- 學位論文
奎寧對橋本氏甲狀腺炎患者甲狀腺機能與抗體之影響
The Effects of Hydroxychloroquine on Thyroid Functions and Anti-thyroid Auto-antibodies in Subjects with Hashimoto’s Thyroiditis
摘要
橋本氏甲狀腺炎（Hashimoto’s thyroiditis）是一種器官特異性的自體免疫疾病，現今又稱為自體免疫性甲狀腺疾病（autoimmune thyroid disease），大多發生於女性，男女比例約為1: 5–10，發生率約為0.8–3.5/1000人年。在碘攝取充足的地區，自體免疫性甲狀腺疾病是造成甲狀腺腫與甲狀腺機能低下症最主要的成因。自體免疫性甲狀腺疾病診斷時，甲狀腺機能多數為正常，約四分之一已是甲狀腺機能低下症（hypothyroidism）。橋本氏甲狀腺炎主要造成甲狀腺腫（goiter）、甲狀腺慢性發炎，逐漸破壞甲狀腺正常組織，最後進展至甲狀腺機能低下症。 自體免疫性甲狀腺疾病致病機轉目前尚未完全明瞭，已知為一種典型的T-細胞媒介的自體免疫疾病，甲狀腺上皮細胞的細胞內蛋白藉由抗原表達細胞激活輔助型T細胞，促使B細胞分泌抗甲狀腺自體免疫抗體，激活細胞毒殺T淋巴球，引發抗體依賴型細胞媒介細胞毒性作用，逐漸破壞甲狀腺組織。 自體免疫性甲狀腺疾病患者的血清，約90%有陽性抗甲狀腺過氧化酶抗體（Anti-TPO antibody），約20 –50%有陽性抗甲狀腺球蛋白抗體（anti-thyroglobulin antibody）。臨床上，也發現抗甲狀腺自體免疫抗體（anti-thyroid autoantibody）價數越高者進展到甲狀腺機能低下的比例也較高，抗甲狀腺過氧化酶抗體的價數和甲狀腺淋巴球浸潤嚴重程度與甲狀腺被破壞程度相關。研究亦顯示血清有陽性抗甲狀腺自體免疫抗體的育齡女性雖然受孕機率不受影響，相較於陰性抗體者，自發性流產的機率較高。相較於一般懷孕婦女，罹患自體免疫性甲狀腺疾病、即使甲狀腺機能正常的懷孕婦女仍有較高自發性流產的風險，同時與一些懷孕相關併發症，包括妊娠高血壓、晚期流產、胎兒死亡、早產、產後憂鬱或其他情緒問題相關。對於母親有罹患自體免疫性甲狀腺疾病的嬰兒也有報告指出他們發生新生兒呼吸窘迫、新生兒短暫性甲狀腺機能低下、血清有抗甲狀腺自體免疫抗體的比例較高，在兒童期與青少年時期發生甲狀腺機能異常與甲狀腺腫的風險亦較高。 然而，針對多數罹患自體免疫性甲狀腺疾病、但甲狀腺機能正常的患者，臨床治療指引上沒有任何建議的治療藥物。醫師會對患者進行衛教，強調低碘飲食的重要性，避免甲狀腺持續腫大與期待減緩病程進展至甲狀腺機能低下症。同時要求患者需規則地追蹤甲狀腺機能與甲狀腺腫的狀況，待疾病惡化至甲狀腺機能低下症後，便開始給予甲狀腺素（levothyroxine）補充治療。另外，針對有較大甲狀腺腫的患者，也可考慮給予甲狀腺素來抑制甲促素（thyroid-stimulating hormone, TSH）治療甲狀腺腫。 另一方面，奎寧（Hydroxychloroquine）原為預防與治療瘧疾之用藥，現今用作為免疫調節劑，已取得美國藥品食品管理局與台灣衛生署的適應症，可用於多種自體免疫疾病包括紅斑性狼瘡、類風溼性關節炎等的治療。臨床上，奎寧能降低高免疫球蛋白血症、促發炎指數以及慢性發炎相關的指標，如貧血等。其免疫調節機轉尚未完全清楚，已知奎寧為親脂性弱鹼，可進入溶酶體改變其酸鹼值，藉由影響細胞中蛋白處理過程，減少抗原表達細胞呈現自體抗原給輔助型T細胞（T helper cells），進而抑制下游細胞毒殺性T細胞與B細胞自體免疫抗體的產生。 已知自體免疫性甲狀腺疾病起源於甲狀腺上皮細胞的細胞內蛋白因某些環境因素或受到傷害，藉由抗原表達細胞處理後，激活輔助型T細胞，造成後續一連串T-細胞媒介的自體免疫反應，加上已知奎寧藉由改變溶酶體的酸鹼值，影響細胞中蛋白處理過程，進而減少細胞激素與免疫媒介物的製造、抗原表達細胞呈現自體抗原給T細胞與自體免疫抗體的產生。因此，我們假設奎寧能阻斷甲狀腺上皮細胞內蛋白的自體抗原藉由抗原表達細胞呈現給輔助型T細胞的過程，抑制後續因激活輔助型T細胞後引發的一連串T-細胞媒介的自體免疫反應，進而減輕甲狀腺發炎與甲狀腺腫的形成。 本研究目的主要探討與比較在罹患自體免疫性甲狀腺疾病患者中，有無接受免疫調節製劑–奎寧治療，對於其血清中抗甲狀腺自體免疫抗體與甲狀腺機能的影響。期待未來對於罹患自體免疫性甲狀腺疾病且甲狀腺機能正常的患者能提供一針對甲狀腺自體免疫性治療的藥物的新方向。 本研究為回溯性病歷回顧。在西元2011年十月至西元2012年六月之間，收集有接受規則抽血追蹤與回診至少18個月的自體免疫性甲狀腺疾病患者共97位。其中22位曾經接受過六個月奎寧治療，作為治療組，剩餘73位沒有接受過奎寧治療的患者作為無治療對照組。針對接受奎寧治療的患者，比較其在治療前、治療中與治療結束時，血清抗甲狀腺自體免疫抗體與甲狀腺機能的變化。另外，比較有無接受奎寧治療的患者之間，其血清抗甲狀腺自體免疫抗體與甲狀腺機能的變化。最後，在停止奎寧治療後的一年間，比較曾接受過奎寧治療與未曾接受過奎寧治療的患者，其血清抗甲狀腺自體免疫抗體與甲狀腺機能的變化。 納入研究的自體免疫性甲狀腺疾病個案以中年女性為主。首先，在治療組中，奎寧能明顯地降低抗甲狀腺過氧化酶抗體指數（anti-TPO antibody在治療前、治療三個月後與治療六個月後指數的中位數[四分差範圍]依序為1162.80 [213.07–1607.90] IU/mL v.s. 541.65 [134.28–946.14] IU/mL v.s. 398.27 [109.95–636.23] IU/mL, p<0.001）；抗甲狀腺球蛋白抗指數在接受奎寧治療後也有下降（TA在治療前、治療三個月後與治療六個月後指數的中位數[四分差範圍]依序為100.90 [24.26–397.80] IU/mL v.s. 54.78 [19.24–295.37] IU/mL v.s. 75.57 [19.50–258.93] IU/mL, p<0.001）；甲狀腺賀爾蒙濃度包括游離四碘甲狀腺素（free T4）與甲促素（TSH）則無顯著差異。比較有無接受奎寧治療的兩組患者的血清，發現治療組血清中抗甲狀腺自體免疫抗體指數的降幅與無治療組有顯著的差異（治療組v.s.無治療對照組變化的中位數[四分差範圍]依序如下：ΔTPO = -460.26 [-949.17– -65.36] IU/mL v.s. -8.91 [-131.82–22.66] IU/mL, adjusted p<0.001; TPO ratio = 0.49 [0.35–0.56] v.s. 0.92 [0.67–1.23], adjusted p=0.032; ΔTA = -16.82 [-89.23– -10.24] IU/mL v.s. 0.04 [-22.1–20.97] IU/mL, adjusted p=0.688; TA ratio = 0.62 [0.48–0.86] v.s. 1.00 [0.59–1.23], adjusted p=0.014），然而，甲狀腺賀爾蒙濃度則無顯著差異。 在停止奎寧治療後繼續追蹤12個月，發現治療組血清中抗甲狀腺自體免疫抗體指數在停藥後有顯著回升（以中位數[四分差範圍]表示，ΔTPO = 452.19 [35.41–772.07] IU/mL v.s. 0 [-48.19–80.93] IU/mL, adjusted p<0.001, TPO ratio = 1.84 [1.06–2.74] v.s. 1.00 [0.77–1.28], adjusted p=0.001）。 本研究顯示奎寧治療對罹患自體免疫性甲狀腺疾病的患者確實有影響，奎寧能顯著降低患者血清中的抗甲狀腺自體免疫抗體指數。然而，對於甲狀腺腫、後續甲狀腺機能變化、其他相關發炎指標與懷孕相關併發症的影響則有待進一步的研究。
並列摘要
Hashimoto’s thyroiditis (HT) is a common form of autoimmune thyroid disease (ATD), which affects up to 2–5 % of general population. It occurs 5–10 times more common in women than men. The annual incidence of HT worldwide is estimated to be 0.8–3.5 cases per 1000 persons. The incidence varies widely in different geographic locations depending on iodine content of diet and various environmental factors. ATD is the most frequent cause of hypothyroidism and goiter in countries where ordinary diet provides sufficient iodine. The three-quarters of subjects with HT have normal thyroid function at presentation, and 15–20% of subjects already have hypothyroidism. The euthyroid phase is often followed by a gradual development of subclinical hypothyroidism, which progress slowly to overt hypothyroidism. The prevalence of anti-thyroglobulin antibody (TA) in subjects with ATD is 25–50%, while 90–95% subjects has positive anti-thyroid peroxidase (TPO) antibody. High serum anti-TPO antibody concentrations predicted the progression of subclinical hypothyroidism to overt hypothyroidism. The anti-TPO antibody concentration is also closely associated with overt thyroid dysfunction, and their presence tends to correlate with thyroidal damage and lymphocyte infiltration. The presence of anti-thyroid autoantibody alone is associated with negative pregnancy outcomes, including placental abruption, gestational hypertension, preeclampsia, late abortion, fetal death, premature delivery, and neonatal respiratory distress. Although hypothyroid patients with ATD require levothyroxine replacement therapy, much less is known about benefits of any medical treatment in euthyroid patients with ATD. Hydroxychloroquine (HCQ) is an anti-malarial agent, and has been used as anti-rheumatic treatment in several autoimmune diseases. It is generally proposed that the mechanism of action of these anti-malarial agents as anti-rheumatic drugs results from their inhibition of antigen processing and presentation. This study is aimed to investigate the effect of HCQ treatment on serum anti-thyroid autoantibodies and thyroid functions in subjects with ATD. This is a retrospective chart review. A total of 97 subjects with HT having regular blood tests and follow-up at outpatient department were enrolled. Twenty-three of them having a six–month Plaquenil® treatment were defined as the treatment groups. The remained 74 subjects without experience of Plaquenil treatment were comprised as the non-treatment groups. ATD was diagnosed by positive serum anti-TPO antibody and/or positive TA concentrations. The differences in thyroid function and serum autoantibodies were compared between before, 3–month, and 6–month of Plaquenil treatment in the treatment group. The differences in thyroid function and serum autoantibodies were also compared between before and after Plaquenil treatment between the treatment and the non-treatment groups. In the present study, the majority of the study population was middle-aged women. The disease durations were 30.6 (6.8–93.4) and 39.1 (17.2–85.8) months in the treatment and the non-treatment group, respectively. The anti-TPO antibody concentration was significantly decreased after three–month of Plaquenil treatment, and continuously decreased after six–month of Plaquenil treatment (presented as median [interquartile range], 1162.80 [213.07–1607.90] IU/mL v.s. 541.65 [134.28–846.14] IU/mL v.s. 398.27 [109.95–636.23] IU/mL at baseline, 3–month, and 6–month, respectively, p<0.001). The TA titer was also decreased significantly at both third and sixth month of Plaquenil treatment comparing to the baseline (presented as median [interquartile range], 100.90 [24.26–397.80] IU/mL v.s. 54.78 [19.24–295.37] IU/mL v.s. 75.57 [19.50–258.93] IU/mL at baseline, 3–month, and 6–month, respectively, p<0.001). Compared the treatment group to the non-treatment group, the anti-TPO antibody concentrations were significantly reduced after Plaquenil treatment (presented as median [interquatile range], ΔTPO = -460.26 [-949.17– -65.36] IU/mL v.s. -8.91 [-131.82–22.66] IU/mL, adjusted p<0.001; TPO ratio = 0.49 [0.35–0.56] v.s. 0.92 [0.67–1.23], adjusted p=0.032; ΔTA = -16.82 [-89.23– -10.24] IU/mL v.s. 0.04 [-22.1–20.97] IU/mL, adjusted p=0.688; TA ratio = 0.62 [0.48–0.86] v.s. 1.00 [0.59–1.23], adjusted p=0.014). There was a significant increase in anti-TPO antibody concentrations twelve months after discontinuing Plaquenil treatment in the treatment group compared to the non-treatment group (presented as median [interquatile range], ΔTPO = 452.19 [35.41–772.07] IU/mL v.s. 0 [-48.19–80.93] IU/mL, adjusted p<0.001, TPO ratio = 1.84 [1.06–2.74] v.s. 1.00 [0.77–1.28], adjusted p=0.001). The study has shown that hydroxychloroquine treatment had significant effects in subjects with autoimmune thyroid disease. It significantly reduced the serum anti-TPO antibody and TA concentrations. However, we need further randomized control trial to evaluate its effects on goiter, subsequent thyroid hormone trends, serum inflammatory markers, and pregnancy complications.