A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

Umehara, Hisanori; Okazaki, Kazuichi; Yasukawa, Masaki; Kawano, Mitsuhiro; Yamamoto, Motohisa; Saeki, Takako; Matsui, Shoko; Sumida, Takayuki; Mimori, Tsuneyo; Tanaka, Yoshiya; Tsubota, Kazuo; Yoshino, Tadashi; Kawa, Shigeyuki; Suzuki, Ritsuro; Takegami, Tsutomu; Tomosugi, Naohisa; Kurose, Nozomu; Ishigaki, Yasuhito; Azumi, Atsushi; Kojima, Masaru; Nakamura, Shigeo; Inoue, Dai

doi:10.1007/s10165-011-0508-6

Cited by 482 publications

(493 citation statements)

References 73 publications

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“…This observation does not indicate that IgG4 thyroiditis is not a member of IgG4-related disease; even if many patients with IgG4-related disease have lesions in multiple organs, either synchronously or metachronously, other patients will still present with the involvement of a single organ. 22 We speculate that IgG4 thyroiditis group of Hashimoto's thyroiditis is likely to occur as an organ-specific IgG4-related lesion.…”

Section: Discussionmentioning

confidence: 82%

Distinct histopathological features of Hashimoto's thyroiditis with respect to IgG4-related disease

Zhou

Ozaki

et al. 2012

Modern Pathology

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A form of Hashimoto's thyroiditis with lymphoplasmacytic sclerosing changes and increased numbers of IgG4-positive plasma cells has recently been reported in the literature. These histopathological features suggest that this subtype of Hashimoto's thyroiditis may be closely related to IgG4-related disease. Therefore, this unique form of IgG4-related Hashimoto's thyroiditis, which is referred to as IgG4 thyroiditis, has its own clinical, serological, and sonographic features that are distinct from those associated with non-IgG4 thyroiditis. IgG4 thyroiditis shares similarities with the well-known fibrous variant of Hashimoto's thyroiditis; however, the detailed histopathological features of IgG4 thyroiditis have not been well established. Based on immunostaining results, 105 patients with Hashimoto's thyroiditis were divided into an IgG4 thyroiditis group (n ¼ 28) and a non-IgG4 thyroiditis group (n ¼ 77). As in our previous reports, IgG4 thyroiditis was associated with a patient population of a younger age, a lower female-to-male ratio, rapid progression, higher levels of thyroid autoantibodies, subclinical hypothyroidism, and diffuse sonographic echogenicity. Histopathologically, this group revealed severe lymphoplasmacytic infiltration, dense stromal fibrosis, marked follicular cell degeneration, numerous micro-follicles, and notable giant cell/histiocyte infiltration. Importantly, the IgG4-related group did not completely overlap with fibrous variant of Hashimoto's thyroiditis. Four cases (14%) in the IgG4 thyroiditis group presented only mild fibrosis in the stroma, whereas 29 cases (38%) in the non-IgG4 thyroiditis group met the diagnostic criteria for fibrous variant of Hashimoto's thyroiditis. Furthermore, we observed three patterns of stromal fibrosis in Hashimoto's thyroiditis: interfollicular fibrosis, interlobular fibrosis, and scar fibrosis. The IgG4 thyroiditis group was significantly associated with the presence of predominant interfollicular fibrosis. In conclusion, IgG4 Hashimoto's thyroiditis presents histopathological features quite distinct from its non-IgG4 counterpart.

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Section: Discussionmentioning

confidence: 82%

Distinct histopathological features of Hashimoto's thyroiditis with respect to IgG4-related disease

Zhou

Ozaki

et al. 2012

Modern Pathology

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“…Clinical findings are dependent on the location of involved tissues and often include forming mass lesions, mimicking malignancies, This condition is reported in the literature by different names: IgG4-related disease, IgG4-associated disease, IgG4-related systemic disease, IgG4-related sclerosing disease, IgG4-related systemic sclerosing disease, IgG4-related autoimmune disease, hyper-IgG4 disease, IgG4-positive multiorgan lymphoproliferative syndrome, systemic IgG4-related plasmacytic syndrome and IgG4 syndrome. Some groups reached a consensus to refer it as IgG4-related disease (5,8).…”

Section: Discussionmentioning

confidence: 99%

“…Laboratory testing revealed a normal hemoglobin level of 15.1 g/dL (normal, 14-18), a normal white blood cell count of 10.4 X 10 3 /µL (normal, [4][5][6][7][8][9][10][11] and an elevated platelet count of 521 X 10 3 /µL (normal, 150-450). Increased erythrocyte sedimentation rate (ESR) of 81 mm/h (normal, < 31) and C-reactive protein of 8.2 mg/dL (normal, < 1) were found, with an elevated thyroid-stimulating hormone (TSH) of 19 mIU/L (normal, 0.1-4) and a normal free thyroxine (FT 4 ) of 0.99 ng/dL (normal, 0.93-1.7).…”

Section: Case Reportmentioning

confidence: 99%

IgG4-related Hashimoto’s thyroiditis – A new variant of a well known disease

Luiz

Gonçalves

Silva

et al. 2014

Arq Bras Endocrinol Metab

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SUMMARYHashimoto's thyroiditis (HT) has been characterized for many years as a well-defined clinicopathologic entity, but is now considered a heterogeneous disease. IgG4-related HT is a new subtype characterized by thyroid inflammation rich in IgG4-positive plasma cells and marked fibrosis. It may be part of the systemic IgG4-related disease. We report a case of a 56-year-old Portuguese man who presented with a one-month history of progressive neck swelling and dysphagia. Laboratory testing revealed increased inflammatory parameters, subclinical hypothyroidism and very high levels of thyroid autoantibodies. Cervical ultrasound (US) demonstrated an enlarged and heterogeneous thyroid gland and two hypoechoic nodules. US-guided fine needle aspiration cytology was consistent with lymphocytic thyroiditis. The patient was submitted to total thyroidectomy and microscopic examination identified typical findings of HT, marked fibrosis limited within the thyroid capsule and lymphoplasmacytic infiltration, with > 50 IgG4-positive plasma cells per high-power field and an IgG4/ IgG ratio of > 40%. After surgery, serum IgG4 concentration was high-normal. Symptoms relief and reduction in laboratory inflammatory parameters were noticed. Thyroid function is controlled with levothyroxine. To our knowledge we report the first case of IgG4-related HT in a non-Asian patient. We also perform a review of the literature regarding IgG4-related disease and IgG4-related HT. Our case highlights this new variant of the well known HT, and helps physicians in recognizing its main clinical features, allowing for proper diagnosis and treatment. Arq Bras Endocrinol Metab. 2014;58(8):862-8 SUMÁRIO A tireoidite de Hashimoto (TH) foi caracterizada durante muitos anos como uma entidade clinicopatológica bem definida, mas é atualmente considerada uma patologia heterogênea. A TH associada a IgG4 apresenta-se como um novo subtipo, sendo caracterizada por inflamação da tireoide com numerosos plasmócitos IgG4-positivos e fibrose extensa. É possível que pertença ao espectro da doença sistêmica associada a IgG4. Relatamos o caso de um homem português de 56 anos que se apresentou com aumento progressivo do volume cervical e disfagia, com um mês de evolução. A avaliação laboratorial revelou elevação dos parâmetros inflamatórios, hipotireoidismo subclínico e níveis muito elevados de autoanticorpos tireoidianos. Por ultrassonografia cervical demonstrou-se tireoide aumentada, heterogênea, com dois nódulos hipoecoicos. Foi realizada citologia aspirativa com agulha fina guiada por ultrassom, compatível com tireoidite linfocítica. O doente foi submetido à tireoidectomia total e o exame histológico revelou achados típicos de TH, extensa fibrose localizada dentro da cápsula tireoidiana e infiltrado linfoplasmocitário, com > 50 plasmócitos IgG4-positivos por campo de grande ampliação e uma relação IgG4/IgG > 40%. Após cirurgia, a concentração sérica de IgG4 encontrava-se no limite superior do normal. Ocorreu melhoria sintomática e redução dos parâmetros inflamatór...

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“…[1][2][3][4] Histological examination of IgG4-related disease has shown diffuse lymphoplasmacytic infiltration, interstitial fibrosis, obliterative phlebitis, and eosinophilic infiltration. Additionally, numerous IgG4-positive plasma cells are observed and the IgG4-positive/IgG-positive cell ratio is elevated above 40% in affected tissues.…”

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confidence: 99%

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

et al. 2014

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IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffinembedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFb1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

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A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

Cited by 482 publications

References 73 publications

Distinct histopathological features of Hashimoto's thyroiditis with respect to IgG4-related disease

Distinct histopathological features of Hashimoto's thyroiditis with respect to IgG4-related disease

IgG4-related Hashimoto’s thyroiditis – A new variant of a well known disease

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

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