Should we avoid using ketoconazole in patients with severe Cushing’s syndrome and increased levels of liver enzymes?

in European Journal of Endocrinology
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To the Editor,

We read with interest the paper of Young et al. in which the authors recommend avoiding ketoconazole in the treatment of Cushing’s syndrome when patients display increased liver enzymes (>2-fold the upper limit of normal (ULN)) (1).

Severe hypercortisolism is a life-threatening condition and is considered as an endocrine emergency requiring a rapid and dramatic decrease in cortisol levels (2). Ketoconazole and metyrapone, in monotherapy or in association, have been recommended in this instance since they inhibit cortisol synthesis within hours and can normalize cortisol levels within days (2,

 

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    Evolution of mean levels of liver enzymes and UFC during the first month of ketoconazole administration in nine patients with severe Cushing’s syndrome. ALT, alanine aminotransferase; AST, aspartate aminotransferase; UFC, urinary free cortisol; ULN, upper limit of normal.

References

1

YoungJBertheratJVantyghemMCChabreOSenoussiSChadarevianRCastinettiF & Compassionalte use Programme. Hepatic safety of ketoconazole in Cushing’s syndrome: results of a Compassionate Use Programme in France. European Journal of Endocrinology 2018 178 447458. (https://doi.org/10.1530/EJE-17-0886)

2

NiemanLKBillerBMKFindlingJWMuradMHNewell-PriceJSavageMOTabarinA & Endocrine Society. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2015 100 28072831. (https://doi.org/10.1210/jc.2015-1818)

3

CorcuffJ-BYoungJMasquefa-GiraudPChansonPBaudinETabarinA. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. European Journal of Endocrinology 2015 172 473481. (https://doi.org/10.1530/EJE-14-0913)

4

KamenickýPDroumaguetCSalenaveSBlanchardAJublancCGautierJ-FBrailly-TabardSLeboulleuxSSchlumbergerMBaudinE Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism 2011 96 27962804. (https://doi.org/10.1210/jc.2011-0536)

5

HazlehurstJMTomlinsonJW. Mechanisms in endocrinology: non-alcoholic fatty liver disease in common endocrine disorders. European Journal of Endocrinology 2013 169 R27R37. (https://doi.org/10.1530/EJE-13-0296)

6

CastinettiFGuignatLGiraudPMullerMKamenickyPDruiDCaronPLucaFDonadilleBVantyghemMC Ketoconazole in Cushing’s disease: is it worth a try? Journal of Clinical Endocrinology and Metabolism 2014 99 16231630. (https://doi.org/10.1210/jc.2013-3628)

7

VerhelstJATrainerPJHowlettTAPerryLReesLHGrossmanABWassJAHSesserGM. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clinical Endocrinology 1991 35 169178. (https://doi.org/10.1111/j.1365-2265.1991.tb03517.x)

8

PivonelloRDe LeoMCozzolinoAColaoA. The treatment of Cushing’s disease. Endocrine Reviews 2015 36 385486. (https://doi.org/10.1210/er.2013-1048)

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