High prevalence of serum autoantibodies against the amino terminal of α-enolase in Hashimoto's encephalopathy

doi:10.1016/j.jneuroim.2007.01.018

Journal of Neuroimmunology

Volume 185, Issues 1–2, April 2007, Pages 195-200

https://doi.org/10.1016/j.jneuroim.2007.01.018 Get rights and content

Abstract

Recently, we discovered autoantibodies against the amino (NH₂)-terminal of α-enolase (NAE) in patients with Hashimoto's encephalopathy (HE) (83.3%; 5/6) [Fujii, A., Yoneda, M., Ito, T., Yamamura, O., Satomi, S., Higa, H., Kimura, M., Suzuki, M., Yamashita, M., Yuasa, T., Suzuki, H., Kuriyama, M., 2005. Autoantibodies against the amino terminal of α-enolase are a useful diagnostic marker of Hashimoto's encephalopathy. J. Neuroimmunol. 162, 130–136]. We further investigated the anti-NAE autoantibodies in 25 patients who fit the diagnostic criteria for HE, based on the presence of anti-thyroid antibodies and responsiveness to immunotherapy. In this study, we demonstrated a high prevalence (68%, 17 of 25) and high specificity of anti-NAE autoantibodies in patients with HE, and clarified the clinical features of HE. This result demonstrated that anti-NAE autoantibodies, in addition to anti-thyroid autoantibodies, are emphasized as useful serological diagnostic markers of HE.

Introduction

Hashimoto's thyroiditis (HT) is the most common disorder affecting the thyroid gland. In 1966, Brain et al. reported the first case of encephalopathy associated with HT, who presented with recurrent neuropsychiatric symptoms accompanied by serum anti-thyroid antibodies in euthyroid states (Brain et al., 1966). Hashimoto's encephalopathy (HE) therefore was recognized as a nomenclature of new disease, distinct from myxoedema encephalopathy associated with hypothyroidism (Behan et al., 1988, Shaw et al., 1991, Chaudhuri and Behan, 2003, Chong et al., 2003).

Autoimmune mechanism has been proposed as an underlying pathogenesis (Brain et al., 1966, Chaudhuri and Behan, 2003, Chong et al., 2003), and immunotherapy such as steroids, immunosuppressants and/or intravenous injection of immunoglobulin (IVIg)/plasmapheresis was successfully administered (Shaw et al., 1991, Boers and Colebatch, 2001, Chaudhuri and Behan, 2003). Over 100 accumulated cases (Shaw et al., 1991, Chaudhuri and Behan, 2003, Chong et al., 2003) reported mainly by neurologists, emphasized this potentially treatable encephalopathy associated with HT in the differential diagnosis of unknown etiology of encephalopathy, and suggested the risk of under-diagnosis of HE (Ghika-Schmid et al., 1996, Maydell et al., 2002).

Several diagnostic criteria for HE have been proposed based on encephalopathy, the presence of anti-thyroid antibodies and/or responsiveness to immunotherapy including steroids (Shaw et al., 1991, Peschen-Rosin et al., 1999). Endocrinologists however argued against the terminology of HE because of the wide spectrum clinical features in patients with HE and the high prevalence of anti-thyroid antibodies in the normal population, which are usually subclinical (Sawka et al., 2002, Fatourechi, 2005).

To resolve such debates on the nomenclature and nature of HE, more specific diagnostic markers are needed (Chong et al., 2003, Fatourechi, 2005). Very recently, we discovered autoantibodies against the amino (NH₂)-terminal of α-enolase (referred to as NAE) that were highly specific in sera from a limited number of HE patients (83%, 5 of 6 with HE; 11%, 2 of 17 with HT without any neuropsychiatric features; none of controls [50 individuals] including those with other neurological or immunological conditions involving encephalopathy [25 individuals]) (Fujii et al., 2005). Thus, the anti-NAE autoantibodies are a potential tool for the diagnosis of HE and resolving the debate over HE described above. We further investigated the prevalence and specificity of anti-NAE autoantibodies, and clarified the clinical features in a large number of patients with HE in this study.

Section snippets

Patients

In this study, we selected 25 patients with HT, who presented with encephalopathy and fit the diagnostic criteria for HE, based on the presence of anti-thyroid antibodies and responsiveness to immunotherapy such as steroids, immunosuppressants and/or IVIg/plasmapheresis. These 25 patients included our own 8 cases and 17 cases from other institutions. Neurological specialists carefully excluded other possible causes of encephalopathy including infections, other autoimmune conditions, vitamin

Anti-NAE autoantibodies

The clinical profiles of patients and immunological characters were summarized in Table 1 and Fig. 1. Of the 25 patients with encephalopathy with HT examined here, 68% of them were NAE(+) (17 of 25) (p < 0.001, compared to patients with HT without encephalopathy [10%, 2 of 20], supplemented by additional data from 3 patients of HT without encephalopathy to our previous study) (Fujii et al., 2005). To our knowledge, there were no sera from 33 patients with 2 Basedow's disease, 4 post-infectious

Discussion

After Brain et al. reported the first case of encephalopathy associated with HT, there has been a debate on the nosology and nature on HE, despite the accumulation of over 100 reported cases (Behan et al., 1988, Chaudhuri and Behan, 2003, Chong et al., 2003). It is because of the wide spectrum clinical features in patients with HE, the high prevalence of anti-thyroid antibodies in the normal population (e.g. 5–10% in male, 10–25% in female in Japan), and the lack of specific diagnostic marker.

Acknowledgments

This work was supported in part by a Neuroimmunological Disease Research Committee grant (to M.Y.) from the Ministry of Health, Labor and Welfare of Japan. We would like to thank Tomomi Kame for technical assistance and the physicians supporting this study.

Attending physicians of patients in this study were as follows:

T Hamano, O Yamamura, K Kinomoto, M Sato, M Ikawa and R Nakachi, our institute; A Kimura, A Iwamura, T Yuasa, Konodai, National Center of Neurology and Psychiatry; H Higa, Naha

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Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis
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A few patients with Hashimoto’s thyroiditis or Graves’ disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto’s encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis.
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Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.
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Hashimoto's thyroiditis, characterized by thyroid-specific autoantibodies, is one of the commonest autoimmune disorders. Although the exact etiology has not been fully elucidated, Hashimoto's thyroiditis is related to an interaction among genetic elements, environmental factors and epigenetic influences. Cellular and humoral immunity play a key role in the development of the disease; thus, a T and B cells inflammatory infiltration is frequently found. Histopathologic features of the disease include lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, and parenchymal atrophy. Moreover, the occurrence of large follicular cells and oxyphilic or Askanazy cells is frequently associated to Hashimoto's thyroiditis. Clinically, Hashimoto's thyroiditis is characterized mainly by systemic manifestations due to the damage of the thyroid gland, developing a primary hypothyroidism. Diagnosis of Hashimoto's thyroiditis is clinical and based on clinical characteristics, positivity to serum antibodies against thyroid antigens (thyroid peroxidase and thyroglobulin), and lymphocytic infiltration on cytological examination. The mainstream of treatment is based on the management of the hypothyroidism with a substitution therapy. A relationship between Hashimoto's thyroiditis and a possible malignant transformation has been proposed in several studies and involves immunological/hormonal pathogenic links although specific correlation is still debated and needs to be further investigated with prospective studies.
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High prevalence of serum autoantibodies against the amino terminal of α-enolase in Hashimoto's encephalopathy

Abstract

Introduction

Section snippets

Patients

Anti-NAE autoantibodies

Discussion

Acknowledgments

Best Pract. Res. Clin. Endocrinol. Metab.

J. Neurol. Sci.

J. Neuroimmunol.

Hashimoto's disease and encephalopathy

Lancet

Recurrent acute disseminated encephalitis in association with Hashimoto's thyroiditis

Hashimoto's encephalopathy responding to plasmapheresis

J. Neurol. Neurosurg. Psychiatr.

The clinical spectrum, diagnosis, pathogenesis and treatment of Hashimoto's encephalopathy (recurrent acute disseminated encephalomyelitis)

Curr. Med. Chem.

Hashimoto encephalopathy. Syndrome or myth?

Arch. Neurol.

Hashimoto's myoclonic encephalopathy: an underdiagnosed treatable condition?

Mov. Disord.