non-diabetic hypoglycemia medical grand rounds may 14, 2004 dr. william harper assistant professor...
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Non-Diabetic HypoglycemiaNon-Diabetic Hypoglycemia
Medical Grand Rounds
May 14, 2004
Dr. William HarperAssistant Professor of Medicine, McMaster University.
Endocrinologist, Hamilton General Hospital
www.drharper.ca
Hypoglycemia: Hypoglycemia: case basedcase based
1. Diagnostic approach to hypoglycemia
2. Iatrogenic hypoglycemia
3. Tumor-associated hypoglycemia
Case 1Case 1
18 year old malePrior ADHD, school suspension-fightingLOC, SZ, CBG 1.8 mMStepfather T2DM: glyburideGrandfather T2DM: insulin
Hypoglycemia: SymptomsHypoglycemia: 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
Response to HypoglycemiaResponse to Hypoglycemia
Blood Glucose Symptoms
< 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
Response to HypoglycemiaResponse to Hypoglycemia
Blood Glucose Hormonal 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
Hypoglycemic DisordersHypoglycemic Disorders
Fasting vs. Post-prandialAppearance: healthy vs. sickHyper-insulinemic vs. Hypo-insulinemic
Post-prandial HypoglycemiaPost-prandial Hypoglycemia
Sympathoadrenal symptoms only:2° to refined sugars/simple CHOAlimentary Surgery (gastrectomy, etc)
Dumping syndrome fluid shifts
Dysglycemia IFG, IGT, Early Type 2 DM 4-5h after
Post-prandial HypoglycemiaPost-prandial Hypoglycemia
Neuroglycopenic symptoms:Unripe ackee fruitBariatric surgery?
Insulinoma, islet hypertrophy
Non-insulinoma pancreatogenous hypoglycemia (NIPHS)
Post-prandial HypoglycemiaPost-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 (only adrenergic) after eating?Symptoms after fastingor skipped meals?
OGTT75g glucose, BS q30min x 5hBS < 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
InsulinomaOHA screen –Prosinsulin: > 5 pM > 10-20%
OHAOHA screen +Proinsulin: < 5 pM < 10-20%
Surreptitious InsulinAnti-insulin Ab’s
•AI, hypothyroid•Liver Disease, EtOH•Enzyme defects•Severe, protracted malnutrition•Non-islet cell tumor
•Secretes IGF-II•Secretes IGFI-BP inhibitor
Case 1Case 1
18 year old malePrior ADHD, school suspension-fightingLOC, SZ, CBG 1.8 mMNo critical BW drawnStepfather T2DM: glyburideGrandfather T2DM: insulin
Critical Blood WorkCritical Blood Work
Prior to treatment send venous BW: Venous BS Insulin, c-peptide, +/- pro-insulin ACTH, cortisol
Criteria: Endogenous hyperinsulinemiaCriteria: Endogenous hyperinsulinemia
BS < 2.8 mM and…Insulin > 21.5 pMC-peptide > 0.2 nMProinsulin > 5 pMInsulin surrogates:
Glucagon 1mg IV BS > 1.4 mM at 30 min H < 2.7 mM (serum ketones)
Whipple’s TriadWhipple’s TriadKoch’s postulates of HypoglycemiaKoch’s postulates of Hypoglycemia
SymptomsBS < 2.8 mMResolution of symptoms with CHO
Hypoglycemia
Symptoms (only adrenergic) after eating?Symptoms after fastingor skipped meals?
OGTT75g glucose, BS q30min x 5hBS < 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
InsulinomaOHA screen –Prosinsulin: > 5 pM > 10-20%
OHAOHA screen +Proinsulin: < 5 pM < 10-20%
Surreptitious InsulinAnti-insulin Ab’s
•AI, hypothyroid•Liver Disease, EtOH•Enzyme defects•Severe, protracted malnutrition•Non-islet cell tumor
•Secretes IGF-II•Secretes IGFI-BP inhibitor
Case 1Case 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?Hypoglycemia: Family Hx of DM?
Access to insulin?Access to oral hypoglycemia agents?
Case 2Case 2
71M, admit with ascitesKnown cirrhotic 2° EtOH, abstinate x 7yBS 6-8 mM in-hospital until day 14Awoke with BS 3.4 mMBS 2.0-2.9 despite + + po CHO intakeNext day BS 1.5-1.9 mMD10W IV gtt @ 100-150/h x 2-3d
Case 2Case 2
Meds: amiodarone, altace, ASA, lasix, aldactone, cipro, ativan qhs PRN
AST, ALT, GGT mildly elevatedAlbumin 39, INR 1.2Critical BW:
Venous BS 1.5 mM Insulin 317 pM, C-peptide 4.0 nM ACTH 7 pM, cortisol 751 nM
Hypoglycemia
Symptoms (only adrenergic) after eating?Symptoms after fastingor skipped meals?
OGTT75g glucose, BS q30min x 5hBS < 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
InsulinomaOHA screen –Prosinsulin: > 5 pM > 10-20%
OHAOHA screen +Proinsulin: < 5 pM < 10-20%
Surreptitious InsulinAnti-insulin Ab’s
•AI, hypothyroid•Liver Disease, EtOH•Enzyme defects•Severe, protracted malnutrition•Non-islet cell tumor
•Secretes IGF-II•Secretes IGFI-BP inhibitor
Case 2Case 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 3Case 3
49M, Fall 2002: LBP & abdominal massRetroperitoneal seminomaChemotherapy:
Etoposide, Cisplatinum, Bleomycin
Tumor: good response
Case 3Case 3
Chemo anorexiaSpells of bizzare behaviour, confusion,
lethargyRandom BS 3.6 mM, HbA1c 3.4%PHx: 10y of early AM spells, relieved with
snacks/O.J., weight gain > 100 lbs.
Case 3Case 3
BS 1.8 mMInsulin 155 pMC-peptide 1.9 nMPro-insulin 133 pM
Hypoglycemia
Symptoms (only adrenergic) after eating?Symptoms after fastingor skipped meals?
OGTT75g glucose, BS q30min x 5hBS < 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
InsulinomaOHA screen –Prosinsulin: > 5 pM > 10-20%
OHAOHA screen +Proinsulin: < 5 pM < 10-20%
Surreptitious InsulinAnti-insulin Ab’s
•AI, hypothyroid•Liver Disease, EtOH•Enzyme defects•Severe, protracted malnutrition•Non-islet cell tumor
•Secretes IGF-II•Secretes IGFI-BP inhibitor
Case 3Case 3
Hypoglycemia treated with: Diazoxide Prednisone (bleomycin lung toxicity)
ICC of retroperitoneal tumor negative for insulin
CT scan: bulky pancreatic tailOctreoscan: negativeMRI: tumor in tail of pancreas
Case 3Case 3
Intraoperative U/S: single tumor confirmed at tail of pancreas resected
Postop: no further spells, weight lossMOT contacted for license resinstatement
InsulinomaInsulinoma
Rare neuroendocrine tumor of pancreas 4 cases/million person-years
Originating outside pancreas: 1-2 cases reports only (cervical cancer)
59% femaleMost (80-90%) benignSporadic or part of MEN-1
InsulinomaInsulinoma
Diagnosis: Biochemical Localization:
– CT Scan
– Octreoscan (60% Sen)
– Intraop U/S – most sensitive test
– Selective arterial Ca2+ stimulation
InsulinomaInsulinoma
InsulinomaInsulinoma
Treatment: Surgical resection Diazoxide Octreotide Inteferon alpha Malignant:
• Octreotide-idium 111
• Chemo: streptozozin, doxorubicin
Case 4Case 4
57M, well until Oct 2003Transient spells: drowsiness, vertigo or
dysequilibriumNo relationship with foodFlorida over the winter…Mar 5, 04: felt drunk despite no EtOH, went
to sleep early, next AM was unable to be aroused
Case 4Case 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 4Case 4
InoperableTPN/D5W, high CHO diet as toleratedDiazoxide, OctreotideHepatic artery embolizationOctreotide-indium 111 ?
Hypoglycemia: Hypoglycemia: case basedcase based
1. Diagnostic approach to hypoglycemia
2. Iatrogenic hypoglycemia
3. Tumor-associated hypoglycemia
Hypoglycemia
Symptoms (only adrenergic) after eating?Symptoms after fastingor skipped meals?
OGTT75g glucose, BS q30min x 5hBS < 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
InsulinomaOHA screen –Prosinsulin: > 5 pM > 10-20%
OHAOHA screen +Proinsulin: < 5 pM < 10-20%
Surreptitious InsulinAnti-insulin Ab’s
•AI, hypothyroid•Liver Disease, EtOH•Enzyme defects•Severe, protracted malnutrition•Non-islet cell tumor
•Secretes IGF-II•Secretes IGFI-BP inhibitor
Criteria: Endogenous hyperinsulinemiaCriteria: Endogenous hyperinsulinemia
BS < 2.8 mM and…Insulin > 21.5 pMC-peptide > 0.2 nMProinsulin > 5 pMInsulin surrogates:
Glucagon 1mg IV BS > 1.4 mM at 30 min H < 2.7 mM (serum ketones)
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