Podcasts

Join Now

Liver toxicity secondary to azathioprine | VETgirl Veterinary Continuing Education Podcasts

Need Help?

In today’s VETgirl online veterinary continuing education podcast, we review liver toxicity secondary to azathioprine administration in dogs. Azathioprine is an immunosuppressive medication that has been gaining popularity in the veterinary community. It is a purine analog that can take up to 6 weeks to take effect (Plumb), and it is often used as a treatment for immune-mediated hemolytic anemia (IMHA), immune-mediated thrombocytopenia (ITP), immune-mediated polyarthritis, inflammatory bowel disease, and other immune-mediated conditions. Some practitioners express discomfort using azathioprine due to its potential for adverse effects, such as hepatotoxicity and bone marrow toxicity. But how worried should we be?

Wallisch et al out of the University of Wisconsin wanted to assess in the study entitled “Incidence, timing and risk factors of azathioprine hepatotoxicosis in dogs.” The authors wanted to characterize the observed incidence, timing, risk factors, and outcomes for hepatotoxicosis in dogs treated with azathioprine, as well as to evaluate the relationship between hepatotoxicosis and either neutropenia or thrombocytopenia. In this retrospective study, the investigators evaluated medical records from dogs that had been treated with azathioprine and that had follow-up data for at least 2 months after starting therapy. Data collected for each patient included signalment and weight, as well as indication for azathioprine therapy, baseline and follow-up CBC and liver enzymes, steroid use, clinical adverse effects, and azathioprine dosing information. Given that steroid usage could complicate interpretation of liver enzyme changes, the authors only included dogs that had a stable or lowered steroid dose during the observation period. Any dogs with new or escalated steroid usage were excluded from the portion of the study evaluating hepatotoxicosis.

So what do the authors mean by hepatotoxicosis? In this study, they defined hepatotoxicosis as a dog with previously normal liver enzymes developing a new increase in ALT levels over 2x the upper limit of the reference range, and this occurring in the absence of the addition of other new medications. Any patient with inadequate medical records was excluded from the study. A total of 52 dogs met the inclusion criteria, with 34 dogs also meeting the criteria for liver enzyme evaluation. The most common indications for azathioprine use were inflammatory disease of the central nervous system, IMHA, and ITP, and the median starting dose prescribed of azathioprine was 1.9 mg/kg/day.

So what did the investigators find? Well, they found that 15% of dogs developed hepatotoxicity within the first 2 months of treatment, but the median time to development of hepatotoxicity was just 14 days. The liver enzyme changes were a mixed hepatocellular and cholestatic pattern in all dogs. Interestingly in people, azathioprine hepatotoxicity can present as solely hepatocellular, solely cholestatic, or mixed (Bastida, Wieser). Again, remember that the authors did not include dogs for evaluation of hepatotoxicity if they were on newly started or an escalated dose of steroids within 3 weeks of assessment. Of the 5 dogs with hepatotoxicity, only 1 showed clinical signs, which included anorexia and diarrhea. However it is important to note this dog was being treated for a protein-losing enteropathy. Fortunately none of the 5 dogs became encephalopathic, jaundiced, or developed ascites. Studies in humans have also shown that the majority of those with azathioprine hepatotoxicity are asymptomatic (Bastida, Wieser).

You may be wondering if there were any differences between those dogs that did or did not develop toxicity. The authors did NOT find a difference in the age of the dogs or in the dosage of azathioprine prescribed between groups. However, one interesting finding was that 3 out of the 5 dogs with hepatotoxicity were German shepherds, compared to zero of those dogs without hepatotoxicity. Does this mean that we should not use azathioprine in German shepherd dogs? Does this breed metabolize the drug differently or have an increased susceptibility to toxicity? Unfortunately the authors could not draw such conclusions based on this study alone, but it is certainly an area that warrants additional investigation. The azathioprine dosage was reduced in 3 dogs with hepatotoxicity, and the drug was discontinued completely in the other 2 dogs. Of those that had a recheck of liver enzymes after making these changes, the values were reduced or stable.

So what about the bone marrow? There were 48 dogs that had a CBC performed both before and after starting therapy. Of these, 8% developed either a neutropenia, thrombocytopenia, or both. Unfortunately since so many dogs in this population had other disease processes that could cause anemia, the authors elected to not attempt to evaluate anemia secondary to azathioprine. That said, of those dogs with other cytopenias, there were none that were also anemic. The median time at which bone marrow toxicity was observed was 53 days. If your recall, the median onset of hepatotoxicity was only 14 days. In other words, when using azathioprine, monitoring of liver values may be most important over the first few weeks, but do not forget to continue monitoring CBCs over the first few months! In this population, none of the patients that had hepatotoxicity also had bone marrow suppression. This is consistent with studies in people that suggest different metabolites are responsible for the 2 types of toxicities (Al Hadithy), which could be similar in dogs. How interesting! As always though, we would need additional studies to determine if this is also true in dogs. Also just a friendly reminder that azathioprine should not be used in cats, as differences in their metabolism cause an increased susceptibility to bone marrow toxicity (Plumb).

An important limitation of this study is that it was retrospective, and therefore the laboratory data was not collected at standardized time points. That makes interpreting the true moment in time for the onset of hepatotoxicity or bone marrow toxicity challenging. Other limitations that the authors discussed include the small number of affected dogs, the lack of complete diagnostic work-ups on all dogs with elevated liver enzymes to rule out causes aside from drug toxicity, and the concurrent use of steroid therapy in many patients.

So, what do we take away from this VETgirl podcast? If you are using azathioprine in your practice, monitoring liver enzymes during the first 1-4 weeks of treatment and monitoring CBCs during the first 2-4 months should be considered a minimum. Liver toxicity appears to occur earlier than bone marrow toxicity, and do not be fooled since many dogs are asymptomatic! There was an interesting over-representation of German shepherd dogs that developed hepatotoxicity in this population, so hopefully we will see some additional studies investigating this finding. No dogs developed both liver and bone marrow toxicity, so perhaps these involve different risk factors. In short, azathioprine is considered an effective treatment for dogs with a variety of conditions, but remember that it is not without side effects, so careful monitoring is essential!

References:
1. Wallisch K, Trepanier LA. Incidence, timing, and risk factors of azathioprine hepatotoxicosis in dogs. J Vet Intern Med 2015;29:513-518.
2. Plumb D. Veterinary Drug Handbook. 6th ed. Ames, IA: Iowa State University Press, 2008.
3. Bastida G, Nos P, Aguas M, et al. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005;22:775-782.
4. Wieser V, Gerner R, Moschen AR, et al. Liver complications in inflammatory bowel diseases. Dig Dis 2013;31:233-238.
5. Al Hadithy AF, de Boer NK, Derijks LJ, et al. Thiopurines in inflammatory bowel disease: Pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dib Liver Dis 2005;37:282-297.

Abbreviations:
ALT – Alanine aminotransferases
CBC – Complete blood count
IMHA – Immune-mediated hemolytic anemia
ITP – Immune-mediated thrombocytopenia

Only VETgirl members can leave comments. Sign In or Join VETgirl now!