AN UNUSUAL CAUSE OF HYPOGLYCAEMIA. Dr Julie Chemmanam, Dr Morton Burt Flinders Medical Centre South Australia

Transcription

1 AN UNUSUAL CAUSE OF HYPOGLYCAEMIA Dr Julie Chemmanam, Dr Morton Burt Flinders Medical Centre South Australia

2 Declaration Of Interests Nil

3 Outline Of The Talk Case presentation Differential diagnosis Final diagnosis and case conclusion Discussion

4 Case 48 year old female Lives with husband and son Cleaner on night-shift at police stations Witnessed collapse and one minute generalized seizure at work

5 History Awoke at 0100 as usual but felt unwell and tired Went to work at 0430 Coffee but no food before work Seizure preceded by flickering lights

6 History From Ambulance Officers Regained consciousness spontaneously Post-ictal drowsiness Complained of headache, blurred vision and fatigue Finger prick BGL was 4.7 mmol/l

7 In Emergency Initial finger prick BGL 4.0 mmol/l Patient became drowsy - Repeat finger prick BGL 2.0 mmol/l - Plasma glucose 2.2 mmol/l Administered 25 g IV dextrose bolus followed by continuous infusion

8 Previous Hypoglycaemia? Witnessed generalised seizure at work - Preceded by tremor and nausea - Concerns re hypoglycaemia but none documented Seizure at work, plasma glucose 1.6 mmo/l in ED - 72 hour fast but no hypoglycaemia

9 Past Medical History Seizures and/or pseudoseizures - Generalised seizures since Treated with sodium valproate - Normal EEG in 2010 and sodium valproate withdrawn by Neurologist as thought to be pseudoseizures but restarted by GP Type 2 diabetes - Elevated fasting plasma glucose in Diet control only

10 Past Medical History Chronic gastrointestinal symptoms - Bloating - Weight loss of 4 kg in 6 months - Endoscopy and colonoscopy in 2010 showed small hiatus hernia and benign tubular adenoma Chronic back pain Hyperlipidaemia

11 Medication And Drug History Sodium valproate 400 mg bd Esomeprazole 40 mg daily MS Contin 30 mg daily Patient denied taking insulin, oral hypoglycaemic agents, other drugs or supplements Current smoker - 20 cigarettes /day Alcohol - nil

12 Family History Two sisters with diabetes but patient reported no contact with either of them for at least 5 years Husband and son do not have diabetes

13 Inpatient Stay Admitted to the ward for a 72 hour fast Seizure prior to commencement of the fast (BGL 7.0 mmol/l)

14 First 72 Hour Fast Generalized seizure after 16 hours (0100) Fingerprick BGL was 2.4 mmol/l Given 25 g IV dextrose by MET team No insulin or C-peptide before IV dextrose

15 Second 72 Hour Fast Time Finger prick BGL (mmol/l) Plasma glucose (mmol/l) Day Symptoms

16 Second 72 Hour Fast Time Finger prick BGL (mmol/l) Plasma glucose (mmol/l) Day Symptoms Day Feeling hot and nauseated Drowsy but rousable to voice Alert

17 Second 72 Hour Fast Time Finger prick BGL (mmol/l) Plasma glucose (mmol/l) Day Symptoms Day Feeling hot and nauseated Drowsy but rousable to voice Alert Day Pseudoseizure Weak and wobbly on feet Unresponsive

18 Second 72 Hour Fast Given 25 g IV dextrose at 17:30 BGL increased to 17.3 mmol/l Recovered slowly to normal level of consciousness

19 Results Test Result Normal range 8 am cortisol (nmol/l) 698 IGF-1 (nmol/l) TSH (miu/l) FT4 (pmol/l) HbA1c (%) 6.0 Sulphonylurea screen Negative

20 Results Time Glucose (mmol/l) βoh B (mmol/l) Day n/a Day Day

21 Results Time Glucose (mmol/l) βoh B (mmol/l) Insulin (mu/l) C-peptide (pmol/l) Day n/a Day < < < Day <0.5 < <0.5 <100

22 Questions Does our patient have pathological hypoglycaemia? If so, what results during the 72 hour fast suggest the mechanism of hypoglycaemia? What is the differential diagnosis?

23 Results Time Glucose (mmol/l) βoh B (mmol/l) Insulin (mu/l) C-peptide (pmol/l) Day n/a Day < < < Day <0.5 < <0.5 <100

24 What Constitutes Hypoglycaemia Clinical hypoglycaemia is, by definition, a plasma glucose concentration low enough to cause symptoms and/or signs, including impairment of brain function There is no single plasma glucose concentration that categorically defines hypoglycaemia Plasma glucose can fall to 2.2 mmol/l or lower in some healthy asymptomatic adults Cryer et al. J Clin Endocrinol Metab March 2009; 94(3):

25 Confirmation Of Hypoglycaemia Documentation of Whipple s triad Our patient Symptoms and/or signs of hypoglycaemia Low plasma glucose concentration Resolution of symptoms and signs when hypoglycaemia resolves Drowsy 2.6 mmol/l Variable

26 Case What results during the 72 hour fast suggest the possible mechanism of hypoglycaemia? Suppression of ketogenesis was evidence of insulin-like activity

27 Ketogenesis Adipocyte Triglycerides Hormone sensitive lipase Free fatty acids Hepatocyte Acetyl CoA carboxylase Lipogenesis Acetyl CoA Acetoacetate Beta OH butyrate Acetone Laffel L. Diabetes Metab Res Rev 1999;15:412-6

28 Insulin Suppresses Ketogenesis Insulin Adipocyte Hepatocyte Lipogenesis Triglycerides Hormone sensitive lipase Free fatty acids Acetyl CoA carboxylase Acetyl CoA Acetoacetate Beta OH butyrate Acetone Laffel L. Diabetes Metab Res Rev 1999;15:412-6

29 Ketones During 72 Hour Fast Our patient Service F et al. J Clin Endocrinol Metab 2005;90:4555-8

30 Differential diagnosis Diagnosis Glucose Ketones Insulinoma OHA Exogenous insulin Insulin auto immunity Proinsulinoma NICTH Cryer et al. J Clin Endocrinol Metab March 2009; 94(3):

31 Differential diagnosis Diagnosis Glucose Ketones Insulin C-peptide Proinsulin OHA Insulin antibody Insulinoma No No OHA Yes No Exogenous insulin Insulin auto immunity No No No Yes Proinsulinoma No No NICTH No No Cryer et al, J Clin Endocrinol Metab March 2009; 94(3):

32 Differential diagnosis Diagnosis Glucose Ketones Insulin C-peptide Proinsulin OHA Insulin antibody Insulinoma No No OHA Yes No Exogenous insulin Insulin auto immunity No No No Yes Proinsulinoma No No NICTH No No Our patient? No n/a Cryer et al, J Clin Endocrinol Metab March 2009; 94(3):

33 Non Islet Cell Tumour-Induced Hypoglycaemia Some mesenchymal and epithelial tumours secrete pro-igf-ii Large tumours >10 cm Pro-IGF-II binds poorly to its binding proteins, more freely enters tissue spaces, has insulin-like actions Insulin and IGF-I are suppressed IGF-II concentration may be normal but ratio of IGF-II to IGF-I is elevated Cryer et al, J Clin Endocrinol Metab March 2009; 94(3):

34 Case Our patient did not have a visible tumour on CT chest or abdomen IGF-I was not suppressed

35 Proinsulinoma Pancreatic endocrine tumours usually produce and secrete both insulin and proinsulin Rare tumours secrete only proinsulin and can present with suppressed insulin and C-peptide and high proinsulin concentration Fadini et al Case reports in Medicine; doi: /2011/930904

36 Case Proinsulin was suppressed (< 3pmol/L) in our patient during the episodes of hypoglycaemia

37 Case Symptomatic hypoglycaemia with low insulin and low ketones Tests for NICTH and proinsulinoma negative

38 Results With Second Insulin Assay Time Plasma glucose (mmol/l) C-peptide (pmol/l) Insulin (mu/l) Roche Day Insulin (mu/l) Centaur Day < < < Day <100 < <100 <0.5 24

39 Results With Second Insulin Assay Time Plasma glucose (mmol/l) C-peptide (pmol/l) Insulin (mu/l) Roche Day Insulin (mu/l) Centaur Day < < < Day <100 < <100 <0.5 24

40 DIAGNOSIS Factitious hypoglycaemia due to surreptitious administration of short-acting insulin analogue

41 Case We explained to the patient that hypoglycaemic episodes were due to exogenous insulin Patient denies taking insulin injections or any close contacts who take insulin No previous insulin prescriptions on PBS

42 Case Driver s licence was suspended for 6 months due to presentation with seizure Patient lost her job as unable to get to work We have encouraged psychiatry review as part of assessment for driver s licence reinstatement No further hypoglycaemia to date

43 DISCUSSION

44 Insulin assay Detection antibody Epitope 2 Insulin Epitope 1 Capture antibody

45 Structure of Insulin

46 Insulin Aspart Asp

47 Insulin Lispro Pro Lys

48 Insulin Glargine Gly Arg Arg

49 Insulin assays Owen et al. Clinical chemistry 50, No.1, 2004; 257-9

50 Insulin Assays in Australia Assay % of laboratories Roche (E170) 33 Siemens (Centaur/Immulite) 32 Abbott (Architect) 26 Beckmann (Dxl) 9

51 Structure of Insulin Antibody in Centaur assay Antibody in Roche assay

52 Factitious Hypoglycaemia Due to Insulin Incidence - unknown Mostly case reports Administration Ten patients admitted to NIH over 13 years - 9 of 10 were young women - 5 of 10 had previously been prescribed insulin - All were either involved in the medical profession or had relatives with insulin-requiring diabetes Grunberger et al, Ann Intern Med1998;108:

53 Factitious Hypoglycaemia Due to Insulin Administration Most patients initially denied surreptitious insulin use Six of 10 patients eventually admitted to insulin self administration Long-term outcome: - No further symptoms: 3 patients - Recurrent symptoms: 4 patients - Lost to follow-up: 1 patient - Suicide: 2 patients (2 and 4 months after discharge) Grunberger et al, Ann Intern Med1998;108:

54 Factitious Hypoglycaemia Secondary To Insulin Analogues Two case reports in French and one in German

55 Summary We present a case of a patient who presented with factitious hypoglycaemia secondary to insulin analogue administration Suppression of ketogenesis provided a clue that insulin activity was present Understanding the variable cross reactivity of insulin analogues with different insulin assays was critical to make the diagnosis

56 References 1. Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. Cryer et al. J Clin Endocrinol Metab March 2009; 94(3): Ketone Bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Laffel. Diabetes Metab Res Rev 1999;15: Increasing serum betahydroxybutyrate concentrations during the 72-Hour fast: Evidence against hyperinsulinemic hypoglycaemia. Service F et al. J Clin Endocrinol Metab 2005;90: Cross-Reactivity of three recombinant insulin analogs with five commercial insulin immunoassays. Owen et al. Clinical chemistry 50, No.1, 2004; Factitious hypoglycaemia due to surreptitious administration of insulin. Grunberger et al. Ann Intern Med 1998;108:252-7

57 Acknowledgements Dr Wilton Braund, Dr George Tallis, Dr Natalie Marijanovic and all the Endocrinologists at Flinders Medical Centre Dr Mohammad Saleem and Dr Graham White, Chemical Pathologists in Adelaide

58 THANK YOU

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61 Drugs causing hypoglycaemia Moderate quality of evidence Cibenzoline Gatifloxacin Pentamidine Quinine Indomethacin Glucagon (during endoscopy) Low quality of evidence Chloroquineoxaline sulfonamide Artesunate/artemisin/artemether IGF-I Lithium Propoxyphene/dextropropoxyph ene Very low quality of evidence Drugs with >25 cases of hypoglycemia identified Angiotensin converting enzyme inhibitors Angiotensin receptor antagonists b-adrenergic receptor antagonists Levofloxacin Mifepristone Disopyramide Trimethoprim-sulfamethoxazole Heparin 6-Mercaptopurine

62 Sensitivity Of 72 Hour Fast Incidence of insulinoma is 4 in a million The prolonged fasting test defined as a positive Whipple s triad in combination with an insulin/cpeptide ratio <1 had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma A positive Whipple s triad of fasting had occurred after 48 hours in 95% and 93%, and after 72 hours in 99%. 93% positivity rate within 48 h of fasting and a 99% positivity rate by 72 h of fasting of patients with insulinoma

63 Evaluation of a patient with hypoglycaemia Concurrent illness Critical illness Hormone deficiency Non-islet cell tumour Seemingly well Endogenous hyperinsulinaemia Accidental, surreptitious or malicious hypoglycaemia Martens,P et al European journal of internal medicine 2014

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66 Roche

67 Centaur

68 Percentage cross-reactivity from the ratio of measured and nominal concentrations of i Cross-reactivities, % Insulin product ARCHITECT Insulin E-test TOSOH (IRI) Aspart (NovoRapid) 10 miu/l miu/l Glargine (Lantus) 10 miu/l miu/l Lispro (Humalog) 10 miu/l miu/l

69 centaur This is the assay we have used at RAH Site. Clearly the antibody used in this assay is not recognising position 21 or 28 ie the modified part of the exogenous insulin. The antibody must be directed to en epitope elsewhere in the molecule which does not contain these aminoacid that are modified. Roche - This is the FMC assay. The antibody used in this assay must be directed at an epitope that includes both position 21 and position 28. Therefore it will not bind to the modified insulin but only to endogenous insulin.

70 Roche This is the FMC assay. The antibody used in this assay must be directed at an epitope that includes both position 21 and position 28. Therefore it will not bind to the modified insulin but only to endogenous insulin.

71 Normal counter-regulatory mechanisms

72 Cross-reactivity of insulin analogues Three insulin analogues insulin aspart, glargine and lispro, with a concentration of 100 IU/mL Diluted using 60 g/l aqueous bovine serum albumin to final insulin concentrations of 30, 100, 300, and 1000 miu/l. All dilutions of each insulin preparation were analysed in five different insulin assays

73 Cross-reactivity of insulin lispro The Elecsys method uses two monoclonal antibodies: - MAK-Bi (R1), which recognizes the A7 A10 portion of the A chain; and - Fab-Ru (R2),which recognizes the C-terminal part of the B chain. The specificity of the R2 antibody explains the poor recognition of insulin lispro by the Elecsys assay. The Bio-Rad insulin assay uses antibodies that bind to a highly conserved region, including the A10 A17 residues

74 Cross-reactivity of insulin analogues There is large variability in insulin analogue crossreactivity with different commercial assays. The E170 method had a cross-reactivity of <0.02% for all three analogues This suggests that one antibody used in this assay recognizes an epitope that includes B28 and the COOH terminus of the B chain. Substitutions at these positions abolished immunoreactivity.

75 Insulin supresses ketogenesis Insulin potently reduces circulating ketone body concentrations via several mechanisms. insulin inhibits lipolysis, decreasing the supply of free fatty acids to the liver for ketogenesis. insulin directly inhibits ketogenesis in the liver, despite their high plasma free fatty acid concentrations. hyperinsulinemia is associated with increased peripheral clearance of ketone bodies uptodate

76 Questions Are our patient s symptoms caused by hypoglycaemia? If so, what results during the 72 hour fast give a clue that glucose concentrations are pathologic? What is the differential diagnosis? What further tests would you order?

77 Cross-reactivity Of Insulin Analogues With Different Insulin Assays Cross-reactivity = observed concentration expected concentration X 100%