< Presentation of Case
>
This 36-year-old woman was admitted to the general ward because of a weight gain of 25 kg for about two years. She had been in her usual state of health until a couple weeks before this admission, when her brother started to notice that her face got round and puffy and she seemed to gain some weight in these days. Her skin became thinner and was easily bruised, and acnes and ecchymoses developed. Multiple purple stretch marks were noted on the abdomen when she took a shower. The patient did not smoke or drink alcohol. She denied any systemic disease, pregnancy, overeating, or taking any medication. She had regular menstrual cycles and normal menstrual blood loss. There was no recent travel and the family history was unremarkable.
On physical examination, the patient's height was 155 cm and her weight 85 kg, with a body-mass index (BMI) (weight in kilogram divided by square of height in meters) of 35.38 kg/m2. Her vital signs were normal. The head and neck examination showed a moon face with oily facial skin and acnes and a buffalo hump. The thyroid was normal in size, with no palpable nodules. She had central obesity with purple striae on the abdomen. Several ecchymoses were noted on the lower extremities. There was no enlargement of the hands or feet, and the remainder of the physical examination was normal.
Chest X-ray showed no cardiomegaly and no definite lung lesions. Electrocardiogaphy (ECG) revealed normal sinus rhythm. Routine laboratory tests, urinalysis, and tests of blood hormonal level were performed.
< Laboratory data >
CBC/DC: (date performed: January 15th, 2010)
WBC /μL |
7200 |
Blast % |
0 |
Mono % |
3 |
RBC M/μL |
4.7 |
Promyl % |
0 |
Lym % |
35 |
Hb g/dL |
14.5 |
Myelo % |
0 |
Aty. Lym % |
0 |
Hct % |
45.3 |
Meta % |
0 |
Plasma cell % |
0 |
MCV fl |
95.2 |
Band % |
0 |
|
|
PLT. /μL |
350,000 |
Seg % |
60 |
|
|
|
|
Eos % |
1 |
|
|
|
|
Baso % |
1 |
|
|
Biochemistry: (date performed: January 15th, 2010)
|
BUN mg/dL |
11.0 |
T-Bil mg/dL |
0.58 |
Creatinine mg/dL |
0.8 |
ALT U/L |
18 |
Na mmol/L |
139 |
UA mg/dL |
4.6 |
K mmol/L |
4.2 |
|
|
Ca mmol/L |
2.26 |
|
|
Mg mmol/L |
0.80 |
|
|
Urinalysis: (date performed: January 15th, 2010)
| SpGr |
1.011 |
RBC Per high power field (HPF) |
0-2 |
pH |
5.4 |
WBC Per HPF |
0-2 |
Protein |
- |
Epithelial cells Per HPF |
2-5 |
Glucose |
- |
Cast |
- |
Ketones |
- |
Nitrite |
- |
OB |
- |
Crystal |
- |
Hormone data: (date performed: January 15th, 2010)
| Hormone |
Unit |
Value |
Reference value |
Hormone |
Unit |
Value |
Reference value |
FSH |
mIU/ml |
2.22 |
1.4-9.6 |
hsTSH |
μIU/ml |
1.47 |
0.1-4.5 |
LH |
mIU/ml |
1.83 |
0.8-15.5 |
fT4 |
ng/dL |
0.94 |
0.6-1.75 |
E2 |
pg/ml |
173.0 |
37.2-201 |
IGF-1 |
ng/ml |
146 |
109-284 |
Progesterone |
ng/ml |
8.05 |
1.0-22.4 |
hGH |
ng/ml |
0.941 |
0.06-5.0 |
Testosterone |
ng/ml |
0.478 |
0.06-0.77 |
|
|
|
|
Hormone data: (date performed: January 15th, 2010)
|
|
8am |
4pm |
11pm |
Reference value |
ACTH |
pg/ml |
37.8 |
49.5 |
25.3 |
10-65 |
Cortisol |
μg/dl |
23.5 |
20.4 |
14.3 |
am: 5-24, pm: 2.5-12.5 |
< Course and Treatment >
Overnight dexamethasone suppression test (administration of 1-mg dexamethasone) on January 16, 2010 showed that cortisol was 11.7 μg/dl. Low-dose dexamethasone suppression test (administration of 0.5-mg dexamethasone Q6H for two consecutive days) on January 18, 2010 showed that cortisol was 6.8 μg/dl. High-dose dexamethasone suppression test (administration of 2-mg dexamethasone Q6H for two consecutive days) on January 21, 2010 showed that baseline cortisol was 19.8 μg/dl and after-test was 2.3 μg/dL. MRI of the brain (see figure 1) on January 22, 2010 revealed pituitary microadenoma. She underwent a trans-sphenoidal surgery to remove the microadenoma. Immunohistochemical studies of the tumor showed the presence of ACTH-producing cells.
< Discussion >
這位病人主要的主訴為體重增加，針對一位年輕女性obesity的鑑別診斷可分為四大類：
- 生活習慣：overeating, decreased energy expenditure, sleep deprivation, smoking cessation
- pregnancy, menopause
- drugs (ex. steroids)
- neuroendocrine (Cushing's syndrome, hypothyroidism, acromegaly, polycystic ovary syndrome)
這位病人聲稱沒有任何系統性疾病和用藥史，也沒有不良的生活習慣如喝酒、大吃大喝、睡不好等等，生理期的時間規律且血量也正常，初步看來obesity不太像是這些因素造成的。Physical examination沒看到goiter或肢端肥大，這些negative signs指出這不太像一般hypothyroidism或acromegaly的表現。Polycystic ovary syndrome（PCOS）通常發生在生育期婦女，這些婦女通常會有不正常的生理期、停止排卵和多毛症，也有可能以insulin resistance、高血壓、高三酸甘油脂表現，但這位病人目前都無以上症狀，所以也不太像有PCOS。最大的可能性為Cushing's syndrome，因為病人自述有體重增加、臉變腫長痘、皮膚變薄且容易瘀青，符合Cushing's syndrome的外型特徵，肚子上的紫色條紋更有助於辨別單純肥胖造成的striae（肥胖紋通常是白色的）。Pseudo-Cushing's syndrome如長期酗酒或憂鬱症者也會有類似的外觀。
Cushing's syndrome和其etiologies必須藉助lab和image studies來幫助診斷，並且，由於neuroendocrine的疾病息息相關，所以初步抽血也會安排所有的hormone檢查以排除其它內分泌疾病的可能性。
Hormone data: (date performed: January 15th, 2010)
|
Hormone |
Unit |
Value |
Reference value |
Hormone |
Unit |
Value |
Reference value |
FSH |
mIU/ml |
2.22 |
1.4-9.6 |
hsTSH |
μIU/ml |
1.47 |
0.1-4.5 |
LH |
mIU/ml |
1.83 |
0.8-15.5 |
fT4 |
ng/dL |
0.94 |
0.6-1.75 |
E2 |
pg/ml |
173.0 |
37.2-201 |
IGF-1 |
ng/ml |
146 |
109-284 |
Progesterone |
ng/ml |
8.05 |
1.0-22.4 |
hGH |
ng/ml |
0.941 |
0.06-5.0 |
Testosterone |
ng/ml |
0.478 |
0.06-0.77 |
|
|
|
|
|
8am |
4pm |
11pm |
Reference value |
ACTH pg/ml |
37.8 |
49.5 |
25.3 |
10-65 |
Cortisol μg/dl |
23.5 |
20.4 |
14.3 |
am: 5-24, pm: 2.5-12.5 |
此病人的抽血檢查報告顯示CBC/DC、biochemistry、urinalysis、hormonal profile都是正常的，唯獨cortisol在晚上時並沒有降到正常值以下，代表失去了diurnal rhythm，再加上病人的臨床表現，初步懷疑為Cushing's syndrome。
Overnight dexamethasone suppression test
|
Cortisol |
μg/dl |
23.5 |
Cut-off point：5 μg/dL |
Overnight dexamethasone suppression test為診斷Cushing's syndrome的screening test，11-12 pm給予病患1 mg dexamethasone，隔九小時後（隔天8-9am）測血液cortisol量，cut-off point為5 μg/dL。若 <5 μg/dL且臨床可疑性不高時，則表示不是Cushing's syndrome；若 <5 μg/dL但臨床可疑性高時，仍無法排除Cushing's syndrome的可能性。若大於 >5 μg/dL且病人有長期酗酒或憂鬱症，可進一步做dexamethoasone-corticotropin-releasing hormone (CRH) test來區分Cushing's syndrome和pseudo-Cushing's state。此病患的cortisol為23.5 μg/dL（大於 >5 μg/dL），且臨床可疑性高，極度懷疑是Cushing's syndrome，需再做進一步檢查確認。
Low-dose dexamethasone suppression test
|
Cortisol |
μg/dl |
6.8 |
Cut-off point：2 μg/dL |
Low-dose dexamethasone suppression test為診斷Cushing's syndrome的confirmation test，兩天內每六小時給予病患0.5mg dexamethasone，分別測量測試前以及測試的第二天24-hour urinary free cortisol，cut-off point為2 μg/dL，>2 μg/dL則暗示Cushing's syndrome的可能性。此病患的cortisol為6.8 μg/dL（大於 > 2 μg/dL），確認是Cushing's syndrome，需再做進一步檢查找出etiologies。
Serum ACTH level
|
ACTH |
pg/ml |
37.8 |
Normal range：10-65 |
確定診斷為Cushing's syndrome後，serum ACTH level可用來區分ACTH-dependent Cushing's（pituitary Cushing's和ectopic ACTH syndrome）和ACTH-independent Cushing's（adrenal Cushing's）。<10 pg/ml暗示ACTH-independent Cushing's（adrenal Cushing's）的可能性；>20 pg/ml暗示ACTH-dependent Cushing's（pituitary Cushing's和ectopic ACTH syndrome）的可能性。此病患的ACTH為37.8 μg/dL（大於 >20 μg/dL），確認是ACTH-dependent Cushing's，需再做進一步檢查找出是pituitary Cushing's還是ectopic ACTH syndrome。
High-dose dexamethasone suppression test
|
baseline |
after test |
Cortisol μg/dl |
19.8 |
2.3 |
確認是ACTH-dependent Cushing's 後，需做high-dose dexamethasone suppression test找出原因，以區分pituitary Cushing's和ectopic ACTH syndrome。兩天內每六小時給予病患2 mg dexamethasone，分別測量並比較測試前以及測試的第二天24-hour urinary free cortisol，cortisol suppression >50% 代表pituitary Cushing's的可能性，cortisol suppression <50% 則暗示ectopic ACTH syndrome的可能性。此病患的baseline cortisol為19.8 μg/dL，after test為2.3 μg/dL，suppression > 50%，確認是pituitary Cushing's，需再做進一步pituitary MRI檢查。
MRI看到pituitary有一顆小於一公分的microadenoma，所以進行trans-sphenoidal surgery切除，之後病理報告顯示tumor的組成細胞是ACTH-producing cells。根據以上所有的檢查可診斷此病患是pituitary Cushing's (or Cushing's disease)。
< Cushing's syndrome的介紹 >
Cushing's syndrome是一種體內glucocorticoids過多的內分泌疾病。常見的原因有pituitary tumor（Cushing's disease）或是non-pituitary tumor（ectopic ACTH syndrome；small cell lung cancer、胰臟癌、腎癌、甲狀腺癌、胸腺癌等）導致ACTH分泌過多，進而造成adrenal hyperplasia和glucocorticoids分泌過量。adrenal adenoma或carcinoma、醫源性（iatrogenic；醫護人員給予過量的glucocorticoids）、外源性（病患長期自行服用glucocorticoids）也會導致Cushing's syndrome。其中，約有65~70%被診斷出的內源性Cushing's syndrome為Cushing's disease。（see figure 2）
Cushing's disease的好發年齡為25到45歲，女性的發生率比男性高；ectopic ACTH syndrome則好發在50歲以上的男性。在小孩常見的原因為Cushing's disease，其次為adrenal carcinoma。
Cushing's syndrome常見的臨床表現有：weight gain, central obesity, abdominal striae, moon face, buffalo hump（dorsocervical fat pad）, glucose intolerance, hypertension, gonadal dysfunction（irregular periods, impotence）, osteoporosis, acne, hirsutism, weakness, proximal myopathy, easy bruising, psychiatric disturbances （depressed mood, anxiety, mild paranoia）等等。（see figures 3 and 4）
懷疑病患有Cushing's syndrome時，可做以下檢查：(see figure 5)
- Late night serum cortisol：健康人體內的cortisol分泌會隨著時間的不同而起伏，早上為5-24 μg/dL，晚上約略為一半：2.5-12.5 μg/dL，呈現出diurnal rhythm。如果沒有diurnal variation，患有Cushing's syndrome的可能性則相對提高了。
Screening test：
- Dexamethasone-corticotropin-releasing hormone (CRH) test：用來區分Cushing's syndrome和pseudo-Cushing's states（如憂鬱症、酗酒），血液cortisol濃度 >1.4 μg/dL則暗示endogenous Cushing's syndrome的可能性，sensitivity和specificity將近100%。
- 24-hour urinary free cortisol level：利用Radioimmunoassay或high-performance liquid chromatography (HPLC) assay來偵測free cortisol的excretion rate，>100 μg/24hr（radioimmunoassay）或 >50 μg/24hr（HPLC assay）即暗示Cushing's syndrome的可能性。此檢查易受藥物（如carbamazepine）和疾病（如腎功能不好）所影響。
- Overnight dexamethasone suppression test：11-12 pm給予病患1mg dexamethasone，隔九小時後（隔天8-9am）量測血液cortisol量，>5 μg/dL即暗示Cushing's syndrome的可能性。
- Late night salivary cortisol level：晚上11點收集病患的口水，>1.3 ng/24hr（radioimmunoassay）則暗示Cushing's syndrome的可能性。
Confirmation test：
- Low-dose dexamethasone suppression test：兩天內每六小時給予病患0.5 mg dexamethasone，分別測量測試前以及測試的第二天24-hour urinary free cortisol，>2 μg/dL則暗示Cushing's syndrome的可能性。
- Serum ACTH level：確定診斷為Cushing's syndrome後，serum ACTH level可用來區分ACTH-dependent Cushing's（pituitary Cushing's和ectopic ACTH syndrome）和ACTH-independent Cushing's（adrenal Cushing's）。< 10 pg/ml暗示ACTH-independent Cushing's（adrenal Cushing's）的可能性；> 20 pg/ml暗示ACTH-dependent Cushing's（pituitary Cushing's和ectopic ACTH syndrome）的可能性。
- High-dose dexamethasone suppression test：可用來找出ACTH-dependent Cushing's的原因，區分pituitary Cushing's和ectopic ACTH syndrome。兩天內每六小時給予病患2mg dexamethasone，分別測量並比較測試前以及測試的第二天24-hour urinary free cortisol，cortisol suppression >50% 則暗示pituitary Cushing's的可能性，cortisol suppression <50% 則暗示ectopic ACTH syndrome的可能性。
- Bilateral inferior petrosal sinus vein sampling (BIPSS)：可用來找出ACTH-dependent Cushing's的原因，為區分ectopic和pituitary ACTH production的gold standard，但是此侵入性檢查非常昂貴
- Adrenal computed tomography (CT)
- Pituitary magnetic resonance imaging (MRI)
Cushing's disease時常是可以根治的，治療的目標為降低cortisol的分泌量至正常值、根治腫瘤，臨床症狀通常會在治療後三到十二個月間慢慢消失。治療方式有：
- Surgical therapy：手術為成人的優先考量，包括trans-sphenoidal adenomectomy（pituitary Cushing's）、adrenalectomy（adrenal Cushing's）和surgical resection of an ACTH-secreting tumor（ectopic ACTH syndrome）。
- Radiation therapy：Pituitary radiation對小孩子或trans-sphenoidal adenomectomy沒有成功的大人也是個選擇。
- Medications：mitotane, ketoconazole, metyrapone, aminogluthimide
總而言之，根據此病人的臨床表現（central obesity, moon face, acnes, buffalo hump, purple striae, easily bruised, ecchymoses）、實驗室檢查（loss of diurnal rhythm, positive overnight dexamethasone suppression test, positive low-dose dexamethasone suppression test, serum ACTH level > 20 pg/ml, positive high-dose dexamethasone suppression test）、MRI（pituitary microadenoma），得知此病人的診斷為Cushing's disease，所以進行trans-sphenoidal surgery後開始追蹤其治療效果。
< References >
- Williams Gordon H, Dluhy Robert G. Disorders of the Adrenal Cortex" (Chapter 336). In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (eds). Harrison's Principles of Internal Medicine, 17e: http://www.accessmedicine.com/content.aspx?aID=2900123.
- Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2003;88:5593-602
- Kirk Jr LF, Hash RB, Katner HP, Jones T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician 2000;62:1119-27,1133-4
- The Pituitary Society: Patient Information: Cushing's Syndrome and Cushing's Disease: Your Questions Answered: http://www.pituitarysociety.org/public/specific/cushing
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Case Discussion
繼續教育考題