Immunoglobulin G4-related disease (IgG4-RD) is a new disease entity recognized at the start of this century noted to be involving many organ systems including endocrine system and thyroid in particular. It represents an immune mediated fibro inflammatory condition with characteristic histopathological appearance affecting single or multiple organs. In general, immunoglobulin G4-related thyroid disease (IgG4-RTD) is rarely considered and it may be isolated or with other organ involvement. Four subcategories of IgG4-RTD have been identified so far: Riedel thyroiditis, fibrosing variant of Hashimoto thyroiditis, immunoglobulin G4-related Hashimoto thyroiditis, and Graves disease with elevated immunoglobulin G4 levels. The diagnostic approach is complex and the work up relies on the coexistence of clinical features, histological features and serological evidence. Demonstration of the classic histopathological features is vital to diagnose IgG4-RD in most cases, and biopsy proof is preferred strongly by most disease experts before the initiation of treatment. The treatments for IgG4-RTD include medical and surgical options. Steroids are first line treatment though it may need further evaluation. Tamoxifen and rituximab are second line treatment for steroid resistant patients. Surgical excision of thyroid gland in presence of compression symptoms is the surgical option. Inspite of pathophysiology of the disease being poorly understood till now, early and prompt diagnosis and an early treatment initiation can improve the outcomes.
引用本文： . Immunoglobulin G4-related thyroid diseases. 華西醫學, 2018, 33(5): 584-588. doi: 10.7507/1002-0179.201803160 復制
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic autoimmune disorder characterized by elevated serum immunoglobulin (Ig) G4 levels, dense lymphoplasmacytic infiltrate, a tendency to form tumefactive lesions, and storiform fibrosis with distinctive histopathologic features that almost always include infiltrates of IgG4 plasma cells, and a swift initial response to glucocorticoids.[1] The first step towards the discovery of IgG4-RD was the description of an autoimmune mediated, steroid responsive form of pancreatitis, today known as IgG4-RD or type 1 autoimmune pancreatitis in 1995.[2] Subsequently, in 2001, Hamano et al. reported an elevation of serum IgG4 levels in patients with autoimmune pancreatitis and positive response to glucocorticoid therapy.[3] The recognition of this disease entity helped to unify several diseases described several years ago which were previously thought to occur in isolation such as Mikulicz syndrome, [4] retroperitoneal fibrosis, [5] Kuttner tumour, [6] and Riedel thyroiditis (RT).[7] Thyroid involvement in IgG4-RD is rare, believed to occur in <4% of cases. [8] However, it is likely that the diagnosis may be grossly under reported due to lack of awareness of this clinical entity. The diagnosis of IgG4-related thyroid disease (IgG4-RTD) is a challenge in the initial time of its recognition due to absence of definite diagnostic criteria, in addition to the lack of availability of specific tests required for its definite diagnosis. However, since the introduction of diagnostic criteria, cases of IgG4-RTD are being reported around the globe with higher awareness of the same.
1 Epidemiology
The epidemiology of this disease and the true prevalence have not been explored in detail, although nearly 80% of patients have been reported from Japan, with a mean age between 50 and 70 years of age at diagnosis and with a male predominance.[9] Uchida et al. estimated the annual incidence of IgG4-RD at 0.28/100 000–1.08/100 000.[10] For the year 2009, a total of 8 000 patients were expected in Japan, which accounted for a prevalence of approximately 62 patients per million inhabitants. However this disease has subsequently been reported from various countries worldwide.
The most commonly involved parts of the body in IgG4-RD are head and neck region. In the head and neck region, orbits are the most commonly involved organs observed in more than 50% of cases, followed by salivary glands (22%) and lacrimal glands (18.6%). Thyroid related disorders in IgG4-RD is rare, believed to occur in 4% of patients.[11] Other organ systems that are involved in IgG4-RD include the kidneys, blood vessels, retro-peritoneum, skin, and lungs.
2 Pathogenesis
Most of the studies regarding pathogenesis are primarily based on autoimmune pancreatitis alone. Genetic factors, antigen-antibody reactions, and allergic phenomenon seem to play an important role. However the pathogenesis of IgG4-RTD is still poorly understood. It is believed that prolonged exposure to certain undetermined antigens leads to production of T helper type 2 (Th2)-mediated immune response and upregulation of regulatory T cells. Increased interleukin (IL)-10, IL-12, and IL-21 favour plasma cells to secrete IgG4.[12] The source of increased circulating levels of IgG4 in these patients is believed to be primarily from the organ/organ system involved. Increased secretion of IL-10 and tissue growth factor-β (TGF-β) from Th2 cells seems to be responsible for increased fibrosis in the organ involved.
Serum IgG4 levels are usually elevated to a level greater than 135 mg/dL in IgG4-RD, but this finding alone is neither necessary nor adequate for diagnosis. Carruthers et al. described conditions that could cause elevation in IgG4 such as infections, connective tissue diseases, and immunodeficiency states, and also demonstrated a specificity and sensitivity of 60 and 90% respectively for diagnosing IgG4-RD when the cut-off for serum IgG4 was set at greater than 135 mg/dL.[13] The measurement of serum IgG4 is also useful in assessing treatment response as well as the recurrence of the disease.[14]
3 Diagnosis
Diagnosis of IgG4-RD needs a high degree of clinical suspicion or else the diagnosis can be easily missed due to highly non specific clinical presenting features. Usually the disease can present as a mass lesion of the organ involved, mass being firm to hard due to significant fibrosis. Hence the diagnosis gets confused with malignant lesion. A diagnostic criteria for IgG4-RD was proposed from Japan in 2012 utilizing presenting clinical features, serological evidence, and histological features （Box 1).[15]
4 Subcategories
Four subcategories of IgG4-RTD have been identified so far: RT, fibrosing variant of Hashimoto thyroiditis, IgG4-related Hashimoto thyroiditis (IgG4-RHT), and Graves disease with elevated IgG4 levels.
4.1 RT
RT is a rare, chronic inflammatory disease of the thyroid gland characterized by a dense fibrosis that replaces normal thyroid parenchyma and the fibrotic process invades adjacent structures and extends beyond thyroid capsule.[16] RT was first recognized and reported in 1896 as an inflammatory sclerosing disorder of thyroid gland, with an estimated incidence of 1.06 cases per 100 000 population.[17] It usually presents as hard mass in the neck, does not move with swallowing or deglutition, often confused with malignancy. It also produces compressive symptoms including respiratory distress, dysphagia, vocal cord paralysis resulting in altered voice.[16-17] A link between RT and IgG4-RD was noticed and shown for the first time by Dahlgren et al., [7] who demonstrated the presence of excessive numbers of IgG4-positive plasma cells in 3 RT histological samples with histopathology consistent for a diagnosis of IgG4-RD. In a study recently performed at Mayo Clinic with 6 cases of RT from 1958 to 2008, 5 cases had IgG4 immunostaining further supporting the link.[18] However it has to be added that elevated levels of serum IgG4 have not been documented in RT.
4.2 FVHT
FVHT is a rare form of Hashimoto thyroiditis (HT), occurring in about 10% of patients with HT. It was first defined by Katz and Vickery in 1974 and proposed the histopathological diagnostic criteria as: (1) a marked fibrous replacement of more than one-third of the thyroid parenchyma and (2) changes typical of HT in the remaining tissue.[19] It was observed that gland was very firm on palpation with rapid enlargement and severe compression symptoms in the neck.[20] Katz and Vickery reported a female predominance with a female to male ration of 9:1, out of 56 cases of FVHT, mostly middle aged women between 40 and 60 years of age.[19] Deshpande et al. studied a group of patients with FVHT and compared them with typical HT patients and found that FVHT patients predominantly have hypothyroidism, a higher mean IgG4-positive cell count in affected thyroid tissue, and a higher IgG4/IgG ratio compared to the typical HT patients.[20] The histological findings were described as an exaggerated lobular pattern, with the lobules separated by cellular storiform-type fibrosis, similar to the findings of fibrosis seen in other forms of IgG4-RD. Hence, considering these evidences, they proposed that FVHT belonged to the IgG4 spectrum of diseases. However, other organ involvement does not seem to feature in FVHT.
4.3 IgG4-RHT
IgG4-RHT is a new disease entity proposed by Li et al. in 2009, [21] considering HT as either IgG4 thyroiditis (IgG4-positive plasma cell-rich group) or non-IgG4 thyroiditis (IgG4-positive plasma cell-poor group). It has not been associated with other systemic manifestations of IgG4-RD unlike RT. The incidence is unknown. Li et al. reported male preponderance for IgG4-RHT with an age range between 47 and 68 years.[21] Distinctive clinical features include more rapid progress, subclinical hypothyroidism, diffuse low echogenicity on ultrasonography, and a higher level of circulating thyroid auto antibodies compared to non-IgG4 thyroiditis.[22] According to a study done in Poland, as high as one third of patients with HT had high levels of IgG4.[23] In a cohort of 53 patients with HT, 32.5% were noticed to have increased levels of IgG4 (> 135 U/mL).[23] Another important observation to be noted was the higher circulating levels of tumor necrosis factor αand higher levothyroxine dose requirement for the management of hypothyroidism in the subset of patients with increased IgG4 levels.[23] Another recent paper from Japan reported that only 6 out of 149 (4%) consecutively evaluated patients with HT had increased levels of IgG4 >135 U/mL. [24] A retrospective study from China reported to have diagnosed 22.64% (12/53) of patients with HT to have IgG4-RTD based on the evidence of immunohistochemical findings of thyroid tissue.[25] Authors revealed that no significant differences were found in the serum levels of IgG4, total IgG and IgG4/IgG ratio in patients with IgG4-RHT compared to those with non-IgG4-RHT.[25] The features differentiating IgG4-RHT from RT are marked fibrosis, extrathyroidal extension, and absence of other systemic manifestations.[7]
4.4 Graves Disease with elevated IgG4 levels
As of now, data regarding the relation of Graves disease and IgG4-RTD is limited. A paper from Japan revealed a small subset of patients with Graves disease were found to have elevated serum IgG4 levels. These patients were older, showed more hypoechoic areas on ultrasonography, but no histological differences were evaluated.[26] An association of Graves ophthalmopathy with elevated serum IgG4 levels has also been found.[27] However, more data needs to be obtained to explain definite link of Graves disease with IgG4-RTD.
IgG4-RTD is one of the newest organ involvement manifestation. Imaging in IgG4-RTD may only support the diagnosis as the findings are not specific for the disease. Ultrasound of the thyroid has been the most commonly used imaging modality and it usually shows diffuse low echogenicity of the thyroid gland in IgG4-RHT, whereas non-IgG4 thyroiditis is associated with diffuse, coarse echogenicity.[22]
Hence, in view of all the above mentioned details it is important to highlight that histopathology remains the investigation of choice for the diagnosis of IgG4-RTD and it is likely that the diagnostic criteria for IgG4-RTD may undergo further subtle changes in the future as more data gets available from all around the world including different ethnic groups.
5 Management
Treatment of IgG4-RTD is believed to be the same as other IgG4-RD treatment as maximum data has been obtained from patients with auto immune pancreatitis ever since it has been explained in 1995 and has been followed for other organ involvements.
5.1 Medical management
Glucocorticoids remain the mainstay of treatment for IgG4-RD. The usage of glucocorticoid early in the disease has shown to reduce the disease progression in IgG4-RD.[28] In cases of RT, early introduction of glucocorticoids produced symptomatic relief for upper airway symptoms, dysphonia, recurrent laryngeal nerve involvement by reducing the size and hardness of the pathological tissue mass.[29] As per the Japanese guidelines, induction regimen for inducing remission is prednisolone at 0.6 mg/(kg·day) (usually at 30–40 mg per day) for a period of three months, followed by a maintenance therapy of low dose prednisolone (2.5–5.0 mg per day) for 6–12 months to maintain remission and prevent relapse.[30] However, remission and relapse rates after glucocorticoid usage are still unclear.
Tamoxifen is considered as the second-line agent for patients who relapse on glucocorticoids. It inhibits fibroblastic function through its influence on the production of TGF-β, which infact is a potent growth inhibitor.[31] Tamoxifen at doses of 10–20 mg as a monotherapy or in combination with continued glucocorticoid therapy has been reported to be successful, especially in symptom control and reduction in pathological tissue mass.[32-33] Soh et al. reported that treatment with rituximab was effective in reducing the extrathyroidal inflammatory mass and associated compressive symptoms in a patient with RT refractory to glucocorticoids and tamoxifen.[34]
5.2 Surgical management
In cases of RT with significant compressive pressure symptoms, debulking surgery has been performed namely isthmectomy to relieve obstruction, other more invasive surgeries are generally considered inappropriate in view of the risk of vocal cord palsy and surgical hypoparathyroidism.[35]
6 Conclusion
IgG4-RTD is a recently recognized new disease entity and it represents one of the hottest areas of research globally in this decade since then. It includes previously known diseases such as RT, FVHT along with newly recognized categories such as IgG4-RHT and Graves disease with elevated IgG4 levels. The pathogenesis of these diseases may need further understanding and diagnostic criteria may undergo subtle modifications with more cases being reported worldwide. IgG4-RTD tends to occur at middle or older age with apparently equal sexual predisposition compared to female predisposition in HT. It is understood to have more sclerosing involvement of the gland, which needs to be differentiated from malignancy. Glucocorticoids remains to be the first-line treatment as is the case of other IgG4-RD. Although IgG4-RTD is an uncommon form of thyroiditis, its prompt recognition is important for further studying pathogenesis and other mechanisms involved in the disease process and to improve the outcomes in the future.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic autoimmune disorder characterized by elevated serum immunoglobulin (Ig) G4 levels, dense lymphoplasmacytic infiltrate, a tendency to form tumefactive lesions, and storiform fibrosis with distinctive histopathologic features that almost always include infiltrates of IgG4 plasma cells, and a swift initial response to glucocorticoids.[1] The first step towards the discovery of IgG4-RD was the description of an autoimmune mediated, steroid responsive form of pancreatitis, today known as IgG4-RD or type 1 autoimmune pancreatitis in 1995.[2] Subsequently, in 2001, Hamano et al. reported an elevation of serum IgG4 levels in patients with autoimmune pancreatitis and positive response to glucocorticoid therapy.[3] The recognition of this disease entity helped to unify several diseases described several years ago which were previously thought to occur in isolation such as Mikulicz syndrome, [4] retroperitoneal fibrosis, [5] Kuttner tumour, [6] and Riedel thyroiditis (RT).[7] Thyroid involvement in IgG4-RD is rare, believed to occur in <4% of cases. [8] However, it is likely that the diagnosis may be grossly under reported due to lack of awareness of this clinical entity. The diagnosis of IgG4-related thyroid disease (IgG4-RTD) is a challenge in the initial time of its recognition due to absence of definite diagnostic criteria, in addition to the lack of availability of specific tests required for its definite diagnosis. However, since the introduction of diagnostic criteria, cases of IgG4-RTD are being reported around the globe with higher awareness of the same.
1 Epidemiology
The epidemiology of this disease and the true prevalence have not been explored in detail, although nearly 80% of patients have been reported from Japan, with a mean age between 50 and 70 years of age at diagnosis and with a male predominance.[9] Uchida et al. estimated the annual incidence of IgG4-RD at 0.28/100 000–1.08/100 000.[10] For the year 2009, a total of 8 000 patients were expected in Japan, which accounted for a prevalence of approximately 62 patients per million inhabitants. However this disease has subsequently been reported from various countries worldwide.
The most commonly involved parts of the body in IgG4-RD are head and neck region. In the head and neck region, orbits are the most commonly involved organs observed in more than 50% of cases, followed by salivary glands (22%) and lacrimal glands (18.6%). Thyroid related disorders in IgG4-RD is rare, believed to occur in 4% of patients.[11] Other organ systems that are involved in IgG4-RD include the kidneys, blood vessels, retro-peritoneum, skin, and lungs.
2 Pathogenesis
Most of the studies regarding pathogenesis are primarily based on autoimmune pancreatitis alone. Genetic factors, antigen-antibody reactions, and allergic phenomenon seem to play an important role. However the pathogenesis of IgG4-RTD is still poorly understood. It is believed that prolonged exposure to certain undetermined antigens leads to production of T helper type 2 (Th2)-mediated immune response and upregulation of regulatory T cells. Increased interleukin (IL)-10, IL-12, and IL-21 favour plasma cells to secrete IgG4.[12] The source of increased circulating levels of IgG4 in these patients is believed to be primarily from the organ/organ system involved. Increased secretion of IL-10 and tissue growth factor-β (TGF-β) from Th2 cells seems to be responsible for increased fibrosis in the organ involved.
Serum IgG4 levels are usually elevated to a level greater than 135 mg/dL in IgG4-RD, but this finding alone is neither necessary nor adequate for diagnosis. Carruthers et al. described conditions that could cause elevation in IgG4 such as infections, connective tissue diseases, and immunodeficiency states, and also demonstrated a specificity and sensitivity of 60 and 90% respectively for diagnosing IgG4-RD when the cut-off for serum IgG4 was set at greater than 135 mg/dL.[13] The measurement of serum IgG4 is also useful in assessing treatment response as well as the recurrence of the disease.[14]
3 Diagnosis
Diagnosis of IgG4-RD needs a high degree of clinical suspicion or else the diagnosis can be easily missed due to highly non specific clinical presenting features. Usually the disease can present as a mass lesion of the organ involved, mass being firm to hard due to significant fibrosis. Hence the diagnosis gets confused with malignant lesion. A diagnostic criteria for IgG4-RD was proposed from Japan in 2012 utilizing presenting clinical features, serological evidence, and histological features （Box 1).[15]
4 Subcategories
Four subcategories of IgG4-RTD have been identified so far: RT, fibrosing variant of Hashimoto thyroiditis, IgG4-related Hashimoto thyroiditis (IgG4-RHT), and Graves disease with elevated IgG4 levels.
4.1 RT
RT is a rare, chronic inflammatory disease of the thyroid gland characterized by a dense fibrosis that replaces normal thyroid parenchyma and the fibrotic process invades adjacent structures and extends beyond thyroid capsule.[16] RT was first recognized and reported in 1896 as an inflammatory sclerosing disorder of thyroid gland, with an estimated incidence of 1.06 cases per 100 000 population.[17] It usually presents as hard mass in the neck, does not move with swallowing or deglutition, often confused with malignancy. It also produces compressive symptoms including respiratory distress, dysphagia, vocal cord paralysis resulting in altered voice.[16-17] A link between RT and IgG4-RD was noticed and shown for the first time by Dahlgren et al., [7] who demonstrated the presence of excessive numbers of IgG4-positive plasma cells in 3 RT histological samples with histopathology consistent for a diagnosis of IgG4-RD. In a study recently performed at Mayo Clinic with 6 cases of RT from 1958 to 2008, 5 cases had IgG4 immunostaining further supporting the link.[18] However it has to be added that elevated levels of serum IgG4 have not been documented in RT.
4.2 FVHT
FVHT is a rare form of Hashimoto thyroiditis (HT), occurring in about 10% of patients with HT. It was first defined by Katz and Vickery in 1974 and proposed the histopathological diagnostic criteria as: (1) a marked fibrous replacement of more than one-third of the thyroid parenchyma and (2) changes typical of HT in the remaining tissue.[19] It was observed that gland was very firm on palpation with rapid enlargement and severe compression symptoms in the neck.[20] Katz and Vickery reported a female predominance with a female to male ration of 9:1, out of 56 cases of FVHT, mostly middle aged women between 40 and 60 years of age.[19] Deshpande et al. studied a group of patients with FVHT and compared them with typical HT patients and found that FVHT patients predominantly have hypothyroidism, a higher mean IgG4-positive cell count in affected thyroid tissue, and a higher IgG4/IgG ratio compared to the typical HT patients.[20] The histological findings were described as an exaggerated lobular pattern, with the lobules separated by cellular storiform-type fibrosis, similar to the findings of fibrosis seen in other forms of IgG4-RD. Hence, considering these evidences, they proposed that FVHT belonged to the IgG4 spectrum of diseases. However, other organ involvement does not seem to feature in FVHT.
4.3 IgG4-RHT
IgG4-RHT is a new disease entity proposed by Li et al. in 2009, [21] considering HT as either IgG4 thyroiditis (IgG4-positive plasma cell-rich group) or non-IgG4 thyroiditis (IgG4-positive plasma cell-poor group). It has not been associated with other systemic manifestations of IgG4-RD unlike RT. The incidence is unknown. Li et al. reported male preponderance for IgG4-RHT with an age range between 47 and 68 years.[21] Distinctive clinical features include more rapid progress, subclinical hypothyroidism, diffuse low echogenicity on ultrasonography, and a higher level of circulating thyroid auto antibodies compared to non-IgG4 thyroiditis.[22] According to a study done in Poland, as high as one third of patients with HT had high levels of IgG4.[23] In a cohort of 53 patients with HT, 32.5% were noticed to have increased levels of IgG4 (> 135 U/mL).[23] Another important observation to be noted was the higher circulating levels of tumor necrosis factor αand higher levothyroxine dose requirement for the management of hypothyroidism in the subset of patients with increased IgG4 levels.[23] Another recent paper from Japan reported that only 6 out of 149 (4%) consecutively evaluated patients with HT had increased levels of IgG4 >135 U/mL. [24] A retrospective study from China reported to have diagnosed 22.64% (12/53) of patients with HT to have IgG4-RTD based on the evidence of immunohistochemical findings of thyroid tissue.[25] Authors revealed that no significant differences were found in the serum levels of IgG4, total IgG and IgG4/IgG ratio in patients with IgG4-RHT compared to those with non-IgG4-RHT.[25] The features differentiating IgG4-RHT from RT are marked fibrosis, extrathyroidal extension, and absence of other systemic manifestations.[7]
4.4 Graves Disease with elevated IgG4 levels
As of now, data regarding the relation of Graves disease and IgG4-RTD is limited. A paper from Japan revealed a small subset of patients with Graves disease were found to have elevated serum IgG4 levels. These patients were older, showed more hypoechoic areas on ultrasonography, but no histological differences were evaluated.[26] An association of Graves ophthalmopathy with elevated serum IgG4 levels has also been found.[27] However, more data needs to be obtained to explain definite link of Graves disease with IgG4-RTD.
IgG4-RTD is one of the newest organ involvement manifestation. Imaging in IgG4-RTD may only support the diagnosis as the findings are not specific for the disease. Ultrasound of the thyroid has been the most commonly used imaging modality and it usually shows diffuse low echogenicity of the thyroid gland in IgG4-RHT, whereas non-IgG4 thyroiditis is associated with diffuse, coarse echogenicity.[22]
Hence, in view of all the above mentioned details it is important to highlight that histopathology remains the investigation of choice for the diagnosis of IgG4-RTD and it is likely that the diagnostic criteria for IgG4-RTD may undergo further subtle changes in the future as more data gets available from all around the world including different ethnic groups.
5 Management
Treatment of IgG4-RTD is believed to be the same as other IgG4-RD treatment as maximum data has been obtained from patients with auto immune pancreatitis ever since it has been explained in 1995 and has been followed for other organ involvements.
5.1 Medical management
Glucocorticoids remain the mainstay of treatment for IgG4-RD. The usage of glucocorticoid early in the disease has shown to reduce the disease progression in IgG4-RD.[28] In cases of RT, early introduction of glucocorticoids produced symptomatic relief for upper airway symptoms, dysphonia, recurrent laryngeal nerve involvement by reducing the size and hardness of the pathological tissue mass.[29] As per the Japanese guidelines, induction regimen for inducing remission is prednisolone at 0.6 mg/(kg·day) (usually at 30–40 mg per day) for a period of three months, followed by a maintenance therapy of low dose prednisolone (2.5–5.0 mg per day) for 6–12 months to maintain remission and prevent relapse.[30] However, remission and relapse rates after glucocorticoid usage are still unclear.
Tamoxifen is considered as the second-line agent for patients who relapse on glucocorticoids. It inhibits fibroblastic function through its influence on the production of TGF-β, which infact is a potent growth inhibitor.[31] Tamoxifen at doses of 10–20 mg as a monotherapy or in combination with continued glucocorticoid therapy has been reported to be successful, especially in symptom control and reduction in pathological tissue mass.[32-33] Soh et al. reported that treatment with rituximab was effective in reducing the extrathyroidal inflammatory mass and associated compressive symptoms in a patient with RT refractory to glucocorticoids and tamoxifen.[34]
5.2 Surgical management
In cases of RT with significant compressive pressure symptoms, debulking surgery has been performed namely isthmectomy to relieve obstruction, other more invasive surgeries are generally considered inappropriate in view of the risk of vocal cord palsy and surgical hypoparathyroidism.[35]
6 Conclusion
IgG4-RTD is a recently recognized new disease entity and it represents one of the hottest areas of research globally in this decade since then. It includes previously known diseases such as RT, FVHT along with newly recognized categories such as IgG4-RHT and Graves disease with elevated IgG4 levels. The pathogenesis of these diseases may need further understanding and diagnostic criteria may undergo subtle modifications with more cases being reported worldwide. IgG4-RTD tends to occur at middle or older age with apparently equal sexual predisposition compared to female predisposition in HT. It is understood to have more sclerosing involvement of the gland, which needs to be differentiated from malignancy. Glucocorticoids remains to be the first-line treatment as is the case of other IgG4-RD. Although IgG4-RTD is an uncommon form of thyroiditis, its prompt recognition is important for further studying pathogenesis and other mechanisms involved in the disease process and to improve the outcomes in the future.
