Case Presentation A 50 year-old woman presented to the clinic with the complaints of insidious onset of facial plethora, weight gain, and hypertension for more than 3 years. This 50 year-old, previously well woman noted to have hypertension that made her take anti-hypertensive agents about 3 years ago. She also noticed her cheeks frequently turning flush with a sense of facial and neck swelling. She gained weight steadily in these 2 years and found the fat gathering mainly at the face, neck, and truncal region. Her skin felt greasy, with more acne formation than before and she also noted to have a proximal muscle weakness with a difficulty in lifting heavy matter. Physically, she had a puffy and plethoric face (Fig.1 ), truncal obesity, and a buffalo hump. The height was 157 cm and the weight was 62.5 kg. The blood pressure was 160/90mmHg, the pulse was 88, the temperature was 37.0℃, and the respirations were 22. Her face and upper chest revealed acneiform eruptions. A non-tender, elastic nodule about 1 cm in diameter was found at the left thyroid lobe. Her abdomen was fatty with whitish but no purple skin striae. The other physical examinations were unremarkable. Laboratory tests were performed (Table 1-3). Table 1. Hematologic Laboratory Values. ___________________________________________________     RBC M/μL Hb g/dL Hct % MCV fl Platelet k/μL WBC k/μ MCHC g/dL On Admission 4.66 13.8 40.6 87.1 301 16.66 34 Seg    %    Eos  % Baso % Mono %  Lym       %                    On Admission 92.5  0 0.1 1.9 5.5 ___________________________________________________ Table 2. Blood Chemical and EnzymeValues. ___________________________________________________      BUN mg/dL Cre mg/dL Alb g/dL Glo g/dL GOT U/L GPT U/L LDH U/L T-Bil mg/dL 16.6 0.7 4.1 3.0 12 16 439 1.0  Na mmol/L K mmol/L Mg mmol/L Cl mmol/L Ca mmol/L TG mg/dL Cho mg/dL AC Glu mg/dl 149 3.6 0.96 106 2.34 81 208 117 ___________________________________________________  Table 3. Urinalysis.   ___________________________________________________ Appearance Yellow; clear Bil  - Sp Gr. 1.038 Nitrite  - PH 6.5 RBC  - Protein - WBC 0-1 Glu ≧1.0g/dL Epi 0-1 Ketone - Cast  - OB - Crystal  - Urobilinogen 1.0EU/dL  Thyroid function test: Free T4: 1.19 ng/dL (0.6-1.75) TSH: 0.274 μIU/mL (0.1-4.5) Thyroid echo: Left multinodular goiter Thyroid aspiration cytology: negative for malignant cells, sheets of follicular cells with colloid. ___________________________________________________ Table 4. Adrenocortical function. ___________________________________________________     ACTH pg/ml Cortisol mcg/dl On 2nd day of admission 9:25AM 4:23PM 20.5 351 >100 82 On 5th day of admission 8AM 4PM 40.3 16.9 50.0 15.3 On 6th day of admission 8AM*    5.3 ___________________________________________________ *1 mg overnight dexamethasone suppression test.   Brain MRI (on 5th day of admission): focal lesion was shown in the pituitary gland on the right side with presentation of less, and delayed enhancement. It measured about 0.5 cm in diameter (Fig.2 ).  <Course and Treatment> She was diagnosed to have Cushing's disease by clinical and laboratory examinations. Brain MRI revealed a microadenoma at the right lobe of anterior pituitary gland. Therefore the patient was referred to the neurosurgeon for surgical intervention of pituitary adenoma. Via endonasal, trans-sphenoidal route, adenomectomy and hemihypophysectomy were performed smoothly on the 10th day of admission. The pathology of the resected tumor showed a pituitary adenoma that was stained positively for ACTH. She was discharged a week later and put on replacement therapy of cortisone acetate and thyroxine. A follow up ACTH level on the 13th post-operative day was low (<1.0 pg/ml). OP finding (On 10th day of admission): poor pneumatization of right half of sphenoid sinus; thin sellar floor (sella not enlarged); a 0.5 cm yellowish soft nodule at right margin of the gland, noted after partially removal of the normal gland. Pathology (On 10th day of admission): a pituitary adenoma with eosinophilic and clear cytoplasm. Scattered ACTH positive cells can be seen.   病案分析 本案例為一庫欣氏病的患者，在臨床上，庫欣氏症候群的診斷，有兩個最重要的盲點：第一、是要如何區分病人之過量的皮質素分泌，是屬於病理性的，而非只是生理上為了因應壓力或其他原因，所引起的皮質素過量分泌；第二、是要確認病理性皮質素過量的原因為何。而其原因，則包括醫源性的皮質類固醇使用，腎上腺皮質腺瘤或腺癌，腦下垂體腺瘤，或是其他異位性腫瘤所引起的腎上腺皮質促素(ACTH)或皮促素之釋放激素(CRH)所導致的皮質素過量分泌。患者可先接受1 mg dexamethasone抑制試驗，若為陽性(無法被抑制到<5μg/dL)，可再讓病患留取24小時尿液，檢測其中free cortisol量，來初步確認是否為病理性的皮質素過量分泌。其次則可用high-dose 2 mg q6h dexamthasone suppression test共48小時，來大致區分是pituitary或adrenal、ectopic來源的皮質素過量分泌，若是腦下垂體腺瘤引起者，或少數情況下由ectopic carcinoid所引起者，通常可以被抑制到小於10%基礎分泌量，亦即，大於90%以上的suppression。若生化檢驗及影像學檢查，如：腦下垂體核磁共振檢查，均難以區分是腦下垂體腺瘤或異位性腫瘤所引起時(有50%腦下垂體腺瘤所導致的皮質素過量分泌，其腫瘤大小< 5mm)，可用Inferior petrosal venous sampling方式來區分。因為臨床上腦下垂體腺瘤所引起的庫欣氏病最為常見，約佔所有病例的70%，且手術預後是較好的，正確區分及鑑別診斷是相當重要的工作。             繼續教育考題 1. (D) The patient receives a midnight dose of 1 mg of dexamethasone and a plasma cortisol level drawn at 8AM the next day is 5.3 μ g/dL. At this point the most appropriate diagnostic maneuver would be A Abdominal CT scan. B Measurement of 24-h 17-OHCS excretion in urine. C CT scanning of the pituitary gland. D Measurement of 24-h urine free cortisol. E A 2-day high-dose dexamethasone suppression test (2.0 mg every 6 h for 48 h). 2. (D) The patient received a 24-h urine free cortisol exam which revealed 210μg/day (normal < 100μ g/day). A high-dose dexamethasone suppression test (2 mg every 6h for 48 h) was performed and the 24-h urine free cortisol on the 2nd day was 18μ g/day. What's the cause of the Cushing's syndrome? A Pituitary. B Adrenal gland. C Ectopic. D  It's still unclear from these information. The tumor could be in the pituitary or could be ectopic. E It's unclear from these information. The tumor could be in the adrenal gland or could be ectopic. 3. (D) This patient underwent a transsphenoidal procedure to cure her Cushing's disease. Six weeks later a 24-h urine free cortisol is 3μg/day. Her thyroid function tests are normal. What's your explanation for the result and what therapy should be started? A The patient still has Cushing's disease. B The patient never had Cushing's disease. C The patient's Cushing's disease is cured and she needs no further treatment. D The patient's Cushing's disease is cured and she should be treated with glucocorticoids. E The surgeon has inadvertly damaged the normal pituitary gland and the patient requires permanent glucocorticoid replacemnt. 4. (D) The patient complained of increased thirst six hours after the transsphenoid resection of her pituitary ACTH-secreting tumor. Her urine output was 300 mL/h for 2 hours. Urine specific gravity was 1.001 and urine osmolality was 200 mosm/L. Her serum sodium ws 147 mmol/L. Appropriate management at this time was A Obtaining a brain MRI. B Performing a water deprivation test. C Placing the patient on 500 mL/day fluid restriction. D Administering 2μ g desmopressin subcutaneously once and encouraging her to drink water when thirsty. E Administering 2μ g desmopressin subcutaneously bid and encouraging her to drink water when thirsty. 5. (A) After the transsphenoid surgery the patient had poor compliance to medications. She visited the emergency room some day because of fever and hypotension and was not responding to antibiotics or pressors. Her cortisol was 2.0μg/dL, T4 4.5μg/dL (Normal 4.5-12), T3 40 ng/dL (Normal 80-200), TSH 0.3μIU/mL (Normal 0.4-4.0), and sodium was 120 mmol/L (Normal 135-145). What's your management for her at this time point? A She sould be given 100 mg hydrocortisone iv q6h, thyroid hormone is unnecessary at this time point. B She has normal pituitary function and other reasons for her symptoms should be investigated. C Her pituitary-adrenal axis status is unclear. A cosyntropin stimulation test should be performed first. D She should be started immediately on levothyroxine therapy. E She should be given both 100 mg hydrocortisone iv q6h and levothyroxine immediately. 6. (B) Which of the following is the least common clinical feature of Cushing's disease (pituitary-dependent Cushing's syndrome)? A Obesity or weight gain. B Hypokalemic alkalosis. C Thin skin. D Hypertension. E Moon face. 7. (E) Which of the following is the most common cause of endogenous Cushing's syndrome? A Adrenal adenoma. B Adrenal carcinoma. C Adrenal macronodular hyperplasia. D ACTH-producing nonendocrine tumor. E Pituitary corticotrope adenoma. 8. (D) Because pituitary MRI is insufficiently sensitive to distinguish small (<2 mm) pituitary ACTH-secreting adenomas from ectopic ACTH-secreting tumors, bilateral inferior petrosal sinus (IPSS) ACTH sampling before and after CRH administration may be required. Which of the following condition is indicative of ACTH-secreting pituitary tumors? A Basal IPSS: peripheral <2, CRH-induced IPSS: peripheral >3. B Basal IPSS: peripheral <2, CRH-induced IPSS: peripheral <3. C Basal IPSS: peripheral >2, CRH-induced IPSS: peripheral <3. D Basal IPSS: peripheral >2, CRH-induced IPSS: peripheral >3. E All the above are wrong. 9. (B) The mechanisms of steroidogenic inhibitors are as follows, which of them is incorrect? A Mitotane suppresses cortisol hypersecretion by inhibiting 11β-hydroxylase and cholesterol side-chain cleavage enzymes. B Ketoconazole inhibits ACTH release and subsequent cortisol production by adrenal gland. C Mitotane suppresses cortisol hypersecretion by destroying adrenocortical cells. D Metyrapone inhigits 11β-hydroxylase and normalizes cortisol levels. E Mifepristone (RU486) antagonizes the peripheral actions of glucocorticoids and progestagens by competitively inhibiting the binding to their cytosolic receptors. 10. (A) Pseudo-Cushing's syndrome occurs frequently in patients with the following underlying conditions. Which is of them is not the so-called pseudo-Cushing's syndrome? A Iatrogenic Cushing's syndrome. B Obesity. C Chronic alcoholism. D Depression. E Acute illness of any type.