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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. Hypoglycemia: case based. Diagnostic approach to hypoglycemia Iatrogenic hypoglycemia
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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
Hypoglycemia: case based • Diagnostic approach to hypoglycemia • Iatrogenic hypoglycemia • Tumor-associated hypoglycemia
Case 1 • 18 year old male • Prior ADHD, school suspension-fighting • LOC, SZ, CBG 1.8 mM • Stepfather T2DM: glyburide • Grandfather T2DM: insulin
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
Hypoglycemic Disorders • Fasting vs. Post-prandial • Appearance: healthy vs. sick • Hyper-insulinemic vs. Hypo-insulinemic
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
Post-prandial Hypoglycemia Neuroglycopenic symptoms: • Unripe ackee fruit • Bariatric surgery? • Insulinoma, islet hypertrophy • Non-insulinoma pancreatogenous hypoglycemia (NIPHS)
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
Hypoglycemia Symptoms after fasting or skipped meals? Symptoms (only adrenergic) after eating? 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 Insulin YES < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 72h fast • AI, hypothyroid • Liver Disease, EtOH • Enzyme defects • Severe, protracted malnutrition • Non-islet cell tumor • Secretes IGF-II • Secretes IGFI-BP inhibitor BG < 2.8 mM? C-peptide NO > 0.2 nM < 0.2 nM • Vigorous exercise • Glucagon stimulation • (rise BS > 1.4 mM) • Insulinoma • OHA screen – • Prosinsulin: • > 5 pM • > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s
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
Critical Blood Work • Prior to treatment send venous BW: • Venous BS • Insulin, c-peptide, +/- pro-insulin • ACTH, cortisol
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)
Whipple’s TriadKoch’s postulates of Hypoglycemia • Symptoms • BS < 2.8 mM • Resolution of symptoms with CHO
Hypoglycemia Symptoms after fasting or skipped meals? Symptoms (only adrenergic) after eating? 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 Insulin YES < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 72h fast • AI, hypothyroid • Liver Disease, EtOH • Enzyme defects • Severe, protracted malnutrition • Non-islet cell tumor • Secretes IGF-II • Secretes IGFI-BP inhibitor BG < 2.8 mM? C-peptide NO > 0.2 nM < 0.2 nM • Vigorous exercise • Glucagon stimulation • (rise BS > 1.4 mM) • Insulinoma • OHA screen – • Prosinsulin: • > 5 pM • > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s
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
Hypoglycemia: Family Hx of DM? • Access to insulin? • Access to oral hypoglycemia agents?
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
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
Hypoglycemia Symptoms after fasting or skipped meals? Symptoms (only adrenergic) after eating? 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 Insulin YES < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 72h fast • AI, hypothyroid • Liver Disease, EtOH • Enzyme defects • Severe, protracted malnutrition • Non-islet cell tumor • Secretes IGF-II • Secretes IGFI-BP inhibitor BG < 2.8 mM? C-peptide NO > 0.2 nM < 0.2 nM • Vigorous exercise • Glucagon stimulation • (rise BS > 1.4 mM) • Insulinoma • OHA screen – • Prosinsulin: • > 5 pM • > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s
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
Case 3 • 49M, Fall 2002: LBP & abdominal mass • Retroperitoneal seminoma • Chemotherapy: • Etoposide, Cisplatinum, Bleomycin • Tumor: good response
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.
Case 3 • BS 1.8 mM • Insulin 155 pM • C-peptide 1.9 nM • Pro-insulin 133 pM
Hypoglycemia Symptoms after fasting or skipped meals? Symptoms (only adrenergic) after eating? 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 Insulin YES < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 72h fast • AI, hypothyroid • Liver Disease, EtOH • Enzyme defects • Severe, protracted malnutrition • Non-islet cell tumor • Secretes IGF-II • Secretes IGFI-BP inhibitor BG < 2.8 mM? C-peptide NO > 0.2 nM < 0.2 nM • Vigorous exercise • Glucagon stimulation • (rise BS > 1.4 mM) • Insulinoma • OHA screen – • Prosinsulin: • > 5 pM • > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s
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
Case 3 • Intraoperative U/S: single tumor confirmed at tail of pancreas resected • Postop: no further spells, weight loss • MOT contacted for license resinstatement
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
Insulinoma • Diagnosis: • Biochemical • Localization: • CT Scan • Octreoscan (60% Sen) • Intraop U/S – most sensitive test • Selective arterial Ca2+ stimulation
Insulinoma • Treatment: • Surgical resection • Diazoxide • Octreotide • Inteferon alpha • Malignant: • Octreotide-idium 111 • Chemo: streptozozin, doxorubicin
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
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…
Case 4 • Inoperable • TPN/D5W, high CHO diet as tolerated • Diazoxide, Octreotide • Hepatic artery embolization • Octreotide-indium 111 ?
Hypoglycemia: case based • Diagnostic approach to hypoglycemia • Iatrogenic hypoglycemia • Tumor-associated hypoglycemia
Hypoglycemia Symptoms after fasting or skipped meals? Symptoms (only adrenergic) after eating? 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 Insulin YES < 3 uU/mL (21.5 pM) Insulin/glucose < 0.3 > 3 uU/mL (21.5 pM) Insulin/glucose > 0.3 72h fast • AI, hypothyroid • Liver Disease, EtOH • Enzyme defects • Severe, protracted malnutrition • Non-islet cell tumor • Secretes IGF-II • Secretes IGFI-BP inhibitor BG < 2.8 mM? C-peptide NO > 0.2 nM < 0.2 nM • Vigorous exercise • Glucagon stimulation • (rise BS > 1.4 mM) • Insulinoma • OHA screen – • Prosinsulin: • > 5 pM • > 10-20% OHA OHA screen + Proinsulin: < 5 pM < 10-20% Surreptitious Insulin Anti-insulin Ab’s
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)