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@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

Top Abstract Introduction Materials and Methods Results Discussion References

 

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[Medline]
2. Leung A, Hedge K 1988 Hashimoto’s thyroiditis simulating de Quervain’s thyroiditis. J Adolescent Health Care 9:434–435[Medline]
3. Leung A, Hedge K 1989 Autoimmune thyroiditis presenting as painful thyroiditis. Eur J Pediatr 149:146
4. Ng TF, Jefferys D 1979 Subacute autoimmune thyroiditis simulating de Quervain’s thyroiditis. Lancet I:622
5. Sulimani R 1997 Lymphocytic thyroiditis presenting as a unilateral painful goiter. East Afr Med J 74:458–459[Medline]
6. Lio S, Pontecorvi A, Caruso M, Monaco F, D’Armiento M 1984 Transitory and permanent hypothyroidism in the course of subacute thyroiditis (de Quervain). Acta Endocrinol (Copenh) 106:67–70[Medline]
7. Shigemasa C, Ueta Y, Mitani Y, Taniguchi S, Urabe K, Tanaka T, Yoshida A, Mashiba H 1990 Chronic thyroiditis with painful tender thyroid enlargement and transient thyroxicosis. J Clin Endocrinol Metab 70:385–390[Abstract]
8. Ishihara T, Mori T, Waseda N, Ikekubo K, Akamizu T, Imura H 1986 Pathological characteristics of acute exacerbation of Hashimoto’s thyroiditis-serial changes in a patient with repeated episodes. Endocrinol Jpn 33:701–712[Medline]
9. Doniach D, Hudson R, Roitt I 1960 Human auto-immune thyroiditis: clinical studies. BMJ 1:365–373
10. Dayan C, Daniels G 1996 Chronic autoimmune thyroiditis. New Engl J Med 335:99–107[Free Full Text]

JOHN SLATOSKY, D.O., BENJAMIN SHIPTON, D.O., and HANEY WAHBA, M.D. Mercy Hospital, Pittsburgh, Pennsylvania

A patient information handout on Hashimoto's disease, written by the authors of this article, is provided on page 1054.

Thyroiditis is a group of inflammatory thyroid disorders. Patients with chronic lymphocytic thyroiditis (also referred to as Hashimoto's thyroiditis) present with hypothyroidism, goiter, or both. Measurement of serum thyroid autoantibodies and thyroglobulin confirms the diagnosis. Subacute granulomatous thyroiditis (sometimes referred to as de Quervain's disease) is a self-limited but painful disorder of the thyroid. Physical examination, elevated erythrocyte sedimentation rate, elevated thyroglobulin level and depressed radioactive iodine uptake (RAIU) confirm the diagnosis. Subacute lymphocytic thyroiditis (silent thyroiditis) is considered autoimmune in origin and commonly occurs in the postpartum period. Symptoms of hyperthyroidism and depressed RAIU predominate. Acute (suppurative) thyroiditis is a rare, infectious thyroid disorder caused by bacteria and other microbes. The rare, invasive fibrous thyroiditis (Riedel's thyroiditis) presents with a slowly enlarging anterior neck mass that is sometimes confused with a malignancy. (Am Fam Physician 2000;61:1047-52,1054.)

Thyroiditis refers to a group of inflammatory diseases affecting the thyroid gland (Table 1). With the help of historical information, a physical examination and diagnostic tests, physicians can classify the type of thyroiditis and initiate appropriate treatment.

TABLE 1 Classification of Thyroiditis Histologic classification Synonyms Chronic lymphocytic Chronic lymphocytic thyroiditis, Hashimoto's thyroiditis Subacute lymphocytic Subacute lymphocytic thyroiditis: (1) postpartum thyroiditis and (2) sporadic painless thyroiditis Granulomatous Subacute granulomatous thyroiditis, de Quervain's thyroiditis Microbial inflammatory Suppurative thyroiditis, acute thyroiditis Invasive fibrous Riedel's struma, Riedel's thyroiditis

Chronic Lymphocytic Thyroiditis

Chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) is the most common inflammatory condition of the thyroid gland and the most common cause of goiter in the United States.^1,2 It is an autoimmune condition characterized by high titers of circulating antibodies to thyroid peroxidase and thyroglobulin.³

Epidemiology
Chronic lymphocytic thyroiditis is the most common cause of hypothyroidism in the United States, and euthyroid persons with Hashimoto's disease develop hypothyroidism at a rate of approximately 5 percent per year.⁴ Up to 95 percent of cases of chronic lymphocytic thyroiditis occur in women, usually between 30 and 50 years of age.⁵ Chronic lymphocytic thyroiditis is also the most common cause of sporadic goiter in children.^5,6 The incidence of Hashimoto's disease has risen exponentially over the past 50 years, and this increase may be related to an increased iodine content in the North American diet.⁶

A genetic predisposition to thyroid autoimmunity exists; it is inherited as a dominant trait.⁷ Hashimoto's disease has been linked to other autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, diabetes mellitus and Sjögren's syndrome.⁵ A rare but serious complication of chronic autoimmune thyroiditis is thyroid lymphoma.⁷ These lymphomas, generally the B-cell, non-Hodgkin's type, tend to occur in women 50 to 80 years of age and are usually limited to the thyroid gland.⁷

Chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) is the most common cause of goiter in the United States.

Clinical Manifestations
Although Hashimoto's thyroiditis is usually asymptomatic, some patients may complain of a feeling of tightness or fullness in the neck; however, neck pain and tenderness are rare^6,7 (Figure 1). At the time of diagnosis, symptoms of hypothyroidism are present in 20 percent of patients.⁶ Physical examination generally reveals a firm, irregular, nontender goiter.⁷ The erythrocyte sedimentation rate (ESR) and white blood cell count are normal. The definitive indicator of chronic lymphocytic thyroiditis is the presence of thyroid-specific autoantibodies in the serum. The three main targets for thyroid antibodies are thyroglobulin (a protein carrier for thyroid hormones), thyroid microsomal antigen (also called thyroid peroxidase) and the thyroid-stimulating hormone (TSH) receptor.⁷ Low levels of circulating antibodies are common in other thyroid diseases, such as multinodular goiter and thyroid malignancy. Antithyroid microsomal antibodies in titers greater than 1:6,400 or antithyroid peroxidase antibodies in excess of 200 IU per mL, however, are strongly suggestive of chronic autoimmune thyroiditis.⁷ Testing of thyroid autoantibodies and measurement of serum thyroglobulin levels will confirm the diagnosis.⁷ Radioactive iodine uptake (RAIU) is variable and can be depressed, normal or increased, depending on the extent of follicular destruction (Figures 2a, 2b and 2c). Patchy uptake is common, providing little diagnostically useful information.⁷ Ultrasonography shows an enlarged gland with a diffusely hypoechogenic pattern in most patients.⁷ RAIU and thyroid ultrasonography are not necessary parts of the work-up for this disease. A dominant nodule in a patient with Hashimoto's disease should prompt a fine-needle aspiration biopsy to exclude malignancy.⁷

Differentiating Thyroiditis *--Graves' disease is not a subtype of thyroiditis. FIGURE 1.Clinical differentiation of the subtypes of thyroiditis. (RAIU = radioactive iodine uptake)

Clinical Management
Because thyroiditis is usually asymptomatic and the goiter is small, many patients do not require treatment.⁶ When hypothyroidism is present, treatment with thyroxine (T₄) is indicated.⁷ Thyroid hormone replacement therapy is also indicated in patients with a TSH level in the normal range, to reduce goiter size and prevent progression to overt hypothyroidism in high-risk patients.⁷ Lifetime replacement of levothyroxine is indicated in hypothyroid patients, at a starting dosage of 25 to 50 µg per day, with gradual titration to an average daily dosage of 75 to 150 µg. A lower starting dosage (12.5 to 25 µg per day) and a more gradual titration are recommended in elderly patients and in patients with cardiovascular disease. The dosage may be increased in these patients 25 to 50 µg every four to six weeks until the TSH level is normal.^6,7

FIGURE 2A. Radioactive iodine uptake scan showing normal condition in a 30-year-old woman with postpartum thyroiditis (subacute lymphocytic thyroiditis).

FIGURE 2B. Radioactive iodine uptake scan showing hyperthyroid (increased uptake) condition in a 52-year-old woman with Graves' disease.

FIGURE 2C. Radioactive iodine uptake scan showing hypothyroid (decreased uptake) condition, or thyroiditis, in a 42-year-old woman with subacute granulomatous thyroiditis.

In patients with an elevated TSH level and a normal thyroxine (T₄) level (subclinical hypothyroidism), indications for treatment are less clear. If the TSH level is greater than 20 mU per mL (20 mU per L) with a normal T₄ level, there is a high probability that the patient will develop hypothyroidism. If the TSH level is elevated but is less than 20 mU per mL and the antimicrosomal antibody titer is greater than 1:1,600, hypothyroidism will develop in 80 percent of patients.⁵ Therefore, it is recommended that treatment be initiated in patients with symptoms of hypothyroidism, in patients with a serum TSH level greater than 10 mU per mL (10 mU per L) and in patients with a high risk of progression to hypothyroidism (e.g., those with high antibody titers).⁷ Because of the risk of developing hypothyroidism, patients with a history of chronic lymphocytic thyroiditis require annual assessment of thyroid function.⁶

Subacute Lymphocytic Thyroiditis

Subacute lymphocytic thyroiditis occurs most often in the postpartum period but may also occur sporadically.⁷ Therefore, it is subdivided into two groups, postpartum thyroiditis and sporadic painless thyroiditis. Antimicrosomal antibodies are present in 50 to 80 percent of patients, while antithyroid peroxidase antibodies are present in nearly all patients.^3,6,7 Subacute lymphocytic thyroiditis starts with an initial hyperthyroid phase, followed by subsequent hypothyroidism and, finally, a return to the euthyroid state. In the postpartum patient, thyrotoxicosis usually develops in the first three months following delivery and lasts for one or two months. Then the patient returns to a euthyroid state or hyperthyroidism ensues for several months.⁸ Patients with an initial episode of postpartum subacute lymphocytic thyroiditis have a notably high risk of recurrence in subsequent pregnancies.^1,6,9 Serum TSH testing is indicated in symptomatic patients.

Epidemiology
Subacute lymphocytic thyroiditis comprises 29 to 50 percent of all cases of thyroiditis³ and occurs most often in women between 30 and 50 years of age.^6,9 There is a higher incidence of antimicrosomal antibodies in the postpartum form (80 percent) of the disease than in the sporadic form (50 percent). A family history of autoimmune thyroid disease is found in 50 percent of patients with the postpartum form of thyroiditis. The severity of the hypothyroid phase correlates directly with the antimicrosomal antibody titer. A titer of 1:1,600 or greater early in pregnancy is associated with a high risk of postpartum hypothyroidism.¹⁰ Approximately 6 percent of patients who have the postpartum form develop chronic hypothyroidism.⁶

Clinical Manifestations
Patients usually present with acute symptoms of hyperthyroidism, such as tachycardia, palpitations, heat intolerance, nervousness and weight loss.^6,9 A small painless goiter is present in 50 percent of patients.^6-9 The ESR and white blood cell count are normal. T₄ and triiodothyronine (T₃) levels are initially elevated, with a disproportionate increase in T₄ compared with T₃.⁹ RAIU is decreased in the hyperthyroid phase of the disease and is almost always less than 3 percent. This situation contrasts markedly with the elevated RAIU found in patients with Graves' disease.^3,5,8,9

Clinical Management
Acute symptoms of hyperthyroidism are managed primarily with beta blockers.^3,6,7,9 Antithyroid drugs, which inhibit the production of new T₄, are not indicated in the management of patients with hyperthyroidism because symptoms are caused by the release of preformed T₃ and T₄ from the damaged gland.^6,9 Replacement of thyroid hormone in the hypothyroid phase is indicated if the patient's symptoms are severe or of long duration.⁷ If the hypothyroid phase lasts longer than six months, permanent hypothyroidism is likely.¹¹

Subacute Granulomatous Thyroiditis
Subacute granulomatous thyroiditis is the most common cause of a painful thyroid gland⁷ (Figure 3). It is most likely caused by a viral infection and is generally preceded by an upper respiratory tract infection.⁷ Numerous etiologic agents have been implicated, including mumps virus, echovirus, coxsackievirus, Epstein-Barr virus, influenza and adenovirus.^3,7

Epidemiology
Women are three to five times more likely to be affected than men. The average age of onset is 30 to 50 years.⁷ The disorder tends to be geographical and seasonal, occurring most often in the summer and fall.^6,7

A painful thyroid following an upper respiratory tract infection is usually a sign of subacute granulomatous thyroiditis.

Clinical Manifestations
Subacute granulomatous thyroiditis presents clinically with acute onset of pain in the thyroid region. The pain may be exacerbated by turning the head or swallowing, and may radiate to the jaw, ear or chest.^3,5,6 Symptoms of hypermetabolism may be present, and the ESR usually is markedly elevated.^6,7 A normal ESR essentially rules out the diagnosis of subacute granulomatous thyroiditis.⁷ The thyroid is firm, nodular and exquisitely tender to palpation. The leukocyte count is normal or slightly elevated.⁷ Thyrotoxicosis is present in 50 percent of patients in the acute phase, and the serum T₄ concentration is disproportionately elevated relative to the T₃ level.⁷ Serum TSH concentrations are low to undetectable.⁷ Thyroglobulin is elevated. A normal thyroglobulin level essentially rules out the diagnosis of subacute granulomatous thyroiditis.⁶ The RAIU is notably low, often less than 2 percent at 24 hours.⁷ In summary, the physical examination, an elevated ESR, an elevated thyroglobulin level and a depressed RAIU confirm the diagnosis.

Clinical Management
The natural history of subacute granulomatous thyroiditis involves four phases that generally unfold over four to six months. The acute phase of thyroid pain and thyrotoxicosis may last three to six weeks or longer. Transient asymptomatic euthyroidism follows. Hypothyroidism often ensues and may last weeks to months or may be permanent (in up to 5 percent of patients).⁵ The final phase is a recovery period, during which thyroid function tests normalize.

FIGURE 3.Causes of microbial infectious thyroiditis. Information from Farwell A, Braverman LE. Inflammatory thyroid disorders. Otolaryngol Clin North Am 1996;29:541-53.

Therapy with antithyroid drugs is not indicated in patients with subacute granulomatous thyroiditis because this disorder is caused by the release of preformed thyroid hormone rather than synthesis of new T₃ and T₄.^6,7 Therapy with beta blockers may be indicated for the symptomatic treatment of thyrotoxicosis. Nonsteroidal anti-inflammatory drugs are generally effective in reducing thyroid pain in patients with mild cases. Patients with more severe disease require a tapering dosage of prednisone (20 to 40 mg per day) given over two to four weeks.³ Up to 20 percent of patients experience the recurrence of thyroid pain on discontinuation of prednisone.⁷ RAIU can assist clinicians in determining patients at high risk for relapse. Low RAIU uptake implies ongoing inflammation, and steroid therapy should be continued.³

Microbial Inflammatory Thyroiditis

Microbial inflammatory thyroiditis, also known as acute suppurative thyroiditis, is a rare subtype most often caused by the presence of Gram-positive bacteria in the thyroid gland. Staphylococcus aureus is the most common infectious agent,⁷ but other organisms have also been implicated (Figure 3). This disorder is rare because of the inherent resistance of the thyroid gland to infection. Microbial inflammatory thyroiditis occurs most often in women 20 to 40 years of age.^5,9 Most patients have a preexisting thyroid disorder, usually nodular goiter.^3,5,9 Anterior neck pain and tenderness are common. Other clinical features include fever, pharyngitis and dermal erythema.^5,9 The pain is typically worse during swallowing and radiates locally.^5,9,12 Tachycardia is common, along with leukocytosis and an elevated ESR level.^3,5,9,12 TSH, T₄ and T₃ levels are typically normal, while RAIU may be normal or show cold nodules in areas of abscess formation.^5,9,13 The cause of infection is first determined by culture and sensitivity of samples obtained through fine-needle aspiration.

When the cause of the infection is determined, appropriate parenteral antibiotics should be prescribed.^5,9,12 Patients with abscesses require surgical drainage and, possibly, a thyroid lobectomy.^5,9,12 Heat, rest and aspirin provide symptomatic relief; steroids may offer additional benefit.¹³ The disease is usually self-limited, lasting weeks to months.¹³

Invasive Fibrous Thyroiditis

First described by Riedel in 1898, this remains the rarest type of thyroiditis. In addition to the development of dense fibrosis of the thyroid gland itself, extracervical sites of fibrosis frequently occur as inflammatory fibrosclerotic processes, including sclerosing cholangitis, retroperitoneal fibrosis and orbital pseudotumor.^9,14,15 Studies suggest that one third of patients with fibrous thyroiditis develop multifocal fibrosclerosis.^14,16 The mean age at presentation is 47.8 years, and 83 percent of all cases occur in females.¹⁶ A stone-hard or woody mass that extends from the thyroid is common.^9,14-16 Symptoms vary according to the structures involved and most commonly result from a thyroid mass that produces dyspnea, dysphagia and, occasionally, stridor.^9,12,14,16 The thyroid mass may grow suddenly or slowly, and is usually unilateral.¹⁴

RAIU is decreased in affected areas of the gland.^12,15 Most patients remain euthyroid, and the ESR is frequently elevated.^5,9,14,16 Thyroid autoantibodies are present in appreciable quantities in 45 percent of patients.^5,9,14,16 Because of the similarity between fibrous thyroiditis and thyroid carcinoma, diagnosis must be made using open biopsy.^5,9,12,14 The disease is usually self-limited, with surgical wedge resection of the thyroid isthmus being the mainstay of treatment in symptomatic patients.^5,9,12,14

TABLE 2 Clinical Manifestations of Thyroiditis Subtypes Subtype Etiology Neck pain RAIU TSH T4 Thyroid autoantibodies Chronic lymphocytic (Hashimoto's disease) Autoimmune No Variable Variable Variable Present Subacute granulomatous Viral Yes Decreased Decreased Increased Absent Subacute lymphocytic Autoimmune No Decreased Decreased Increased Present Microbial inflammatory Bacterial, fungal, parasitic Yes Variable Normal Normal Absent Hashitoxicosis Autoimmune No Decreased Decreased Increased Present Invasive fibrous Unknown No Variable Normal Normal Variable RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone; T4 = thyroxine.

Final Comment

Thyroiditis is a heterogeneous disease with several subtypes. These subtypes mimic other diseases as well as each other. Differentiation of the subtypes of thyroiditis requires an understanding of their unique clinical presentations, radiologic studies, laboratory data and indications for pharmacotherapy (Table 1).

Authors

JOHN SLATOSKY, D.O.,
is currently in private practice in Liberty, N.C. A graduate of Kirksville College of Osteopathic Medicine, Kirksville, Mo., he completed a residency in family practice at Mercy Hospital, Pittsburgh, Pa.

BENJAMIN SHIPTON, D.O.,
is a third-year resident in family practice and chief resident for the department of family medicine at Mercy Hospital. He is a graduate of Philadelphia College of Osteopathic Medicine, Philadelphia, and completed an internship at Delaware County Memorial Hospital, Drexel Hill, Pa.

HANEY WAHBA, M.D.,
is a faculty member at the Mercy Hospital family practice residency program and a clinical assistant professor in the department of family medicine at Jefferson Medical School of Thomas Jefferson University, Philadelphia. Dr. Wahba received his medical degree from the University of Cairo School of Medicine and completed a residency in family practice at Latrobe Area Hospital in Latrobe, Pa.

Address correspondence to Haney Wahba, M.D., Mercy Family Health Center, Penn Center Building 2, 3436 William Penn Hwy., Pittsburgh, PA 15235. Reprints are not available from the authors.

REFERENCES

1. Hamburger JI. The various presentations of thyroiditis. Diagnostic considerations. Ann Intern Med 1986;104:219-24.
2. Hay ID. Thyroiditis: a clinical update. Mayo Clin Proc 1985;60:836-43.
3. Farwell AP, Braverman LE. Inflammatory thyroid disorders. Otolaryngol Clin North Am 1996;29: 541-56.
4. Nagataki S. The concept of Hashimoto disease. In: Nagataki S, Mori T, Torizuka K, eds. Eighty years of Hashimoto disease. Amsterdam: Elsevier Science, 1993:539-45.
5. Sakiyama R. Thyroiditis: a clinical review. Am Fam Physician 1993;48:615-21.
6. Schubert MF, Kountz DS. Thyroiditis: a disease with many faces. Postgrad Med 1995;98:101-12.
7. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99-107.
8. Roti E, Emerson CH. Clinical review 29: postpartum thyroiditis. J Clin Endocrinol Metab 1992;74:3-5.
9. Singer PA: Thyroiditis: Acute, subacute, and chronic. Med Clin North Am 1991;75:61-77.
10. Jansson R, Bernander S, Karlsson A, Levin K, Nilsson G. Autoimmune thyroid dysfunction in the postpartum period. J Clin Endocrinol Metab 1984;58:681-7.
11. Braverman LE, Utiger RD, eds. Werner and Ingbar's The thyroid: a fundamental and clinical text. 7th ed. Philadelphia: Lippincott-Raven, 1997:583.
12. Levine SN. Current concepts of thyroiditis. Arch Intern Med 1983;143:1952-6.
13. Szabo SM, Allen DB. Thyroiditis: Differentiation of acute suppurative and subacute. Clin Pediatr [Phila] 1989;28:171-3.
14. Malotte MS, Chonkich GD, Zuppan CW. Riedel's thyroiditis. Arch Otolaryngol Head Neck Surg 1991;117:214-7.
15. Lange WE, Freling NJ, Molenaar WM, Doorenbos H. Invasive fibrous thyroiditis (Riedel's struma): a manifestation of multifocal fibrosclerosis? Q J Med 1989;72:709-717.
16. Schwaegerle SM, Bauer TW, Esselstyn CB Jr. Riedel's thyroiditis. Am J Clin Pathol 1988;90:715-22.

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