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Original Article |
Departments of Endocrinology (H.X., B.Y.), Radiology (W.Z.), Thyroid Surgery (S.W., G.C.), and Pathology (M.Z.) of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China, 510080; and Department of Biochemistry and Molecular Biology (N.C.W.W.), Libin Gene Therapy Unit, Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada, T2N 4N1
Address all correspondence and requests for reprints to: Dr. Haipeng Xiao, Division of Endocrinology, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, Guangdong, China 510080. E-mail: . xhpcy{at}gzsums.edu.cn
Abstract
Despite the availability of effective treatments for Graves’ disease, there are patients who are unable to tolerate, or choose not to accept, current therapies (oral medication, radioactive iodine, or surgery). In this study, we have examined the use of thyroid arterial embolization as an option for patients who suffer from Graves’ disease and who fit into one of the preceding patient groups. Selective arteriography, followed by embolization of thyroid arteries, was performed using Seldinger’s technique in 22 patients with Graves’ disease. Six of the patients received both arterial embolization and surgery at 2–3 wk after embolization. No serious complications were noted in any patient. In those who were treated with only interventional embolization, 14 of 22 (63.6%) became euthyroid and remained in this state for the duration of the study. The remaining 2 patients required a maintenance dose of antithyroid drug therapy (tapazole, 5–10 mg/d; or propylthiouracil, 50–100 mg/d). Patients were followed for a median time of 27 months (range, 6–50). At the end of the follow-up period, all 22 patients were euthyroid, the size of thyroid gland had decreased by one third to one half its original volume, but 2 patients continued to require antithyroid drugs. Histologic analysis of thyroid tissue from 6 patients who had embolization followed by surgery showed that embolization blocked both the superior and inferior thyroid arteries plus most of their branches. Evidence of chemical inflammation, necrosis, and fibrosis were observed in embolized thyroid tissue. The average diameter of capillary network within the body of the thyroid adjacent to superior and inferior artery was 0.12–0.25 mm, with the smallest ones ranging from 0.04–0.11 mm. The diameter of the capillaries in the isthmus ranged from 0.13–0.15 mm. The average diameters of the superior and inferior arteries were 2–5.5 and 3–3.75 mm, respectively, measured using radiographs from angiography. Based on the measured diameters of arteries, the appropriate size of embolizing granules can be selected, and complete embolization of the majority of the thyroid glands was achieved with a high frequency of therapeutic success. Histological examination of the thyroid tissue and clinical follow-up after embolization indicate that this procedure is an effective, minimally invasive, and safe method for the treatment of Graves’ disease patients who cannot, or choose not to, accept current therapies.
ALTHOUGH EFFECTIVE TREATMENTS exist for a host of diseases that affect the thyroid gland, there remain difficult cases that may not be amenable to current therapeutic options. In this report, we describe a novel treatment for Graves’ disease, a common cause of spontaneous hyperthyroidism (1). Considerable progress has been made in understanding the pathogenesis of this disease (2, 3, 4), but we await the development of specific therapies that abrogate the underlying cause (5, 6). Current therapies for Graves’ disease include: antithyroid drugs, radioiodine, or surgery (7, 8). These three therapies result in the inhibition of thyroid hormone synthesis, destruction, or removal of thyroid tissue, respectively. All three treatments are very effective in alleviating hyperthyroidism. Each patient is offered the option of receiving any one of these treatments. However, there are some patients who choose not to receive any one of the options, for various reasons, and others in which the available treatments may be contraindicated.
For example, some patients (especially the elderly) cannot tolerate the thionamides, they are poor surgical candidates, and cannot receive radioactive iodine therapy, either because the disease process does not respond to this therapy or because a more immediate therapeutic effect is desired (9, 10). This scenario is present in elderly patients who have cardiac arrhythmias complicated with amiodarone-induced thyroiditis and thus pose a special therapeutic challenge (11, 12, 13, 14, 15). Other patients who may also be classified as challenging include young women of the child-bearing age who are allergic to antithyroid medications (16). These patients may refuse radioactive iodine therapy for fear of effects on pregnancy. Additionally, this same group also does not accept surgical treatment because of concern about the cosmetic consequences. A third group of patients who may not accept current therapies are those with large goiters who have severe hyperthyroidism, which is difficult to control with oral medications alone. In these patients, surgery is often technically difficult because of increased vascularity in the tissue (17, 18). The above list of challenging patients is, by no means, complete; but it underscores the need for additional therapeutic options to treat hyperthyroidism.
Recent advances in the use of interventional radiology prompted us to examine the use of arterial embolization as a possible alternative for the treatment of Graves’ disease and other thyroid conditions requiring thyroid ablation (19, 20, 21, 22). The intent of arterial embolization is to decrease the amount of thyroid tissue and thus alleviate or attenuate the consequences of hyperthyroidism. Although there is one previous study describing the use of arterial embolization as a potential treatment for Graves’ disease (23), the clinical experience in the use of this technique is minimal. Furthermore, the underlying histologic changes after embolization have not been examined. In an attempt to further examine the clinical feasibility of this approach, we summarize below the clinical and histological changes associated with arterial embolization of thyroid gland in selected patients with Graves’ disease.
Subjects and Methods
Subjects
A total of 22 patients with Graves’ disease, who could not or did not choose to have conventional therapy, were enrolled in the study from January 1997 to December, 2000 (Table 1
). Six of the subjects were men, and 16 were women (ages ranging from 20–55 yr). The study protocol was approved by the internal review board and ethics committees of our hospital. The patients were informed of the procedure, its risk, and potential side effects and then signed a consent form before undergoing arterial embolization. The presence of a large (4–6 times normal) goiter, drug-induced granulocytopenia, or agranulocytosis; recurrence of the disease, with poor response to conventional therapies; and refusal to take current therapies were the main reasons for these patients being offered the option of arterial embolization therapy. All patients were free of infiltrative exophthalmos and did not have accompanying hemorrhagic diseases. Laboratory examination showed a normal complete blood count, urinalysis, and serum electrolytes, as well as renal and liver function studies.
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The major blood supply to the thyroid gland comes from two pairs of vessels: the left and right superior thyroid arteries that arise from the external carotic artery; and the left and right inferior thyroid arteries originating from the subclavian artery. Collateral vessels from the trachea and esophagus might augment thyroid blood supply. The superior thyroid artery divides into an anterior and a posterior branch. The anterior branch supplies principally the anterior surface and sends a branch across the upper border of isthmus to form anastomoses with the artery from the opposite side. The posterior branch descends along the posterior border of the gland, supplying the medial and lateral surfaces of the thyroid, and anastomoses with the inferior artery. Not infrequently, a lateral branch supplies blood to the lateral surface of the gland. The inferior thyroid artery divides into a medial and a lateral branch, these vessels anastomose freely with ones from the superior thyroid artery as well as those from the trachea and esophagus. It is common to find that blood flows between each lobe of the thyroid via branches across the isthmus. The highly vascular nature of the thyroid gland dictates the use of extra measures to ensure safety of this procedure by performing selective angiography before embolization, to be certain of catheter placement. Repetition of this step, post embolization, is important to confirm success of the procedure (24).
Selective angiography of bilateral superior and unilateral inferior arteries was performed by a qualified radiologist using the Seldinger technique (25). A typical procedure required less than 1.5 h. In brief, the patient was placed in a supine position. The inguinal pulsation point of either the left or right femoral artery was chosen as the puncture site. A small skin incision was made under local anesthesia (1% procaine, 2–3 ml). The puncture needle, along with a cannula, was inserted into the femoral artery through the incision. Next, the needle was removed while the cannula remained in the vessel lumen as an entry portal for a 5F-size angiographic catheter (Torcon NB Advantage, type: Headhunter Cerebral H1; A Cook Group Company, Bloomington, IN). The catheter was advanced from the femoral artery via the abdominal aorta and sequentially to both superior and one of the inferior thyroid arteries. Migration of the catheter was visualized through use of a digital subtraction x-ray device (model V 8000, Toshiba, Tokyo, Japan). Before embolization, contrast media (Ultravist 300; Schering AG Germany) was injected into the vessels, thus allowing us to visualize the arteries and regions of the thyroid to which they supplied blood. This angiogram helped us determine the portion of thyroid blood supply originating from the superior and the inferior arteries. The availability of this information allowed us to decide whether or not to extend embolization of both superior arteries to include one of the inferior vessels. The extension of embolization beyond the two superior arteries, to include an inferior artery, to three arteries was necessary in patients with large goiters. The occlusion of both superior arteries plus or minus one inferior vessel seemed sufficient to block the majority of the blood supply to the gland. Granules comprised of polyvinyl alcohol (PVA, Cook Company), ranging from 150–300 mm in diameter, were predicted to be sufficient to block the lumen of the vessel, because histologic analysis of thyroid tissue (removed surgically) showed that the diameter of the small arteries varied from 0.04–0.11 mm. These particles were injected slowly into the vessels. The procedure began with infusion of 150- to 200-mm particles, because this size exceeded the diameter of the smallest vessel. Particles of this size range should occlude the vessel lumen with no chance of passing through into the systemic circulation. Next, slightly larger particles, of 200–300 mm, were used to completely block the vessel, a standard technique in embolization. An added step for embolizing the superior arteries involved use of a stainless wire coin (Cook Company) of appropriate size, depending on the diameter of the lumen. Selective angiography was performed post embolization to ensure that the targeted arteries were completely occluded.
Sedation (diazepam, 5–10 mg) was given to all patients on the evening before the procedure. All patients received a ß-blocker (propranolol, 10 mg, three times a day; or metoprolol, 25–50 mg, three times a day) before the procedure and maintained on this dose of the drug, followed by a gradual decrease when patients returned to the euthyroid state. All patients were treated with the antibiotic, Cephradine (2 g, twice daily, administered iv) and prednisone (15 mg/d, for up to 7 d following embolization). The antibiotic was used prophylactically, and prednisone served to ameliorate symptoms of chemical inflammation of the thyroid gland that followed embolization.
Pathological examination and measurement of arterial diameters
Embolized thyroid tissue from six patients with large goiters, who underwent embolization followed by subtotal thyroidectomy, was carefully studied. The surgery was performed 2–3 wk after the embolization because of persistent hyperthyroidism. Multiple slides of embolized thyroid tissue from the superior pole, body, and inferior pole of the resected thyroid glands were obtained. Slices of the tissue were processed for histologic analysis, using a modified procedure, as described in the literature (26, 27). In brief, the resected thyroid tissues were fixed with 10% formalin, followed by dehydration in alcohol (80–100%), and then cleared with dimethylbenzene. This material was then infiltrated with paraffin in a thermostatic apparatus, for 2 h, and then embedded in paraffin. Multiple slices of 4 µm in thickness were sectioned with an automatic microtome (SM 2000R; Leica Corp., Nussloch, Germany). Sections were stained with hematoxylin-eosin staining. Histologic features of the thyroid tissue were assessed by a qualified pathologist, and diameters of arteries in various parts of the thyroid glands were measured using a microscope fitted with calipers (Olympus Corp., Tokyo, Japan).
Determination of the levels of free T3, free T4, and TSH
Serum levels of free T3, free T4, and TSH (Ultra, hTSH II) were measured with a microparticle enzyme immunoassay (AxSYM System; Abbott Laboratories, Diagnostics Division, Abbott Park, IL), 1 wk before and at 1, 2, 4, and 8 wk after embolization. The intraassay and interassay coefficients of variation for the three assays were 4.96 and 6.06%, 5.47 and 5.26%, and 9.41 and 7.65%, respectively.
Results
Radiographic documentation of thyroid embolization
The study group of 22 patients was comprised of 8 patients who were thyrotoxic before embolization because of intolerance of antithyroid medications that caused allergic reactions (Table 1
) and 14 patients who were euthyroid before embolization because of treatment with antithyroid medication.
Thyroid artery embolization is a procedure without established guidelines or protocols. Therefore, before performing this procedure, it was important to define the arteries to be targeted. Selective angiography of bilateral superior and unilateral inferior arteries was performed to demonstrate that these vessels supplied the majority of the blood supply to the thyroid gland (Fig. 1A). This essential information allowed us the option of embolizing 2 or 3 of these vessels. All patients received 2-vessel (meaning bilateral superior) thyroid artery embolization. In addition, 5 of 22 patients with the larger goiters in the study group also received inferior artery embolization. A repeat angiogram, performed after embolization, using PVA granules (150–300 µm in diameter) showed that the majority (more than 70%) of the blood supply to the thyroid gland was affected (Fig. 1B). Embolization of both the left and right superior thyroid arteries also blocked the capillary network that supplied the isthmus. The average diameters of superior and inferior arteries were measured and noted to range between 2–5.5 and 3–3.75 mm, respectively, in angiographic studies. The above findings demonstrate that the embolization successfully blocks patency of selected arteries, which supply blood to a majority of the thyroid gland.
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Next, we examined the size of the blood vessels affected by embolization. Access to this feature of the procedure was possible because there were six patients who received embolization before surgical removal of thyroid tissue. Microscopic analysis of this tissue showed that the average diameter of an embolized capillary arising from the superior or inferior artery varied from 0.12–0.25 mm (Fig. 2, A and B). The smallest diameter of unembolized capillaries ranged from 0.04–0.11 mm. In the isthmus, there was a slightly different range of arteries affected (0.13–0.15 mm).
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). Not surprisingly, there was infiltration of multinucleated giant cells present in the lumen of embolized arterioles (Fig. 2C). Additionally, we noted that the follicular epithelium of the thyroid changed to a flat or cuboidal shape, and volume of colloid in the lumen of the follicles decreased (Fig. 2A and D). Furthermore, the interstitium was separated by fibrous tissue, and the presence of lymphocytic infiltrates or follicles was observed (Fig. 2B). Together, these findings show that embolization blocks blood supply to selected regions of the thyroid gland, and this procedure gives rise to an associated inflammatory response. Effect of arterial embolization on thyroid hormone levels
In this study, all 22 patients with Graves’ disease underwent arterial embolization of bilateral superior thyroid arteries. Additionally, 5 of the subjects also received unilateral inferior thyroid artery embolization, chosen on the basis of the presence of a large goiter (4–6 times normal) and angiographic demonstration that one of the inferior thyroid arteries provided significant blood supply to the thyroid. To determine whether the procedure affected thyroid function, we measured the levels of free T3, free T4, and TSH in all patients, at 1 wk prior and at 1, 2, 4, and 8 wk after the embolization procedure (Fig. 3, A–C). The values obtained from these tests were divided into groups 1 and 2, based on the presence or absence of hyperthyroidism, respectively. Fourteen of the 22 patients (group 2) were euthyroid before embolization, as a result of treatment with oral antithyroid drugs. In the 8 patients (group 1) who were hyperthyroid at 1 wk before embolization, the levels of free T3 (Fig. 3A) and free T4 (Fig. 3B) were either increased or unchanged after embolization of the thyroid gland. This finding is probably attributed to release of thyroid hormones arising from thyroiditis of the embolized gland. However, both free T3 and free T4 quickly reverted to near-normal or normal levels at the 2-wk time point after the procedure. These patients remained euthyroid from wk 4 until the end of the monitoring at 8 wk after embolization.
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) were opposite to those of free T3 and free T4. Subjects with suppressed TSH levels (group 1) before embolization had a gradual increase in TSH levels after embolization, and that occurred in conjunction with the return of free T3 and free T4 to normal. In contrast, the 14 subjects who were euthyroid, with near-normal or normal (group 2) TSH levels (normal reference for TSH is 0.49–4.67 mU/liter) before embolization, were found to have transiently suppressed TSH levels at 1 wk after embolization, attributable most likely to transient release of thyroid hormones resulting from the thyroiditis. Whereas 16 patients received only embolization as the sole treatment, the remaining 6 patients required added treatment of subtotal thyroidectomy, because of a large goiter, at 2–3 wk after the embolization procedure. Although the size of the thyroid gland had decreased by one third to one half of the original volume before embolization, surgery was necessary because these 6 patients still had enlarged goiter post embolization and continued to require antithyroid medication to maintain a euthyroid state. The operative procedure in all patients was uneventful. In the 16 patients that were treated with only embolization, the period of follow-up ranged from 6–50 months. Fourteen of these patients were euthyroid both clinically and biochemically without the need for further treatment. However, the 2 remaining patients were also euthyroid but still required maintenance doses of antithyroid drug therapy (methimazole, 5–10 mg/d; or propylthiouracil, 50–100 mg/d). Hyperthyroidism persisted in these 2 patients with large goiters, despite embolization of bilateral superior and unilateral inferior thyroid arteries. Two different young female patients became pregnant, 6–9 months after embolization, and delivered healthy babies. In all cases, the size of the thyroid gland decreased significantly, by at least one third to one half of their original volume, as determined with clinical examination within 0.5–3 months after embolization. Together, these findings show that selective arterial embolization of the thyroid gland abolished blood flow to targeted areas of the thyroid. This blockage in blood flow is associated with tissue necrosis and an inflammatory process.
Untoward reactions and complications
There were no life-threatening complications associated with the embolization procedure. Nineteen out of 22 subjects had moderate fever, ranging from 37.5–38.5 C, after the procedure. Return to normal temperature occurred within 5–7 d after the onset of fever. All patients complained of moderate neck pain that was relieved with the use of a nonsteroid antiinflammatory drug (diclofenac acid, 25 mg, 3 times per day) or prednisone (5 mg, 3 times per day, for 3–7 d). Calcium was measured in all patients, at 1 wk before and 1, 2, 4, and 8 wk post embolization; only 1 patient experienced a transient episode of hypocalcemia at 1 wk after the procedure, which resolved with oral replacement. This subject had bilateral superior and unilateral thyroid artery embolization, followed by a transient episode of hypocalcemia (total serum calcium, 1.7–2.0 mM) associated with numbness of the hand but no evidence of tetani. After oral supplementation with a calcium preparation (calcium carbonate, 500 mg, twice daily), serum calcium returned to normal within 1 month, and calcium preparation was withdrawn. No progression of proptosis, hypothyroidism, or recurrence of hyperthyroidism was found in any of the patients during the 6–50 months of follow-up, with the exception of 2 cases who still required maintenance doses of antithyroid medications.
Discussion
The known limitations of existing therapies for Graves’ disease underlie our interest in investigating a potential new treatment. Emergence of interventional radiology provides the methodology that allows us to examine thyroid arterial embolization as an alternative approach to ablating thyroid tissue (19, 20, 21, 22, 23). In day-to-day clinical practice, some patients with thyroid disease cannot be controlled with available therapies. For example, there are patients who have suffered a serious allergic reaction to antithyroid agents such as granulocytopenia or agranulocytosis, requiring immediate withdrawal of the drugs (28). Another group of patients are females of the reproductive age, who cannot be controlled by antithyroid drugs alone and refuse treatment with radioactive iodine because of an unfounded, albeit prevalent, belief that it may affect their ability to conceive. All patients who fit into the above groups, and others not mentioned here, are usually offered surgical therapy (29, 30). However, some refuse or may not be acceptable surgical candidates because of uncontrolled hyperthyroidism or other underlying diseases. Therefore, an alternative approach for such patients has been examined in this communication.
The application of interventional embolization provides an alternative for the treatment of selected cases of hyperthyroidism. The application of this procedure in our patients with Graves’ disease led to a long-term euthyroid state, as long as 50 months after embolization. Although only patients with Graves’ disease were included in the present series, this procedure may also serve as an alternative method to prepare patients, before surgery, in those who have severe thyrotoxicosis, especially ones with huge goiters that need thyroidectomy (31).
The results of the angiographic studies showed that the blood supply of the thyroid gland comes from bilateral superior and bilateral inferior arteries (32). The bilateral superior thyroid arteries account for nearly 70% of the total blood supply in the majority of patients (32). There is extensive communication between superior and inferior thyroid arteries. Therefore, embolization of both superior arteries is expected to destroy 70–80% of the gland, with or without embolization of unilateral inferior thyroid arteries.
The smallest diameter of thyroid arterioles we measured was 0.04–0.11 mm. This finding suggests that PVA granules of approximately 150 µm in diameter seem to be of ideal size for use in embolizing thyroid arteries. PVA granules that are too small in diameter would pass through the arteriole directly into veins and exit the thyroid. This would affect extrathyroidal tissue or tissues, an undesirable outcome. In contrast, granules that are too large might lead to a reduction in the embolized thyroid volume and thus affect clinical efficacy of the procedure. The experience gained from our study suggests that embolization initially with PVA granules of 150 µm, followed by larger granules ranging between 200–300 µm, is predicted to achieve complete embolization. In regard to the size of stainless wire coin, it should be varied according to the diameter of superior or inferior thyroid arteries measured using angiography before embolization. The common size of stainless wire coin we used ranged from 2–5 mm in diameter.
The expense of the embolization procedure in our hospital is roughly 8000 RMB. The cost of medication or radioactive iodine ranges from 1200–3000 RMB for 1 yr and 2000 RMB for single dose, respectively. These figures show arterial embolization to be more expensive than 2.5 yr of antithyroid treatment or four doses of radioactive iodine. However, these latter costs do not include physician costs for the administration of the oral medications and the subsequent follow-up. When physician costs are added to conventional therapies, the costs of antithyroid medication and radioactive iodine will likely be higher. However, the inability of some patients to tolerate (or their choice of treatments other than) the current therapies makes the use of arterial embolization an attractive alternative.
There is one previously published study on embolization of the diffuse toxic thyroid, in the non-English literature, that targets both superior thyroid arteries (23). However, the current report improves, extends, and confirms results of the preceding study. Our findings suggest that the number of thyroid arteries to be embolized should be individualized and based on the size of the thyroid and the amount of tissue supplied by each artery. This information will come from the preembolization angiogram. In five of the patients who had moderate-to-large goiters, arteriography before embolization showed that one inferior thyroid artery was responsible for substantial perfusion of the gland (Fig. 1A, lower part). Therefore, these patients received both bilateral superior thyroid arteries and unilateral inferior thyroid artery embolization. The posttreatment study documented the success of the procedure and that a large volume of the goiter lost its blood supply (Fig. 1B, lower part). Of these five subjects, only one had transient hypoparathyroidism. The significance of this observation is that we do not recommend the embolization of all thyroid arteries, i.e. both bilateral superior and inferior thyroid arteries, because of the risk of hypoparathyroidism.
Based on the results reported here, we suggest that the treatment of Graves’ disease with arterial embolization may be offered as an option for patients who will not or cannot accept existing therapies for Graves’ disease. The outcome of embolization resembles that of subtotal thyroidectomy. Embolization of bilateral superior thyroid arteries, with or without unilateral embolization of unilateral inferior thyroid artery, has an outcome similar to that of surgical subtotal thyroidectomy. The majority of patients achieved long-term remission. Embolization of a majority of the thyroid gland is associated with good therapeutic effect. This outcome can be achieved by selecting an appropriate size of embolizing granules based on the diameters of thyroid arteries identified on histology of thyroid tissue. The findings summarized here support this technique as a new, effective, minimally invasive, and safe method for the treatment of Graves’ disease. For patients being considered for this procedure, the findings of our study lead to the following recommended protocol: 1) Use a pretreatment angiogram to establish whether both superior thyroid arteries provide the majority of the blood supply to the gland. If so, then targeting these two vessels is sufficient. 2) If the thyroid gland is larger than four times normal size, consider the addition of unilateral embolization. 3) Use PVA particles of 150 µm for initial embolization, followed by larger particles of 200–300 µm. The use of wire coins of 2–5 mm is dependent on the vessel diameter assessed on the angiogram. 4) Perform a posttreatment angiogram to ensure blockage of the desired vessels and success of embolization. 5) Use antiinflammatory medication to control possible pain or fever and, if necessary, add prednisone. 6) Monitor thyroid functions before and at weekly intervals for 4–6 wk after the procedure. 7) If hyperthyroidism persists, consider undertaking partial thyroidectomy within 4 wk of embolization.
Whether this technique will be used for the treatment of other thyroid diseases that are not amenable to existing therapies remains a challenge for the future. For wider clinical application of interventional embolization of thyroid tissue, it is clear that more patients will need to be studied and possibly at multiple institutions.
Acknowledgments
We extend our thanks to Dr. Kent Kuang, of the People’s Republic Hospital of Guangdong, for his pivotal contribution to the presentation of the data.
Footnotes
Abbreviation: PVA, Polyvinyl alcohol.
Received January 21, 2002.
Accepted April 24, 2002.
References
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 G Birrell and T Cheetham Juvenile thyrotoxicosis; can we do better? Arch. Dis. Child., August 1, 2004; 89(8): 745 - 750. [Abstract] [Full Text] [PDF]
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