本文關(guān)鍵詞：橋本氏甲狀腺炎與IgG4相關(guān)性疾病有關(guān)的臨床病理學(xué)特征的相關(guān)研究，，由筆耕文化傳播整理發(fā)布。

        [研究背景與目的]橋本氏甲狀腺炎(Hashimoto’s thyroiditis, HT)又被稱為橋本氏病(Hashimoto’s disease, HD)或慢性淋巴細(xì)胞性甲狀腺炎(Chronic lymphocytic thyroiditis),是世界上飲食富碘地區(qū)引發(fā)甲狀腺腫性甲狀腺功能減退的最常見原因。橋本氏甲狀腺炎多發(fā)于30至50歲中年女性,其發(fā)病率通常是男性的10倍左右,同時(shí)也是引發(fā)兒童非地方性甲狀腺腫的最主要病因。甲狀腺對(duì)稱性增大且質(zhì)地堅(jiān)韌通常是橋本氏甲狀腺炎患者最初的臨床表現(xiàn)。腫大的甲狀腺一般呈中等度增大,體積約為正常甲狀腺的2-4倍大小,并且進(jìn)展緩慢。然而在某些情況下,甲狀腺體積可顯著快速增大,并且伴發(fā)甲狀腺的壓痛及疼痛。這些癥狀極易使之與亞急性甲狀腺炎相混淆。橋本氏甲狀腺炎的另一臨床特征為多數(shù)患者可呈現(xiàn)不同程度的疲乏,嗜睡,怕冷,皮膚蒼白干燥,食欲不振而體重增加等甲狀腺功能減退的癥狀。與Ⅰ型糖尿病類似,作為人類最常見的一種自身免疫性疾病,橋本氏甲狀腺炎患者的血清學(xué)特征為抗甲狀腺球蛋白抗體(TgAb)和抗甲狀腺過氧化物酶抗體(TPOAb)的出現(xiàn)。檢測(cè)上述甲狀腺特異性自身抗體,已成為國(guó)際上通用的診斷橋本氏甲狀腺炎的重要方法。超聲學(xué)檢查是診斷甲狀腺疾病的最重要的影像學(xué)手段。橋本氏甲狀腺炎的超聲學(xué)表現(xiàn),多為彌漫性低回聲區(qū)的出現(xiàn),或者呈現(xiàn)粗細(xì)不等的網(wǎng)絡(luò)狀回聲區(qū)。日本學(xué)者Hayashi和Johns Hopkins大學(xué)的研究人員證實(shí),在橋本氏甲狀腺炎中,彌漫性低回聲區(qū)的出現(xiàn)與患者甲狀腺功能的減退及嚴(yán)重的濾泡變性顯著相關(guān)。1912年,日本橋本策博士首先報(bào)告并描述了四例橋本氏甲狀腺炎的組織病理學(xué)特征。經(jīng)過100多年的探索和總結(jié),目前國(guó)際公認(rèn)的橋本氏甲狀腺炎組織病理學(xué)表現(xiàn)包括：彌漫性淋巴細(xì)胞/漿細(xì)胞浸潤(rùn),有成熟生發(fā)中心的淋巴濾泡的形成以及甲狀腺濾泡上皮的嗜酸性變。盡管上述特征在病理學(xué)方面較好地定義了橋本氏甲狀腺炎的概念,然而一系列的研究表明橋本氏甲狀腺炎并非單一型的病變,它包含了若干亞型。目前研究最為廣泛,在日常診斷工作中最為常見的是橋本氏甲狀腺炎纖維化亞型(Fibrous variant of Hashimoto’s thyroiditis, FVHT)。橋本策在他的論著中首先描述了這種纖維化亞型。1974年,Katz和Vickery重新定義了纖維化亞型的病理學(xué)特征,并且指出與典型的橋本氏甲狀腺炎相比,纖維化亞型表現(xiàn)出了一系列獨(dú)特的臨床特征包括：短期內(nèi)甲狀腺體積顯著增大,嚴(yán)重的頸部壓迫癥狀,容易被誤診為惡性腫瘤以及抗甲狀腺球蛋白抗體的顯著升高。根據(jù)上述臨床,實(shí)驗(yàn)室,影像學(xué)以及病理學(xué)的特征,我們可以看出橋本氏甲狀腺炎雖然不像惡性腫瘤那樣直接威脅患者的生命安全,但是其發(fā)生率較高,病程漫長(zhǎng),尤其是出現(xiàn)甲狀腺功能減退癥狀后將嚴(yán)重影響患者的生活質(zhì)量。目前國(guó)際上通用多年的治療方案為甲狀腺片劑替代治療,然而大多數(shù)患者需要長(zhǎng)期或終生服藥,且有不可避免的副作用。當(dāng)甲狀腺腫大嚴(yán)重影響患者日常生活,或者穿刺活檢結(jié)果不能排除甲狀腺惡性腫瘤時(shí),橋本氏甲狀腺炎患者還需接受手術(shù)治療,切除全部或部分甲狀腺組織。因此,如何突破橋本氏甲狀腺炎的傳統(tǒng)定義,及早發(fā)現(xiàn)可能引發(fā)嚴(yán)重臨床表現(xiàn)的亞型,提出切實(shí)有效的診斷標(biāo)準(zhǔn),同時(shí)引入新的治療理念,就成為了擺在醫(yī)務(wù)工作者面前的革命性課題。免疫球蛋白G4(Immunoglobulin G4, IgG4)是免疫球蛋白G (Immunoglobulin G, IgG)所有亞型中所占比例最低的一種,它只占正常人血清IgG的3-6%。過去我們認(rèn)為血清IgG4水平的升高僅見于少數(shù)幾種情況,如特異性皮炎,寄生蟲疾病以及自身免疫性大皰性皮膚病。因此有很長(zhǎng)一段時(shí)間,鮮有關(guān)于IgG4的研究,直到2001年Hamano等首先報(bào)告在自身免疫性胰腺炎(Autoimmune pancreatitis, AIP)的患者血清中發(fā)現(xiàn)了IgG4水平的顯著升高。隨后,該研究組進(jìn)一步證實(shí)了在AIP患者的胰腺組織中發(fā)現(xiàn)了大量IgG4陽性漿細(xì)胞的浸潤(rùn)。在此之后,Kamisawa等提出AIP常合并其他器官和組織,如唾液腺,膽管和腹膜后組織的類似病變,而這些器官組織的標(biāo)本都顯示有大量IgG4陽性漿細(xì)胞浸潤(rùn)�；谏鲜霭l(fā)現(xiàn),Kamisawa研究組首次提出了IgG4相關(guān)性疾病(IgG4-related disease, IgG4-RD)的概念。此后,隨著研究范圍的不斷擴(kuò)大,更多的胰腺外病變被證實(shí)為IgG4-RD這一疾病系列的成員。這其中包括硬化性膽管炎,硬化性唾液腺炎,肝炎性假瘤,炎性主動(dòng)脈瘤以及腎小管間質(zhì)性腎炎等。作為IgG4-RD成員,上述病變呈現(xiàn)出了極為相似的組織病理學(xué)表現(xiàn),包括彌漫性淋巴細(xì)胞漿細(xì)胞浸潤(rùn)(diffuse lymphoplasmacytic infiltration),間質(zhì)纖維化(stromal fibrosis),阻塞性靜脈炎(obliterative phlebitis)以及大量IgG4陽性漿細(xì)胞的浸潤(rùn)(large amount of IgG4-positive plasma cell infiltration)。臨床方面,IgG4-RD則以血清IgG4水平升高和對(duì)類固醇激素治療反應(yīng)良好為特征。IgG4-RD概念的提出對(duì)于臨床和病理工作者來說意義重大：它促使我們對(duì)一些過去熟知的疾病進(jìn)行重新認(rèn)識(shí)和分類,進(jìn)而調(diào)整治療方案,避免不必要的手術(shù)治療,提高患者的生活質(zhì)量。2009年,作者所在的研究組率先將IgG4-RD的概念引入橋本氏甲狀腺炎的研究領(lǐng)域,并證實(shí)了在橋本氏甲狀腺炎中存在一種特殊的亞型,該亞型表現(xiàn)出與其他器官IgG4-RD極為相似的病理學(xué)特征其中包括有大量IgG4陽性漿細(xì)胞浸潤(rùn),我們稱之為IgG4亞型(IgG4related, IgG4-positive plasma cell-rich group)。同時(shí),我們提出區(qū)分IgG4亞型與非IgG4亞型(non-IgG4related, IgG4-positive plasma cell-poor group)的免疫組織化學(xué)標(biāo)準(zhǔn)。該研究填補(bǔ)了國(guó)內(nèi)外IgG4相關(guān)性疾病研究的空白,為重新認(rèn)識(shí)橋本氏甲狀腺炎提供了全新的思路。本研究分為兩個(gè)部分。第一部分研究?jī)?nèi)容為分析比較橋本氏甲狀腺炎IgG4亞型與非IgG4亞型在臨床表現(xiàn),實(shí)驗(yàn)室檢查以及超聲學(xué)檢查方面的差異,為今后的臨床診斷工作提供有益的參考。第二部分內(nèi)容旨在全面系統(tǒng)分析IgG4亞型與非IgG4亞型在組織病理學(xué)方面的差異,為最終確立橋本氏病IgG4亞型的病理學(xué)診斷標(biāo)準(zhǔn)奠定基礎(chǔ)。[研究方法]收集1983-2010年在日本隈病院接受甲狀腺全切術(shù)的橋本氏甲狀腺炎病例105例。建立患者的臨床信息數(shù)據(jù)庫,內(nèi)容包括年齡,性別,接受甲狀腺全切術(shù)的原因,手術(shù)前的罹病時(shí)間,切除甲狀腺的重量,術(shù)前接受L-T4治療的劑量,隨訪資料以及在隨訪過程中是否發(fā)生甲狀腺外IgG4-RD。實(shí)驗(yàn)室檢查患者手術(shù)前血清中TgAb和TPOAb水平,同時(shí)選擇有可用血清標(biāo)本的病例檢測(cè)手術(shù)前血清中IgG各亞型的水平,以及手術(shù)后的相應(yīng)變化。檢查病變甲狀腺的超聲學(xué)表現(xiàn)：將頸內(nèi)靜脈,頸動(dòng)脈的內(nèi)腔設(shè)置為無信號(hào)區(qū),在此系統(tǒng)中正常甲狀腺組織表現(xiàn)為統(tǒng)一的中等強(qiáng)度超聲信號(hào),高于周圍的肌肉組織。彌漫性低信號(hào)被定義為超聲信號(hào)明顯低于正常甲狀腺組織；粗細(xì)不等信號(hào)被定義為低信號(hào)與正常信號(hào)交織出現(xiàn)。所有石蠟標(biāo)本4μm連續(xù)切片,進(jìn)行HE, EvG以及MT染色,兩位病理醫(yī)生鏡下觀察8項(xiàng)組織病理學(xué)指標(biāo)并進(jìn)行分級(jí),包括：淋巴細(xì)胞漿細(xì)胞浸潤(rùn),間質(zhì)纖維化,阻塞型靜脈炎,甲狀腺濾泡大小,濾泡細(xì)胞變性程度,淋巴濾泡形成,巨細(xì)胞/組織細(xì)胞浸潤(rùn),以及實(shí)性細(xì)胞巢/扁平上皮樣化生。免疫組化檢測(cè)IgG4及IgG表達(dá)情況,選擇陽性細(xì)胞最密集區(qū)域的5個(gè)高倍視野進(jìn)行拍照,使用WinROOF version5.8軟件計(jì)數(shù)陽性細(xì)胞,并計(jì)算一個(gè)高倍視野陽性細(xì)胞數(shù)的平均值。最后,使用Graphpad軟件對(duì)上述臨床病理學(xué)指標(biāo)進(jìn)行統(tǒng)計(jì)分析。[研究結(jié)果]1.根據(jù)IgG4及IgG免疫組化結(jié)果,以及本研究組提出的IgG4亞型診斷標(biāo)準(zhǔn)(即每高倍鏡IgG4陽性漿細(xì)胞大于20個(gè)且IgG4陽性漿細(xì)胞占IgG陽性漿細(xì)胞比例大于30%),105例橋本氏甲狀腺炎可被分成IgG4亞型(28例)和非IgG4亞型(77例)。2.與非IgG4亞型相比,橋本氏甲狀腺炎的IgG4亞型表現(xiàn)出一系列獨(dú)特的臨床特征。首先,IgG4亞型患者接受甲狀腺全切術(shù)時(shí)的年齡顯著低于非IgG4亞型患者(P=0.0034)。其次,通常橋本氏甲狀腺炎的女性比男性的比例在8-9：1,但是在IgG4亞型中,此比例顯著性降低(P=0.0033)。再次,與非IgG4亞型相比,IgG4亞型患者手術(shù)前的罹病時(shí)間顯著性縮短(P=0.0028),但是比較兩組之間的手術(shù)指征卻未見明顯差異(P=0.5035)。隨訪期間,在所有IgG4亞型患者中,未見其他器官IgG4-RD的發(fā)生。3.血清學(xué)檢查發(fā)現(xiàn),與非IgG4亞型相比,IgG4亞型患者血清中的TgAb,TPOAb水平顯著性升高(P=0.0015；P=0.0047)。并且,IgG4亞型患者血清中IgG4水平顯著性升高(P=0.0032),而其他三種IgG亞型則未見明顯變化；接受甲狀腺全切術(shù)后,IgG4亞型患者血清中IgG4水平明顯下降(P=0.0034)。4.參與此研究的105位橋本氏甲狀腺炎患者,絕大多數(shù)在接受甲狀腺全切手術(shù)之前已接受了TSH抑制水平的L-T4治療。在此情況下,甲狀腺功能表現(xiàn)為亞臨床甲狀腺功能減退,正常功能,以及亞臨床甲狀腺功能亢進(jìn)等三種狀態(tài)。IgG4亞型被證實(shí)與亞臨床甲狀腺功能減退呈現(xiàn)顯著性相關(guān)。5.超聲學(xué)檢查發(fā)現(xiàn),IgG4亞型與彌漫性低信號(hào)的出現(xiàn)存在顯著性相關(guān)關(guān)系；而非IgG4亞型與粗細(xì)不等信號(hào)的出現(xiàn)存在顯著性相關(guān)關(guān)系(P=0.002)。6,組織病理學(xué)方面,IgG4亞型也呈現(xiàn)出一系列特殊表現(xiàn)。首先,從手術(shù)切除的大體標(biāo)本來看,多數(shù)IgG4亞型的標(biāo)本切面呈顯著的蒼白色并有分葉現(xiàn)象,而多數(shù)非IgG4亞型則呈現(xiàn)出與正常甲狀腺組織類似的形態(tài)。其次,作為與IgG4-RD密切相關(guān)的一類疾病,IgG4亞型呈現(xiàn)出與其他器官IgG4-RD相似的組織病理學(xué)表現(xiàn),包括：彌漫性淋巴漿細(xì)胞浸潤(rùn),間質(zhì)纖維化,以及大量IgG4陽性漿細(xì)胞的浸潤(rùn)；而非IgG4亞型則沒有或僅有輕度的上述表現(xiàn)。阻塞性靜脈炎未在IgG4亞型及非IgG4亞型中發(fā)現(xiàn)。IgG4亞型的病理學(xué)表現(xiàn),特別是間質(zhì)纖維化的表現(xiàn),與我們通常熟知的FVHT極為相似。有學(xué)者甚至認(rèn)為,上述兩者是同一種病變,而僅僅命名不同。本研究通過比較表明,這兩者并不完全重合：在我們發(fā)現(xiàn)的28例IgG4亞型中,有4例不符合FVHT的診斷；而在77例非IgG4亞型中,有29例可以被定義為FVHT。在此基礎(chǔ)上,我們進(jìn)一步提出了橋本氏甲狀腺炎間質(zhì)纖維化的三種類型,分別為小葉間型(interlobular fibrosis),濾泡間型(interfollicular fibrosis)和瘢痕型(scar fibrosis),同時(shí)證明了IgG4亞型與濾泡間型纖維化呈顯著性相關(guān)關(guān)系,而在非IgG4亞型中間質(zhì)纖維化多表現(xiàn)為小葉間型。其次與其他器官的IgG4-RD相比,橋本氏甲狀腺炎IgG4亞型又表現(xiàn)出了一系列甲狀腺特有的組織病理學(xué)特征,包括：甲狀腺濾泡的縮小,濾泡上皮細(xì)胞的顯著變性,以及顯著的巨細(xì)胞或組織細(xì)胞浸潤(rùn)。上述特征在非IgG4亞型中缺失或表現(xiàn)輕微。[結(jié)論及意義]1.橋本氏甲狀腺炎,根據(jù)是否存在大量IgG4陽性漿細(xì)胞的浸潤(rùn),可分為IgG4亞型與非IgG4亞型。2.相比較非IgG4亞型,橋本氏甲狀腺炎IgG4亞型表現(xiàn)出一系列獨(dú)特的臨床,實(shí)驗(yàn)室檢查以及超聲學(xué)特征。3.檢測(cè)血清中IgG4水平,可作為發(fā)現(xiàn)和診斷橋本氏甲狀腺炎IgG4亞型的重要手段。4.相比較非IgG4亞型,橋本氏甲狀腺炎IgG4亞型表現(xiàn)出一系列獨(dú)特的組織病理學(xué)特征。5.橋本氏甲狀腺炎IgG4亞型可以被認(rèn)為是IgG4相關(guān)性疾病在甲狀腺的主要表現(xiàn)形式。6.引入IgG4相關(guān)性疾病的全新概念,為研究橋本氏甲狀腺炎的發(fā)生發(fā)展提供了全新的視角；認(rèn)識(shí)橋本氏甲狀腺炎的IgG4亞型,可以幫助我們從臨床和病理學(xué)兩個(gè)方面早期發(fā)現(xiàn)重癥患者,提高其治療效果和生活質(zhì)量；同時(shí)也為臨床工作者尋找和制定新的治療方案提供了全新的思路。

    [Background and Objective]Hashimoto’s thyroiditis (HT), also known as Hashimoto’s disease (HD) and chronic lymphocytic thyroiditis, is the most common cause of goitrous hypothyroidism in areas of the world in which dietary iodine is sufficient. It is more common in middle-aged women, ten times more frequent in women than in men and also a major cause of non-endemic goiter in the pediatric population. A firm, bumpy, painless and symmetric goiter is often the initial finding in HT. The goiter is generally moderate in size (2or4times normal size) and develops gradually. However, on some occasions, the thyroid gland enlarged rapidly and, when accompanied by tenderness and pain, may cause differential diagnosis from de Quervain’s or subacute thyroiditis becoming difficult. The other hallmark of HT is the presence of symptoms and signs of hypothyroidism, such as such as fatigue, cold intolerance, constipation, dry skin, and weight gain. Similar with type I diabetes, as the most common organ-specific autoimmue disease, the hallmark of HT is the presence of thyroid-specific autoantibodies in serum, including anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb). When HT is suspected, a laboratory test for thyroid autoantibodies is generally sufficient to confirm the clinical diagnosis. Thyroid ultrasonogram is usually considered to be useful for diagnosing thyroid disease, measuring thyroid size, monitoring size change after therapy, assessing thyroid echotexture and confirming the appearance of thyroid nodules. In HT, the unltrasound examination of thyroid generally reveals diffuse low echogenicity or coarse echogenicity. Several investigators have found a relation between the sonographic findings and the degree of thyroid function impairment suggesting the degree of disease severity. Hayashi et al. first reported that hypoechogenicity of the thyroid may be a good indicator suggesting hypothyroidism and severe follicular degeneration. In1912, Hakaru Hashimoto first described four patients with a chronic disorder of the thyroid that now termed Hashimoto’s thyroiditis and reported the histopathological features of these cases. After100year’s discovery and investigation, the worldwide accepted histopathological characteristics of HT include:diffuse lymphoplasmacytic infiltration, lymphoid follicle formation with mature germinal centers and the presence of large follicular cells with abundant granular eosinophilic cytoplasm. Although diagnostic criteria describe a well defined clinicopathological entity, HT is not a homogeneous lesion, as explained above. Several histological subrgroups of HT, different from classical Hashimoto’s thyroiditis have been reported, which present unique gross and microscopic charactertistics. The best known subtype is the fibrous variant of Hashimoto’s thyroiditis (FVHT). This variant was first reported by Hashimoto in his orginal description. In1974, Katz and Vickery redefined the histological concept of FVHT and pointed out that FVHT presents a clinical picture quite distinct from that of typical HT. Distinctive clinical features include a very firm goiter, often with a striking recent enlargement, severe neck pressure symptoms, frequent diagnostic confusion with malignant disease, and a markedly elevated TgAb levels in the serum. Based on the above clinical, laboratory, sonographic and pathological charactertistics of HT, we can note that although not like other malignant disease of thyroid, HT will not a life-threatening disease, it has a high morbidity and long disease duration, and affect the quality of patients’life especially after the occurance of hypothyroidism. Internationally accepted treatment of choice for Hashimoto thyroiditis is thyroid hormone replacement. The drug of choice is orally administered levothyroxine sodium, usually for life and may casuse some kinds of side-effect. Usually, HT is treated medically; however, thyroidectomy is sometimes indicated. When the thyroid is extremely enlarged or the pathologists can not rule out thyroid malignancy through aspiration biopsy, surgical treatment is still required. Therefore, considering break-through the traditional concept of Hashimoto’s thyroiditis, making an earlier discovery of a special subtype that will cause severe symptoms, proposing practical diagnostic criteria and bring into new therapeutic strategy has become great challenges for medical doctors.Immunoglobulin (Ig) G4is the least abundant of the IgG subclasses and accounts for only3to6percent of total IgG in the serum of normal human subjects. High serum IgG4concentrations are found in only limited number of conditions: such as atopic dermatitis, some parasitic diseases, and autoimme bullous skin diseases. Therefore little attention has been paid to this minor component of IgG until a landmark study, in which Hamano et al. reported elevated serum IgG4level in patients with autoimmune pancreatitis (AIP). Moreover, Hamano’s group also reported that abundant IgG4-positive plasma cells were characteristically identified in pancreatic tissues in AIP. Shortly thereafter, Kamisawa reported that tissue infiltration with numerous IgG4-positive cells was a characteristic feature not only of AIP but also the other organs involved in AIP. Based on this observation they proposed the term IgG4-RD to describe this condition. Since then, many entities have been added to the growing list of IgG4-RD. They include:sclerosing sialoadenitis, hepatic inflammatory pseudotumor, sclerosing cholangitis, retroperitoneal fibrosis, inflammatory aortic aneurysm, and tubulointerstitial nephritis etc. Most of those reported cases shared histologic characteristics of IgG4-RD, as noted in AIP, such as diffuse lymphoplasmacytic infiltration by many IgG4-positive plasma cells, stromal fibrosis, and obliterative phlebitis. At present, these histopathological features have been applied as morphological hallmarks of IgG4-RD. On ther other hand, clinically, IgG4-RD is characterizied by elevated serum IgG4levels, and alleviation of symptoms after steroid therapy. Recognizing these new entities does not just contribute to the pathological re-classification, but also help clinicians to guide identification of this disease and its treatment, avoid unnecessary surgery and promote the quality of patients’life. In2009, our group noted that a small number of HT patients show indistinguishable histologic features with IgG4-RD. We speculated that this subgroup of HT may have close relationship with IgG4-RD. On the basis of immunohistochemistry of IgG4and IgG, we originally described two subtypes of HT:IgG4thyroiditis (IgG4related, IgG4-positive plasma cell-rich group) and non-IgG4thyroiditis (non-IgG4related, IgG4-positive plasma cell-poor group). Although the cut-off value of IgG4-positive plasma cell has not been standardized currently, we adopt>20/HPF IgG4-positive plasma cells and>30%IgG4/IgG ratio as the diagnostic threshold, because it has high specificity and sensitivity for defining a significant increase of IgG4-positive plasma cells in thyroid tissues. This study is the first report in the world described about the relationship between IgG4-RD and HT and filled the blank of the HT research field. It also provides us a new point-view to recognize HT. The thesis composed of two parts. The specific aim of the first study was analyzing and comparing the clinical, laboratory and sonographic characteristics between IgG4thyroiditis group and non-IgG4thyroiditis group, and providing valuable information for clinical diagnosis. The second part of study was focused on systemic evaluation of morphological features of IgG4thyroiditis and non-IgG4thyroiditis. This work may also be valuable for pathologists to establish practical diagnostic criteria for IgG4-related HT in the future.[Methods] A total of105cases of HT between1983and2010were selected from the pathology files of Kuma Hospital (Kobe, Japan). There were10male and95female patients with an average age of57.49years involved in this study. The patients underwent total thyroidectomies for various reasons. A clinical database was settled to collect the following information:patients’age, gender, indications for total thyroidectomy, disease duration before sugery, weight of resected thyroid glands, the dose of L-T4before operation, and disease outcomes especially whether there are extrathyroidal IgG4-RD or not. All the information was obtained from the referral forms submitted at the time of the operation and the patients’medical records. Ultrasonography of the neck was performed in all patients. The follow-up period was calculated from the first and last visits to Kuma Hospital. Peripheral blood samples were obtained from all individuals. Then, serum samples were collected for routine laboratory examination, including TgAb and TPOAb measurment. Moreover, serum samples (before and after thyroidectomy) from patients with recent diagnosis of HT were examined to determine serum IgG4concentrations. Ultrasonographic examinations were performed by well-trained registered medical sonographer. The gain was adjusted to produce an echo-free appearance of the lumen on the internal jugular vein, carotid arteries, and neck-strap muscles. In this setting, a normal thyroid gland has a medium gray-scale homogeneous echo pattern, and the level of echogenicity is higher than that of the surrounding muscles. The diffuse low was defined as a diffuse echo density clearly lower than normal subjects, while coarse was defined as heterogeneous echogenicity or mixed with the signal of normal subjects. The resected thyroid tissues were routinely fixed in10%neutral-buffered formalin and embedded in paraffin. Serial sections (4-μm thick) from each patient were prepared for hematoxylin and eosin (H&E), Elastica van Gieson (EvG), Masson’s trichrome (MT) and immunohistochemical staining. Two pathologists, YL and KK, retrospectively reviewed more than five H&E sections in each case. We identified the presence or absence of the following histological features from the stained specimens:stromal fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, follicular size, follicular cell degeneration, lymphoid follicle formation, giant cell and/or histiocyte infiltration, and the presence of a solid cell nest and or squamous metaplasia. The immunostaining of IgG4and IgG was carried out using the En Vision immunohistochemical detection system according to the manufacturer’s instructions. For the quantification of IgG4-positive or IgG-positive cells, the areas with the highest density of positive cells were evaluated. Five high-powered fields (HPF) in each section were analyzed, and the average number of positive cells per HPF was calculated using Win ROOF version5.8image analysis software. The ratio of the IgG4-positive plasma cells to the IgG-positive plasma cells was also calculated in each case. Finally, statistical analyses were performed using the GraphPad software.[Results]1. On the basis of the immunostaining for IgG4and IgG and the cutoff value proposed in our previous report (>20/HPF IgG4-positive plasma cells and a IgG4/IgG ratio>30%), the105patients with HT were sub-classified as having IgG4thyroiditis (n=28) or non-IgG4thyroiditis (n=77).2. Compared with with its non-IgG4counterpart, IgG4thyroiditis present a series of distinct clinical characteristics. First, the patients in the IgG4thyroiditis group were significantly younger than those in the non-IgG4thyroiditis group (P=0.0034). Second, although the female-to-male ratio is approximately8-9:1for HT, the IgG4thyroiditis group had a lower female-to-male ratio (P=0.0033). Additionally, patients in the IgG4thyroiditis group had a significantly shorter disease duration of HT than those in the non-IgG4thyroiditis group before they underwent total thyroidectomies; however, there was no significant difference in the indications for thyroidectomy between the two groups(P=0.5035). During the whole follow-up periods, no ocurrance of extrathyroidal IgG4-RD was noted in all28cases of IgG4thyroiditis.3. In terms of routine laboratory examinations and the circulating thyroid autoantibody levels, both the TPO-Ab and Tg-Ab levels, were significantly higher in the IgG4thyroiditis subgroup than in the non-IgG4thyroiditis subgroup (P=0.0015; P=0.0047, respectively). Serum concentrations of IgG4were significantly higher in IgG4thyroiditis group than non-IgG4thyroiditis group (P=0.0032). However, serum levels of IgGl, IgG2and IgG3did not differ between the two groups. Postoperative serum IgG4concentrations of patients in IgG4thyroiditis group were also measured. The data of preoperative and postoperative serum IgG4levels of each patient were compared. Importantly, as we expected, serum IgG4concentrations were significantly reduced after total thyroidectomies (P=0.0034).4. The majority of patients involved in this study were treated with L-T4at a TSH-suppressive dose before surgery. With the thyroid hormone treatment, the patients demonstrated different levels of thyroid function, including subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, and the IgG4thyroiditis subtype was more strongly associated with subclinical hypothyroidism.5. Furthermore, the sonographic examinations revealed that the IgG4thyroiditis group was significantly correlated with diffuse low echogenicity, whereas the non-IgG4thyroiditis patients showed an association with diffuse coarse echogenicity (P=0.0002).6. IgG4thyroiditis group of HT also presents a series of histopathological features quite different from non-IgG4thyroiditis group. First, grossly, the cut surfaces of the thyroid glands from the IgG4thyroiditis patients showed a marked pale-white color with lobulations. In the non-IgG4thyroiditis group, the thyroid glands presented with varying degrees of mahogany-brown to tan-yellow color on the cut surfaces. Second, because of its close relationship with IgG4-RD, IgG4thyroiditis shared certain histopathological features with extrathyroidal IgG4-RD, including diffuse lymphoplasmacytic infiltration, marked stromal fibrosis and the infiltration of a large amount of IgG4-positive plasma cells, while, in non-IgG4thyroiditis group, these features were mild or absent. Obliterative phlebitis is a characteristic feature of IgG4-RD. However, it was not identified in any of the105cases of HT. As we suspected, the majority of the IgG4thyroiditis cases could be classified as FVHT as well, but these two entities do not completely overlap. In the IgG4thyroiditis group, marked stromal fibrosis was observed in24cases, supporting the designation of these cases as FVHT. However, there were still four cases that presented with only mild fibrosis. Even in the non-IgG4thyroiditis group, there were29cases with notable fibrosis that met the diagnostic criteria for FVHT. To further delineate the relationship between IgG4thyroiditis and FVHT, an analysis of the pattern of fibrosis was conducted in this study. We formally proposed to classify the stromal fibrosis of HT into the three following patterns:interlobular fibrosis, interfollicular fibrosis, and scar fibrosis. We demonstrated that IgG4thyroiditis is significantly associated with a predominant interfollicular pattern of fibrosis. A predominant interlobular fibrosis is commonly seen in non-IgG4thyroiditis. Additionally, the IgG4thyroiditis group also demonstrated thyroid-specific histological features, including the presence of small thyroid follicles, marked follicular cell degeneration, and increased giant cell/histiocyte infiltration, whereas the non-IgG4thyroiditis patients presented with relatively mild aspects or complete absence of these histopathological characteristics. [Conclusions]1. Based on the presence or absence of large amount of IgG4-positive plasma cell infiltrationin thyroid tissue, HT can be subclassified into two groups:IgG4thyroiditis and non-IgG4thyroiditis.2. From clinical aspect, IgG4thyroiditis presented distinct clinical, laboratory and sonographic features, compared with non-IgG4thyroiditis.3. Measuring serum IgG4concentration is a practical and useful method to identify and define IgG4thyroiditis.4. IgG4thyroiditis reveals a series of unique histopathological characteristics, which are quite different from non-IgG4thyroiditis.5. IgG4thyroiditis group of HT might account for the majority of IgG4-RD in thyroid.6. Bringing the novel IgG4-RD concept into the research field of thyroid provide us a new view-point to investigate the potential pathogenetic mechanisms underlying HT; recognizing IgG4thyroiditis group of HT may help us to identify the patients who will have severe symptoms clinically and pathologically, and contribute to promote the life-quality of the patients. Meanwhile, the current study is also valuable for clinical doctors to investigate the appropriate therapeutic approaches.

橋本氏甲狀腺炎與IgG4相關(guān)性疾病有關(guān)的臨床病理學(xué)特征的相關(guān)研究

中文摘要6-11英文摘要11-18符號(hào)說明19-21第一部分 橋本氏甲狀腺炎IgG4亞型的發(fā)現(xiàn)及其獨(dú)特的臨床,實(shí)驗(yàn)室檢查,超聲學(xué)特征的研究21-57    前言21-31    材料與方法31-35    結(jié)果35-43    討論43-47    結(jié)論47-48    參考文獻(xiàn)48-57第二部分 橋本氏甲狀腺炎IgG4亞型獨(dú)特的組織病理學(xué)特征及診斷標(biāo)準(zhǔn)的研究57-80    前言57-59    材料與方法59-62    結(jié)果62-72    討論72-76    結(jié)論76-77    參考文獻(xiàn)77-80創(chuàng)新點(diǎn)與局限性80-81致謝81-82攻讀博士學(xué)位期間發(fā)表的學(xué)術(shù)論文82-83攻讀博士學(xué)位期間獲得獎(jiǎng)勵(lì)83-84外文文章184-115外文文章2115-124外文文章3124-130學(xué)位論文評(píng)閱及答辯情況表130

  本文關(guān)鍵詞：橋本氏甲狀腺炎與IgG4相關(guān)性疾病有關(guān)的臨床病理學(xué)特征的相關(guān)研究，由筆耕文化傳播整理發(fā)布。