桥本氏甲状腺炎与IgG4相关性疾病有关的临床病理学特征的相关研究
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摘要
[研究背景与目的]
桥本氏甲状腺炎(Hashimoto's thyroiditis, HT)又被称为桥本氏病(Hashimoto's disease, HD)或慢性淋巴细胞性甲状腺炎(Chronic lymphocytic thyroiditis),是世界上饮食富碘地区引发甲状腺肿性甲状腺功能减退的最常见原因。桥本氏甲状腺炎多发于30至50岁中年女性,其发病率通常是男性的10倍左右,同时也是引发儿童非地方性甲状腺肿的最主要病因。甲状腺对称性增大且质地坚韧通常是桥本氏甲状腺炎患者最初的临床表现。肿大的甲状腺一般呈中等度增大,体积约为正常甲状腺的2-4倍大小,并且进展缓慢。然而在某些情况下,甲状腺体积可显著快速增大,并且伴发甲状腺的压痛及疼痛。这些症状极易使之与亚急性甲状腺炎相混淆。桥本氏甲状腺炎的另一临床特征为多数患者可呈现不同程度的疲乏,嗜睡,怕冷,皮肤苍白干燥,食欲不振而体重增加等甲状腺功能减退的症状。与Ⅰ型糖尿病类似,作为人类最常见的一种自身免疫性疾病,桥本氏甲状腺炎患者的血清学特征为抗甲状腺球蛋白抗体(TgAb)和抗甲状腺过氧化物酶抗体(TPOAb)的出现。检测上述甲状腺特异性自身抗体,已成为国际上通用的诊断桥本氏甲状腺炎的重要方法。超声学检查是诊断甲状腺疾病的最重要的影像学手段。桥本氏甲状腺炎的超声学表现,多为弥漫性低回声区的出现,或者呈现粗细不等的网络状回声区。日本学者Hayashi和Johns Hopkins大学的研究人员证实,在桥本氏甲状腺炎中,弥漫性低回声区的出现与患者甲状腺功能的减退及严重的滤泡变性显著相关。1912年,日本桥本策博士首先报告并描述了四例桥本氏甲状腺炎的组织病理学特征。经过100多年的探索和总结,目前国际公认的桥本氏甲状腺炎组织病理学表现包括：弥漫性淋巴细胞/浆细胞浸润,有成熟生发中心的淋巴滤泡的形成以及甲状腺滤泡上皮的嗜酸性变。尽管上述特征在病理学方面较好地定义了桥本氏甲状腺炎的概念,然而一系列的研究表明桥本氏甲状腺炎并非单一型的病变,它包含了若干亚型。目前研究最为广泛,在日常诊断工作中最为常见的是桥本氏甲状腺炎纤维化亚型(Fibrous variant of Hashimoto's thyroiditis, FVHT)。桥本策在他的论著中首先描述了这种纤维化亚型。1974年,Katz和Vickery重新定义了纤维化亚型的病理学特征,并且指出与典型的桥本氏甲状腺炎相比,纤维化亚型表现出了一系列独特的临床特征包括：短期内甲状腺体积显著增大,严重的颈部压迫症状,容易被误诊为恶性肿瘤以及抗甲状腺球蛋白抗体的显著升高。根据上述临床,实验室,影像学以及病理学的特征,我们可以看出桥本氏甲状腺炎虽然不像恶性肿瘤那样直接威胁患者的生命安全,但是其发生率较高,病程漫长,尤其是出现甲状腺功能减退症状后将严重影响患者的生活质量。目前国际上通用多年的治疗方案为甲状腺片剂替代治疗,然而大多数患者需要长期或终生服药,且有不可避免的副作用。当甲状腺肿大严重影响患者日常生活,或者穿刺活检结果不能排除甲状腺恶性肿瘤时,桥本氏甲状腺炎患者还需接受手术治疗,切除全部或部分甲状腺组织。因此,如何突破桥本氏甲状腺炎的传统定义,及早发现可能引发严重临床表现的亚型,提出切实有效的诊断标准,同时引入新的治疗理念,就成为了摆在医务工作者面前的革命性课题。
免疫球蛋白G4(Immunoglobulin G4, IgG4)是免疫球蛋白G (Immunoglobulin G, IgG)所有亚型中所占比例最低的一种,它只占正常人血清IgG的3-6%。过去我们认为血清IgG4水平的升高仅见于少数几种情况,如特异性皮炎,寄生虫疾病以及自身免疫性大疱性皮肤病。因此有很长一段时间,鲜有关于IgG4的研究,直到2001年Hamano等首先报告在自身免疫性胰腺炎(Autoimmune pancreatitis, AIP)的患者血清中发现了IgG4水平的显著升高。随后,该研究组进一步证实了在AIP患者的胰腺组织中发现了大量IgG4阳性浆细胞的浸润。在此之后,Kamisawa等提出AIP常合并其他器官和组织,如唾液腺,胆管和腹膜后组织的类似病变,而这些器官组织的标本都显示有大量IgG4阳性浆细胞浸润。基于上述发现,Kamisawa研究组首次提出了IgG4相关性疾病(IgG4-related disease, IgG4-RD)的概念。此后,随着研究范围的不断扩大,更多的胰腺外病变被证实为IgG4-RD这一疾病系列的成员。这其中包括硬化性胆管炎,硬化性唾液腺炎,肝炎性假瘤,炎性主动脉瘤以及肾小管间质性肾炎等。作为IgG4-RD成员,上述病变呈现出了极为相似的组织病理学表现,包括弥漫性淋巴细胞浆细胞浸润(diffuse lymphoplasmacytic infiltration),间质纤维化(stromal fibrosis),阻塞性静脉炎(obliterative phlebitis)以及大量IgG4阳性浆细胞的浸润(large amount of IgG4-positive plasma cell infiltration)。临床方面,IgG4-RD则以血清IgG4水平升高和对类固醇激素治疗反应良好为特征。IgG4-RD概念的提出对于临床和病理工作者来说意义重大：它促使我们对一些过去熟知的疾病进行重新认识和分类,进而调整治疗方案,避免不必要的手术治疗,提高患者的生活质量。2009年,作者所在的研究组率先将IgG4-RD的概念引入桥本氏甲状腺炎的研究领域,并证实了在桥本氏甲状腺炎中存在一种特殊的亚型,该亚型表现出与其他器官IgG4-RD极为相似的病理学特征其中包括有大量IgG4阳性浆细胞浸润,我们称之为IgG4亚型(IgG4related, IgG4-positive plasma cell-rich group)。同时,我们提出区分IgG4亚型与非IgG4亚型(non-IgG4related, IgG4-positive plasma cell-poor group)的免疫组织化学标准。该研究填补了国内外IgG4相关性疾病研究的空白,为重新认识桥本氏甲状腺炎提供了全新的思路。本研究分为两个部分。第一部分研究内容为分析比较桥本氏甲状腺炎IgG4亚型与非IgG4亚型在临床表现,实验室检查以及超声学检查方面的差异,为今后的临床诊断工作提供有益的参考。第二部分内容旨在全面系统分析IgG4亚型与非IgG4亚型在组织病理学方面的差异,为最终确立桥本氏病IgG4亚型的病理学诊断标准奠定基础。[研究方法]
收集1983-2010年在日本隈病院接受甲状腺全切术的桥本氏甲状腺炎病例105例。建立患者的临床信息数据库,内容包括年龄,性别,接受甲状腺全切术的原因,手术前的罹病时间,切除甲状腺的重量,术前接受L-T4治疗的剂量,随访资料以及在随访过程中是否发生甲状腺外IgG4-RD。实验室检查患者手术前血清中TgAb和TPOAb水平,同时选择有可用血清标本的病例检测手术前血清中IgG各亚型的水平,以及手术后的相应变化。检查病变甲状腺的超声学表现：将颈内静脉,颈动脉的内腔设置为无信号区,在此系统中正常甲状腺组织表现为统一的中等强度超声信号,高于周围的肌肉组织。弥漫性低信号被定义为超声信号明显低于正常甲状腺组织；粗细不等信号被定义为低信号与正常信号交织出现。所有石蜡标本4μm连续切片,进行HE, EvG以及MT染色,两位病理医生镜下观察8项组织病理学指标并进行分级,包括：淋巴细胞浆细胞浸润,间质纤维化,阻塞型静脉炎,甲状腺滤泡大小,滤泡细胞变性程度,淋巴滤泡形成,巨细胞/组织细胞浸润,以及实性细胞巢/扁平上皮样化生。免疫组化检测IgG4及IgG表达情况,选择阳性细胞最密集区域的5个高倍视野进行拍照,使用WinROOF version5.8软件计数阳性细胞,并计算一个高倍视野阳性细胞数的平均值。最后,使用Graphpad软件对上述临床病理学指标进行统计分析。
[研究结果]
1.根据IgG4及IgG免疫组化结果,以及本研究组提出的IgG4亚型诊断标准(即每高倍镜IgG4阳性浆细胞大于20个且IgG4阳性浆细胞占IgG阳性浆细胞比例大于30%),105例桥本氏甲状腺炎可被分成IgG4亚型(28例)和非IgG4亚型(77例)。
2.与非IgG4亚型相比,桥本氏甲状腺炎的IgG4亚型表现出一系列独特的临床特征。首先,IgG4亚型患者接受甲状腺全切术时的年龄显著低于非IgG4亚型患者(P=0.0034)。其次,通常桥本氏甲状腺炎的女性比男性的比例在8-9：1,但是在IgG4亚型中,此比例显著性降低(P=0.0033)。再次,与非IgG4亚型相比,IgG4亚型患者手术前的罹病时间显著性缩短(P=0.0028),但是比较两组之间的手术指征却未见明显差异(P=0.5035)。随访期间,在所有IgG4亚型患者中,未见其他器官IgG4-RD的发生。
3.血清学检查发现,与非IgG4亚型相比,IgG4亚型患者血清中的TgAb,TPOAb水平显著性升高(P=0.0015；P=0.0047)。并且,IgG4亚型患者血清中IgG4水平显著性升高(P=0.0032),而其他三种IgG亚型则未见明显变化；接受甲状腺全切术后,IgG4亚型患者血清中IgG4水平明显下降(P=0.0034)。
4.参与此研究的105位桥本氏甲状腺炎患者,绝大多数在接受甲状腺全切手术之前已接受了TSH抑制水平的L-T4治疗。在此情况下,甲状腺功能表现为亚临床甲状腺功能减退,正常功能,以及亚临床甲状腺功能亢进等三种状态。IgG4亚型被证实与亚临床甲状腺功能减退呈现显著性相关。
5.超声学检查发现,IgG4亚型与弥漫性低信号的出现存在显著性相关关系；而非IgG4亚型与粗细不等信号的出现存在显著性相关关系(P=0.002)。
6,组织病理学方面,IgG4亚型也呈现出一系列特殊表现。首先,从手术切除的大体标本来看,多数IgG4亚型的标本切面呈显著的苍白色并有分叶现象,而多数非IgG4亚型则呈现出与正常甲状腺组织类似的形态。其次,作为与IgG4-RD密切相关的一类疾病,IgG4亚型呈现出与其他器官IgG4-RD相似的组织病理学表现,包括：弥漫性淋巴浆细胞浸润,间质纤维化,以及大量IgG4阳性浆细胞的浸润；而非IgG4亚型则没有或仅有轻度的上述表现。阻塞性静脉炎未在IgG4亚型及非IgG4亚型中发现。IgG4亚型的病理学表现,特别是间质纤维化的表现,与我们通常熟知的FVHT极为相似。有学者甚至认为,上述两者是同一种病变,而仅仅命名不同。本研究通过比较表明,这两者并不完全重合：在我们发现的28例IgG4亚型中,有4例不符合FVHT的诊断；而在77例非IgG4亚型中,有29例可以被定义为FVHT。在此基础上,我们进一步提出了桥本氏甲状腺炎间质纤维化的三种类型,分别为小叶间型(interlobular fibrosis),滤泡间型(interfollicular fibrosis)和瘢痕型(scar fibrosis),同时证明了IgG4亚型与滤泡间型纤维化呈显著性相关关系,而在非IgG4亚型中间质纤维化多表现为小叶间型。其次与其他器官的IgG4-RD相比,桥本氏甲状腺炎IgG4亚型又表现出了一系列甲状腺特有的组织病理学特征,包括：甲状腺滤泡的缩小,滤泡上皮细胞的显著变性,以及显著的巨细胞或组织细胞浸润。上述特征在非
IgG4亚型中缺失或表现轻微。
[结论及意义]
1.桥本氏甲状腺炎,根据是否存在大量IgG4阳性浆细胞的浸润,可分为IgG4亚型与非IgG4亚型。
2.相比较非IgG4亚型,桥本氏甲状腺炎IgG4亚型表现出一系列独特的临床,实验室检查以及超声学特征。
3.检测血清中IgG4水平,可作为发现和诊断桥本氏甲状腺炎IgG4亚型的重要手段。
4.相比较非IgG4亚型,桥本氏甲状腺炎IgG4亚型表现出一系列独特的组织病理学特征。
5.桥本氏甲状腺炎IgG4亚型可以被认为是IgG4相关性疾病在甲状腺的主要表现形式。
6.引入IgG4相关性疾病的全新概念,为研究桥本氏甲状腺炎的发生发展提供了全新的视角；认识桥本氏甲状腺炎的IgG4亚型,可以帮助我们从临床和病理学两个方面早期发现重症患者,提高其治疗效果和生活质量；同时也为临床工作者寻找和制定新的治疗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.
桥本氏甲状腺炎(Hashimoto's thyroiditis, HT)又被称为桥本氏病(Hashimoto's disease, HD)或慢性淋巴细胞性甲状腺炎(Chronic lymphocytic thyroiditis),是世界上饮食富碘地区引发甲状腺肿性甲状腺功能减退的最常见原因。桥本氏甲状腺炎多发于30至50岁中年女性,其发病率通常是男性的10倍左右,同时也是引发儿童非地方性甲状腺肿的最主要病因。甲状腺对称性增大且质地坚韧通常是桥本氏甲状腺炎患者最初的临床表现。肿大的甲状腺一般呈中等度增大,体积约为正常甲状腺的2-4倍大小,并且进展缓慢。然而在某些情况下,甲状腺体积可显著快速增大,并且伴发甲状腺的压痛及疼痛。这些症状极易使之与亚急性甲状腺炎相混淆。桥本氏甲状腺炎的另一临床特征为多数患者可呈现不同程度的疲乏,嗜睡,怕冷,皮肤苍白干燥,食欲不振而体重增加等甲状腺功能减退的症状。与Ⅰ型糖尿病类似,作为人类最常见的一种自身免疫性疾病,桥本氏甲状腺炎患者的血清学特征为抗甲状腺球蛋白抗体(TgAb)和抗甲状腺过氧化物酶抗体(TPOAb)的出现。检测上述甲状腺特异性自身抗体,已成为国际上通用的诊断桥本氏甲状腺炎的重要方法。超声学检查是诊断甲状腺疾病的最重要的影像学手段。桥本氏甲状腺炎的超声学表现,多为弥漫性低回声区的出现,或者呈现粗细不等的网络状回声区。日本学者Hayashi和Johns Hopkins大学的研究人员证实,在桥本氏甲状腺炎中,弥漫性低回声区的出现与患者甲状腺功能的减退及严重的滤泡变性显著相关。1912年,日本桥本策博士首先报告并描述了四例桥本氏甲状腺炎的组织病理学特征。经过100多年的探索和总结,目前国际公认的桥本氏甲状腺炎组织病理学表现包括：弥漫性淋巴细胞/浆细胞浸润,有成熟生发中心的淋巴滤泡的形成以及甲状腺滤泡上皮的嗜酸性变。尽管上述特征在病理学方面较好地定义了桥本氏甲状腺炎的概念,然而一系列的研究表明桥本氏甲状腺炎并非单一型的病变,它包含了若干亚型。目前研究最为广泛,在日常诊断工作中最为常见的是桥本氏甲状腺炎纤维化亚型(Fibrous variant of Hashimoto's thyroiditis, FVHT)。桥本策在他的论著中首先描述了这种纤维化亚型。1974年,Katz和Vickery重新定义了纤维化亚型的病理学特征,并且指出与典型的桥本氏甲状腺炎相比,纤维化亚型表现出了一系列独特的临床特征包括：短期内甲状腺体积显著增大,严重的颈部压迫症状,容易被误诊为恶性肿瘤以及抗甲状腺球蛋白抗体的显著升高。根据上述临床,实验室,影像学以及病理学的特征,我们可以看出桥本氏甲状腺炎虽然不像恶性肿瘤那样直接威胁患者的生命安全,但是其发生率较高,病程漫长,尤其是出现甲状腺功能减退症状后将严重影响患者的生活质量。目前国际上通用多年的治疗方案为甲状腺片剂替代治疗,然而大多数患者需要长期或终生服药,且有不可避免的副作用。当甲状腺肿大严重影响患者日常生活,或者穿刺活检结果不能排除甲状腺恶性肿瘤时,桥本氏甲状腺炎患者还需接受手术治疗,切除全部或部分甲状腺组织。因此,如何突破桥本氏甲状腺炎的传统定义,及早发现可能引发严重临床表现的亚型,提出切实有效的诊断标准,同时引入新的治疗理念,就成为了摆在医务工作者面前的革命性课题。
免疫球蛋白G4(Immunoglobulin G4, IgG4)是免疫球蛋白G (Immunoglobulin G, IgG)所有亚型中所占比例最低的一种,它只占正常人血清IgG的3-6%。过去我们认为血清IgG4水平的升高仅见于少数几种情况,如特异性皮炎,寄生虫疾病以及自身免疫性大疱性皮肤病。因此有很长一段时间,鲜有关于IgG4的研究,直到2001年Hamano等首先报告在自身免疫性胰腺炎(Autoimmune pancreatitis, AIP)的患者血清中发现了IgG4水平的显著升高。随后,该研究组进一步证实了在AIP患者的胰腺组织中发现了大量IgG4阳性浆细胞的浸润。在此之后,Kamisawa等提出AIP常合并其他器官和组织,如唾液腺,胆管和腹膜后组织的类似病变,而这些器官组织的标本都显示有大量IgG4阳性浆细胞浸润。基于上述发现,Kamisawa研究组首次提出了IgG4相关性疾病(IgG4-related disease, IgG4-RD)的概念。此后,随着研究范围的不断扩大,更多的胰腺外病变被证实为IgG4-RD这一疾病系列的成员。这其中包括硬化性胆管炎,硬化性唾液腺炎,肝炎性假瘤,炎性主动脉瘤以及肾小管间质性肾炎等。作为IgG4-RD成员,上述病变呈现出了极为相似的组织病理学表现,包括弥漫性淋巴细胞浆细胞浸润(diffuse lymphoplasmacytic infiltration),间质纤维化(stromal fibrosis),阻塞性静脉炎(obliterative phlebitis)以及大量IgG4阳性浆细胞的浸润(large amount of IgG4-positive plasma cell infiltration)。临床方面,IgG4-RD则以血清IgG4水平升高和对类固醇激素治疗反应良好为特征。IgG4-RD概念的提出对于临床和病理工作者来说意义重大：它促使我们对一些过去熟知的疾病进行重新认识和分类,进而调整治疗方案,避免不必要的手术治疗,提高患者的生活质量。2009年,作者所在的研究组率先将IgG4-RD的概念引入桥本氏甲状腺炎的研究领域,并证实了在桥本氏甲状腺炎中存在一种特殊的亚型,该亚型表现出与其他器官IgG4-RD极为相似的病理学特征其中包括有大量IgG4阳性浆细胞浸润,我们称之为IgG4亚型(IgG4related, IgG4-positive plasma cell-rich group)。同时,我们提出区分IgG4亚型与非IgG4亚型(non-IgG4related, IgG4-positive plasma cell-poor group)的免疫组织化学标准。该研究填补了国内外IgG4相关性疾病研究的空白,为重新认识桥本氏甲状腺炎提供了全新的思路。本研究分为两个部分。第一部分研究内容为分析比较桥本氏甲状腺炎IgG4亚型与非IgG4亚型在临床表现,实验室检查以及超声学检查方面的差异,为今后的临床诊断工作提供有益的参考。第二部分内容旨在全面系统分析IgG4亚型与非IgG4亚型在组织病理学方面的差异,为最终确立桥本氏病IgG4亚型的病理学诊断标准奠定基础。[研究方法]
收集1983-2010年在日本隈病院接受甲状腺全切术的桥本氏甲状腺炎病例105例。建立患者的临床信息数据库,内容包括年龄,性别,接受甲状腺全切术的原因,手术前的罹病时间,切除甲状腺的重量,术前接受L-T4治疗的剂量,随访资料以及在随访过程中是否发生甲状腺外IgG4-RD。实验室检查患者手术前血清中TgAb和TPOAb水平,同时选择有可用血清标本的病例检测手术前血清中IgG各亚型的水平,以及手术后的相应变化。检查病变甲状腺的超声学表现：将颈内静脉,颈动脉的内腔设置为无信号区,在此系统中正常甲状腺组织表现为统一的中等强度超声信号,高于周围的肌肉组织。弥漫性低信号被定义为超声信号明显低于正常甲状腺组织；粗细不等信号被定义为低信号与正常信号交织出现。所有石蜡标本4μm连续切片,进行HE, EvG以及MT染色,两位病理医生镜下观察8项组织病理学指标并进行分级,包括：淋巴细胞浆细胞浸润,间质纤维化,阻塞型静脉炎,甲状腺滤泡大小,滤泡细胞变性程度,淋巴滤泡形成,巨细胞/组织细胞浸润,以及实性细胞巢/扁平上皮样化生。免疫组化检测IgG4及IgG表达情况,选择阳性细胞最密集区域的5个高倍视野进行拍照,使用WinROOF version5.8软件计数阳性细胞,并计算一个高倍视野阳性细胞数的平均值。最后,使用Graphpad软件对上述临床病理学指标进行统计分析。
[研究结果]
1.根据IgG4及IgG免疫组化结果,以及本研究组提出的IgG4亚型诊断标准(即每高倍镜IgG4阳性浆细胞大于20个且IgG4阳性浆细胞占IgG阳性浆细胞比例大于30%),105例桥本氏甲状腺炎可被分成IgG4亚型(28例)和非IgG4亚型(77例)。
2.与非IgG4亚型相比,桥本氏甲状腺炎的IgG4亚型表现出一系列独特的临床特征。首先,IgG4亚型患者接受甲状腺全切术时的年龄显著低于非IgG4亚型患者(P=0.0034)。其次,通常桥本氏甲状腺炎的女性比男性的比例在8-9：1,但是在IgG4亚型中,此比例显著性降低(P=0.0033)。再次,与非IgG4亚型相比,IgG4亚型患者手术前的罹病时间显著性缩短(P=0.0028),但是比较两组之间的手术指征却未见明显差异(P=0.5035)。随访期间,在所有IgG4亚型患者中,未见其他器官IgG4-RD的发生。
3.血清学检查发现,与非IgG4亚型相比,IgG4亚型患者血清中的TgAb,TPOAb水平显著性升高(P=0.0015；P=0.0047)。并且,IgG4亚型患者血清中IgG4水平显著性升高(P=0.0032),而其他三种IgG亚型则未见明显变化；接受甲状腺全切术后,IgG4亚型患者血清中IgG4水平明显下降(P=0.0034)。
4.参与此研究的105位桥本氏甲状腺炎患者,绝大多数在接受甲状腺全切手术之前已接受了TSH抑制水平的L-T4治疗。在此情况下,甲状腺功能表现为亚临床甲状腺功能减退,正常功能,以及亚临床甲状腺功能亢进等三种状态。IgG4亚型被证实与亚临床甲状腺功能减退呈现显著性相关。
5.超声学检查发现,IgG4亚型与弥漫性低信号的出现存在显著性相关关系；而非IgG4亚型与粗细不等信号的出现存在显著性相关关系(P=0.002)。
6,组织病理学方面,IgG4亚型也呈现出一系列特殊表现。首先,从手术切除的大体标本来看,多数IgG4亚型的标本切面呈显著的苍白色并有分叶现象,而多数非IgG4亚型则呈现出与正常甲状腺组织类似的形态。其次,作为与IgG4-RD密切相关的一类疾病,IgG4亚型呈现出与其他器官IgG4-RD相似的组织病理学表现,包括：弥漫性淋巴浆细胞浸润,间质纤维化,以及大量IgG4阳性浆细胞的浸润；而非IgG4亚型则没有或仅有轻度的上述表现。阻塞性静脉炎未在IgG4亚型及非IgG4亚型中发现。IgG4亚型的病理学表现,特别是间质纤维化的表现,与我们通常熟知的FVHT极为相似。有学者甚至认为,上述两者是同一种病变,而仅仅命名不同。本研究通过比较表明,这两者并不完全重合：在我们发现的28例IgG4亚型中,有4例不符合FVHT的诊断；而在77例非IgG4亚型中,有29例可以被定义为FVHT。在此基础上,我们进一步提出了桥本氏甲状腺炎间质纤维化的三种类型,分别为小叶间型(interlobular fibrosis),滤泡间型(interfollicular fibrosis)和瘢痕型(scar fibrosis),同时证明了IgG4亚型与滤泡间型纤维化呈显著性相关关系,而在非IgG4亚型中间质纤维化多表现为小叶间型。其次与其他器官的IgG4-RD相比,桥本氏甲状腺炎IgG4亚型又表现出了一系列甲状腺特有的组织病理学特征,包括：甲状腺滤泡的缩小,滤泡上皮细胞的显著变性,以及显著的巨细胞或组织细胞浸润。上述特征在非
IgG4亚型中缺失或表现轻微。
[结论及意义]
1.桥本氏甲状腺炎,根据是否存在大量IgG4阳性浆细胞的浸润,可分为IgG4亚型与非IgG4亚型。
2.相比较非IgG4亚型,桥本氏甲状腺炎IgG4亚型表现出一系列独特的临床,实验室检查以及超声学特征。
3.检测血清中IgG4水平,可作为发现和诊断桥本氏甲状腺炎IgG4亚型的重要手段。
4.相比较非IgG4亚型,桥本氏甲状腺炎IgG4亚型表现出一系列独特的组织病理学特征。
5.桥本氏甲状腺炎IgG4亚型可以被认为是IgG4相关性疾病在甲状腺的主要表现形式。
6.引入IgG4相关性疾病的全新概念,为研究桥本氏甲状腺炎的发生发展提供了全新的视角；认识桥本氏甲状腺炎的IgG4亚型,可以帮助我们从临床和病理学两个方面早期发现重症患者,提高其治疗效果和生活质量；同时也为临床工作者寻找和制定新的治疗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.
引文
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1. Hashimoto H. Zur Kenntnis der lymphomatosen Veranderung der Schilddruse (Struma lymphomatosa). Arch Klin Chir 1912; 219-248.
2. Slatosky J, Shipton B, Wahba H. Thyroiditis:differential diagnosis and management. Am Fam Physician 2000; 61:1047-1052,1054.
3. Kakudo K, Li Y, Hirokawa M, et al. Diagnosis of Hashimoto's thyroiditis and IgG4-related sclerosing disease. Pathol Int 2011; 61:175-183.
4. Ozaki T, Nagashima K, Kusakabe T, et al. Development of thyroid gland and ultimobranchial body cyst is independent of p63. Lab Invest 2010; 91:138-146.
5. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003; 348:2646-2655.
6. LiVolsi VA. The pathology of autoimmune thyroid disease:a review. Thyroid 1994; 4:333-339.
7. Lloyd RV, Douglas BR, WF Y (eds). Endocrine Diseases. The American Registry of Pathology:Washington, DC.,2002,91-149 pp.
8. Katz SM, Vickery AL, Jr. The fibrous variant of Hashimoto's thyroiditis. Hum Pathol 1974; 5:161-170.
9. Li Y, Bai Y, Liu Z, et al. Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis. Pathol Int 2009; 59:636-641.
10. Tanaka G, Nakahara Y, Nakazima Y. [Japanese reference man 1988-Ⅳ. Studies on the weight and size of internal organs of Normal Japanese]. Nihon Igaku Hoshasen Gakkai Zasshi 1989; 49:344-364.
11. Zen Y, Nakanuma Y. IgG4-Related Disease:A Cross-sectional Study of 114 Cases. Am J Surg Pathol 2010; 34:1812-1819.
12. Li Y, Nishihara E, Kakudo K. Hashimoto's thyroiditis:old concepts and new insights. Current Opinion in Rheumatology 2011; 23:102-107.
13. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol 2011; 23:57-66.
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17. Hennessey JV. Clinical review:Riedel's thyroiditis:a clinical review. J Clin Endocrinol Metab 2011; 96:3031-3041.
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20. Beahrs OH, McConahey WM, Woolner LB. Invasive fibrous thyroiditis (Riedel's struma). J Clin Endocrinol Metab 1957; 17:201-220.
21. Comings DE, Skubi KB, Van Eyes J, et al. Familial multifocal fibrosclerosis. Findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel's thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med 1967; 66:884-892.
22. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD):general concept and details. Mod Rheumatol 2012; 22:1-14.
23. Dahlgren M, Khosroshahi A, Nielsen GP, et al. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken) 2010; 62:1312-1318.
2. Slatosky J, Shipton B, Wahba H. Thyroiditis:differential diagnosis and management. Am Fam Physician 2000; 61:1047-1052,1054.
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1. Hashimoto H. Zur Kenntnis der lymphomatosen Veranderung der Schilddruse (Struma lymphomatosa). Arch Klin Chir 1912; 219-248.
2. Slatosky J, Shipton B, Wahba H. Thyroiditis:differential diagnosis and management. Am Fam Physician 2000; 61:1047-1052,1054.
3. Kakudo K, Li Y, Hirokawa M, et al. Diagnosis of Hashimoto's thyroiditis and IgG4-related sclerosing disease. Pathol Int 2011; 61:175-183.
4. Ozaki T, Nagashima K, Kusakabe T, et al. Development of thyroid gland and ultimobranchial body cyst is independent of p63. Lab Invest 2010; 91:138-146.
5. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003; 348:2646-2655.
6. LiVolsi VA. The pathology of autoimmune thyroid disease:a review. Thyroid 1994; 4:333-339.
7. Lloyd RV, Douglas BR, WF Y (eds). Endocrine Diseases. The American Registry of Pathology:Washington, DC.,2002,91-149 pp.
8. Katz SM, Vickery AL, Jr. The fibrous variant of Hashimoto's thyroiditis. Hum Pathol 1974; 5:161-170.
9. Li Y, Bai Y, Liu Z, et al. Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis. Pathol Int 2009; 59:636-641.
10. Tanaka G, Nakahara Y, Nakazima Y. [Japanese reference man 1988-Ⅳ. Studies on the weight and size of internal organs of Normal Japanese]. Nihon Igaku Hoshasen Gakkai Zasshi 1989; 49:344-364.
11. Zen Y, Nakanuma Y. IgG4-Related Disease:A Cross-sectional Study of 114 Cases. Am J Surg Pathol 2010; 34:1812-1819.
12. Li Y, Nishihara E, Kakudo K. Hashimoto's thyroiditis:old concepts and new insights. Current Opinion in Rheumatology 2011; 23:102-107.
13. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol 2011; 23:57-66.
14. Sostre S, Reyes MM. Sonographic diagnosis and grading of Hashimoto's thyroiditis. J Endocrinol Invest 1991; 14:115-121.
15. Hayashi N, Tamaki N, Konishi J, et al. Sonography of Hashimoto's thyroiditis. J Clin Ultrasound 1986; 14:123-126.
16. Papi G, LiVolsi VA. Current concepts on Riedel thyroiditis. Am J Clin Pathol 2004; 121 Suppl:S50-63.
17. Hennessey JV. Clinical review:Riedel's thyroiditis:a clinical review. J Clin Endocrinol Metab 2011; 96:3031-3041.
18. Fatourechi MM, Hay ID, Mclver B, et al. Invasive fibrous thyroiditis (Riedel thyroiditis):the Mayo Clinic experience,1976-2008. Thyroid 2011; 21:765-772.
19. Hay ID. Thyroiditis:a clinical update. Mayo Clin Proc 1985; 60:836-843.
20. Beahrs OH, McConahey WM, Woolner LB. Invasive fibrous thyroiditis (Riedel's struma). J Clin Endocrinol Metab 1957; 17:201-220.
21. Comings DE, Skubi KB, Van Eyes J, et al. Familial multifocal fibrosclerosis. Findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel's thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med 1967; 66:884-892.
22. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD):general concept and details. Mod Rheumatol 2012; 22:1-14.
23. Dahlgren M, Khosroshahi A, Nielsen GP, et al. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken) 2010; 62:1312-1318.
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