01-21 Hypoglycemia and Islet Tumors Flashcards
1. Define hypoglycemia from a physiologic vantage point 2. Explain the difference between adult and child glucose homeostasis 3. Describe the broad categories of disorders that cause neonatal and childhood hypoglycemia 4. Explain the genetic causes of persistent hyperinsulinism of infancy 5. Explain the differential diagnosis of adult hypoglycemia syndromes 6. Review a flow diagram for evaluation of adult hypoglycemia 7. Overview of insulinoma and islet cell tumors
[OBJECTIVE] Define hypoglycemia from a physiologic vantage point
CLINICAL DEFINITION: Whipple’s Triad
—1) Sx 2) sugar < 40 mg/dL
—level at which neuroglycopenia sets in
[OBJECTIVE] Explain the difference between adult and child glucose homeostasis
—kids produce twice as much hepatic glucose than adults between meals and while fasting
—likely because their brains are a larger % of body mass and brain tissue can only metab sugar
—thus, any hepatotoxicity in kids (esp EtOH!) causes acute hypoglycemia
[OBJECTIVE] Describe the broad categories of disorders that cause neonatal and childhood hypoglycemia
I. Genetic
—Inborn errors of nutrient metab
—e.g. glycogenolysis, AA & FA metab
II. Transient Hyperinsulinemia
—post-partum kids of diabetic moms
III. Medication-related
—insulin, oral hypoglycemics, EtOH
IV. Hormone deficiencies
—GH, cortisol, hypopit (both GH & Cort)
[OBJECTIVE] Explain the genetic causes of persistent hyperinsulinism of infancy
—AKA
—Mechanism (3)
—HISTO
AKA
—idiopathic hypoglycemia of infancy, nesidioblastosis
MECHANISM (3)
1. glucokinase GoF mutation
2. mito glutamate DH GoF mutation —Leu activates GDH (Leu-free diet) — Glut —GDH→ ↑↑α-KG —↑↑ α-KG → more ATP : ADP —ATP inhibs K+ channel —cell depolarizes —voltage-gated Ca2+ channels —insulin is released —**effectively: cell perceives ↑↑ [glucose]
- β-cell ATP-depend K+ channel LoF mutation
HISTO
—islet cell hyperplasia w/ glucokinase mutation (only?)
[OBJECTIVE] Explain the differential diagnosis of adult hypoglycemia syndromes
Most common: DM drugs
—also factitious hypoglycemia
Toxins:
—rat poison (lyses β cells)
—EtOH
—Ackee fruit
Post-meal hypoglycemia
—see separate card
Excess Insulin secretion
—insulinoma, nesidioblastosis, non-insulinoma pancreatogenous hyperinsulinemia
Hepatic Dysfxn
—septic shock, R CHF, fulminant hepatitis
Tumoral Hypoglycemia “very rare”
—IGF-2-mediated
Autoimmune “very rare”
—Abs activated insulin receptor
Post-meal hypoglycemia
—Cause (kids vs. adults)
BOTH KIDS & ADULTS
—S/p upper abd surgery (e.g. Roux-en-Y)
—Reactive hypoglycemia (see separate card)
KIDS
—Hyperinsulinism-hyperammonia syndrome (protein ingestion) = glutamate DH mutation
ADULTS
—non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
—Occasionally insulinomas
Reactive hypoglycemia
1-4hr postprandial (usu. breakfast/large carb load)
—don’t know cause
—usually self-limited
—tx w/ diet ∆ or acarbose
Decision Tree for Hypoglycemia Dx
- Ask Fasting or Post-Pran
- Verify: gluc 5, c-pep (+)
——Fasting: 48hr observed fast
——Post-pran: observed food challenge
—nl gluc/insulin/no c-peptide? no pathology
—↓ gluc/↑ insulin/c-pep + → pathology
—↓ gluc/↑ insulin/c-pep - → factitious
- Next steps
FASTING
—DDx: ↑ insulin, ↓ insulin, insulinoma, tumor
—Tests: endoscopic panc US; ateriogram w/ Ca to stim insulin release; abd CT for mets
—Tx: surgery
POST-PRAN —DDx: post-surg, NIPH, GDH mutation —Tests: ——Prior surg: motility studies ——No surg: insulinoma work-up —Tx: low carb diet, acarbose (slows starch), surgery if insulinoma
Most comon islet cell neoplasm?
insulinoma (β-cell tumor)
Insulinoma rule of 10s
10% malignant
10% multifocal
10% diffuse
Insulinomas —size —histo —criteria for malignancy —assoc'd syndrome?
SIZE
—small, 1mm to 2cm diam; usu. encapsulated
HISTO
—encapsulated usu.
—cords & nests of wel-defined β-cells w/ typical granules by EM
MALIGNANCY CRITERIA
—only absolute criteria is invasion & metastasis at presentation
SYNDROME
—Assoc’d w/ MEN1 PPP:
—parathyroid, pituitary and pancreatic (β-cell)
Other islet cell tumors besides insulinoma?
60% are non-functioning —gastrinoma (ectopic prod of gastrin by β-cells) —glucagonoma —VIPoma (vasoactive intestinal peptide) —somatostatinoma
GHRH-oma
CRH-oma
