, imaging, and clinical pathology suggested an underlying and progressive hepatopathy. Sampling included blood collection for hemogram, serum chemistries (anesthesia 1 and 2, Table 1), and extensive infectious disease serology; multiple source cultures; ultrasound; computed tomography; and bone marrow biopsy. Attempts at percutaneous hepatic biopsy were unsuccessful.

Table 1. Relevant serum chemistry parameters for a 15-year-old male gorilla (Gorilla gorilla gorilla) with probable enalapril-induced hepatotoxicity. Upward trending of hepatocellular enzymes from this individual’s baseline were particularly relevant to the presumptive diagnosis.^10,11

*Historic values are presented from this individual’s most recent preventive health assessment after 2 years on enalapril treatment, and 1.5 years prior to the current presentation.

Probable diagnosis of enalapril-induced hepatotoxicity was made after the second examination, as no other cause was identified, and a review of medical literature supported the diagnosis.^10,11 Medical management included oral hepatoprotectant^b (Denosyl, 1700 mg PO, divided BID to QID), which was continued over 21 weeks based on personal experience managing hepatic insult with this nutraceutical in other species, and the expected course based on medical literature. The gorilla was considered clinically recovered by 3 weeks after enalapril discontinuation. A convalescent examination was conducted (anesthesia 3, Table 1), and a laparoscopic hepatic biopsy was collected to support the presumptive diagnosis; histopathology demonstrated neutrophilic hepatitis without detection of infectious agents. As the potential for this ADE may occur with any ACE inhibitor, future cardiac evaluation will determine if other cardiac pharmacologic agents are indicated.

Endnotes

a. Wockhardt USA Ltd., Parsippany, NJ, USA
b. Denosyl, s-adenosyl methionine, Nutramax Laboratories Veterinary Sciences, Inc., Lancaster, SC, USA

Acknowledgments

Curator Jill Moyse and Regenstein Center of African Apes staff provided intensive supportive care required during this animal’s presentation. Sarah Weinberg, ZooMed Support Intern of Lincoln Park Zoo, provided extensive support and time with literature acquisition and data organization. Histopathologic review of the hepatic biopsy was conducted by the University of Illinois Zoological Pathology Program. Support and endorsement of this case investigation was provided by the Gorilla Species Survival Plan (SSP) and its advisors including Pathology Advisor Linda J. Lowenstine, DVM, PhD, DACVP. Contribution of contextual data is appreciated and was received from current and historic SSP institutions including: ABQ BioPark Zoo (Albuquerque, NM); Audubon Zoo (New Orleans, LA); Birmingham Zoo (Birmingham, AL); Buffalo Zoo (Buffalo, NY); Busch Gardens Tampa Bay (Tampa, FL); Calgary Zoo (Calgary, AB); Cheyenne Mountain Zoo (Colorado Springs, CO); Chicago Zoological Society’s Brookfield Zoo (Brookfield, IL); Cleveland Metroparks Zoo (Cleveland, OH); Cincinnati Zoo and Botanical Garden (Cincinnati, OH); Columbus Zoo and Aquarium (Columbus, OH); Como Park Zoo and Conservatory (St. Paul, MN); Dallas Zoo (Dallas, TX); Denver Zoo (Denver, CO); Detroit Zoological Society (Royal Oak, MI); Disney’s Animal Kingdom (Orlando, FL); Erie Zoo (Erie, PA); Fort Worth Zoo (Fort Worth, TX); Gladys Porter Zoo (Brownsville, TX); Granby Zoo (Granby, QC); Houston Zoo (Houston, TX); Jacksonville Zoo (Jacksonville, FL); Kansas City Zoo (Kansas City, MO); Lincoln Park Zoo (Chicago, IL); Little Rock Zoo (Little Rock, AR); León Zoo (León, Mexico); Los Angeles Zoo and Botanical Garden (Los Angeles, CA); Louisville Zoo (Louisville, KY); Memphis Zoo (Memphis, TN); Milwaukee County Zoo (Milwaukee, WI); North Carolina Zoo (Asheboro, NC); Oklahoma City Zoo (Oklahoma City, OK); Omaha’s Henry Doorly Zoo and Aquarium (Omaha, NE); Philadelphia Zoo (Philadelphia, PA); Riverbanks Zoo and Garden (Columbia, SC); San Diego Zoo (San Diego, CA); San Diego Zoo Safari Park (Escondido, CA); San Francisco Zoo and Gardens (San Francisco, CA); Saint Louis Zoo (St. Louis, MO); Santa Barbara Zoo (Santa Barbara, CA); Sedgwick County Zoo (Wichita, KS); Smithsonian’s National Zoo and Conservation Biology Institute (Washington, D.C.); Toledo Zoo and Aquarium (Toledo, OH); Topeka Zoo and Conservation Center (Topeka, KS); Toronto Zoo (Toronto, ON); Utah’s Hogle Zoo (Salt Lake City, UT); Wildlife Conservation Society Bronx Zoo (Bronx, NY); Woodland Park Zoo (Seattle, WA); Zoo Atlanta (Atlanta, GA); Zoo Knoxville (Knoxville, TN); Zoo Miami (Miami, FL); Zoo New England Franklin Park Zoo (Boston, MA).

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