1. Non-Diabetic Hypoglycemia Medical Grand Rounds May 14, 2004 Dr. William Harper Assistant Professor of Medicine, McMaster University. Endocrinologist, Hamilton General Hospital www.drharper.ca

2. Hypoglycemia: case based 1. Diagnostic approach to hypoglycemia 2. Iatrogenic hypoglycemia 3. Tumor-associated hypoglycemia

3. Case 1 18 year old male Prior ADHD, school suspension-fighting LOC, SZ, CBG 1.8 mM Stepfather T2DM: glyburide Grandfather T2DM: insulin

4. Hypoglycemia: Symptoms Sympathoadrenal: diaphoresis, warmth, anxiety, tremor, nausea, hunger, palpitations/tachycardia Neuroglycopenic: Fatigue, dizziness, H/A, visual disturbance, drowsiness, difficulty speaking, inability to concentrate, amnesia, abnormal behaviour, mood changes, loss of consciousness, seizure, focal neurological deficit

5. Response to Hypoglycemia Blood GlucoseSymptoms < 3.3 mM Sweating, tremor, anxiety, palpitations, hunger 2.8 – 3.1 mM Early cognitive dysfn. (confusion, mood changes) 2.5 – 2.8 mM Lethargy, obtundation < 1.7 mM Coma < 1.1 mM Convulsions …Death

6. Response to Hypoglycemia Blood GlucoseHormonal response < 4.4 mM Insulin  to low levels 3.6 - 3.9 mM Glucagon & catecholamines < 3.3 mM Growth Hormone & cortisol < 2.5 mM Pancreas: no insulin release

8. Hypoglycemic Disorders Fasting vs. Post-prandial Appearance: healthy vs. sick Hyper-insulinemic vs. Hypo-insulinemic

9. Post-prandial Hypoglycemia Sympathoadrenal symptoms only: 2° to refined sugars/simple CHO Alimentary Surgery (gastrectomy, etc) Dumping syndrome  fluid shifts Dysglycemia IFG, IGT, Early Type 2 DM 4-5h after

10. Post-prandial Hypoglycemia Neuroglycopenic symptoms: Unripe ackee fruit Bariatric surgery? Insulinoma, islet hypertrophy Non-insulinoma pancreatogenous hypoglycemia (NIPHS)

11. Post-prandial Hypoglycemia Non-insulinoma pancreatogenous hypoglycemia (NIPHS) Adult nesidioblastosis (islet hypertrophy) Postprandial severe neuroglycopenia 72h fast negative Rare, M > F (insulinoma F > M) Ca+ stimulation test Rx: partial pancreatectomy

13. Hypoglycemia Symptoms (only adrenergic) after eating? Symptoms after fasting or skipped meals? OGTT 75g glucose, BS q30min x 5h BS < 2.8 mM? If yes: avoid refined sugars Fasting Hypoglycemia FPG >2.8 mM< 2.8 mM 72h fast BG < 2.8 mM? Vigorous exercise Glucagon stimulation (rise BS > 1.4 mM) YES NO Insulin > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 C-peptide > 0.2 nM < 0.2 nM Insulinoma OHA screen – Prosinsulin: > 5 pM > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s AI, hypothyroid Liver Disease, EtOH Enzyme defects Severe, protracted malnutrition Non-islet cell tumor Secretes IGF-II Secretes IGFI- BP inhibitor

14. Case 1 18 year old male Prior ADHD, school suspension-fighting LOC, SZ, CBG 1.8 mM No critical BW drawn Stepfather T2DM: glyburide Grandfather T2DM: insulin

15. Critical Blood Work Prior to treatment send venous BW: Venous BS Insulin, c-peptide, +/- pro-insulin ACTH, cortisol

16. Criteria: Endogenous hyperinsulinemia BS < 2.8 mM and… Insulin > 21.5 pM C-peptide > 0.2 nM Proinsulin > 5 pM Insulin surrogates: Glucagon 1mg IV   BS > 1.4 mM at 30 min  H  < 2.7 mM (serum ketones)

17. Whipple’s Triad Koch’s postulates of Hypoglycemia Symptoms BS < 2.8 mM Resolution of symptoms with CHO

18. Hypoglycemia Symptoms (only adrenergic) after eating? Symptoms after fasting or skipped meals? OGTT 75g glucose, BS q30min x 5h BS < 2.8 mM? If yes: avoid refined sugars Fasting Hypoglycemia FPG >2.8 mM< 2.8 mM 72h fast BG < 2.8 mM? Vigorous exercise Glucagon stimulation (rise BS > 1.4 mM) YES NO Insulin > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 C-peptide > 0.2 nM < 0.2 nM Insulinoma OHA screen – Prosinsulin: > 5 pM > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s AI, hypothyroid Liver Disease, EtOH Enzyme defects Severe, protracted malnutrition Non-islet cell tumor Secretes IGF-II Secretes IGFI- BP inhibitor

21. Case 1 Serum screen negative for OHA x 2 Admit 72h fast: Lowest CBG 4.1 mM, VBG 3.9 mM Serum ketones trace during fast End of fast: 1 mg IV glucagon Glucose rise < 1.4 mM D/C home without any imaging No further episodes LOC/SZ/low BS Advised to avoid insulin, OHA Final Diagnosis: surreptitious use insulin +/- OHA

22. Hypoglycemia: Family Hx of DM? Access to insulin? Access to oral hypoglycemia agents?

23. Case 2 71M, admit with  ascites Known cirrhotic 2° EtOH, abstinate x 7y BS 6-8 mM in-hospital until day 14 Awoke with BS 3.4 mM BS 2.0-2.9 despite + + po CHO intake Next day BS 1.5-1.9 mM D10W IV gtt @ 100-150/h x 2-3d

24. Case 2 Meds: amiodarone, altace, ASA, lasix, aldactone, cipro, ativan qhs PRN AST, ALT, GGT mildly elevated Albumin 39, INR 1.2 Critical BW: Venous BS 1.5 mM Insulin 317 pM, C-peptide 4.0 nM ACTH 7 pM, cortisol 751 nM

28. Hypoglycemia Symptoms (only adrenergic) after eating? Symptoms after fasting or skipped meals? OGTT 75g glucose, BS q30min x 5h BS < 2.8 mM? If yes: avoid refined sugars Fasting Hypoglycemia FPG >2.8 mM< 2.8 mM 72h fast BG < 2.8 mM? Vigorous exercise Glucagon stimulation (rise BS > 1.4 mM) YES NO Insulin > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 C-peptide > 0.2 nM < 0.2 nM Insulinoma OHA screen – Prosinsulin: > 5 pM > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s AI, hypothyroid Liver Disease, EtOH Enzyme defects Severe, protracted malnutrition Non-islet cell tumor Secretes IGF-II Secretes IGFI- BP inhibitor

29. Case 2 Serum glyburide: Oct 22, 2003:60 nM Oct 23, 2003:66 nM (Patient not prescribed glyburide) Diagnosis: iatrogenic hypoglycemia 2° to dispensing error Treatment: P&T committee  review OHA stock drawer policy

30. Case 3 49M, Fall 2002: LBP & abdominal mass Retroperitoneal seminoma Chemotherapy: Etoposide, Cisplatinum, Bleomycin Tumor: good response

31. Case 3 Chemo  anorexia Spells of bizzare behaviour, confusion, lethargy Random BS 3.6 mM, HbA1c 3.4% PHx: 10y of early AM spells, relieved with snacks/O.J., weight gain > 100 lbs.

32. Case 3 BS 1.8 mM Insulin 155 pM C-peptide 1.9 nM Pro-insulin 133 pM

34. Hypoglycemia Symptoms (only adrenergic) after eating? Symptoms after fasting or skipped meals? OGTT 75g glucose, BS q30min x 5h BS < 2.8 mM? If yes: avoid refined sugars Fasting Hypoglycemia FPG >2.8 mM< 2.8 mM 72h fast BG < 2.8 mM? Vigorous exercise Glucagon stimulation (rise BS > 1.4 mM) YES NO Insulin > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 C-peptide > 0.2 nM < 0.2 nM Insulinoma OHA screen – Prosinsulin: > 5 pM > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s AI, hypothyroid Liver Disease, EtOH Enzyme defects Severe, protracted malnutrition Non-islet cell tumor Secretes IGF-II Secretes IGFI- BP inhibitor

35. Case 3 Hypoglycemia treated with: Diazoxide Prednisone (bleomycin lung toxicity) ICC of retroperitoneal tumor negative for insulin CT scan: bulky pancreatic tail Octreoscan: negative MRI: tumor in tail of pancreas

36. Case 3 Intraoperative U/S: single tumor confirmed at tail of pancreas  resected Postop: no further spells, weight loss MOT contacted for license resinstatement

37. Insulinoma Rare neuroendocrine tumor of pancreas 4 cases/million person-years Originating outside pancreas: 1-2 cases reports only (cervical cancer) 59% female Most (80-90%) benign Sporadic or part of MEN-1

39. Insulinoma Diagnosis: Biochemical Localization: –CT Scan –Octreoscan (60% Sen) –Intraop U/S – most sensitive test –Selective arterial Ca 2+ stimulation

41. Insulinoma

42. Insulinoma Treatment: Surgical resection Diazoxide Octreotide Inteferon alpha Malignant: Octreotide-idium 111 Chemo: streptozozin, doxorubicin

43. Case 4 57M, well until Oct 2003 Transient spells: drowsiness, vertigo or dysequilibrium No relationship with food Florida over the winter… Mar 5, 04: felt drunk despite no EtOH, went to sleep early, next AM was unable to be aroused

44. Case 4 Taken to Florida ER, given IV glucose, d/c from ER, told to “eat more” Next AM: unable to be aroused –EMS called again, this time admitted BS 1.8 mM Insulin 20 pM, C-peptide 3.1 nM CT scan: large retroperitoneal mass contiguous with pancreas Octreoscan positive…

45. Case 4 Inoperable TPN/D5W, high CHO diet as tolerated Diazoxide, Octreotide Hepatic artery embolization Octreotide-indium 111 ?

46. Hypoglycemia: case based 1. Diagnostic approach to hypoglycemia 2. Iatrogenic hypoglycemia 3. Tumor-associated hypoglycemia

47. Hypoglycemia Symptoms (only adrenergic) after eating? Symptoms after fasting or skipped meals? OGTT 75g glucose, BS q30min x 5h BS < 2.8 mM? If yes: avoid refined sugars Fasting Hypoglycemia FPG >2.8 mM< 2.8 mM 72h fast BG < 2.8 mM? Vigorous exercise Glucagon stimulation (rise BS > 1.4 mM) YES NO Insulin > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 C-peptide > 0.2 nM < 0.2 nM Insulinoma OHA screen – Prosinsulin: > 5 pM > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s AI, hypothyroid Liver Disease, EtOH Enzyme defects Severe, protracted malnutrition Non-islet cell tumor Secretes IGF-II Secretes IGFI- BP inhibitor

48. Criteria: Endogenous hyperinsulinemia BS < 2.8 mM and… Insulin > 21.5 pM C-peptide > 0.2 nM Proinsulin > 5 pM Insulin surrogates: Glucagon 1mg IV   BS > 1.4 mM at 30 min  H  < 2.7 mM (serum ketones)

49. END