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< Presentation of a Case
>
A 40-year-old man was seen
because of progressive fatigue, constipation, and weight gain
(3 kg/month) for one month. His daily activity didn’t
decrease, and his appetite and intake didn’t increase. There
was no abdominal pain, diarrhea, vomiting, fever, or cough. He
had been receiving interferon-α (3 MIU 3 times/week
subcutaneous injection) and ribavirin (600 mg b.i.d) for
chronic hepatitis C since 7 months ago. Before therapy, the
serum aspartate aminotransferase (AST) was 28 U/L; alanine
aminotransferase (ALT) was 162 U/L; anti-HCV was positive;
free thyroxine (free T4 )
was 0.85 ng/dL (normal reference
0.6-1.75 ng/dL); thyrotropin (TSH) was 1.09 μIU/mL
(normal reference 0.1-4.5 μIU/mL); and anti-microsomal antibody (AMA) was
negative. During therapy, he had fever, anemia, nausea, insomnia, fatigue,
diarrhea, poor appetite, itching and weight
loss. Iron supplement and some medicines were given to
relieve the symptoms. The liver function profile (AST
& ALT) declined to normal range (18 & 20,
respectively) one month later. Serum HCV RNA was not detectable
after 2 months of therapy. The patient did not consume alcohol
or tobacco. He had no history of animal contact
or travel recently.
On examination, he had clear consciousness
but was ill-looking. His height was 170 cm and weight
was 67 kg. The temperature was 36.1°C, the pulse rate, 62
beats per minute and the respirations, 13 breaths per minute.
Blood pressure while in supine position was 102/68 mmHg.
The skin was dry and there was no cyanosis, petechiae,
purpura or pigmentation. His conjunctivae were pink, the
sclerae were anicteric and the pupils were isocoric with
prompt light reflexes. The neck was supple without
lymphadenopathy, engorged jugular veins, palpable thyroid
gland or carotid bruits. The chest wall expansion was
symmetric and breath sounds were bilaterally clear. The heart
beats were regular without audible murmur. The abdomen was
soft. Bowel sounds were hypoactive, and liver and spleen were
impalpable. The liver span was estimated 10 cm at the right
mid-clavicular line. His extremities were freely movable
without edema.
< Laboratory data
>
1. CBC
|
WBC |
RBC |
HB |
HCT |
MCV |
MCHC |
PLT |
|
K/μL |
M/μL |
g/dL |
％ |
fL |
g/dL |
K/μL |
|
5.34 |
4.2 |
13.1 |
41.7 |
83.2 |
31.4 |
184 |
2. BCS+e-
|
ALB |
TP |
T-Bil |
D-Bil |
AST |
ALT |
ALP |
γ-GT |
|
g/dL |
g/dL |
mg/dL |
mg/dL |
U/L |
U/L |
U/L |
U/L |
|
3.7 |
6.9 |
1.2 |
0.8 |
14 |
16 |
182 |
15 |
|
UN |
CRE |
Na+ |
K+ |
Ca2+ |
Glucose |
LDH |
|
mg/dL |
mg/dL |
mmol/L |
mmol/L |
mmol/L |
mg/dL |
U/L |
|
10.5 |
0.7 |
138 |
4.2 |
2.0 |
90 |
215 |
3.Thyroid function tests
|
hsTSH |
free T4
|
AMA |
|
0.1-4.5 μIU/mL |
0.60-1.75 ng/dL |
- |
|
25.8 |
0.48 |
1:1280 (+)
| *high sensitivity
thyroid-stimulating hormone＝hsTSH; free thyroxine＝free T4;
AMA＝anti-microsomal
antibodies
< Course
and treatment
>
Hypothyroidism and presence of AMA were
noted. Because liver function profile was normal and serum
HCV RNA was undete ctable, interferon-α and ribavirin were
discontinued after 6 months of therapy. However, he still felt
fatigue and had persistent weight gain 24 days after
discontinuation of anti-HCV therapy. AMA retuned to negative,
but the thyroid function tests still showed hypothyroidism
(fT4 0.45 ng/dL, hsTSH 67 μIU/mL). He began to
receive thyroid hormone replacement with levothyroxine sodium
100 μg q.d. The symptoms, including fatigue, constipation and
weight gain, resolved gradually. Follow-up serum hsTSH was
0.24 μIU/mL 4 months later and levothyroxine was reduced in
dose, which was subsequently discontinued 2 months later.
Follow-up hsTSH was 1.96 μIU/mL and AMA was negative one month
after discontinuation of thyroid hormone replacement. He was
followed-up regularly at OPD without thyroid hormone
replacement.
< Discussion
>
根據世界衛生組織估計，全世界約有3％的人口患有慢性C型肝炎。感染C型肝炎病毒後20年，約有20~40％會進展成肝硬化，一旦進行到肝硬化，每年約2
~5％會產生肝癌，嚴重之肝炎患者（肝發炎指數升高及肝臟切片出現纖維化）尤其容易發生，因此需要非常積極的治療。治療之目的是為了清除體內的C型肝炎病毒、延緩肝臟纖維化及硬化，以及預防肝癌的產生。目前的治療方式包括短效型干擾素（interferon-α，每週皮下注射3次）合併口服抗病毒藥物（ribavirin）及長效型干擾素（每週皮下注射1次）合併口服抗病毒藥物（ribavirin），需連續治療半年或1年。
干擾素是身體被病毒感染時產生的醣蛋白，可調節免疫系統，抑制淋巴細胞增生，增強細胞毒性 T
細胞與自然殺手細胞的反應，當體內干擾素製造不足時，會增加疾病感染的嚴重性，因此可用來治療病毒性肝炎和一些癌症。然而，使用上也會受限於其副作用，包括感冒症狀（如發燒、畏寒、頭痛、全身無力、肌肉酸痛）、腸胃不適（噁心、嘔吐、腹瀉、厭食、食慾不振）、憂鬱、失眠、注意力不集中、煩燥不安、體重減輕、皮膚搔癢、掉髮、甲狀腺功能異常、誘發自體免疫疾病、視網膜病變及血液檢驗學變化，如白血球減少，使得抵抗力差；紅血球減少，出現貧血；血小板數減少，導致易出血及流血不止。醫師應定期監測，必要時減少治療劑量。Ribavirin的副作用，包括出現溶血性貧血、咳嗽、呼吸困難、出現疹子、搔癢、食慾減退，及致畸胎。女性病人或男性病人之伴侶，在其治療期間及治療結束一年內應避免懷孕。
C型肝炎本身是否會引發甲狀腺抗體及功能異常頗受爭議，一般懷疑可能是透過C型肝炎病毒引發B淋巴球增生，製造許多不同的自體免疫抗體而引起的。但是interferon-α會引發自體免疫性甲狀腺疾病卻是無庸置疑的，西元1985年時發表了首位病例，之後陸續有相關的病例報告，發生率為2.7~14.3％，以女性居多，但是與interferon-α的劑量和治療效果無關，確切的病理機轉不明，因為interferon-α引起的甲狀腺功能低下患者大多數都有出現甲狀腺微粒體抗體（anti-microsomal
antibody），所以一般認為是經由自體免疫反應所造成。Interferon-α引發的甲狀腺疾病分為三種：自體免疫性甲狀腺功能低下、破壞性甲狀腺炎、及葛瑞夫茲氏病甲狀腺功能亢進，其中以甲狀腺功能低下的發生率比亢進高。開始發生甲狀腺功能異常的時間差異很大，可以在開始使用interferon-α後4週出現，也可能晚至23個月後才發生。雖然interferon-α引發的甲狀腺功能低下者大部分都有甲狀腺微粒體抗體，但是停藥後不一定會消失。
幾乎所有發生甲狀腺功能異常的病患，在甲狀腺素或抗甲狀腺藥物控制下都能完成C型肝炎的療程，只有少數人需要將藥物減量，但是目前臨床處理方法尚未有準則。總之，對於使用interferon-α和ribavirin治療C型肝炎的病人都應事先告知可能的副作用，治療期間醫師也應提高警覺。
< References
>
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Hepatitis C: global prevalence. Wkly Epidemiol Rec 1997;
72:341-344.
- Wong V, Fu AX, George J, Cheung NW.
Thyrotoxicosis induced by alpha-interferon therapy in
chronic viral hepatitis. Clin Endocrinol 2002; 56:793-798.
- Antonelli A, Ferri C, Pampana A, et
al. Thyroid disorders in chronic hepatitis C. Am J Med
2004;117:10-13.
- Prummel MF, Laurberg P.
Interferon-alpha and autoimmune thyroid disease. Thyroid
2003;13:547-551.
- Fentiman IS, Thomas BS, Balkwill
FR, Rubens R, Dm Hayward JL. Primary hypothyroidism
associated with interferon therapy of breast cancer. Lancet
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- Doi F, Kakizaki S, Takagi H, et al. Long-term outcome of
interferon-alpha-induced autoimmune thyroid disorders in
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Case Discussion
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