Serum-negative autoimmune thyroiditis: what’s in a name?

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Chronic autoimmune thyroiditis (CAT) is the main cause of hypothyroidism in the general population. Autoantibodies to thyroperoxidase (TPO) and to thyroglobulin (Tg) are the circulating hallmark of this autoimmune thyroid disease. Positive tests for TPO Ab and Tg Ab are present in nearly 90 (TPOAb) and 60 % (Tg Ab) of hypothyroid patients with CAT. This implies that despite the high sensitivity of modern assay methods for thyroid auto Ab, there still is a considerable number of patients presenting with hypothyroidism in whom the humoral markers of thyroid autoimmunity are found to be negative. The widespread use of ultrasound in the diagnostic work-up of thyroid diseases allowed to ascertain that most of these patients display a hypoechoic pattern of the thyroid at ultrasound [1]. Further characterization of this echographic finding indicated that this peculiar echopattern is mainly due to lymphocytes infiltrating the thyroid parenchyma, as confirmed by fine needle aspiration biopsy. On this basis, a new clinical entity was identified, the so-called serumnegative chronic autoimmune thyroiditis (SN-CAT). There are no published studies on large series of patients with SN-CAT, which however is not a rare clinical entity. Although epidemiologic data are lacking, the prevalence of the disease can be roughly estimated at around 5 % of patients presenting with hypothyroidism by taking into consideration the rate of hypothyroid patients showing positive tests for thyroid autoantibodies in published studies [2]. It is likely that in the last two decades, a raise in the prevalence of SN-CAT occurred due to the routine use of ultra-sensitive TSH measurements, which increased the detection rate of patients with subclinical hypothyroidism, and to the widespread use of ultrasound in clinical endocrine practice. A brief discussion on the mechanisms involved in autoimmune thyroid diseases may provide arguments for explaining the physiopathology of SN-CAT. Early studies showed that TPO Ab fix complement and bind TPO expressed on the thyroid cell membrane, thus producing in vitro complement-mediated cytotoxicity of cultured human thyroid cells [3]. However, the notion that in vivo TPO is expressed at the inner follicular pole of thyroid cells, where it is un-accessible to circulating TPO-Ab, clearly indicated that the cytotoxic effect of these autoantibodies is a secondary phenomenon, only occurring when the follicle integrity is already disrupted by auto-reactive T cells. Studies in mothers with circulating TPO Ab confirmed this assumption, because their newborns had a normal thyroid gland in spite of the trans-placental passage of TPO Ab [4]. Nowadays, an array of experimental data demonstrate the prominent pathogenic role of cellular immune responses in autoimmune thyroid diseases and the involvement of proinflammatory cytokines and chemokines in producing thyroid cell apoptosis [5]. Thus, it became evident that chronic autoimmune inflammation does not require the presence of auto-Ab to induce thyroid damage [5]. Whichever its physiopathology, when SN-CAT leads to hypothyroidism there is no difference in treating the condition as compared to treating hypothyroidism due to any other etiology. On the other hand, several methodological and clinical aspects should be taken into consideration to render a correct diagnosis of SN-CAT. This is mainly based on the occurrence of a raised serum TSH associated with a hypoechoic pattern of the thyroid parenchyma at M. Rotondi F. Coperchini F. Magri L. Chiovato (&) Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, Fondazione Salvatore Maugeri I.R.C.C.S, University of Pavia, Via S. Maugeri 10, 27100 Pavia, Italy e-mail: luca.chiovato@fsm.it