Case history: Herein, we report the case of a 79-year-old male who presented acutely to A&E with recurrent episodes of symptomatic hypoglycaemia. A random glucose at presentation was low at 1.4 mmol/l and upon correction symptoms resolved. While hospitalized, he continued having episodes of symptomatic hypoglycaemia, requiring treatment with intravenous dextrose and per os steroids. Once stable, he was discharged with advice.
Investigations: A contrast-enhanced CT scan of his abdomen revealed liver/omental deposits and a biopsy with subsequent immunohistochemistry was positive for CD117 (C-kit), Dog1, and CD34 with focal expression of SMA confirming the diagnosis of a metastatic gastrointestinal stromal tumour (GIST). Genetic testing for c-kit activating mutations was carried-out to predict his therapy response and guide anti-CD117 dose with Imatinib Mesylate revealing an exon 11 deletion. Non-islet cell tumour hypoglycaemia (NICTH) was suspected, with an IGF-2 (105.9 nmol/l) to IGF-1 (4.6 nmol/l) ratio of 23 supporting the diagnosis (UNL <10).
Results and treatment: Following discussion at the upper gastrointestinal malignancy MDT, treatment with Imatinib Mesylate 400 mg daily was initiated and prednisolone was gradually weaned. Surveillance imaging at six months post-treatment initiation revealed partial response and there were no hypoglycaemic episodes for the next 21 months.
Conclusions and points for discussion: The incidence of NICTH remains scarce, typically seen with metastatic or advanced mesenchymal tumours. This presents as recurrent hypoglycaemia mostly affecting elderly patients with advanced disease. Occasionally, NICTH can predate the diagnosis of the underlying malignancy. Most cases are caused by tumour cell production of IGF2. The expression of big IGF2 has been reported the result of high concentrations of pre-pro-IGF2 levels that are not properly glycosylated, resulting in high molecular weight IGF2. This has a significantly higher affinity to the insulin receptor, and lower affinity to its binding protein (IGFBP3), leading to increased bioavailability, enhanced peripheral glucose consumption and suppressed hepatic glucose production. GIST diagnosis is confirmed by immunohistochemical positive staining of C-kit. Mutational analysis in GIST is crucial for identifying less sensitive/resistant genotypes (PDGFR-D842V) to selective Imatinib Mesylate and allows dose adjustment for patients with rarer C-kit exon 9 deletions. Surgical removal of primary tumour remains most rapid/effective therapy for normalising glucose metabolism in most cases of NICTH when indicated. NICTH is a poorly recognised cause of hypoglycaemia and consequently may remain undiagnosed. This case highlights the importance of recognising NICTH as a potential cause of hypoglycaemia in cases of patients with advanced malignancy and adds to limited cases confirming GIST as source of abnormal secretion of IGF-2.
12 Mar 2020 - 12 Mar 2020