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hypoglycemia

Also see Whipple's triad Classification: - fasting - reactive (postprandial) Etiology: 1) hypoglycemic agents - common among diabetics at all levels of glycemic control (HgbA1c) [12] ~11% of patients/year - serious hypoglycemia in type 2 diabetes most common at high & low HgbA1c [19] - causes in diabetics taking hypoglycemic agent(s) - meal-related misadventures, missing a meal (46%) [13,14] - using wrong insulin product (22%) - wrong insulin dose or confusing dosing units (12%) - intentionally taking an additional dose (6.0%) - surreptitious use of hypoglycemic agent - hypoglycemic agents least likely to cause hypoglycemia - metformin - SGLT2 inhibitors (flozins) - GLP-1 receptor agonists (incretin mimetics, glutides) - tirzepatide - thiazolidinediones (glitazones) - dipeptidyl peptidase-4 inhibitors (gliptins) 2) reactive (postprandial): a) within 1st 5 hours after eating b) infrequent, over diagnosed (self diagnosed); - rarely true hypoglycemia (glucose < 50 mg/dL) - unlikely to occur after eating in a patient with type 2 diabetes - see Differential diagnosis: (below) c) gastrointestinal surgery - vagotomy, pyloroplasty, gastrectomy, gastrojejunostomy d) early diabetes (unusual) e) idiopathic "functional" hypoglycemia 3) fasting: a) more than 5 hours after eating b) more common form of hypoglycemia c) pharmacologic agents 1] insulin (including surreptitious injection) 2] oral hypoglycemics 3] quinine (intravenous for cerebral malaria) 4] alcohol impairs gluconeogenesis 5] propranolol (often in hemodialysis patients) 6] salicylates (mostly children) 7] pentamidine in undernourished AIDS patients 8] disopyramide (Norpace) - elderly non-diabetics with liver or renal failure 9] haloperidol 10] tramadol d) renal insufficiency e) severe malnutrition f) pregnancy (generally asymptomatic) g) hepatic failure: cirrhosis h) septicemia i) insulinoma: 1] may be benign or malignant - may occur as component of MEN-1 2] nesidioblastosis in children g) hormone deficiency 1] adrenal insufficiency (more common in children) 2] growth hormone deficiency 3] thyroxine deficiency 4] catecholamine deficiency 5] glucagon deficiency (unusual) h) abdominal tumors 1] mesenchymal tumor: abdomen, pelvis, thorax 2] carcinoma of the adrenal, kidney, GI tract 3] hepatoma 4] may be secondary to IGF-2 i) glycogen storage disease j) systemic carnitine deficiency k) congestive heart failure l) leukemia may result in artifactual hypoglycemia - leukocyte consumption of glucose, use NaF tubes m) insulin autoimmune hypoglycemia [3] - anti-insulin & anti-insulin receptor antibodies 4) relative hypoglycemia [3]; plasma glucose > 70 mg/dL 5) overnight hypoglycemia Epidemiology: - hospital admission for hypoglycemia now exceed those for hyperglycemia among older adults [14] Clinical manifestations: 1) plasma glucose levels < 50 mg/dL usually, but not always produce hypoglycemia a) fasting young, healthy women may have serum glucose levels < 50 mg/dL without symptoms b) poorly controlled diabetics may experience symptoms of hypoglycemia > 70 mg/dL 2) cholinergic symptoms - sweating 3) adrenergic symptoms a) anxiety b) hunger, nausea c) diaphoresis d) tachycardia e) tremulousness f) PVC's g) irritability h) hyperthermia i) palpitations j) hypothermia 4) neurologic symptoms a) headache b) behavioral changes (combativeness, agitation) c) cognitive change d) seizures e) coma f) hemiparesis g) aphasia h) visual changes i) Babinski's sign 5) nocturnal hypoglycemia may not cause awakening from sleep but lead to fatigue, sweating & headache in the morning [3] * syncope is NOT a manifestation Diagnostic criteria: - see Whipple's triad Laboratory: 1) serum glucose a) hypoglycemia is defined as laboratory serum glucose or plasma glucose - < 54 mg/dL (serious hypoglycemia) [3] - < 70 mg/dL [3] b) fasting serum glucose of < 50-60 mg/dL may occur in asymptomatic normal people & does not need further evaluation [3] 2) known diabetic a) serum alcohol b) serum cortisol level c) liver function tests d) serum urea nitrogen e) serum creatinine f) C-peptide in serum - elevated serum insulin with low C-peptide in serum suggests insulin overdose g) sulfonylurea level if serum insulin & serum C-peptide are inappropriately increased for degree of hypoglycemia 3) non-diabetic a) 5 specimens 6 hours apart for fasting hypoglycemia [3] ?? -> 30 hours b) collect but do not analyze unless simultaneous serum glucose < 60 mg/dL [3] c) routine tests [3] - serum insulin - serum insulin > 6 mU/mL in association with serum glucose < 50 mg/dL in males & < 40 mg/dL in females indicates hyperinsulinemia - serum proinsulin - C-peptide levels (obtain when glucose is < 50 mg/dL) - C-peptide level > 0.2-0.4 nM (0.9-4.0 ng/mL) suggests a beta-cell lesion (insulinoma) or serruptitious ingestion of sulfonylurea [3] - plasma insulin with low plasma C-peptide suggests surreptitious injection of insulin - serum beta-hydroxybutyrate d) mixed meal testing for postprandial hypoglycemia - baseline (routine tests except serum beta-hydroxybutyrate) - draw specimens 30 minutes apart for 5 hours - if serum glucose < 60 mg/dL, reanalyze baseline tests (see above) e) insulin antibodies f) anti-insulin receptor antibodies if insulin is increased, no insulin antibodies & C-peptide is normal or low 4) 72 hour fast - increased serum insulin & serum C-peptide in the absence of insulin antibodies & measurable serum sufonylureas indicates insulinoma 5) increased serum insulin-like growth factor-2 (serum IGF-2) suggests mesenchymal tumor 6) 5 hour glucose tolerance test: (NOT useful) - serum glucose < 50 mg/dL with symptoms of hypoglycemia occurs commonly in normal individuals 7) see ARUP consult [7] * do not use home glucometers to diagnose hypoglycemia [3] Special laboratory: - continuous glucose monitoring in patients with diabetes mellitus [3] Radiology: - CT of abdomen - only after confirmation of elevated endogenous plasma insulin - not routinely indicated unless carcinoma (insulinoma) suspected Differential diagnosis: 1) self diagnosed hypoglycemia a) anxiety b) panic attacks c) hyperventilation d) pheochromocytoma 2) neurologic manifestations of hypoglycemia a) seizure disorder b) psychosis c) drug or alcohol intoxication d) transient ischemic attack or stroke e) etiologies of coma 3) acute coronary syndrome in the elderly - nausea, vomiting, dyspnea after eating Complications: - even mild hypoglycemia associated with increased mortality in critically ill patients - severe hypoglycemia is associated with increased risk of cardiovascular disease & death [6,12] Management: 1) asymptomatic hypoglycemia does not require treatment 2) acute therapy a) 6-12 oz (200-400 mL, 120-240 mL [21]) of juice or non diet soda if awake - 15-25 g of glucose = 3-4 glucose tablets [21] b) 50 mL of 50% glucose IV: followed by 10% glucose IV until patient is able to eat c) repeated boluses of 50% glucose may be required d) fructose is alternative to glucose e) glucagon 1 mg IV or IM if unresponsive 3) treatment of underlying disorder a) functional assessment/cognitive assessment for multiple episodes of hypoglycemia in elderly who had been stable on insulin-containing regimens for years [20] b) pseudo (self diagnosed) hypoglycemia - high protein diet, frequent meals c) discontinue use of alcohol d) discontinue or decrease sulfonylureas - substitute with metformin or shorter-acting sulfonylurea (i.e. glypizide) [3,10] e) adjust insulin dose - review functional status in elderly first - taper insulin in patients with type 2 diabetes (1st line) [21] - switching from NPH to degludec, detemir or glargine my reduce episodes of hypoglycemia & improve glycemic control [21] - degludec may be associated with less hypglycemia than glargine (RR=0.70) [22] - continous glucose monitoring may be indicated [3] - glycemic control variability & hemoglobin A1c not at goal [3] - Medicare currently approves continuous glucose monitoring only for patients who require >= 3 insulin injections daily [20] f) discontinue other offending pharmacologic agents g) patients with renal failure not on dialysis require higher carbohydrate diets with more frequent feedings h) patients on dialysis may benefit from a decrease in dialysis glucose concentration i) patients with hepatic failure require continuous intravenous glucose until recovery has begun j) malnutrition requires adequate nutrients k) cortisol replacement for adrenal insufficiency l) insulinomas & mesenchymal tumors - consult endocrinology & surgery - non operable insulinomas may be managed with - diazoxide - thiazides - tumor debulking & chemotherapy for mesenchymal tumors m) counseling may benefit anxiety disorder n) psychiatric evaluation for factitious hypoglycemia [3] o) postprandial hypoglycemia due to gastrectomy or gastric bypass - small mixed meals containing protein, fat, high-fiber complex carbohydrates [3] 4) prevention - slow correction of long-standing hyperglycemia to avoid relative hypoglycemia by preventing large variations in blood glucose [2] Comparative biology: - glucose deprivation in a tauopathy mouse model triggers tau pathology & synaptic dysfunction [15] - memory impairment - reduction of synaptic long-term potentiation - increased tau phosphorylation mediated by activation of P38 MAPK Kinase [15]

Related

glucose in serum/plasma hyperglycemia hypoglycemic agent

Specific

familial hyperinsulinemic hypoglycemia; persistent hyperinsulinemic hypoglycemia of infancy (PHHI); congenital hyperinsulinism leucine-induced hypoglycemia; leucine-sensitive hypoglycemia of infancy neuroglycopenia overnight hypoglycemia; nocturnal hypoglycemia relative hypoglycemia

General

sign/symptom

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 668-670
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Egi M et al Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc 2010 Mar; 85:217. PMID: 20176928
  5. Neonatal hypoglycemia Maine Medical Center (MMC) http://www.mmc.org/mmc_bush/clinical_services_clinician_hypoglycemia.htm
  6. Zoungas S et al, Severe Hypoglycemia and Risks of Vascular Events and Death N Engl J Med 2010; 363:1410-1418 PMID: 20925543 http://www.nejm.org/doi/full/10.1056/NEJMoa1003795
  7. ARUP Consult: Hyperinsulinemic Hypoglycemia The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hyperinsulinemic-hypoglycemia
  8. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008 Dec;57(12):3169-76 PMID: 19033403
  9. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes. Diabetes Care. 2010 May;33(5):1004-8 PMID: 20200306
  10. Greco D, Pisciotta M, Gambina F, Maggio F. Severe hypoglycaemia leading to hospital admission in type 2 diabetic patients aged 80 years or older. Exp Clin Endocrinol Diabetes. 2010 Apr;118(4):215-9 PMID: 20072965
  11. Cryer PE, Axelrod L, Grossman AB, Heller SR Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94(3):709-28 PMID: 19088155
  12. Lipska KJ et al HbA1c and Risk of Severe Hypoglycemia in Type 2 Diabetes. The Diabetes and Aging Study Diabetes Care. July 30, 2013 PMID: 23900589 http://care.diabetesjournals.org/content/36/11/3535 - Goto A et al Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013;347:f4533 PMID: 23900314 http://www.bmj.com/content/347/bmj.f4533
  13. Geller AI, Shehab N, Lovegrove MC et al. National estimates of insulin-related hypoglycemia and errors leading to emergency department visits and hospitalizations. JAMA Intern Med. 2014;174(5):678-686 PMID: 24615164 - Lee SJ So much insulin, so much hypoglycemia. JAMA Intern Med. 2014 May;174(5):686-8. PMID: 24614940
  14. Lipska KJ, Ross JS, Wang Y et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med. 2014;174(7):1116-1124 PMID: 24838229
  15. Lauretti E, Li JG, Di Meco A, Pratico D. Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model. Transl Psychiatry. 2017 Jan 31;7(1):e1020. PMID: 28140402 Free PMC Article
  16. Service FJ Hypoglycemic Disorders. N Engl J Med 1995; 332:1144-1152. April 27, 1995. PMID: 7700289 http://www.nejm.org/doi/full/10.1056/NEJM199504273321707
  17. Karter AJ, Warton EM, Lipska KJ et al, Development and Validation of a Tool to Identify Patients With Type 2 Diabetes at High Risk of Hypoglycemia-Related Emergency Department or Hospital Use. JAMA Intern Med. Published online August 21, 2017 PMID: 28828479 http://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2649265
  18. Cryer PE, Axelrod L, Grossman AB et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008 Dec 18; 94:709. PMID: 19088155
  19. Zhong VW, Juhaeri J, Cole SR et al. Proximal HbA1C level and first hypoglycemia hospitalization in adults with incident type 2 diabetes. J Clin Endocrinol Metab 2019 Jun 1; 104:1989 PMID: 30608562 https://academic.oup.com/jcem/article-abstract/104/6/1989/5270382
  20. Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  21. NEJM Knowledge+ Endocrinology
  22. Wysham C, Bhargava A, Chaykin L et al Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes. The SWITCH 2 Randomized Clinical Trial. JAMA. 2017;318(1):45-56. PMID: 28672317 http://jamanetwork.com/journals/jama/article-abstract/2635630