Imaging of Thyrotoxicosis

Abstract

The diagnostic algorithm for patients with Graves’ disease frequently involves the use of thyroid autoantibody testing and radioisotope scanning. However, ultrasound has myriad uses in the evaluation of patients with hyperthyroidism. The purpose of this paper is to review the medical literature outlining the important role that ultrasonography (US) can play in the diagnosis and management of patients with hyperthyroidism. Further, we aim to make a case for the use of ultrasonography in the initial evaluation of all patients with thyrotoxicosis.

A highly sensitive and specific test for diagnosing various causes of hyperthyroidism, US has an accuracy rate closely approximating that of nuclear scintigraphy. We will delineate the advantages of ultrasonography compared to nuclear medicine imaging. Serial ultrasonographic exams using traditional US techniques and color-flow Doppler sonography (CFDS) after initiation of medical therapy can help predict relapse or remission of Graves’ disease, aiding the clinician in determining the best form of therapy. An additional tool available on most modern US machines is color-flow Doppler sonography, a device that measures the vascularity in the area being imaged. Information gathered from this exam may help delineate the cause of the hyperthyroidism and may be used to predict remission of Graves’ disease after initiation of medical therapy. Finally, this paper will detail the importance of ultrasonography in the workup of hyperthyroidism during pregnancy. We will also outline its utility for predicting fetal thyroid dysfunction in maternal Graves’ disease without the need for cordocentesis and its attendant complications.

Introduction

The use of ultrasonography (US) for the evaluation of thyroid disorders was first described in the mid-1960s[1] but it has gained more widespread acceptance as an important diagnostic tool in the last 15-20 years[2]. The superficial location of the gland in the anterior neck and the ability to visualize multiple planes real-time make US an ideal imaging modality for thyroid disorders. With recent advances in technology, most US probes have excellent spatial resolution; nodules as small as 2-3mm may be readily distinguished with modern machines. Further, the addition of color Doppler sonography to new devices improves the diagnostic capacity for clinicians at the bedside through its ability to quantify vascularity in the gland. Recognition of its superior diagnostic accuracy has led to a trend of increasing reliance on US at the bedside among Endocrinologists. Ultrasound training increasingly has become a part of the educational curriculum for Endocrine fellows. While it is most commonly used for the detection of thyroid nodules and guidance for fine-needle aspirations (FNAs), ultrasound is also an important tool in the initial workup of patients with hyperthyroidism.

There are numerous causes of hyperthyroidism, the two most common are Graves’ disease (GD) and toxic adenoma(s). Because only 50% of thyroid nodules measuring between 1-2cm are palpable[3], distinguishing between Graves’ disease and toxic nodules sometimes can be challenging. Other, less frequent, causes of hyperthyroidism include the various types of destructive thyroiditis. This paper will outline the characteristic ultrasonographic features of each of these conditions and how US can help predict outcomes after treatment of Graves’ disease. We will also explain the applications of US during pregnancy for the noninvasive monitoring of maternal and fetal thyroid function.

Ultrasonographic findings in Autoimmune Thyroid Disease

Composed of lakes of colloid surrounded by a single layer of follicular cells, the characteristic appearance of a normal thyroid gland on US is the result of this interface between the thyroid cells and colloid. The change in phase from solid to liquid results in a high acoustic impedance that reflects a high frequency back to the US probe. Consequently, the gland is a distinctive medium-gray color on US that is referred to as isoechoic echotexture, having a brighter echogenicity compared to the surrounding musculature. Disruption of the homogeneous echogenicity of the gland may be an early clue of an underlying thyroid disorder[4]. Patients with autoimmune thyroid disease (AITD) have an inflammatory response in their gland which introduces significantly more cellularity to the architecture of the thyroid, reducing the size of follicles and the quantity of colloid. As a result, the gland may appear hypoechoic (darker) relative to normal thyroid echotexture[4]. Typically, this process is initially focal (see figure 1a), with involvement of more thyroid tissue as the disease progresses. In the later stages of the AITD, the entire gland may be encompassed by inflammation (see figure 1b). The result is a very hypoechoic gland that may be enlarged or atrophic. These US findings are very useful tools in predicting autoimmune thyroid disorders; studies have found that reduced echogenicity on US has a positive and negative predictive value of 88-95% and 91-93%, respectively[4],[5],[6]. Further, ultrasonography has been found to be more sensitive than antibody testing for predicting autoimmune thyroid dysfunction. In one prospective study, reduced echogenicity predicted future thyroid dysfunction in 100% of patients and was present prior to antibody positivity in 13.7%, whereas, none of those with normal echogenicity went on to develop AITD during the three years of follow up[7].

Another early clue to the presence of a diffuse thyroid disorder is a thickened isthmus. The normal isthmus size in the transverse view is less than 3-4 mm; a measurement of >5mm may be an indication of an underlying disorder[8]. While not specific for AITD, it can be an early harbinger.

As a result of the lymphocytic involvement, patients with autoimmune thyroid disease may also have reactive lymphoid hyperplasia[9]. While this reactive lymphadenopathy is more commonly associated with patients with Hashimoto’s thyroiditis, it may also be seen in Graves’ disease. More easily visualized lateral to the carotid arteries, reactive nodes may also be found inferior and superior to the thyroid gland in the ‘central neck’[8]. The distribution of these nodes symmetrically in the neck and their reactive appearance are reassuring features. The nodes may be enlarged up to 1-2 cm but have a characteristic fusiform shape (relatively flat with width greater than two times the height) and retain their normal architecture with a prominent hilar stripe[9]. Absence of these reassuring features or any doubts about the benignity of the nodes should prompt the clinician to consider FNA to determine their malignant potential[10].

Graves’ disease versus Hashimoto’s thyroiditis

Reduced echogenicity, increased isthmus thickness, and reactive lymphoid hyperplasia may all be seen in patients with either Hashimoto’s thyroiditis (HT) or Graves’ disease. A distinguishing ultrasonographic parameter between these two conditions is vascular flow through the gland[11]. One of the hallmark findings of patients with untreated GD is markedly increased Doppler flow throughout the gland. In extreme cases, this has been dubbed “thyroid inferno” (see figure 2a)[12]. Such increased intrathyroidal blood flow may also be recognized on physical examination by auscultation of the gland; a thyroid bruit is highly suggestive of GD. In contrast, patients with HT typically have a normal or reduced distribution of color Doppler flow compared to healthy controls (see figure 2b)[13].

Because the amount of vascularity in a gland may be a qualitative parameter, peak systolic velocity (PSV) is a convenient quantitative index that is simple to measure with modern US machines[11]. Medium-sized arteries within the thyroid gland or in the inferior thyroidal artery are examined to determine the velocity of flow. Absolute values vary for each study, but the comparison to normal healthy controls reveals a marked difference in rates. For example, one group found that mean normal intraparenchymal peak systolic velocity was 4.8 ± 1.2cm/s compared to patients with untreated GD who had velocities of 15 ± 3cm/s[14].

Ultrasonographic findings in toxic adenomas versus cold nodules

Vascular flow has also been used to distinguish toxic adenomas from cold nodules[11],[15]. The pattern associated with autonomous adenomas is controversial, however. Some studies find that perinodular flow is increased in toxic nodules compared to cold nodules[14],[16],[17], whereas others have found that intranodular flow is increased in functioning adenomas[15],[18]. Still others[19],[20] have found that both intra- and perinodular flow is increased in toxic nodules. It is important to note, though, that malignant thyroid nodules may also have increased Doppler flow within them[21]. Vascular analysis may be a helpful component of the overall evaluation of thyroid nodules, but its use as a single determinant in assessing the risk of malignancy or autonomy of a nodule remains limited.

Ultrasound findings with destructive thyroiditis

Destructive thyroiditis (DT) causes a rapidly-progressive tissue injury followed by the release of large quantities of preformed hormone into the peripheral circulation. The traditional mode of detection of DT is based on historical clues, thyrotoxicosis, high thyroglobulin, and a low uptake on radioiodine scanning. It should be noted, however, that Tc-99m pertechnetate uptake is not always suppressed in subacute thyroiditis[22] and uptake may be normal or high if scintigraphy is performed during the recovery phase of the illness. When radioiodine uptake is either not available or not feasible (lactating mothers), ultrasound can play an important role in the diagnosis of destructive thyroiditis. The majority of patients with DT will have enlargement of the gland, in one study a median volume of 40 mL (normal is 15-20mL) was seen during the acute phase[23]. There was a 68% reduction (p<0.00001) in thyroid volume to a median of 13mL at 18 months of follow up[23]. An additional feature of destructive thyroiditis is the characteristic ill-defined hypoechogenicity (see figure 3a)[23],[24]. The percentage involvement of the thyroid with the hypoechogenicity is likewise noted to decline over time[23],[25]; some have suggested this changing echotexture is pathognomonic for destructive thyroiditis (see figure 3b)[24]. In the hyperthyroid phase of destructive thyroiditis, the reduced echogenicity of the gland and the presence of a goiter may be confused with Graves’ disease. Color-flow Doppler sonography may be used to distinguish between these two conditions; patients with Graves’ disease typically have significantly increased CFDS compared to destructive thyroiditis. In one recent study, increased peak systolic blood flow through the inferior thyroidal vein was seen in 32 of 34 patients with GD, whereas low flow was seen in all patients with destructive thyroiditis (see figure 2c)[26]. These results correlated significantly with findings on pertechnetate scanning, establishing a comparable sensitivity and specificity of 95% and 96%, respectively[26]. Other studies have confirmed the utility of this ultrasonographic parameter with a sensitivity of 84% and specificity of up to 92%[27],[28].

Amiodarone

Amiodarone-induced thyrotoxicosis (AIT) may be divided into two main forms: type 1, a form of iodine-induced hyperthyroidism (Jod-Basedow phenomenon), which is treated with antithyroid drugs; and type 2, a drug-induced destructive thyroiditis, which is treated with glucocorticoids[29]. Because the treatment varies with the type of thyroiditis, distinction of these conditions is important. Radioiodine uptake, in theory, should help discriminate between these two entities. In reality, however, the values of iodine uptake can overlap between type 1 and type 2 AIT[30],[31]. Ultrasound, specifically color-flow Doppler, has been studied to differentiate these two disorders[30],[32],[33],[34]. Patients with type 1 AIT are found to have increased blood flow through the inferior thyroidal artery[34], a vascular pattern similar to untreated Graves’ disease[32], or a hypervascular nodular pattern[33]. Conversely, patients with type 2 AIT had absent or markedly decreased vascularity on color-flow Doppler[30],[32],[33],[34]. One retrospective study found that CFDS was able to distinguish type 1 and 2 in 80% of cases[35]. Ultrasound, therefore, may be considered in the initial workup of patients suspected of having AIT.

Nuclear imaging for hyperthyroidism

Though it was long recognized that iodine is avidly taken up in large goiters, the clinical utility of iodine for diagnostic and therapeutic measures was not realized until isotopes were formulated and the emission of beta and gamma rays in situ was captured. Several isotopic variations were created in the late 1930s and testing in rabbits revealed its efficacy for the treatment of hyperthyroidism[36]. In the early 1940s radioiodine was being used in humans for both the diagnosis and treatment of Graves’ disease[37]. The overwhelming success of this treatment is based on the fact that normal glands take up relatively small amounts of the isotope, converging greater concentrations of radiation in the hyperplastic portions of the gland.

The use of radionuclide imaging in the diagnostic workup of hyperthyroidism remains widely popular amongst Endocrinologists and primary care physicians, particularly in the United States. In fact, radionuclide scanning is the recommended initial step in the diagnosis of patients with hyperthyroidism in some guidelines[38], even though the diagnosis can often be made on physical examination alone. There is no doubt that it is a highly effective method for diagnosing Graves’ disease, one study found that 123I scanning had a specificity of 96% when >20% uptake was seen at 5-6 hours[39].

Comparison of ultrasound and nuclear imaging

While there is clearly an established role for nuclear scintigraphy in the diagnosis of hyperthyroidism, there are also important limitations to its use (see Table 1). When compared with ultrasound, scintigraphy is significantly less sensitive for diagnosing thyroid nodules[40],[41]. In one prospective study of 426 patients with Graves’, ultrasound identified 68 (16%) thyroid nodules, whereas pertechnetate scanning only detected 9 (2.1%) nodules (p<0.001)[40]. In another study, US uncovered nodules that palpation and scintigraphy failed to identify in 12.1% of patients[41]. It is important to consider the size of the nodules as radionuclide scanning may not distinguish thyroid nodules measuring less than 1-1.5 cm[31]. However, even when considering only those nodules measuring over a centimeter, scintigraphy performs poorly, it was only able to localize 30% of cold nodules[40]. In this same cohort, 30/68 (47.7%) patients were diagnosed with thyroid cancer, only four of which were found by scintigraphy[40].

Another drawback of radionuclide scanning is the significant cost. For an ultrasound in the United States, physicians bill the patients or their insurance companies $401; actual Medicare reimbursement is $115 (personal communication with medical billing department at Ohio State University). A 123I uptake and scan will incur a cost of $1,049; Medicare reimburses $219.49. Pertechnetate scanning is slightly less expensive at $928; the reimbursement rate from Medicare is $132.79. One study in Italy performed a cost analysis comparing pertechnetate scanning and US in the initial workup of Graves’ disease and found that the total cost to obtain a diagnosis by US for all patients in the study was €14,645.34 compared to €19,922.71 for scintigraphy[40]. The authors recommend US as a first step in the diagnosis of all hyperthyroid patients, and that scintigraphy should be limited only to uncommon cases where the diagnosis cannot be made with clinical clues and laboratory data[40].

Because it has traditionally played such a large role in the diagnosis of hyperthyroidism, nuclear scanning is readily available in most areas. Routine use of ultrasound for the evaluation of thyrotoxicosis, on the other hand, is significantly limited by a lack of familiarity with its applicability in this condition. More education is needed to acquaint providers with the role of US in the diagnosis and management of thyrotoxicosis.

Increasingly it is being recognized that US has a significant role in the diagnosis of Graves’ disease; it is a convenient, inexpensive, and noninvasive technique to determine the underlying pathophysiology of thyrotoxicosis[42]. Furthermore, US and scintigraphy are equally accurate at diagnosing Graves’ disease; in one large study, each were able to make the correct diagnosis in 95.2% and 97.4% of patients, respectively (p=0.763)[40]. Ultrasonography offers the additional advantage of making the diagnosis without exposing the patient to ionizing radiation. One recent study found that thyroid scintigraphy and uptake studies did not influence the diagnosis or treatment outcomes in most cases of hyperthyroidism[43]. The authors recommend against its routine use, except when clinical features, laboratory assays, and ultrasound exams are not diagnostic, to reduce unnecessary costs and exposure to radioisotopes[43].

Utility of ultrasonography for post-treatment follow up in Graves’ disease

Up to 60% of patients will achieve a remission of their Graves’ disease with medical therapy alone, but the course of the disease is heterogeneous and difficult to predict[44],[45]. A clinical tool that could distinguish which patients will go into remission would be extremely useful during the early phases of the disease to help the patient and clinician decide which therapy to choose. Patients who are highly likely to go into remission may elect medical management initially so that lifelong therapy with thyroid hormone supplementation could be avoided, as would be expected after radioiodine treatment or surgery. Thyroid appearance on ultrasound has been used as a tool to predict which patients with Graves’ disease will have a remission. Investigators have found that those patients requiring active antithyroid drug treatment had significantly lower thyroid echogenicity compared with those whose disease was inactive (p<0.001)[46],[47]. Two prospective trials have confirmed that echogenicity after thionamide treatment is predictive of remission[48],[49]. One group found that a normal thyroid echogenicity score at withdrawal of methimazole had a higher specificity (95%) than TRAb values (86%) for prediction of remission two years after initiation of therapy[49]. Likewise, another study revealed a relationship between thyroid echogenicity and the clinical course and immunologic parameters in Graves’ disease[48]. Patients who had a hypoechoic, micronodular appearance on US were more likely to have a high TRAb titer and were at a higher risk of recurrence of hyperthyroidism after treatment withdrawal[48].

Vascularity has also been investigated to establish its value in predicting the relapse of hyperthyroidism in Graves’ patients after withdrawal of antithyroid drugs[50],[51],[52]. One group found that patients who were able to be withdrawn from thionamides had significantly lower thyroid blood flow and vessel numbers compared to the untreated and the active treatment groups[51]. Furthermore, these vascular indices were significantly higher in those who relapsed, compared to those in a stable remission[51]. This relationship retained its predictive value on multivariate analysis. Similarly, another group found significantly increased blood flow parameters (including volume flow, systolic maximum velocity, end-diastolic velocity, and resistive index) in patients with active hyperthyroidism before treatment and in euthyroid patients who had a relapse after withdrawal of antithyroid treatment versus normal controls[53]. On the other hand, those patients who remained in stable remission had no significant difference in the blood flow parameters compared to normal controls[53]. Looking only at patients about to be withdrawn from thionamide therapy, one group found that higher blood flow at the inferior thyroid artery was an early predictor for Graves’ disease relapse[52]. Based on these studies, it appears that thyroid blood flow changes may be related to the course of Graves’ disease.

The use of ultrasonography in pregnancy

Nuclear imaging is contraindicated during pregnancy because of its toxicity to the developing fetal thyroid. Ultrasound therefore is a useful tool to distinguish between various forms of hyperthyroidism during pregnancy. One group showed that thyroid volume is significantly higher in patients with Graves’ disease compared with gestational thyrotoxicosis or destructive thyroiditis (18.9 ± 1.5cm3 vs. 12.1 ± 2.4cm3, p<0.05)[54]. Thyroid vascularity and inferior thyroidal artery flow velocity were also greater in the Graves’ disease group compared with the non-Graves’ patients (p<0.05)[54].

Although Graves’ disease during pregnancy is rare, affecting only 0.2% of pregnancies, recognition of the effects of maternal TSH receptor antibodies on the developing fetus is critical[55]. Maternal TSH receptor antibodies freely cross the placenta and can stimulate the fetal thyroid gland in the later stages of the pregnancy, causing hyperthyroidism[56]. Conversely, antithyroid drugs also cross the placenta and can induce fetal hypothyroidism[55]. Ultrasound is a noninvasive test that can detect fetal thyroid disorders; in conjunction with cord blood tests, one study found that detection of a fetal goiter on US has a sensitivity of 92% and a specificity of 100% for identifying clinically relevant fetal thyroid dysfunction[55]. A second study utilized serial in utero US alone to measure fetal size in mothers with Graves’ disease to see if they could avoid the use of invasive blood sampling[57]. When thyroid size was above the 95th percentile for gestational age, maternal dose of thionamide was reduced. The three fetuses whose thyroid volume declined to the normal range were born euthyroid. In the two fetuses whose thyroid size was unaffected by reduction in dosage, both were thyrotoxic at birth. The authors suggest that US is an effective method to monitor maternal antithyroid drug dose, preventing intrauterine hypothyroidism. If the goiter is not reduced in size by dose adjustment of the thionamide, they suggest that transplacental passage of thyroid-stimulating antibodies may be causing thyrotoxicosis in the fetus. Further, they recommend consideration of fetal thyroid status by cord blood sampling to determine if the fetus is thyrotoxic[57]. Treatment consists of administering methimazole to the mother and reassessing fetal tachycardia and goiter size[58]. A recent study confirmed that fetal thyroid goiter can be detected by US and that a reduction in dose of PTU prevented development of neonatal hypothyroidism[59]. It is now recommended that fetal US should be performed to look for evidence of fetal thyroid dysfunction in women with an elevated TRAb or in those treated with antithyroid drugs[60].

Summary

Ultrasound has myriad uses in the evaluation of patients with hyperthyroidism. It is a sensitive and specific test for diagnosing various causes of hyperthyroidism, particularly during pregnancy. In experienced hands, US can help predict relapse or remission of Graves’ disease after medical therapy, aiding the clinician in determining the best form of therapy. Finally, it can help predict fetal thyroid dysfunction without increasing the risk of cordocentesis-related complications. We therefore recommend its use in the initial workup of patients with thyrotoxicosis.

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