Are You Confident of the Diagnosis?

Characteristic findings on physical examination

Generalized myxedema is a manifestation of severe hypothyroidism developing over an extended period of time causing skin that appears waxy, doughy, swollen (although non-pitting) and dry. The initial symptoms include mental and physical sluggishness, constipation, loss of appetite, hoarseness in voice, leg cramps, cold intolerance, and unexplained weight gain. Over time, this leads to characteristic skin features including broad nose, swollen lips, macroglossia, edematous eyelids, and brittle nails (Figure 1).

The skin is pale, cool, and waxy with a potential absence of sweating. As a result of carotenemia, a yellowish discoloration of palms and soles may appear. Due to the overall decreased metabolic activity, hypercarotenemia results from both the associated increased serum lipids and impaired conversion of beta-carotene into retinol .With advanced disease purpura involving the extremities, telangiectasias of the nailfolds, alopecia involving the later one third of the eyebrows, and significantly brittle nails with longitudinal and transverse striations may be present.

Severe psychiatric disease may be noted. This disease may be fatal if the patient’s neurologic system is extensively involved, resulting in myxedema coma.

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Expected results of diagnostic studies

The essential diagnostic studies include TSH and free thyroxine (T4). The vast majority (90% to 95%) of cases of myxedema occur in primary hypothyroidism. The serum TSH should be elevated, and low levels of circulating T4 should be present In secondary hypothyroidism, the serum TSH can be normal, low or undetectable in the setting of low free thyroxine. In addition, triiodothyronine (T3) resin uptake is decreased and the free T4 index (T3 resin uptake x total serum T4) is low.

In primary hypothyroidism mediated by autoimmune disease of Hashimoto’s thyroiditis, anti-thyroid peroxidase antibodies are typically elevated. Secondary causes include pituitary and hypothalamic disorders such as neoplasm, irradiation or trauma, and infiltrative diseases such as amyloidosis and sarcoidosis.

Punch biopsy of the skin in involved areas demonstrates many perivascular and perifollicular mucin deposits These deposits may extend to the subcutaneous fat. Elastic fibers are decreased in number, and there is no change in amount of fibroblasts. Mucin stains highlight the increased deposition. Stains include Mowry’s colloidal iron, alcian blue, periodic acid-Schiff (PAS) or mucicarmine (Figure 2).

Diagnosis confirmation

The differential diagnosis for this condition includes pretibial myxedema, reticular erythematous mucinosis, Degos disease, and scleredema.

Pretibial myxedema can be differentiated because this condition is caused by hyperthyroidism (not hypothyroidism), namely Graves disease (most predominately in the third or fourth decade in females). It is characterized by purple-brown yellowish waxy nodules on the anterolateral aspect of the lower legs and feet.

Reticular erythematous mucinosis is a persistent papular eruption on the midline of the chest and back that is exacerbated by UV light. It occurs most often in middle-aged women and clinically presents as pink to red papules that coelesce into larger plaques, predominantly on the chest and back. The history usually includes exacerbation by sunlight.

Degos disease is a malignant atrophic papulosis that appears equally in men and women and begins during the second and fourth decade of life. It typically presents with erythematous papules on the trunks and extremities that evolve over 3 to 4 weeks into a white scar with telangiectasias at the border.

Scleredema is a symmetric diffuse induration of the upper back and neck of individuals. It is strongly associated with diabetes mellitius. Of all of these potential diseases, generalized myxedema is the only one with significantly increased TSH level and decreased free T4 levels.

Who is at Risk for Developing this Disease?

:Primarily women in the age bracket of 30 to 60. The most common cause is the autoimmune thyroid disease (Hashimoto’s thyroiditis). The second most common cause is iatrogenic secondary to treatment for hyperthyroidism resulting in iatrogenic hypothryroidism.

What is the Cause of the Disease?

The pathogenesis of this disease is due to low levels of thyroid hormone, especially free T3 and T4. Due to the absence of circulating thyroid hormones, there is increased production of skin fibroblasts, leading to increased deposition of dermal acid mucopolysaccharides.

Systemic Implications and Complications

The most important complication of this disease is a myxedema coma, which has a high mortality level. Systemic manifestations include carpal tunnel disease, seventh nerve palsy, dementia, cardiomegaly, and toxic megacolon. Fortunately, with treatment, all the manifestations (including the skin manifestations) are completely reversible. However, symptoms can recur if treatment is stopped.

Treatment Options

Treatment of underlying hypothyroidism is essential with levothyroxine. Recommended treatment for generalized myxedema (without coma): 1.6 mcg/kg/day orally; higher doses may be required in pregnancy, in the elderly and in those with coronary disease or severe COPD (chronic obstructive pulmonary disease). Start at 25 to 50mcg/day orally, increase by 25 to 50mcg/d q4 to 8wk until desired response achieved.

Recommended treatment for myxedema coma: 200 to 250mcg IV bolus, followed by 100mcg the next day and then 50mcg/day orally or IV along with T3.

An endocrinology consult is recommended.

Optimal Therapeutic Approach for this Disease

The optimal treatment is replacement of thyroid hormone (levothyroxine) in appropriate doses.

Patients need to be followed continually throughout life as spontaneous remission of hypothyroidism is unusual. Monitoring with a TSH frequently (every few weeks to months) until it is normalized with treatment is warranted. Once in the normal range, periodic monitoring on a less frequent basis (once or twice a year) is recommended, unless there is any clinical suspicion of hypothyroidism (undertreatment) or hyperthyroidism (overtreatment).

Patient Management

Patient’s with severe disease should be admitted to the hospital for IV levothyroxine replacement. Endocrinology consult is recommended. The most important aspect of patient management is early detection; all patients that are suspected of having this disease should receive appropriate laboratory work.

Patients need to be followed continually throughout life as spontaneous remission of hypothyroidism is unusual. Monitoring with a TSH frequently (every few weeks to months) until it is normalized with treatment is warranted. Once in the normal range, periodic monitoring on a less frequent basis (once or twice a year) is recommended, unless there is any clinical suspicion of hypothyroidism (undertreatment) or hyperthyroidism (overtreatment).

Unusual Clinical Scenarios to Consider in Patient Management

Myxedema coma is a life-threating illness that requires the expertise of an endocrinologist in terms of replacing thyroid hormone. Replacement of the hormone must be in very small doses, as standard doses may provoke life-threatening cardiac arrhythmias or myocardial infarction.

What is the Evidence?

Ai, J, Leonhardt, J, Heymann, WR. “Autoimmune thyroid disease: etiology, pathogenesis, and dermatologic manifestations”. J Am Acad Dermatol. vol. 48. 2003. pp. 641(A thourough, complete and wonderful review on the skin manifestations seen in autoimmune thyroid disease. Detailed discussion on many topics.)

Bull, RH, Coburn, PR, Mortimer, PS. “Pretibial myxoedema: a manifestation of lymphedema”. Lancet. vol. 341. 1993. pp. 403-4. (Authors propose that lymphedema may predispose or cause pretibial myxedema.)

Fatourechi, V. “Pretibial myxedema: pathophysiology and treatment options”. Am J Clin Dermatol. vol. 6. 2005. pp. 295-309. (Relatively current discussion on pretibial myxedema including current trends in therapy and etiology.)

Miller, JJ, Roling, D, Spiers, E, Davies, A, Rawlings, A, Leyden, J. “Palmoplantar keratoderma associated with hypothyroidism”. Br J Dermatol. vol. 1998. pp. 139-741. (Case report of PPK in association with thyroid disease)

Heymann, WR. “Cutaneous manifestations of thyroid disease”. J Am Acad Dermatol. vol. 25. 1992. pp. 885(Discusses the many manifestations of thyroid disease that one can see in the skin.)

Rashtak, S, Pittelkow, MR. “Skin involvement of autoimmune diseases”. Curr Dir Autoimmun. vol. 10. 2008. pp. 344-58. (Although the entire article does not deal with autoimmune thyroid disease, there is a nice discussion on the cutaneous manifestations of autoimmune thyroid disease.)

Roberts, CG, Ladenson, PW. “Hypothyroidism”. Lancet. vol. 363. 2004. pp. 793-803. (Outstanding discussion on hypothyroidsim)

Smith, SA. “Commonly asked questions about thyroid function”. Mayo Clin Proc. vol. 70. 1995. pp. 573-7. (Nice review of common thyroid function testing and the role of the thyroid)

Wartofsky, L, Ingbar, SH, Wilson, JD, Braunwald, E. “Diseases of the thyroid”. 1991. pp. 1692-1712.