Yap L B, Turner H E, Adams C B T, Wass J A H
Department of Endocrinology, Radcliffe Infirmary, Oxford, UK.
Clin Endocrinol (Oxf). 2002 Jan;56(1):25-31. doi: 10.1046/j.0300-0664.2001.01444.x.
An undetectable postoperative serum cortisol has been regarded as a definition of cure in Cushing's disease. However, we noted disease recurrence amongst patients with Cushing's disease despite undetectable postoperative cortisol levels, and this led us to audit our data. We have also previously assessed surgical outcome for acromegaly and microprolactinoma for a single surgeon. The aims of this study were two-fold: (i) to investigate the treatment and surgical outcome of patients with Cushing's disease. In particular, we wished to compare the data with outcome for other pituitary tumours in our centre; and (ii) to determine whether undetectable cortisol following surgery is predictive of long-term cure for Cushing's disease.
We performed a retrospective audit of 97 patients; mean age 39.1 (range: 14-82) years, 78/97 (80.4%) female, mean follow-up 92 months (range: 6 months to 29 years), with Cushing's disease seen in our unit between 1969 and 1998. We documented diagnostic investigation, immediate surgical outcome and disease recurrence in these patients.
All patients had elevated urinary free cortisol (mean 1270.6 nmol/l, range: 327-3245 nmol/l). In total, 95.5% of patients did not suppress with low-dose dexamethasone suppression testing. Hypokalaemia (K < 3.2 mmol/l) was present in 15.6% of patients; 17.5% of patients did not show cortisol suppression with high-dose dexamethasone and 15.8% of patients did not show an ACTH rise of > 50% following corticotrophic releasing hormone (CRH) administration. There was no significant (> 3) gradient in ACTH or cortisol following CRH during inferior petrosal sinus sampling in 27.3% of patients who had the test. A pituitary tumour was demonstrated on imaging in 55.8% of patients; 10.3% were macroadenomas. Mortality rate following trans-sphenoidal surgery was 1%. Following surgery, the immediate postoperative remission rate (undetectable postoperative cortisol) was 68.5%. However, 11.5% of these patients developed disease recurrence during a mean follow-up period of 36.3 months. Considering microadenomas, Cushing's disease patients had an immediate postoperative remission rate of 63.2% which is significantly lower (P < 0.05) compared to a remission rate of 91.1% in acromegaly. Additionally, new postoperative gonadotrophin deficiency (13.9%) and TSH deficiency (25.8%) was higher in patients with Cushing's disease compared to patients with acromegaly or microprolactinoma. Immediate postoperative remission rates improved from 50% in the first decade of a surgeon's career to consistently above 60% in the second and third decades, demonstrating a trend which may be attributed to surgical experience.
(i) Despite strict criteria for immediate postoperative remission and recurrence, undetectable postoperative cortisol is not always predictive of long-term remission. (ii) Despite an aggressive surgical approach, immediate postoperative remission rates for Cushing's disease are lower compared to other microadenomas. The development of new pituitary hormonal deficiency following surgery is also commoner than that seen amongst other microadenomas. These data have important implications for the follow-up of patients with Cushing's disease.
术后血清皮质醇检测不到一直被视为库欣病治愈的定义。然而，我们注意到尽管术后皮质醇水平检测不到，但库欣病患者仍有疾病复发的情况，这促使我们审核我们的数据。我们之前还评估了同一外科医生治疗肢端肥大症和微泌乳素瘤的手术结果。本研究的目的有两个：（i）调查库欣病患者的治疗和手术结果。特别是，我们希望将这些数据与我们中心其他垂体肿瘤的结果进行比较；（ii）确定术后皮质醇检测不到是否能预测库欣病的长期治愈。
我们对97例患者进行了回顾性审核；平均年龄39.1岁（范围：14 - 82岁），78/97（80.4%）为女性，平均随访92个月（范围：6个月至29年），这些患者于1969年至1998年在我们科室被诊断为库欣病。我们记录了这些患者的诊断检查、即刻手术结果和疾病复发情况。
所有患者尿游离皮质醇均升高（平均1270.6 nmol/l，范围：327 - 3245 nmol/l）。总体而言，95.5%的患者低剂量地塞米松抑制试验不能被抑制。15.6%的患者存在低钾血症（血钾<3.2 mmol/l）；17.5%的患者高剂量地塞米松不能抑制皮质醇，15.8%的患者注射促肾上腺皮质激素释放激素（CRH）后促肾上腺皮质激素（ACTH）升高未超过50%。在接受该检查的患者中，27.3%的患者在岩下窦采样时CRH刺激后ACTH或皮质醇无显著（>3）梯度变化。55.8%的患者影像学检查发现垂体肿瘤；10.3%为大腺瘤。经蝶窦手术的死亡率为1%。术后即刻缓解率（术后皮质醇检测不到）为68.5%。然而，这些患者中有11.5%在平均36.3个月的随访期内出现疾病复发。对于微腺瘤，库欣病患者术后即刻缓解率为63.2%，与肢端肥大症91.1%的缓解率相比显著更低（P<0.05）。此外，与肢端肥大症或微泌乳素瘤患者相比，库欣病患者术后新发促性腺激素缺乏（13.9%）和促甲状腺激素缺乏（25.8%）的发生率更高。外科医生职业生涯第一个十年的术后即刻缓解率为50%，到第二个和第三个十年持续高于60%，显示出一种可能归因于手术经验的趋势。
（i）尽管术后即刻缓解和复发有严格标准，但术后皮质醇检测不到并不总是能预测长期缓解。（ii）尽管采取了积极的手术方法，但库欣病术后即刻缓解率低于其他微腺瘤。术后新发垂体激素缺乏的发生率也比其他微腺瘤更常见。这些数据对库欣病患者的随访具有重要意义。
