Immunoglobulin G4-Related Thyroid Diseases

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is a new disease category involving many organ systems, including the endocrine system in general and the thyroid in particular. Since an initial association was made between hypothyroidism and autoimmune (IgG4-related) pancreatitis, more forms of IgG4-related thyroid disease (IgG4-RTD) have been recognized. Four subcategories of IgG4-RTD have so far been identified: Riedel thyroiditis (RT), fibrosing variant of Hashimoto thyroiditis (FVHT), IgG4-related Hashimoto thyroiditis, and Graves disease with elevated IgG4 levels. Although a male predominance is seen for IgG4-RD in general, RT and FVHT have a female preponderance. The pathogenesis of IgG4-RD is not completely understood; however, genetic factors, antigen-antibody reactions, and an allergic phenomenon have been described. Diagnosis of IgG4-RD requires a combination of clinical features, serological evidence, and histological features. Histology is the mainstay of diagnosis, with IgG4 immunostaining. Although serum IgG4 levels are usually elevated in IgG4-RD, raised serum IgG4 is neither necessary nor adequate for diagnosis. Imaging supports the diagnosis and is a useful tool in disease monitoring. Management of IgG4-RTD is both medical and surgical. Steroids are the first-line treatment and may produce a swift response. Tamoxifen and rituximab are second-line agents used in steroid-resistant patients. Surgical debulking is carried out in RT solely as a procedure to relieve obstruction. Other endocrine associations described with IgG4-RD are hypophysitis and Hashimoto encephalopathy. IgG4-RTD is an uncommon disease entity, and prompt diagnosis and treatment can improve outcomes.

Keywords: Graves disease; Hashimoto thyroiditis; Immunoglobulin G4; Riedel thyroiditis; Rituximab; Tamoxifen.

Fig. 1

IgG4-related conditions. Many diseases have been reported to be IgG4-related. Modified from Umehara et al. [7] with permission.

Fig. 2

Schematic model of CD4+ cytotoxic T lymphocytes (CTLs) in IgG4-RD pathogenesis. Clonal expansion of CD4+ CTLs and their infiltration into tissue sites may be the cause of this disease state. Reactivation of these CD4+ CTL cells may require antigen presentation by plasmablasts or other activated B cells in tissue sites. Activated CD4+ CTLs presumably mediate fibrosis and inflammation as a result of cytokine secretion or possibly the induction of cell death. The mechanisms by which CD4+ CTLs may cause disease remain speculative. Reproduced from Maehara et al. [13] with permission.

Fig. 3

a Active inflammation at the left neck before rituximab (SUVmax, 6.5). b Decrease in inflammation at the left neck 6 weeks after rituximab (SUVmax, 5.2). c Persistent decrease in inflammation at the left neck 10 months after rituximab (SUVmax, 3.7). d Active inflammation at the mediastinum before rituximab (SUVmax, 8.8). e Decrease in inflammation at the mediastinum 6 weeks after rituximab (SUVmax, 4.9). f Persistent decrease in inflammation at the mediastinum 10 months after rituximab (SUVmax, 4.2). Reproduced from Soh et al. [50] with permission.