| 【Presentation of Case】
A 36-year-old man, previously healthy, was seen at our clinic because of progressive weight gain and abdominal distention for three months. Physical examination revealed blood pressure 158/86 mmHg, weight 70 kilograms and height 165 cm. A round face with acne, plethora over the cheeks, enlarged fat pads filling the supraclavicular fossae and buffalo hump were noted with truncal obesity and purplish abdominal striae. There was no ecchymosis or pedal edema. These findings suggested a typical cushingoid appearance. He was admitted to the hospital for clinical testing and analysis. Laboratory investigations revealed no leukocytosis and normal serum electrolytes. A fasting glucose of 114 mg/dL indicated impaired fasting glucose. Cortisol values at 8 a.m. was 38 μg/dL (normal range, 7 to 25 μg/dL), which was not suppressed by administration of 1-mg dexamethasone over night. Plasma adrenocorticotropic hormone (ACTH) level was markedly suppressed (less than 10 pg/ml). His 24-hour urinary cortisol excretion was 470 μg (normal range, 20 to 90 μg), which did not decrease in response to the administration of dexamethasone (0.5 mg every six hours for two consecutive days). Diurnal variation of plasma cortisol was not observed. Plasma renin activity, aldosterone concentration, T3, free T4, thyroid-stimulating hormone (TSH), and urinary catecholamine levels were all within normal limits. Under the diagnosis of ACTH-independent Cushing syndrome, a high-dose dexamethasone test was performed, in which 2-mg dexamethasone was administered every six hours for two consecutive days; no suppression of morning plasma cortisol was observed. Further computed tomography of the abdomen revealed a left adrenal tumor measuring 2.5 cm in diameter (Figure1). Laparoscopic resection of the adrenal tumor was performed. After surgery, he was treated with replacement doses of hydrocortisone and fludrocortisone. The clinical manifestations of Cushing's syndrome disappeared gradually, and his fasting plasma glucose and blood pressure returned to normal range 2 months later.
【Laboratory data】
1. Results of baseline biochemistry
Lab test |
BUN |
Cr |
Na |
K |
ALT |
T-bil |
Reference value |
<24
mg/dL |
<1.3
mg/dL |
135-145
mmol/L |
3.5-5.3
mmol/L |
<37
U/L |
0.2-1.0
mg/dL |
value |
22.5 |
0.8 |
143 |
3. 6 |
28 |
0.3 |
2. Results of the baseline endocrine tests
Lab test
|
24 hr urine VMA |
PRA (ng/ml/hr) |
PAC
(ng/dL) |
TSH |
free T4 |
Reference value |
1-7μg/24h |
1-5 ng/ml/hr |
5-30ng/dL |
0.4- 4
μIU/mL |
0.60-1.75
ng/dL |
value |
4.3 |
2.6 |
19.2 |
0.82 |
1.48 |
ACTH
( am8) |
Plasma cortisol
( am8 ) |
Plasma cortisol
(pm 4) |
24 hr Urine
Cortisol |
10-65
pg/mL |
5-25
μg/dL |
2.5-12.5
μg/dL |
20-90
μg |
4.2 |
38 |
36.2 |
470 |
***VMA= vanillylmandelic acid
***PRA= plasma rennin activity
***PAC= plasma aldosterone concentration
***TSH= Thyroid-stimulating hormone
***free T4= free thyroxine
***ACTH= adrenocorticotropin
3. Low-dose dexamethasone suppression test (DST)
Lab test
|
Plasma cortisol after administration of 1-mg dexamethasone overnight |
24 hr urine cortisol after administration of low dose dexamethasone for 2 days |
Reference value |
<2μg/dL |
<10 μg |
value |
24.7 |
112 |
4. Differential diagnosis by high-dose DST
Plasma cortisol
before DST |
Plasma cortisol
After DST |
36.8 |
33.2 |
5.Figure legend of figure 1: Contrast-enhanced CT demonstrates the left adrenal adenoma, measuring 2.5 cm in size.
【病例解析】
庫欣氏症候群( Cushing's syndrome，CS )的症狀表徵起源於腎上腺皮質醇過量分泌，病因包括內源性及外源性。內源性最常因腦下垂體腺瘤（庫欣氏病，Cushing's disease，CD）過度分泌皮促素（ACTH）所致。其他還包括腎上腺腺瘤(adenoma)、腺癌(carcinoma)分泌皮質醇(cortisol)，及異位性腫瘤(如肺癌或類癌(carcinoid)等)分泌皮促素（ACTH）或皮釋素（CRH）。至於外源性庫欣氏症候群則多是病患服用類固醇製劑不當造成。其外觀常見中心型肥胖、水牛肩、鎖骨上脂肪墊、月亮臉、皮膚變薄、容易瘀血、多毛、痤瘡等，甚至會造成月經失調(若為女性)、高血壓、糖尿病、骨質疏鬆、或肌病變等。一般在門診檢查若因病人的主訴及外觀而懷疑的話，篩檢可測量24小時尿液游離皮質醇（urine free cortisol，UFC）及安排低劑量dexamethasone抑制試驗(dexamethasone suppression test, DST)(於晚上11點服用1 mg dexamethasone，然後測隔天早上8點血漿皮質醇濃度)，若UFC超過正常上限4倍，或隔日測的血中cortisol濃度無法被抑制到<2μg/dL，進一步可安排標準的低劑量皮醇抑制試驗（standard 2-day low dose DST）(連續二天每六小時給予dexamethasone 0.5 mg，在給藥第二天收集24小時尿液(UFC)或在服用第一次劑量後48小時抽血，若UFC≧10μg，或血中cortisol濃度≧2μg/dL則確診。另外，cortisol分泌的早晚節律性（diurnal rhythm）也會有消失的現象。下一步則應區分病因是腦下垂體、腎上腺或異位性腫瘤。最簡單的方法為測早上8點血中的基礎ACTH及cortisol值。若ACTH＜5 pg/mL，表示其為腎上腺來源，若ACTH＞20 pg/ml，表示為ACTH依賴性CS(腦下垂體或異位性腫瘤)，而若ACTH介於5-20 pg/ml之間，以ACTH依賴性CS (即腦下垂體或異位性腫瘤)占大部分。但值得注意的是ACTH在檢體運送時要用事先冰涷的紫頭 EDTA管，置入冰浴後盡快離心，不然會有溶血、裂解(degradation)的可能，便會影響檢驗的結果。而若懷疑是ACTH依賴性CS，則下一步應追查這些異常分泌的ACTH來源。可用高劑量DST(連續二天每六小時給予dexamethasone 2 mg，在服用第一次劑量前及後48小時抽血)，若血中cortisol濃度可被抑制到50%以上，則由腦下垂體腺瘤引起的可能機會較大(腎上腺及異位性腫瘤多半不受抑制)。然而，有10%的異位性腫瘤(如支氣管類癌)可被抑制、少數大的腦垂體腫瘤又不被抑制，便須用腦垂體磁振攝影作輔助診斷。但是，即使作磁振攝影 (magnetic resonance imaging; MRI)，對於太小的腦垂體腫瘤也不易偵測，故當影像判斷與實驗室結果不符時便須作inferior petrosal sinus sampling來作鑑別診斷。靜脈注射皮釋素（CRH）15分鐘後，於兩側inferior petrosal sinus和週邊靜脈抽血測量cortisol，若注射前相對比值在2倍以上或注射後相對比值在三倍以上則可確定為腦下垂體腫瘤所造成。至於腎上腺腫瘤的定位則可以利用腎上腺的CT或MRI掃描來定位( CT的空間解析度較佳，MRI偵測癌症力較佳)；異位性ACTH腫瘤的定位，則可以CT或MRI掃描胸腔、腹部及骨盆腔來定位或核醫octreotide scan來加以定位。
【參考文獻】
- Nieman LK, et al.The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab. 2008 May;93(5):1526-40
- Pivonello R, et al. Cushing's Syndrome. Endocrinol Metab Clin North Am. 2008 Mar;37(1):135-49
- Makras P, et al. The diagnosis and differential diagnosis of endogenous Cushing's syndrome. Hormones. 2006 Oct-Dec;5(4):231-50.
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Case Discussion 
繼續教育考題