GD – Graves’ disease

TRAb – Thyrotropin receptor antibodies

TSH – Thyroid stimulating hormone

GO – Graves’ Orbitopathy

PTM – Pretibial Myxedema

TA – Thyroid Acropachy

GAG - Glycosaminoglycan’s

Graves’ disease (GD), the most common cause of hyperthyroidism, is an autoimmune disease of the thyroid with an annual incidence of 20 to 50 cases per 100,000 persons and a peak incidence between ages 30 to 50 [1]. Hyperthyroidism is caused by the production of thyrotropin receptor autoantibodies (TRAb) against the thyroid stimulating hormone (TSH) receptor. TRAbs similarly stimulate the TSH receptor consequently increasing thyroxine and triiodothyronine production [2]. Extra-thyroidal manifestations of GD include Graves’ orbitopathy (GO) (30%) and infrequently, pretibial myxoedema (PTM) (5%), a localised dermopathy [3]. Even less common is Graves’ or thyroid acropachy (TA) which occurs in less than 1% of cases. Due to the rarity of PTM and TA, available data is limited to individual case reports or small cohort studies. We describe a patient with GD who presented with severe PTM and TA, more than a decade post-thyroidectomy.

A 59-year-old woman attended the outpatient endocrine clinic with a background history of GD, type II diabetes mellitus and hypertension. She had been diagnosed with GD 26 years ago. At the point of diagnosis, she was thyrotoxic with a diffuse non-tender goitre and mild, inactive GO. Notably, at initial presentation there was no clinical evidence of PTM or TA. Following initial therapy with anti-thyroid medication, radioactive iodine ablation was performed. After this proved unsuccessful, a total thyroidectomy was performed at the patients’ request. She was rendered hypothyroid and thyroid hormone replacement therapy was commenced. Following surgery, her GO resolved however she was subsequently lost to follow-up.

Sixteen years following total thyroidectomy she re-presented complaining of intermittent lower limb pain and an inability to comfortably wear shoes. Whilst initially mild, these symptoms had gradually worsened over the last 10 years with resultant limitation in mobility. She had an 8.8 pack-year smoking history and a family history of type 2 diabetes and GD.

Clinical examination revealed a thyroidectomy scar and no residual GO. There was significant hyper-pigmentation, indurated skin and non-pitting oedema bilaterally of the shins, feet, and legs, in keeping with PTM. (Figure 1). In addition, there was softening of the nail bed, thickening of the distal phalanx (drumstick fingers) and a positive Schamroth’s sign [4], suggestive of TA (Figure 2). She was biochemically euthyroid and her TRAb level was >40.00 U/L (< 1.8 U/L).

Figure 1: Pretibial Myxoedema. Scaly, irregular circumscribed, and nonpitting diffuse swelling with orange peel-like appearance at lower two-thirds circumference of lower legs.

Figure 2: Thyroid Acropachy. Clubbing and swelling of the digits.

Radiographs of the hands demonstrated significant soft tissue swelling and digital clubbing bilaterally. Irregular, fluffy periosteal bone formation was noted on the proximal phalanges of the second, third and fifth digits of the right hand and second, fourth and fifth digits of the left hand. Tufting of the distal phalanges was also noted (Figure 3).

Figure 3: Radiographs of the hands demonstrating significant soft tissue swelling bilaterally, digital clubbing and irregular, fluffy periosteal bone formation of the proximal phalanges and metacarpals with tufting of the distal phalanges.

Irregular periosteal bone was also noted in the first and second metacarpals of both hands, the proximal and distal phalanges of the first and second toes bilaterally and the distally aspects of both tibia and fibulas. These features were in keeping with TA. A skin punch biopsy of the left pretibial region was performed. Haemotoxylin eosinophil (Figure 4) staining of this specimen showed pallor of the mid- and deep dermis as a result splaying apart of the collagen fibres due to the increased interstitial mucin demonstrated by the Alcian blue stain (Figure 5), consistent with the diagnosis of PTM. These findings were consistent with PTM and TA. Thyroid hormone replacement was continued and she was started on topical corticosteroids for the PTM. The patient was counselled to stop smoking and referred to podiatry for more comfortable footwear to be arranged. She will continue to follow-up at the endocrine outpatient department.

Figure 4: Haematoxylin and Eosin (H&E) stained sections: (100x magnification) demontrates pallor of the mid- and deep dermis as a result splaying apart of the collagen fibres.

Figure 5: Alcian blue stained section (100x magnification) showing increased interstitial mucin.

Pretibial Myxedema (PTM)

PTM, also called localized myxedema, thyroid dermopathy, Graves’ dermopathy or infiltrative dermopathy, forms the third component of the classic triad of GD (goitre, GO and PTM). Whilst PTM usually occurs in just 5% of patients with GD, this may increase to 13% if the patient has concurrent GO [3]. The development of PTM is independent of thyroid function and is only rarely the presenting feature of GD.

The term PTM is a misnomer, as it is not only restricted to the pretibial area and may also occur in other regions including the dorsum of the foot, ankle, elbows, knees, upper back, ears, shoulders, umbilicus and neck [3]. Additionally, it may also be found in areas of previous trauma and scarring [3].  PTM is characterised by hyperpigmented, asymmetrical and indurated non-pitting lesions. They are usually asymptomatic, however in some cases pruritis, pain and scaling have been reported [3].  Well demarcated papules and nodules may also occur giving the skin a peau d’orange (orange peel) appearance [3]. Lesions usually appear over a period of several months and generally stabilize, however in some cases spontaneous regression may occur [3].

The diagnosis of PTM is based on the history and the classic dermatological appearance. Punch biopsy is rarely required except in cases of absent active hyperthyroidism (as in our case) or when the diagnosis is in doubt. The differential diagnosis for PTM include stasis dermatitis, chronic dermatitis and cutaneous mucinosis.

The pathogenesis of PTM is not entirely known but is considered similar to the retro-orbital manifestation of GO. Patients with PTM almost always have GO (97%) and commonly have very high serum TRAb concentrations [3]. Studies suggest that environmental (dietary iodine intake, obesity, smoking, infections and stress), genetic, epigenetic and local or mechanical factors all play a role in the cutaneous manifestations of GD [1]. In addition, the occurrence and severity of PTM may be influenced by race, sex, ethnicity, and age [3]. It is known that smoking (tobacco) has a negative influence on patients with GD, with an increased incidence of GO and likely PTM and TA [3].

The demonstration of TSH receptor protein expression by normal dermal fibroblasts suggest that TRAb may initiate the inflammatory response. Sensitised T-cells infiltrate the dermis and produce cytokines including interferon-α and transforming growth factor β, which stimulate fibroblast differentiation, fibroblast proliferation and synthesis of glycosaminoglycans (GAG). The accumulation of GAG results in fluid retention and expansion of connective tissues leading to obstruction of lymphatic drainage and subsequent lymphedema. Secondary lymphatic obstruction has been postulated to reduce the clearance of cytokines and chemokines in tissue thereby prolonging their disease producing effects [3].

The treatment of PTM is based on clinical experience and case studies [3,5-7] It is reasonable to treat mild and early lesions in the hope of preventing progression. Non-pharmacological treatment include minimizing risk factors such as weight loss, cessation of smoking, avoiding trauma and wearing appropriate fitting shoes are recommended. Compression stockings may be used to improve lymphedema [3,5,6].

Corticosteroid therapy (oral, intravenous pulses, topical dressings, intra-lesional) is the mainstay of treatment for PTM. This may be combined with non-pharmacological treatment to improve outcomes [3,5] Pain management is an important factor to consider [3]. Systemic immunomodulation (plasmapheresis, immunoglobulin therapy, receptor blocking monoclonal antibodies) and octreotide therapy are all currently under investigation [8]. Surgical excision often precipitates a recurrence of disease and should not be attempted [9].

The outcome of PTM treatment depends on the severity of presentation and those with delayed presentation and treatment have a poorer outcome [3]. Mild cases respond well to therapy and some may even resolve spontaneously once the patient is euthyroid. However, severe cases are difficult to treat and usually require a combination of therapies before any improvement is noted.

Thyroid Acropachy

Thyroid acropachy (TA) is a rare clinical feature of GD and is almost always associated with PTM and GO [3,10] Chronologically, TA appears as the final dermatological manifestation of GD. Females are also more prone to develop TA than males [11].

Clinically, TA is characterised by digital clubbing and soft tissue swelling of the hands and feet [3]. The first, second, and fifth metacarpals, the proximal phalanges of the hands, and the first metatarsal and proximal phalanges of feet are the most affected [8].

Fortunately, TA is relatively benign and often asymptomatic, however, some patients may present with pain and loss of function because of extreme swelling [3]. TA is a clinical diagnosis although radiological imaging may be useful. Periosteal new bone formation on radiographs of the hand or feet is highly specific for the disease. The new bone is irregular and spiculated and described as having a feathery appearance [3,11]. Small bone deletion due to severe inflammation can be seen. However this is very rare [12]. Isotopic bone scan shows increased uptake in the periosteum and may rarely show involvement of long bones [3].

The exact aetiology of TA is unknown, but like PTM and GO, there appears to be a role for TRAb in the pathophysiology. There is no effective treatment for TA.

The presence of PTM and TA are indicative of severe autoimmune thyroid disease and patients presenting with these features have been noted to have higher circulating TRAb levels [13]. TRAb are mainly produced by intrathyroidal lymphocytes and to a lesser extent by immune cells in lymph nodes and bone marrow [14]. Treatment of GD with radioactive iodine ablation or thyroidectomy (both total and subtotal) is followed by a steady decline in TRAb levels [14-17]. This steady decline as opposed to immediate resolution of antibody production has been attributed to the continued production of TRAb by peripheral lymphocytes after removal/ablation of the thyroid [14,15].

Long term follow-up comparing these treatment modalities has demonstrated the superiority of total thyroidectomy in reducing TRAb levels [14-17]. Generally, a 100% elimination of TRAb is noted after 7 years following total thyroidectomy [15]. The presence of active GO, smoking and raised thyroglobulin values are risk factors for prolonged TRAbs half-life and may result in delayed decline following thyroidectomy [17].

In our patient, persistent smoking and high TRAb levels, contributed to the delayed presentation and severity of her PTM and TA, more than a decade postthyroidectomy. Whilst smoking may have played a role, we are uncertain as to the exact mechanism of persistently elevated TRAb levels in our patient. To our knowledge there is only one other reported case of severe PTM and TA developing decades after thyroidectomy [18].

GD is a common autoimmune disease frequently seen by clinicians. The commonest extra-thyroidal manifestation is GO, with PTM and TA being rare. The diagnosis of PTM and TA are made clinically. More research regarding the prevalence, epidemiology, pathogenesis and treatment of dermatological manifestations of GD are necessary.

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