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A 36-year-old woman
was seen because of persistent fever and sore throat
for 5 days. Two months before this admission, she
began to develop resting tremor of the hands, palpitation, heat intolerance, and
weight loss of 3 kg in one
month. Thyroid function tests revealed a value of high sensitivity thyroid-stimulating hormone
(hsTSH) that was less than 0.004 μIU/mL, and a
value of free thyroxine (free T4) more than 4.8
ng/dL. Both anti-microsomal antibody (AMA) and TSH receptor antibody were present.
Graves' disease was diagnosed, and carbimazole 10
mg t.i.d and betaxalol 10 mg q.d
were prescribed. Because carbimazole-related skin rashes and pruritus
occurred, anti-histamine agents were administered and anti-thyroid agents were
changed to propylthiouracil (PTU) 50 mg t.i.d. Skin rashes subsided gradually.
However, fever, sore throat, cough and rhinorrhea occurred on
the fifth day of PTU initiation. She visited
a local clinic where some medicines were prescribed for symptom relief.
Because of persistent fever and sore throat for 5 days, she
visited our ER.
She had no other systemic disease
and did not consume alcohol, or tobacco. She had no
history of animal contact or travel recently.
On examination, she had clear
consciousness but was ill-looking. Her height was 154.2 cm and
weight was 56 kg. The temperature was 37.6°C, the pulse rate
90 beats per minute and the respiratory rate 18 breaths per
minute. Blood pressure while in supine position was 122/70
mmHg. There was no cyanosis, petechiae, purpura, skin rashes,
pigmentation or exophthalmus. Her conjunctivae were pink, the
sclerae anicteric and the pupils isocoric with prompt light
reflexes. Injected throat and enlarged tonsils were noted.
There was no oral ulcer, vesicle or gum bleeding. The neck was
supple without lymphadenopathy, engorged jugular veins, or
carotid bruits. Grade I diffuse goiter was noted. The chest
wall expansion was symmetric and breath sounds were
bilaterally clear. The heart beats were regular without
audible murmur. The abdomen was soft and bowel sounds were
normoactive. The liver and spleen were impalpable. The liver
span was estimated 10 cm at the right mid-clavicular line. The
extremities were freely movable without edema.
< Laboratory Data
>
1. CBC/DC
|
WBC |
RBC |
HB |
HCT |
MCV |
MCHC |
PLT |
|
K/μL |
M/μL |
g/dL |
% |
fL |
g/dL |
K/μL |
|
3.10 |
5.12 |
13.4 |
35.8 |
80.7 |
33.2 |
231 |
|
Band |
Seg |
Eos |
Baso |
Mono |
Lymph |
|
% |
% |
% |
% |
% |
% |
|
8 |
8 |
2.0 |
1.0 |
24 |
58 |
2. BCS + e-
|
UN |
CRE |
T-Bil |
AST |
ALT |
Na+ |
K+ |
LDH |
|
mg/dL |
mg/dL |
mg/dL |
U/L |
U/L |
mmol/L |
mmol/L |
U/L |
|
10 |
0.7 |
0.47 |
17 |
27 |
139 |
3.8 |
254 |
3.
Urine analysis
|
Appearance |
Sp. Gr |
pH |
Protein |
Glucose |
Ketone |
Porphyrin |
|
|
|
|
g/dL |
mg/dL |
|
|
|
Y;C |
1.12 |
5.5 |
- |
- |
- |
+ |
|
Urobilirubin |
Bilirubin |
Nitrate |
WBC |
RBC |
Epi |
Cast |
|
|
|
|
|
|
HPF |
|
|
1.0 |
- |
- |
- |
- |
1-3 |
- |
4. Chest X ray : normal
<
Treatment and Course >
The hemogram showed neutropenia (496 cells/μL).
Propylthiouracil (PTU) was discontinued during hospitalization because
PTU-related agranulocytosis was suspected. Empiric antibiotics
were administered for acute tonsillitis. The granulocytes
gradually increased to normal. Lithium was prescribed for
control of hyperthyroidism. She was discharged in a stable
condition. Radioactive iodine therapy was subsequently
initiated.
< Discussion
>
甲狀腺機能亢進(hyperthyroidism)是一種常見的疾病，原因很多，最常見的是Graves'
disease，其次是多發性甲狀腺結節或甲狀腺腺瘤，治療上雖有些許差異，但不外乎抗甲狀腺藥物(anti-thyroid
agents)、放射線與手術治療，貝他阻斷劑(β-blocker)、鋰鹽(lithium)及碘劑也有其用處。抗甲狀腺藥物是指thionamide類藥物，包括propylthiouracil
(Procil)、methimazole (Tapazole)和carbimazole
(Neothyreostat、Newmazole)。carbimazole在體內可迅速變為
methimazole，因此，後兩種藥可視為相同。抗甲狀腺藥物的作用機轉相當複雜，包括甲狀腺內及甲狀腺外之作用，前者含抑制碘有機化、抑制iodotyrosine相結合成為甲狀腺素、和thyroglobulin結合而改變其結構，及抑制thyroglobulin合成；後者含抑制T4轉變成T3
(propylthiouracil)及抑制免疫反應。
抗甲狀腺藥物的副作用包括皮膚疹(5%)、發燒、腸胃道症狀、味覺及嗅覺異常(methimazole)、關節炎、肝炎(propylthiouracil)、再生不良貧血、膽汁滯留性黃疸(methimazole)、血管炎、紅斑性狼瘡、低血糖(由於產生胰島素抗體，methimazole)、血小板缺乏症、顆粒白血球缺乏症(agranulocytosis，0.5%)。雖然有許多的副作用都很嚴重，但是少見，其中最需要注意的就是顆粒白血球缺乏症，其定義為顆粒白血球小於500
cells/μL，且常常會低到接近零。根據台大醫院統計(1987~1997年)，在5653個服用抗甲狀腺藥物患者中，有13個病人(0.23%)發生顆粒白血球缺乏症合併嚴重感染，臨床上主要以發燒(92%)及喉嚨痛(85%)為表現，剛開始的感染包括急性咽炎(acute
pharyngitis，46%)、急性扁桃腺炎(acute
tonsillitis，38%)、肺炎(15%)及泌尿道感染(8%)，主要的病菌為Pseudomonas
aeruginosa，所以建議合併有嚴重感染病患應使用可以對抗Pseudomonas
aeruginosa之廣效抗生素。一般在開始用藥的前三個月內發生，但是一年後也有可能會出現，使用低劑量的methimazole可能比propylthiouracil或高劑量的methimazole有較低的機率產生顆粒白血球缺乏症，由於常常快速地出現顆粒白血球缺乏症，所以定期檢查白血球並沒有幫助。
使用抗甲狀腺藥物若發生輕微副作用，可考慮換成另一種抗甲狀腺藥物
(如methimazole換成propylthiouracil)，但是如果產生嚴重副作用，則終身不可再用此類藥物。當發生顆粒白血球缺乏症時，應立即停藥，給予隔離及適當的抗生素治療，一般約二週左右，白血球即可慢慢恢復，另可給予顆粒白血球生長素(granulocyte
colony stimulating factor，GCSF)縮短白血球低下的時間。
Graves疾病通常需服用抗甲狀腺藥物1-2年，如果復發，就使用放射碘或手術治療。
< 參考資料
>
- Sheng WH, et al. Antithyroid drug-induced
agranulocytosis complicated by life-threatening infections.
QJM 1999;92:455-61.
- Franklyn JA. The management of hyperthyroidism. N
Engl J Med 1994; 330:1731-8.
- Hirsch D, et al. Treatment of antithyroid
drug-induced agranulocytosis by granulocyte
colony-stimulating factor: a case of primum non nocere.
Thyroid 1999;9:1033-5.
- Tajirl J, Noguchi S, et al. Antithyroid
drug-induced agranulocytosis: the usefulness of routine
white blood cell count monitoring. Arch Intern Med
1990;150:621-4.
- Meyer-Gessner M, Benker G, et al.
Antithyroid drug induced agranulocytosis: clinical
experience with ten patients treated at one institute and
review of literature. J Endocrinol Invest 1994;17: 29-36.
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Case Discussion
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