Hashimoto’s Thyroiditis Epidemiology
Hashimoto’s thyroiditis (HT) was fi rst reported in 1912 by Hakaru Hashimoto, who described four patients with a chronic disorder of the thy- roid gland, termed struma lymphomatosa [ 3 ]. This entity was rarely identifi ed for many years, but an increase in its incidence was noticed since 1940 [ 4 ]. The diagnosis was usually made after surgery. Furthermore, the routine use of the fi ne needle aspiration biopsy (FNAB) and measure- ment of thyroid autoantibodies have contributed to a signifi cant rise in its frequency.
The annual incidence of HT for women and men is approximately 3.5 and 0.6 cases per 1000 population, respectively [ 5] and its estimated prevalence is about 8 cases per 1000 [ 6 ]. Women are at least six to eight times more likely to develop the disease. It occurs especially between 40 and 60 years of age, but it may be seen in any age group, including children [ 5 , 6 ].
HT is now considered the most common cause of hypothyroidism in areas of the world where dietary iodine is suffi cient [ 7 ], the most frequent autoimmune disease [ 8] and one of the main endocrine disorders [ 9 ].
It is also reported in the literature as chronic lymphocytic thyroiditis or chronic autoimmune thyroiditis.
Etiology and Pathogenesis
HT is an autoimmune disorder, thought to be caused by a combination of genetic susceptibility and environmental factors.
It seems that there is no dominant gene con- ferring major susceptibility to the disease. However, an association was described with human leukocyte antigen (HLA) alleles and with other genes, namely CTLA-4, thyroglobulin (Tg), PTPN22, FCRL3 and IL2RA [ 10 , 11 ].
Some precipitating factors have been identi- fi ed, but their role remains unknown. They include infection (e.g. hepatitis C virus, human T lymphotrophic virus-I, rubella virus, herpes sim- plex virus, parvovirus and Epstein-Barr virus), stress, postpartum period, iodine intake, selenium and vitamin D defi ciency, drugs such as interleu- kin- 2 (IL-2) and interferon-alpha (IFN-α), envi- ronment pollutants and radiation exposure. More women than men have HT, which can be explained by skewed X chromosome inactiva- tion, the role of sex steroids and fetal microchi- merism. The prevalence of the disease increases with age, which may refl ect an increasing loss of tolerance to self. Smoking has a surprisingly ben- efi cial effect on HT, in contrast to its detrimental role on Graves’ disease (GD) [ 11 , 12 ].
Several mechanisms have been proposed to be related to HT, namely: molecular mimicry, bystander activation, thyroid-cell expression of HLA antigens with subsequent activation of T cells, and thyroid expression of functional Fas and Fas ligand contributing to thyroid cell apop- tosis [ 13 ].
Thyroid infl ammation is typically character- ized by both T and B lymphocytes. T cells are thought to play the main role in the disease and can act by inducing antibody production, activat- ing cytotoxic T cells with apoptotic destruction of thyroid cells and regulating the local immune response. Type 1 and type 2 T helper cells are present in patients with HT, with a predominance of the former [ 14 ]. In addition, patients may have dysfunctional regulatory T cells [ 15 ]. B cells can
Table 6.1 Classifi cation of thyroiditis based on the pres- ence or absence of pain and tenderness
No thyroid pain and tenderness Hashimoto’s thyroiditis
Painless thyroiditis Postpartum thyroiditis
Amiodarone-associated thyroiditis
Thyroiditis induced by other drugs (lithium, interferon-alpha, interleukin-2, tyrosine kinase inhibitors)
Riedel’s thyroiditis
Infi ltrative thyroid disorders (amyloidosis, sarcoidosis) Thyroid pain and tenderness
Subacute thyroiditis Suppurative thyroiditis Radiation-induced thyroiditis
produce antibodies and nearly all individuals have high serum concentrations of Tg antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb), which are polyclonal and have the potential to fi x complement. As a result, complement- mediated cytotoxicity may contrib- ute to thyroid damage, but this is thought to be a second line effect [ 16 ]. Thyroid-stimulating hor- mone receptor antibodies (TRAb) can also be identifi ed in the serum of patients with HT. However, these antibodies block the action of thyroid-stimulating hormone (TSH) rather than activating thyroid tissue as seen in GD [ 17 ].
Clinical Features
The disease usually occurs as a painless, diffuse and gradual enlargement of the thyroid gland [ 18 ]. The goiter is often fi rm and symmetrical with pyramidal lobe enlargement. The presence of well-defi ned nodules is unusual. Rare patients have pain and tenderness [ 19] or symptoms related to neck pressure such as dyspnea or dys- phagia, particularly if there is a rapid thyroid swelling. The thyroid gland may also remain unchanged for several years and some patients do not develop goiter or have an atrophic gland. In fact, two forms of HT, goitrous and atrophic, were described representing extremes within the distribution rather than separate disorders [ 20 ].
The patient is usually euthyroid but symptoms and signs of mild hypothyroidism may be present [ 18 ]. Occasionally, clinical features of mild thy- rotoxicosis can occur, especially during the early phase of the disease [ 21 ].
One uncommon and controversial fi nding of HT is Hashimoto’s encephalopathy. A review published in 2006 identifi ed only 121 cases in the literature [ 22 ]. Its mechanism is unknown and it does not appear to be related to thyroid dysfunc- tion, as the majority of reported patients are euthyroid at the time of presentation. Evidence suggests an autoimmune vasculitis, but the role of thyroid antibodies is not clear [ 23 ]. Patient most often have an acute to subacute onset of confusion with alteration of consciousness and other neurologic signs, such as seizures, myoclo- nus, tremor, hyperrefl exia and psychosis [ 22 , 24 ]. The diagnosis is usually performed by the pres-
ence of clinical manifestations in patients with elevated thyroid antibodies. A response to corti- costeroids can also favor the diagnosis [ 25 ]. Other exams may be performed and are impor- tant in the differential diagnosis. Most patients respond to steroid therapy and prognosis is usu- ally good [ 22 , 24 ].
Diagnostic Evaluation
Patients with HT usually undergo a gradual loss of thyroid function. Approximately 75 % have normal thyroid function at diagnosis but they can develop subclinical or overt hypothyroidism [ 18 ], which is permanent in most cases. However, some patients may recover and reach euthyroid- ism, possibly explained by the decrease over time of TSH receptor blocking antibodies [ 26 ]. Rarely, the infl ammatory process in the early course of the disease may cause severe apoptosis and thy- roid damage, with subsequent thyroid hormone release and transient hyperthyroidism; this condi- tion is termed Hashitoxicosis and usually evolves into permanent hypothyroidism [ 18 , 21 ].
Serum concentrations of thyroid antibodies are almost always elevated. TPOAb and TgAb are positive in about 95 % and 60–80 % of patients, respectively [ 18 ].
A cervical ultrasound (US) may display an enlarged gland with very low echogenicity, or a suggestion of multiple ill-defi ned nodules. Most commonly the gland is two to four times the nor- mal size.
Radioactive iodine uptake (RAIU) test, although rarely required, is variable and ranges from below normal to elevated values. Thyroid scan is not necessary in most cases and the typi- cal fi nding is a diffuse or mottled uptake in an enlarged gland.
FNAB can be useful in patients with nodular disease. It usually reveals lymphocytes, macro- phages, scant colloid and epithelial cells which may show Hurthle cell features. However, some aspirates lack infl ammatory cells and consist almost exclusively of Hurthle cells, leading to a misleading result of Hurthle cell tumor [ 27 ].
Histological examination often reveals lym- phoplasmacytic infi ltration, lymphoid follicles with germinal center formation, epithelial cell
destruction, the presence of large follicular cells with abundant granular eosinophilic cytoplasm, known as oxyphilic, Hurthle or Askanazy cells, and various degrees of fi brosis [ 18 ].
HT is often associated with type 1 diabetes mellitus (T1DM), celiac disease, Addison’s dis- ease, Sjögren syndrome and other autoimmune disorders in the context of polyglandular autoim- mune syndromes. The link between HT and thy- roid cancer remains controversial. This association was fi rst described by Dailey et al. in 1955 [ 28 ]. Some authors reported that patients with HT have a threefold increased risk of papil- lary thyroid carcinoma (PTC) as compared to non-HT patients [ 29 ], but others stated that there is inconsistent evidence favoring a causal rela- tionship between these entities [ 30 ]. Thyroid can- cer may be associated with a less aggressive disease and a better prognosis in patients with coexisting HT [ 31 ].
The diagnosis of HT is usually performed in a patient with a diffuse goiter and one other bio- chemical or histological feature, such as positive TPOAb, positive TgAb or lymphocytic infi ltra- tion of the thyroid gland [ 32 ]. However, goiter can be absent and the presence of serum thyroid autoantibodies may be suffi cient evidence of the diagnosis. For many years, HT has been charac- terized as a well-defi ned clinicopathologic entity. However, it is now considered a heterogeneous disease, with several subtypes: classic form, fi brous variant, IgG4-related variant, juvenile form (presented before 18 years of age), Hashitoxicosis and painless thyroiditis, the latter occurring either sporadically or in the postpar- tum period. They share the diagnostic character- istics of HT but have some interesting particularities [ 18 ].
The fi brous variant accounts for 10–13 % of HT cases and usually affects older patients. Its diagnostic criteria were defi ned by Katz and Vickery in 1974 and included a marked fi brous replacement of more than one-third of the thyroid parenchyma and changes typical of HT in the remaining tissue [ 33 ]. Most patients are hypothy- roid at presentation.
The IgG4-related variant of HT is a new subtype, fi rst recognized by Li et al. in 2009 [ 34]. It may be part of the systemic IgG4- related disease. The diagnosis of this systemic
disorder includes, independently of the affected organ, histological features such as a dense lymphoplasmacytic infi ltrate, storiform-type fi brosis and obliterative phlebitis, along with the demonstration of an increased population of IgG4-positive plasma cells [ 35 , 36 ]. Cheuk and Chan considered that it requires an increase in the absolute number of IgG4-positive cells of > 50 per high power fi eld and a raised IgG4- positive/IgG-positive ratio of > 40 % [ 37 ]. Deshpande et al. stated that histological data are the mainstay for diagnosis, since both ele- vated numbers of IgG4-positive plasma cells and IgG4/IgG ratios have been described in other infl ammatory conditions and malignan- cies [ 38 ]. A high serum IgG4 concentration is often present but approximately 20–30 % of patients with classic histopathological and immunochemical fi ndings of the disease have normal serum levels [ 39 ].
Therefore, the IgG4 variant of HT is charac- terized by thyroid infl ammation rich in IgG4- positive plasma cells and marked fi brosis (Fig. 6.1). It is usually associated with male gender, rapid progress requiring surgery, more subclinical hypothyroidism, higher levels of thyroid autoantibodies and more diffuse low echogenicity on US, when compared with the non-IgG4 variant [ 40 ]. In 2012, Kakudo et al. studied 105 patients with HT and classifi ed 28 cases (27 %) as IgG4 thyroiditis based on immu- nohistochemistry [ 41]. We recently presented the fi rst case of IgG4-related HT in a non-Asian patient [ 42] (Fig. 6.2). Since this condition seems to be more common than previously thought, we suggest performing the immunos- taining in a patient who presents with these typical clinical features and with lymphoplas- macytic infi ltration and marked fi brosis of the thyroid gland.
Differential Diagnosis
HT has to be distinguished from nontoxic multi- nodular goiter, thyroid cancer and GD.
In multinodular goiter, thyroid function tests are usually normal and thyroid autoantibodies are absent or identifi ed at low titers. Cervical US shows well-defi ned nodules and the thyroid scan can also be helpful. FNAB can distinguish these entities but is usually not performed.
a b
d
c
Fig. 6.1 Typical histopathological fi ndings of a patient with the diagnosis of IgG4-related Hashimoto’s thyroiditis. ( a ) Large thyroid gland with a hard consistency. ( b ) An infl ammatory infi ltrate is seen, along with lymphoid folli- cles with germinal centers ( black arrow ) and marked fi bro- sis (hematoxylin and eosin, 40×). ( c ) Lymphoplasmacytic
infi ltration is found and atrophic follicles with oxyphilic cells predominate (hematoxylin and eosin, 200×). ( d ) Increased number of IgG4-positive plasma cells are seen, with > 50 cells per high-power fi eld (IgG4 immunostain- ing, 400×). (From Luiz et al. [ 42 ], with permission)
Fig. 6.2 A male patient with IgG4-related Hashimoto’s thyroiditis, presenting with a diffuse neck swelling of rapid growing. ( a ) anterior view. ( b ) lateral view
Thyroid carcinoma must also be considered, especially if there is rapid growth of the gland or evidence of pain. Clinical fi ndings, cervical US, thyroid scan and FNAB can be useful in the dif- ferential diagnosis. Thyroid lymphoma may also be considered in a patient with progressive and asymmetric enlargement of the thyroid gland, or if pain and tenderness appear. HT is a known risk factor for primary thyroid lymphoma [ 43 ].
The differentiation between HT and GD relies on clinical, biochemical and image exams, but the distinction of these entities is sometimes dif- fi cult because fi ndings may overlap.
Treatment
Patients with HT should have regular follow-up. Treatment options are dependent on the thyroid function and the presence of symptoms. Asymptomatic and euthyroid patients do not require treatment. When hypothyroidism devel- ops, it is usually permanent and replacement treatment with levothyroxine (L-T4) is required indefi nitely in these patients. We suggest starting L-T4 in those with overt hypothyroidism or sub- clinical hypothyroidism with a TSH level above 10 mIU/L. Treatment can also be considered in patients with a TSH level between 4.5 and 10 mIU/L and positive thyroid antibodies. Ideal body weight is used for dose calculations, usually 1.6–1.8 μg/Kg of ideal body weight daily in adults. It is recommended to start with the full calculated dose in healthy young and middle- aged patients. A low starting dose should be given to older patients and those with coronary heart disease, with gradual dose increase. Some authors also recommend L-T4 therapy if a large goiter causing local pressure symptoms is present [ 1 , 2 ]. The size of the thyroid gland decreases at least 30 % in about half of treated cases. The results are better in younger patients possibly because of the presence of fi brosis in those with a long-standing goiter.
Glucocorticoids are not usually recommended but can be used in cases presenting with pain.
Surgery is not indicated, unless signifi cant pain, cosmetic and pressure symptoms occur, or in the presence of a nodule with a cytology suspi- cious for malignancy [ 44 ].
When a preoperative suspicion of IgG4- related HT is high, glucocorticoid therapy may improve local symptoms and clinical outcomes. However, as these patients usually present with a rapidly progressing neck swelling, surgery is often the fi rst choice for treatment.
Painless Thyroiditis Epidemiology
Painless thyroiditis is considered a subtype of HT [ 1 ].
It accounts for 1–23 % of hyperthyroidism cases [ 45 ] and usually presents between 20 and 40 years of age. When compared to other forms of thyroiditis, it has a lower female to male ratio of 2:1 to 3:1 [ 46 ].
Synonyms for this disorder include silent thy- roiditis, subacute lymphocytic thyroiditis, and lymphocytic thyroiditis with spontaneously resolving hyperthyroidism.
Postpartum thyroiditis is considered a similar condition but, because of the particular features of the postpartum period, it will be discussed separately.
Etiology and Pathogenesis
Painless thyroiditis is an autoimmune disorder [ 1 ]. It seems to be associated with specifi c HLA hap- lotypes, suggesting a genetic susceptibility [ 47 ].
The infl ammatory process damages thyroid follicles with a release of stored thyroid hor- mones into the circulation. The resulting hyper- thyroidism is transient and occurs only until the stores are exhausted. New hormone synthesis is absent due to thyroid infl ammation and destruction of follicular cells, and also because of the low levels of TSH during the hyperthyroid state. Thereafter, a transient period of hypothy- roidism may ensue. As infl ammation subsides, thyroid follicles recover and normal thyroid func- tion occurs in most cases (Fig. 6.3 ).
Clinical Features
This disorder is classically characterized by a tri- phasic course of hyperthyroidism followed by hypothyroidism, and then recovery, similar to the
pattern found in postpartum and subacute thy- roiditis [ 1 , 2 ]. However, some patients only have a transient hyperthyroid or hypothyroid phase.
Hyperthyroid symptoms have an abrupt onset over 1–2 weeks but are usually mild, lasting from 4 to 8 weeks. Hypothyroidism is also mild or even asymptomatic, and may be present for 2–9 months [ 48 , 49 ]. Some patients have no symp- toms or signs related to thyroid dysfunction and are diagnosed incidentally by routine exams.
The thyroid gland is not painful or tender and has a normal or slightly increased size [ 49 , 50 ].
Diagnostic Evaluation
The diagnosis of painless thyroiditis relies on clinical manifestations, laboratory fi ndings and thyroid scan images.
If clinical suspicion is high, measurement of serum thyroid function is recommended. The results vary over the course of the disease, and changes in free thyroxine (T4) and triiodothyro- nine (T3) usually precede those of TSH. During the early period, overt or subclinical hyperthy- roidism may be present and an increase of free T4 over T3 is typically found. Thyroid function tests should be monitored on a regular basis (e.g. every 4–8 weeks). Some patients may recover and others develop overt or subclinical hypothy- roidism. When infl ammation subsides, euthy- roidism is almost always achieved, but some may
remain hypothyroid. Chronic thyroid disease can also appear in almost 50 % of patients during subsequent follow-up, usually related to the development of goiter but permanent hypothy- roidism may occur in 6 % of patients [ 45 , 51 ].
Positive serum TPOAb and TgAb are present in about 57 and 38 % of patients, respectively, with lower titers when compared to HT [ 46 , 49 ]. The white blood cell (WBC) count is often nor- mal, and the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are also nor- mal or slightly increased [ 46 , 49 ].
The RAIU test can be performed in the hyper- thyroid phase if the diagnosis is uncertain, yield- ing a low result of about 1 % [ 46 , 48 , 49 ]. Similarly, thyroid scan shows a very low radio- tracer accumulation in the thyroid gland.
Cervical US may be helpful in some patients, showing a normal-sized or slightly enlarged, heterogeneous and hypoechogenic thyroid gland. Color fl ow Doppler sonography (CFDS) is nor- mal or low during the hyperthyroid period.
FNAB is not typically performed. It can reveal lymphocytes and macrophages, thyroid epithelial cells and masses of colloid.
Histological features are similar to those found in HT, but patients with painless thyroiditis often show fewer lymphoid follicles and germi- nal centers, less fi brosis and lack Hurthle cells [ 46 , 52 ].
0 1 2 3 4 5 6
Months
Hyperthyroid Euthyroid Euthyroid
T4 TSH RAIU Hypothyroid
7 8 9 10 11 12
Fig. 6.3 Characteristic triphasic course of painless, postpartum and subacute thyroiditis. Abbreviations: RAIU radioac- tive iodine uptake, T4 thyroxine, TSH thyroid-stimulating hormone
Differential Diagnosis
During the hyperthyroid period, painless thy- roiditis must be distinguished from the more common GD. The former is usually self-limited, lacks ophthalmopathy, presents with mild thy- roid enlargement and has a low thyroid RAIU, which contrast to the fi ndings found in the latter. Laboratory data suggesting painless thyroiditis include a predominance of T4 over T3 and absence of TRAb, while in GD the rise in T3 prevails and antibodies are typically elevated. In addition, thyroid CFDS is normal or decreased in patients with painless thyroiditis and increased in Graves’ hyperthyroidism [ 2 , 53 ]. During the hypothyroid phase, the differential diagnosis between painless and HT may be dif- fi cult. Clues that suggest the former include the presence of self-limited symptoms of hyperthy- roidism preceding hypothyroidism and sponta- neous normalization of thyroid function over weeks.
Treatment
Some patients do not need treatment during either the hyperthyroid or the hypothyroid periods,