|Ahead of print publication
Recurrent thyroiditis: Rare but resistant
Pramila Kalra, KM Prasanna
Department of Endocrinology, Ms Ramaiah Medical College and Hospitals, Bengaluru, Karnataka, India
|Date of Submission||15-Aug-2021|
|Date of Acceptance||10-Nov-2021|
|Date of Web Publication||18-Feb-2022|
Department of Endocrinology, M S Ramaiah Medical College, Bengaluru - 560 054, Karnataka
Source of Support: None, Conflict of Interest: None
Recurrent thyroiditis is defined as a repeat attack of subacute thyroiditis. The recurrence rates may vary from 1.4% to 20%. The recurrence may happen at any time ranging from weeks to years after the first episode. The patients with recurrent thyroiditis not responding to nonsteroidal anti-inflammatory drugs may require steroids. The recovery to euthyroidism is mostly complete but a small percent may develop transient and less commonly permanent hypothyroidism. The mainstay of treatment is medical therapy but surgery may be needed in resistant cases.
Keywords: Prednisolone, recurrent, thyroiditis
| Introduction|| |
Recurrent thyroiditis is defined as a repeat attack of subacute thyroiditis (SAT). The recurrence of SAT is seen in 1.4%–20% of patients.
SAT is also called granulomatous thyroiditis or de Quervain's thyroiditis. Furthermore, it is an inflammatory thyroid disease that is triggered probably by a preceding viral infection. The prevalence of SAT is higher in women than men and is predominantly seen in middle age and is also seen in even younger age group. The prevalence is four to seven times higher in women than in men, and most patients are middle-aged.,, In our country, the prevalence is seen earlier than the third decade or so.
Although SAT is seen secondary to a viral infection that may include coxsackie, EBV, even HIV, and lately secondary to COVID-19, it has been rarely reported secondary to bacterial infections. The COVID-19 has also been shown to directly affect the thyroid because of the presence of ACE2 mRNA on the thyroid.,, There are case reports of thyroiditis and hypothyroidism post-COVID-19 infections.
The most common complaint of patients with SAT is pain over the thyroid gland, which typically radiates ipsilaterally up to the jaw and ear and the upper mediastinum. Fever occurs the majority of cases, frequently reaching over 39°C, and rising especially at night. The initial symptoms include muscle pain, fatigue, and malaise. Laboratory markers of mild to moderate thyrotoxicosis are often found, but the levels of anti-thyroid antibodies are normal in over 70% of patients. In some individuals, low-to-moderate-intensity symptoms of thyrotoxicosis are present. In rare cases, a history of weight loss, tremor, and palpitations may dominate the clinical presentation. Thyrotoxicosis usually lasts for 2–8 weeks due to the destruction of thyroid follicles and the release of thyroid hormones. A subsequent hypothyroid phase may occur frequently, and a persistent one is extremely rare in the SAT course but studies have shown it to be 20% at 1 year. A high erythrocyte sedimentation rate (ESR), reaching even three-digit values, is a characteristic feature of SAT. C reactive protein elevation is also seen. The ultrasound features of SAT include hypoechoic and heterogeneous areas with blurred margins, poorly vascularized on color Doppler. A diagnostic scale has been formulated if radioisotope scanning is not available. Reduced radioactive iodine uptake confirms the diagnosis. Technetium 99 uptake studies also are commonly used because of the easy availability and short half-life of technetium. The presentation can be painless in many patients who may pose a diagnostic challenge. Firm thyroid nodules in SAT are common and can grow rapidly, initially suggesting thyroid malignancy.
| Prevalence and Incidence|| |
Recurrence has been reported in about 14% of cases with SAT. This has been reported in various studies. In our series, recurrence was reported in 3% of cases. A follow-up of our center data showed recurrence in about 2.8% of the patients during 8 years' follow-up.
Silent thyroiditis is uncommon after excluding postpartum thyroiditis and destructive amiodarone thyroiditis. In a series of four patients with recurrent silent thyroiditis, the number of episodes ranged from 2 to 9. There are reports of outbreak of “hamburger thyrotoxicosis” resulting from inadvertent consumption of beef contaminated with bovine thyroid gland. It can present rarely as recurrent thyroiditis as reported in a single patient who experienced recurrent episodes of this phenomenon over 11 years.
Reidel's thyroiditis has also been reported to present as recurrent thyroiditis., Thyroid amyloidosis can also present as recurrent thyroiditis.
| Why Does Recurrence Happen?|| |
There are many theories that explain recurrence. Some studies have shown HLA association for recurrence.
In a study done by Stasiak et al., 14% patients reported SAT recurrence at least once. The mean age of patients in the nonrecurrence group was 42.7 years, and in the recurrence, the group was 44.4 years and was more frequently seen in females.
The recurrence rate of SAT has been about 20%–30%, but the reason for SAT relapse is still unknown. Studies have demonstrated the association between SAT and the presence of HLA-B*18:01, DRB1*01, and C*04:01, apart from the previously known HLA-B*35. HLA-A, -B, -C, -DQB1, and -DRB1. The higher recurrence rate was seen in patients with HLA-B*18:01 plus HLA-B*35. The risk of SAT recurrence was shown to be HLA-dependent, and the co-presence of HLA-B*18:01 and -B*35 was the major determinant. These patients can benefit from the use of steroids, and the dose reduction should be slow. In some studies have shown that HLA-A26 may be associated with late recurrences after 10 years.
| Treatment Related - Is Therapy Important? Does it Predict Relapse?|| |
There are therapeutic effects of steroid and nonsteroidal anti-inflammatory drugs (NSAIDs) in SAT recurrence. In a study done to see long-term results of 295 SAT patients treated with ibuprofen or methylprednisolone, it was seen that in 59.5% of 126 patients treated with ibuprofen, there was no adequate clinical response at the first visit. In 54% of patients, the treatment was changed to steroids in a mean of 9.5 days. In about 2 weeks, there was symptomatic remission in all patients treated with methylprednisolone. The total recurrence rate was 19.8%, and the recurrence was more frequent in patients who received only steroids than those who received NSAIDs.
There are many reasons postulated for SAT relapse. A too short period of steroid therapy has been postulated to be one of the causative factors. The studies have shown that a short period of steroid therapy may result in relapse. The recurrence of SAT may be seen because of faster steroid withdrawal before the complete resolution of the disease. Nevertheless, some studies have shown relapse with prolonged steroid usage also. The recurrence of SAT also occurs in several percent of patients treated with steroids according to the prolonged regimen (i.e., starting from 40 mg of prednisone and tapering the dose for 5 mg every week). Steroid dependence has been documented, and any attempt to discontinue treatment may result in SAT relapse. Thus, other factors seem to be more crucial for the risk of recurrence than the period of steroid treatment. However, most of the studies have shown that the longer time of steroid administration is protective. Thus there can be more factors that predict relapse.
| Other Complications of Recurrent Subacute Thyroiditis|| |
SAT can present with rare complications. Recurrent laryngeal nerve paralysis during an episode of thyroiditis has been reported.
It has also been reported as Reidel's thyroiditis in a case report of a 54 years old woman after repeated episodes of SAT. The patient had a history of right hemithyroidectomy for a benign thyroid nodule and presented with an episode of SAT associated with unilateral vocal cord paralysis. The patient underwent a completion thyroidectomy with intravenous antibiotics. Postoperatively, the vocal cord function recovered successfully. This unilateral vocal cord paralysis can be seen in patients with thyroiditis.
There can be ethnic variations in the risk of recurrence of thyroiditis. Even in patients treated properly, the rate of SAT recurrence is rather high, varying significantly between studied groups, ranging from 1.6% to over 20%. The observed discrepancies between different studies seem to be dependent on the studied population (Caucasian vs. Asian). There may be immediate recurrences or many years after the first episode also. The occurrence of one relapse increases the risk of the next one. The recurrence of symptoms often occurs when the dose of prednisone is tapered to 5–10 mg. The recurrence rate during treatment with prednisolone (PSL) was reported to range from 2.2% to 35%., In such patients, the tapering regimen should be very slow, and prolonged steroid treatment is required.
| Recurrence in Silent Thyroiditis|| |
Silent thyroiditis is an uncommon entity excluding postpartum thyroiditis, and destructive amiodarone thyroiditis and recurrent cases of silent thyroiditis are even rarer. A case series of four patients with recurrent silent thyroiditis has been reported. The number of episodes ranged from 2 to 9. All four patients had episodes that were similar in duration (4–6 weeks) as well as in their clinical (no viral prodrome or neck pain), biochemical (high total triiodothyronine [T3], free thyroxine [T4], and low thyrotropin [TSH] presence of antibodies to thyroid antigens), and scintigraphic (low radioiodine uptake) findings. Individual symptoms and symptom-free duration (from 1 to 4 years) were more variables. No associations were found concerning medications, pregnancies, or other disease states previously implicated in thyroiditis. Three patients were treated with radioablative iodine therapy during the recovery phase of an episode; they became hypothyroid and were later started on replacement levothyroxine. They were symptom free on follow-up.,
Thyroiditis includes a group of disorders characterized by thyroid inflammation. Postpartum thyroiditis occurs in women within 12 months after delivery, and recurrence of postpartum thyroiditis in subsequent pregnancies is common, but recurrent silent thyroiditis is rare. A patient with recurrent episodes of thyroiditis, unrelated to pregnancy, after an episode of postpartum thyroiditis, has been reported. Although postpartum thyroiditis and silent thyroiditis could occur close to each other; however, the link between these disorders is not well established. The case reports in literature suggest the possibility of recurrent silent thyroiditis in women with a history of postpartum thyroiditis.
A case of Riedel's thyroiditis can also present as SAT. There are reports of patients diagnosed with SAT based on clinical manifestation and laboratory results treated with glucocorticoids and later diagnosed as Reidel's thyroiditis. A patient was followed up after 3 years of initial presentation and was diagnosed to have Riedel's thyroiditis. Until now, few cases of Riedel's thyroiditis in patients with a history of SAT have been reported in the literature. Although the etiology of Riedel's thyroiditis is unknown, it may develop in SAT.
In another report of two cases, both patients had very tender, diffuse, firm goiters with low thyroidal radioactive iodine uptake values being low and increased ESRs. They responded dramatically to glucocorticoid therapy. These patients had persistence of goiter even in remission, repeated exacerbation of STLS, pain always localized in the same site, and gastrointestinal, renal, and cardiac abnormalities, unlike patients with SAT. The histological examination of the patients' thyroid glands revealed amyloid deposition and no evidence of SAT. Another patient presented with low T3 thyrotoxicosis with an elevated rT3/T3 ratio which suggested impaired peripheral conversion of T4 to T3. There was immunological and histological evidence of Hashimoto's thyroiditis. There may be an association of thyroid amyloidosis with silent thyroiditis. A possibility of thyroid amyloidosis should be considered in patients having an unusual course of SAT.
| Can Recurrence be One-Sided|| |
Thyroiditis can rarely be one-sided as reported in a case with elevated ESR and anti-TPO antibody positivity. The serum thyroglobulin levels were raised during an acute episode. The underlying disease appeared to be chronic thyroiditis since tests for anti-microsomal or anti-thyroid peroxidase antibodies were consistently positive during her illness. The changes in the titers of these antibodies were not apparent during and after the attacks of thyroiditis. The clinical course suggested that the hemithyroiditis was induced by recurrent upper respiratory infection.
| Recurrence of Suppurative Thyroiditis|| |
Recurrent acute left-sided suppurative thyroiditis (AST) has been reported in children and adults secondary to a pyriform sinus fistula. AST occurs most commonly as a result of the persistence of a connection between the throat and the thyroid gland, which is otherwise extremely resistant to infection. AST is usually left-sided and not associated with thyroid dysfunction. Recurrences are common unless the congenital fistula is identified and completely excised.,
| Vitamin D Deficiency and Subacute Thyroiditis|| |
Vitamin D levels in SAT patients have been found to be significantly lower. Although there is no relationship between Vitamin D level and disease prognosis, Vitamin D deficiency may increase the rate of respiratory tract infections (especially influenza, coxsackievirus, measles, adenovirus, and retroviruses) and eventually SAT development.
| Treatment of Recurrent Thyroiditis|| |
The current treatment protocols for SAT are not uniform, and treatment ranges from NSAIDS to PSL. PSL is chosen more often for treatment when NSAIDs are not effective and symptoms are severe. Most of the cases recur after cessation of PSL. The recurrence rate of SAT treated with PSL has been reported to be about 20%, and no difference has been seen in the laboratory parameters before starting the therapy between recurrent and nonrecurrent groups. Thus, a modified protocol of PSL administration to decrease the early recurrent rate of SAT may be needed.
| The Impact of Surgery on Thyroiditis|| |
The treatment remains the same as thyroiditis, but some patients with repeated episodes may benefit from thyroidectomy.
The indications for surgery in thyroiditis may vary from compressive symptoms to cosmesis. A study was done to analyze the complications in patients who underwent total thyroidectomy (TT) in goiters associated with thyroiditis. A retrospective study was done in an endocrine surgical center over 4 years. Seven hundred twenty-four patients, who underwent TT for benign thyroid disorders, were included in the study. The patients were divided based on histopathology findings into nonthyroiditis cases and thyroiditis cases. The thyroiditis group was subdivided into nodular goiter with associated thyroiditis and Hashimoto's thyroiditis. Both groups were age and sex matched. All preoperative and intraoperative parameters, including serum calcium, serum Vitamin D, serum parathyroid hormone, and vocal cord status, were comparable among groups matched for age and gender. Both transient complications (<6 months) were higher in thyroiditis cases. Transient hypocalcemia was higher in the thyroiditis group (39.70%) than the nonthyroiditis group (24.77%) (P = 0.001). Transient hypocalcemia was higher in the nodular goiter group (36.58%) than Hashimoto's thyroiditis (44.44%) (P = 0.014). Transient RLN palsy was higher in the thyroiditis group (9.55%) than the nonthyroiditis group (7.52%) (P = 0.040). Transient RLN palsy was higher in nodular goiter (8.53%) than Hashimotos thyroiditis (11.11%) (P = 0.039). Permanent hypoparathyroidism and permanent RLN palsy were comparable between the groups and subgroups.
The incidences of transient complications are higher in patients with thyroiditis. Careful analysis of surgical indications will avoid unnecessary surgery in thyroiditis cases.
A case report of a 47-year-old man who presented with typical clinical and laboratory features suggesting painless thyroiditis. The patient underwent surgical resection of the thyroid due to the severity of thyrotoxicosis to prevent a thyrotoxic storm. Histological examination revealed typical lymphoid infiltration of the thyroid gland.
An atypical variant of Hashimoto's thyroiditis is painful Hashimoto's thyroiditis, presenting with thyroid pain and fever. These patients may require long-term pain management as anti-inflammatory agents are not always effective as in those with SAT. The literature search showed a case report of four cases of painful Hashimoto's thyroiditis requiring TT to relieve thyroiditis. All the patients had high titers of anti-thyroperoxidase (TPO) and thyroglobulin antibodies. Three of them were hypothyroid, and the other was euthyroid. At the first visit, all four patients had typical clinical and laboratory features of SAT. Oral corticosteroids were given continuously or intermittently for 9–48 months. In view of the recurrent painful attacks, surgery was performed. The symptoms resolved after TT. The histopathologic characteristics of these hypothyroid cases were advanced fibrosis and destructive thyroid architecture. the histopathologic characteristics included advanced fibrosis and destructive thyroid architecture. Thus, TT may be a treatment option for these patients.
| Use of Colchicine|| |
The recurrence of SAT is approximately 10%–20%. Sometimes, it is difficult for these patients to stop glucocorticoid treatment, and they are usually bothered with recurrent pain and the side effects of glucocorticoids for more than several months. Three cases have been described in literature who had recurrent SAT after a reduction in PSL dose, either immediately on the cessation of PSL or shortly thereafter and were treated with colchicine. The dose of colchicine was administered 1 mg per day for 1–2 months to control the recurrence of SAT. The patients were monitored for their routine blood parameters every 2 weeks. All three patients were successfully tapered off of PSL treatment and were free of frequently recurrent SAT. Thus, Colchicine may be therapeutic in patients with PSL-refractory, recurrent SAT. However, a large-scale, double-blind, controlled, prospective multicenter study is required to provide a solid body of evidence.
| Summary|| |
The recurrence of SAT, which is considered to be a viral illness, is very rare. The recurrent disease could be debilitating. A high index of clinical suspicion is very important to make the diagnosis as it may have varied presentations. Prompt assessment, treatment, and follow-up are paramount. The steroids may be needed for a longer period in recurrent cases and surgery may have a role in few.
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Conflicts of interest
There are no conflicts of interest.
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