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 Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 198-200

Unusual antithyroid drug-induced hypoglycemia


1 Department of Medicine, King George's Medical College, Lucknow, Uttar Pradesh, India
2 Department of Radiodiagnosis, King George's Medical College, Lucknow, Uttar Pradesh, India

Date of Web Publication13-Jul-2017

Correspondence Address:
Manish Gutch
Department of Medicine, King George's Medical College, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjhr.cjhr_14_17

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  Abstract 

Insulin autoimmune syndrome is defined as the occurrence of spontaneous hypoglycemia attacks with high titers of anti-insulin autoantibodies in patients with no previous exposure to insulin. This rare syndrome has mostly been reported from the Japanese population and is frequently associated with other autoimmune conditions and certain drugs, especially those containing a sulfhydryl group. Most cases undergo spontaneous remission following removal of the offending drug. We hereby describe the case of a female who developed this rare syndrome following intake of carbimazole for Graves' disease.

Keywords: Anti-insulin antibody, carbimazole, Graves' disease, hypoglycemia, insulin autoimmune syndrome


How to cite this article:
Gutch M, Bhattacharya A, Kumar S, Pahan RK, Singh RS. Unusual antithyroid drug-induced hypoglycemia. CHRISMED J Health Res 2017;4:198-200

How to cite this URL:
Gutch M, Bhattacharya A, Kumar S, Pahan RK, Singh RS. Unusual antithyroid drug-induced hypoglycemia. CHRISMED J Health Res [serial online] 2017 [cited 2020 Apr 2];4:198-200. Available from: http://www.cjhr.org/text.asp?2017/4/3/198/210481


  Introduction Top


Insulin autoimmune syndrome (IAS), also known as Hirata's syndrome, is a rare cause of hypoglycemia characterized by spontaneous hypoglycemia, high serum insulin levels and high titers of anti-insulin autoantibodies (IAAs) without any prior exposure to insulin. The majority of the cases have been reported from the Japanese population who are more commonly affected owing to genetic susceptibility.[1] Antithyroid drugs used for the treatment of Graves' disease are a known precipitant of IAA as was seen in this case described below.


  Case Report Top


A 46-year-old homemaker from Gorakhpur was admitted to the emergency department of our hospital in an unconscious state. It was spontaneous in onset with no evidence of precipitating factors. There were no signs of head injury, tongue bite from convulsions or urinary incontinence. Initial rapid diagnostic tests revealed the presence of hypoglycemia; her capillary plasma glucose levels were too low to be detectable by glucometer. Past medical records did not reveal any personal or family history of diabetes mellitus. However, she had suffered from two similar episodes of hypoglycemia in the last 1 month during which she was treated with intravenous dextrose drip and discharged without an evaluation for her cause of hypoglycemia. Besides, she was diagnosed with Graves' disease 3 months ago for which she was prescribed carbimazole at a dose of 20 mg TID. We ruled out other common precipitants of hypoglycemia like the presence of systemic infection, prolonged fasting state or the use of insulin and oral antidiabetic drugs. Family history her sister was on levothyroxine treatment for hypothyroidism since past 3 years.

On examination, she was unconscious (Glasgow Coma Scale = 6/15), pupils bilaterally normal size and reactive to light, no neck rigidity, and no apparent neurological deficit. Optic fundus examination was normal. A diffuse goiter was noted, while proptosis, pretibial myxedema, and acropachy were absent. Her pulse rate = 80/min, blood pressure = 124/80 mm Hg, respiratory rate = 20/min, and temperature = 99°F. Systemic examination did not reveal any significant findings. After obtaining adequate blood samples, she was given intravenous dextrose following which she gradually regained consciousness and could take oral feeds.

Laboratory investigations revealed the following: hemoglobin –11.6 g/dl, total leukocyte count –8900/mm 3, blood glucose = 26 mg/dl (at the time of admission), creatinine –0.8 mg/dl, Na = 132 mEq/L, K = 3.8 mEq/L, Ca (ionised) = 1.4 mmol/L, T3 = 2.97 ng/ml (normal range 0.60–1.81), T4 = 18 μg/dl (normal range 5.01–12.45), thyroid stimulating hormone = 0.32 mIU/ml (normal range 0.35–5.50). Technetium uptake scintigraphy of the thyroid was suggestive of Graves' disease, as it showed enlargement of both lobes of thyroid with homogeneous increased tracer uptake of 17.2% (normal 1%–4%) in both lobes [Figure 1]. In the presence of hypoglycemia, her serum insulin level was 168.2 μU/ml (normal 5–25 μU/ml), and C-peptide level was 26 nmol/l. Her cortisol level was 18 μg/dl (normal 11–18 μg/dl), excluding the possibility of adrenal insufficiency.
Figure 1: Thyroid scintigraphy showing enlargement of both lobes of thyroid with homogeneous increased tracer uptake

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Since her insulin and C-peptide levels were high in the background of hypoglycemia and she was on carbimazole therapy, we suspected the presence of IAS. To confirm, we ordered anti-IAA titles which came out to be 76 U/ml (positive >15 U/ml). Hence, the presence of autoimmune hypoglycemia was confirmed. Subsequently, we stopped her carbimazole and shifted her to propylthiouracil at a dose of 200 mg TID. She was advised to take small intermittent meals to avoid hypoglycemia.

We discharged her after educating her and her family members about the identification of hypoglycemic signs and symptoms and their management at home. In the next 6 months, she did not experience any further episode of hypoglycemia. Her thyroid functions normalized and her anti-IAA titers declined. She continues to remain compliant with her prescribed medications and is on regular follow-up.


  Discussion Top


IAS is a rare disorder first described by Hirata et al. in 1970.[2] Most cases till date have been reported from Japan. IAS seems to be strongly associated with human leukocyte antigen class II alleles which are much more prevalent in the Japanese and Korean population.[1] Affected patients usually have an underlying autoimmune disorder such as Graves' disease,[3] systemic lupus erythematosus, rheumatoid arthritis, and chronic hepatitis. Drugs implicated with the formation of anti-IAAs are mostly those which contain a sulfhydryl group, for example, methimazole, carbimazole, penicillamine, captopril, glutathione, and imipenem.[4],[5],[6],[7] It has been suggested that the sulfhydryl groups of the culprit drugs interact with the disulfide bonds of insulin, making it more immunogenic. Rarely, IAA may be produced by multiple myeloma or other benign monoclonal gammopathy.[7] Similarly, there are many syndrome associated with autoimmune type 1 diabetes mellitus.[8] Thioamide-induced hypoglycemia is an unusual drug reaction which can occur with various other drugs in a variety of ways, such as isoniazid-induced diabetes, amlodipine-induced gum hypertrophy, and Rifampicin-induced erythrocytopenia.[9],[10],[11]

The majority of the IAA are polyclonal, belonging to IgG class. In general, two types of antibodies are produced: those with high affinity and low binding capacity and those with low affinity and high binding capacity (associated with hypoglycemia). The antibodies generally appear a few weeks following the initiation of the drug and may result in both postprandial and fasting hypoglycemia. It is believed that insulin secreted after a meal gets bound to circulating autoantibodies, which gets later dissociated from the complex and exerts its hypoglycemic effects.[4],[6] The direct stimulation of pancreas by IAA leading to insulin secretion and cross-linking of the insulin-insulin receptor complex by antibodies leading to prolonged insulin action are other probable mechanisms accounting for hypoglycemia associated with this syndrome.

In IAS, the serum insulin levels measured are extremely high, usually more than 100 μIU/ml, because of the high capacity of the anti-IAAs.[7] Even the C-peptide levels remain high in the context of hypoglycemia owing to stimulation of pancreatic insulin secretion by the antibodies. Insulin antibody titers are also elevated in IAS. This syndrome must be distinguished from insulinoma (where insulin levels are rarely more than 100 μIU/ml) and exogenous insulin administration (where C-peptide levels are low in the face of high insulin levels).

Most patients suffering from IAS undergo spontaneous remission without any long-term sequelae. The suspected culprit medication must be stopped to allow for improvement. In some cases, oral prednisone therapy and plasmapheresis have been tried to reduce the antibody titers.[4]

IAS has been reported in very few instances outside Japan [12],[13] and is a rare occurrence in the Indian population.[14] Although rare, it must be suspected in the differential diagnosis of hypoglycemia with raised insulin levels, especially in patients receiving antithyroid drugs for Graves' disease. Prompt recognition and discontinuation of offending drugs are all that is required to prevent further catastrophic hypoglycemic episodes in the affected patients.


  Conclusion Top


IAS is a rare but known cause of hyperinsulinemic hypoglycemia and must be ruled out in appropriate circumstances, especially where known offending drugs are being administered to the patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am 1999;28:603-18, vii.  Back to cited text no. 1
[PUBMED]    
2.
Hirata Y, Ishizu H, Ouchi N, Motomura M, Abe M, Hara Y. et al, Insulin autoimmunity in a case of spontaneous hypoglycemia. J Jpn Diabetes Soc 1970;13:312-20.  Back to cited text no. 2
    
3.
Chen HD, Lin HD, Chang PY, Lin CY, Ching KN. Insulin autoimmunity study in Graves' disease: A preliminary report. J Chin Med Assoc 1986;38:103.  Back to cited text no. 3
    
4.
Sahni P, Trivedi N, Omer A. Insulin autoimmune syndrome: A rare cause of postprandial hypoglycemia. Endocrinol Diabetes Metab Case Rep 2016;2016. pii: 16-0064.  Back to cited text no. 4
    
5.
Chen CH, Huang MJ, Huang BY, Liu RT, Juang JH, Lin JD, et al. Insulin autoimmune syndrome as a cause of hypoglycemia: Report of four cases. Chang Gung Med J 1990;13:134-42.  Back to cited text no. 5
    
6.
Burch HB, Clement S, Sokol MS, Landry F. Reactive hypoglycemic coma due to insulin autoimmune syndrome: Case report and literature review. Am J Med 1992;92:681-5.  Back to cited text no. 6
    
7.
Uchigata Y, Tokunaga K, Nepom G, Bannai M, Kuwata S, Dozio N, et al. Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata's disease) and monoclonal insulin autoimmune syndrome. Diabetes 1995;44:1227-32.  Back to cited text no. 7
    
8.
Gutch M, Kumar S, Saran S, Gupta KK, Mohd Razi S, Philip R. Prevalence of autoimmune disorders in pediatrics type-1 diabetes mellitus in Western, Uttar Pradesh, India. Int J Med Public Health 2015;5:29-31.  Back to cited text no. 8
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9.
Manish G, Keshav GK, Syed RM, Sukriti K, Abhinav G. Isoniazid induced childhood diabetes: A rare phenomenon. J Basic Clin Pharm 2015;6:74-6.  Back to cited text no. 9
    
10.
Gutch M, Kumar S, Bhattacharjee A, Shakya S. Amlodipine induced reversible gum hypertrophy. Arch Pharm Pract 2016;7:103-5.  Back to cited text no. 10
    
11.
Agrawal A, Gutch M, Jain N, Singh A. Do not miss rifampicin-induced thrombocytopenic purpura. BMJ Case Rep 2012;2012. pii: Bcr1220115282.  Back to cited text no. 11
    
12.
Gomez Cruz MJ, Jabbar M, Saini N, Eng D, Crawford B, Vazquez DM, et al. Severe hypoglycemia secondary to methimazole-induced insulin autoimmune syndrome in a 16 year old African-American male. Pediatr Diabetes 2012;13:652-5.  Back to cited text no. 12
    
13.
Virally ML, Timsit J, Chanson P, Warnet A, Guillausseau PJ. Insulin autoimmune syndrome: A rare cause of hypoglycaemia not to be overlooked. Diabetes Metab 1999;25:429-31.  Back to cited text no. 13
    
14.
Ahamed A, Unnikrishnan AG, Nisha B, Praveen VP, Jayakumar RV, Nair V, et al. Insulin autoimmune syndrome (Hirata disease) associated with carbimazole therapy. Thyroid Res Pract 2010;7:22.  Back to cited text no. 14
  [Full text]  


    Figures

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This article has been cited by
1 Thyroid Dysfunction and Type 2 Diabetes Mellitus: Screening Strategies and Implications for Management
Sanjay Kalra,Sameer Aggarwal,Deepak Khandelwal
Diabetes Therapy. 2019;
[Pubmed] | [DOI]



 

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