LOCALIZED MYXEDEMA AND THYROID ACROPACHY

Localized pretibial myxedema often develops in association with infiltrative ophthalmopathy. In a study of 150 consecutive patients with pretibial edema, only one patient had no GO^153. Some minor evidence of pretibial myxedema is seen in 5-10% of patients with Graves' disease 153d. Cosmetically significant lesions occur in 1-2%, and severe cases are even less frequent.

This lesion is a firm localized thickening, usually over the lateral aspect of the lower leg just above the ankle, but may manifest itself as a scar infiltrate (153a) and has even been found in a donor graft (153b). Patches may be 0.5-6.0 cm in the greatest dimensions, or much more, and are elevated, firm, and nonpitting. Rarely, the infiltrations may be so extensive that they become confluent, giving the leg below the knee a swollen, beefy appearance and the skin a brawny, porcine texture (Figs. 12-6,12-7). The infiltrates are usually bilateral. The color ranges from pink to russet to salmon. The surface over the lesion is usually shiny, but it may be scaly and is frequently puckered, like the surface of an orange, or is thrown into fine irregular folds. Sometimes the lesions on the ankles may take the form of heaped-up masses that interfere with the wearing of shoes. Similar lesions may exist on the dorsum of the feet and the dorsum of the phalanges. Most rarely, they may appear on the abdominal wall and the face. Rarely, there is associated clubbing of the fingers and osteoarthropathy, including periosteal new bone formation. These two phenomena constitute thyroid acropachy. Thyroid acropachy differs from hypertrophic pulmonary osteoarthropathy in several respects. The lesions affect mainly the distal portion of the bones. The soft tissue reaction associated with periosteal new bone formation is firm, pale and of normal temperature, rather than warm and erythematous, as in the lesion associated with pulmonary disease. In the same series of 150 patients with pretibial myxedema, 7% also had acropachy.^153. In a follow up of 26 years of 40 patients with acropachy, the frequency of association with one ore more other manifestations of Graves’ disease are described. Acropachy also seems to be causally related to smoking, as is the case with GO 153d.

Fig. 12-6. A case of severe pretibial myxedema showing the coarsened, nodular, infiltrated, pigmented lesions on the lower extremities.

Fig. 12-7. (a) Massive infiltrative, localized myxedema in a female patient with Graves' disease and progressive exophthalmos. The lesions have become confluent over the lower extremities. (b) In the same patient, localized myxedema, involving the phalanges, is evident.

Apart from the unsightly appearance of localized pretibial myxedema, the lesions usually cause no symptoms. At times they may be somewhat painful, or, more frequently, the source of much itching. If severe, the lesions can be quite troublesome, since stasis changes may occur and it may be impossible to wear ordinary shoes. Studies with quantitative lymphoscintigraphy and fluorescence microlymphography showed functional and structural changes in dermal lymphatics caused by glycosaminoglycans (GAG) deposition and leading to lymphatic compression.¹⁵⁴ Nerve entrapment by the lesion has been reported and was cured by local steroid therapy.¹⁵⁵

Glycosaminoglycans (GAG) are the polysaccharide chains in proteoglycans and are made up of disaccharide repeating units containing a derivative of an aminosugar, either glucosamine or galactosamine. Hyaluronate, chondroitin sulfate, keratin sulfate, heparin sulfate, dermatin sulfate and heparin are the major glycosaminoglycans. Proteoglycans are very large polyanions that bind water and cations and thereby form the extracellular medium, or ground substance of connective tissue. In localized myxedema collagen appears to be fragmented due to infiltration of GAG and edema formation. The principal abnormality in pretibial myxedema is the marked increase in GAG concentration in the skin. This may be 6-16 times normal.¹⁵⁶ Whereas in normal skin approximately 5% of the acid mucopolysaccharides are hyaluronic acid, in pretibial myxedema this amount increases to 90%. Coupled with the manyfold increase in total GAG this increase indicates an enormous deposition of hyaluronic acid. Several reports^157,158 on the ultrastructure of pretibial myxedema describe an organized network of microfibrils with knobs within the widened interfibrous spaces. The knobs were supposed to contain glycoprotein and this material was also found in the coating of collagen bundles and on the surface of fibroblasts. From these studies it is suggested that as in GO, the fibroblasts may play a central role in the pathogenesis of localized myxedema. This notion is further substantiated by the finding of limited variability of T cell receptor V gene usage in pretibial myxedema, pointing to a primary immune response of antigen-specific T lymphocytes.¹⁵⁹ Furthermore, as is the case with acropachy, lymphocytes do recognize local fibroblasts.¹⁶⁰ Immunoglobulin G from patients with pretibial myxedema was shown to stimulate proteoglycan synthesis by human skin fibroblasts.¹⁶¹ Fibroblasts from control pretibial tissues were found to increase synthesis of hyaluronic acid when exposed to sera of patients with Graves' hyperthyroidism, while fibroblasts from pretibial myxedema were stimulated by both normal and patient’s sera.¹⁶²

Cheung and co-workers reported that a non-IgG dialyzable peptide from serum of patients with pretibial myxedema stimulated fibroblast production of hyaluronic acid,¹⁶³ especially by fibroblasts from the area of the lesions. Shishiba et al¹⁵⁶ found in vitro studies that skin fibroblasts both of normals and of skin affected by pretibial myxedema produced GAG's. However, the rate of synthesis of patients' skin was increased. Synthesis was not affected by normal or patients' serum. Since proteoglycan accumulation is only seen in patients' skin, these authors suspect that impaired clearance of mucopolysaccharides play a causative role in pretibial myxedema. The situation becomes even more confusing analyzing the results of a study¹⁶⁴ in which whole serum and the serum immunoglobulin fraction of 20 patients with dermopathy was tested for its activity to alter synthesis of GAGs in rat FRTL cells and in fibroblasts from pretibial skin and from other origins. It was found that serum and IgG fractions did stimulate GAG formation in FRTL-5 cells but not in fibroblasts of any origin, whereas sera and IgG fractions of patients with Graves' disease without dermopathy did not stimulate GAG formation in FRTL-5 cells more than normal serum. It has also been recently reported that thyroid hormone excess stimulates proteoglycan synthesis in normal human skin fibroblasts.¹⁶⁵

Attention has been focused on the possible role of heat shock proteins (HSPs) in the development of pretibial myxedema. HSP may have an immunological role in intracellular antigen processing and presentation of cell membrane-anchored antigens to the immune system. Using fibroblasts from retroocular space and pretibial skin from sites affected by Graves' manifestations, it was found that HSPs are differently expressed as compared to tissue taken from unaffected locations.¹⁶⁶ HSP 72 reactivity in fibroblasts, when exposed to various cytokines and to heat stress, was exclusively detected in those taken from affected tissues, and HSP 70 expression was significantly greater in fibroblasts from these tissues as compared to those from uninvolved tissues. The same group further reported that HSP 72 expression is attenuated both by oxygen radical scavengers, and by the antithyroid drugs propylthiouracil and methimazole.⁹² The authors suggested that the beneficial effect of these antithyroid drugs on the clinical course of Graves' disease and its extra-thyroidal manifestation may be related to their oxygen free-radical scavenging properties.

Recent work has been directed towards the possibility that TSH-R antibodies might also (as in OG) play a role in the pathogenesis of pretibial myxedema. High titers of these antibodies were found in sera of patients with Graves hyperthyroidism and pretibial myxedema as well as TSH and TSH-R antibody binding sites on fibroblast plasma membranes from affected pretibial skin.¹⁶⁷ The same group subsequently reported the presence of the complete TSH-R transcript in pretibial skin fibroblasts from patients with myxedema and from healthy controls¹⁶⁸ Also others showed the presence of this transcript in pretibial myxedema skin fibroblasts of 3/3 patients and 1/11 normals and in addition the TSH-R protein in the same fibroblasts of 3/3 patients but in 0/11 normals¹⁶⁹

Summarizing the reported literature on the pathogenesis of localized myxedema, there is still confusion and no clear-cut answers can be given at present. Despite this it seems warranted to predict that, as in OG, in pretibial myxedema mucopolysaccharide synthesis is increased by local fibroblasts stimulated by autoimmune processes. Also in acropachy increased GAG deposits are found.¹⁷⁰ There is thus evidence that the three best known extra-thyroidal manifestations of Graves' disease i.e. ophthalmopathy, dermatopathy and acropachy are pathogenically related in that mucopolysaccharide synthesis and deposition is increased probably by stimulation of local fibroblasts by autoimmune processes. Not only in OG, but also in the other two manifestations, the TSH-R may be the autoantigen. These facts corroborate the clinical observation that the three manifestations frequently occur in the same patient often at the same time, but also at different time points. In a recent study it was shown that dermopathy also occurred in a transplant of skin from a normal donor when it was transplanted at the location of removed myxedematous tissue. From this and other observations the authors suggest that, opposed to the present concept emphasizing the role of preadipocytes, extrathyroidal manifestations are primarily caused by local factors superimposed on a low-grade connective tissue inflammation^170a.

It is obvious that treatment of the thyrotoxicosis does somehow favor decreased autoimmunity, and thus indirectly favors resolution of pretibial myxedema. Usually the process gradually increases in intensity for a period of months or years and then remains stable or very slowly regresses. In a mean follow up of 3.2 years of 120 patients, complete remission was present in only 10%. Partial sustained remission was seen in 38% patients who were treated with topical corticosteriods and 18% of the group not receiving local treatment.¹⁵³ In a recent review, only 26% experienced remission and 24% some improvement over 8 years of observation(153c). Occlusive dressings with clobetasol propionate have produced gratifying improvement in some patients.¹⁷¹ If necessary, repeated treatments are advised until such time that clinical remission occurs.¹⁷² When localized mxedema is severe and extensive, steroid pulse therapy, or decongestive physiotherapy, a combination of manual lymphatic drainage, bandaging, exercise, and scrupulous skin care, may be tried.^172a,b In a patient with very severe and debilitating pretibial myxedema a combined treatment of surgical excision and octreotide treatment showed a successful effect that was still present after 9 years of follow-up 172d.