Subacute Thyroiditis – an Underestimated Diagnosis: Description of a Case Series

CASE REPORTS 10.2478/amb-2020-0007

Subacute thyroiditis – an underestimated diagnosis: description of a case series

Y. Vlahov1, A-M. Borisova1, M. Nikolova2, A. Kundurdjiev2, R. Ivanova2

1University Hospital Sofiamed, Medical Faculty, University „Sv. Kl. Ohridski“ – Sofia, Bulgaria 2University Hospital Sv. Ivan Rilski, Medical University – Sofia, Bulgaria

Abstract. Subacute thyroiditis is a relatively rare thyroid disease that develops after acute viral upper respiratory tract infection and manifests with neck pain, fever and transient hy- perthyroidism. The diagnosis is often delayed due to the non-specific presentation and laboratory findings. It is misdiagnosed with upper respiratory tract infections, cervical lymphadenitis, even with acute pyelonephritis. The authors present a series of 12 patients with subacute thyroiditis and discuss the main steps in the diagnosis, differential diagnosis and treatment of this disease.

Key words: subacute thyroiditis, diagnosis, differential diagnosis, treatment

Corresponding author: Yordan Vlahov, MD, Clinic of Endocrinology, University Hospital Sofiamed, Medical Faculty, Sofia University „Sv. Kl. Ohridski“, e-mail: [email protected]

Introduction disease is frequently misdiagnosed for other conditions, such as upper respiratory tract infections, cer- ubacute thyroiditis (ST) is a rare immune- vical lymphadenitis, bronchitis, etc. According to the mediated inflammatory thyroid disorder that Rochester Epidemiology Project in Olmsted county, Sdevelops as non-suppurative painful thyroid- Minnesota [3], the average annual incidence is 12.1 itis, manifesting with tender and diffuse enlargement cases per 100 000 per year, with a higher incidence of the thyroid gland and non-specific constitutional in females than in males (females : males = 19.1 : 4.1 symptoms (fever, fatigue loss of appetite), usually af- per 100 000 per year), and in middle aged persons, ter upper respiratory tract infection [1]. Nodular and with the incidence decreasing in elderly. painless forms also have been described [1]. ST can The pathogenesis of ST is not well understood. It is present as fever of unknown origin with painless thy- presumed to be caused by pathological immune re- roid gland and subtle functional abnormalities [2]. The sponse against the thyroid gland after viral infections histological examination of the thyroid gland reveals (antigen mimicry, cross-reactivity, implantation of vi- granulomatous inflammation with giant cells. Thyroid ral antigens within the thyroid, etc.). The incidence function usually changes in time with a predictable shows seasonal changes – higher in summer, and course: thyrotoxicosis due to cell destruction, fol- increase in epidemical areas with viral infections – lowed by euthyroid and short hypothyroid states and Coxsackie, mumps, measles, adenovirus, etc. [4 ,5]. ultimately – normalization of thyroid function. Yet, other studies reveal relatively steady incidence ST is also known as de Quervain’s thyroiditis. It usu- throughout the year [3, 6]. ally affects middle-aged and young adults, more of- ST shows strong association with HLA-B35 molecule, ten women (female : male ratio = 3-5 : 1) [3]. The expressed by human macrophages. It has been spec- incidence of ST is not well-understood because the ulated that the thyroid damage is due to activation of

Acta Medica Bulgarica, Vol. XLVII, 2020, № 1 // Case report 45 cytotoxic T-cells by the complex (viral) antigen-B35 roid. Recovery to euthyroid state is observed in the and subsequent thyroid cell destruction by T-cells and majority of cases, rarely permanent hypothyroidism by antibodies both directed against the antigen-B35 requiring LT4 supplementation is observed [3,8]. The complex that has structural similarity to thyroid fol- disease can recur in the same patient [3, 8]. licular cell antigens (i.e., antigen mimicry and cross- Pathohistological examination of the thyroid reveals reactivity) [7, 8]. Viral inclusion bodies have not been enlarged gland on gross examination, with wide- described in ST [7]. Due to the transient character of spread neutrophil, lymphocyte and histiocyte infiltra- the viral infections and the elimination of the viral an- tion, giant-cell-containig granulomatous inflamma- tigens from the human body by the immune system, tion, follicle destruction and follicular cell necrosis ST has a self-limiting course, unlike the chronic and on microscopic examination [8]. As it was mentioned progressive or relapsing-remittent course of immune above, no viral inclusion bodies within the thyroid tis- thyroid diseases, such as Hashomoto’s thyroiditis and sue have been described [8]. Fine-needle aspiration Graves-Basedow’s disease. biopsy shows the presence of inflammatory cells, Independent of the triggering factor, ST usually leads clusters of follicular cells and colloid masses [8] and to predictable changes in thyroid function, divided in rarely demonstrates giant cells. four major stages, each lasting from 2 to 8 weeks The clinical manifestations of ST are non-specific: (table 1) [8]. edema and pain in the thyroid region, often irradiating After immune-mediated destruction of the follicular towards the upper neck, ears, jaw or even upper chest, cells has begun, the thyroid gland becomes swollen constitutional symptoms (fever, fatigue, loss of appetite, and painful, constitutional symptoms develop (fever, myalgia, arthralgia, etc.), symptomatic thyrotoxicosis fatigue, loss of appetite, etc.). The cellular destruc- [8]. As it was mentioned above, the thyroid can be pain- tion is associated with liberation of thyroid hormones less and ST can manifest as fever or thyrotoxicosis of and transient increase in their blood levels with clini- unknown origin. The symptoms can develop gradually cal and biochemical signs of thyrotoxicosis (stage 1) or appear abruptly, with or without preceding respiratory without increase of thyroid function (increased FT4 tract infection. Due to the non-specific clinical symp- and FT3 levels, suppressed TSH), along with in- toms, ST is often misdiagnosed for other inflammatory creased leukocyte count, ESR and CRP levels. After condition, affecting the neck or the respiratory tract. The the viral infection subsides, the immune-mediated de- course of the disease is usually self-limiting, even with- struction of the follicular cells ceases and restoration out treatment, but ST may recur. to euthyroid state (stage 2, it could be shorter than 2 The diagnosis is based on the typical pain and ede- weeks) is usually observed, with decrease in leuko- ma of the thyroid plus fever, increased acute-phase cyte count, ESR and CRP, and decrease in edema, markers (ESR, CRP, leukocyte count), changes in tenderness and thyroid pain. This stage is followed thyroid hormone and TSH levels (depending on the by transient hypothyroid state (stage 3), explained stage of ST, as described above), and imaging stud- by the restoration of the normal thyroid tissue and ies [8]. Positive antithyroid antibodies (antithyroid hormonal secretion, and restoration of normal thyroid peroxidase or antithyroglobulin antibodies) have function (stage 4). This cyclic course is explained by been described in ST patients, probably as a result of the changes in immune-mediated destruction of the immune response against the liberated thyroid anti- gland and the natural restoration abilities of the thy- gens from the destructed follicular cells, as a process

Table 1. Clinical and laboratory stages of subacute thyroiditis

Parameter Stages Stage 1 Stage 2 Stage 3 Stage 4 Thyroid function Thyroto-xicosis Euthyroid Transient hypothyroidism Eurthyroid (reconvalescence) Neck pain, constitutional symptoms Marked Subsiding Subsiding Absent (fever, fatigue, etc.) FT3, FT4 ↑ Normal ↓ Normal TSH ↓ Normal ↑ Normal Marked Start to ESR, CRP (almost) Normal Normal increase decrease

46 Y. Vlahov, A-M. Borisova, M. Nikolova et al. of natural cleansing of the intracellular constituents steroid treatment offers rapid alleviation of symptoms from the necrotic cells [9]. and decrease in acute-phase markers of inflamma- The imaging studies are one of the pillars of ST dition but it does not prevent the development of early- agnosis. Ultrasound examination reveals normal or or late-onset thyroid dysfunction, nor the relapse of enlarged thyroid gland with diffuse or local hypoecho- ST after subsequent upper respiratory tract or other genicity with low flow on Color-Doppler during thyro- infections. When overt thyrotoxicosis is observed, toxicosis stage, as opposed to Graves-Basedow’s dis- beta-blockers are indicated. When transient hypothy- ease where the flow is increased during thyrotoxicosis roidism is observed, LT4 may be needed for a short [10, 11]. After recovery thyroid ultrasound returns to period of time. In patients with frequent relapses sur- normal [11]. Radionuclide assays demonstrate low up- gical treatment may be needed. take during thyrotoxicosis stage (< 1-3%) or heterog- enous and faint radionuclide uptake [8]. Description of the case series The differential diagnosis should be made with acute For the period October 1, 2015 – June 1, 2018 we suppurative thyroiditis, autoimmune thyroid disease observed overall 12 patients with subacute thyroiditis (Hashimoto’s thyroiditis and Graves-Basedow’s dis- (ST), 3 male and 9 female, mean age 42.2 +/- 11.1 ease), thyroid cancer, especially in nodular forms, years (18-56 years). The diagnosis ST was based on neck lymphadenitis and lymphadenopathy of other the typical clinical presentation and physical signs origin, infectious diseases, especially in the cases of (neck pain, enlarged and painful thyroid gland with fever of unknown origin, acute inflammatory condi- or without tachycardia and fever), laboratory signs tions of the upper respiratory tract, dental problems, (elevated ESR and/or CRP, hyperthyroid state) and temporal (giant-cell) arteriitis, other inflammatory dis- ultrasound characteristics (enlarged hypoechogenic eases, including bronchitis, pneumonia, pyelonephri- thyroid gland with decreased flow) [2, 3, 6, 10, 11]. tis, endocarditis, etc. Two male patients had metabolic syndrome with type The treatment strategies in ST have several goals: 2 diabetes mellitus on oral anti-diabetic medications, a) decreasing the pain, fever and general symptoms one female and one male patient had Hashimoto’s with non-steroid anti-inflammatory drugs (NSAIDs) thyroiditis. Overall 8 patients were initially referred to and/or corticosteroids, the latter being the primary otorhinolaryngologist or internal medicine specialist treatment option in most cases; b) maintaining eu- for suspected year-nose-throat, respiratory or other thyroid state – beta-blockers in the thyrotoxic phase infection, and only 4 were referred directly to endocri- and LT4 in the hypothyroid phase, where clinically nologist for suspected subacute thyroiditis. indicated; c) general supportive measures, including All patients presented with neck pain and subfebrile proper hydration, bed rest, gastroprotection, etc. fever, enlarged and tender thyroid gland, increased Up to date, there are no trials on the treatment of ST. ESR (67.7 +/- 30.7 mm/I h., 25-106 mm/I h.), 7 had Therefore, all treatment recommendations are based mild anemia (hemoglobin levels of 106-122 g/l), CRP upon observational data and clinical experience. The was investigated in 5 patients and was found in- pain and thyrotoxicosis may require temporary ad- creased in all of them (16.7 – 318 mg/l, normal range ministration of non-steroidal anti-inflammatory drugs < 5 mg/l). All patients presented in hyperthyroid state and/or corticosteroids plus beta-blocker treatment, – thyrotoxicosis in 10 and subclinical hyperthyroid- respectively. Corticosteroids are generally more ef- ism in 2. Anti-thyroid peroxidase antibodies were in- fective than NSAIDs, and gastroprotection is needed vestigated in 10 and were found positive in 2, anti- in both cases. Different NSAIDs have been adminis- thyreoglobulin antibodies were investigated in 4 and tered in ST patients and all have shown clinical effect were found positive in 1. The comparative analysis in therapeutic doses. When the symptoms are severe of female and male patients revealed no differences and when NSAIDs are ineffective of partially effec- concerning the levels of ESR, TSH, FT4. The only tive, corticosteroids are indicated – prednisolone 40 borderline statistical difference (trend) between male mg (8 tablets a day, or equivalent) with rapid reduc- and female patients was in the age – 50.7 +/- 9.2 in tion of the dose (decrease with 1 tablet every 5-7 male compared to 36.7 +/- 9.6 years in female sub- to 14 days) to a maintenance dose of 5-10 mg (1-2 group (p = 0.052). tablets) a day. If pain and edema re-occur, the dose Two patients underwent fine-needle aspiration bi- should be increased by 1 or 2 tablets to the previous opsy and non-specific changes were found in all of dose where the patient was asymptomatic. Usually them – inflammatory cells, follicular cells and colloid within 2-8 weeks the symptoms and the thyroid dys- in the aspirate. No giant cells were detected in our function resolve. One should not forget that cortico- series.

Subacute thyroiditis – an underestimated diagnosis... 47 Overall 11 patients were started on corticosteroid lent effect in all our patients. Until now, we observed treatment with prednisolone 0.5 mg/kg/day (30 to 40 no relapses of ST. mg prednisolone a day) with excellent therapeutic re- Our case series brings forward several interesting sults. Only one male patient was started on NSAID problems. First, one female and one male patient treatment due to underlying diabetes mellitus and had history of Hashimoto’s thyroiditis, but present- laboratory data for subclinical hypothyroidism with ed with typical clinical course of ST with negative borderline increased ESR interpreted as reconvales- thyroid antibodies in the female patient and posi- cent ST, but due to insufficient effect was switched to tive anti-thyroid peroxidase antibodies in the male. prednisolone 0.5 mg/kg/day. The clinician should not forget that the presence of Overall 2 patients required temporary beta-blocker one thyroid disease does not preclude the possibil- treatment for tachycardia. ity of another. Second, ST can develop in diabetic patients and this association underlines the im- portance of diabetes for the corticosteroid treatment of immune- medi- ated diseases. Two patients had concomitant type 2 diabetes mellitus at the background of metabolic syndrome. The presence of diabetes should not preclude the use of corticosteroid treatment if needed, Fig. 1. Thyroid ultrasound examination of the thyroid gland – enlarged gland with decreased parenchy- mal echogenicity but close blood glucose monitoring is mandatory in such cases and ap- Discussion propriate changes in antidiabetic treatment should be made if required. Moreover, in patients with ST Subacute thyroiditis is a relatively rare immune-me- and metabolic syndrome without overt diabetes, diated inflammatory thyroid disease presumed to be close monitoring of blood glucose is needed be- caused by a post-viral inflammatory process [8]. It is cause of the risk of full-blown diabetes after the characterized by pain in the neck and the presence of initiation of corticosteroids. And third, subacute swollen and tender thyroid gland, fever, fatigue, an- thyroiditis may be misdiagnosed for other inflam- orexia, with or without symptoms of dysthyroid con- matory diseases and should not be forgotten as a dition. The clinical course of ST follows well-defined cause of fever of unknown origin, especially when and predictable changes in thyroid function: usually neck pain is present. initial hyperthyroid phase at presentation, followed by In conclusion, we present a series of 12 patients transient euthyroidism, hypothyroidism and returning with ST, the majority are female, middle-aged and to euthyroid state. For a period of 29 months we ob- otherwise healthy, only 2 patients had an estab- served overall 12 cases of ST, diagnosed with neck lished thyroid disease (Hasminoto’s thyroiditis), and pain, the presence of painful goiter, laboratory signs 2 patients were diabetic (one of them with Hashi- of acute inflammation and dysthyroid state. The ma- moto’s thyroiditis). The diagnosis ST was based jority of patients were female (female : male ration = on the typical clinical picture, laboratory findings of 3:1), middle-aged and otherwise healthy. The major- acute inflammation and hyperthyroid state, and ul- ity of patients were initially misdiagnosed for other in- trasound changes. Fine-needle aspiration biopsy is flammatory conditions (8 of 12 were misdiagnosed for usually not needed in ST patients and the results having ear-nose-throat, respiratory or other infection) are non-specific. The treatment consisted in anti-in- but eventually were referred to endocrinologist with flammatory agents (corticosteroids in 11 and NSAID suspected subacute thyroiditis. Corticosteroid treat- in 1, followed by corticosteroids due to insufficient ment was initiated in 11/12 and the last patient was effect), short course with beta-blockers in 2. In all first started on NSAID and subsequently switched to patients we observed subsiding of inflammation and corticosteroids. Corticosteroid treatment had excel- restoration of thyroid function.

48 Y. Vlahov, A-M. Borisova, M. Nikolova et al. The results of our study show that ST should be con- 5. Desailloud R, Hober D. Viruses and thyroiditis: an update. Vi- sidered as a cause of neck pain and fever of unknown rol J 2009;6:5-18. origin. In patients with diabetes mellitus corticoste- 6. Benbassat CA, Olchovsky D, Tsvetov G, Shimon I. Subacute roid treatment is not contraindicated but it requires thyroiditis: clinical characteristics and treatment outcome in close monitoring of blood glucose levels. fifty-six consecutive patients diagnosed between 1999 and 2005. J Endocrinol Invest 2007;30:631-635. 7. Ohsako N, Tamai H, Sudo T, et al. Clinical characteristics of Disclosure Summary: The authors have nothing to disclose. subacute thyroiditis classified according to human leukocyte antigen typing. J Clin Endocrinol Metab 1995;80:3653-3656. References 8. Burman KD. Subacute thyroiditis. https://www.uptodate.com/ contents/subacute-thyroiditis . 1. Li LX, Wu X, Hu B, et al. Localized subacute thyroiditis 9. Volpé R, Row VV, Ezrin C. Circulating viral and thyroid an- presenting as a painful hot nodule. Endocrine Disorders 2014;14:4-7. tibodies in subacute thyroiditis. J Clin Endocrinol Metab 2. Dalugama C. Asymptomatic thyroiditis presenting as pyrexia 1967;27:1275-1284. of unknown origin: a case report. Journal of Medical Case 10. Park SY, Kim EK, Kim MJ, et al. Ultrasonographic character- Reports 2018;12:51-53. istics of subacute granulomatous thyroiditis. Korean J Radiol 3. Fatourechi V, Aniszewski JP, Fatourechi GZ, et al. Clinical 2006;7:229-234. features and outcome of subacute thyroiditis in an incidence 11. Hiromatsu Y, Ishibashi M, Miyake I, et al. Color Doppler ul- cohort: Olmsted County, Minnesota, study. J Clin Endocrinol trasonography in patients with subacute thyroiditis. Thyroid Metab 2003;88:2100-2105. 1999;9:1189-1193. 4. Martino E, Buratti L, Bartalena L, et al. High prevalence of subacute thyroiditis during summer season in Italy. J Endocri- nol Invest 1987; 10:321-322. Received: June, 2019 – Accepted: June, 2019

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