JRSM >
Volume 96, Number 1 >
Pp. 50
Sezione di Endocrinologia del Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, University of Messina School of Medicine, Policlinico Universitario, padiglione H 4 piano, 98125 Messina, Italy
Correspondence to: S Benvenga E-mail: s.benvenga{at}me.nettuno.it
The case report by Dr Chan and colleagues (October 2002, JRSM1) reminds us of a similar case we described twenty years ago2. Although Chan et al. did not demonstrate formally the nature of the circulating substance that caused the inter-assay discrepancy in free thyroxin (T4) measurement, it is very likely to have been autoantibody to T4, not cross-reacting with T3.
The case is of particular interest to us because of the underlying non-thyroid disease and the transience of the antibodies, which Chan et al. relate to short-term treatment with interferon-alpha. Their patient was being treated for a haematological malignancy (chronic myelogenous leukaemia). So was ours (Waldenström's macroglobulinaemia), in whom we demonstrated circulating thyroid hormone autoantibodies of both IgM and IgG classes which preferentially bound T42. Thyroid assays were discrepant, and, to add to the similarity, our patient was hypothyroid (thyroid stimulating hormone 40 mU/L, antithyroglobulin negative). This patient had been treated with prednisone and an alkylating drug (cyclophosphamide) which we now know can transiently disturb thyroid hormone metabolism3. Because the patient died, we cannot know whether the thyroid hormone binding autoantibodies would have been transient or permanent.
In light of our recent work in this field4,5,6,7,8, we believe that there is a common triggering mechanism between the two patients1,2 Description of this mechanism requires mention that our patient also had circulating autoantibodies against steroid hormones which are transported by the corticosteroid-binding globulin (CBG)9. Concerning the patient of Chan et al. we think that interferon-alpha caused the same thyroid cytotoxic effects as those caused by cytokines produced by and released from the lymphocytes that infiltrate the thyroid10, resulting ultimately in release of iodinated heterogeneous molecules of thyroglobulin (Tg) with T4 exposed on their external surface. The cytokine effects are reversible, so that the said release of Tg molecules ends when interferon-alpha treatment is stopped. With regard to our patient, alkylating drugs probably caused transient release of T4 from non-thyroid pools, especially from the liver, even when administered in association with corticosteroids3.
We postulate that alkylating drugs might also cause release of other molecules, including the serine protease inhibitors (SERPINs) such as the liver-synthesized alpha1-antitrypsin, alpha1-antichymotrypsin and CBG. SERPINs are acute phase reactants that increase under conditions such as inflammatory or neoplastic processes11 and can bind thyroid hormones12. Perhaps the cyclophosphamide-induced release of a SERPIN with both steroid and thyroid hormone binding capacity, in a patient who was under treatment with corticosteroids, somehow incited appearance of autoantibodies capable of interacting with both steroids and thyroid hormones.
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