Elephantiasic Pretibial Myxedema: Insight into and a Hypothesis Regarding the Pathogenesis of the Extrathyroidal Manifestations of Graves' Disease

Abstract

The basis for the extrathyroidal manifestations of Graves' ophthalmopathy (GO) and dermopathy are not well understood. We describe immunohistochemical studies on the skin of a patient with an extreme, elephantiasic form of Graves' dermopathy that developed after periods of prolonged standing with dependent edema. Excision of part of the lesion with subsequent skin grafting from a normal donor site resulted in recurrence of the disease at the original site as well as in development of disease at the donor site. A murine monoclonal antibody reacted with the thyrotropin receptor (TSHR) or a cross-reacting protein in fibroblast-like cells in the patient's upper dermis and, surprisingly, with dermal cells from unaffected individuals. The patient's dermis containing lymphoid follicles comprising B cells and CD3+, CD4+ T cells, with few CD8+ T cells. CD21+ cells (most likely follicular dendritic cells) were also present in the dermis. Based on past and present observations, we raise an unifying hypothesis to explain the diverse extrathyroidal manifestations of Graves' disease and their apparent lack of association with TSHR autoantibodies. As opposed to the present concept that these phenomena relate to site-specific properties on preadipocytes or fibroblasts, we suggest that clinically evidence GO and dermopathy are primarily caused by local factors (particularly in the orbit) superimposed on a systemic, low-grade connective tissue inflammation.

Genetic Profiling in Graves' Disease: Further Evidence for Lack of a Distinct Genetic Contribution to Graves' Ophthalmopathy

“…GO may be a most disabling condition with very unsatisfactory treatment approaches (30,39,40). The primary antigen appears to be the TSHR expressed on fibroblasts and adipocytes throughout the body, but they find themselves in a retroorbital environment that exacerbates the immune response to their presence (40)(41)(42). The argument over whether GO is a disorder distinct from GD and simply inherited at the same time appears less impressive now that the TSHR has been identified as an important antigen and that titers of TSHR antibodies correlate with the disease (40,41).…”

Pathogenesis of Graves Ophthalmopathy: Implications for Prediction, Prevention, and Treatment

“…17 Similarly, TSHR appears to be more abundant in pretibial dermopathy than in normal pretibial skin. 9 A relationship between adipogenesis and TSHR expression appears also to be present in cultures of orbital preadipocyte fibroblasts undergoing in vitro differentiation. Levels of TSHR mRNA, as well as leptin and adiponectin mRNA (encoding genes expressed exclusively by mature adipocytes, used here as markers of differentiation), are approximately tenfold higher in cultures containing mature adipocytes than in undifferentiated cultures.…”

“…9 The unyielding bony orbit predisposes to compression of low-pressure venous channels, increasing retrobulbar pressure and periorbital edema. Similarly, prolonged standing contributes to compromise of channels in the lower extremities, most likely contributing to the dependent edema seen in thyroid dermopathy.…”

“…This supports the concept that environmental or mechanical factors, such as tissue trauma or orbital shape and volume, may be important in ocular disease development. 9 The advice to stop smoking forms the centerpiece of patient counseling for prevention of GO. Current or former smokers constitute 64% of Graves patients with GO, 48% of those without overt GO, and only 28% of healthy individuals.…”

Clinico-pathological Study of Pretibial Region Changes in Graves’ Disease

“…The hypothesis of immunological factor is well known but other scientists have presented the reasoning that these lesions are the result of local factors superimposed on chronic low grade inflammation [2]. Thyroid dermopathy occurs in <5% of cases of Graves' disease [3].…”