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Conclusion

Thyroid Study Unit The University of Chicago Chicago, Illinois 60637

	Introduction

Top Introduction

 
THE discussions in this Controversy by Davies and by Roti and Braverman revolve around four questions:

1. Is TRab assay useful in diagnosis and differential diagnosis of thyrotoxicosis?
   
2. Is TRab useful at the start of antithyroid drug therapy, for comparative purposes with later values?
   
3. Is TRab assay useful at the end of antithyroid drug therapy for predicting remission?
   
4. Is TRab useful in certain special instances, such as in pregnant women who have had Graves’ disease, to predict fetal disease?
   

Regarding the first question, in most cases the combination of elevated FTI, suppressed TSH, goiter, and often some eye signs, allows definitive diagnosis, and the relatively cheap and readily available TPO antibody assay adds some certainty and reassurance that autoimmunity is the cause. Many clinicians do not routinely order TPO antibodies. TRab assay is commonly done for special problems including those patients who present with initial unilateral exophthalmos, or sometimes subclinical hyperthyroidism, or for example, hyperemesis with thyrotoxicosis, and sometimes in differential diagnosis of postpartum painless thyroiditis. Often in such cases, the values are indeterminate when the clinical signs are equivocable.

Actually, the TRAb assay is currently not much used in the United States. The reason for this is not certain. It was introduced much later than the TPO and Tg antibody assays. There is also a question that, in some areas of the world where it is widely employed, there may be financial incentive to its use, which is not the case in the United States. There is not much evidence that lack of use alters our approach to diagnosis or treatment. Perhaps, if the assay was as generally available and comparably costly to the TPO assay, it would serve the same purpose (recognizing anti-thyroid immunity) and might be substituted. At the present time, the TPO assay appears to be equally sensitive, more available, and less costly than any of the TRAb assays.

Regarding the second question, it is useful to remember that only a minority of patients with Graves’ disease are treated with antithyroid drugs to induce cure. This group represents less than 20% or so of the total population and is mainly comprised of younger patients. Measurement of an "initial value" would only apply to this subgroup. The data provided by Roti and Braverman point out the generally low predictive value of TRAb measurement at initiation of antithyroid drug therapy. A value at the beginning and end of antithyroid therapy does not provide any more information than a single value at the end of the contemplated period of treatment.

Certainly TRAb assay, at the end of a planned period of antithyroid drug therapy, is a useful predictor of outcome for a group of patients. For the individual patient, it does not appear to be much superior to an observed reduction in the size of the goiter or to ease of control on low doses of antithyroid drugs. The basic problem that has limited its widespread use is lack of precision. When we contemplate either giving up antithyroid drug therapy for another treatment such as radioactive iodide, or continuing drugs for another year, we want to have, effectively, 100%—not 90%—precision in our interpretation of the clinical situation. The degree of imprecision is seen in Fig. 1 in Davies’ article. Many more reports show a much greater lack of accuracy in predicting outcome of a course of therapy, and these are fully reported by Roti and Braverman. Roughly 20% of patients enter apparent clinical remission with detectable TRab in the serum, and about 10–20% relapse even though TRab are not measurable by available assays. While it is probably true, as Davies points out, that high or significant levels would be more predictive of relapse, high levels occur in only a small proportion of patients.

General practice is to gradually reduce antithyroid drugs over a period of 2 or 3 months, intermittently checking TSH or FTI to see if they have altered. This allows certain knowledge whether another course of therapy or different therapy is required, or if the patient has at least temporarily entered remission.

One problem pointed out by both discussants is that there may be imprecise correlation between TSab antibody levels and function of the thyroid. As assays improve, TSab levels that do not increase function above normal will become measurable, and some patients will have thyroiditis that limits the response to even elevated levels. Thus it is quite possible that improved sensitivity and precision in the assay may accentuate rather than diminish the overlap and thereby reduce diagnostic certainty.

Cost effectiveness is, much to our distaste, an important consideration, and it is not easy to prove that TRab assay is going to provide information that saves money, when the same information can be provided very easily by reducing antithyroid drug therapy and observing the patient.

For the last of the four questions posed above, it is considered prudent by most clinicians to measure a TRAb assay in pregnant women who, because of past or present Graves’ disease, could pass thyroid stimulatory antibodies to their infant. However, in this situation and despite the fair correlation between binding and stimulating antibody levels, it is the TSAb assay that is really required and not a binding assay. We do not want to guess, as suggested by one discussant, but rather we want to know for certain whether stimulating antibodies are present in high concentration.

We can all agree that, in a situation in which cost was no object, the addition of TRab assays would provide marginal benefit. But experience over the past two decades has shown that the assays are rarely required and have a specific effect on therapy in only a very small fraction of cases of Graves’ disease.

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