Retinoic acid as a therapy for Cushing’s disease in dogs: evaluation of liver enzymes during treatment77AST (Fig 1c) showed a significant increase (P
78L. Ortemberg, M. Loiza, B. Martiarena, M. F. C. Blatter, M. C. Ghersevich, V. Castilloobserved before with o,p’-DDD and trilostane (26,27). Thus, when the secretion of both hormones iscontrolled, this event will be reflected in the correlationsobserved with regards to the analyzed hepaticenzymes. The cortisol-induced effect on ALT is diminishedwith treatment, which is demonstrated inits significant decrease in the RG. With regard to AP,individual decrease is observed, with values remainingabove 1,500 UI/L only in two dogs (see Figure 1).Considering the correlation between ACTH and AP,the cortisol action on the isoenzyme (23) is probablyless important. This would explain the absence ofcorrelation between AP and C/C. However, it is notknown at the present if AP would decrease afterlonger time period than the one reported in thepresent study.The lack of correlation between AST, ACTH andC/C would indicate that this enzyme is only marginallyinfluenced by cortisol and that the isotretinoin9-cis do not produce, at the indicated dose and time,hepatic damage. Therefore, when PDH is controlledas described in the RG group, the metabolic pathwayswhere both enzymes interact are normalizedand the activity of ALT and AST decrease in RG.It is evident in the second group that the lack orloss of correlation between studied variables is dueto the effects of ketoconazole. On one hand, as itdoes not completely normalize the synthesis of glucocorticoids,its inducing effect over these enzymespersists, adding to the choleostasis caused byhepatomegaly. On the other hand, this effects couldbe due to initial stages of liver damage after 180days of treatment. The significant increase of ALTand AST in this group could be due to lesser controlof the hypercortisolism, however, it could be also bynecroinflammatory event with the consequent passageof the enzymes to the portal circulation (6, 24).The behaviour of the studied enzymes and theirrelationship with the ACTH and C/C in the RG indicatesthat the isotretinoin 9-cis in the prescribeddoses does not produce hepatocyte damage duringthe treatment period (180 days), being safe in PDHtherapy. The elevated serum concentration of ALTand AP at the diagnosis time is not a contraindicationfor use of this drug. By contrast, Ketoconazolecould imply a certain hepatoxicity risk accordingto the behaviour of ALT and AST, and therefore itsuse should be interrupted in case of a sustained increasein the activity of these two enzymes. Therefore,we conclude that AST enzyme must be closelymonitored during PDH therapy as this enzyme couldbe a marker for hepatic damage in these patients.AcknowledgementsThis study was supported by grant from Scienceand Technique of University of Buenos Aires (UBA-CyT, ref. V045). We thank Dr. Stalla of Max PlanckInstitute, Germany, to measure plasma ACTH.References1. Orth DN. Cushing’s syndrome. N Engl J Med1995; 332: 791-803.2. Castillo VA, Lalia JC, Casal J et al. Aminoglutetimide:alternativa terapéutica en caninos con Enfermedadde Cushing (hipófiso-dependiente). Avan Med Vet 1996;11:93-6.3. Feldman EC, Bruyette DS, Nelson RW. Plasma cortisolresponse to ketoconazoles administration in dogswith hyperadrenocorticism. Am J Vet Med Assoc 1990;19: 71-8.4. Komanicky P, Spark RF, Melby JC. Treatment ofCushing‘s syndrome with trilostane (WIN 24,540), an inhibitorof adrenal steroid biosynthesis. J Clin EndocrinolMetab 1978; 47:1042-51.5. Sonino N, Boscaro M. The medical management ofCushing’s syndrome. Ann NY Acad Sci 2002; 970: 119-33.6. Rodriguez RJ, Buckholz CJ. Hepatotoxicity of ketoconazolein Sprangue-Dawey rats. Glutathione depletion,flavin-containing monooxygenases-mediated bioactivationand hepatic covalent binding. Xenobiotica 2003; 33:429-41.7. Kang H. Retinoic acid and its receptors repress theexpression and transactivation functions of Nurr77: apossible mechanism for the inhibition of apoptosis byretinoic acid. Exp Cell Res 2000; 256: 545-54.8. Merino R, Hurlé JM. The molecular basis of retinoidaction in tumors. Trends Mol Med 2003; 12: 508-11.9. Giacomini DP, Páez-Pereda M, Theodoropoulou Met al. Bone morphogenetic protein-4 inhibits corticotrophtumor cells: involvement in the retinoic acid inhibitory action.Endocrinology 2006; 147: 247-56.10. Páez-Pareda M, Kovalovsky D, Hopfner U et al.Retinoic acid prevents experimental Cushing syndrome.J Clin Invest 2001; 108:1123-31.11. Castillo VA, Giacomini DP, Páez-Pered M et al.Retinoic acid as a novel medical therapy for Cushing’sdisease in dogs. Endocrinology 2006, 147: 4438- 44.12. Ling GV, Stabenfeldt GH, Comer KM. Canine hyperadrenocorticism:pretreatment clinical and laboratoryevaluation of 117 cases. J Am Vet Med Assoc 1979; 174:1211-6.13. Beale EG, Hamme RE, Antoine B, Forest C. Disregulatedglyceroneogenesis: PCK1as a candidate diabetesand obesity gene. Trends Endocrinol Metab 2004;15:129-35.
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