Case Presentation:
A 79-year-old Caucasian non-diabetic male with history of renal cell carcinoma, s/p left nephrectomy in 2005 and coronary artery stent placement 2 months prior and on Clopidogrel, presented with acute onset sweating and palpitations. Monitoring revealed fasting serum glucose as low as 29mg/dL with concurrent insulin level of 9,600 uIU/mL. Further investigations for the cause of his hyperinsulinemic hypoglycemia showed a C-Peptide of 18.9ng/mL ruling out exogenous insulin, a negative sulfonylurea screen, negative anti-islet cell antibodies and Chromogranin A of 24ng/mL suggesting a neuroendocrine tumor. A work up for Insulinoma included an MRI of the Pancreas and EUS both of which came back negative. Given the negative Insulinoma work-up and such uncharacteristically high Insulin levels, a Paraneoplastic syndrome with ectopic Insulin secretion versus a drug-induced autoimmune process was considered. A negative whole body PET/CT ruled out a paraneoplastic process but the anti-Insulin antibody titer was high (11 nmol/L, range 0.00-0.02) confirming the diagnosis of Insulin Autoimmune Syndrome
The patient was started on Diazoxide 80mg TID and Dexamethasone 2mg BID on day 10. Serum glucose ranged from 50-80mg/dL to >350 mg/dL post-prandial. Clopidogrel was determined to be a possible inciting cause and was replaced on day 18 with Tacagrelor. Total serum insulin then measured was 20,900uIU/mL with a normal free insulin level. With no further hypoglycemic episodes the patient was discharged on the above treatment on day 22 with Endocrine follow-up.
Discussion:
Insulin Autoimmune Syndrome (IAS) is described as spontaneous hypoglycemia due to insulin autoantibodies in the absence of exogenous insulin. IAS is a leading cause of hypoglycemia in Japan but is rarely diagnosed in the US. This case illustrates the need to consider drug-induced IAS in patients with acute onset hyperinsulinemic hypoglycemia and no history of exogenous insulin exposure. In IAS antibody-bound serum insulin builds and is released erratically resulting in extreme hypoglycemia. Literature review suggests that medications with a sulfhydryl group are known to trigger IAS particularly in patients who are positive for the HLA-DRB1 gene. The most common offending drug is alpha-lipoic acid, with Methimazole, Glutathione, Imipenem, and Hydralazine also implicated. Stopping the suspected drug typically reverses IAS. Our patient tested positive for HLA-DRB1-04:04 and all his medications including OTC supplements were reviewed. Clopidogrel whose active metabolite contains a sulfahydryl group was felt to be the offending agent and was discontinued. He has had no episodes of hypoglycemia since discharge.
Conclusions:
Hospitalists are often the first physicians to work up patients admitted with hypoglycemia. Even though IAS is a rare cause of hypoglycemia in the US, hospitalists should be aware of this disorder since early diagnosis can eliminate unnecessary procedures and delay in treatment.