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739© Springer International Publishing Switzerland 2018 R.R. Bonamigo, S.I.T. Dornelles (eds.), Dermatology in Public Health Environments, https://doi.org/10.1007/978-3-319-33919-1_36

Diseases of Thyroid

Sérgio Ivan Torres Dornelles, Carlos Alberto Werutsky, Ana Eliza Antunes Bomfim, Camila Boff, and Renan Rangel Bonamigo

Epidemiology

Thyroid diseases are considered very frequent dis-eases. Estimates report that hyperthyroidism affects about 2% of the general population, with a 15% increase among the elderly, occurring predomi-nantly in females and in iodine ingestion–deficient regions [1]. Congenital hypothyroidism (cretinism) has an incidence of 1 case per 4000 births; 19% are

S.I.T. Dornelles (*) Sanitary Dermatology Service of Health Department of Rio Grande do Sul State (ADS-SES), Porto Alegre, Brazile-mail: [email protected]

C.A. Werutsky Nutrology and Endocrinology, Hospital 9 de Julho, São Paulo, Brazil

A.E.A. BomfimSanitary Dermatology Service of Health Department of Rio Grande do Sul State (ADS-SES), Porto Alegre, Brazil

Department of Dermatology, Clinica Duarte, Pelotas, RS, Brazil

C. Boff Sanitary Dermatology Service of the Department of Health of Rio Grande do Sul State, Porto Alegre, Brazil

R.R. Bonamigo Dermatology Service, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

Sanitary Dermatology Service of the Department of Health of Rio Grande do Sul State (ADS-SES), Porto Alegre, Brazil

Graduate Pathology Program of Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil

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Key Points Summary• Hyperthyroidism and hypothyroidism

are disorders with important interaction with the skin

• Iodine intake levels below and above the recommended level are associated with the occurrence of thyroid disorders

• Thyroid hormone deficiency causes thickening, hyperkeratosis, diffuse loss of scalp hair, and nail atrophy

• Generalized myxedema is a severe disease that may occur in hypothyroid-ism, when mucin is deposited in the skin and other organs resulting in a series of dermatologic and systemic outcomes

• Pretibial myxedema is less frequent, being present in only 5% of cases of Graves’ disease. About 90% of pretibial myxedema patients have hyperthyroidism

• Thyroid acropachy is a rare manifesta-tion of thyroid autoimmune disease and can display finger or toe clubbing and edema

• Thyroglossal cyst and cutaneous metas-tases of thyroid cancer are other dis-eases associated with the thyroid gland

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sporadic and 5% are genetic. Hashimoto’s thyroid-itis mainly affects women between the ages of 30 and 50 years, with a female-to-male ratio of 7:1. Postpartum thyroiditis occurs in about 8–10% of women [2]. Hyperthyroidism has a lower preva-lence (2% in women and 0.2% in men (English data)) [1]. Regarding Graves’ ophthalmopathy in the general population, there are incidence reports of 16 women and 3 men in every 100,000 popula-tion per year [3].

Among many dermatologic manifestations, pruritus sine materia seems to be a significant manifestation of thyroidopathies (Artantas et al. [4] report a pruritus prevalence of 2.7% in patients with thyroid disturbances).

The Thyroid and the Environment

Iodine (as iodide) is widely but unevenly distributed in the earth’s environment. Most iodide is found in the oceans (about 50 μg/L), and iodide ions in the seawater oxidize to form elemental iodine, which is volatile and evaporates into the atmosphere and returns to the soil through rain, completing the cycle. However, the cycle of iodine in many regions is slow and incomplete, and soils and groundwater become deficient in iodine. Crops grown in these soils will contain low iodine concentrations, and humans and animals consuming food grown in these soils become deficient in iodine [2].

Iodine consists of 65% and 59% of the weights of thyroxine (T4) and tri-iodothyronine (T3), respectively. Thyroid function is crucial for the metabolism of almost all tissues and for the development of the central nervous system in fetuses and children.

Iodine deficiency is the result of insufficient dietary iodine intake, and the physiologic conse-quence is abnormal thyroid function, hypothyroid-ism, and goiter [3]. In nearly all regions affected by iodine deficiency, the most effective way to control iodine deficiency is through salt iodization. The World Health Organization / United Nations Children’s Fund / International Council for the Control of the Iodine Deficiency Disorders (WHO/UNICEF/ICCIDD) recommends that iodine be added at a concentration of 20–40 mg iodine/kg of salt, depending on local salt intake [3].

A sudden increase in iodine intake in an iodine-deficient population may induce thyroid autoimmunity. It is well established that indi-vidual patients with autoimmune thyroiditis may develop hypothyroidism when exposed to excess iodine. Considering the very frequent occurrence of thyroid autoimmunity in the population, it would be expected that a high iodine intake would be associated with a high frequency of subclinical (with elevated serum thyroid- stimulating hormone (TSH) but a free T4 estimate within the reference range) and overt (elevated TSH and a low estimate of free T4) hypothyroidism, and this has indeed been convincingly demonstrated [4, 5].

Four methods are generally recommended to assess iodine intake: urinary iodine concentra-tion, goiter rate, serum TSH, and serum thyro-globulin [4]. The spectrum of disorders that somehow depend on the iodine intake level of the population can be based on the median or range of urinary iodine concentrations, or both. High intake of iodine results in a urinary iodine con-centration of 100–200 μg/L. Below these concen-trations (50–25 μg/L) insufficient iodine intake occurs, resulting in diseases ranging from cretin-ism and low IQ to goiter with hypothyroidism or hyperthyroidism. High urinary concentrations of iodine (>300 μg/L) may result in early Graves’ disease (GD) [2].

Thus, the thyroid gland contains an advanced set of processes that may enhance or block the use of iodine for thyroid hormone production. Because the processes activated with low and high iodine intakes are different, the type of dis-ease that dominates thyroid pathology in popula-tions may be different depending on the level of iodine intake.

Skin Manifestations of Hyperthyroidism

Hyperthyroidism, or excess circulating thyroid hormone, results from a disturbance in any por-tion of the hypothalamic-pituitary-thyroid axis. In normal subjects, TSH is made by the pitu-itary gland and stimulates the thyroid gland to generate and secrete T4 (thyroxine) and T3

S.I.T. Dornelles et al.

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( triiodothyronine). In the periphery, T4 is con-verted into T3 by enzymes mainly in the liver and kidney. T3 (and to some extent T4) then binds to specific nuclear receptors in the tissues (e.g., heart, brain, muscle, and perhaps skin) and medi-ates the thyroid hormone action [6].

Furthermore, the amount of T4 and T3 secreted by the thyroid gland is regulated by a negative feedback system of the pituitary gland. Specifically, when the body recognizes it has excess thyroid hormone levels, T3 (and T4) binds to the TSH gene regulatory elements in the pituitary gland and inhibits TSH production [7].

Hyperthyroidism is more commonly seen in women than in men (5:1 ratio). The most charac-teristic (although rare) skin finding in GD is pretibial myxedema, although other more com-mon cutaneous manifestations of hyperthyroid-ism include warm, flushed, moist skin, with generalized increased sweating [7, 8].

The skin changes, and the hair may become thin and soft; loss of scalp, eyebrow, axillary, pubic, or body hair is common. Hair loss without scarring (alopecia areata) is most often associ-ated with autoimmune disease (GD) [9].

Up to 25% of patients with GD have clinically obvious Graves’ ophthalmopathy at the time of the diagnosis of hyperthyroidism [9].

The nails may become soft and friable, and separation of the distal nail plate from the nail bed may occur, producing Plummer’s nails [10].

A definitive treatment of hyperthyroidism var-ies depending on the etiology of the disorder, but usually involves rendering the patient euthyroid with antithyroid drugs (i.e., methimazole or propylthiouracil).

These antithyroid agents can cause pruritic erythematous skin rash, hepatotoxicity, arthral-gias, or bone marrow suppression [11].

The implementation of a definitive therapy may include long-term antithyroid agents, radio-active iodine therapy, or thyroidectomy. It requires radioactive iodine from 2 to 3 months to cause hypothyroidism [6].

The skin manifestations associated with hyperthyroidism are classically cleared with treatment of the underlying cause of the hyper-thyroidism state as described below [10].

Etiopathogenesis

GD results from stimulation of the TSH recep-tor through receptor-binding antibodies. Thus, the usual negative report promoted by the T3 and T4 levels of TSH production by the hypophysis is interrupted. The outcome of this abnormal mechanism is excessive T3 and T4 in the peripheral circulation, which entails the clinical manifestations of hyperthyroid-ism. High levels of T3 and T4 promote the usually seen clinical symptoms of the disease, such as nervousness, anxiety, weight loss, heat intolerance, fatigue, muscle weakness, and palpitations [12].

The dermatologic and ophthalmologic mani-festations specific to the thyroid diseases result from the autoimmune effects of antibodies of the TSH, rather than being related to the circulating thyroid hormone levels. In the dermatologic dis-eases nonspecific to the cutaneous thyroid, altera-tions are directly related to the circulating levels of T3 and T4 [12].

Clinical Presentation

Dermatologic manifestations of hyperthyroidism vary. The skin is warm, soft, humid, blushed, and tender, and an association with cutaneous pruri-tus is frequent. Hyperhidrosis may be noticed mainly in the hand palms and feet soles [4].

The hair may become thinner and soft, and hair loss in the scalp, eyebrows, axillae, pubic area, or throughout the body is common.

Complementary Examinations

The blood dosage of free TSH, T3, and T4 levels added to the clinical signs and symptoms of hyperthyroidism seal the diagnosis.

Therapeutic Approach

Treatment includes normalizing the thyroid func-tion, either through medication or the thyroid function ablation [12, 13].

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Special Considerations

Graves OphthalmopathyThyroid ophthalmopathy is an autoimmune orbit disease closely associated with GD, although both conditions may exist separately [13].

Around 20–25% of GD patients have ophthal-mopathy [14]. The ophthalmopathy develops before the hyperthyroidism presentation in around 20% of patients; concomitantly in 40%; and in 40% of the cases 6 months after the diagnosis [15]. It is worth bearing in mind that the ocular disease may become evident after hyperthyroidism treatment, usually in patients treated with radioiodine [16].

EtiopathogenesisThe most often accepted theory to explain the association between thyroid ophthalmopathy and autoimmune thyroid disease is a possible cross- relationship of sensitized T lymphocytes and/or antibodies against the thyroid and the orbit com-mon antigens [17].

The volume of retro-orbital connective and adi-pose tissue and the volume of extraocular muscles are increased by cell proliferation, inflammation, and glycosaminoglycan accumulation, mainly hyaluronic acid. Glycosaminoglycan secretion by the fibroblasts is activated by the T-cell cyto-kines (tumor necrosis factor, interferon-γ), thus showing that T- and B-cell activation is impor-tant for the immunopathogenesis of Graves’ ophthalmopathy. Glycosaminoglycan accumula-tion brings about changes in the osmotic pres-sure which lead to liquid accumulation, muscular edema, and increased pressure inside the orbit. These changes, with the addition of retro-orbital adipogenesis, move the eyeball outside, possibly also interfering in the function of the extraocular muscles and the orbit’s venous drainage [12, 13].

Clinical PresentationThe extraocular muscles are the main impaired targets and show increased volume, and together with other important clinical signs determined by inflammatory changes and/or vascular conges-tion include upper and lower eyelid retraction, conjunctival hyperemia, and preorbital edema [17, 18], as well as sequelae of extraocular mus-

cle hypertrophy translated into visual loss that results from corneal ulceration, secondary to pro-ptosis and optical neuropathy by compression of the optic nerve [17, 19]. Exophthalmos is almost always bilateral and symmetric. The lower rectus muscle is the most often involved muscle fol-lowed by the medial rectus, the upper rectus, and the lateral rectus muscles (Figs. 36.1 and 36.2).

Complementary ExaminationsThe diagnosis is clinical, and imaging methods are indicated when the diagnosis is difficult or an opti-cal neuropathy is suspected [17, 18]. Computed tomography (CT) and magnetic resonance imag-ing (MRI) are useful to confirm the diagnosis through visualization of the muscle hypertrophy and the orbital fat, and also to assess the critical area of the orbital apex. Often the only finding is increased orbital fat, with resulting proptosis [20].

Therapeutic ApproachPatients are treated according to the degree of dis-ease impairment, always having in mind that most

Fig. 36.1 Thyroid ophthalmopathy

Fig. 36.2 Another aspect of thyroid ophthalmopathy


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patients display a mild disease with no progres-sion during the follow-up. Graves’ ophthalmop-athy patients display hyperthyroidism reversal (when present), symptom relief, and decreased periorbital tissue inflammation [13, 21].

Symptom treatment comprises the use of arti-ficial tears, raised head during sleeping hours, facial support when sleeping, and use of blinders that are often enough for symptom relief. Photophobia and sensitivity to wind or cold air can be reduced with sunglasses [13, 22]. Some studies suggest that use of selenium (100 μg 2×/day, over 6 months) may improve soft tissue edema, besides the implementation of quality-of- life measures, although such results require con-firmation [23].

For patients with eye inflammation (red eyes) and increased diplopia and proptosis, a corticosteroid (prednisone 30 mg/day for 4 weeks) course should be started. If large doses are necessary they are intravenously administered. Cases whereby vision is lost, usually preceded by color vision loss, require the patient to immediately undergo corticoste-roid therapy (intramuscular dexamethasone 4 mg, or prednisone 100 mg orally) and hos-pital admission for probable surgical decom-pression. Rituximab, radiation, and surgical decompression can be also used in select cases [13, 22, 24–26].

Pretibial MyxedemaThe cutaneous manifestations of GD may result from excessive thyroid circulating hormone or from the autoimmune nature of GD [27, 28]. The most common clinical findings are oph-thalmopathy, acropachy, and pretibial myx-edema; the presence of the three findings make up the classic triad of GD, present in only 1% of cases [29].

Pretibial myxedema is a less often seen mani-festation, present in only 5% of GD cases and in 15% of cases of patients with GD and ophthal-mopathy [30]. About 90% of the patients with pretibial myxedema have hyperthyroidism and 10% are hypothyroid or euthyroid patients, although all of them display laboratory evidence of autoimmune thyroid disease [31]. About 50%

of the pretibial myxedema cases occur after the patient undergoes treatment for thyroidopathy either with radioactive iodine or thyroidectomy [32]. The ophthalmopathy is associated with most of the cases, usually coming before pretibial myxedema occurring within 1–2 years [31]. Its incidence has decreased possibly due to the early diagnosis and treatment implementation for GD. Contrary to what is prompted by its name, it is not limited to the pretibial area, and can reach the ankles and the feet dorsa, and be present in the elbows, knees, upper portion of the trunk and neck [33].

EtiopathogenesisPretibial myxedema results from glycosamino-glycan accumulation, specifically hyaluronic acid secreted by cytokine-stimulated fibroblasts. By showing the expression of the TSH receptor proteins by the dermis fibroblasts, the possibility arises that antibodies and/or T-cell-specific anti-gens start an inflammatory reaction that stimu-lates glycosaminoglycan production; excessive glycosaminoglycans are deposited in the dermis and the subcutaneous tissue [34–37].

Clinical PresentationPretibial myxedema is characterized by a bilat-eral asymmetric cutaneous thickening, usually with one or more less delimited papules or nod-ules that can display different diameters [37]. There is color variation from yellowish chest-nut to violet, and an “orange skin” aspect due to the cutaneous thickening associated with the follicular prominence is frequently noticed [31, 37]. Lesions are usually asymptomatic although they can be pruritic or even painful [37]. Hyperpigmentation, hyperkeratosis, and hyperhidrosis may also be present. The most frequent sites include the medium and lower third of the pretibial region and, occasion-ally, the feet dorsa (Fig. 36.3). Other impaired regions are seldom noticed, although there are reports of atypical location, such as the fingers, hands, upper limbs, torso, shoulder, and face, albeit that in most of those reports there was history of trauma, vaccination, local scar, or surgery [31, 32, 37].


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The lesions usually develop along many months and then stabilize, or, in some cases, spontaneously recede [37]. Rarely the lesions evolve and reach the feet, hands, or legs, in such cases showing a more elephantiasis format [31, 32].

The differential diagnosis can be made with stasis dermatitis, cutaneous mucinosis (in lupus erythematosus, dermatomyositis, scleroderma), amyloidosis, hypertrophic lichen planus, and lipoid necrobiosis [33].

Complementary ExaminationsThe diagnosis of pretibial myxedema is based on the GD history and clinical characteristics of the lesion (location, nonpitting nature, and badly delimited margins). A biopsy is seldom neces-sary for the diagnosis, although it can be required when patients display disease-suggestive lesions but with no history of thyroid disease.

Therapeutic ApproachMost of the cases do not require treatment, with resolution occurring some years later. Treatment indications include pruritus, local discomfort, or aesthetic reasons. It is wise, nevertheless, to treat all new lesions so that they do not undergo a chronic process. Treatment encompasses minimization of the risk factors: quitting smoking, weight loss, and treatment of the disturbed thyroid. Improvement in thyroid function does not necessarily improve the myxedema [33]. As initial therapy, medium- to high-potency corticosteroids, with or without

occlusion, are indicated; no improvement after 4–12 weeks of treatment leads to the use of intra-lesional corticosteroid, mainly for a presentation such as plaques and nodules [38]. Some authors support the use of compression stockings (20–30 mmHg) for lymphedema improvement [33, 37]. There are reports of pentoxifylline used in resis-tant cases [39]. Other reports mention rituximab and plasmapheresis in severely affected patients [40–43]. Immunoglobulin was effective in a series of noncontrolled cases [44]. When trauma is a precipitating factor of disease recurrence, sur-gical treatments must be avoided.

Thyroid AcropachyThe exact incidence of acropachy is not known, although estimates refer to 0.1–1% of GD patients [45].

EtiopathogenesisAcropachy pathogenesis is similar to that of der-mopathy. A research study investigated whether fibroblast activation in the periosteum and mucin deposition may be a triggering factor [46].

Clinical PresentationThyroid acropachy is a rare manifestation of thy-roid autoimmune disease, present in extreme forms of dermopathy, and possibly showing fin-ger or toe edema and clubbing. More seldom seen is acropachy together with distal arthritis [46]. It is part of the acropachy, pretibial myx-edema, and ophthalmopathy triad [45].

Three manifestations of acropachy are noticed: finger and toe clubbing (88%); edema, and hardening of the skin of fingers and toes (20%); and presentation of arthritis and periosti-tis (10%) [46].

The most ordinary form of acropachy is digital clubbing, which occurs in 20% of dermatopathic patients. Digital edema and periosteal reaction in adjacent bone is the total clinical presentation, though less often seen. Thyroid acropachy always occurs in association with Graves’ ophthalmopa-thy and thyroid dermopathy. Involvement of joints is unusual. Acropachy is not usually painful, although some patients have pain and function loss due to severe edema [45, 47].

Fig. 36.3 Pretibial myxedema


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Complementary ExaminationsSkin biopsy shows typical pretibial myxedema findings, including fibroblast activation and gly-cosaminoglycan deposits [48]. The diagnosis is made with a combination of the thyroid disease history, clinical characteristics typical of ophthal-mopathy and pretibial myxedema, and radio-graphic features of the hands and feet [45]. Fusiform edema of the soft tissues both in the patient’s fingers and toes, and subperiosteal bone formation are radiographic findings. Subperiosteal reaction is uncommon in long bones [45–47].

Therapeutic ApproachThere is no specific treatment available besides the basal immunologic treatment and manage-ment of the associated dermopathy. Painful acro-pachy periostitis requires use of anti-inflammatory agents [47].

Skin Manifestations of Hypothyroidism

Hypothyroidism, or a deficiency of thyroid hor-mone, is most often caused by a chronic autoim-mune disease (Hashimoto’s thyroiditis), but may also result from pituitary tumor or failure, iatro-genic thyroid ablation, goiter, or iodine defi-ciency [46].

Relatively common causes of primary hypo-thyroidism also include a prior history of therapy for hyperthyroidism, or a thyroidectomy (partial or total). External radiation given to the head, neck, or chest areas for lymphoma, for example, may also result in hypothyroidism [47].

Patients with hypothyroidism typically have cold, pale skin that is rough, dry, and scaly [10]. The skin may appear yellow because of caroten-emia. The most characteristic skin change of hypothyroidism is myxedema, the accumulation of mucopolysaccharides in the skin. Patients seem to have puffiness around the eyes and swell-ing of the hands. There is often loss of the lateral third of the eyebrows, coarse brittle hair and nails, and generalized hair loss [48].

Cutaneous manifestations of Hashimoto’s thyroiditis include acanthosis nigricans,

alopecia, melasma, onycholysis, and vitil-igo, among others [49].

The assessment of a hypothyroid patient requires a detailed history and physical exami-nation. Many clinicians will also obtain a thy-roid sonogram if there is a suspicion for nodules. Serum tests will include TSH initially (with T4 and T3 added if TSH is abnormal or if there is suspicion of central hypothyroidism), as well as measurement of thyroid peroxidase antibodies.

Once the diagnosis is made, the process involves levothyroxine administration, although it will not directly help the autoimmune- mediated aspects of the disease, such as pretibial myx-edema and ophthalmopathy [50].

General Skin Manifestations and Generalized Myxedema

Endemic cretinism can result from iodine defi-ciency in the uterus, although it may result from the transplacental passage of substances that inhibit the production of thyroid hormones by interfering with iodine absorption in the thyroid gland (goitrogens). In 33% of children with con-genital hypothyroidism, signs or symptoms of cutaneous abnormality are not found [51].

In Brazil, the bloodspot test (“Teste do Pezinho”) is carried out up to the 30th day of life; it is now part of the Sistema Único de Saúde (SUS) (the publicly funded healthcare system) incorporated in 1992 (Portaria GM/MS no. 22, de 15 de Janeiro de 1992), with a legislation that made the test mandatory for all live newborns; it also includes assessment for phenylketonuria and congenital hypothyroidism [52].

Adult hypothyroidism develops insidiously, thus possibly persisting for many years. Adult hypothyroidism is a common type, more fre-quently occurring in women from 40 to 60 years old [51].

Generalized myxedema is a severe manifesta-tion that may be seen in hypothyroidism, when mucin is deposited in the skin and other organs leading to a series of dermatologic and systemic changes [51].


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EtiopathogenesisThere are no exact causes to determine the dis-ease besides its association with low levels of thyroid hormones, associated with relevant dermal accumulations of mucopolysaccha-rides, mainly hyaluronic acid and chondroitin sulfate [51].

Clinical PresentationPatients often display early tiredness, a feeling of fatigue, weakness, cramps mainly in the legs, and severe discomfort on cold days. The myxedema is characterized by typical periorbital swelling, thick lips, acral swelling, and widened tongue. Macroglossia may display a smooth and red aspect. The yellowish skin is explained by caro-tene accumulation in the stratum corneum (as result of the lesser hepatic conversion of β-carotene to vitamin A), and anemia [51, 53]. The carotenemia may be seen in hand palms and soles of feet, and nasolabial folds. Clavicular fat accumulation may be often noticed. The skin is dry, cold, and pale, mainly in the extension areas. Xerosis can be so severe that it may be consid-ered a form of acquired ichthyosis. It becomes pale because of the higher levels of water and mucopolysaccharides in the dermis, which change the light refraction. It also shows a periph-eral vasoconstriction that may determine features of cutis marmorata. Hypohidrosis is also noticed. The palms may become significantly drier, pos-sibly mimicking an acquired keratoderma. The skin is diffusely swollen and becomes sturdy when touched. Despite the edematous aspect, the skin is not depressed if pressure is applied upon it. The presence of cutaneous edema may be par-tially explained by the hygroscopic characteris-tics of the mucopolysaccharides, although an increase in the transcapillary escape of albumin was shown, possibly resulting in its extravascular accumulation, thus playing a part in this edema. In addition, inappropriate lymphatic drainage can account for the development of exudates in the serous cavities that become visible in the myx-edematous state [51–54].

Body and head hair may be dry and brittle. Hair loss results in partial alopecia. Irregular alopecia plaques can be noticed with persistent lanuginous

hair. The eyebrows exhibit a characteristic loss of the lateral third bilaterally. Hair growth is slow. Patients with spontaneous or iatrogenic myxedema may also show a greater amount of hair in the telo-gen phase. This may indicate that the hypothyroid-ism alopecia is being mediated by hormonal effects [51–54].

The nails show a slow growth and a fragile structure.

In the myxedematous state wound scarring can be impaired, thus determining such a slow process. Purpura may sometimes be noticed as a consequence of the decrease in clotting factor, or loss of vascular support resulting from the pres-ence of mucin in the dermis may be seen [53, 54].

Some reported uncommon observations in the literature can be deduced as actual manifes-tations of the hyperthyroid state. A manifesta-tion similar to ectodermal dysplasia, possibly inherited in a recessive autosomal manner, was reported by the acronym ANOTHER (alope-cia, ungual dystrophy, ophthalmologic compli-cations, dysfunctional thyroid, hypohidrosis, ephelides and enteropathy, and respiratory tract infections) [51].

The systemic manifestations of hypothyroid-ism are numerous and are not covered in this chapter. It is important to know that mucin depo-sition also occurs in many organs other than the skin, such as the heart, intestines, and the kid-neys, resulting in functional outcomes.

Complementary ExaminationsThe diagnosis is clinically suspected and con-firmed by the low levels of free circulating T4. The TSH serum level is high in primary hypothy-roidism and low in secondary hypothyroidism. Myxedema is not seen in secondary hypothyroid-ism [53, 54].

The anatomopathologic examination shows a mild epidermal hyperkeratosis and development of corneal plugging in the pilous follicles, and small dermal deposits of mucopolysaccharides. In the most noticeable cases edema is seen with separated collagen bundles. In some cases pre- eminent amounts of dermal mucin can be noticed, mainly perivascular and perifollicular. The num-ber of elastic fibers is decreased [53].


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Therapeutic ApproachIf the impairment happens in newborns, immedi-ate treatment is crucial for their appropriate mental development. This important treatment begins before the 4th month of life [53, 54].

Whatever the situation, symptoms recede when the therapy employs thyroxine.

Skin Manifestations Related to the Thyroid Gland and Not to Its Function

Thyroglossal Duct Cyst

Thyroglossal duct cyst results from a failed oblit-eration of the duct developed in the embryogen-esis during thyroid migration, and represents the most common median line cyst. Ectopic neopla-sias of the thyroid tissues are rare, and rarer if associated with this duct [55].

EtiopathogenesisIn the fourth week of fetal development the thy-roid tissue is located in the pharyngeal floor, and through the thyroglossal duct this tissue migrates into its usual position in the thyroid. During the thyroid descent, the gland keeps its connection to the base of the tongue through the thyroglossal duct, and when migration is concluded the duct is obliterated at around the 8th gestational week. This channel persistence is called remnant thyro-glossal duct [56].

This congenital remnant is usually noticed as a cyst coated with a secretory epithelium. Both men and women can show this condition, which can be located anywhere in the thyro-glossal duct, found in 60% of the cases between the hyoid bone and the thyroid cartilage; 24% suprahyoid; 13% substernal; and 2% intralin-gual [57].

The diagnosis is made up to 10 years of age in about 30% of the cases; from 10 to 20 years of age in 20%; from 20 to 30 years of age in 15%, and after 30 years of age in 35% of cases. Ectopic thyroid tissue is seen in 62% of cases and is subject to the same pathology of the thy-roid itself [56].

Clinical PresentationThe clinical presentation shows a nodular lesion of cystic consistency at the medium line of the neck at the level of the thyroid membrane. Cyst infection may happen simultaneously with epi-sodes of airway infection, and signs of local inflammation can be seen (Fig. 36.4). A fistula secondary to the cyst infection may also be apparent [58].

Complementary ExaminationsUltrasonography of the cervical region is the method used to identify the cyst, with an accu-racy of 90% [58]. When facing a doubtful diag-nosis, an aspiration puncture can be conducted to confirm the presence of thyroid tissue.

Therapeutic ApproachThe treatment of choice is cyst removal per-formed using the Sistrunk technique, comprising removal of the central part of the hyoid bone. If infection is ascertained, the use of systemic anti-biotics may be necessary [36].

Thyroid Cancer and Cutaneous Metastases

Thyroid papillary carcinoma accounts for most of the cases of cancers of this type in children,

Fig. 36.4 Thyroglossal duct cyst


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usually occurring as metastases in regional lymph nodes. Papillary carcinoma is made up of Hürthle cells, usually noticed in middle-aged and elderly persons. Among the elderly population, the most common metastases are distant metastases. On the other hand, tumors of undifferentiated cells are characteristic of older people, and may pre-dispose distant metastases besides involvement of regional lymph nodes [56].

Cutaneous metastasis is a rare event [60]. In a series of 724 patients, thyroid metastatic carci-noma accounted for less than 1% of the cutane-ous metastases [61], and no thyroid metastasis was noted in a series of 4020 individuals with cutaneous metastases [62].

EtiopathogenesisThyroid follicular carcinoma displays meta-static dissemination mainly through hematog-enous spread, which occurs in 10–15% of cases of more advanced tumors. The most often affected sites include the bones and the lungs, and less frequently the brain, liver, bladder, and skin.

In 2005 Quinn et al. described four patients with thyroid cutaneous metastasis, three men and one woman, with a medium age range of 64 years, all of whom had invasive thyroid follicular carcinoma [60]. Two of these patients displayed scalp metastases: one in the neck, and another in the sacral skin. In three cases the specific mor-phology and immunohistochemistry were con-ducted, revealing that one of these patients showed primarily spinal metastasis of character-istic morphology, although he underwent ana-plastic change after treatment. Including these four cases a total of 14 were reported in the litera-ture, with cutaneous metastasis of thyroid follicu-lar carcinoma in most patients: that is, 10 out of 14 patients had primary site histopathology [60].

Clinical PresentationThe morphology of cutaneous metastases is variable. The lesions may manifest as macules, plaques, papules or nodules. They can imitate other conditions, such as alopecia, infections (erysipelas and paronychia), benign cysts (epi-dermoid or pilar), pyogenic granuloma, and

cutaneous malignant neoplasias (basal cell car-cinoma and keratoacanthoma) [63–65].

Cutaneous manifestations common to the thy-roid papilliferous carcinoma are nodules in the scalp and neck [63, 66, 67], and lesions in the scar of thyroidectomy [68]. A metastatic tumor at the site of thin-needle aspiration biopsy was also noticed by Tamiolakis et al. [67]. Cutaneous metastases of thyroid papillary carcinoma have also been described on the abdominal wall, arms, buttocks, thoracic wall, face, shoulders, and thighs [60] (Fig. 36.5).

Cutaneous thyroid metastases can occur after an early diagnosis of thyroid cancer, thus making the cutaneous lesion diagnosis easier, as well as being the first identified manifesta-tion of the pathology. Since cutaneous lesions are accessible to clinical examination and patient visualization, they may easily trigger the investigation leading to the primary site of the neoplasia.

Complementary ExaminationsComplementary examinations are crucial to the proper identification of the cutaneous metastases because they allow the identification of the lesion’s primary site.

Anatomopathologic examination of cutaneous metastases of papilliferous carcinoma and thy-roid follicular carcinoma also show characteris-tics similar to those of the primary site. Immunohistochemistry may be also useful for diagnostic confirmation and exclusion of tumors originating in other organs.

Fig. 36.5 Thyroid papilliferous carcinoma


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Thyroid papillary and follicular carcinomas express the thyroid transcription factor 1 (TTF-1) and thyroglobulin (a glycoprotein synthesized in the cytoplasm of the thyroid follicular cells, and detected in 95% of papillary carcinomas) [69].

Therapeutic ApproachThe therapeutic approach is determined accord-ing to clinical staging of the neoplasia. Management includes a partial or total thyroidec-tomy followed by adjuvant radiotherapy to treat invasion of the cervical region. It can be associ-ated with chemotherapy with isolated doxorubi-cin, or associated with other chemotherapeutic agents, as well as the use of radioactive iodine. Molecular targeted therapy aimed at specific receptors has shown promising outcomes.

The prognosis for patients with thyroid met-astatic papilliferous carcinoma of the skin is usually unfavorable [64, 66]. There are, never-theless, individuals with thyroid cutaneous metastases who survived many years after the diagnosis [68, 66, 70]. Furthermore, with the advent of molecular targeted therapies, such as tyrosine kinase inhibitors, the prognosis for patients with metastatic disease, and mainly for those with a rearrangement during aberrant transcription of the oncogenesis (RET), is bet-ter than the observed prognosis in individuals with thyroid papilliferous carcinoma who underwent treatment before the discovery of these agents [71].

Glossary

Cutis marmorata Manifests as skin changes displaying violet spots on the trunk and limbs, which can be highlighted by cold temperature.

Diplopia The condition when an individual sees two images of the same object.

Glycosaminoglycans Components of the connective tissue. They represent 30% of the body’s organic material and can exist as dif-ferent types, such as chondroitin sulfate for cartilage, bone, or cornea; dermatan sulfate for the dermis and the tendons; and heparan sulfate for the liver, lungs, and aorta.

Hyaluronic acid A biopolymer made of the glucuronic acid and N-acetylglucosamine. With a viscous texture, it exists in the syno-vial fluid, the vitreous humor, and the connec-tive tissue of numerous organisms, being an important glycosaminoglycan in articulation composition.

Lymphedema The accumulation of interstitial fluid rich in proteins of high molecular weight.

Macroglossia The abnormal growth of the tongue so that it reaches a size larger than the one allowed by the buccal cavity, resulting in impaired phonation and respiratory, suction, and/or swallow function.

Plasmapheresis An extracorporeal process by which the blood collected from a patient is separated into its plasma and cell element compounds.

Proptosis Proptosis is characterized by a dis-placement of the eyeball to the front of one eye, or both eyes.

Proto-oncogene (RET) RET proto-oncogene activating mutations may result in the devel-opment of the thyroid medullary carcinoma. Its research study is useful for the genetic tracking of thyroid medullary carcinoma.

Radioactive iodine Radioactive iodine treats hyperthyroidism by gradually shrinking the thyroid, ultimately destroying the gland.

Rituximab A monoclonal chimeric antibody (murine/human) against an antigen that is the protein of the cell surface, CD20

Thyroxine (T4) A hormone that plays a role in several body functions, including growth and metabolism.

Tri-iodothyronine (T3) T3 and T4 (thyroxine) are hormones produced by the thyroid gland. They help to control the rate at which the body uses energy, and are regulated by a feedback system.

Thyroid-stimulating hormone (TSH) TSH stimulates the production and release of T4 (primarily) and T3. As necessary, T4 is converted to T3 by the liver and other tissues.

Thyroid transcription factor 1 (TTF-1) TTF-1 regulates the transcription of the spe-cific genes of the thyroid, the lung, and the diencephalon. It is used in anatomic pathology as a marker to determine whether a tumor has its origin in the lung or the thyroid.


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