RAPID DEVELOPMENT OF IATROGENIC CUSHING SYNDROME IN A PATIENT ON RITONAVIR: THE ADVERSE METABOLIC CONSEQUENCE OF TOPICAL STEROID USE

Abstract

Objective:

Topical steroid use is common, but its association with Cushing syndrome is rare. We report the rapid development of iatrogenic Cushing syndrome in a patient on ritonavir who applied a moderate-potency topical steroid cream, triamcinolone, on his genital mucosa for treatment of phimosis.

Methods:

Clinical and diagnostic challenges associated with topical steroid use are presented and discussed.

Results:

A 41-year-old man with human immunodeficiency virus infection on stable antiretroviral therapy that included ritonavir, a cytochrome P450 3A4 inhibitor, presented with new onset diabetes and development of overt cushingoid features over a 4-week period. He reported no known history of steroid use. A midnight salivary cortisol using a quantitative enzyme immunoassay was obtained and reported at >15.0 μg/dL (normal, <0.112 μg/dL). However, free cortisol in a 24-hour urine collection was undetectable by high-performance liquid chromatography and morning plasma cortisol was also unexpectedly low at 1.1 μg/dL (normal, 4.5 to 23.0 μg/dL). Further investigation revealed that the patient had been applying a topical cream with triamcinolone acetonide (0.1%) on the glans penis for treatment of phimosis. The salivary enzyme immunoassay for cortisol appears to have detected the absorbed triamcinolone, a compound known to cross-react with cortisol in this assay.

Conclusion:

This case raises awareness on the severe metabolic consequence resulting from the seemingly benign use of a topical steroid medication when applied to the genital mucosa in the setting of stable therapy with ritonavir and illustrates the limitations of salivary cortisol enzyme immunoassays for the evaluation of Cushing syndrome in this setting.

INTRODUCTION

Antiretroviral therapy (ART) is the mainstay treatment for human immunodeficiency virus (HIV) infected patients. Ritonavir, a protease inhibitor, is often used as part of ART. The potent cytochrome P450 3A4 (CYP3A4) inhibition of ritonavir increases the therapeutic levels of other protease inhibitors (e.g., darunavir and atazanavir), allowing for lower or less frequent dosing and a decreased risk of antiretroviral medication resistance (1). However, the inhibition of CYP3A4 activity may also result in the development of drug-drug interactions with other medications metabolized by CYP3A4, including glucocorticoids. Iatrogenic Cushing syndrome in patients with HIV on ritonavir has been previously reported with the use of intraarticular, epidural, and inhaled glucocorticoid regimens (2–5). To our knowledge, there have been no reported cases of iatrogenic Cushing syndrome resulting from the use of midpotency topical steroids in adult patients with HIV on ART with ritonavir. We present the case of a 41-year-old man with HIV infection on ritonavir who presented with new onset diabetes and development of overt cushingoid features a month after starting topical triamcinolone acetonide (0.1%) for treatment of phimosis. His case highlights the need for increased awareness of this potential medication interaction with severe metabolic consequences involving a commonly used topical steroid.

CASE REPORT

A 41-year-old man with HIV infection on a ritonavir-boosted regimen was admitted to the hospital after being found to have a blood glucose level of 572 mg/dL (normal, 70 to 110 mg/dL) during a routine clinic follow-up. He had a history of well-controlled HIV infection (CD4 count 783 cells/μL, viral load <40 copies/mL), hypertension, chronic kidney disease (stage 3b A2), a previous cerebrovascular accident, and gout. He had no previous diagnosis of diabetes mellitus. His hemoglobin A1c was elevated at >14% (>130 mmol/mol) but had been normal at 5.5% (37 mmol/mol) a year earlier. The patient reported a month-long history of polyuria, polydipsia, blurry vision, and easy bruising. Examination was significant for new findings of facial plethora, right supraclavicular fat pad, buffalo hump, and violaceous abdominal striae, raising concern for underlying Cushing syndrome. The patient denied use of systemic, intranasal, inhaled, or intraarticular glucocorticoids. A midnight salivary cortisol using a quantitative enzyme immunoassay was obtained and reported to be high at >15.0 μg/dL (normal, 0.122 to 1.551 μg/dL). However, urine free cortisol in a 24-hour urine collection was undetectable (cortisol level of <4 μg/24 hours by high-performance liquid chromatography), and a morning plasma cortisol level was also unexpectedly low at 1.1 μg/dL (normal, 4.5 to 23.0 μg/dL). Further questioning revealed that the patient had been using topical triamcinolone acetonide (0.1%) cream for a diagnosis of phimosis for a month prior to admission. He had been applying a fingertip amount of the cream twice daily to the glans penis after retracting the foreskin, and had continued its use on his own during hospitalization until told to discontinue. It was unclear to him until then that the cream was a topical steroid. The patient underwent a 250 μg adrenocorticotropin stimulation test 4 days after discontinuation of the topical steroid, demonstrating adrenal insufficiency, with a baseline cortisol of 0.4 μg/dL and a peak level of 6.4 μg/dL at 60 minutes (expected peak level >20 μg/dL). The patient was instructed to discontinue topical steroid use. He was placed on hydrocortisone replacement therapy at a dose of 10 mg in the morning and 5 mg in the evening for 1 month. His antiretroviral regimen was changed to avoid drug interactions and a follow-up appointment was scheduled.

DISCUSSION

The seemingly unexpected coexistence of Cushing syndrome and adrenal insufficiency points to exogenous steroid use. Our patient had clinical evidence of cortisol excess, but his plasma cortisol and free urine cortisol levels were low or undetectable, indicating suppressed endogenous production. The inconsistent finding of an extremely elevated midnight cortisol level in saliva was the result of assay antibody cross-reactivity with triamcinolone (6), which is a known limitation of the immunoassay technique (7). There are several methods to measure salivary cortisol, including automated immunoassays and liquid chromatography/tandem mass spectrometry (LC/TMS) (7–10). Immunoassays for salivary cortisol detection are simple and inexpensive, but they have the potential to cross-react with synthetic steroids like triamcinolone (7–10). In our patient, triamcinolone suppressed endogenous cortisol production but was detected by the saliva enzyme immunoassay (6) and reported as cortisol. To differentiate synthetic steroids from cortisol, LC/TMS is needed (10).

Topical corticosteroids are widely used for the treatment of multiple skin diseases and have rarely been implicated in the development of Cushing syndrome (11). Cases have been mostly limited to the use of high potency preparations, such as clobetasol propionate, and in settings that maximize their absorption. The use of clobetasol propionate in pediatric patients, who have a high surface area to body weight ratio, and in adults with psoriasis and skin atrophy from years of topical steroid use, represent characteristic examples (12,13). However, our patient developed Cushing syndrome despite using triamcinolone acetonide, a midpotency topical steroid (14) after only 4 weeks of use. His symptoms developed while receiving ART with darunavir ethanolate, dolutegravir, and ritonavir. Ramanathan et al (15) measured plasma triamcinolone levels in a patient with HIV infection on chronic ART with ritonavir who developed Cushing syndrome after receiving 2 epidural triamcinolone injections. The authors found very high serum levels of triamcinolone and estimated that the half-life of the synthetic steroid was prolonged at least 170-fold due to ritonavir use. As in that case, our patient developed overt Cushing syndrome within a month of steroid initiation. It is possible that the application of triamcinolone to the genital mucosa in our patient (he would retract the foreskin and apply cream between the glans and internal surface of the foreskin), a body surface that is known to have a higher systemic steroid absorption (11,16), may have likely contributed to the enhanced triamcinolone absorption, resulting in the rapid development of Cushing syndrome and the inhibition of endogenous cortisol production. Management required a multidisciplinary decision with alterations to his ART regimen and hydrocortisone replacement therapy after discontinuation of the synthetic steroid, while awaiting recovery of the hypothalamic-pituitary-adrenal axis.

CONCLUSION

This case emphasizes the importance of alerting physicians and patients about the interaction of ritonavir with steroids. Topical application of corticosteroids may affect the adrenal axis and, when applied to the genital area in this setting, may result in the rapid development of Cushing syndrome. The report also highlights the limitations of salivary enzyme immunoassays in the interpretation of endogenous cortisol production, particularly when a history of exogenous steroid use is difficult to elicit.

Abbreviations

ART

antiretroviral therapy;

CYP3A4

cytochrome P450 3A4;

HIV

human immunodeficiency virus;

LC/TMS

liquid chromatography/tandem mass spectrametry