A Diagnostic Challenge: Hypoglycaemia due to a Proinsulin Secreting Pancreatic Neuroendocrine Tumour

P Valsalakumari, JF Todd, S Robinson, D Spalding, J Jackson, A Al-Nahhas, P Vlavianos, E Walker, F Wernig, Hammersmith Hospital, Imperial College.

A 69 year old lady presented with a 20 year history of recurrent blackouts. Previous investigations had been inconclusive. More recently, these attacks had become more frequent and severe. On several occasions she was found unconscious with capillary blood glucose readings of less than 2.0 mmol/L. She had no other past medical history of note and her diet was balanced. Clinical examination was unremarkable with a BMI of 19 kg/m2.

She was admitted for a 72 hour fast. Her blood glucose dropped to 1.9 mmol/L after 26 hours with insulin of 0.3 mU/L and C-peptide of 96 pmol/L. Sulfonylurea screen was negative. Similar to previous investigations, the appropriately suppressed insulin was not consistent with the diagnosis of an insulinoma, hence causes of non-islet cell related hypoglycaemia were sought. Interestingly, the IGF2/IGF1 ratio was found to be mildly elevated at 10.3 (normal <10).

Multiple pancreatic tail lesions seen on MRI, CT as well as endoscopic ultrasound were found to be significantly DOTATATE avid on a Gallium68 DOTATATE PET-CT and therefore highly suggestive of a neuroendocrine tumour.

A presumptive diagnosis of non-islet cell hypoglycaemia was made. Her case was discussed at the ICHNT neuroendocrine tumour MDT and it was felt that she should be offered pancreatic surgery. She proceeded to have a distal pancreatectomy. The histology showed multiple grade 1 neuroendocrine tumours with lymph node invasion. Immunohistochemistry was positive for CD56 and insulin consistent with an insulinoma. At this stage the blood sample from the initial 72 hour fast was analysed for proinsulin. Surprisingly, the proinsulin level was found to be inappropriately elevated at 37pmol/l (normal <10pmol/L) making a proinsulin secreting neuroendocrine tumour the most likely diagnosis. Postoperatively, the patient remains very well with no further episodes of spontaneous hypoglycaemia.

Proinsulin secreting neuroendocrine tumours are a rare entity of insulinomas and can pose significant diagnostic challenges.  Measurement of proinsulin levels in patients with suspected insulinoma, but appropriately suppressed insulin levels associated with hypoglycaemia, may reveal the diagnosis.