Subacute Thyroiditis

Destruction of follicular epithelium and loss of follicular integrity are the primary events in the pathophysiology of subacute granulomatous thyroiditis. Thyroglobulin (TG), thyroid hormones, and other iodinated compounds are released into the blood, often in quantities sufficient to elevate the serum thyroxine (T4) and triiodothyronine (T3) concentrations and suppress thyroid-stimulating hormone (TSH) secretion. This state lasts until the stores of TG are exhausted or until healing occurs. Thyroidal iodine uptake and new hormone synthesis temporarily ceases because of the low level of TSH.

As inflammation subsides, the thyroid follicles regenerate and thyroid hormone synthesis and secretion resume. In some patients, several months are required for thyroid hormone synthesis to return to a normal rate; during that period, clinical hypothyroidism may be evident.

Thyrotoxicosis

The hypermetabolic effect of thyrotoxicosis is the same, regardless of cause. Thyrotoxicosis affects every organ system, because thyroid hormones made in the thyroid travel via the circulation to reach every cell in the body. Thyroid hormone is necessary for normal growth and development, and it regulates cellular metabolism.

Excess thyroid hormone causes an increase in metabolic rate that is associated with increased total body heat production, increased cardiovascular activity (eg, increased heart contractility, heart rate, vasodilation) to remove heat to the periphery and remove metabolic wastes, and perspiration to cool the body.

The major symptoms of thyrotoxicosis include palpitations, nervousness, sweating, hyperdefecation, and heat intolerance. Women often note a reduction in menstrual flow, or oligomenorrhea. Common signs of thyrotoxicosis include the following:

• Weight loss despite increased appetite

• Lid lag and stare

• Sinus tachycardia

• Atrial fibrillation or high-output failure (in elderly persons)

• Fine tremor

• Muscle weakness

Synergism occurs between thyrotoxicosis and the adrenergic system, with increases in nervousness, stare, tremor, and tachycardia.

The manifestations of thyrotoxicosis vary among patients. Younger patients tend to exhibit more sympathetic activations (eg, anxiety, hyperactivity, tremor), while older patients have more cardiovascular symptoms (eg, dyspnea, atrial fibrillation) and unexplained weight loss. The clinical manifestation of thyrotoxicosis does not always correlate with the extent of the biochemical abnormality.

Papillary thyroid carcinoma

A retrospective study by Gül et al suggested that papillary thyroid carcinoma is more prevalent in subacute thyroiditis than has previously been indicated. While one report found the rate of papillary thyroid carcinoma to be 0.4% in subacute thyroiditis, and another found no cases of such carcinomas in patients with the condition, the prevalence in this study was 4.4% (6 out of 137 patients). ^[4]

A study by Nishihara et al reported that under ultrasonographic evaluation, hypoechoic inflammatory regions in subacute thyroiditis can severely obscure coexisting papillary carcinoma. Consequently, the investigators advised that ultrasonographic reexamination be performed after a sufficient interval in patients with subacute thyroiditis. ^[5]

The causes of subacute thyroiditis, other than those of subacute granulomatous thyroiditis, are not entirely clear.

Subacute granulomatous thyroiditis

The most accepted etiology for this condition is a viral illness. ^[6] Viral particles have never been identified within the thyroid, but episodes often follow upper respiratory infections and are associated with falling postconvalescent viral titers of various viruses, including influenza, adenovirus, mumps, and coxsackievirus. The occurrence of subacute granulomatous thyroiditis in the course of novel H1N1 influenza infection has been reported from Greece. ^[7]

De Quervain thyroiditis is not associated with autoimmune thyroiditis. The transient presence of autoantibodies (eg, inhibitory immunoglobulins that bind to TSH, antibodies that block thyroid stimulation, thyroid antimicrosomal antibodies, thyroglobulin [TG] antibodies) has been noted in the acute phase of the disease, but this has been attributed to a virally induced autoimmune response and has not been implicated in the pathologic process. (Viral inclusion bodies are not observed in thyroid tissue in subacute granulomatous thyroiditis.)

It is unclear, however, whether the destructive thyroiditis in De Quervain patients is caused by direct viral infection of the gland or by the host's response to the viral infection.

In contrast to autoimmune thyroid disease, the immune response in subacute granulomatous thyroiditis is not self-perpetuating; therefore, the process is limited.

HLA-B35

A genetic predisposition to the development subacute granulomatous thyroiditis clearly exists; risk for developing the disease in patients with human leukocyte antigen (HLA)–Bw35 is 6-fold that of the general population. ^[8] In one study, as many as 72% of patients with subacute thyroiditis manifested HLA-Bw35.

A proposed etiologic mechanism suggests that the disease results from a viral infection that provides an antigen, one that is either viral or that results from virus-induced host tissue damage, that uniquely binds to HLA-B35 molecules on macrophages. The antigen–HLA-B35 complex activates cytotoxic T lymphocytes that damage thyroid follicular cells, because these cells have some structural similarity to the infection-related antigen.

In Japanese patients, an association seems to exist between subacute granular thyroiditis and HLA-B67. In a study, 87% of Japanese patients with subacute thyroiditis had either HLA-B35 or HLA-B67. Research indicates that HLA-B67 is associated with a greater risk of developing a hypothyroid phase than is HLA-Bw35.

Growth factors

The role of growth factors in the development of subacute thyroiditis has received some attention. In the granulomatous stage of subacute thyroiditis, growth factor–rich monocytes and/or macrophages infiltrating follicular lumina are thought to trigger the granulomatous reaction, with this reaction probably being mediated by vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor beta 1 (TGF-β1) produced by the stromal cells.

In the regenerative phase, endothelial growth factor (EGF) mediates follicular regeneration through its mitogenic effect on thyrocytes, along with cofactors. In addition, the decreased expression of TGF-β1, a fibrogenic factor, contributes to thyroid tissue repair. VEGF and bFGF may be responsible for angiogenesis in both stages.

Subacute lymphocytic thyroiditis

This condition most likely is autoimmune in nature. Patients develop an autoimmune goiter and permanent hypothyroidism more often than they do with subacute granulomatous thyroiditis. An HLA association may be present, suggesting a genetic predisposition to subacute lymphocytic thyroiditis.

Certain drug exposures relating to excess iodine and cytokines may cause this form of silent thyroiditis. These drugs include amiodarone (iodine-rich), interferon alfa, interleukin 2, and lithium. Cases of thyroiditis resulting from these drugs are typically treated in a similar way.

Amiodarone

Amiodarone has multiple established effects on thyroid function. One of the 2 types of amiodarone-induced thyrotoxicosis is a destructive subacute lymphocytic thyroiditis. This form of thyroiditis is more common in men, likely due to the higher prevalence of amiodarone therapy in men. Subacute lymphocytic thyroiditis typically occurs after more than 2 years of amiodarone therapy. ^[9]

Interferon alfa

Up to 5% of patients taking interferon alfa may experience subacute lymphocytic thyroiditis. This condition is detected biochemically, after 3 months of therapy, more often than it is found clinically. Subacute lymphocytic thyroiditis in patients taking interferon alfa is associated with an increased antithyroid antibody concentration.

Interleukin 2

Although case reports exist that interleukin 2 is associated with subacute lymphocytic thyroiditis, its causative role is less established than that of interferon alfa.

Lithium

Lithium is a well-known cause of either subclinical or clinical hypothyroidism, as well as of goiter. Because of lithium’s ability to inhibit the release of thyroid hormone, it has been used as a treatment for thyrotoxicosis. However, reports exist of lithium-associated thyrotoxicosis due to a subacute lymphocytic thyroiditis, with the classic picture of hyperthyroidism, absent neck tenderness, and low radioactive iodine uptake.

Subacute lymphocytic thyroiditis can occur during lithium administration, as well as up to 5 months following discontinuation of lithium therapy. Increased thyroid antibodies in lithium users and a direct toxic effect of lithium have been proposed as possible mechanisms.

Subacute postpartum thyroiditis

This condition is likely autoimmune in nature. ^[10] Patients develop an autoimmune goiter and permanent hypothyroidism more often than they do with subacute granulomatous thyroiditis. In iodine-sufficient countries, such as the United States, postpartum thyroiditis occurs in approximately 5-8% of pregnant women. In Japan where the diet is rich in iodine, nearly 20% of pregnancies are associated with this condition.

Patients with positive test results for thyroid autoantibodies either before their pregnancy or during the third trimester are at much higher risk of developing postpartum thyroiditis.

Cigarette smoking is also associated with an increased incidence of postpartum thyroiditis. Once patients have an episode of subacute postpartum thyroiditis, they are likely to have additional episodes following each pregnancy.

Additional causes of subacute thyroiditis

Other causes of subacute thyroiditis, or at least conditions that have been associated with the disease, include the following:

• Radioiodine therapy for Graves disease can result in transient thyroidal inflammation, causing thyroiditis

• Subacute thyroiditis also has been described following external radiation to the neck

• Subacute thyroiditis has presented as a paraneoplastic manifestation of renal cell carcinoma

• An association between subacute thyroiditis and febrile neutrophilic dermatoses (Sweet syndrome) has been reported

• Concurrence of giant cell arteritis has been reported in patients with classic de Quervain thyroiditis

• Subacute thyroiditis has been described after bone marrow transplantation for chronic granulocytic leukemia

COVID-19

A case study by Brancatella et al suggested that in some patients, subacute thyroiditis may arise from coronavirus disease 2019 (COVID-19). The report involved a woman aged 18 years who was found to have no thyroid disease before then testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About three weeks later, she tested negative for the virus, but, a few days after that, presented with symptoms of subacute thyroiditis, which was subsequently diagnosed. The timing of the thyroiditis, the investigators believe, points to a COVID-19 origin, particularly in light of the fact that subacute thyroiditis is commonly thought to develop in response to viral infection or a postviral inflammatory reaction in persons with a genetic predisposition. ^{[11, 12]}

Additional research has continued to point to the development of a condition resembling subacute thyroiditis in persons with COVID-19. This includes an Italian study that found that among 85 patients with COVID-19 admitted to high-intensity-care units (HICUs), up to 13 (15%) were thyrotoxic, compared with just 1% of HICU patients from pre-pandemic 2019 who were studied in the report. ^{[13, 14]}

Further investigation indicates that subacute thyroiditis may persist months later in patients in whom the thyroid gland becomes inflamed during acute COVID-19 illness, even after normalization of thyroid function. In addition, the effects of SARS-CoV-2 on thyroid function appear to be multifactorial, with the thyroiditis being atypical in that no neck pain seems to be involved and more men than women appear to be affected. In addition, patients who were examined exhibited low TSH and free T3 levels, while free T4 levels were normal or elevated. ^[15]

There may also be an association between COVID-19 vaccination and the development of subacute thyroiditis, including with regard to mRNA and non-mRNA vaccines. However, a study by Ippolito et al indicates that the subacute thyroiditis cases are primarily of mild to moderate severity, with the investigators stating that most of these can be treated via symptomatic therapy or a short course of steroids. Therefore, according to the report, the vaccination/thyroiditis association “should not raise any concern regarding the need to be vaccinated, since the risks of COVID-19 undoubtedly outweigh the risks of the vaccination.” ^[16]

Ippolito and colleagues also mention the possibility that in persons who receive an mRNA COVID-19 vaccine, the likelihood of developing subacute thyroiditis may be greater in those who have a previous history of thyroid disease. They found that out of the 51 patients in their study who developed subacute thyroiditis, approximately 12% (all of whom had been given an mRNA vaccine) had thyroid disease history; however, they indicate that further research is needed to support this contention. ^[16]

Subacute granulomatous thyroiditis occurs in less than 5% of all patients with thyroid pathology, although estimates indicate that together, the 3 forms of subacute thyroiditis account for 20-25% of thyrotoxicosis cases. De Quervain thyroiditis tends to have a seasonal and geographic distribution and is most common during the summer and fall. It tends to follow viral epidemics.

A systematic review of all cases of subacute granulomatous thyroiditis diagnosed between 1960 and 1997 in Olmsted County, Minnesota, revealed an age- and sex-adjusted annual incidence of 4.9 cases per 100,000 population. ^[17]

Postpartum thyroiditis has an incidence of 5.4% in the general population. An isolated hypothyroid phase occurs in 48% of women with the condition, while isolated thyrotoxicosis is found in 30% patients, and a presentation of hyperthyroidism followed by hypothyroidism is seen in 22% of them. ^[2]

Sex-related demographics

As is the case for most thyroid diseases, de Quervain thyroiditis appears more frequently in females, with a female-to-male ratio of 3-5:1. Subacute lymphocytic thyroiditis occurs twice as often in women as it does in men.

Postpartum thyroiditis occurs 1-6 months after giving birth. If a woman has postpartum thyroiditis with one baby, all other pregnancies are likely to be associated with this condition.

Age-related demographics

Subacute lymphocytic thyroiditis can occur in any age group, while postpartum thyroiditis occurs in women of childbearing age.

Subacute granulomatous thyroiditis usually occurs in adults (ie, aged 20-60 y), with the incidence peaking in the fourth and fifth decades of life. It is rare in the first decade and relatively infrequent in people older than 50 years, although it has been reported in extreme age groups. ^[18] Occurrence during pregnancy has been reported as well. ^[19]

The prognosis is excellent in 90-95% of patients who experience subacute thyroiditis. Approximately 5-10% of patients have permanent thyroid dysfunction, usually hypothyroidism, after an episode of subacute thyroiditis. Permanent goiter and thyroid dysfunction occur most frequently after postpartum thyroiditis.

Thyrotoxicosis

Thyrotoxicosis from subacute thyroiditis is brief, usually lasting no longer than 6-8 weeks. Patients can be extremely thyrotoxic during this period and can appear extremely ill, but concerns regarding left ventricular hypertrophy and osteoporosis are not as great as those associated with conditions of permanent hyperthyroidism. However, sudden-onset thyrotoxicosis and severe thyrotoxicosis can be associated with atrial arrhythmia and congestive heart failure (CHF).

Subacute granulomatous thyroiditis

This condition generally resolves completely in more than 90-95% of patients. No special thyroidal follow-up is needed. Morbidity is caused during the initial phase by pain, which usually prompts the patient to consult a physician. Hyperthyroidism, usually a mild, transient form, occurs in approximately 50% of patients with subacute granulomatous thyroiditis; in up to half of all patients, hypothyroidism may later develop.

Acute complications

When acute complications do occur, they can include the following:

• Severe hyperthyroidism - May be observed during the inflammatory phase

• Severe anterior neck pain over the thyroid - Usual treatment is nonsteroidal therapy, but emerging studies suggest that prednisolone 15 mg/day with a taper of 5 mg every 2 weeks is safe and effective to quickly reduce pain; in a study of prednisolone use by Kubota et al, most patients had resolution of symptoms by 6-8 weeks, although the longest period of therapy was 40 weeks ^[20]

• Multiple system organ failure - May complicate the course of the disease in exceptionally rare cases

• Pancreatitis or splenomegaly - Associated with de Quervain thyroiditis in case reports only

• Vocal cord paralysis - Occurs occasionally in cases with severe thyroid gland inflammation

• Cerebral venous thrombosis - has been reported in some cases; in one case, the patient was a heterozygous carrier for the G20210A mutation of the prothrombin gene, which predisposed her to this complication

Long-term complications

Permanent hypothyroidism is the most frequent long-term complication of de Quervain thyroiditis. It is observed in less than 5-10% of the patients and requires thyroid replacement therapy.

Disease recurrence has been documented in occasional cases (up to 20% of cases in some series). Recurrence is more frequent in the first year but has been reported even 30 years after the initial diagnosis. The risk of recurrence cannot be correlated with initial thyroid function, inflammatory syndrome, or ultrasonographic aspect (ie, thyroid volume, echogenicity).

Subacute lymphocytic thyroiditis

Occasionally, patients have recurrent episodes of painless thyrotoxicosis. ^[21] No treatment exists to prevent the recurrences except subtotal thyroidectomy. However, this condition generally resolves completely in more than 90-95% of patients. Patients with goiters or permanent thyroid dysfunction should be monitored with a thyroid examination and thyroid function tests every 6 months.

Subacute postpartum thyroiditis

Usually, repeat episodes occur after each pregnancy; no known treatment exists to prevent these. Patients may have a residual goiter and thyroid hypofunction after postpartum thyroiditis, because this condition is associated with chronic autoimmune thyroiditis. Patients should be observed routinely for goiter enlargement and thyroid hypofunction every 6-12 months.