Pretibial Myxedema 

Updated: Feb 02, 2016
Author: Ranjodh Singh Gill, MD, FACP, CCD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Pretibial myxedema (PTM) or, more appropriately, thyroid dermopathy is a term used to describe localized lesions of the skin resulting from the deposition of hyaluronic acid, usually as a component of thyroid disease. Thyroid dermopathy occurs rarely. Although PTM is most often confined to the pretibial area, it may occur anywhere on the skin, especially the ankle, dorsum of the foot, knees, shoulders, elbows, upper back, pinnae, nose, and neck.[1] It is nearly always associated with autoimmune thyroid disease (ie, Graves Disease for more information).

Pathophysiology

Pretibial myxedema (PTM) occurs as a result of the deposition of hyaluronic acid in the dermis and subcutis. The precise cause of this phenomenon remains uncertain. A leading theory proposes that fibroblasts are stimulated to produce abnormally high amounts of glycosaminoglycan under the influence of cytokines due to exposure to thyrotropin receptor antibody (TRAB) and antigen-specific T cells. TRAB-binding sites are found in the plasma membranes of fibroblasts derived from the skin of patients with PTM. TRAB is present in the serum of most patients with PTM (80-100%), but it has also been found in the serum of patients without PTM.[2]

Research published in 2006 suggests that it may not be just the high level of glycosaminoglycans, but the change in percentage of the constituents of the glycosaminoglycans in the blood that leads to the development of PTM. Thyroid hormones, by means of their influence on prostaglandin metabolism, alter the synthesis and degradation of glycosaminoglycans. Prostaglandin degradation may be what is changed in the course of Graves disease, based on findings that glycosaminoglycan synthesis is reduced, as is extracellular matrix assembly in vitro with exposure to T3 excess.[3]

Cell-mediated immunity, using differentially expressed T-cell surface receptors in localized PTM, has also been proposed as having a causative role.[4] The fact that PTM frequently develops in areas of injury suggests that trauma may contribute to local fibroblast activation. In addition, extrathyroid manifestations of Graves disease often occur in the skin and eyes—fibroblasts within the orbits and skin were found to have phenotypic differences from other fibroblasts throughout the body.

Epidemiology

US frequency

Pretibial myxedema (PTM) occurs in 0.5-4.3% of patients with Graves disease. PTM has also been reported, but much less frequently, in patients with Hashimoto thyroiditis, primary hypothyroidism, and euthyroidism. Peak incidence occurs in the fifth to sixth decades of life.

Sex

Women are affected more frequently than men, with a female-to-male ratio of 3.5:1.

Age

PTM may occur in children and young adults, but most cases occur in older adults, with a peak age at onset in the fifth to sixth decades of life.

 

Presentation

History

The onset of pretibial myxedema (PTM) most commonly occurs 1-2 years after the diagnosis of Graves disease, but it may occur before or after the onset of thyrotoxicosis. PTM in the absence of Graves disease is uncommon. Most patients who develop PTM also have Graves ophthalmopathy, with the onset of dermopathy typically following the onset of ophthalmopathy by 6-12 months. The natural history of PTM is not well defined. Available data indicate that about 10-26% of patients eventually experience complete remission, and about 24% have partial remission. Rare cases of PTM without ophthalmology have been recorded.[5, 6]

Skin lesions or areas of non-pitting edema appear on the anterior or lateral aspects of the legs or in sites of old or recent trauma in patients with Graves disease.

Otherwise unexplained skin lesions or areas of non-pitting edema occur in patients with thyroid disease.

 

Physical

A retrospective analysis of pretibial myxedema (PTM) patients revealed that the pretibial area was most commonly involved (99%), nonpitting edema was the most common form of dermopathy (43%), and the majority of patients had coexisting ophthalmopathy (96%).[7]

[8] Thyroid acropachy occurs in 1% of patients with Graves disease. It is clinically characterized by clubbing of the fingers and the toes, periosteal proliferation of the shafts of the phalanges and other distal long bones, and swelling of the soft tissues overlying affected bony structures. When present, acropachy usually follows dermopathy. Graves dermopathy and acropachy appear to be markers of severe ophthalmopathy. See the image below.

Bilateral erythematous infiltrative plaques in the Bilateral erythematous infiltrative plaques in the pretibial areas.

Early lesions are bilateral, firm, nonpitting, asymmetrical plaques or nodules. Hair follicles are sometimes prominent, giving a peau d'orange texture. Areas of nonpitting edema may develop. In the elephantiasic form of PTM, lesions may coalesce to give the entire extremity an enlarged, verruciform appearance. Overlying hyperhidrosis or hypertrichosis may be present in these cases.

Lesions characteristically appear on the lateral or anterior aspect of the legs, but they may occur on the thighs,[9] the shoulders, the hands, the forehead, or any other skin surface. Lesions often occur in areas of recent or prior trauma or skin graft donor sites.

Lesions are characteristically shiny pink to purple-brown.

Causes

Pretibial myxedema (PTM) is generally considered a cutaneous manifestation of thyroid disease.

 

DDx

 

Workup

Laboratory Studies

Thyroid-stimulating hormone levels may be abnormally high, normal, or low, depending on whether the underlying thyroid disease has been recognized and treated.

Thyrotropin receptor antibody (TRAB) levels are elevated in about 80-100% of patients with pretibial myxedema (PTM).[10]

Histologic Findings

The characteristic histopathologic features consist of the deposition of mucin (glycosaminoglycans) throughout the reticular dermis and with attenuation of collagen fibers. Mucin may appear as individual threads and granules. With extensive deposition of mucin, the collagen fibers are frayed, fragmented, and widely separated. Stellate fibroblasts are often observed, but the number of fibroblasts is not increased. The overlying epidermis may show hyperkeratosis. The mucin is hyaluronic acid that stains blue with Alcian-blue at a pH of 2.5 and colloidal iron stains; metachromasia is shown with toluidine blue stain. Findings of mucin deposition restricted to an expanded papillary dermis, nodular angioplasia, and hemosiderin deposition are more suggestive of stasis dermatitis. See the images below.

Deposition of mucin in the reticular dermis (hemat Deposition of mucin in the reticular dermis (hematoxylin and eosin stain, original magnification X25).
Blue staining of mucin with colloidal iron stain ( Blue staining of mucin with colloidal iron stain (original magnification X25).
 

Treatment

Medical Care

The lesions of pretibial myxedema (PTM)  are primarily of cosmetic concern, although severe elephantiasic forms may lead to significant limb enlargement and impair function.

Surgical treatment should be avoided because scarring may aggravate the dermopathy, and benefits are equivocal.

Local application of corticosteroids remains the mainstay of treatment.

Compression wraps or stockings that provide 20-40 mm Hg of pressure can be useful as an adjunctive therapy.

Consultations

Consult a dermatologist for an evaluation of lesions in suspected pretibial myxedema (PTM).

Consult an endocrinologist for an evaluation of possible underlying thyroid disease.

 

Medication

Medication Summary

Various medical treatments, including plasmapheresis and cytotoxic therapy, have been tried, but the efficacy of these therapies in pretibial myxedema (PTM)  is unproven. Intralesional or topical therapy with corticosteroids is currently the only treatment that offers demonstrated efficacy.[11, 12] Systemic use should be avoided because of undesirable adverse effects.

Combinations reported as helpful include oral pentoxifylline and topical clobetasol propionate ointment[13, 14] and pentoxifylline with intralesional triamcinolone acetonide.[15]

Newer treatment regimens that are promising but require further investigation include octreotide, a somatostatin analog, and high-dose intravenous immunoglobulin (IVIG).[16] The basis for use of octreotide stems from research of refractory PTM patients who had increased expression of insulinlike growth factor-1 receptor on up-regulated fibroblasts. Intralesional injections of octreotide have led to decreased amounts of hyaluronic acid within the lesion. Some studies report success with weekly injections, and patients have remained symptom free for up to 15 months[17, 18] ; however, others do not.[19] Surgical removal is generally ill advised because scarring may worsen dermopathy; however, at least one patient with thick plaques prior to surgical shaving of the lesion and daily octreotide injections for 6 months did not have recurrence after 9 years of surveillance.[20]

The mongraphs below are a few examples of topical preparations available (in order of decreasing potency).[21, 22]

Corticosteroids

Class Summary

These agents are applied topically under an occlusive dressing, and they provide symptomatic relief in many patients. A variety of ointments, creams, and gels are available. The following are a few examples of topical preparations available (in order of decreasing potency).

Betamethasone topical (Diprolene)

Topical betamethasone is for inflammatory dermatoses responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It affects the production of lymphokines and has an inhibitory effect on Langerhans cells. Use 0.05% cream or ointment. Betamethasone has similar potency to clobetasol and halobetasol.

Fluocinonide (Fluonex, Lidex)

Fluocinonide is a high-potency topical corticosteroid that inhibits cell proliferation; it is immunosuppressive and anti-inflammatory. Use 0.05% ointment or gel. Fluocinonide has similar potency to mometasone and fluticasone.

Hydrocortisone topical (LactiCare HC, Westcort, Dermacort, DermaGel, Cortaid)

Topical hydrocortisone is an adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It has mineralocorticoid and glucocorticoid effects resulting in anti-inflammatory activity.

Triamcinolone topical (Kenalog)

Topical triamcinolone is for inflammatory dermatoses responsive to steroids; it decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. Use 0.1% ointment.

 

Follow-up

Complications

Pretibial myxedema (PTM)  rarely causes significant morbidity.

Prognosis

Pretibial myxedema (PTM) is primarily of cosmetic concern and rarely causes significant morbidity. Local discomfort and difficulty wearing shoes are expected. The prognosis is good. PTM may persist for months or years but often regresses spontaneously. About 10-26% of patients experience eventual complete remission.

Patient Education

For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center. Also, see eMedicineHealth's patient education article Thyroid Problems.