Evaluation of hypoglycemia

1. Andrew Maclennan, MD April 23, 2010 Morning Report & Insulin Autoimmune Syndrome (Hirata disease) Evaluation of hypoglycemia

3. “Neuroglycopenic symptoms” • Cognitive impairment, behavioral changes, psychomotor abnormalities, coma, death • “Neurogenic symptoms” • Tremors, palpitations, anxiety/arousal, sweating, hunger, paresthesias Symptoms of hypoglycemia

4. Whipple’s Triad: • Symptoms consistent with hypoglycemia • A low plasma glucose - measured with a precise method (not a glucometer) • Relief of symptoms after glucose level normal Who to evaluate? Allen Oldfather Whipple

5. Fast (overnight or post-prandial) • 72 hr fast if initial fast is negative • End fast when • glucose ≤45 mg/dL • Pt has signs/sx of hypoglycemia • 72 hours have elapsed • glucose <55 mg/dL if Whipple's triad documented previously • Check Q6 hrs, more frequently when glucose < 60 mg/dL • plasma glucose, insulin, C-peptide, proinsulin, BHOB, and oral hypoglycemic agents • At end of fast • IV glucagon and measure glucose 10, 20, and 30 minutes later • Feed patient Diagnostic Approach

6. In symptomatic patients with hypoglycemia • Insulin > 3 microU/mL is excess insulin; consistent w/ insulinoma • Caution! Glucose < 50 mg/dL in some normal subjects & >50 mg/dL in some patients with insulinoma. • Proinsulin > 5 pmol/L consistent w/ insulinoma • Beta-hydroxybutyrate - Insulin is antiketogenic • BHOB levels lower in insulinoma patients than in normal subjects. • C-peptide - distinguishes endogenous from exogenous hyperinsulinemia • Sulfonylurea and meglitinide screen • Glucose response to glucagon • Insulin is antiglycogenolytic and hyperinsulinemia permits retention of glycogen within the liver. • In insulin-mediated hypoglycemia, response to glucagon is release of glucose • Normal patients have virtually exhausted hepatic glycogen stores after 72hrs and can’t respond as vigorously. • (Insulin & insulin receptor antibodies) What to measure?

8. Radiologic studies — CT, MRI, transabdominal US can detect most insulinomas • Arterial calcium stimulation — to distinguish between insulinoma and a diffuse process (islet cell hypertrophy/nesidioblastosis). • Inject calcium gluconate into gastroduodenal, splenic and superior mesenteric artery • Sample hepatic vein for insulin • Increased insulin secretion localizes area of hyperfunctioning islets. Localizing studies

9. Insulinoma – surgical resection of tumor Nesidioblastosis – partial or subtotal pancreatectomy Antibodies to insulin receptors – immunosuppressants (poor response) Antibodies to insulin – glucocorticoids (good response) Treatment of hyperinsulinemic hypoglycemic states

10. Insulin autoimmune syndrome

11. Episodes of hyperinsulinemic hypoglycemia • Often post-prandial, after exercise • Paradoxic hyperglycemia • May occur after meal or oral glucose challenge Clinical Manifestations

12. Extremely uncommon in West (58 case reports in non-Asian populations) • 3rd leading cause of hypoglycemia in Japan • No sex preference • Age > 40yrs • Associated with rheumatologic disease • SLE, RA, • May see positive ANA, anti DSDNA, RF • Association with medications • Captopril, penicillamine, hydralazine, procainamide, INH, penicillin G • Meds with sulfhydryl group (especially methimazole) Epidemiology

13. Insulin secreted after meal bound by antibodies (IgG) Hyperglycemia persists causing more insulin secretion (results in high A1C over time) As hyperglycemia abates, insulin-bound to antibodies is released, with inappropriately high insulin levels Hypoglycemia results. Pathophysiology

14. Laboratory and clinical findings Autoimmune Forms of Hypoglycemia. Lupsa, Beatrice; Chong, Angeline; Cochran, Elaine; MSN, CRNP; Soos, Maria; Semple, Robert; MB, PhD; Gorden, Phillip Medicine. 88(3):141-153, May 2009. DOI: 10.1097/MD.0b013e3181a5b42e

15. Lupsa BC et al, Autoimmune Forms of Hypoglycemia. Medicine, vol 88(3):141-153; May 2009. UpToDate References