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- idiopathic myxedema
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satisfactory answer. At this stage, it is likely that more than one mechanism is involved
and this would be consistent with antibody heterogeneity. Different groups have
suggested that there could be an antigenic stimulation at the initial step of antibody
production. For example, it has been proposed that a viral infection such as subacute
thyroiditis could induce occult antigenic changes within the thyroid. This is rather
unlikely in Graves' or Hashimoto's diseases where a vast majority of cases arise without
any recent history of thyroid infection. Similarly, almost all patients with subacute
thyroiditis recover and do not develop thyroid antibodies (6).
In contrast, no pathological role has been found, until now, for thyroglobulin antibodies.
For thyroperoxidase antibodies, the situation is unclear. These antibodies are
complement fixing and it has been thought that they were implicated in the thyroid cell
damage characteristic of autoimmune thyroiditis. TPO antibodies are able to inhibit TPO
enzymatic activity in vitro. Thyroid peroxidase has been extensively studied by Taurog
et al. (10) and is known to catalyze iodination of tyrosine and oxidative coupling of two
diiodotyrosine residues in thyroglobulin to form thyroxin. It is reasonable to think that
blocking this mechanism will induce thyroid disorders but does not explain the cell
destruction process characteristic of thyroid autoimmunity. While there is no firm
evidence against a cytotoxic role of TPO Abs, other antibodies are certainly involved in
cell destruction, via the complement pathway (11, 12). These IgG are not well
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characterized and are found in patients with or without Tg and TPO antibodies.
Methodological aspects
Several methods have been used to detect Tg and TPO Abs since the tanned red cell
hemagglutination technique described by Boyden in 1951 for Tg Abs. They include
immunofluorescence, radioimmunoassay and ELISA. Immunofluorescence and RIA are
gradually abandoned for practical reasons while both passive hemagglutination assays
and ELISA are widely used in routine. Independently of the intrinsic quality of
commercial assays, it seems that ELISA techniques are more suitable for quantitative
determinations and may reflect more accurately the response of the autoimmune
process to treatment (20).
There has been some debate regarding the immunoglobulin classes to be detected in
these assays. Most radioimmunoassays use 125I-Protein A as radioligand and are able
to detect IgM and all IgG antibodies except IgG 3. In contrast, most ELISA methods
measure selectively IgG antibodies. This may explain some discrepancies between the
results obtained with different tests.
Another controversial issue has been the cross-reaction of Tg Abs in assays for TPO Abs.
Originally, some assays were using microsomal preparations contaminated with Tg so
that artefactual cross-reactions were indeed present. This can be prevented by adding
large amounts of Tg to the incubation buffer as it is done for passive hemagglutination
tests and for some RIA assays or by using highly purified microsomal antigen
preparations as it is done for ELISA techniques. In fact, the issue is of academic interest
but has little clinical relevance since thyroperoxidase antibodies are present much more
frequently than Tg antibodies while Tg antibodies are rarely detected in the absence of
TPO Abs (21). Moreover, as seen previously, a certain degree of cross-reaction has to be
expected due to the fact that Tg and TPO share some antigenic determinants or have
epitopes with extremely close structures.
Finally, major difficulties have been encountered by most groups who attempted to
correlate numerically test results obtained with different methods. Besides what has
been previously mentioned, there is here a clear unitage problem. All passive
hemagglutination kits provide results in titers while most ELISA's (or RIA's) express
results in arbitrary or international units. There is an obvious interest in standardizing all
test results in international units. This would certainly harmonize the results and ease
comparative studies but would not solve all problems. The two currently available
reference preparations (anti-Tg Abs; MRC 1st international 65/93; anti-TM/TPO Abs:
serum 66/387) are pools of pathological sera and the heterogeneity of the antibodies
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that they contain may influence assay calibration.
A last observation made by Lukinac suggests that some passive hemagglutination tests
are subject to an interference by an unknown compound present in the serum from
patients with chronic renal failure and partially removable by hemodialysis (24).
Common symptoms include nervousness and/or tremor, weight loss (usually in face of
an increased appetite), palpitations, heat intolerance and excessive perspiration,
emotional lability, muscle weakness and hyperdefecation.
Overt Graves' disease has obvious symptoms and is easily diagnosed when
thyrotoxicosis is accompanied by proptosis. Laboratory tests will concentrate on the
evaluation of the thyroid function in order to normalize it with antithyroid drugs
(thionamides), 131-iodine or surgery. Thyroid autoantibody testing has limited clinical
value in these cases, except for TSI Abs in women in gestational age. Tg Abs are
present in about 25 % of cases while TPO Abs are present in 90 % of cases so that
combined Tg/TPO Ab testing will identify virtually all cases.
Hashimoto's disease
Autoimmune destruction of the thyroid gland accounts for 95% of primary
hypothyroidism, of which Hashimoto's thyroiditis and idiopathic myxedema represent
the majority of cases.
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The diagnosis of Hashimoto's disease is normally not difficult but two conditions deserve
a special mention:
- patients with chronic renal disease may have symptoms that mimic those of
hypothyroidism; in addition, free T4 tests are not always reliable here so that
Tg/TPO Abs testing will allow a differential diagnosis;
In some cases, Tg and/or TPO Abs will be found together with normal or borderline TSH
and free T4. These patients will have to be monitored closely since autoimmune
thyroiditis may develop very insidiously. If antibody levels remain persistently high, the
criteria to initiate treatment will be the TSH response to TRH. As soon as this response
is impaired, treatment has to be considered.
In contrast, antibody testing, if negative, will rule out autoimmune thyroiditis for the
numerous cases of non-toxic goiters where the cause of the thyroid enlargement must
be identified (dietary goitrogens or goitrogenic drugs and chemicals).
Thyroid cancers
The determination of Tg and TPO antibodies in differentiated thyroid cancers has no
intrinsic clinical value. Tg Ab determination is of interest, as previously discussed, to
validate Tg determinations. Thyroid autoantibodies are often detected in these patients,
mainly, as expected in females and may represent either a reaction of the immune
system against the tumor cells or the coexistence of a thyroid autoimmune disorder and
of a carcinoma.
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they are involved, it is still unclear whether these antibodies play an active role in the
pathogenesis of thyroid autoimmunity or if they simply reflect the development of these
diseases. However, since both antibodies are directed against molecular entities playing
a key-role in the physiological secretion of thyroid hormones, it is not a surprise that
their presence at high concentrations is invariably associated with thyroid disorders.
In the view of most clinicians, assessment of TSH and thyroid hormone circulating levels
are more important than thyroid antibody determination. This is quite logical since
thyroid autoimmunity can easily be treated but not cured by supplementation of the
deficient hormonal secretion or by antithyroid drugs. However, if new treatments
become available to cure or to treat the cause i.e. a deregulation of the immune system
instead of treating the effects, the situation may entirely change.
Clinical suspicion Absence of Tg and TPO Abs together with normal thyroid function
of Graves' disease tests rule out Graves' disease and suggest other causes
without thyroid or (diabetes, pheochromocytoma,...).
ocular signs
Pregnancy - Elevated TPO Abs represent a risk factor for post partum
asymptomatic thyroiditis. The test has to be performed in early pregnancy.
Pregnancy - overt Elevated TPO and Tg Abs levels establish the autoimmune origin
hyperthyroidism in of the disease.
patients without
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previous thyroid
dysfunction (rare)
Thyroid cancers Elevated Tg Abs are common in differentiated cancer. They have
no clinical value but they suggest caution in the interpretation
of serum thyroglobulin determinations.