Case Discussion      A 62-year-old man sought medical attention at this hospital because of general malaise, limbs weakness, and nausea for half a month. He had chronic obstructive pulmonary disease (COPD) but had poor drug compliance. He often developed intermittent dyspnea and visited local clinics for treatment. He was noted to have progressive facial swelling and obesity, and then, he stopped medications by himself. One month prior to this admission, he experienced general malaise, fatigue and nausea gradually. He denied having hemiparesis, dysarthria, easy chocking, an unstable gait, or stool or urine incontinence. There was neither epigastric pain nor diarrhea. Because of the above symptoms, adrenal insufficiency or hypothyroidism was suspected. A test of serum cortisol level in the morning showed a relatively low level of cortisol (8.2 μg/dL). Thyroid functions were within normal limits. Throughout his whole disease course, there was no visual deficit, headache, joint pain or paresthesis. He did not consume alcohol, undergo operation or have a family history of endocrine disorders.      On physical examination, his consciousness was clear, height was 168 cm and weight was 80 kg. The body temperature was 36.8°C, pulse rate was 72 beats per minute, respiratory rate was 20 breaths per minute, and the blood pressure was 126/80 mmHg. Moon face, plethora, buffalo hump, central obesity with abdominal striae was noted. There was supraclavicular fat pad and thin skin with easy ecchymosis. The conjunctivae were pink, sclerae were anicteric and the pupils were isocoric with prompt light reflex. The neck was supple without a goiter, palpable masses, engorged jugular veins or lymphadenopathy. Neurological examinations were unremarkable. < Laboratory data > 1. Hemogram WBC RBC HB HCT MCV MCHC PLT K/μL M/μL g/dL ％ fL g/dL K/μL 11.98 4.1 13 37.0 89.4 34.8 189 2. Biochemistries and electrolytes  ALB TP T-Bil AST ALT ALP  γ-GT Glucose g/dL g/dL mg/dL U/L U/L U/L U/L  mg/dL 3.4 6.2 0.6 33 36 152 17 103  UN CRE Na K Ca Mg  P CRP  mg/dL mg/dL mmol/L mmol/L mg/dL mmol/L mg/dL mg/dL 14.2 0.7 139 3.7 8.8 0.92 3.1 <0.8 3. Results of endocrinologic studies  hsTSH Free T4 ACTH Cortisol 0.4- 4 IU/mL 0.60-1.75 ng/dL 10-65 pg/mL 5-25μg/dL 0.68 1.56 12 8.2  4. The ACTH stimulation test (250μg synthetic ACTH intravenous injection)     ACTH Cortisol   10-65 pg/mL 5-25 g/dL   0’ 12 8.2 60’ 11 13.4 < Course and treatment >            After admission, the ACTH stimulation test with 250μg synthetic ACTH injection was performed which yielded a relatively low serum cortisol level (13.4 μg/dl). Under the diagnosis of iatrogenic adrenal insufficiency, physiological dosage of steroid with cortisone acetate at a daily dose of 37.5 mg was given. The symptoms improved gradually. Steroid dosage was tapered according to clinical symptoms of the patient. After he deferred one daily dose of steroid, morning cortisol on the next day showed 16 μg/dL and serum cortisol was within normal range (26 μg/dL) after ACTH stimulation test. Steroid replacement was continued. The patient had no significant discomfort after subsequent withdrawal of steroid replacement. < Discussion > 腎上腺功能不足的症狀可輕可重，輕者表現無力倦怠、噁心嘔吐等胃腸道症狀；重者會低血糖、低血壓甚至休克。腎上腺功能不足的原因很多，可以是原發性的, 也可以是次發性的。原發性腎上腺不足最常見是因自體免疫所引起；其次，諸如：腎上腺的結核菌、病毐、黴菌感染及出血等等也會導致功能不足。至於次發性腎上腺功能不足，除了腦垂體或下視丘出問題以外，醫源性 (如：服用類固醇)造成的次發性腎上腺功能不足也是一大原因。這類情形多可藉由藥物史得到蛛絲馬跡。一般而言，類固醇的服用若是以下的情況，皆有可能因類固醇藥物抑制上游腦下垂體而間接對腎上腺造成抑制: (1)、長久服用卻突然停藥者；(2)、頻繁的短期類固醇療程者 (如氣喘多次發作而常間歇性服用者)；(3)、服用類固醇生理劑量超過3週以上者 (但劑量並非絕對)。此類病患往往因長期類固醇藥物而造成類似腎上腺功能過高的庫欣氏症狀群 ( Cushing syndrome)外觀，諸如：月亮臉(moon face)、臉色紅潤 (plethora)、水牛肩（buffalo hump)、鎖骨上脂肪墊(supraclavicular fat pad)、肚子暗紅紋路 (abdominal striae)、薄而脆弱的皮膚及易淤血的體質。然而，實際上身體的腎上腺功能卻顯現為功能不足的狀態。而若有上述服用情形或臨床症狀高度懷疑腎上腺功能不足者，便不能貿然停藥。此時須停用原口服或點滴注射的類固醇至少12-24小時，然後作基礎的早晨腎上腺皮質素濃度測量及皮質刺激素激發測試 (ACTH stimulation test)。若基礎早晨腎上腺皮質素濃度可達10 μg/dL或激發測試後的皮質素濃度可到18-19 μg/dL時，多半表示病人的腎上腺功能尚在可容許的範圍，而可以馬上直接停藥。但若濃度不能達到，表示腎上腺功能可能已受抑制，則須要繼續服用補充類固醇 (多半須要6-9個月的時間，等待腎上腺功能回復)，於爾後再慢慢調低類固醇劑量，於較低劑量時再進行如上測試來決定是否可停藥。一般而言，醫源性的腎上腺功能不足為次發性腎上腺功能不足， 故相較原發性功能不足者而言，較不會伴隨低鈉高鉀等電解質不平衡的情況，也不會有皮膚色素增加 (hyperpigmentation) 出現。 < References > Dixon RB, Christy NP. On the various forms of the corticosteroid withdrawal syndrome. Am J Med 1980; 68:224-30 Byyny RL. Withdrawal from glucocorticoid therpy. N Engl J Med 1976;295:30-32. Williams textbook of endocrinology, the 10th edition. 繼續教育考題 1. (E) 會造成腎上腺功能不足的原因如下，何者正確？ A  TB adrenalitis B  Long-term steroid C  Adrenal hemorrhage D  Hypopituitarism E  All of above 2. (D) 腎上腺功能不足的症狀，並不包括？ A  Malaise/fatigue B  Nausea/vomiting/diarrhea C  Hypotension D  Ｂradycardia 3. (C) 腎上腺功能不足的診斷，何者錯誤？ A  基礎早晨腎上腺皮質素大於10 μg/dL B  ACTH stimulation test中，皮質素濃度大於18-19 μg/dL C  壓力狀況下及非壓力狀況下的皮質素濃度診斷標準皆相同 D  有時會伴隨鈉鉀電解質的不平衡 4. (D) 有關steroid-induced iatrogenic adrenal insufficiency的描述，何者錯誤？ A  A cause of primary adrenal insufficiency B  Presentation of hyperpigmentation C  Almost combined with hyperkalemia and hyponatremia D  All of above 5. (D) 有關腎上腺功能不足的治療, 何者錯誤？ A  須補充類固醇 B  必要時也要伴隨補充礦物性腎上腺皮質素 C  壓力狀況下及非壓力狀況下的補充劑量不一樣 D  終生皆需補充類固醇 6. (D) 何者可能是iatrogenic adrenal insufficiency的臨床表現？ A  Adrenal crisis B  Moon face C  fatigue D  All of above 答案解說 ( E ) 會造成腎上腺功能不足的原因很多，可以是原發性的, 也可以是次發性的。原發性腎上腺不足最常見是因自體免疫所引起；其次，諸如：腎上腺的結核菌、病毐、黴菌感染及出血等等也會導致功能不足。至於次發性腎上腺功能不足，除了腦垂體或下視丘出問題以外，醫源性 (如：服用類固醇)造成的次發性腎上腺功能不足也是一大原因。 ( D ) 腎上腺功能不足的症狀可輕可重，輕者表現無力倦怠、噁心嘔吐等胃腸道症狀，前述為較常見的症狀；重者，如腎上腺功能不足急症(adrenal crisis)則會低血糖、低血壓甚至休克，然而多半因血管內容積減少，多半會反射性的心律變快，較少以單純的心跳過慢來表現。 ( C ) 腎上腺功能不足的診斷隨病人是否在壓力狀況而有不同的評判標準。在沒有壓力的狀況下，若基礎早晨腎上腺皮質素濃度可達10 μg/dL或ACTH激發測試後的皮質素濃度可到18-19 μg/dL時，多半表示病人的腎上腺功能尚在可容許的範圍。至於壓力狀況下, 與非壓力狀況下的標準不同, 若基礎早晨腎上腺皮質素濃度可達34 μg/dL或ACTH激發測試後的皮質素濃度”上升的幅度”可到9 μg/dL, 則腎上腺的功能便認為在可接受的範圍。  ( D )服用類固醇會抑制腦垂體及下視丘的中樞而進一步抑制下游的腎上腺，而造成次發性的腎上腺功能不足，非原發性腎上腺功能不足；原發性腎上能功能不足者因上游ACTH代償性分泌過多，而易造成皮膚色素沈積 ( hyper- pigmentation)，另因原發性腎上腺皮質功能的破壞常不只侷限於分泌糖性皮質素 ( glucocorticoid) 的皮質層，往往也涉及分泌礦物性皮質素的那一層，故常伴隨低血鈉及高血鉀。至於次發性腎上腺功能不足則無上述情況。 ( D ) 腎上腺功能因應身體壓力狀況的大小所該反應出的幅度會有所不同，故視病人現存的狀況而有不同的補充劑量，一般而言，壓力愈大的病危狀態所需的劑量愈大。原發性腎上腺功能不足常需額外再補充礦物性皮質素，而且常因腎上腺皮質的損壞為不可逆的，而需終生服用補充劑量。至於次發性的腎上腺功能不足，諸如醫源性等原因則有機會回復功能而只需暫時補充。 ( D )長期類固醇藥物所造成的醫源性腎上腺功能不足會造成類似腎上腺功能過高的庫欣氏症狀群 ( Cushing syndrome) 外觀，諸如：月亮臉 (moon face)、臉色紅潤 (plethora)、水牛肩 （buffalo hump)、鎖骨上脂肪墊 (supraclavicular fat pad)、肚子暗紅紋路 (abdominal striae)、薄而脆弱的皮膚及易淤血的體質。然而，實際上身體的腎上腺功能卻顯現為功能不足的狀態，故同時也會表現全身倦怠無力、胃腸道不適等常見功能不足的症狀。綜上所言，功能過多及不足的臨床症狀表現皆有。