New aspects in the pathogenesis and management of subacute thyroiditis.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease, whose pathogenesis and determinants of the clinical course were unclear for many decades. The last few years have brought many clinically significant new data on the epidemiology, pathogenesis and management of SAT. Several human leukocyte antigen (HLA) alleles were demonstrated not only to increase the risk of SAT, but also to correlate with SAT clinical course and determine the risk of recurrence. The world-wide epidemic of the coronavirus disease 19 (COVID-19) has provided new observations that the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can be a potent SAT-triggering factor, and that the clinical course of SAT in patients affected by COVID-19 is different from a typical one. Additionally, many new trends in the clinical course are emerging. In the last years, painless course of SAT is more and more often described, constituting a special challenge in patients hospitalized due to COVID-19. Despite an excellent availability of diagnostic methods, several difficulties in SAT differential diagnosis can be currently encountered and the proper diagnosis and treatment is frequently delayed. False positive diagnoses of SAT in patients with malignancies of poor prognosis constitute a life-threatening problem. Taking into account all the new aspects of SAT pathogenesis and of its clinical course, the new - modified - SAT diagnosis criteria have been proposed.

[Non-autoimmune thyroiditis]. / Tiroiditis no-autoinmunes.

The term thyroiditis comprises a group of thyroid diseases characterized by the presence of inflammation, including autoimmune and non-autoimmune entities. It may manifest as an acute illness with severe thyroid pain (subacute thyroiditis and infectious thyroiditis), and conditions in which the inflammation is not clinically evident evolving without pain and presenting primarily thyroid dysfunction and/or goiter (drug-induced thyroiditis and Riedel thyroiditis). The aim of this review is to provide an updated approach on non-autoimmune thyroiditis and its clinical, diagnostic and therapeutic aspects.

Graves' disease following subacute thyroiditis.

Subacute thyroiditis is a painful, inflammatory disease frequently accompanied with fever. It is suspected to be a viral infectious disease, while Graves' disease is an autoimmune disease. Thus, there appears to be no etiological relationship between the two diseases. A total of 25,267 thyroid disease patients made their first visits to our thyroid clinic during a period of 24 years between 1985 and 2008. Among them, subacute thyroiditis and Graves' disease accounted for 918 patients (3.6%) and 4,617 patients (18.2%), respectively. We have encountered 7 patients (one male and six female) with subacute thyroiditis followed by Graves' disease in this period (0.15% of the 4,617 patients with Graves' disease and 0.76% of the 918 patients with subacute thyroiditis). The age ranges were 40~66 years (mean 48.7 years) at the onset of subacute thyroiditis. The intervals between the onsets of subacute thyroiditis and Graves' disease were 1~8 months (mean 4.7 months). Because Graves' disease was preceded by subacute thyroiditis, the signs and symptoms of both diseases were evident together in the intervening period. The diagnosis of Graves' disease in those patients is always difficult because of atypical signs and symptoms and an unclear onset time. The causes of the Graves'disease that followed subacute thyroiditis are still unknown. However, the inflammatory nature of subacute thyroiditis may lead to the activation of the autoimmune response in susceptible subjects, resulting in the onset of Graves' disease. Graves' disease should be suspected when a high blood level of thyroid hormone persists after subacute thyroiditis.

Subacute thyroiditis as a presenting manifestation of COVID-19: a report of an exceedingly rare clinical entity.

The SARS-CoV-2 has wreaked havoc globally and has claimed innumerable lives all over the world. The symptoms of this disease may range from mild influenza-like symptoms to severe acute respiratory distress syndrome with high morbidity and mortality. With improved diagnostic techniques and better disease understanding, an increased number of cases are being reported with extrapulmonary manifestations of this disease ranging from renal and gastrointestinal to cardiac, hepatic, neurological and haematological dysfunction. Subacute thyroiditis is a self-limiting and painful thyroid gland inflammation most often secondary to viral infections. We report a case of subacute thyroiditis in a 58-year-old gentleman presenting with a painful swelling in the neck who was subsequently detected to be positive for SARS-CoV-2. We seek to highlight the broad clinical spectrum of the COVID-19 by reporting probably the first case of subacute thyroiditis possibly induced by SARS-CoV-2 infection from India.

Decreasing TNF-alpha results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced in DBA/1 mice by adoptive transfer of mouse thyroglobulin (MTg)-primed spleen cells. TNF-alpha is an important proinflammatory cytokine and apoptotic molecule involved in many autoimmune diseases. To study its role in G-EAT, anti-TNF-alpha mAb was given to recipient mice. Disease severity was comparable between mice with or without anti-TNF-alpha treatment at days 19-21, the time of maximal severity of G-EAT, suggesting TNF-alpha is not essential for development of thyroid inflammation. However, thyroid lesions resolved at day 48 in anti-TNF-alpha-treated mice, while thyroids of rat Ig-treated controls had fibrosis. These results suggested that reducing TNF-alpha contributed to resolution of inflammation and inhibited fibrosis. Gene and protein expression of inflammatory molecules was examined by RT-PCR and immunostaining, and apoptosis was detected using TUNEL staining and an apoptosis kit. Thyroids of anti-TNF-alpha-treated controls had reduced proinflammatory and profibrotic molecules, e.g., IFN-gamma, IL-1beta, IL-17, inducible NOS and MCP-1, at day 19 compared with thyroids of rat Ig-treated mice. There were more apoptotic thyrocytes in rat Ig-treated controls than in anti-TNF-alpha-treated mice. The site of expression of the anti-apoptotic molecule FLIP also differed between rat Ig-treated and anti-TNF-alpha-treated mice. FLIP was predominantly expressed by inflammatory cells of rat Ig-treated mice and by thyrocytes of anti-TNF-alpha-treated mice. These results suggest that anti-TNF-alpha may regulate expression of proinflammatory cytokines and apoptosis in thyroids, resulting in less inflammation, earlier resolution, and reduced fibrosis.

Association of the ultrasonographic findings of subacute thyroiditis with thyroid pain and laboratory findings.

We aimed to determine whether ultrasonography is a useful diagnostic tool by correlating its findings with biological data of patients with subacute thyroiditis (SAT). Thirty-two SAT patients were evaluated in a retrospective study. Thirty-one patients (96.9%) had tenderness, 14 (43.8%) had localized pain, and 11 patients (34.4%) had radiating pain during a state of SAT. With ultrasonography, we found 51 hypoechoic areas in 32 patients. The hypoechoic volume per unilateral thyroid gland (%) was significantly larger in areas accompanied with pain (P<0.001). Out of 27 patients measured, 18 (67%) were positive for thyroglobulin antibodies (TgAb), of whom all were females. TgAb levels ranged from 0.3 to 13.8 U/ml. During therapy, TgAb levels gradually increased in 2 of the 7 patients who were measured several times. Both thyroglobulin antigen (TgAg) and free thyroxine (FT4) correlated well with total hypoechoic volume (cm (3) ), and the TgAg level showed a strong correlation with the FT4 level (r = 0.7; P<0.0001). The area (%) that the hypoechoic volume occupied in the total thyroid gland, even if the area was over half, was not related to the need of L-T4 replacement therapy. Also, none of the other variables (age, days from onset until diagnosis, serum levels of FT4, TgAg, CRP, autoantibodies, therapies, treatment) differed between the patients with and without replacement therapy. In summary, we found that the hypoechoic area in patients with SAT reflected the degree of inflammation and thyroid hormone levels, though it was difficult to predict continuous hypothyroidism.

A rare case of subacute thyroiditis causing thyroid storm.

Thyroid storm is a rare but potentially fatal condition that is most frequently associated with Graves' disease. We present the case of a young woman who presented in thyroid storm, later diagnosed as being due to severe subacute thyroiditis. We discuss the diagnostic approach to thyroid storm, the initial management, and eventual treatment and course of subacute thyroiditis. This case illustrates the necessity to include subacute thyroiditis in the differential diagnosis of severe thyrotoxicosis and thyroid storm.

Demographic and clinical features of patients with subacute thyroiditis: results of 169 patients from a single university center in Turkey.

BACKGROUND: Turkey is an endemic area for thyroid diseases. The Aegean region is well documented for increased prevalence of thyroid disorders. In this study we investigated the demographic and clinical features of subacute thyroiditis (SAT) patients who had been diagnosed and treated in Ege University. METHODS: The hospital files of patients admitted to the endocrinology clinic of Ege University between January 1987 and December 2001 were retrospectively evaluated. Patients who had been diagnosed as having any thyroid disorder were determined. RESULTS: 176 fulfilled diagnostic criteria for SAT. The majority of patients with SAT were diagnosed as having subacute granulomatous thyroiditis (169/176) (134 females, 35 males, mean age 34.0+/-17.8 yr); 69% of the patients were between 30-50 yr of age. Thyroid pain was present in 97.1% of female patients, and in 100% of male patients. High fever was evident in 78 patients (46.2%). Mean erythrocyte sedimentation rate (ESR) was 43.42+/-39.68 mm/h. Anti-thyroglobulin antibody was positive in 20%, and anti-thyroid peroxydase antibody was positive in 4% of patients. Among patients who were treated with non-steroidal anti-inflammatory drugs (NSAD) 10 female patients (10.6%), and 3 male patients (12%) developed recurrence of the disease. Among patients who were treated with prednisolone 7 female patients (17.5%), and one male patient (10%) developed recurrence. There was no significant difference regarding the recurrence rates between patients who were treated with NSAD and patients who were treated with prednisolone. CONCLUSION: With the exception of ESR, demographic, clinical, laboratory, and imaging findings and prognoses of our patients were comparable to the previous reports.

Long-term outcome of thyroid function after amiodarone-induced thyrotoxicosis, as compared to subacute thyroiditis.

BACKGROUND: Two main forms of amiodarone- induced thyrotoxicosis (AIT) exist: type 1 AIT is a condition of true hyperthyroidism developing in patients with pre-existing thyroid disorders, and usually requires thyroid ablative treatment. On the other hand, type 2 AIT is a form of destructive thyroiditis occurring in normal thyroids, the management of which usually consists in glucocorticoid treatment. AIM: To assess the long-term outcome of thyroid function in a prospective study of type 2 AIT patients, as compared to patients with De Quervain's subacute thyroiditis (SAT). PATIENTS AND METHODS: Sixty consecutive patients with type 2 AIT were evaluated during oral glucocorticoid treatment (oral prednisone 30 mg/day, gradually tapered and withdrawn over a 3-month period) and followed for 38+/-4 months (range 6-72) thereafter. Sixty consecutive patients with SAT, referred to our Institutes during the same period and treated with the same therapeutic schedule, served as controls. RESULTS: Type 2 AIT patients were older (p<0.0001) and showed a larger male preponderance (M:F 3.6:1 vs 0.5:1, p<0.0001) than SAT patients. Mean serum free T4 (FT4) and free T3 (FT3) concentrations at diagnosis were increased in both conditions, but higher in type 2 AIT than in SAT (FT4 47.6+/-18.8 and 29.6+/-8.3 pmol/l, respectively, p<0.0001; FT3 15.4+/-7.0 and 11.2+/-3.0 pmol/l, respectively, p<0.001). Correction of thyrotoxicosis was obtained in all patients in both groups, but restoration of euthyroidism occurred earlier in SAT than in type 2 AIT (p=0.006). Ten type 2 AIT patients (17%) and 3 SAT patients (5%, p<0.03) became permanently hypothyroid after glucocorticoid withdrawal and required levothyroxine replacement. CONCLUSIONS: A relevant proportion of type 2 AIT patients develop permanent hypothyroidism after correction of thyrotoxicosis. Thus, periodic surveillance of thyroid status is required after type 2 AIT.

Syndromes of thyrotoxicosis with low radioactive iodine uptake.

It is very important to diagnose correctly the etiology of thyrotoxicosis, because the course and treatment of thyrotoxicosis with low radioactive iodine uptake differ significantly from that of hyperthyroidism due to Graves' disease or toxic nodular goiter. Many causes of subacute thyroiditis have been identified producing a characteristic course of transient hyperthyroidism, followed by hypothyroidism, and usually recovery. Ectopic hyperthyroidism includes factitious thyroid hormone ingestion, struma ovarii, and, rarely, large deposits of functioning thyroid cancer metastases. Iodine-induced hyperthyroidism may be associated with low radioiodine uptakes. Amiodarone-associated hyperthyroidism may be the result of subacute thyroiditis or iodine-induced hyperthyroidism; assessment and treatment can be quite challenging.

Thyroiditis. Acute, subacute, and chronic.

Inflammatory diseases of the thyroid are collectively the commonest thyroid disorder. Individually, they range from the rare case of acute bacterial thyroiditis to the other end of the spectrum, the even rarer Riedel's thyroiditis. Relatively common thyroid inflammatory diseases include the subacute thyroiditis syndromes. Of particular interest to endocrinologists is that both subacute granulomatous (painful) thyroiditis and subacute lymphocytic (painless) thyroiditis are very similar in terms of clinical course, although most likely have different etiologies. Nevertheless, their similarities suggest the possibility that there may be etiologic heterogeneity for the syndromes. From a clinical standpoint, it is essential to differentiate subacute painless thyroiditis from Graves' disease, because these two disorders also may mimic each other, yet only Graves' disease requires specific therapy. Chronic lymphocytic (Hashimoto's) thyroiditis, the commonest of the thyroiditides, presents with goiter and either hyperthyroidism (uncommon), hypothyroidism (common), or euthyroidism (most common). When L-T4 therapy is used in the treatment of Hashimoto's thyroiditis, the physician must be alert to the possibility of excess thyroid hormone administration. Sensitive TSH measurements help to avoid this therapeutic pitfall.

The management of subacute (DeQuervain's) thyroiditis.

Subacute (DeQuervain's) thyroiditis is a transient inflammatory thyroid disease usually associated with pain and tenderness of the gland, as well as generalized somatic symptoms, which can cause great discomfort or even complete prostration for weeks or months if left untreated. It is almost certainly the result of a viral infection. There is no definitive therapy for painful subacute thyroiditis, but there is effective treatment that will ameliorate the symptoms and allow the disease to run its spontaneous course in an asymptomatic fashion. Salicylates and nonsteroidal antiinflammatory drugs can be used in patients with mild or moderate forms of the disorder. In more severe forms of the condition, corticosteroids in suitable pharmacological dosage will generally cause a rapid relief of symptoms within 24-48 h. Prednisone may be initiated in dosages of 40 mg daily, with a gradual reduction in dosage thereafter over several weeks. Recurrences do appear in a small percentage of patients, necessitating restoration of a higher dose once again. Repeat exacerbations are uncommon. Other less common forms of treatment include triiodothyronine or thyroxine, generally to prevent repeated exacerbations. Irradiation is no longer employed. Thyroidectomy should be considered only in that very small minority of patients who have repeated relapses despite appropriate treatment. During the period of transient hypothyroidism, thyroxine may be provided but can usually be discontinued subsequently. General recovery is almost the universal rule and only less than 1% become permanently hypothyroid.

The value of ultrasonography in the diagnosis and follow-up of subacute thyroiditis.

Twenty-three consecutive patients with clinical and biochemical suspicion of subacute thyroiditis (SAT) were evaluated by ultrasonic scanning of the thyroid. Ultrasonic findings supported the diagnosis in all cases. In the 16 patients in whom thyroid scintigraphy was performed this was compatible with SAT. Initially, median thyroid volume was 40 mL (range 20-289) and a very low echogenicity was demonstrated in all patients. The extension of hypoechogenicity exceeded 75% in the majority of patients. Thyroid volume was significantly reduced to a median of 13 mL (range 9-40) (68% reduction, p < 0.00001) at a median follow-up period of 18 months (range 6-33) and a majority of the patients (60%) had persistent morphological abnormalities. No correlation between thyroid function and the extension of hypoechogenicity initially or at end of follow-up could be demonstrated. Recurrence was noted in 8 patients (35%), two of whom were positive for anti-TPO antibodies, but the risk of recurrence could not be correlated to the extension of hypoechogenicity or initial thyroid function. Recurrence was related to the further extention of hypoechoic areas and increase in thyroid volume, as evidenced by ultrasonography in our series. None developed thyroid antibodies, and all were euthyroid at the end of the observation period. We believe that high resolution ultrasonography has a useful supporting role in the diagnosis of subacute thyroiditis. In case of doubt and differential diagnostic considerations, it facilitates guided biopsies. Additionally, it allows determination of disease activity and thyroid size.

Inflammatory thyroid disorders.

Inflammatory disorders of the thyroid, including autoimmune thyroiditis, are among the most common endocrine abnormalities encountered in clinical practice. The association of pain with these disorders, however, is relatively uncommon. Despite this observation, painful thyroid disorders comprise a significant component of the spectrum of thyroid disease. A rational approach to such patients, including history, physical examination, laboratory evaluation, radionuclide or ultrasonographic imaging, and fine needle aspiration biopsy, will allow the appropriate diagnosis to be made in the vast majority of cases.

Henoch-Schonlein nephritis associated with subacute thyroiditis.

We present a 12-year-old boy who developed subacute thyroiditis during the course of rapidly progressive glomerulonephritis due to Henoch-Schonlein purpura (HSP) proven by clinical findings and percutaneous renal needle biopsy. The thyroid gland of the patient suddenly enlarged with mild tenderness while he was on steroid and dipyridamole therapy. Thyroid hormone levels revealed T3 0.31 ng/ml (nl: 0.52-1.75 ng ml), T4 2.53 ug/dl (nl: 4.8-12.8 ug/dl), free T3 0.80 pg/ml (nl: 2.14-5.34 pg/ml), free T4 0.2 ng/dl (nl: 0.73-1.95 ng/dl) and TSH 1.02 U/ml (nl: 0.36-3.25 U/ml). Antimicrosomal antibody was negative while antithyroglobulin antibody was slightly positive (1/80+). Hypoactivity with a spotty pattern was demonstrated by thyroid scanning. Serologically proven mumps infection was detected and may have been a triggering factor in the development of both HSP and subacute thyroiditis.

[A painful inflammation of the thyroid]. / Een pijnlijke ontsteking van de schildklier?

Four women aged 30, 29, 52 and 43 years presented with what appeared to be subacute thyroiditis (De Quervain's thyroiditis). This disease is characterized by fatigue, a painful thyroid gland and thyrotoxic manifestations. The diagnosis is further based on a high erythrocyte sedimentation rate and low tracer uptake during thyroid scintigraphy. Only the first patient showed a typical course. In the second and third ones the painful thyroid was associated with nodular enlargement. Fine needle aspiration cytology was at first consistent with subacute thyroiditis but a repeated aspiration showed papillary carcinoma in the second and anaplastic carcinoma in the third patient. In the fourth one, subacute thyroiditis was accompanied by normochromic anaemia, a low serum albumin concentration and liver function disorders. She made a full recovery without treatment. Thyroid malignancies can mimic subacute thyroiditis. Persistent nodular enlargement of the thyroid is suspicious and requires careful investigation.