Download Autoimmune Thyroid Disease

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REVIEW ARTICLE
Autoimmune Thyroid Disease
Matthias Schott, Werner A. Scherbaum
SUMMARY
Introduction: The clinical manifestations of autoimmune thyroiditis (AIT) are highly variable.
Graves' disease (GD) is constantly associated with hyperthyroidism. Methods: Literature
search from 1980 to 2006 using PubMed. Results: On ultrasound the parenchyma frequently
appears inhomogeneous with increased blood flow ("thyroid storm") in case of GD.
Thyreoperoxidase (TPO) represents the major autoantigen in AIT. On this basis there is
a moderate positive correlation between levels of anti-TPO antibodies and risk of
hypothyroidism. However, the risk cannot be exactly quantified. For diagnosis of GD TSHreceptor-autoantibodies (TRAb) should be determined. A new TRAb-assay (units given in IU/l)
should be preferred because of the higher sensitivity without loss of specificity compared to
the first generation assay (units in U/l). Discussion: Anti-TPO-Antibodies in AIT should only
be measured in the context of elevated serum TSH levels. In GD, TRAbs may be determined
after 6 months of initial diagnosis. When TRAbs are > 10 IU/l virtually no patient will reach
remission. TRAbs are also associated with worsening of Graves' ophthalmopathy.
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Key words: thyroid disease, autoimmune disease, hyperthyroidism, hypothyroidism,
Graves' disease
A
utoimmune thyroid disease is the commonest category of autoimmune disease in
humans. Prevalences of up to 10% are quoted, with a higher prevalence in women
than men. The two leading types are Hashimoto's type autoimmune thyroiditis (AIT),
including the atrophic form, which presents as primary myxedema, and autoimmune
thyroiditis, which is also known as Graves' disease (or Basedow's disease in a number of
European countries). Rarer forms of autoimmune thyroiditis are silent thyroiditis, the
iatrogenic thyroiditides, and postpartum thyroiditis. De Quervain's sub acute thyroiditis
and Riedel's goiter are additional types of thyroiditis which are of non-autoimmune etiology,
and will therefore be excluded from this discussion.
Methods
A literature search of PubMed was conducted from 1980 to 2006, using the following terms:
Hashimotos's thyroiditis, autoimmune thyroiditis, Graves' disease, etiology, pathogenesis,
anti-TPO auto antibodies, anti-Tg auto antibodies, TSH receptor auto antibodies, outcome
prediction, endocrine ophthalmopathy.
Autoimmune thyroiditides
Classification
The commonest form of autoimmune thyroiditis (AIT) is hypertrophic thyroiditis of the
Hashimoto type. As part of the process of lymphocytic destruction, this can develop into a
secondary atrophic form. Silent thyroiditis is a clinically milder variant. In clinical practice
this is often subsumed under the heading of AIT, and in any case, a definite categorization
is only possible during the course of the illness. In postpartum thyroiditis, and in the iatrogenic
thyroiditides, autoimmune elements can often be demonstrated, which is why this form is
counted among the autoimmune thyroiditides.
Genetic and environmental factors
Studies have shown an association between HLA class 2 molecules DR3, DR4 and DR5
and the incidence of Hashimoto's thyroiditis. However, the data are as yet inconclusive. The
cytotoxic T cell surface molecule clearly has a role in AIT. Predisposing environmental
Klinik für Endokrinologie, Diabetologie und Rheumatologie, Universitätsklinikum Düsseldorf (PD Dr. med. Schott, Prof. Dr. med.
Scherbaum)
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a
b
c
FIGURE
Ultrasound image of a thyroid. a) Normal thyroid with homogeneous, echogenically normal
thyroid parenchyma. B) Hashimoto's type autoimmune thyroiditis is typically associated with
diffuse reduction of echogenicity. The atrophic form is also characterized by a reduction in
total thyroid volume (here 5ml). c) Autoimmune hyperthyroidism (Graves' disease) shows, as
well as diffuse reduction in echogenicity, and an increase in thyroid volume, increased blood
flow (thyroid storm). This can be shown with duplex sonography.
factors have also been described, including smoking and high iodine intake, both of which
are associated with an increased incidence of AIT (1).
Etiology and pathogenesis
A recently published study using a transgenic mouse model suggested that a particular
epitope of thyroperoxidase is recognized by cytotoxic T lymphocytes (2). All mice developed
a lymphocytic infiltration similar to that seen in patients, a fall in serum T4 and T3 levels,
and a rise in TSH (2). This suggests that parts of the thyroperoxidase molecule are the key
locus of the immune process. Close analysis of the lymphocytic infiltrates of affected
patients shows a Th1 cytokine profile, equating to a cytotoxic immune reaction (3). Cellular
reactions against thyroglobulin (Tg), a further potential thyroid specific antigen, are currently
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viewed as secondary phenomena. The etiology of postpartum thyroiditis was unclear until
recently. Recent studies point to an infiltration of the maternal thyroid by fetal cells (4).
This leads to an immunological reaction with measurable thyroid specific antibodies.
Iatrogenic thyroiditides are often seen following treatment with Th1 cytokines such as
interferon alpha (IFN α) and Interleukin 2 (IL 2).
Clinical picture
The clinical picture can vary markedly between and within the various autoimmune
thyroiditides. Symptoms and signs relate primarily to thyroid function, and can vary from
a classical hyperthyroid picture, with tachycardia, weight loss and restlessness, to one of
hypothyroidism, with tiredness, lassitude, bradycardia, constipation and cold intolerance.
The initial hyperthyroid picture is explained by a lymphocytic destructive process with
increased release of thyroid precursor hormone. Many patients with autoimmune thyroiditis,
especially those with silent thyroiditis, are asymptomatic. In these patients the diagnosis is
often made incidentally. The clinical course of postpartum thyroiditis is very variable and
is masked by other factors such as the increased energetic demands placed upon the mother
in the postpartum period. It can be characterized both by hyperthyroid and hypothyroid
phases. In the longer term, a return to normal, physiological functioning is just as likely as
persistent hypothyroidism.
Imaging
In addition to the history and physical examination, ultrasound is helpful in investigating
AIT. The thyroid parenchyma is typically inhomogeneous and shows a diffuse pattern of
reduced echogenicity, by contrast with healthy thyroid tissue, where the parenchyma is
homogeneous and the echogenicity normal (figure). The thyroid is usually enlarged in
Hashimoto's disease, but can be of normal size. Duplex sonography, however, shows
increased vascularity. The atrophic form is characterized by a marked reduction in
parenchymal volume (diagram 1). Thyroid scintigraphy is seldom necessary, and should
only be used in exceptional circumstances such as in hyperthyroidism with uncertain antibody
status.
Biochemistry
Thyroid hormones
Under physiological conditions, the central regulatory mechanism for thyroid function is
the pituitary release of thyroid stimulating hormone (TSH). The serum TSH level is therefore
an indirect marker of current thyroid hormone release, and hence of its delivery to end organs.
In many cases basal TSA assay alone is therefore a satisfactory investigation for thyroid
function. Where serum thyroid hormone levels are required, free hormone levels should be
measured, as these represent a true reflection of peripherally available hormone. Total
thyroxin assay without reference to protein binding (over 99% of thyroxin is protein bound)
is unhelpful. Triiodothyronine (T3) can be assayed as total T3, because of the much-reduced
protein binding of free T3. A single reading of increased T4 in the context of AIT suggests
destructive hyperthyroidism.
Antibody assay
The immunological process triggered by thyroperoxidase is reflected in the patient's antibody
status. It is known that the prevalence of TPO and thyroglobulin antibodies increases with
increasing age, and that the prevalence of TPO antibodies is higher in all age groups than
that of Tg antibodies (5). The Whickham survey, which studied 2 779 individuals over
20 years showed that women are significantly more likely to produce thyroid antibodies
than men (6). At the end of the observation period thyroid specific antobodies were found
in 26.4 % of women (median age 59 years) and 8.8 % of men (median age 58). It is notable
that in 2% of women and 0.5 % of men, thyroid antibodies detected initially were later no
longer detectable.
A cross sectional study of more than 17 000 US citizens from 1988 to 1994 (NHANES III)
showed that 13% had TPO antibodies and 11.5% Tg antibodies (7). Of the Tg antibody
positive individuals, 69.9 % were also positive for anti-TPO. Whereas of the TPO antibody
positive individuals, only 54.5 % had Tg antibodies. An increased TSH level (> 4.5 mU/l) and
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clinical hypothyroidism were highly significantly associated with TPO antibodies, but not
with Tg antibodies. No anti-Tg antibodies were found in anti-TPO negative individuals with
hypothyroidism. A metaanalysis carried out by the American Medical Association came to
similar conclusions (8). No clear statement about the correlation between antibody titers
and the risk of (subclinical) hypothyroidism is possible on the basis of current data.
Silent thyroiditis is often associated with a low or only transiently detectable anti TPO titer.
Around 50% of pregnant women with TPO antibodies develop postpartum thyroiditis, of
whom only 90% have anti TPO antibodies at the time of presentation. The relapse rate for
postpartum thyroiditis is around 70% in antibody positive women.
In cytokine-induced thyroiditides, the probability of clinical hypothyroidism in IFN α
treatment is 3% to 4%. More than 5% of patients treated in this way develop anti-TPO antibodies.
Some patients also show signs of hyperthyroidism, in the early stages. Similar results have
been found in IL 2 treatment.
Antibodies against sodium iodide symporter play a secondary role in all AIT patients.
Commercial assays for these antibodies are currently unavailable.
Autoimmune hyperthyroidism
In addition to autoimmune hyperthyroidis, Graves' disease is associated with ocular
involvement. However, the two terms are often used synonymously in practice. The incidence
of Graves' disease is about 40 cases per 100 000 population per year.
Genetic and environmental factors.
Early evidence of genetic associations with Graves' disease came from studies in identical
twins, which showed a concordance for Graves' disease of around 20 % (9). Positive associations
have been described for the HLA molecules DR 3 and DQA1*0501. HLA DRB*0701 appears
to be protective. However, the published data on these associations differ. An association
with the CTLA-4 polymorphism has been described for both Hashimoto's and Graves'
thyroiditides. Smokers have an increased, dose dependent risk of Graves' disease (10).
Etiology and pathogenesis
Anti TSH receptor antibodies (TRAB), which, like TSH, bind the receptor and have a
stimulatory effect with resulting hyperthyroidism, are pathognomonic for autoimmune
thyroiditis. Hence, the TSH receptor (TSHR) is the principal antigen in hyperthyroidism.
The cause of the development of these antibodies remains unclear. The receptor consists
of a large N terminal extra cellular domain, which is responsible for the specificity of
hormone recognition and binding, and seven transmembrane regions, across which
the signal is transferred to the G protein. Most studies point to epitope regions in the
N terminal extra cellular domain of the TSH receptor as the target for the autoimmune
process (11–13).
Clinical presentation
Karl von Basedow first described the classic symptoms of autoimmune hyperthyroidism –
tachycardia, exophthalmos and goiter – known as the "Merseburg triad" – in 1840. Because
of the TSH receptor stimulation hypothyroidism is almost always present. 50% of cases also
show eye signs, including exophthalmos, retro bulbar pressure sensation, double vision,
and increased tear production. These effects may in part be attributable to antibody binding
to TSH receptors in the retro bulbar tissue (14). Pretibial myxedema and acropachy (clubbing
and subperiostial new bone formation in the hands and feet) are extremely rare, occurring
in only around 1% of cases.
Imaging
Ultrasound is, again, a key investigation in autoimmune hyperthyroidism. The thyroid
gland is typically enlarged, mainly due to an increase in depth, with an inhomogeneous,
diffuse, echo-poor parenchyma, which can sometimes appear in a fielded pattern. Duplex
sonography often shows increased blood flow, which can be palpated, known as "thyroid
storm" (diagram 1). Thyroid scintigraphy often shows an increased uptake of technetium.
This investigation is generally unnecessary in diagnosing autoimmune hyperthyroidism,
but can be useful where thyroid nodules are also present.
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DIAGRAM 1
Differential diagnosis of autoimmune thyroid disease, TSH = thyroid stimulating hormone; fT3 = free T3 (triiodothyronine);
fT4, free T4 (thyroxine); AB = antibodies; *Graves' disease
Biochemistry
Thyroid hormones: to determine the extent of hyperthyroidism it is necessary to ascertain
the levels of basal TSH, free T4 and, where appropriate, free T3. Following initial down
regulation and normalisation of the free hormone levels, treatment can be further refined on
the basis of basal TSH alone.
The use of TSH receptor antibody assay to clarify the diagnosis: two basic methods
exist for determining thyroid receptor antibody (TRAB) levels. The old test system is based
on the competitive binding of the antibody in question with radioactively labelled bovine
TSH (TBII assay) in a homogenized pig thyroid cell membrane. Results are quoted in U/l
and have a normal range of up to 10 U/l with a grey area up to 15 U/l. The cloning of human
TSH receptors has facilitated the establishment of a new TRAB test (15, 16). Various
groups (17, 18) including our own have demonstrated markedly higher sensitivities without
loss of specificity, compared with the older test. A further advantage of this assay is its
comparability with the WHO standard, as it is measured in IU/l, rather than U/l. The diagnostic
threshold value is in the region of 1.5 IU/l with a grey area between 1 and 1.5 IU/l (19). This
assay allows a diagnosis of Graves' disease to be made with a very high positive predictive
value. This test is significantly more sensitive but also more expensive.
The use of TRAB assay in determining prognosis: a TRAB test based on the new assay
is also useful in determining prognosis. This was only possible to a limited extent with the
first generation assay. In one of their own studies, the authors showed that the relapse rate
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DIAGRAM 2
Prediction of the clinical course of
Graves’ disease based on TSH receptor
antibody titers 6 months after initial
diagnosis. At TRAB levels >10 remission
can almost be excluded: only 1 of 29
patients achieved remission in a study
by the authors (positive predictive value:
96.4%, n=93 patients). Schott et al (20).
increases with increasing TRAB titers, and that the TRAB levels at six months after disease
onset are important predictors of prognosis. A TRAB level of > 10 IU/l is associated with
an extremely low probability of remission (diagram 2) (20).This was true for only a third
of patients studied, in whom a positive predictive value of 96.4 % was measured. Below
this level no reliable prognostic conclusions could be drawn. The Essen group were able to
confirm these findings in patients with 12 months' illness (21). On the basis of these results,
it may in future be possible to make decisions about the need for definitive treatment
(radio iodine or surgery) just six months into the course of the illness. At present these
decisions are not made until around 18 months.
The use of TRAB in predicting endocrine orbitopathy: the new TRAB assay allows the
clinician to predict the course of endocrine orbitopathy (EO). As with the prediction of
prognosis in thyroid function, TRAB titers relate to the progression of EO. Hence TRAB
measurement is also useful from an ophthalmologic viewpoint (22).
Stimulating TRABs and blocking TRABs: in addition to quantitative measurement using
commercially available assays, there is also the possibility of bioassay (23). This allows
stimulating and blocking TRABs to be distinguished from one another. In bioassay, the
cAMP content is measured in the culture medium of host cells transfected with TSH receptors
following cultivation with the relevant sera. The authors have shown for stimulating
TRABs that a stimulation index of 10 allows patients with persistent disease to be
distinguished from those in remission. These results were also valid for antibody measurements
six months into the disease process (24). Where the primary diagnosis was made later, this
distinction was not possible (25). The difference between these two studies is most likely to
relate to continually falling TRAB levels throughout the course of the disease. No differences
exist between the two groups of patients for blocking TRAB antibodies. Because of the
high laboratory costs, these investigations are confined to research settings, at present.
Further antibodies in Graves' disease: 60 to 80 % of patients with Graves' disease also
have Po antibodies. This is essentially a secondary phenomenon arising in increased antigen
presentation on the thyroid cells, is of no therapeutic significance, and need not be pursued
as part of the diagnostic work up of Graves' disease. The same is true for Tg antibodies.
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Conflict of Interest Statement
The authors declare that no conflict of interest exists according to the Guidelines of the International Committee of Medical Journal
Editors.
Manuscript received on 7 February 2006, final version accepted on 7 April 2006.
Translated from the original German by Dr. Sandra Goldbeck-Wood.
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Dtsch Arztebl 2006; 103(45): A 3023–32 ⏐ www.aerzteblatt.de
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This text is a
translation from
the original
German which
should be used
for referencing.
The German
version is
authoritative.
25. Quadbeck B, Hoermann R, Hahn S, Roggenbuck U, Mann K, Janssen OE: Binding, stimulating and blocking TSH
receptor antibodies to the thyrotropin receptor as predictors of relapse of Graves' disease after withdrawal of
antithyroid treatment. Horm Metab Res 2005; 37: 745–50.
Corresponding author
PD Dr. med. Matthias Schott
Prof. Dr. med. Werner A. Scherbaum
Klinik für Endokrinologie, Diabetologie und Rheumatologie
Universitätsklinikum Düsseldorf
Moorenstr. 5, 40225 Düsseldorf, Germany
[email protected]
Dtsch Arztebl 2006; 103(45): A 3023–32 ⏐ www.aerzteblatt.de
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