Diagnostic Dilemma: Pretibial Myxedema

Department Editor: Tania Phillips, MD, FRCPC Overall Learning Objectives: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Recognize the associations of pretibial myxedema with thyroid disease 2. Recognize the lack of specific laboratory values for pretibial myxedema 3. Describe the treatment modalities of pretibial myxedema. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Chakrabarty, Stefanato, and Phillips disclose no financial conflicts. Accreditation: HMP Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing education activity for .1 CEUs available to participating podiatrists. Method of Participation: Read the article, take, submit, and pass post-test by December 15, 2003. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: December 15, 2002 Expiration date: December 15, 2003 Presentation A 55-year-old Caucasian woman presented to the clinic complaining of skin lesions on both shins. During the course of the year, the patient traumatized her leg, which resulted in several chronic, tender wounds. She had been applying hydrocolloid dressings without improvement. The patient also mentioned a history of peripheral neuropathy of the distal feet bilaterally. She denied symptoms of heat intolerance, anxiety, change in appetite, and fatigue. Her past medical history was significant for type 2 diabetes, hypercholesterolemia, hypertension, peptic ulcer disease, gout, severe asthma, and chronic back pain. She had a past surgical history of hysterectomy, osteomyelitis resection, and necrotizing fasciitis of the right leg with debridement and skin grafting. The patient’s medications included rosiglitazone, atorvastatin, hydrochlorothiazide, omeprazole, allopurinol, montelukast, salmeterol inhaler, mometasone nasal spray, prednisone, and tramadol. She was allergic to aspirin and sulfa drugs. There was no personal or family history of thyroid disorders. Physical Examination Physical examination revealed an obese woman with a scar over the right calf with loss of muscle bulk from surgical debridement due to necrotizing fasciitis. There were erythematous, yellow plaques on both anterior shins of the lower extremities. There were also superficial ulcers on both shins, the largest one measuring 2cm x 2cm on the left anterior shin (Figures 1 and 2). Some induration was noted over the medial aspect of the left lower extremity. The patient had slight pitting edema and peripheral neuropathy on the plantar aspect of the feet and distal toes. Peripheral pulses and capillary refill time were normal. There was no thyroid enlargement. Investigations A biopsy illustrated marked dermal edema and mucin deposition involving the superficial and deep dermis consistent with pretibial myxedema (Figures 3a and b). ANA screen, lupus anticoagulant, anticardiolipin antibody, cryoglobulin, and cryofibrinogen levels were negative. Erythrocyte sedimentation rate (ESR) was elevated at 53 (N: 0-30mm/hr). Thyroid function tests, complete blood count (CBC), and HgbA1c were in the normal range. Vascular studies did not find any evidence of venous insufficiency. Diagnosis The clinical distribution of the yellow, pebbly plaques combined with the histologic findings favored the diagnosis of euthyroid pretibial myxedema, an atypical presentation given the more common association with hyperthyroidism Discussion Clinical features. Pretibial myxedema usually is a late, uncommon dermopathy of Graves’ disease affecting 0.5 to 4.3 percent of patients. It can, however, occur with primary hypothyroidism, Hashimoto’s thyroiditis, or euthyroid patients. Women are more commonly affected than men (3.5:1). The peak age incidence is 50 to 60 years but it can affect children. The physical exam reveals nonpitting, waxy, yellow-to-red, indurated plaques usually on the anterior shins but sometimes seen at other sites, such as the head, neck, and arms. In one retrospective study of 150 cases, the nodular and plaque forms of pretibial myxedema to occurred with equal frequency followed by the extremely rare polyploid and elephantiasic variants.1 Other extrathyroidal manifestations of Graves’ disease include exophthalmos and thyroid acropachy. Most often, pretibial myxedema develops after the diagnosis of hyperthyroidism and onset of ophthalmopathy. There are rare case reports of pretibial myxedema occurring prior to the diagnosis of Graves’ disease and in the absence of ophthalmopathy.2,3 Pathogenesis. The exact mechanism of pretibial myxedema is unknown. The differential diagnosis includes lichen simplex chronicus, lymphedema, elephantiasis, and hypertrophic lichen planus. A common theory is that a target cell, probably a fibroblast, is stimulated to produce an increased level of glycosaminoglycans, notably hyaluronic acid, by autoantibodies targeted against a thyroid antigen. Cloning and sequencing of ribonucelic acid (RNA) transcripts have demonstrated the presence of thyrotropin (TSH) receptors on pretibial fibroblasts.4 A possible etiology is that the T-lymphocytes secrete cytokines that stimulate the TSH receptors on the pretibial fibroblasts to produce glycosaminoglycans (mucopolysaccharides). Further in-vitro studies of pretibial fibroblasts have illustrated enhanced sensitivity to the serum of patients with pretibial myxedema, which may explain the reason for the site predilection.5 There have been some conflicting reports of thickening of the skin on the extensor surfaces of the forearms, a clinical counterpart of pretibial myxedema.6,7 Skin biopsies of pretibial myxedema reveal increased deposition of glycosaminoglycans, notably hyaluronic acid, in the dermis and distortion of collagen bundles into fibers, which are widely separated. One histologic study mentions biopsy reports of patients without Graves’ disease as having features of stasis dermatitis in addition to the mucin deposition.8 The glycosaminoglycans or mucin accumulation involves the papillary and reticular dermis of patients without thyroid disease as opposed to just the reticular dermis in patients with Graves’ disease. There are no specific laboratory studies specific for the diagnosis of pretibial myxedema. Treatment Pretibial myxedema is not a life-threatening condition and may resolve spontaneously after many years. Treatment of the underlying hyperthyroidism does not necessarily eradicate the skin lesions of pretibial myxedema, which occasionally become more pronounced after the treatment of the thyrotoxicosis. Mild pretibial myxedema does not require treatment. The standard form of therapy involves topical or intralesional corticosteroids particularly for moderate to severe pretibial myxedema.9 The long-term remission rates from corticosteroid therapy are unknown.1 Compression bandages can provide additional benefit. A preliminary trial with pentoxifylline 400mg intravenously followed by 800mg by mouth daily for a week diminished the size of pretibial myxedema lesions.10 Third-line therapy involving intravenous immunoglobulins have shown some benefit in the treatment of pretibial myxedema as well as ophthalmopathy according to one study.11 Surgical excision has been shown to be effective in a minority of cases. Three cases were successfully treated with octreotide therapy, a somatostatin analogue, at 100µg subcutaneous three times daily. The mechanism of action is postulated as inhibition of insulin-like growth factor.12 Overall, patients diagnosed with pretibial myxedema have good prognoses. Patient Management The patient in this case report was treated conservatively with compression stockings and cadexomer iodine gel dressings. Her ulcers healed completely within three weeks. The patient is on oral prednisone for her severe asthma history, and the dosage has not been modified. The authors continue to monitor her thyroid function and will order antimicrosomal and antithyroglobulin antibodies for further analysis of thyroid disease. Questions 1. What laboratory value is specific for pretibial myxedema? A. Antimicrosomal antibody B. Antithyroglobulin antibody C. No specific value D. Serum hyaluronic acid 2. What distinguishes euthyroidal pretibial myxedema versus pretibial myxedema associated with Graves’ disease? A. Collagen fiber appearance B. Location of myxedema lesions C. The distribution of mucin in the dermis D. The clinical appearance of pretibial myxedema 3. What is the standard form of therapy in the treatment of pretibial myxedema? A. Intravenous immunoglobulins B. Octreotide therapy C. Intralesional/topical corticosteroid D. Somatostatin 4. What areas are affected by pretibial myxedema? A. Bilateral shins B. Head, neck, and arms in rare cases C. The shoulders and the shins D. A and B 5. The distribution of mucin in the pretibial myxedema patients with Graves’ occurs most commonly in: A. Both superficial and deep dermis B. Papillary dermis only C. Dermal-epidermal junction and deep dermis D. Reticular dermis 6. Name a third-line form of therapy in pretibial myxedema: A. Pentoxyfilline B. Intravenous immunoglobulin C. Intravenous immunoglobulin and pentoxyfylline D. Intralesional steroids and compression bandages Pretibial Myxedema Answer Form and Evaluation Please complete (if submitting offline, print clearly): Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions below) Click on or circle one letter for each answer: 1. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D 6. A B C D Evaluation (Click on or circle one) Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning objectives: 4 3 2 1 Effectiveness of the teaching/learning methods: 4 3 2 1 This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1. Recognize the associations of pretibial myxedema with thyroid disease? YES NO 2. Recognize the lack of specific laboratory values for pretibial myxedema? YES NO 3. Describe the treatment modalities of pretibial myxedema? YES NO What questions do you still have?___________________________________ How will you use what you have learned from this activity?________________ All tests must be received by 12/15/03.