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Evaluation of Recurrent Hypoglycemia Endocrinology of Utah Updated by Miriam Padilla, MD, CDE Nov 2015 Possible Causes of hypoglycemia: 1. Malnutrition/prolonged starvation 2. Liver or Kidney damage (liver produces 80% of glucose Kidneys produce 20% of glucose) 3. Iatrogenic- too much insulin or sulfonylurea 4. Insulinoma 5. Addison’s Disease or pan hypopituitarism or adrenal insufficiency where patient lacks cortisol 6. End stage diabetic patients will lack glucagon 7. Beta cell hyperplasia 8. Sepsis 9. Cystic fibrosis 10. Chronic pancreatitis 11. Chronic ETOH 12. Cirrhosis 13. Severe hyperthyroidism 14. Insulin autoimmune hypoglycemia (Ab to insulin, Ab to insulin receptor) 15. Post bariatric surgery 16. IFG-2 mediated hypoglycemia (Non-islet cell tumor) 17. Nesidioblastosis ( functional beta cell disorders): Non insulinoma pancreatogenous hypoglycemia Work up for Hypoglycemia: A. Confirm Whipple's triad before embarking on extensive work-up 1. Glucose ≤50 mg/dL (2.77 mmol/L) 2. Clinical manifestations of hypoglycemia 3. Resolution of symptoms upon treatment of hypoglycemia B. Exclude identifiable systemic causes before proceeding 1. Hormone deficiencies Primary adrenal insufficiency Hypopituitarism with secondary adrenal insufficiency 2. Critical illness Severe renal, hepatic or cardiac failure Sepsis 3. Starvation 4. Drugs: salicylates, quinine, pentamidine, alcohol, accidental or surreptitious intake of insulin, and oral hypoglycemia agents C. Focus on insulin-related hypoglycemia (insulinoma, post-gastric bypass hypoglycemia, non-insulinoma pancreatogenous hypoglycemia, anti-insulin antibodies, and antibodies against insulin receptor) 1. Measure glucose, insulin, pro-insulin, C-peptide, β-hydroxybutyrate, and glucose at the time of suspected hypoglycemia 2. Measure blood levels of antibodies against insulin and against the insulin receptor 3. Obtain hypoglycemic agent screen panel D. Focus on IGF-2-omas in patients with hypoglycemia with low insulin, C-peptide, pro-insulin, and βhydroxybutyrate levels 1. Measure levels of big–IGF-2: elevated level expected 2. Look for depressed levels of IGF-1, GH, and IGFBP-3, any of which would support the diagnosis 3. Measure total IGF-2: elevated level helpful; normal level is not exclusionary 4. Search for large tumors, especially in the thorax and retroperitoneum: large tumors supportive of diagnosis; small tumors may or may not be related to hypoglycemia Mayo Protocol to Evaluate Hypoglycemia: - Fast for 72 hrs, patient may have water or drinks that are calorie free and caffeine free - Check glucose Fingerstick every 6 hrs - Once glucose concentration is <60 mg/dL, Collect blood for: insulin, c-peptide, proinsulin, beta hydroxybutyrate, glucose - Check Insulin antibodies (this does not have to be measured during hypoglycemia) - Fast is ended when either the glucose <45mg/dL, or 72 hours have passed or when the plasma glucose concentration is less than 55 mg/dL (3 mmol/L) if Whipple's triad was documented on a prior occasion - Ending the fast collect glucose, insulin, c-peptide, proinsulin, beta hydroxybutyrate, and sulfonylurea - After the fast is completed and all blood work is drawn, Administer 1mg glucagon IV and measure plasma glucose 10, 20 and 30 minutes later - Feed patient after the fast is completed 72 hour fast interpretation: - Plasma insulin concentration of 3mU/mL when glucose <55mg/dL indicates excess inulin - Plasma c-peptide > 0.2nmol/L consistent with hyperinsulinemia - Plasma beta hydroxybutyrate is lower in insulinoma patients, BHOB level general 2.7mmol/L or less consistent with insulinoma. - After glucagon administration: Patients with insulin mediated hypoglycemia respond to glucagon by releasing glucose, normal subject cannot respond as vigorously compared to insulinoma patients because insulin is antiglycogenolytic and hyperinsulinemia permits retention of glycogen within the liver.- At the end of the fast insulinoma patients have an increase in plasma glucose of 25mg/dL or more in 20-30 minutes whereas normal subjects have a smaller increment - Proinsulin will be elevated in insulinoma >5 pmol/L Confirmatory Testing: Non Invasive Testing: 1. Transabdominal US 2. Spiral CT or MRI 3. To eval for insulinoma:111I-In-pentetreotide imaging or Fluorine-18-L-dihydroxyphenylalanine PET (18-F-DOPA PET) Invasive Testing: 1. Selective arterial calcium stimulation test: - Inject calcium gluconate into arteries supplying the pancreas with frequent checking of insulin levels - A positive result is double or tripling of the basal hepatic venous serum insulin concentration (indicated hyperfunctioning lesion) - In Insulinoma – reponse is positive in one artery alone or two if lesion is fed by two arteries - In pancreatogenous hypoglycemia syndrome – response is positive in multiple arteries (example in Diffuse hypertrophy of islet cells or Nesideoblastosis) 2. Endoscopic Ultrasonography 3. Pancreatic biopsy to diagnose Nesidioblastosis Treatment on Insulinoma or Non Islet Cell tumor : 1. Oral glucose and/or IV glucose or dextrose containing fluids - Not a desirable long term strategy 2. Complete removal of tumor or reduction of tumor mass - Surgical removal is the treatment of choice for insulinoma and Non Islet Cell tumors 3. Local Antitumor Therapy - Selective embolization of tumor - Localized Chemotherapy (example line streptozocin/doxorubicin or a temozolomide-based regimen) - Radiation Therapy 4. Glucocorticoids: - Dexamethasone, Hydrocortisone, Prednisolone, and Prednisone Equivalent to Prednisone 30-60mg/d are most effective stimulation of hepatic gluconeogenesis inhibition of peripheral glucose uptake mobilization of amino acids from extrahepatic sites promotion of lipolysis with fatty acid release from adipose tissue decrease production of IGF-2 5. Recombinant Human Growth Hormone - stimulates hepatic gluconeogenesis and glycogenolysis - Suppresses peripheral glucose uptake dose required is very high and has only modest efficacy - 3-12mg daily - concern with long term tx of GH is potential to elevate levels of IGF-1 and insulin and undo beneficial effects - theoretical risk of stimulating growth of tumor itself - Can lead to volume overload 6. Glucagon - Increases hepatic glucose output Effect is short lived; best used as adjunctive therapy in setting of acute hypoglycemia 0.06-0.3 mg/hr IV continuous infusion 7. Somatostatin Analogues such as Octreotide or Lanreotide: - Works minimally in some intra abdominal hemangiopericytomas in combination with glucocorticoids by reducing big IGF-2 Generally does not work in other NICTH because the somatostatin receptors, if present in tumor, are usually non-functional inhibits GH secretion but in large doses also inhibits the secretion of TSH, insulin, and glucagon 8. Diazoxide - given in divided doses of up to 1200 mg/day Nondiuretic benzothiadiazine derivative initially used as an antihypertensive but found to have hyperglycemic effect inhibits pancreatic insulin release Can lead to fluid retention, edema, and hirsutism Not very successful Post Treatment Surveillance for Insulinoma or Non-islet Cell Tumors: ●Three and six months postresection – History and physical examination, tumor markers, and computed tomography (CT) or magnetic resonance imaging (MRI). ●Long-term – History and physical examination with tumor markers every 6 to 12 months for years one to three, and as clinically indicated thereafter. Imaging studies are recommended only as clinically indicated. References: Dynkevich, Y. et all. Tumors , IGF-2, and Hypoglcemia; Insights From the Clinic, the Laboratory, and the Historical Archive. Endocrine Reviews, December 2013, 34 (6): 798-826. Bodnar, T. et all. Management of Non-islet Cell-Tumor Hypoglycemia: a Clinical Review. Journal of Clinical Endocrinology and metabolism. March 2014, 99 (3):713-722. Service, John. Hypoglycemia in adults without diabetes mellitus: Diagnostic approach. UpToDate Oct. 2015.