Cushing's syndrome (Hypercortisolism)

定義:

  Cushing's syndrome = cortisol 過多
  Cushing's dz = Cushing's syndrome due to pituitary ACTH hypersecretion


腎上腺皮質由3層構成，
   -球狀帶（zona glomerulosa）15%-最外層-aldosterone
   -束狀帶（zona fasciculata）78%-佔大部分-glucocorticoid
   -網狀帶（zona reticularis）7%-最內層-glucocorticoid, 少量sex hormone


Etiology:

  Iatrogenic (最常見) (長期使用類固醇 or ACTH)
  Cushing's dz (60-70%):
      -腦垂體adenoma (通常是microadenoma) or
      -腦垂體hyperplasia
            -macronodular,
            -micronudular: sporadic or familial (Carney's syndrome)
  Adrenal tumor (15-25%): adenoma or (rarely) carcinoma
  Ectopic ACTH (5-10%):
     肺癌 (SCLC),
     Carcinoid tumor (thymus, 胰臟, 卵巢),
     Islet cell tumors,
     甲狀腺髓質癌,
     嗜鉻細胞瘤

*雙側Hyperplasia:
    1) Cushing's dz
    2) Ectopic ACTH or CRH tumor 


臨床表現:
* loss of circadium rhythm of ACTH, cortisol secretion

 -most specific: 皮膚萎縮變薄, 自發性瘀青, 近端myopathy, 紫斑條紋(wide striae), 低血鉀
 -more specific: 身材改變
     中心性肥胖 [central (truncal) obesity] [腹腔網膜脂肪增加]; 四肢wasting 
     月亮臉, 水牛肩
 -non-specific:
     -glucose intolerance or DM,
     -高血壓, 高血脂(TG),
     -肥胖,
     -oligomenorrhea (月經數變少, 不規則或無),
     -骨質疏鬆症
 -其他:
     -精神: 疲憊, 憂鬱/失眠, psychosis, impaired cognition
     -面紅(facial plethora),
     -男性化: hirsutism (多毛症), acne
     -hyperpigmentation (皮膚變黑) (if ACTH昇高)
     -皮膚黴菌感染
     -泌尿系統: 腎結石, 多尿症



---------------------------------------------------
診斷:

 A) 篩選診斷: (三種方式)
   1) Overnight (O/N) 1 mg DST (dexamethasone suppression test) (睡前服用1mg dexa, 隔天早上空腹抽血(cortisol)驗尿(cortisol)
          -血中cortisol < 1.8 ug/dL, 表示有被抑制
          -約1-2%呈偽陽性
          -主要用來評估 subclinical Cushing's in adrenal "incidentalomas".
   *24-h UFC (urine free cortisol) (正常應 <50 ug/dL)
   * 11 pm 唾液腺 cortisol (正常應 <3.6 nmol/mL) (此法少做)

偽陽性:  酗酒, 憂鬱, 生病期間

    2) 48h LD DST (Low dose dexamethasone suppression test)  (0.5mg po q6h x2d: suppress if <10% of base) (recheck if pt acute illness, 酗酒, 憂鬱)

 B) 確診:
    3) O/N HD DST (8mg 11pm, 隔天9AM [cortisol] (suppress if <32% baseline)
            not suppress ->Ectopic (胸腹MRI, somatostatin scan)
            suppress ->Cushing's dz (腦垂體MRI)

ACTH level:
   1) 低 (< 10 or undetectable)
           -> adrenal CT or MRI  (尿17KS (ketosteroid), 血DHEA-S)
           -> adrenal tumor

   2) 正常-高 ->48h or Overnight 高劑量(8mg)DST (or CRH test)
          30-150
                  ->cortisol 下降32% ->有被抑制->pituitary MRI ->Cushing's dz
          >200, or >500
                  ->Cortisol 未被有效抑制->胸/腹MRI, somatostatin scan->Ectopic ACTH


治療:

  手術切除 (腦垂體adenoma, adrenal tumor, ectopic ACTH-secreting tumor)
  If Transsphenoidal surgery (TSS)手術失敗:
      腦垂體 RT, + Medical adrenalectomy (mitotane) (500mg/#)  or bil surgical adrenalectomy
      Ketoconazole (± metyrapone) to↓cortisol

Medical Treatment of Cushing’s Syndrome

-Several drugs have been used in the treatment of Cushing’s syndrome. 278  

Metyrapone:

 -inhibits 11β-hydroxylase

-the most commonly given

-with a goal of lowering cortisol before definitive therapy or while awaiting benefit from pituitary irradiation.

-The dose must be determined by plasma or urinary free cortisol. 

-The  aim  should  be  to achieve  a  mean  plasma  cortisol  concentration  of  about 11 µg/dL during the day or a normal urinary free cortisol level.

-The drug is usually given in doses ranging from 250 mg bid to 1.5 g q6h.

-Nausea is a side effect that can be helped (if  it  is  not  caused  by adrenal insufficiency) by giving the drug with milk.

Aminoglutethimide 

-more toxic; 

-high dose blocks earlier enzymes in the steroidogenic pathway and therefore affect the secretion of steroids other than cortisol.

-In doses of 1.5 to 3 g /d (starting with 250 mg q8h), it commonly produces nausea, marked lethargy, and a high incidence of skin rash. 290  It is commonly prescribed as combination therapy with metyrapone.

Trilostane, 

-a 3β-HSD inhibitor,

-Cushing’s dz無效, because the block in steroidogenesis is overcome by the rise in ACTH.

-However, it can be effective in patients with adrenal adenomas.

Ketoconazole (200mg/#)

-an imidazole that has been widely used

-as an antifungal agent but causes abnormal liver function tests in about 15% of patients. 

-blocks a variety of steroidogenic cytochrome P450–dependent enzymes ->↓[cortisol]. 

-1-2# bid

ketoconazole的不良反應:
1.急性肝炎：因藥品毒性造成肝細胞破壞。
2.膽汁鬱積性肝炎:體內alkaline phosphatase(ALP)值顯著上升伴隨有或無之黃膽症，主因為膽道阻塞性黃膽、致膽汁鬱積之藥品反應、第一級膽汁性肝炎、硬化性膽道炎。
3.無症狀肝功能異常，致病率5~10%，指甲黴菌感染服用本品引致臨床肝炎症狀致病率小於3%，老年人最易發病，女性致病率為男性之2倍，病發時間具變化性，於使用後2~26週病發，肝細胞受傷引發黃膽，偶而接著產生猛爆性肝衰竭、膽汁鬱積性肝炎亦會發生，復原緩慢。
4.過敏反應徵象不會伴生肝傷害，致病因是直接之肝毒性。
5.其他不良反應:皮膚傷害、高血壓反應、急性肝炎、膽汁鬱積性肝炎、急性肝實質性及膽汁鬱積性肝傷害、促性腺激素及性激素功能不佳、女樣男乳、胃腸道疼痛、噁心、腹瀉、眩暈、頭疼、hypoadrenalism、低甲狀腺素血症、降低血中維生素D濃度、影響脂肪代謝、增加血中SHBG濃度、增加血中AST活性、低血鈉症、骨疾病、減少血中ACP活性、性功能障礙...
★禁與下列藥品併服:1.制酸劑:ketoconazole藥效降低. 2.酒精:產生disulfiram-like反應. 3.cyclosporine之作用及腎毒性增加. 4.corticosteroids血中濃度增加、毒性亦增加. 5.astemizole, terfenadine:心毒性反應. 6.warfarin抗凝血作用增加…

Thiazolidinedione, (ACTH-secreting pituitary tumor)

 * expression of the PPAR-γ receptor in ACTH-secreting pituitary tissue, a novel therapy for Cushing’s dz was devised

rosiglitazone. (avendia)

-Doses up to 8 mg/day are required to suppress cortisol secretion, and

-the drug seems to have lasting benefit in approximately 20% of cases studied. 294 

-Further studies are required.

Mitotane (o,p′-DDD) (Lysodren 500mg/#) (Adrenal CA)

-an adrenolytic drug that is taken up by both normal and malignant adrenal tissue, causing adrenal atrophy and necrosis.  -Because of its toxicity, used mainly in adrenal carcinoma. 

-up to 5 g/day (evidence that the drug causes tumor shrinkage or improves long-term survival is lacking). 

-Adrenal Ca:

  Adult: 初: 1-2g (2-4#) b-tid, titrate to 9-10g/d (6# tid) (max: 18-19g/d)

  Child: 0.5-1g bid, (max: 5-7g/d)

-Cushing’s synd:

  Adult: 初: 0.5-1g (1-2#) hs-tid, titrate to 4-12g/d (4-6#bid~6-8#tid)

-This agent also produces mineralocorticoid deficiency, -> glucocorticoid and mineralocorticoid replacement may be required. 

-[副]: common, fatigue, skin rashes, neurotoxicity, and GI disturbance.

Somatostatin analogues (octreotide and lanreotide are generally ineffective in Cushing’s dz).

 Pasireotide

-a novel somatostatin analogue, which demonstrates high-affinity binding to somatostatin receptor subtypes 1, 2, 3, and 5. 

-↓cortisol secretion was reported in 75% of Cushing’s dz patients treated for 15 days with pasireotide, 

-600 µg SC bid, 

-但urinary free cortisol 正常化不到 20%.