Elenius Henrik, McGlotten Raven, Nieman Lynnette K
Diabetes and Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1109, USA.
J Endocr Soc. 2025 Jul 18;9(9):bvaf118. doi: 10.1210/jendso/bvaf118. eCollection 2025 Sep.
Ketoconazole (KTZ) and metyrapone (MET) are used to normalize cortisol in Cushing syndrome (CS). Available recommendations can delay time to control.
This work aimed to identify predictors of treatment success and hepatotoxicity during rapid titration of KTZ and MET and to assess differences in blood pressure or potassium.
A retrospective evaluation was conducted at a tertiary referral center. Participants included 52 patients receiving treatment for adrenocorticotropin (ACTH)-dependent CS from 2004 to 2023. Interventions included KTZ or MET. The main outcome measures included the number of patients achieving target morning serum cortisol (AM F), defined as 12 mcg/dL or less (≤331 nmol/L), or increased liver function tests (LFTs) suggesting drug-induced liver injury (alanine/aspartate transaminase and alkaline phosphatase ≥3-fold upper limit of normal [≥3ULN], total bilirubin [Bili] ≥2ULN).
KTZ achieved target AM F in 39% (95% CI 24%-56%) of patients, compared to 74% (95% CI 49%-90%) on MET. Lower baseline AM F predicted success only with MET. Among KTZ responders, maximal effect occurred by 2 days after a dose increase. LFTs worsened with KTZ and improved with MET. A similar proportion of patients had an LFT reach or exceed 3ULN with KTZ (22%; 95% CI 10%-39%) and MET (25%; 95% CI 4%-64%). Higher doses of KTZ, but not MET, predicted this. Bili reached or exceeded 2ULN in 3% (95% CI 0%-15%) of patients receiving KTZ and none receiving MET. Blood pressure and hypokalemia improved with KTZ but did not change with MET.
Hypercortisolism can likely be controlled faster with rapid titration of KTZ or MET. LFT abnormalities increased with KTZ but were common with MET treatment, likely reflecting underlying liver pathology in CS.
酮康唑（KTZ）和甲吡酮（MET）用于使库欣综合征（CS）患者的皮质醇水平恢复正常。现有建议可能会延迟控制时间。
本研究旨在确定快速滴定KTZ和MET期间治疗成功和肝毒性的预测因素，并评估血压或钾的差异。
在一家三级转诊中心进行回顾性评估。参与者包括2004年至2023年期间接受促肾上腺皮质激素（ACTH）依赖性CS治疗的52例患者。干预措施包括KTZ或MET。主要结局指标包括达到目标晨间血清皮质醇（AM F）的患者数量，目标晨间血清皮质醇定义为12 μg/dL或更低（≤331 nmol/L），或肝功能检查（LFT）升高提示药物性肝损伤（丙氨酸/天冬氨酸转氨酶和碱性磷酸酶≥正常上限的3倍[≥3ULN]，总胆红素[Bili]≥2ULN）。
KTZ使39%（95%CI 24%-56%）的患者达到目标AM F，而MET为74%（95%CI 49%-90%）。仅在MET治疗中，较低的基线AM F可预测治疗成功。在KTZ治疗有反应的患者中，剂量增加后2天达到最大效果。LFTs在KTZ治疗时恶化，在MET治疗时改善。接受KTZ治疗（22%；95%CI 10%-39%）和MET治疗（25%；95%CI 4%-64%）的患者中，LFT达到或超过3ULN的比例相似。较高剂量的KTZ可预测此情况，但MET不能。接受KTZ治疗的患者中，3%（95%CI 0%-15%）的患者Bili达到或超过2ULN，接受MET治疗的患者中无此情况。血压和低钾血症在KTZ治疗时改善，但在MET治疗时无变化。
快速滴定KTZ或MET可能能更快地控制高皮质醇血症。LFT异常在KTZ治疗时增加，但在MET治疗中也很常见，这可能反映了CS患者潜在的肝脏病变。
