’80 year old woman was found collapsed at home with bradycardia and hypothermia.

1. ’80 year old woman was found collapsed at home with bradycardia and hypothermia. A blood glucose concentration of 2.0 mmol/L was recorded using a near-patient testing device. Discuss the differential diagnosis and laboratory investigation of the case’ Prepared by Dr Gwen Wark, Consultant Clinical Scientist, SAS Peptide laboratory

2. Demonstrating hypoglycaemia Low blood glucose should be confirmed by laboratory glucose analysis (fluoride oxalate)

3. Demonstrating hypoglycaemia • Even if glycolytic inhibitors in tubes, they do not work straightway and there will still be a loss of glucose. • May also be ‘pseudohypoglycaemia’ if delayed sample separation, samples are old and if leukocytosis, thrombocytosis or erythrocytosis is present.

4. Hypoglycaemia - definition • Arbitrary – point at which symptoms occur varies between individuals • Not possible to state a single plasma glucose concentration that categorically defines hypoglycaemia • Therefore variation in glucose cut offs used

5. Hypoglycaemia - definition • Need to be clear which sample types are being used i.e. plasma vs whole blood or arterial vs venous etc as glucose levels different • Symptoms start to appear when venousplasmaglucose < 3 mmol/L This is the cut off used in the Endocrine Society Clinical Practice Guideline which is increasing being adopted in UK

6. Investigation of hypoglycaemia • Demonstrate Whipple’s triad • Symptoms (may need to do fasting studies etc) • confirmed hypoglycaemia • administration of glucose relieves symptoms • Elucidate the cause • samples taken during the hypoglycaemic episode before treatment

8. (Anti arrhythmia) (Antibiotic) (Anti microbial) (Anti malarial) (NSAID)

9. Causes of hypoglycaemia • Commonest cause is drugs • Insulin, insulin secretagogues (sulphonylurea), alcohol etc • Can occur sepsis and critical illness including renal cardiac and liver failure • Occurs rarely in cortisol deficiency • Endogenous hyperinsulinism and non islet cell tumours are rare

10. Investigation of hypoglycaemia-history and physical examination • Drugs (?patient diabetic or has access to medication via diabetic relative) e.g. samples for ethanol, insulin, C-peptide, oral hypoglycaemic agent screens (sulphonylurea commonest cause as oral agent) • Organ failure (renal, hepatic, cardiac) - e.g. renal & liver profiles, ?BNP ?Troponin requested

11. Investigation of hypoglycaemia-history and physical examination • Endocrine deficiency • Cortisol, GH and pituitary hormone profile requested – in this case thyroid function tests should definitely be done • Infection • CRP, FBC (WBC), blood cultures, ?procalcitonin etc • Starvation • (Unlikely at this age that there is an IEM)

12. Laboratory Investigations so far…. • Laboratory glucose • U&E • LFT’s • Endocrine profile • BNP, Troponin • Insulin • C-Peptide • Oral hypoglycaemic agents • CRP, FBC, blood cultures

14. Insulin assay issues • The previous algorithm is for an insulin assay that detects proinsulin (investigation of proinsulinomas) and synthetic analogues (exogenous insulin administration). Some insulin assays do not detect these so procedures need to be in place to ensure these can be tested for.

15. Other investigations • Insulin antibodies and insulin receptor antibodies – rare cause of hypoglycaemia but assays are available. - Insulin antibodies can affect insulin assays and often cause elevated results. However low insulin results can occur depending on the insulin assay. • Pattern of results expected to see in different causes of hypoglycaemia shown on next slide

16. The cut-offs for insulin, C-peptide, proinsulin and -hydroxybutyrate are assay dependent

17. Comments on essay responses • Most candidates indicated the need to confirm the near patient testing (NPT) device glucose analysis with a laboratory glucose measurement. Fewer candidates reflected on potential issues with the NPT glucose result e.g. peripheral perfusion - hypotension, assay range, whole blood vs plasma glucose differences in results etc

18. Comments on essay responses • Few candidates reflected on the likelihood that treatment would have been started to raise the glucose level before appropriate samples were collected for the investigation of hypoglycaemia. • Limited mention of Whipples triad. It may be necessary to provoke symptoms by performing a diagnostic fast (or a mixed meal test – not an OGTT) if the low NPT glucose is to be investigated further as it may be artifactual.

19. Comments on essay responses • Essay responses reflected a variation in the glucose cut-offs used to define hypoglycaemia. This is to be expected as the definition of hypoglycaemia is arbitrary.

20. Comments on essay responses • Often emphasis on investigation of rarer causes of hypoglycaemia e.g. insulinoma or non-islet cell tumour • Some very clear and systematic approaches to investigation and for the interpretation of results was provided. However none suggested that the cut-offs that they mentioned would be assay dependent.

21. Comments on essay responses • Only a few candidates reflected on cross-reactivity issues with insulin assays: e.g. proinsulin so that cases of proinsulinoma are not missed e.g. synthetic insulin analogues. Cases of exogenous insulin administration can be missed with some insulin assays as assays vary in their cross-reactivity for these preparations.

22. Comments on essay responses • Essays tended to focus on the investigation of the low blood glucose due to the NPT result. • Only some of the essays mentioned any causes or investigation of bradycardia (e.g. TSH, cortisol, K+, digoxin, amiodarone etc) or hypothermia since this glucose result could be artifactual.

23. Structure • Demonstration of hypoglycaemia • Definition of hypoglycaemia • Mention BRIEFLY potentially differences between POCT and laboratory • Causes of hypoglycaemia - tables • Laboratory investigation of causes including limitations – tables, algorithms • Investigation of bradycardia and hypothermia if glucose result is artifactual