Objectives: Insulin autoimmune syndrome (IAS) or Hirata disease is a rare cause of autoimmune hypoglycemia with apparent high insulin levels and anti-insulin autoantibodies and was first described by Hirata in Japan in 1970. IAS cases are usually related to exposure to sulfhydryl-containing drugs, which stimulate the production of insulin autoantibodies. Among sulfhydryl-containing compounds, alpha lipoic acid (ALA) has recently emerged as a cause of IAS. After the first observations of ALA-induced IAS were reported in Japan in 2006, an increasing number of cases related to ALA administration have been described. An Italian group recently reported on six cases of IAS of which one was associated with HLA-DRB1*04:06 and the remaining five with HLA-DRB1*04:03. This suggests that the latter is potentially involved in the genetic susceptibility of people of European descent to IAS. Methods: Here, we describe two new cases of IAS in women that were triggered by ALA. Results: Both cases are associated with HLA-DRB1*04:03 and confirm the evidence that HLA-DRB1*04:03 rather than HLA-DRB1*04:06 is specifically related to IAS susceptibility in Europeans. Conclusions: Case reports of ALA-induced hypoglycemic episodes highlight the need for greater care in prescribing ALA supplementation as well as the identification of specific and personalized therapeutic targets.

Introduction

Insulin autoimmune syndrome (IAS) or Hirata disease is a rare cause of autoimmune hypoglycemia that is characterized by the occurrence of spontaneous hypoglycemic episodes, either fasting or postprandial, with apparent high insulin levels and anti-insulin autoantibodies in individuals with no prior exogenous insulin administration [1]. IAS was first reported by Hirata et al. [2] in 1970 in Japan and since then, more than 300 cases have been identified among Asians and IAS represents the third leading cause of spontaneous hypoglycemia in Japan [3]. On the contrary, only 58 cases have been described so far among non-Asian individuals [4]. The investigation into possible genetic causative markers has revealed a strong association between IAS and HLA-DR4 [5]. Indeed, the HLA type of 27 patients with IAS showed that DR4 was commonly expressed, but it was expressed only in 43% of healthy controls. Furthermore, analysis of the nucleotide sequences of DRB1, DQA1, and DQB1 genes showed that all patients expressed DRB1*0406 [6]. This association has been subsequently confirmed for the HLA-DRB1*04:06 allele as well as HLA-DRB1*04:03 but at a lower level [7]. Moreover, IAS cases have also been observed to relate to exposure to sulfhydryl-containing drugs (i.e., thiamazole, methimazole, D-penicillamine, tiopronin, or glutathione) [8], which stimulate the production of insulin autoantibodies. The mechanism that underlies the occurrence of hypoglycemia in IAS is still debated but sulfhydryl-containing compounds, through their reducing activity, have been hypothesized to mediate cleavage of disulfide bonds in the insulin molecule, which in turn becomes more immunogenic [9] Among sulfhydryl-containing compounds, alpha lipoic acid (ALA) recently emerged as a potential determinant of IAS [10]. After the first observations of ALA-induced IAS were reported in Japan in 2006 [10], an increasing number of cases that were related to ALA administration have been described [11,12] with a similar association with HLA-DRB1*04:06 and fewer with HLADRB1*04:03. An Italian group recently reported on six cases of IAS. Of these, one was associated with HLA-DRB1*04:06 and the remaining five with HLA-DRB1*04:03, which suggests that the latter is potentially involved in the genetic susceptibility of people of European descent to IAS. [13] Here, we describe two new cases of IAS in white women that were triggered by ALA and associated with HLA-DRB1*04:03.

مقدمه

سندروم خود ایمنی انسولین (IAS) یا بیماری Hirata، دلیلی نادر در کاهش قند خون خود ایمنی است که به وسیله ی کاهش خود به خودی قند خون– چه ناشتا چه بعد از صرف غذا- با سطوح بالای انسولین و آنتی بادی های خودی ضد انسولین در افرادی که تزریق خارجی انسولین نداشته اند مشخص شده است. سندروم خود ایمنی انسولین اولین بار توسط Hirata و همکاران در سال ۱۹۷۰ در ژاپن گزارش شد و از آن روز، بیش از ۳۰۰ مورد در میان آسیایی ها شناسایی شده و به عنوان سومین علت ابتلا به کاهش خود به خودی قند خون در ژاپن معرفی شده است. در مقابل تنها ۵۸ مورد ابتلا به IAS در میان افراد غیر آسیایی گزارش شده است. بررسی در مورد احتمال نقش نشانگرهای ژنتیکی در ابتلا به IAS، نشان داد که پیوستگی ای قوی بین IAS و HLA-DR4 وجود دارد. در واقع نوع HLA، ۲۷ بیمار مبتلا به IAS نشان داد که ژن DR4 معمولا در تمام بیماران بیان می شود، اما این ژن تنها در ۴۳ درصد نمونه های سالم بیان شده است. علاوه بر این، آنالیزهای توالی های نوکلئوتیدی ژن های DRB1، DQA1 و DQB1، نشان داد که ژن DRB1*0406 در همه ی بیماران بیان شده است. این پیوستگی متعاقبا برای آلل های HLA-DRB1*04:04 نیز همانند آلل های HLA-DRB1*04:03، اما در سطحی پایین تر، تایید شده است. همچنین مشاهده شد که ابتلا به IAS با قرار گرفتن در معرض داروهای حاوی سولفیدریل ( مانند: تیامازول، متیمازول، دی پنیسیلامین، تیوپرونین یا گلوتاتیون ) که محرک تولید آنتی بادی های خودایمنی انسولین هستند، مرتبط است.