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Antibodies against the human TSH receptor (TRAb) are considered to be the
causal agents that target autoimmunity to TSH receptor and result in uncontrolled
hyperstimulation of the thyroid gland and hyperthyroidism. Assays to detect
these pathological antibodies in Graves| patients have been very efficient.
A simple method using solubilized porcine thyroid membranes has become
commercially available as a standard routine method. From our long-term
experience with this method, we would recommend standardization of the
assay in TSH equivalents mandating a TSH standard curve to be included.
By this way, sensitivity and specificity of the method could be enhanced
resulting in better separation of insignificant and significant TRAb. Cut-off
values may best be found by establishing receiver operating curves (ROC)
and should not solely rely on the manufacturer's guidelines (Figure 1).
Figure 2 depicts a scheme of the proposed diagnostic strategy in hyperthyroidism
and the role of autoantibody determination. The incidence of detectable
TRAb in the sera of patients with untreated active Graves' hyperthyroidism
tends to considerably decline during the course of antithyroid drug therapy
with after one year of treatment about half of the patients converting
to negative antibody status (Table 5). Despite of their pathogenetic relevance
and demonstration of treatment associated changes, use of TRAb determination
has been disappointing with respect to prediction
of remission or relapse of hyperthyroidism after withdrawal of antithyroid
medication. A great number of retrospective and prospective studies have
addressed this problem. From a clinical point of view we can briefly summarize
that only persistence of high antibody titers is a rather specific indicator
of persistence or imminent relapse of Graves' hyperthyroidism.
Figure 1:
Receiver operating curve (ROC) of a radioligand assay for determination
of TRAb (TRAK-Assay, BAHMS-Diagnostika, Germany).
Figure 2:
Diagnostic strategy in hyperthyroidism
Table 5: Incidence of TRAb in thyroid patients with and controls
| Graves' Disease |
|
before antithyroid treatment
|
N = 111 |
89% |
|
after 3-12 month of antithyroid treatment
|
N = 73 |
56% |
|
|
| Hashimoto thyroiditis and primary myxedema |
N = 37 |
8% |
|
|
| Autonomously functioning thyroid nodules |
N = 275 |
1% |
|
|
| Nontoxic goiter |
N = 108 |
8% |
|
|
| Healthy controls |
N = 40 |
0% |
It is important to note that TSH receptor antibodies do pass the placenta
barrier and the presence of markedly elevated antibody titres in the blood
of the mother indicates a risk of the newborn to develop intrauterine and/or
neonatal hyperthyroidism.
Although TRAb are very useful in the clinical setting,
their measurement has some limitations that should not be overlooked. These
relate to the use of non-human thyroid tissue and to assessment of receptor
binding instead of functional activity at the receptor. The latter may
be particularly relevant for prognostic implications of antibody determination,
because we could clearly demonstrate dissociation of TSH binding inhibiting
antibodies and T3- release stimulating antibodies in some patients with
Graves' disease during the course of antithyroid therapy. Similarly, with
the use of more advanced techniques based on expression of recombinant
human TSH receptor in stably transfected cell lines we observed a discordant
(positive/negative) behaviour of binding inhibiting and stimulatory activities
at recombinant TSH receptor in about one third of patients that have been
treated up to 6-12 months with antithyroid drugs. This discrimination is
not possible with the TRAb assay, in which both types of antibodies give
a positive result. In patients with untreated Graves' disease, stimulatory
and receptor binding activities were correlated (Figure 5).
Figure 5:
Correlation between TRAb measured in a radioligand assay (TRAK-Assay,
BRAHMS-Diagnostiks, Germany) and thyroid stimulating antibodies measured
in an in vitro system using CHO-cells which are stably transfected with the
human TSH receptor.
Establishment of a reliable and practical functional, i.e. based on measurement
of stimulation or inhibition of the TSH receptor, TRAb assay seems therefore
to be a desirable goal which we are currently pursueing at our laboratory.
It is an intriguing question, if assessment of functional antibody activity
would improve reliability of antibody determination as a prognostic marker.
The method would certainly allow to definitively characterize a subgroup
of patients with autoimmune thyroiditis that present with TRAb in the binding
test but what appear to be blocking antibodies in the functional test.
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