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Painful Hashimoto’s Thyroiditis as an Indication for Thyroidectomy: Clinical Characteristics and Outcome in Seven Patients

Thyroid Study Unit, University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Leslie J. DeGroot, Thyroid Study Unit, Endocrinology Section, Department of Medicine, MC 3090, University of Chicago, Chicago, Illinois 60637. E-mail: ldegroot{at}medicine.bsd.uchicago.edu.

	Abstract

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Patients with chronic lymphocytic thyroiditis, or Hashimoto’s thyroiditis (HT), usually present with goiter, hypothyroidism, or both. Thyroid pain and tenderness are rare and suggest an alternative diagnosis of subacute granulomatous thyroiditis or other forms of thyroiditis. We report seven patients with painful HT who had temporary or no relief from L-thyroxine replacement or steroid treatment and required surgical intervention for unremitting pain. Antithyroid antibodies were elevated in all except one patient, in whom fine-needle aspiration and surgical pathology were diagnostic of HT. All patients underwent either a subtotal or near-total thyroidectomy. Pathology showed lymphocytic thyroiditis in all specimens, with varying degrees of fibrosis. Giant cells and granulomas characteristic of subacute thyroiditis were not seen. After surgery, four patients obtained total and permanent relief of pain after subtotal (two patients) or near total (two patients) thyroidectomy, whereas one patient had minimal residual discomfort. One patient had relapse of pain, despite adjunct radioiodine ablation. In this patient with documented total thyroid ablation but persistent pain, the overall clinical picture suggested a strong psychological element in her medical problem. In conclusion, thyroidectomy is an uncommon but necessary therapy for patients with painful HT not responding to medical therapy.

	Introduction

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PATIENTS WITH CHRONIC lymphocytic thyroiditis, or Hashimoto’s thyroiditis (HT), usually present with goiter, hypothyroidism, or both. Although a feeling of tightness in the neck is common, thyroid pain and tenderness are rare and suggest an alternative diagnosis of subacute granulomatous thyroiditis (SAT), other forms of thyroiditis, or even malignancy, the latter especially if associated with rapid or asymmetric growth of goiter or cervical lymphadenopathy. Patients with SAT may respond dramatically to steroids, whereas those with painful HT may have only temporary or no benefit at all. Some patients with painful HT respond to L-thyroxine and aspirin, whereas others may require surgical intervention for unremitting pain (1). We report the cases of seven patients who presented with painful HT who failed medical therapy, and their surgical outcome.

	Materials and Methods

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Between January 1993 and February 2000, seven patients who had tender thyroid secondary to HT were seen at our institution. All patients underwent thyroidectomy. Their charts were reviewed, and patients were contacted and asked to recall and grade their severity of pain out of a maximum score of 10. All patients were female, with ages ranging from 22–48 yr (Table 1). Antimicrosomal antibodies were elevated in five of seven patients, at a 1280 or above titer in four of five patients. In one patient with negative antibodies, surgical pathology was diagnostic of HT. Four patients (patients 2, 4, 5, and 7) had fine-needle aspiration (FNA) cytology results compatible with a diagnosis of HT. Patient 3 had an inconclusive FNA result. In two of these patients (patients 5 and 7), occasional giant cells were seen on FNA, cytologic findings reminiscent of subacute thyroiditis. Pathology showed lymphocytic thyroiditis in all specimens, with varying degrees of fibrosis. Giant cells and granulomas characteristic of subacute thyroiditis were not seen in any of the surgical pathology specimens.

	Results

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Patient 1 was given 112 µg L-thyroxine daily for 2 months, but her goiter pain persisted, and she developed iatrogenic thyrotoxicosis [free T₄ index (FTI), 16.7; TSH, 0.03 mU/liter). She became transiently hypothyroid (FTI, 4.8–7.5; maximum TSH, 24 mU/liter) when subsequently overtreated with methimazole, but this was discontinued at 9 months. During this time, her goiter size had remained stable at about 25 g. Subsequently, she received prednisone 30 mg/d, tapered over 10 wk without relief of pain. A near-total thyroidectomy was performed, which gave her total and permanent relief.

Patient 2 was diagnosed with HT at age 23 yr, with a 50-g multinodular goiter associated with mild hypothyroidism (FTI, 6.2; TSH, 10.3 mU/liter). She had a history of active chronic interstitial pneumonitis/bronchiolitis on high-dose prednisone (40 mg) over several months, as well as a past history of recurrent spontaneous miscarriages associated with positive anticardiolipin antibody. At age 26 yr, she first presented with severe painful thyroiditis while on 175 µg L-thyroxine daily, but neither this nor steroids given for her pulmonary disease had improved her thyroid pain. A further tapering course of prednisone was administered without relieving her pain. One month later, she underwent near-total thyroidectomy, with total relief of pain. Two months after surgery, she received 30 mCi ¹³¹I ablative therapy. Thyroid ablation was confirmed 1 yr later by a negative diagnostic whole body scan and undetectable serum thyroglobulin (TSH, 111 mU/liter). However, at that time, she reported that her neck pain and dysphagia had recurred. The reason for her recurrent symptoms is unknown, because she was subsequently lost to follow-up.

Patient 3 complained of severe thyroid pain and tenderness over 3 yr, experiencing three to four bouts in a year lasting about 1 wk and controlled with tapering courses of oral prednisone. However, her most recent bout had lasted 3 months, only partially relieved by 10–30 mg prednisone daily, and she was referred to us for ablative treatment. She underwent near-total thyroidectomy 1 month later with permanent relief of pain.

Patient 4 presented with a clinical picture typical of subacute thyroiditis. She was treated with 30 mg/d prednisone, and her thyroid swelling and tenderness, fatigue, and weakness rapidly resolved. After 1 month on high-dose steroids, her prednisone was tapered by 5 mg every 5 d. Thyroid pain and swelling recurred when the dose was reduced to 15 mg daily, but resolved on increasing the dose back to 30 mg/d. Her prednisone was finally tapered off after 3 months. Over the next 3 months, she experienced intermittent flares of neck pain, swelling, and fatigue lasting 1–2 wk. Thyroid function tests remained normal. Seven months after her initial presentation, she complained of relapse of severe pain in the thyroid area unresponsive to ketorolac [a nonsteroidal antiinflammatory drug (NSAID)] but responding to prednisone 30 mg/d. Sonography revealed the thyroid to be normal in size and echotexture. Patient 4 was started on 0.05–0.1 mg L-thyroxine daily (FTI, 8.4–13.1; TSH, 1.1–0.04 mU/liter), while her steroids were tapered off over the next 3 months. At a dose of prednisone 5 mg daily, she complained of persistent neck pain, and fine-needle aspiration cytology at that time revealed florid lymphocytic thyroiditis. Subsequently, she was also diagnosed to have primary hyperparathyroidism complicated by a right pelviureteric stone and osteoporosis. Hence, bilateral subtotal thyroidectomy and excision of a 0.8-cm right lower parathyroid adenoma were performed 6 months later, with permanent relief of her neck pain.

Patient 5 was found to be mildly hyperthyroid [total T₃, 432 ng/dl (normal range, 90–185 ng/dl); FTI, 7.2; TSH, undetectable] 5 months after diagnosis of HT. Ten months later, she complained of a painful diffuse goiter for the first time, with odynophagia and was found to be hypothyroid (FTI, 3.6; TSH, 17.6 mU/liter). Her pain and tenderness markedly improved after she was started on 125 µg L-thyroxine daily. She then became pregnant, when she noted that her goiter pain and swelling markedly improved. Her goiter began to enlarge after pregnancy, and over the next 5 yr, she complained of numerous episodes of neck pain and tenderness despite adequate T₄ replacement. She was unable to tolerate naprosyn. Because she had a large intermittently painful goiter that did not regress with T₄ therapy, she agreed to undergo surgical resection. Her thyroid gland was found to be densely adherent to surrounding tissue. Subsequent to surgery, her neck pain resolved completely.

Patient 6 presented with pain localized only to the right thyroid lobe, although she had a diffuse goiter. On thyroid ultrasound, both lobes were enlarged, were heterogeneously echogenic, and showed numerous small relatively hypoechogenic nodules. Neither aspirin nor NSAIDs provided relief of her pain. Four months later, at surgery, her thyroid appeared diffusely enlarged, hyperemic, and adherent to surrounding soft tissue. A right total lobectomy and left subtotal lobectomy was performed. Postoperatively, she reported minimal residual discomfort and has not returned for follow-up.

Patient 7 complained of worsening constant pain over her thyroid gland 1 yr after presenting with a diffuse goiter at age 39 yr associated with mild hypothyroidism, treated with 100 µg L-thyroxine daily replacement. She was given several 1- to 2-wk courses of prednisone with some improvement. An ultrasound-guided FNA showed both thyroid lobes to be heterogeneous and hypoechoic in echotexture, cytology revealing scant but normal follicle cells on a background of increased number of lymphocytes. At age 41 yr, she had a particularly severe relapse. She had finished a course of steroids 1 month earlier and was currently taking an NSAID. Antithyroid antibody assay was repeated and again found to be negative. FNA biopsy was repeated and showed lymphocytes as well as some giant cells. Her T₄ dose was increased to 200 µg daily, which suppressed serum TSH to 0.05–0.1 mU/liter but did not improve her pain. At subtotal thyroidectomy, her thyroid was noted to be very hyperemic, firm, and attached very firmly to the trachea and surrounding tissues. Two thirds of her right lobe, the isthmus, and half of the left lobe were resected. Initially, most of the neck pain disappeared, especially on the right, but within a few weeks her pain recurred, particularly on the left. Postoperative sonography demonstrated a 0.8-g thyroid remnant, which was ablated 6 months postoperatively with 156 mCi of ¹³¹I. Shortly after radioiodine treatment, her chronic neck pain resolved completely. However, 2 months later, her neck pain recurred, similar in nature to her previous pain. Inflammatory markers, including white cell count, had always been negative or normal. Although follow-up thyroid ultrasound and ¹²³I scan demonstrated no thyroid tissue, and thyroid bed uptake was less than 0.2%, the patient continued to have persistent pain, for which combination narcotic, NSAID, and anticonvulsant analgesics were given.

All 7 patients received thyroid hormone therapy at some time during their course of tender thyroiditis (Table 2). In patients 2 and 7, who were already on T₄ for HT with hypothyroidism, increasing the dose of T₄ did not seem to improve or prevent painful episodes. In patients 1 and 4 with euthyroid HT, administering thyroid hormone provided no relief or partial relief of pain and resulted in iatrogenic thyrotoxicosis. Patient 5 reported marked pain improvement to T₄ therapy when she was hypothyroid, but she had multiple relapses after 1 yr despite continued adequate T₄ replacement. Of the five patients treated with steroids for thyroid pain, two reported no response (patients 1 and 2), whereas in one patient, thyroid pain either worsened when steroids were tapered (patient 4), or relapsed after steroids were discontinued (patients 3, 4, and 7). Of four patients given either aspirin or nonsteroidal agents, two patients reported no response, one patient had partial pain relief, and one patient was intolerant of NSAIDS.

	Discussion

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HT is common, usually presents as a firm, diffuse, painless goiter, but rarely causes severe persistent neck pain (2, 3, 4, 5). One should consider other diagnostic possibilities, including gastroesophageal reflux disease with reflux, esophageal spasm, dental problems with referred pain, angina with referred pain, several posterior pharyngeal and otic problems and globus hystericus, etc., all of which are more common causes of neck pain than painful HT, so as to avoid subjecting the patient to thyroid surgery for the wrong diagnosis.

However, when there clearly is pain in a goiter or thyroid tenderness, painful thyroiditis should be considered. It is important to differentiate HT from SAT, the commonest cause of painful thyroiditis, because the clinical course and treatment options and response may be different. Although patients with HT, especially those with high-titer antimicrosomal [anti-thyroid peroxidase (TPO)] antibodies, are at risk for developing permanent hypothyroidism, only 5% of those with SAT eventually do so (6). Patients with painful HT may run an intractable course. The pain may not respond to corticosteroids, or it may be difficult to withdraw corticosteroids from patients who do respond without precipitating a relapse (1). In contrast, patients with SAT usually show a dramatic and sustained remission to steroids. Indeed, if corticosteroids are used and pain and swelling do not resolve within 72 h, SAT is unlikely to be the etiology, although a positive response does not preclude other differential diagnoses.

Shigemasa et al. (7) reported eight patients (seven females and one male; age range, 34–58 yr) with HT confirmed by needle biopsy. Their initial clinical presentation resembled that of SAT. All patients presented with fever and painful tender goiter for less than 1 month, with markedly elevated erythrocyte sedimentation rate (ESR). One patient had a previous similar episode. Six patients had transient thyrotoxicosis associated with a markedly depressed radioactive iodine uptake (RAIU; 0.8–3%). Two patients had past treated Graves’ disease, one had known HT, one had been on L-thyroxine for primary hypothyroidism, and seven patients had prior awareness of goiter. In contrast, none of 11 patients with SAT had prior goiter or autoimmune thyroid disease. In both groups of patients, ESR and C-reactive protein (CRP) were elevated to the same extent. Thyroid ultrasound revealed very low amplitude echoes in both groups. Only one patient received oral prednisolone and had recurrent exacerbations when steroid therapy was tapered. Six patients developed persistent goitrous (4) or atrophic (2) hypothyroidism when last examined 2–9 yr later, whereas none of the patients with SAT became permanently hypothyroid or had persistent goiter.

Zimmerman et al. (1) reported eight patients (seven female and one male; age range, 38–52 yr) with HT confirmed by needle biopsy. Seven patients presented with neck pain and a diffuse tender goiter (gland weight, 25–50 g). One patient presented with unilateral enlargement and tenderness, which progressed to a diffuse tender goiter over several days. Their clinical characteristics were different from Shigemasa’s series (7). Painful episodes lasted from 10 d to 9 months, although one patient had three episodes over 5 yr. The ESR was normal in seven patients, and none of the patients were hyperthyroid. The 24-h radioiodine uptake measured in seven patients was normal in five, increased in one, and low in one patient. The low uptake was attributed to thyroid hormone treatment.

All seven of our patients had the diagnosis of HT confirmed on surgical pathology, and none showed giant cells or granulomas characteristic of SAT. All patients were female, and the age range was slightly younger, from 22–48 yr. Duration of symptoms ranged from 1 month to 3 yr. Similar to Shigemasa’s series (7), the majority (six of seven) of our patients had prior goiter, the duration of goiter ranging from 9 months to 9 yr. Two (patients 2 and 3) were known to have HT on T₄ replacement before first onset of pain, whereas one (patient 5) had known HT associated with mild hypothyroidism at first onset of pain. One (patient 4) without prior goiter presented initially like SAT with fever, an acute painful goiter, and a markedly depressed RAIU after an upper respiratory tract infection (URTI) prodrome. However, her thyroid function was normal, ESR was not raised, steroid taper was difficult, and she continued to have painful relapses despite her shrinking goiter. At onset of pain, all patients were euthyroid, except one (patient 5) who was hypothyroid. Of note, one of our patients presented as a seronegative chronic painful HT (patient 7).

The pain in HT may involve the whole gland, one lobe, or part of one lobe, similar to SAT. In patients with unilateral tenderness, the pain may remain confined to one lobe although the pathology is diffuse, as in one of our patients, or may sequentially involve the contralateral lobe after a few days (1), or after many months (5). The reason for thyroid tenderness in patients with HT remains unknown. Thyroid capsule distension from rapid goiter growth may be contributory in some, but clearly not all patients. Ishihara et al. (8) described an edematous inflammation with loosely arranged collagen fibers that seemed unique to tender areas and that rapidly reversed after local steroid injection, but Zimmerman et al. (1) found no difference in pathology from the more common nonpainful HT.

Patients with painful HT may be hypothyroid, euthyroid, or even thyrotoxic, and have normal, reduced, or increased RAIU, as with nonpainful HT (9). Patients who are hypothyroid may have increased RAIU from raised serum TSH, provided there are enough functional thyrocytes, whereas patients who present like SAT may have low RAIU because TSH is suppressed or because of intense widespread thyroiditis. The overlapping and variable clinical and laboratory findings in this and other series of patients with apparent autoimmune painful thyroiditis, compared with nonautoimmune painful thyroiditis, demonstrate our current lack of a precise understanding and classification of thyroiditis. The clinical picture may reflect an interaction between the thyroid gland and a variety of ill-understood cellular immune determinants as well as humoral factors that are active locally in the thyroid gland. One or more of these factors may be associated with pain and the other features that lead to the wide spectrum of clinical characteristics. Doniach et al. (9) in an early study had remarked that "complete invasion of the thyroid may take 30 yr, or may sweep through the gland in a few months." It is interesting to note that in one of our patients (patient 5), goiter pain and swelling improved at the time of pregnancy and relapsed after pregnancy, reflecting the effect of immune modulation on the clinical course of disease.

The clinical features that help to differentiate painful HT from classical SAT are listed in Table 3. Preexisting goiter or autoimmune thyroid disease and markedly elevated anti-TPO antibodies are helpful clues to diagnosing HT. However, anti-TPO antibodies are absent in 5% of patients with HT (10), many patients with SAT have moderate increases in antithyroid antibodies, and both SAT and HT could occur simultaneously by coincidence (1, 7). Thus, biopsy showing diffuse lymphocytic infiltration with differing degrees of fibrosis and follicular cell destruction, but without giant cells and granulomas characteristic of SAT, remains the diagnostic gold standard.

Total pain relief was achieved in four of seven patients after thyroidectomy. Conceptually, removing as much thyroid tissue as is safely possible may offer the greatest likelihood of enduring and complete pain relief, and we advocate near-total or total thyroidectomy by an experienced thyroid surgeon. Because the thyroid gland may be small or fibrosed, the risk of surgery is increased, and this type of patient should have thyroidectomy performed by a skilled, experienced, high-volume thyroid surgeon to avoid complications.

In patients with persistent pain after surgery that can be attributed to remnant thyroiditis, radioiodine ablation may be used. The efficacy of radioiodine depends on adequate uptake in relation to thyroid gland size. Based on this study, radioiodine ablation does not appear to be useful (patients 2 and 7). However, this is a small series of patients, and the two patients had either negative stimulated thyroglobulin levels or negative postablation scan, suggesting that perhaps their recurrent pain may be due to other causes. Hence, in patients who require definitive treatment for intractable thyroid pain, near-total thyroidectomy performed by an experienced surgeon, followed by ¹³¹I ablation if pain continues, may still be the best approach.

	Footnotes

 
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FNA, fine-needle aspiration; FTI, free T₄ index; HT, Hashimoto’s thyroiditis; NSAID, nonsteroidal antiinflammatory drug; RAIU, radioactive iodine uptake; SAT, subacute thyroiditis; TPO, thyroid peroxidase; URTI, upper respiratory tract infection.

Received September 24, 2002.

Accepted February 28, 2003.

	References

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1. Zimmerman R, Brennan M, McConahey W, Goellner J, Gharib H 1986 Hashimoto’s thyroiditis: an uncommon cause of painful thyroid unresponsive to corticosteroid therapy. Ann Intern Med 104:355–357
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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kon, Y. C. Articles by DeGroot, L. J. Search for Related Content PubMed PubMed Citation Articles by Kon, Y. C. Articles by DeGroot, L. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LEVOTHYROXINE Medline Plus Health Information Palliative Care