Evaluation of Hypoglycemia

1. Evaluation of Hypoglycemia

2. A 39-year-old man was referred for evaluation of repeated episodes of sweating, slurred speech, and confusion during the last four years that could be aborted by eating. On two occasions, he drove his car off the side of the road; both times he was found to be confused, his serum glucose concentrations ranged from 30 to 40, and he improved after intravenous glucose administration. Physical examination was normal.

3. Does He Have Whipple’s Triad? • Symptoms and/or signs of hypoglycemia • Low plasma glucose • Resolution of symptoms and/or signs after plasma glucose is raised He was admitted for a 72-hour fast. After fasting for 12 hours, he began to sweat and became confused and combative.

4. What lab tests do you want at this time? •    Glucose - 22 mg/dl •   Insulin - 110 microU/mL (normal < 3 microU/ml) • C-peptide - 3200 pmol/L (normal < 200 pmol/L) •   Proinsulin - 800 pmol/L (normal < 5 pmol/L) •    Sulfonylurea screen – negative • Glucose increase after glucagon - 39 mg/dL

5. What is the most likely diagnosis? A) Surreptitious insulin use B) Antibodies to insulin receptor C) Antibodies to insulin D) Insulinoma E) None of the above

6. What is the most likely diagnosis? A) Surreptitious insulin use B) Antibodies to insulin receptor C) Antibodies to insulin D) Insulinoma E) None of the above

9. Counterregulatory effects of Epinephrine during Hypoglycemia

10. ADRENERGIC NEUROGLYCOPENIC DiaphoresisHungerTinglingTremulousnessPalpitationsAnxiety Visual changesConfusionUnusual behavior WeaknessWarmthLethargyDizzinessSeizuresComa Classification of symptoms of hypoglycemia

11. When Do Counter-regulatory Hormone Kick In? • Glucagon and epinephrine secretion rises when plasma glucose concentrations fall below 70 mg/dL • Growth hormone secretion increases when plasma glucose concentrations fall below 60 to 65 mg/dL • Cortisol secretion increases when plasma glucose concentrations fall below 60 mg/dL

15. Insulinomas are the most common pancreatic endocrine tumors (60%) • 15% non-functional, 20% gastrinomas • Become clinically apparent in 50%, • subclinically dx’d in 50% with MEN-1 • Absence or presence of metastases defines malignancy • Histologic, immunohistochemical , molecular prognostic factors cannot predict clinical behavior • DNA ploidy, proliferative rate and evidence of necrosis correlate to overall survival

17. Histology

18. Demographics • Very rare 4 per 1 million person-years • Mayo Clinic cohort (1927-1986) n=224, • Only pts initially op at Mayo • Age median=47, 59%F • Durations sx’s prior dx< 1.5 y • 20% prior misdx neuro or psych d/o • Wt gain in 18% • 5% multiple islet cell tumors, 6% malignant • Malignant 77% M, age 18-61 • 8 cases in Olmsted county in same time (.4/million/yr) • 17=MEN1(53%F, 8-61yrs, PTH w/ 3prol, 3 gastrin, 1 Cush. 10 multiple islet tumors (59%)

19. 72-HOUR FAST • Date the onset of the fast as the time of the last intake of calories • Discontinue all non essential medications • Allow the patient to drink calorie-free and caffeine-free beverages • Collect blood specimens for measurement of plasma glucose, insulin, C-peptide, and proinsulin every six hours until the plasma glucose concentration is below 60 mg/dL at this point, the frequency of sampling should be increased to every one to two hours

20. Test end points and duration • the plasma glucose concentration is ≤45 mg/dL (<55 if Whipple’s triad previously documented) • the patient has symptoms or signs of hypoglycemia • 72 hours have elapsed • Plasma beta-hydroxybutyrate and sulfonylurea levels are measured • 1 mg of glucagon is given intravenously and the plasma glucose measured 10, 20, and 30 minutes later

21. Interpretation of values after 72 hour test

22. Interpretation of values after 72 hour test

23. Interpretation of values after 72 hour test

24. Interpretation of values after 72 hour test

25. Interpretation of values after 72 hour test

26. Interpretation of values after 72 hour test

31. Biochemical Imitators Non-insulinoma pancreatogenous hypoglycemia • Adults, islet hypertrophy and nesidioblastosis • Seen in post-gastric bypass patients • Postprandial hypoglycemia (2-4 hrs postmeal) • Fasting hypoglycemia is rare

32. Non-insulinomapancreatogenous hypoglycemia(NIPHS) • Post-prandial hypoglycemia and nesidioblastosis w/IC hypertrophy • 16-78 yo, 70% male, all neuroglycopenic sx’s after meals, rare w/ fast • All had  insulin, c-peptide, proinsulin w/ sxs • All had negative 72 hr fast and localization testing but + arterial Ca stimulation • If underwent surgery, no tumor found but islet cell hypertrophy, exocrine cell budding, chromogranin A staining c/w nesidioblastosis

33. Nesidioblastosis

34. A 76 y/o Caucasian male is admitted with the h/o recurrent episodes of confusion related to missing of meals. He has been taking meals every 2 to 3 hours to prevent these episodes. During one episode blood glucose level was 29 mg/dL. P/E HR 82/min, BP 130/84, HEENT: normal, exam of heart and lung normal. Abdomen examination reveals a 10 cm upper abdominal mass. He was admitted for a fast. Serum values at that time were :  Glucose - 29 mg/dL Insulin – 2 microU/mL (normal < 3 microU/ml)  C-peptide - < 15 pmol/L (normal < 200 pmol/L)  Proinsulin - < 2 pmol/L (normal < 5 pmol/L)  Glucose increase after glucagon - 39 mg/dL  Sulfonylurea screen – negative

35. What is the most likely diagnosis? A) Surreptitious insulin use B) Antibodies to insulin receptor C) Antibodies to insulin D) Insulinoma E) None of the above

36. What is the most likely diagnosis? A) Surreptitious insulin use B) Antibodies to insulin receptor C) Antibodies to insulin D) Insulinoma E) None of the above

37. Non-islet Cell tumor-induced hypoglycemia • IGF-2 production (or precursor) • Multiple mets to liver, or massive tumor burden in which high metabolic demand of tumor cells depletes glycogen

38. Nonislet Cell Neoplasms Associated with Hypoglycemia • Mesenchymal • Mesothelioma • Fibrosarcoma • Rhabdomyosarcoma • Leiomyosarcoma • Hemangiopericytoma • Carcinoma • Hepatic: hepatoma, biliary carcinoma • Adrenocortical carcinoma • Genitourinary: hypernephroma, Wilms’, prostate • Reproductive: cervical or breast carcinoma • Neurologic/neuroendocrine • Pheochromocytoma • Carcinoid • Neurofibroma • Hematologic • Leukemia • Lymphoma • Myeloma

39. Mechanisms of Tumor induced Hypoglycemia • IGF-2 • IGF-1 • Insulin • Hormone-mediated insulin receptor proliferation

41. 18 y.o. man in his first year at USNA with a 6 month history of fatigue and a 20 pound weight loss developed post-prandial fatigue about 2 hours after a breakfast of cottage cheese, peanut butter, granola and a banana. His blood glucose was 34 mg/dl which improved to 84 mg/dl after Gatorade but without improvement in symptoms. His exam was normal. His weight was 141 (BMI 19) and heart rate 46 bpm. He was admitted for a 72-hour fast

43. What is the most likely diagnosis? A) Surreptitious insulin use B) Antibodies to insulin receptor C) Antibodies to insulin D) Insulinoma E) None of the above

44. What is the most likely diagnosis? A) Surreptitious insulin use B) Antibodies to insulin receptor C) Antibodies to insulin D) Insulinoma E) None of the above

45. Factitious Hypoglycemia • Most commonly is covert self-administration of hypoglycemic drug • F>M, 30-40 yo, in health-related fields • Mimics Brittle Diabetes in diabetic • One type 1 Diabetic with confirmed insulinoma • Check insulin, BS, c-peptide, sulfonylurea when hypoglycemic and insulin AB • Insulin < 600 pmol/L in insulinoma, >600 factitious unless have Ab’s to insulin • Sulfonylurea and meglitinide tests by lab that looks for second-gen sulfonyureas • 1:1 insulin:c-peptide= endogenous insulin secretion • Anti-insulin Ab can be found w/ autoimmune hypoglycemia, insulinoma, insulin-treated patients, and interferes with insulin and C-peptide measurements—measure free levels

46. Questions?

47. Healthy patient Ill patient Drug-induced TumorsIslet CellNon-islet cellNesidioblastosisFactitious hypoglycemiaMalnutritionAutoimmune-induced MiscellaneousPregnancyExerciseReactive hypoglycemia Drug-inducedSepsis, Trauma and BurnsCardiac FailureRenal DiseaseLiver DiseaseHormone DeficienciesTPN with insulin therapy Classification of hypoglycemic disorders