CASE REPORT

Insulin AutoimmuneSyndrome after the

Third Therapy with Methimazole
Mutsumi Hakamata, Mitsuyasu Itoh*, Yuichiro Sudo** and Norikazu Miyata
In 1986, a 26-year-old female had been diagnosed as having Graves' disease and had been
treated with methimazole for four months. After the treatment with propylthiouracil for another
four months, she had been treated with methimazole once again. She was in complete remission for
two years. She again experienced symptomsof hyperthyroidism, and treatment with methimazole
was started again. Onthe thirteenth day after treatment, she experienced hypoglycemic attacks
with skin eruption. The plasma glucose was 57 mg/dl, 125I-Insulin binding 69%, free IRI 196 |iU/
ml. The patient had the HLA-DRBl*0406.
(Internal Medicine 34: 410-412, 1995)
Key words: hypoglycemia, hyperthyroidism,
insulin antibody, insulin autoantibody, Graves'
disease, hyperinsulinemia

Introduction

pregnant and the treatment was continued for four months.

Since she did not become pregnant she was treated with

Since the first report of insulin autoimmunesyndromeby methimazole once again. Symptomsofhypoglycemia, eruption
Hirata and colleagues in 1970, 244 cases have been reported or abnormal liver function tests had not been elicited during
throughout the world ( 1^). This syndrome is characterized by these treatments. The patient entered complete remission and
spontaneous hypoglycemia,
hyperinsulinemia
and auto- the drugs were not necessary for two years. She delivered her
antibodies to insulin without previous immunization. The re- first child in April 1989. She visited our hospital because of
cent report by Uchigata and colleagues has identified specific palpitation and finger tremor in November 1989. Her presentHLA antigens strongly linked to the development of this ing symptomssuggested the relapse of Graves' disease. The
findings
showed high levels
in plasma
syndrome (5). Certain drugs, such as methimazole, which have laboratory
sulfhydryl groups trigger this syndrome, but little is known
triiodothyronine
(T3), 3.3 ng/ml and thyroxine (T4), 14.5 |Lig/dl
about the mechanisms of this autoantibody production. These
drugs induce the syndrome after rechallenge with the same drug
in some cases (6-13). We treated a patient with Graves' disease
who presented with this syndrome after the third treatment of
methimazole. This case strongly suggested that the priming

concomitant with suppressed

thyroid-stimulating

hormone

(TSH) as below 0. 1 |LiU/ml. TSH receptor antibody was positive

(22.3%) and 123I thyroidal uptake was high (61.2% at 24 hours).
Treatment with methimazole was resumed, and eleven days
later, she transiently complained of urticaria after taking a bath.
effect is important in this drug-induced autoimmune phenom- Thirteen days later, she noticed a cold sweat, palpitation, finger
enon.
tremor, and thirst
before lunch.
These symptoms disappeared

after intaking

sugar. This

attack occurred again at fasting and then she visited our hospiCase Report
tal. Her height was 156 cm, and she weighted 48 kg. Her
A 26-year-old female visited our hospital because of palpi- temperature was 36.4C, pulse 84 per minute, and blood prestation and weight loss in November1986. Three years earlier sure 98/60 mmHg.Exophthalmos was noted bilaterally. The
the patient was diagnosed with Graves' disease and had been thyroid was diffusely enlarged without tenderness. The heart,
treated with methimazole for four months. Methimazole was lung and abdomenwere normal. The results of urinalysis were
changed to propylthiouracil because she wanted to become normal. Laboratory findings were as follows; plasma glucose,
From the Department of Internal Medicine, Enshu General Hospital, Hamamatsu, *the Department of Internal Medicine, Fujita Health University School of
Medicine, Toyoake and **the Third Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu
Received for publication June 23, 1994; Accepted for publication December 15, 1994
Reprint requests should be addressed to Dr. Mutsumi Hakamata, the Department of Internal Medicine, Enshu General Hospital, 144-6, Tokiwa-cho, Hamamatsu,
Shizuoka430

410

Internal

Medicine Vol. 34, No. 5 (May 1995)

Insulin AutoimmuneSyndrome
57 mg/dl; 125I-insulin
binding, 69%; free IRI, 196 jiU/ml; total
was continued, and hypoglycemic attacks disappeared after a
week (Fig. 2).
IRI, 19,038 (aU/ml; C-peptide, 33 ng/ml.
Insulin autoantibodies were mainly IgG with kappa type
Discussion
light chains. Scatchard analysis of insulin autoantibodies in this
case showed the characteristic binding site with lower affinity
Insulin autoimmunesyndrome was first reported and has
and higher capacity for insulin than those of insulin-treated
ethnic preponderance in Japan (1-4). The studies of this syncases (Fig. 1). HLA typing of the patient showed A2, A26 (10),
BW62 (13), BW61 (40), CW4 and DR4. Analysis of the drome have been increasing, but its pathogenesis remains
nucleotide sequence of the DR showed DRB1*0406, unclear. Some drugs which have sulfhydryl groups such as
DQAl*0301, DQB 1 *0302. The treatment with methimazole
methimazole are closely related to this syndrome (6-16). Nineteen cases of this syndrome have been reported in patients with
Graves' disease treated with methimazole (6-13). Fifteen of
them had hypoglycemic attacks after the initial treatment with
this drug, four had the attacks after rechallenge with the same
drug. However,no cases developed this syndrome after the
ki
0.177X1081/mol
third treatment with methimazole as the present case. HLA
bi
12.4xlO-8mol/l
typing and analysis of the nucleotide sequence of the DRgenes
k2 0.0042X
1081/mol
in this case revealed similar types whichare characteristic in
b2
24 x lO-8mol/l
this syndrome (4, 5, 17-20). Therefore, the background in this
case for generating insulin autoantibodies may be the same as
that in other cases. The scatchard plots of insulin autoantibodies
in this case showed two binding sites with high and low affinity.
The affinity of the high affinity constants was lower than that of
insulin-treated cases. On the other hand, the capacity was larger
than those insulin-treated cases (1 8). Hence, we suggested that
large volume of insulin released from these antibodies might

lead to hypoglycemia. It is not clear why hypoglycemic attacks

appeared only whenmethimazole was administered for the
third time, and not after the second time in this case. Unfortunately we failed to examine the titer of insulin autoantibodies at
the first and second therapy with methimazole. The appearance

-i-

10

-i-

20

Bound insulin

(10~8 mol/1)

Fig. 1. Scatchard analysis of insulin autoantibodies in this case. Two of insulin

autoantibodies
may have occurred without
binding sites with high and low affinity were found. The affinity of the high
affinity constants showed lower affinity and higher capacity for insulin than hypoglycemia during these periods (21). In addition to genetic
those of insulin-treated cases.
predisposition, other acquired autoimmuneabnormalities such
'86

'87

Nov.Jan.

TreatmentI

'89

Mar.

May Jul.

Sep.

'90

Dec.

3^rToi===?MMI5^g

Plasma |30mg^-lpropranolol
10
^___^l^ypoglycemia
Glucose 75
" "
mg/dl

Nov.

5Q.

Jan.

Apr.

Jul.

Aug.

Sep.

10mg ' 5mg

'
^

\&^*^^
69
19,038

/^f^
" ^ ^ ^

-^^

68
830 890

49

47

460

42
330

29
280

^v _"
-^

("10- ^^--^^X*-^_

Fig. 2. Clinical course in this case. MMI: methimazole,

immunoglobulin, TRAb: TSH receptor antibody.

Medicine Vol. 34, No. 5 (May 1995)

Jim.

f; V^

FreeT4
"-^
ng/dl ^;^\___tH_-#

Internal

May

1 r- Propranolol ^^__^^^

IRI

TRAb 20-

Mar.

"^

12.5I-insulin
binding
Total

Feb.

--

PTU: propylthiouracil,

.
--

---

TBII: TSH binding inhibiting

411

Hakamataet al
as a relapse of Graves' disease and pregnancy might have
promoted the production of insulin autoantibodies. In spite of
maintaining the methimazole therapy, the hypoglycemia disappeared and the titer of insulin autoantibodies was decreased.
These findings suggested that the production of insulin
autoantibodies might depend on the dose of methimazole. All
previous patients with this syndrome (with hypoglycemia)

triggered by methimazole therapy were given large doses of

methimazole (30 or 40 mg/day). On the other hand, in the
present case methimazole was given in small doses (5 mg/day)
during the second therapy. The accumulative dose of methimazole up to the onset of symptomswas about 6 g in this case. It
is impossible

to speculate

whether there is a critical

dose

because not all case reports discussed the dose of the drug.
However, it seems likely that there may be a dose-dependent
relationship between the generation of insulin autoantibodies
and methimazole. Further studies of this syndromewill be
necessary to resolve this question.
Acknowledgments: We would like to Dr. Y. Uchigata and the late Dr. Y.
Eguchi (Diabetes Center, Tokyo Women's Medical College) for study ofHLA
typing and insulin autoantibodies.

References

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