Background of Pretibial Myxedema
Pretibial myxedema is an alternative term for thyroid dermopathy. It is a localized skin lesion resulting from an accumulation of hyaluronic acid. Thyroid dermopathy is a rare disease that almost always occurs associated with autoimmune thyroid disease. However, it has been reported in other thyroid conditions, such as Hashimoto thyroiditis, euthyroidism, and primary hypothyroidism. Pretibial myxedema often occurs in the pretibial region, as the name indicates, but it can happen in the skin overlying any body part. For example, the skin overlying :
1. Neck
2. Nose
3. Pinnae
4. Upper back
5. Elbows
6. Shoulders
7. Knees
8. Dorsum of the foot
Pretibial myxedema is usually a cosmetic issue and associated morbidity is rare. It can present in various morphological forms, which can be:
Oedema that is not pitting [ 43.3 percent]
Plaque [ 27 percent ]
Nodule [ 18.5 percent ]
Elephantiasis [ 2.8 percent ]
Pretibial myxedema usually produces no symptoms, but lesions with itching and pain have also been seen with hypertrichosis [ excessive hair growth] and hyperhidrosis [ excessive sweating ].
The primary treatment step is the local application of corticosteroids. Compression stockings can be helpful as an adjunct with an average pressure of 20 to 40 mmHg.
The following resources are helpful for patient education:
Thyroid metabolism center
Thyroid problems
Pathophysiology of Pretibial Myxedema
Pretibial myxedema occurs from the deposition of hyaluronic acid. It accumulates in multiple skin layers, i.e., dermis and subcutis. The exact mechanism of this process is unknown.
There are many theories regarding this abnormal accumulation. Cytokine exposure to thyrotropin antibodies and antigen-specific T cells stimulates fibroblasts. These stimulated fibroblasts produce abnormally high amounts of glycosaminoglycans. The plasma membrane of fibroblasts contains thyrotropin receptor antibodies in a patient with pretibial myxedema, and it is found in the blood of most patients with thyroid dermopathy [80 to 100 percent]. The blood of other people may also contain these antibodies.
A research was published in 2006. This research suggested that high glycosaminoglycans are not the only cause of Pretibial myxedema. There are different compositions of glycosaminoglycans. Change in the percentage of these compositions leads to the formation of pretibial myxedema. Thyroid hormones have a role in the production of prostaglandins. Thyroid hormones change the formation and breakdown of glycosaminoglycans by affecting the prostaglandins synthesis pathway. An increase in T3 has many effects. As found in the experiments, it causes the reduced formation of glycosaminoglycans and decreased formation of extracellular matrix as an assembly.
Cell-mediated immunity is another causative factor in the formation of Pretibial myxedema. It has been proposed that cell-mediated immunity plays a role in localized pretibial myxedema by differentially expressed T-cell surface receptors. Trauma may have a role in forming pretibial myxedema by activating fibroblasts at the injury site. That is the reason myxedema most frequently develops at these sites. Moreover, eyes and skin are the common sites of manifestations of Graves disease outside of the thyroid. Fibroblasts in these sites have different phenotypes than those found in the other parts of the body.
Epidemiology
0.5 to 4.3 percent of patients with Graves disease develop pretibial myxedema. It has also been associated with other thyroid conditions like Primary hypothyroidism, euthyroidism, and Hashimoto thyroiditis, but with a lower frequency. Pretibial myxedema occurs more frequently in females than males, and the woman-to-man ratio is 3.5 to 1. Children and young adults can also develop pretibial myxedema, but it is most common in older adults with the peak onset in their fifties and sixties.
One study on thyroid disease in outpatients was carried out in China. This study was carried out between 2000 to 2006 at a single center. Researchers analyzed the records of 44,646 outpatients with thyroid disease.
PTM was prevalent in 1.6% of the patients. The disease occurrence was 41.1 years on average, with a men-to-women ratio of 3.7 to one. The percentage of occurrence was 63.9% in those with normal thyroid functions, 22% in hyperthyroidism, 11.4% in hypothyroidism, and 2.7% with unclear thyroid functions. The total period of disease was ten days to ten years. The average course of the disease was 37.8 months.
History of pretibial myxedema
Graves disease is usually diagnosed before the development of pretibial myxedema. It takes almost one to two years to diagnose pretibial myxedema after the Graves disease is diagnosed. Thyrotoxicosis can occur before or after the development of pretibial myxedema. Patients having thyroid dermopathy also have graves eye disease. Dermopathy typically occurs after six to twelve months of the development of Graves eye disease. The natural history of the development of pretibial myxedema has yet to be well known.
Available research data shows that total remission of thyroid dermopathy occurs in 10 to 26 percent of the patients eventually, while 24 percent of the patients experience partial remission. Thyroid dermopathy without thyroid ophthalmopathy is rare.
In Graves disease, skin lesions or edema [non-pitting] can occur on different surfaces in the lower limb, for example, anterior or lateral surface or in the areas of a previous or new injury.
However, those with a thyroid condition may have undetermined skin problems and non-pitting edema.
Physical examination
Researchers did a retrospective analysis of patients with thyroid dermopathy. The results were as follows:
1. The pretibial area ( 99 percent) was the most common site of involvement.
2. The most common presentation was non-pitting edema ( 43 percent).
3. Ophthalmopathy ( 96 percent) coexisted with dermopathy.
One percent of patients with Graves disease had thyroid acropachy. Thyroid acropachy can manifest as follows:
1. The fingers and the toes can manifest clubbing,
2. Shafts of the phalanges and other distal long bones have periosteal proliferation,
Inflammation of the structures covering the affected bones. It usually develops after pretibial myxedema. 3. Graves’s skin disease and acropachy are markers of the severity of Graves’s eye disease.
The early lesions are asymmetrical, nonpitting, firm, bilateral plaques or nodules. A peau d’orange texture may appear by the prominence of hair follicles. An enlarged, verruciform appearance can be present in the whole limb in the elephantiasic form of pretibial myxedema due to the coalescence of lesions. In these cases, there may be a presence of overlying hyperhidrosis or hypertrichosis. Pretibial myxedema often occurs in the pretibial region, as the name indicates, but it can happen in the skin overlying any body part. For example, the skin overlying :
1. Neck
2. Nose
3. Pinnae
4. Upper back
5. Elbows
6. Shoulders
7. Knees
8. Dorsum of the foot
The lesions are typically shiny pink to purple-brown.
Laboratory studies
Thyroid hormone levels depend upon the underlying disease. They can be normal, low, or high in pretibial myxedema, depending upon the recognition and management of underlying thyroid disease.
There are high levels of thyrotropin receptor antibodies in about 80 to 100 percent of the patients.
Histological studies :
Histopathological findings
The characteristic histopathological feature is the accumulation of mucin (glycosaminoglycans) in the reticular dermis with decreased collagen fibers. Mucin can accumulate in the form of single fibers and granules. Excessive accumulation of mucin affects the assembly of collagen fibers, causing them to be frayed, broken into fragments, and separated widely. Stellate fibroblasts are stellate in nature that can also seen, but they are not increased in total. Hyperkeratosis may be seen in the overlying skin. 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 a toluidine blue stain. If mucin is deposited to the expanded papillary dermis, deposition of hemosiderin and nodular hyperplasia suggest stasis dermatitis is more likely.
Differential diagnosis of pretibial myxedema
- Lymphedema [ particularly in the foot ]
- Lymphedematous mucinosis
- Necrobiosis lipoidica diabeticorum.
- Erythema Nodosum
- Bites by insects
- Lichen Myxedematosus
- Lichen Planus
- Lichen Simplex Chronicus
- Necrobiosis Lipoidica
- Stasis Dermatitis
Approach considerations
Peritibial myxedema is usually a cosmetic issue. However, it can develop into a severe elephantiasic variety, leading to a significantly enlarged limb with impaired functions. The benefits of surgical treatment are uncertain. Surgical scars may exacerbate the dermopathy; hence, surgical procedures should not be performed.
The primary treatment step is the local application of corticosteroids. Compression stockings can be helpful as an adjunct with an average pressure of 20 to 40 mmHg. The fractional laser ablation technique also has some benefits, as reported.
An evaluation by a dermatologist and endocrinologist is necessary for skin lesions and thyroid disease.
Medications summary
Different medical options like plasmapheresis and cytotoxic therapies have been tried. These therapies have not shown promising results in thyroid dermopathy. Corticosteroids are the only treatment of choice available with proven efficacy. Corticosteroids can be applied topically or in the lesions. Avoid systemic use of corticosteroids because of their unwanted side effects.
Different medication combinations have been reported to be helpful. They include :
1. Topical clobetasol propionate ointment and oral pentoxifylline combination
2. Triamcinolone acetonide in the lesions and oral pentoxifylline combination.
3. High-dose intravenous immunoglobulins and octreotide are promising new treatment options but with limited data.
Patients with refractory pretibial myxedema were studied. Some fibroblasts are upregulated, and they have increased expression of insulin-like growth factor-1 in refractory pretibial myxedema. These results were the basis of octreotide use. Decreased amounts of intralesional hyaluronic acid were observed using intralesional octreotide injections.
Different outcomes were observed in various studies. Some studies found the benefits of weekly octreotide injections. Patients remained symptom-free for up to fifteen months. In comparison, other studies do not support these results.
Surgical scars may exacerbate the dermopathy; hence, surgical procedures should not be performed. One patient was treated with daily octreotide injections for six months and surgical shaving of the lesion. He had thick plaques before treatment. He was observed for nine years. There was no recurrence of the disease in this patient.
Corticosteroids
Class Summary
These corticosteroids are applied to the skin. Occlusive dressing is applied over them. Many patients observe relief from their symptoms. Corticosteroids are available in different preparations like gel, cream, ointment, etc.
Topical treatment options are given below. They are provided in order of decreasing strength.
Topical Betamethasone
It has anti-inflammatory properties, which are achieved through different effects:
It reverses capillary leakage, which results in the suppression of polymorphonuclear leukocyte migration.
Lymphokine production is affected along with an inhibitory effect on Langerhans cells.
0.05 percent cream or ointment should be used. Betamethasone is similar to clobetasol and halobetasol in potency.
Fluocinonide
It has immunosuppressive and anti-inflammatory properties. Fluocinonide is one of the high-potency corticosteroids available. It has an inhibitory effect on the cell proliferation.
0.05 percent ointment or gel should be used. It is similar to mometasone and fluticasone in potency.
Topical Hydrocortisone
It has both glucocorticoid and mineralocorticoid properties, which help in decreasing inflammation. It should be applied to External mucous membranes or skin.
Topical triamcinolone
Topical triamcinolone has an anti-inflammatory effect. It reverses capillary leakage, which results in the suppression of polymorphonuclear leukocyte migration. 0.1 percent ointment should be used.
Prognosis of pretibial myxedema
Peritibial myxedema is usually a cosmetic issue and associated morbidity is rare. Local discomfort occurs due to edema. Difficulty can be expected while wearing footwear. It carries a good prognosis. There is often a spontaneous regression, but this condition can persist for months, even years. Complete remission occurs in 10 to 26 percent of the patients. However, it takes an average of 9 years to complete remission.