1. Hypoglycemia Karen Tordjman Institute of Endocrinology Tel Aviv Sourasky Medical Center October 24, 2007

2. Hypoglycemia History Recognition of hypoglycemia Counterregulation Incidence Classification Causes Approach to the patient with hypoglycemia Insulinoma NIHPS October 24, 2007

3. 19 th century: identification of hypoglycemia in some severe illnesses 1920’s: recognition of spontaneous symptoms similar to those seen with insulin Rx excess, “hyperinsulinism” 1927: 1 st patient with hypoglycemia due to malignant islet cell tumor 1929: 1 st successful surgical treatment of insulinoma 1960’s: development of RIA proves hyperinsulinemia in insulinoma 1950-present: better understanding of physiology and genetics of glucose metabolism and counterregulation allows identification of other causes of hypoglycemia Hypoglycemia- History October 24, 2007

4. When should we suspect true hypoglycemia?When should we suspect true hypoglycemia? Whipples’ triadWhipples’ triad Symptoms of hypoglycemia Low plasma glucose Relief of symptoms with glucose Hypoglycemia- Recognition October 24, 2007

5. Symptoms of hypoglycemia Neuroglycopenic: fatigue, drowsiness, difficulty thinking and speaking, confusion, blurred vision, fainting Neurogenic-autonomic:  Cholinergic: hunger, sweating, tingling  Adrenergic: shakiness, palpitations, nervousness Hypoglycemia- Recognition October 24, 2007

6. Hypoglycemia- Recognition Signs of hypoglycemiaSigns of hypoglycemia Pallor, diaphoresis, tachycardia, elevated BP, impaired cognition October 24, 2007

7. Biochemical evidenceBiochemical evidence Unequivocal: fasting (post-absorptive) plasma glucose<50 mg/dl Suggestive: fasting 50-70 mg/dl Postprandial: no good definition <50 mg/dl Hypoglycemia- Recognition Artifactual causes of biochemical hypoglycemiaArtifactual causes of biochemical hypoglycemia Prolonged sample standing, continued glycolysis Polycythemia, leukocytosis, leukemia October 24, 2007

8. Hypoglycemia- Counterregulation 1 2 3 Threshold for counterregulatory hormone secretion ~65-68 mg/dl October 24, 2007

9. Hypoglycemia-Counterregulation October 24, 2007

10. Counterregulatory mechanisms are Hierarchic Redundant Prolonged hypoglycemia due to failure of hormonal counterregulation is very rare (T1DM excepted) Hypoglycemia-Counterregulation October 24, 2007

11. Incidence of insulinoma: 4/10 6 person years (Olmsted county, Mayo Clinic) Hypoglycemia in adults is almost always due to drugs! Hypoglycemia- General October 24, 2007

12. Incidence and Scope of Hypoglycemia 1.2%-20% of adult inpatients Marker of poorer outcome in elderly non diabetic subjects Type 1DM patients are 10% of the time in hypoglycemia. Average of 2 mild episodes/week, 1 severe/year Hypoglycemia in T2DM~10% that in T1DM October 24, 2007

13. Hypoglycemia- Classification Treated diabetic vs. no diabetes Fasting vs. postprandial Insulin-mediated (hyperinsulinemic) vs. non insulin-mediated Healthy- vs. ill-appearing patient October 24, 2007

14. Drugs Ethanol (especially binge-drinking with no food) Salicylates Halidol, fluoxetine Fibrates Antibiotics: sulfonamides, fluoroquinolones (gatofloxacin) Surreptitious or erroneous administration of hypoglycemic agents: insulin or oral agents (mostly insulin-secretagogues) Causes of Hypoglycemia in the Healthy-Appearing Patient October 24, 2007

15. Endogenous hyperinsulinemia Insulinoma, very rare Non Insulinoma Pancreatogenous Hypoglycemia Syndrome: NIPHS. (1 st report 1999, increasingly recognized, still extremely rare) Autoimmune, insulin autoantibodies, extremely rare Beta-cell stimulating autoAb, theoretical Causes of Hypoglycemia in the Healthy-Appearing Patient October 24, 2007

16. Reactive (post-prandial) hypoglycemia Post-gastric surgery hypoglycemia (to be distinguished from earlier Dumping Synd. Sx) Alimentary hypoglycemia (rapid glucose absorbtion, enhanced incretin secretion, brisk and vigorous insulin response) NIPHS Causes of Hypoglycemia in the Healthy-Appearing Patient October 24, 2007

17. Drugs are again the main offenders Same drugs, but also anti malarial, pentamidine Predisposing or causative illnesses Starvation Renal failure Hepatic failure Congestive heart failure Sepsis Hypopituitarism Addison’s disease Large mesenchymal tumors Hematologic malignancies Causes of Hypoglycemia in the Ill-Appearing Patient October 24, 2007

18. Approach to the Patient with Hypoglycemia Establish the diagnosis of hypoglycemiaEstablish the diagnosis of hypoglycemia Clinical suspicion (recurring neuroglycopenic symptoms) Hypoglycemia needs to be proven (venous glucose<50 mg/dl, Whipple’s triad) October 24, 2007

19. Fasting hypoglycemiaFasting hypoglycemia Document hypoglycemia after O/N fast if possible Prolonged fast if needed Evaluate drugs and clinical condition In case of emergency obtain: glucose, insulin, C-peptide, SU, prior to treating Approach to the Patient with Hypoglycemia October 24, 2007

20. Approach to the Patient with Hypoglycemia Fasting hypoglycemiaFasting hypoglycemia Measurable insulin: consider one of the hyperinsulinemic conditions (C-peptide, SU screen essential) Insulin suppressed: search for potential drugs or/and clues to other conditions (tumors, chronic diseases, rare genetic metabolic dis.) October 24, 2007

21. Postprandial hypoglycemiaPostprandial hypoglycemia True condition very uncommon Suspect with appropriate story and timing Check out gastric surgery OGTT not appropriate (10 th percentile<47 mg/dl, no symptoms) Mixed meal (no standardization), documentation of Whipple’s triad Subject patients with postprandial hypoglycemia to prolonged fast to R/O insulinoma Approach to the Patient with Hypoglycemia October 24, 2007

22. Treatment of postprandial hypoglycemiaTreatment of postprandial hypoglycemia Low carbohydrate high protein diet Frequent feeding   -glucosidase inhibitor (prandase)  All unproven  Surgery for NIHPS Approach to the Patient with Hypoglycemia October 24, 2007

23. Clinical clues Recurrent neuroglycopenic symptoms with fast or upon exercise in healthy-appearing patient Approach to the Patient with Suspected Insulinoma Diagnosis Demonstrated fasting hypoglycemia with Whipple’s triad If necessary patient is subjected to inpatient prolonged fast Relative hyperinsulinemia with commensurate C-peptide (and proinsulin) Lower  OH-butyrate( 25 mg/dl) Increased chromogranin A Negative SU screen October 24, 2007

24. Issues with prolonged fast Hypoglycemia possible in normal individuals but no Whipple’s triad Because of lower threshold for symptoms in subjects with insulinoma Biochemical determination of hypoglycemia in the lab (not glucometer) Goal reached within 12 h in 35%, 24 in 75%, and 48h in 92%, essentially 100% within 72 h. No need for a stimulatory test! Approach to the Patient with Suspected Insulinoma October 24, 2007

25. US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive Localization of Insulinoma October 24, 2007

26. Localization of Insulinoma October 24, 2007

27. US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive Octreoscan positive in 50% Localization of Insulinoma October 24, 2007

28. Localization of Insulinoma October 24, 2007

29. US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive Octreoscan positive in 50% Arteriography obsolete (poor accuracy) Endoscopic US (positive ~90%) Localization of Insulinoma October 24, 2007

30. Localization of Insulinoma October 24, 2007

31. Localization of Insulinoma US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive Octreoscan positive in 50% Arteriography obsolete (poor accuracy) Endoscopic US (positive ~90%) Intraoperative US, yield 98% October 24, 2007

32. Localization of Insulinoma October 24, 2007

33. Localization of Insulinoma US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive Octreoscan positive in 50% Arteriography obsolete (poor accuracy) Endoscopic US (positive ~90%) Intraoperative US, yield 98% Selective arterial calcium stimulation October 24, 2007

34. Localization of Insulinoma Selective arterial calcium stimulation October 24, 2007

35. April 10, 2006 Localization of Insulinoma Selective arterial calcium stimulation An insulinoma was excised from the tail, patient was cured

36. >450 histologically proven cases Age ~50 y(8-85) F/M (58/42) MEN-1 7.6% Malignant insulinoma 5.8% Insulinoma - The Mayo Clinic Experience 1927-2005 October 24, 2007

37. Intraoperative glucose monitoring Intraoperative palpation/US Enucleation if possible (~60%) Distal pancreatic resection/splenectomy (~36%) Whipple’s operation rarely needed Laparoscopic surgery still under study Insulinoma – Surgical Treatment October 24, 2007

38. Diazoxide Verapamil Chemotherapy (adria/STZ, 60% response rate) Octreotide for symptomatic relief (SST2r in ~50%) Somatostatin-receptor targeted therapy (investigational) New modalities based on molecular biology of tumors (tyr-kinase receptors present, potential for inhibitors) Insulinoma – Medical Treatment

39. Insulinoma in the Ferret Insulinoma is the most common neoplastic disease in the ferret, followed by adrenocortical tumors Zuki lived with recurring insulinoma for 4 years and lived a full and active life till age 7 1/2. October 24, 2007

40. First reported in 1999, increasingly diagnosed Represents ~4% of endogenous hyperinsulinemia Men > women Post prandial neuroglycopenic symptoms Usually fast negative, mixed meal positive Insulin levels lower than in insulinoma Negative imaging SACS positive Not tumor, islet cell hyperplasia and nesidioblastosis Curable with surgery NIPHS April 10, 2006

41. NIPHS-Pathology October 24, 2007

42. Thank you!