CASE REPORT

Insulin Autoimmune Syndrome (Hirata's Disease): Severe Hypoglycemic Episodes in Graves' Hyperthyroidism Patient Treated with Methimazole
Johan S Masjhur

INTRODUCTION

Table 1. Initial Laboratory Data Hemoglobin

WBC

Insulin Autoimmune Syndrome (1.4s) or Hirata's disease is characterized by severe hypoglycemic episodes, a high level of immunoreactive insulin, and a high titer of insulin autoantibody in a person who has never received exogenous insulin. It is noted that IAS has a strong genetic predisposition and the majority of the IAS cases were reported from Japan, where it is the third leading cause of hypoglycemia.' It is also known that some drugs with sulphydlyl groups in their chemical structures can induce the formation of insulin autoantibodies in predisposed individuals, and Graves' patient who possesses Bw621Cw4DR4 canying DRB120406 maybe at risk of developing IAS when methimazole is admini~tered.~,~ following is the first IAS (Hirata's The disease) case reported from Indonesia, in a patient with Graves' disease who was treated with methimazole.
CASE ILLUSTRATION

Platelet count PCV Fasting Blood Sugar Total cholesterol Triglyceride Creatinine Uric acid
ff4

TSHs Based on the above findings, treatment with thiamazole (methimazole), propranolol, and vitamins was commenced. On August 4, the author received an emergency call from the hospital telling that the lady was admitted due to hypoglycemic coma. She fully recovered after receiving intravenous dextrose. During admission (almost three weeks), an interesting phenomenon occured. She suffered from severehypoglycemicepisodes almost everyday, mostly occurring between 03.00-05.00 am, although she took sufficient regular hospital meals. The hypoglycemic episodes were prevented by giving dextrose firstly by intravenous infusion or oral solution, and thereafter by dividing her meals into 6 times per day plus late supper with a total of 1700 calorieslday, without any specific medication. No more hypoglycemic episodes occurred during the last few days of admission. Table 2. Laboratory Data at One of Hypoglycemic Episode Blood sugar 46 mgldL Serum Insulin 67.9 ulU1rnl (Normal : 6-27 mlU/ml) C-peptide > 7 nglml (Normal : 1.I 5.0 nglml) In an attempt to investigate the possibility of insulinoma, ultrasonography and CT-scan of abdomen were performed; the results were negative. Blood sugar,

Mrs. EH, a Chinese lady, born on June 2, 1960, manied, PlAO, was present in my clinic for the first time on July 23, 2004, with typical symptoms and signs of thyrotoxicosis. She had no history of serious illness, was not on any kind of medication, and had never been treated with insulin. Family history revealed that her father may suffer from mild diabetes mellitus. Physical examinatiou revealed aperson of normal weight (weight 42 kg, height 145 cm), normal blood pressure, tachycardia, diffuse goiter grade I, bruit (-), fine tremor, wet skin, ophthalmopathy (-), organomegalia (-), and no autoimmune stigmata was detected. She brought her initial laboratory data from another hospital, which revealed ahigh serum f l 4 and suppressed sensitive TSH (Table 1).

Dr. Hasan Sadikin HospitaUSchaol of Medicine, Padjadjaran University, Bandung Indonesia.

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October - December 2005

Insulin Autoimmune Syndrome (Hirata's Disease)

Table 3. Immunology Study and W A Typing Antimicrosomal antibody Antithyroglobulin antibody Insulin antibody HLA typing Note : CW4 was not included due to a technical error Titer 116400 Negative
> 100.0 Ulml (ref.range< 1.O Ulml DQA*0102;DQA'0301/02103;DQBB0302; DQB0502; A0203 & A24; 83802 & 63901; DRBl* 1601102 & DRBI' 0406120: DRB4'

serum insulin, and C-peptide levels during one of hypoglycemic episode were as shown in table 2. The results of the immunology study and HLA typing are shown in table 3; HLA typing data were received after she left the hospital. She was discharged on 24 August 2004, with strong recommendation to divide her meals at least 6 times per day plus a late supper. Thiamazole and propranolol were continued. Surprisingly, one month after discharge, she came again in an euthyroid state (clinically and laboratory). No more hypoglycemic episodes occurred, although she resumed her regular pattern of having three meals per day. Fasting and two ho~rpost-prandi~blood sugar and f f 4 levels were normal (Table 4). She was still on low dose methimazole without propranolol. Table 4. Laboratory Data at One Month After Hospital Discharae ff4 Total T3
TSHs

Fasting Blood Sugar 2h pp Blood Sugar

1.77 ng/dL 2.18 nglml 0.004 ulUlml 98 mg/dL 112 mgIdL

DISCUSSION

The reported case is a patient with newly diagnosed Graves' hyperthyroidism, who had never been treated with antithyroid dmg or received exogenous insulin. The first hypoglycemic episode occurred 10 days after treatment with thiamazole (methimazole) was started. During admission, several severe hypoglycemic episodes occurred which were prevented by administering dextrose, and thereafter by dividing her meals into 6 times per day with a total intake of 1700 cal, without giving any specific medication. The hypoglycemic episode in this case did not occur in response to blood glucose changes or food intake, and can be classified as post-absorptive (fasting) hypoglycemia. Hyperinsulinemic hypoglycemia can be the result of hugs, critical illness, hormonal deficiencies, non-beta cell tumors, endogenous hyperinsulinism (includinginsulinoma, autoimmune process, etc.), or metabolic disorders of infancy and childhood. Underlying autoimmune disorders or exposure to specific drugs were presumed to be

responsible for the development of insulin autoimmune syndrome. Some dmgs have been reported to trigger autoantibody production in the syndrome, among others sulphydril drugs (such as methimazole, alphamercaptopropionyl glycine, and gluthatione),hydralazine, isoniazide, procainamide, and penicillin. Rarely, IAS may also result from monoclonal insulin-binding autoantibodies produced by multiple myeloma or benign monoclonal gammopathy. Dmgs containing sulphydryl groups in their chemical structure can induce the formation of insulin antibodies in predisposed individuals.' Of 190Japanesepatients with IAS, 42% received medication containing SH group, such as methimazole, alpha-mercaptopropionyl glycine, and gl~tathione.~is also known that patients with Graves' It hyperthyroidism who were treated with methimazole are at high risk to have 1.4s.Methimazole is considered as a reducing agent, cleaving the disulfide bonds of insulin, and will be presented and recognized in the context of the DRB1*0406 gene product on the APC of Graves' patienk3 The possibility of insulinoma as the most prevalent cause of hypoglycemia had been considered in the diagnostic work-up of this case. However, the results of ultrasonography and CT-scan were normal (although negative findings do not definitely exclude insulinoma). Furthermore, to exclude the possibility of dmg-induced hypoglycemia, methimazole and propranolol were temporarily discontinued for several days, but hypoglycemic episodes persisted. Insulin autoimmune syndromeis a quite rare condition and associated with a strong genetic predisposition. Since Hirata reported the first case of IAS in 1970, to date majority of the cases are Japanese, and only few cases are reported among caucasians/non-oriental ethnic groups. Uchigata et a1 showed that the HLA-DR4 allele, DRB l"0406, is associated with increased susceptibility to IAS among Japanese, while DRB 1*0403 and DRB1*0407 are not. The extremely low prevalence of IAS among C aucasians can be explained by the low prevalence of DRB1*0406 in this p0pu1ation.l.~ This case shows similasity with other reported cases of Hiiata's disease, that l they al possess HLA-DRB1*0406, supporting the theory of a genetic predisposition.
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l o h a n S Masjhur

Acta Med Indones-Indones II n t e r n Med

Synonyms Molecular Formula : Fonnula Weight:

e melh~maza crystalline 2 Mercaplo-l mclnyitm~~azofor syntbes~sth amazo e e 1-Methy m aazole-2-thlol Metnlmazoe-I-Melny mldazo'e-2-th ol Mernmazoe Thiamazole; 1-Methyl-2-lmidazoiethione ClHaNzS 114.16 Figure 1. Molecular Formula and Synonims of Methimazole

Several other reports also came from outside Japan. In 1992, Burch et a1reviewed 16 cases of IAS outside of Japan from different sources with various causes, besides his own case of IAS in a hypertensive patient Cavaco et a1 (2001) reported treated with hydrala~ine.~ two Portuguese with IAS who had different HLA-DR4 allele (subtype) and insulin autoamtibody:DRB 1*0406and a polyclonal antibody in apatient treated with penicillin, and DRB 1*0403 and monoclonal antibody in a patient with 'idiopathic' IAS6 Recently, Moreira et al. (2004) from Brazil reported a case of IAS in a Caucasian man, which may have been triggered by antibiotic^.^ Ma et al (2005) from Taiwan reported a patient with pulmonary tuberculosis who developed IAS after treatment with antituberculous drugs, presumably isoniazid; unfortunately, no data on HLA typing were p r o ~ i d e d . ~ It was hypothesized that inappropriate (non-regulated) release of autoantibody-bound insulin produces hypoglycemia. High levels of serum insulin probably may result from the dissociation of insulin from its antibodies, several hours after meals, when no further absorption of glucose is occurring (as cited by Dozio e t al).9 Hypoglycemia and the impairment of glucose metabolism occur as a result of a buffering effect of high levels of antibody on insulin bioavailability to target tissues and release of insulin from the circulating autoantibody pool is expected to be afunction of the laws of equilibrium of mass action, and not in response to changes in blood glucose level? According to Hirata, insulin antibodes peaked 2-3 months after the start of antithyroid treatment and then concentrations fell spontaneously even when methimazole was continued. After a year, hardly any insulin antibody could be found, even in previously positive cases.' In the majority (of the Japanese patients), no treatment was required, and spontaneousremission occurs within 6 months of onset.' In prolonged hypoglycemia and severe cases, IAS can be treated by plasmapheresis, immunosuppressive drugs, or by glucagon injection.
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Spontaneous remission was also observed in this reported case; she was in remission three months after methimazole, despite continuing the medicine. No special treatment was given, except dietary regulation. Based on the clinical course and laboratory findings, the reported case fullfiled the criteria of insulin autoimmune syndrome (Hirata's disease) in Graves' hyperthyroidism patient treated with methimazole. The evidences are as follows: 1). Clinical course: the patient was diagnosed with Graves' hyperthyroidism and was treated with methimazole, which was followed by severe post-absorptive (fasting) hypoglycemic episodes, which spontaneously remitted within 3 months after methimazole treatment was started; 2).Laboratory findings: high serum insulin, C-peptide, and insulin antibody levels (during hypoglycemic episode), and she possesses the HLA-subtype DRB1*0406.
CONCLUSION To the best of the author's knowledge, this is the first case of IAS reported from Indonesia. The case was of an Oriental (Chinese) lady with Graves' hyperthyroidism, who fulfilled the criteria for insulin autoimmune syndrome.Hypoglycemic episodes occurred after methimazole treatment. Her serum insulin, C-peptide, and insulin antibody levels were high; she has the HLA sub-type DRB1*0406. She had not been treated with exogenous insulin before. During follow-up, she demonstrated spontaneous remission without any specific treatment despite still being on methimazole. IAS should be considered as the cause of hypoglycemia in Graves' patients treated with methimazole, particularly in OrientallAsian populations. To exclude insulinoma and avoid unnecessary invasive procedures, it is recommended to determine the insulin antibody in any case of hyperinsulinemic hypoglycemia.

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Insulin Autoimmune Syndrome (Hirata's Disease) Uchigata Y, Hirata Y, Omori Y, Iwamoto Y, and Tokunaga K. Worldwide differences in the incidence of insulin autoimmune syndrome (Hirata's disease) with respect to the evolution of HLA-DR4 alleles. Human Immunol. 2000;61:154-7. 5. Burch HB, Clement S, Sokol MS and Landry E Reactive hypoglycemic coma due toinsulin autoimmune syndrome : case report and litteratwe review. Am J Med 1992;92:681-5. 6. Cavaco B, Uchigata Y, Porto T, Amparo-Santos M, Sobrinho L and Leite V. Hypoglycemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies. Eur J Endocrin. 2001;145:3 11-6. 7. Moreira RO, Lima GAB, Peixoto PCB, Farias MLF, andvaisman M. Insulin autoimmune syndrome : case report. Sao Paulo Med J. 2004:122(4k178-80. . .. 8. Ma WY, Won JGS, Tang KT, andLin HD. Severe hypoglycemic coma due to insulin autoimmune syndrome. J Chin Med Assoc 2005;68(2):82-6. 9. DozioN. Scavini M. Beretta A. SarueeriE. Sartori S, Belloni C. et al. Imaging of the buffering effect of insulin antibodies in the autoimmune hypoglycemic syndrome. J Clin Endocrinol Metab. 1998;83:643-8.

ACKNOWLEDGMENT

I thank Dr. Andi Wijaya & staff from Prodia Clinical Laboratory, Bandung, for the kind support in the measurement of insulin antibody level and KLA typing.
REFERENCES
1. UchigataY, Kuwata S,TokunagaK, EguchiY, Takayama-Hashumi S.. Mivamoto M. et a]. Strone association of insulin autoimune , syndrome with HLA-DR4. Lancet. 1992;339:393-4. 2. Hirata Y. Methimazole and insulin autoimmune syndrome with hypoglycemia. Lancet. 1983;29:1037-8. 3. Uchigata Y, Kuwata S, Tsushima T, Tokunaga K, Miayamoto M, Tsuchikawa K, et al. Patients with Graves' disease who developed insulin autoimmune syndrome (Hirata's disease) posses HLA-Bw62/Cw4/DR4 carrying DRB1*0406. J Clin EndocrinolMetab. 1993;77:249-54.