Autoimmune Thyrotoxicosis: Diagnostic Challenges

Katharina A. Ponto1
George J. Kahaly2

1) Gutenberg University Medical Center, Department of Ophthalmology, Mainz, Germany
2) Gutenberg University Medical Center, Department of Medicine I, Mainz, Germany

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Abstract

Autoimmune thyrotoxicosis or Graves’ disease (GD) is the most common cause of hyperthyroidism in the United States. GD occurs more often in women (ratio 5:1) and has a population prevalence of 1-2%. A genetic determinant to the susceptibility to GD is suspected because of familial clustering of the disease, a high sibling recurrence risk, and the familial occurrence of thyroid autoantibodies. GD is a systemic autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid-antigen-specific T cells into the thyroid and thyroid stimulating hormone receptor (TSHR) expressing tissues, i.e. orbit, skin, with the production of autoantibodies to well-defined thyroidal antigens. Stimulatory autoantibodies in GD activate the TSHR leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow on neck ultrasound) thyroid gland, associated orbitopathy, biochemically confirmed thyrotoxicosis, positive TSHR autoantibodies, and often a family history of autoimmune disorders.

Introduction and pathomechanism

Thyrotoxicosis is defined as the state of thyroid hormone excess and is synonymous with hyperthyroidism, which is the result of excessive thyroid function. The major etiologies of thyrotoxicosis are hyperthyroidism caused by Graves’ disease (GD), toxic multinodular goiter, and toxic adenomas. GD accounts for 60 to 80% of thyrotoxicosis, though the prevalence varies among populations, depending mainly on iodine intake[1]. GD occurs more often in women than in men with a female: male ratio of 5:1 and a population prevalence of 1-2%[2]. The disorder rarely begins before adolescence and typically occurs between 20 and 50 years of age, though it also occurs in the elderly[3].

GD is an autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid-antigen- specific T cells into the thyroid and thyroid stimulating hormone receptor (TSHR) expressing tissues, with the production of autoantibodies to well-defined thyroidal antigens such as thyroid peroxidase, thyroglobulin, and the TSHR. A genetic determinant to the susceptibility to GD is suspected because of familial clustering of the disease[4],[5], a high sibling recurrence risk, the familial occurrence of thyroid autoantibodies and concurrent autoimmune diseases[6],[7], and the 30% concordance in disease status between identical twins[8],[9]. Smoking and other lifestyle factors also increase the risk for Graves ́ hyperthyroidism[10]. The TSHR expressed on the plasma membrane of thyroid epithelial cells, is central to the regulation of thyroid growth and function. However, it is also expressed on a variety of other tissues, including adipocytes and bone cells. The TSHR is the major autoantigen in the autoimmune hyperthyroidism of GD where T cells and autoantibodies are directed at the TSHR antigen. Stimulatory autoantibodies in GD activate TSHR on thyroid follicular cells, leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion[11].

The close clinical relationship between Graves’ hyperthyroidism and Graves’ orbitopathy (GO) has suggested that immunoreactivity against TSHR present in both the thyroid and orbit underlies both conditions[12]. A prerequisite for involvement of TSHR as an autoantigen in GO is that it be expressed in affected orbital tissues[13]. Numerous studies did demonstrate that TSHR mRNA and protein are present in GO. Further, TSHR expression has been shown to be higher in GO orbital fat compared with normal orbital adipose tissues. Also, there exists a positive correlation between TSHR mRNA levels in individual GO orbital connective tissue specimens and the patient’s clinical disease activity[14]. The extrathyroidal manifestations of GD i.e. GO and dermopathy are due to immunologically mediated activation of fibroblasts in the extraocular muscles and skin, with accumulation of glycosaminoglycans, leading to the trapping of water and edema[15]. Later, fibrosis becomes prominent. The fibroblast activation is caused by proinflammatory cytokines derived from locally infiltrating T cells and macrophages[16].

Clinical Spectrum

Table 1:
Causes of Thyrotoxicosis

Primary hyperthyroidism

Graves’ disease
Toxic multinodular goiter
Toxic adenoma
Amiodarone, iodine excess
Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue
Subacute thyroiditis
Silent thyroiditis
Activating mutation of the TSH receptor (autosomal dominant)
Struma ovarii
Functioning thyroid carcinoma metastases

Secondary hyperthyroidism

TSH-secreting pituitary adenoma
Thyroid hormone resistance syndrome
Chorionic gonadotropin-secreting tumors
Gestational thyrotoxicosis

Table 2:
Signs and Symptoms of Thyrotoxicosis

Symptoms

Hyperactivity, irritability
Heat intolerance and sweating
Palpitations
Dysphoria
Fatigue and weakness
Weight loss with increased appetite
Diarrhea
Polyuria
Oligomenorrhea, loss of libido

Signs

Tachycardia
Atrial fibrillation in the elderly
Tremor
Goiter
Warm, moist skin
Muscle weakness, proximal myopathy
Lid retraction or lag
Gynecomastia

Signs and symptoms include features that are common to any cause of thyrotoxicosis (Table 1) as well as those specific for GD[17]. The clinical presentation depends on the severity of thyrotoxicosis, the duration of the disease, individual susceptibility to excess thyroid hormone, and the age of the patient. In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, leading to apathetic hyperthyroidism. Thyrotoxicosis may cause unexplained weight loss, despite an enhanced appetite, and is due to the increased metabolic rate (Table 2). Weight gain occurs in 5 to 10% of patients, however, as a result of increased food intake. Other prominent features include hyperactivity, nervousness, and irritability, ultimately leading to a sense of easy fatigability in some patients. Insomnia and impaired concentration are common; apathetic thyrotoxicosis may be mistaken for depression in the elderly[18].

In GD the thyroid is usually diffusely enlarged to two to three times its normal size. The consistency is firm, but less so than in multinodular goiter. There may be a thrill or bruit due to the increased vascularity of the gland and the hyperdynamic circulation. The most common cardiovascular manifestation is sinus tachycardia, often associated with palpitations and sometimes due to supraventricular tachycardia. The high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic systolic murmur, and can lead to worsening of angina or heart failure in the elderly or those with preexisting heart disease[19]. Atrial fibrillation is more common in patients > 50 years. Treatment of the thyrotoxic state alone reverts atrial fibrillation to normal sinus rhythm in fewer than half of patients, suggesting the existence of an underlying cardiac problem in the remainder.

The skin is usually warm and moist, and the patient complains of sweating and heat intolerance, particularly during warm weather. Palmar erythema, onycholysis, and less commonly, pruritus, urticaria, and diffuse hyperpigmentation may be evident. Hair texture may become fine, and a diffuse alopecia occurs in up to 40% of patients, persisting for months after restoration of euthyroidism.

Fine tremor is a very frequent finding, best elicited by asking patients to stretch out the fingers and feeling the fingertips with the palm. Common neurologic manifestations include hyperreflexia, muscle wasting, and proximal myopathy without fasciculation. Chorea is a rare feature. Thyrotoxicosis is sometimes associated with a form of hypokalemic periodic paralysis; this disorder is particularly common in Asian males with thyrotoxicosis. Gastrointestinal transit time is decreased, leading to increased stool frequency, often with diarrhea and occasionally mild steatorrhea. Women frequently experience oligomenorrhea or amenorrhea; in men there may be impaired sexual function and, rarely, gynecomastia.

The direct effect of thyroid hormones on bone resorption leads to osteopenia in long-standing thyrotoxicosis; mild hypercalcemia occurs in up to 20% of patients, but hypercalcuria is more common. There is a small increase in fracture rate in patients with a previous history of thyrotoxicosis.

Extrathyroidal manifestations

Lid retraction, causing a staring appearance, can occur in any form of thyrotoxicosis and is the result of sympathetic overactivity. However, GD is associated with specific eye signs that comprise Graves’ orbitopathy (GO). This condition may occur in the absence of GD in 10% of patients. Most of these individuals have autoimmune hypothyroidism or thyroid antibodies. The onset of GO occurs within the year before or after the diagnosis of thyrotoxicosis in 75% of patients but can sometimes precede or follow thyrotoxicosis by several years, accounting for some cases of euthyroid GO. Many patients with GD have little clinical evidence of GO. However, the enlarged extraocular muscles typical of the disease, and other subtle features, can be detected in almost all patients when investigated by ultrasound or computed tomography (CT) imaging of the orbits[20]. Unilateral signs are found in up to 10% of patients.

The earliest manifestations of GO are a sensation of grittiness, eye discomfort, and excess tearing. About a third of patients have proptosis, best detected by visualization of the sclera between the lower border of the iris and the lower eyelid, with the eyes in the primary position. Proptosis can be measured using an exophthalmometer. In severe cases, proptosis may cause corneal exposure and damage, especially if the lids fail to close during sleep. Periorbital edema, scleral injection, and chemosis are also frequent. In 5 to 10% of patients, the muscle swelling is so severe that diplopia results, typically but not exclusively when the patient looks up and laterally. The most serious manifestation is compression of the optic nerve at the apex of the orbit, leading to papilledema, peripheral field defects, and, if left untreated, permanent loss of vision.

Clinical features of GO vary from a mild grittiness of the eyes to severe diplopia, disfiguring proptosis and loss of vision. There is a natural tendency towards spontaneous improvement: the spontaneous course depicts an active phase, which slowly abates after which an inactive phase ensues[21]. The most common symptoms of GO are eyelid retraction (90%), soft tissue involvement (80%), proptosis (50-60%), dry eye syndrome (50%), motility disorders (40%), optic neuropathy (3-5%) and superior limbic keratitis (2%)17. The autoimmune process leads to an accumulation of collagen and hydrophilic glycosaminoglycans within the orbit. Inflammatory changes of the eyelids cause visible edema and erythema. If extraocular muscles are affected motility disorders may occur. Patients with these motility disturbances, with diplopia, severe and active disease have a severely impaired health related quality of life[22].

Activity and severity of GO

Many scoring systems have been used to gauge the extent and severity of the orbital changes in GD. The NOSPECS scheme[23],[24] includes six classes of eye changes (Table 3). GO is classified as severe if corneal involvement, severe proptosis, constant diplopia or optic neuropathy are present[25].

Table 3:

The Clinical Severity Score according to the “NOSPECS classification”, modified according to [23],[24].

NOSPECS-Class	0	I	II (soft tissue involvement)	III (proptosis)	IV (extraocular muscle involvement)	V (corneal involvement)	VI (sight loss due to optic nerve compression)
Grade	No physical signs or symptoms	Only signs	0 = absent	0 = absent	0 = absent	0 = absent	0 = absent
			a = minimal	a = minimal	a = limitation of motion in extremes of gaze	a = stipping of the cornea	a = minimal
			b = moderate	b = moderate	b = evident restriction in motion	b = ulceration	b = moderate
			c = marked	c = marked	c = fixation of a globe	c = necrosis, perforation	c = marked (no light perception)

Figure 1a: Active Graves’ orbitopathy with eyelid edema, mild injection of the conjunctiva, severe redness and swelling of the plica and caruncle, and subtle redness of the eyelids.

Figure 1b: Active Graves’ orbitopathy with eyelid erythema, severe injection of the conjunctiva, and chemosis. Additionally, an orbital fat prolapse is present.

Figure 2: (click to enlarge) The Clinical Activity Score (CAS) of Graves’ orbitopathy (GO). The CAS consists of seven items. GO is active if CAS is equal or above three of seven points.

Evaluating the activity of GO is required to choose the most effective and stage adjusted therapy. Immunomodulatory therapies are aimed at the edematous, lymphocyte infiltration and the activated fibroblasts. GO is active when inflammatory symptoms like redness and swelling are dominating (Figure 1 a/b). Several groups have tried to develop methods to assess activity of GO. These include purely clinical assessments (clinical activity score, CAS[26], Figure 2), laboratory measurements (cytokines, glycosaminoglycan excretion, thyroid stimulating immunoglobulins[27]), and imaging techniques[20]. The clinical evaluation of the CAS together with the measurement of the TSI serum levels often accurately document the activity of the disease.

General ophthalmic assessment should include examination of anterior and posterior eye segment, applanation tonometry, Hertel exophthalmometry, and motility tests. Additionally, the observer classifies whether there are optic disc oedema or disc pallor and records whether choroidal folds are present. In addition to fundoscopy relative afferent pupillary defects, vision field defects, colour vision abnormalities, visual evoked potentials and visual acuity are tested in order to exclude optic neuropathy.

Cigarette smoking can profoundly influence the occurrence and the course of Graves’ eye disease[28], and also impairs its response to conservative treatment[29]. Accordingly, patients should be strongly urged to stop smoking. Refraining from smoking favorably influences the course of GO. Also, emotional distress and stressful life events are risk factors for GO and should therefore be minimized[30], [31].

Graves’ dermopathy and Graves’ acropachy

Figure 3a: Graves’ dermopathy

Figure 3b: Graves’ acropachy

Graves’ dermopathy is characterized by a localized thickening of the skin (mostly in the pretibial area, Figure 3a), whereas in Graves’ acropachy there is digital clubbing, thickening of the skin of the digits (Figure 3b), and sometimes periostitis of the distal bones[32]. While GO usually precedes dermopathy, acropachy appears around the same time or subsequent to dermopathy. Dermopathy and acropachy may be regarded as markers of severe GO. The rate of orbital decompression surgery is significantly higher in GO-patients who suffered from dermopathy. Also, patients with dermopathy have higher TSI serum levels compared with those with Graves’ thyroidal disease only[33]. It is recommended to rule out other skin diseases if Graves’ dermopathy without eye involvement is present. Topical local steroid therapy may help[34], however severe skin involvement requires long term management with high doses of IV steroids. Patients with systemic involvement i.e. Graves’ dermopathy and/or acropachy are best managed in a multidisciplinary Graves’ center with a joint thyroid eye clinic during the active phase of the disease.

Laboratory evaluation and imaging

In GD, below-normal to suppressed levels of baseline serum TSH, normal to elevated serum levels of T4, elevated serum levels of T3 and of TSHR autoantibodies, as well as a diffusely enlarged, heterogeneous, hypervascular thyroid gland (increased Doppler flow in the ultrasound evaluation of the neck) confirm diagnosis of GD. In 2 to 5% of patients (and more in areas of borderline iodine intake), only T3 is increased (T3 toxicosis). The converse state of T4 toxicosis, with elevated total and free T4 and normal T3 levels, is occasionally seen when hyperthyroidism is induced by excess iodine, providing surplus substrate for thyroid hormone synthesis. Associated abnormalities that may cause diagnostic confusion in thyrotoxicosis include elevation of bilirubin, liver enzymes, and ferritin. Microcytic anemia and thrombocytopenia occur less often.

The clinical relevance of anti-TSHR antibodies

During entire pregnancy of patients with GD circulating anti-TSHR-autoantibodies can pass to the baby and cause either neonatal autoimmune thyrotoxicosis (functionally stimulating immunoglobulins) or hypothyroidsm (blocking autoantibodies). Currently, two different methods of assessing antibodies directed against TSHR are used. The TSHR binding inhibitory immunoglobulin (TBII) assay detects immunoglobulins that inhibit the binding of TSH to purified or recombinant TSHR. It thus measures both thyroid-stimulating (TSI) and thyroid-blocking antibodies that target the receptor. The second method is a bioassay that can distinguish between TSHR-stimulating, -neutral (binding) and –blocking autoantibodies through their effect on cyclic adenosine monophosphate (cAMP) production in a cell line stably transfected with the receptor[27],[35],[36],[37]. The levels of TSI closely correlate with activity and severity of GO[33], and in approximately 50% of the cases also are of prognostic value regarding the course of the disease[38].

The commercially available TBII tests that are used to measure the binding of sera to TSHR display high sensitivity and specificity for TSHR autoantibodies, but unfortunately do not measure the functional activity of immunoglobulins and do not distinguish between stimulatory, blocking or neutral activity. In contrast, anti-TSHR bioassays offer the following advantages: 1) the biological activity of specific immunoglobulins is directly assessed on a fully functional TSHR holoreceptor expressed on intact live cells, a platform that is easily adaptable and tailored to detect antibodies of specific function; 2) the bioassay measures the specific function of autoantibody that highly correlates with Graves’ activity; 3) the monitoring of TSI levels and TSI titers add another dimension to the assessment of GO severity in individual patients.

Differential Diagnosis

Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, diffuse goiter on palpation, associated GO, positive TSHR antibodies, and often a personal or family history of autoimmune disorders[1],[2]. For patients with thyrotoxicosis who lack these features, the most reliable diagnostic methods are ultrasound evaluation of the neck looking for a hypervascular gland (“thyroid storm”) and/or a radionuclide scan of the thyroid, which will distinguish the diffuse, high uptake of Graves’ disease from nodular thyroid disease, destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis. In secondary hyperthyroidism due to a TSH-secreting pituitary tumor, there is also a diffuse goiter. The presence of a non suppressed TSH level and the finding of a pituitary tumor on CT or magnetic resonance imaging (MRI) scan readily identify such patients[20]. MRI is the optimal imaging procedure for the differential diagnosis of GO[39]. Clinical features of thyrotoxicosis can mimic certain aspects of other disorders including panic attacks, mania, pheochromocytoma, and the weight loss associated with malignancy. The diagnosis of thyrotoxicosis can be easily excluded if the TSH level is normal. A normal TSH also excludes GD as a cause of diffuse goiter.

Clinical Course of Graves’ disease

Clinical features generally worsen without treatment; mortality was 10 to 30% before the introduction of satisfactory therapy. Some patients with mild GD experience spontaneous relapses and remissions. Rarely, there may be fluctuation between hypothyroidism and hyperthyroidism due to changes in the functional activity of TSHR antibodies. About 15% of patients who enter remission after conservative treatment develop hypothyroidism 10 to 15 years later as a result of the destructive autoimmune process. The clinical course of GO does not follow that of the thyroid disease. GO typically worsens over the initial 3 to 6 months, followed by a plateau phase over the next 12 to 18 months, with spontaneous improvement, particularly in the soft tissue changes. However, the course is more fulminant in up to 5% of patients, requiring intervention in the acute phase if there is optic nerve compression or corneal ulceration. Diplopia may appear late in the disease due to fibrosis of the extraocular muscles. Radioiodine treatment for hyperthyroidism worsens the eye disease[40] in approximately 15-20% of patients (especially smokers). Antithyroid drugs or surgery have no adverse effects on the clinical course of GO[41]. Dermopathy, when it occurs, usually appears 1 to 2 years after the development of Graves’ hyperthyroidism; it may improve spontaneously.