[Presentation of Case]
A 27-year-old woman presented to the endocrine clinic with progressive hepatitis and jaundice for 2 months. She had a medical history of Graves' disease for 9 years, for which she received regular anti-thyroid medications that consisted of carbimazole and propranolol at an outside hospital. She reported no prior allergy to anti-thyroid drugs before. Although she drank in moderation, she denied other habits such as smoking and betel-nut consumption. She worked as a stylist at a beauty parlour and performed outstandingly up until this present illness. She lived in the urban area of north Taiwan.
Because of preparation for pregnancy, carbimazole was switched to propylthiouracil (PTU), and she reported no discomfort until six months later, when she developed progressive jaundice, tea-color urine, and general malaise. The symptoms persisted, for which she visited the emergency department. She did not report abdominal pain, but experienced poor appetite, post-prandial discomfort, fever, and chills. The results of the laboraotory tests showed total bilirubin 16.9 mg/dl with direct form 16.8 mg/dl, AST 974 IU/L, ALT 1058 IU/L, ALP 130IU/L, GGT 107 IU/L, and coagulopathy (INR, 1.59). Free T4 was 2.31 ng/dl and TSH, <0.03 uIU/ml). Tests for HBsAg and anti-HCV antibody were both negative. The abdominal ultrasonography showed no specific finding or space occupying lesions.
PTU was changed to lithium for control of hyperthyroidism. The serum levels of IgG, IgM, and ceruloplasmin were within normal limits. Tests for anti-smooth muscle antibody and anti-mitochondrial antibody were negative, but positive ANA (1:40X) and low C3 (44.9 mg/dl) and C4 (7.7 mg/dl) were noted. Later, lithium was switched back to carbimazole. Mild elevation of serum p-ANCA level (7.8 U/ml) was noted but the level of serum c-ANCA was normal. A liver biopsy was performed because of slow recovery of abnormal liver function.
[Laboratory Study]
1.Biochemistry data:
|
AST
(IU/L) |
ALT
(IU/L) |
T-Bil.
(mg/dl) |
D-Bil.
(mg/dl) |
ALP
(IU/L) |
GGT
(IU/L) |
Alb
(gm/dl) |
Glo
(gm/dl) |
09-18 |
974 |
1058 |
16.9 |
16.8 |
130 |
107 |
|
|
09-22 |
626 |
658 |
20.8 |
11.9 |
113 |
62 |
|
|
09-27 |
456 |
456 |
19.4 |
|
|
|
|
|
10-04 |
349 |
341 |
16.0 |
|
|
|
|
|
10-12 |
151 |
169 |
8.6 |
6.3 |
131 |
68 |
3.4 |
2.8 |
10-18 |
112 |
101 |
6.1 |
4.5 |
129 |
72 |
3.1 |
2.6 |
10-26 |
96 |
81 |
4.6 |
3.0 |
147 |
82 |
3.1 |
2.8 |
2.Prothrombin time (PT):
|
Prothrombin time (sec) |
INR |
09-18 |
17.2 |
1.59 |
09-22 |
18.0 |
1.70 |
10-12 |
14.2 |
1.32 |
10-18 |
13.4 |
1.25 |
10-26 |
12.7 |
1.18 |
3.Serologies
Anti-HAV (IgM) |
HBsAg |
Anti-HBcAb (IgM) |
Anti-HCV Ab |
Negative |
Negative |
Negative |
Negative |
P-CNCA |
C-ANCA |
Anti-
Thyroglobulin Ab |
Anti-
Microsomal
Ab |
Anti-
Smooth
Muscle Ab |
Anti-
Mitochondrial Ab |
Positive |
Negative |
Postitive |
Positive |
Negative |
Negative |
HSV-1 IgM |
HSV-2 IgM |
CMV |
Negative |
Negative |
Negative |
4.Thyroid ultrasonography: Diffuse goiter, hypoechoic without nodular lesions.
圖一
5.Pathology of liver biopsy: Lymphocytic and scanty eosinophilic infiltration, and bridging fibrosis and prominent picecmeal necrosis
[Course and treatment]
A diagnosis of PTU-related toxic hepatitis was made based on the treatment course and pathology of liver biopsy. Carbimazole was continued with resolution of jaundice, elevated aminotranferases, and coagulopathy. Because of her intention of becoming pregnant, total thyroidemctomy with ablation was performed later.
[病例分析]
甲狀腺位在頸部脖子的淺層組織內，就在氣管的前方。血液的流量甚大，正常的甲狀腺摸起來具有彈性，有時候會摸到一些較硬的增生組織，稱為甲狀腺結節(nodular goiter)。甲狀腺荷爾蒙缺乏會造成人體對寒冷的耐受性減低，體重異常增加、身體黏性水腫(myxedema)、神智和身體活動變的笨拙和遲鈍。尤其在幼年期四歲以前缺少甲狀腺荷爾蒙，更會造成智力不足、身材矮小且終身不可逆的呆小症(cretinism)。反而言之，如果甲狀腺過度分泌，則會造成身體消瘦，情緒緊張焦慮，心跳加速(palpitation and tachycardia)，雙手顫抖(fine tremor)，有時甚至會造成心臟衰竭。甲狀腺機能亢進的病患女性較多，男性較少，根據不同的流行病學研究顯示，女性發病之比例約為男性的2至5倍，發病的年齡約在二十到四十歲之間最多見。60歲以上之老年人有時也會發現此類患者，但是診斷不易，因為老年人的症狀與年輕病患相較之下並不明顯，但常以心律不整表現，其中心房顫動(atrial fibrillation)是常見的異常。因為老年人發病時，可能因已經罹患另外的全身性疾病，如糖尿病、高血壓、心臟病等，而掩蔽了甲狀腺亢進的主要症狀，診斷產生偏差的比率也就更高了。
典型之甲狀腺機能亢進症狀多為「非特異性症狀」 (non-specific symptoms)，因此必須配合抽血測定血液中甲狀腺荷爾蒙的濃度(free T4, TSH, total T3/T4)來作完整的診斷。這些非特異性症狀包括：怕熱、容易流汗、心跳加快、心悸、雙手發抖、食慾增加但體重減輕、精神狀態焦慮緊張、容易失眠、大便次數增多且糞便變得較軟、女性病患更可見月經量減少、經期延後等。
甲狀腺機能亢進治療的藥物一般包括: propylthiouracil (PTU) 可以明確抑制T4轉變成T3，methimazole 及carbimazole，交感神經乙型阻斷劑 (beta-blocker:如 propranolol ) ：這是一種輔助性藥物，但是也可以輕微抑制組織內的T4去碘轉化為T3，主要是用來降低心跳速率及其不適，但應注意如果病患同時患有氣喘(asthma)或慢性氣管炎(chronic bronchitis)、慢性阻塞性肺疾病(COPD)的話，則須小心使用。而當甲狀腺機能亢進藥物產生明顯之過敏之現象時，過去文顯也報告過以燥症 (mania) 之治療藥物鋰鹽 (lithium) 治療甲狀腺機能亢進，但效果未能與傳統之藥物相比，且鋰鹽用藥之安全濃度範圍較小，易有危險，一般不做第一線治療。懷孕時甲狀腺機能亢進，propylthiouracil因較少穿透胎盤及無畸胎發生之相關報告，根據美國甲狀腺學會及美國食品藥物管理局(Food and Drugs Administration, FDA)的建議，在懷孕的前12週(first trimester)為比其他藥物理想的選擇。但是FDA在2010年時，根據過去相關之研究，提醒醫師必須謹慎使用propylthiouracil，因為propylthiouracil可以造成嚴重之肝毒性(hepatotoxicity)，甚至於急性肝衰竭 (acute liver failure)。而因為肝毒性可出現於使用propylthiouracil的任何階段，因此應該於使用propylthiouracil時，持續追蹤肝功能(AST及ALT)。但並無相關研究顯示持續追蹤肝功能可以預防propylthiouracil造成之猛爆性肝毒性。本病例即為此類之病患。
除了以上提及之嚴重副作用外，在甲狀腺機能亢進藥物的副作用及過敏方面，皮膚皮疹、搔癢及蕁麻疹(skin rash, pruritus and urticaria)約佔用藥病患的15~20%，治療倒是相當單純，多半會自動緩解或以antihistamine治療，即可迅速緩解。但研究也指出有 0.3~0.7% 的機會白血球缺乏症 (agranulocytosis) ，一般出現在使用抗甲狀腺藥4到6週左右，但也有用藥兩年後才出現之病例報告，由於會造成致命的感染，以往此類發生白血球缺乏症的病患約有25%之死亡率，必需立即停藥住院治療，現在因為白血球生成刺激素 (G-CSF) 的出現，病患因此合併症致命的機率已大幅降低了。
而甲狀腺風暴(thyroid storm) 則是目前較少見的，但極端與致命的甲亢現象，多見於甲狀腺機能亢進未接受藥物控制的病患，肇因於嚴重外傷、嚴重感染、分娩，或未接受術前藥物控制即貿然作甲狀腺切除等情況。因此甲狀腺機能亢進之病患，如果出現臨床上:（1）發燒，體溫上升且不易退燒，體溫多高於38.5℃；（2）極度的心跳過速，由於甲狀腺素大量釋出，造成代謝極度增加，心跳每分鐘均於120下以上，此時會有心臟衰竭的現象；（3）黃膽；（4）意識狀態模糊等症狀時，必須考慮甲狀腺風暴的可能。 |
Case Discussion
繼續教育考題