Keywords
Hirata disease - hypoglycemia - hypoglycemia induce by carbimazole - insulin autoimmune
syndrome - insulinoma differential diagnosis - insulinoma mimics
Introduction
Insulin autoimmune syndrome (IAS) was described first by Hirata et al. in 1970.[[1]] IAS is characterized by spontaneous episodes of hypoglycemia, a high titer of insulin
autoantibodies, and an increased level of immunoreactive insulin not treated previously
with insulin or oral hypoglycemic agents.[[1]] IAS is associated with other autoimmune diseases (e.g. Graves' disease [GD], rheumatoid
arthritis) and association with the human major histocompatibility complex, Class
II, DR4 (human leukocyte antigen [HLA]-DR4) serotype has been demonstrated in 96%
of Japanese patients with IAS.[[2]] There is a significant genetic predisposition to IAS (as suggested by its association
with specific HLA Class-II alleles), and it is often associated with previous exposure
to a drug with a sulfhydryl group in its chemical structure (e.g. methimazole, captopril).
Most cases of IAS have been reported in Japan, where IAS is the third leading cause
of hypoglycemia (325 patients diagnosed at the end of 2007).[[1]] The syndrome is rare in the Caucasian/non-Japanese populations: 60 cases in Caucasians
and 20 cases in East Asians have been reported.[[3]],[[4]]
Case Report
We report a 16-year-old Saudi woman not known to have any illness until she was diagnosed
with GD in 2016 after palpitations, weight loss, and heat intolerance. Physical examination
revealed lid lag but no exophthalmos, lid retraction, or pretibial myxedema. Laboratory
investigations showed a very low level of thyroid-stimulating hormone (0.1 mlU/I),
high level of free thyroxine (66.6 pmol/L) and high level of anti-thyroid peroxidase
(197.9 IU/mI). Thyroid uptake scans done at that time showed high homogeneous uptake.
She was started on carbimazole (20 mg, b. d.) and propranolol as needed. After that,
her symptoms subsided. Thereafter, she started to have recurrent episodes of dizziness,
sweating, palpitations, and hunger pangs. These symptoms occurred once or twice a
day and improved after eating sweet food. These symptoms occurred usually while she
was fasting and sometimes after meals: Hypoglycemia was suspected.
Consequently, she underwent multiple investigations for hypoglycemia and was admitted
to hospital for a supervised 72-h fast. During admission, results showed a high level
of c-peptide, high level of insulin, and negative urinary screen for sulfonylurea.
Computed tomography and magnetic resonance imaging of the abdomen were unremarkable.
The cortisol level in the morning was normal (479 nmol/L), glycated hemoglobin was
5.5%, glutamic acid decarboxylase was negative, and Islet cell antibody was negative.
[[Table 1]] provides more details about laboratory results after hospital admission.
Table 1: Laboratory results after hospital admission
IAS was suspected based on clinical presentation and laboratory investigations (extremely
high level of insulin associated with low blood sugar, recent carbimazole use, high
level of c-peptide, and unremarkable imaging findings). Insulin autoimmune antibody
was measured: 0.82 nmol/L. IAS was diagnosed.
IAS can be treated by several modalities, including ≥6 low-carbohydrate meals per
day to prevent postprandial hypoglycemia.[[5]] Some patients have been treated with corticosteroids or other medications (e.g.
acarbose, somatostatin, and diazoxide) with variable results. Immunosuppressive treatment
with prednisolone (30–60 mg/day) or azathioprine, or six-mercaptopurine treatment
with plasmapheresis, may be an option for refractory cases.[[6]] The monoclonal antibody rituximab has been shown to decrease the titer of insulin
autoantibodies.[[7]]
In our case, we used acarbose and withdrew carbimazole. Her symptoms improved, but
she continued to suffer hypoglycemia. After 1 week of carbimazole withdrawal, she
underwent radioactive iodine ablation. With time, symptoms started to become less
frequent and eventually, stopped. The test for insulin autoantibodies was repeated
and was negative. Finally, the patient became asymptomatic and required a low dose
of levothyroxine.
Discussion
IAS is one of the rare causes of endogenous hyperinsulinemic hypoglycemia (EHH). IAS
may be associated with autoimmune disorders such as GD, systemic lupus erythematosus,
systemic sclerosis, or rheumatoid arthritis.[[2]],[[8]] The exact mechanism of hypoglycemia in IAS is incompletely understood but interaction
of a sulfhydryl group with a disulfide bond in the insulin molecule has been postulated
to have a role.[[4]] Methimazole is the most commonly prescribed agent, but D-penicillamine, procainamide,
isoniazid, hydralazine, glutathione, captopril, and imipenem can be prescribed. Case
reports of IAS associated with the use of a-lipoic acid have been published.[[9]],[[10]],[[11]]
The differential diagnoses for hypoglycemia must take into account several pathologic
conditions [[Table 2]], but diabetes mellitus-controlling medications and alcohol are considered to be
the leading causes of hypoglycemia. Other well-known causes of hypoglycemia include
endogenous hyperinsulinism (e.g. insulinoma, critical illnesses, and endocrine deficiencies).[[12]]
Table 2: Differential diagnoses of hypoglycemia
IAS is characterized by the presence of an autoantibody to native insulin. The autoantibody
stays in the blood and binds to insulin.[[2]] Such binding reduces the availability of the secreted insulin to receptors in the
liver and peripheral tissues, resulting in hyperglycemia and further insulin secretion.
Conversely, hypoglycemia is caused by release of antibody from insulin, resulting
in an inappropriately high concentration of free insulin for glucose in blood. This
process of hyperinsulinemia occurs without asynchrony of the prevailing glucose concentration.
This mismatch between the free-insulin concentration and blood glucose due to insulin
autoantibodies is the widely accepted hypothesis for the mechanism of hypoglycemia
for patients with IAS.[[13]] The extremely high level of insulin (>600 μIU/mL) measured in our patient favored
a diagnosis of IAS. According to retrospective analyses of 84 EHH patients from 1998
to 2012 presenting at a University Hospital in Korea, the median insulin level was
14.1 μIU/mL in patients with insulinoma and >1000 μIU/mL in patients with IAS.[[14]] In patients with insulinoma, the serum insulin level is seldom >100 μIU/mL.[[13]] This increase in the insulin level found in IAS can be explained by delayed clearance
of insulin as a result of insulin binding to autoantibodies.[[15]] C-peptide and insulin are secreted in equimolar ratios from pancreatic β-cells
into the portal circulation. However, insulin is metabolized primarily in the liver
and C-peptide is metabolized in the kidneys at a slower rate. The half-life of insulin
is 5–15 min and the half-life of C-peptide is 30–35 min.[[13]] Therefore, the molar ratio of insulin: C-peptide is usually <1 even though equal
amounts are secreted. This ratio is >1 in two conditions as follows: (i) IAS [as in
our patient, [[Table 1]]; and (ii) if exogenous insulin is present.[[16]] The molar ratio of insulin: C-peptide, C-peptide level, and insulin level in different
causes of hypoglycemia are summarized in [[Table 3]].[[16]] Furthermore, the criteria favoring a diagnosis of IAS are summarized in [[Table 4]].
Table 3: Insulin level, C-peptide level, and molar ratio of insulin: C-peptide in different
causes of hypoglycemia
Table 4: Criteria favoring a diagnosis of insulin autoimmune syndrome
Conclusion
This was one of the first cases of IAS reported in Saudi Arabia/Gulf region. Even
though IAS is considered one of the rarest causes of EHH, a person with EHH with an
extremely high level of insulin increases the suspicion of IAS. This suspicion increases
even more for a patient with an autoimmune disease or who has used of a medication
containing a sulfhydryl group recently. In term of IAS diagnosis, other common causes,
such as insulinoma or sulfonylurea intoxication, should be excluded. Finally, hypoglycemia
is one of the common complaints that should not be ignored when looking for IAS.
Declaration of patient consent
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