non-diabetic hypoglycemia medical grand rounds may 14, 2004 dr. william harper assistant professor...

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)

ENDEND