1. Hypoglycemia Hasan AYDIN, MD Yeditepe University Medical Faculty
Department of Endocrinology and Metabolism

2. What is it? Hypoglycemia refers to a low level of serum glucose
Occurs when a mismatch of endogenous glucose need with exogenous and endogenous glucose availability
Often defined as a plasma glucose level < mg/dL

3. Hypoglycemia: Cause
Imbalance between factors raising and lowering blood glucose levels
 Blood Glucose
 Blood Glucose
Food
Insulin/Oral Meds
Counterregulatory Hormones
Physical Activity

4. Diagnosis of Hypoglycemia
Hypoglycemia was defined by the Third International Symposium on Hypoglycemia is a blood glucose value of less than 50mg/dl.
Whipple’s triad:
Symptoms consistent with hypoglycemia
A low plasma glucose concentration
Relief of those symptoms.

5. Definition An abnormality, not a disease
Abnormally low blood glucose level
Caused by
Pathologic conditions or disease states
Physiological conditions

6. Definition Condition of patient
Glucose concenatration (mg/dL) Fasted Fed*
Plasma < 60 < 50
Whole blood < 50 < 40
* After ingestion of glucose or meal

7. General Approach Documentation of low blood glucose concentration
Systematic efforts to determine what condition is responsible for
Fasting or fed state
Symptoms developing when missing a meal
Symptoms developing after meals

8. Insulin is the “key” that allows special “gates” for sugar transport across cell membranes to be opened

9. Because hypoglycemia can kill
Why do we care about it?
Because hypoglycemia can kill

10. Why do we care about it? Physiology
Glucose is an obligate metabolic fuel for the brain under physiologic conditions, while other organs can use other forms of fuel (i.e. fatty acids)
The brain can not synthesize its own glucose; it requires a continuous supply via arterial blood

11. Why do we care about it? Maintenance of glucose homeostasis
Narrow plasma glucose range is normally maintained despite fluctuations in food intake and activity levels
Maintenance through diet, glycogen breakdown (liver) and gluconeogenesis (liver and kidney)

12. Glucose Metabolism Glycogen stores can last 8-12 hours
Precursors for gluconeogenesis coordinated amongst liver, muscle and adipose tissue
Muscle: lactate, pyruvate, amino acids
Adipose: glycerol, fatty acids

13. Hormonal Control
Insulin- inhibits glycogenolysis and gluconeogenesisdecreased serum glucose
Glucagon- promotes glycogenolysis and gluconeogenesis
Epinephrine- limits utilization of glucose by insulin-sensitive tissues
Growth hormone and cortisol have a role during prolonged hypoglycemia

14. Signs and Symptoms Adrenergic Neuroglucopenic Weakness Sweating
Tachycardia
Palpitations
Tremor
Nervousness
Irritability
Tingling of mouth
Hunger
Nausea
Vomiting
Neuroglucopenic
Headache
Hypothermia
Visual disturbances
Mental dullness
Confusion
Amnesia
Seizures
Coma

15. Response to Hypoglycemia
Blood Glucose
Symptoms
< 60 mg/dL
Sweating, tremor, anxiety, palpitations, hunger
50-55 mg/dL
Early cognitive dysfn. (confusion, mood changes)
45-50 mg/dL
Lethargy, obtundation
< 30 mg/dL
Coma
< 20 mg/dL
Convulsions
…Death

16. Response to Hypoglycemia
Blood Glucose
Hormonal response
< 80 mg/dL
Insulin decrease to low levels
65-70 mg/dL
Glucagon & catecholamines
< 60 mg/dL
Growth Hormone & cortisol
< 45 mg/dL
Pancreas: no insulin release

17. SEVERITY OF HYPOGLYCEMIA
MILD
Autonomic symptoms are present
Individual is able to self-treat
MODERATE
Autonomic and neuroglycopenic symptoms are present
SEVERE
Individual requires assistance of another person
Unconsciousness may occur
Plasma glucose is typically < 50 mg/dL

18. TREATMENT
GOALS: To detect and treat a low blood glucose level promptly by using an intervention that provides a rapid rise is blood glucose to a safe level, eliminating the risk of injury, and relieving symptoms quickly. It is also important to avoid over-treatment with resulting rebound hyperglycemia and risk of weight gain.
15 g of glucose will usually increase blood glucose by 40 mg/dL within 20 minutes with adequate symptom relief for most people.
20 g will usually increase blood glucose by 65 mg/dL within 45 minutes.

19. TREATMENT Mild to moderate hypoglycemia Severe hypoglycemia, conscious
15 g of oral carbohydrate (CHO), preferably as glucose or sucrose tablets or solution. Retest blood glucose in 15 minutes; repeat treatment if BG still < 70 mg/dL
Severe hypoglycemia, conscious
20 g of oral CHO (glucose tablets or equivalent); retest in 15 minutes, repeat treatment if BG still < 70 mg/dL
Severe hypoglycemia, unconscious adult
1 mg glucagon subcutaneously or intramuscularly or 10 to 25 g of glucose intravenously (20 – 50 cc of D50W)
Severe hypoglycemia, unconscious child
0.5 mg glucagon (if < 5 years old) or intravenous glucose (0.5 – 1.0 g / kg body weight)

20. TREATMENT 15 g of glucose in the form of glucose tablets
Examples of 15 g of CHO for the treatment of mild to moderate hypoglycemia:
15 g of glucose in the form of glucose tablets
15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water
175 mL (3/4 cup) of juice or regular soft drink
6 Life Savers
15 mL (1 tablespoon) of honey

21. Etiology Classified into three groups: 1. Medications or toxins.
2. Disorders associated with fasting hypoglycemia.
3.Disorders associated postprandial hypoglycemia.

22. Clinical Classification of Hypoglycemia
Fasting Hypoglycemia
Drugs
Insulin,sulfonylureas,alcohol,
Pentamidine, quinine
Salicylates, sulfonamides
Critical illnesses
Hepatic failure
Cardiac failure
Renal failure
Sepsis
Hormonal deficiencies
Cortisol or growth hormone, or both
Glucagon and epinephrine
Non-beta cell tumors
Endogenous hyperisulinism
Pancreatic beta cell disorders
Tumor(insulinoma)
Nontumor Beta cell secretagogue Autoimmune hypoglycemia
Insulin antibodies
Insulin receptor antibodies
？Bate cell antibodies
？Ectopic Insulin secretion
Hypoglycemias of infancy and childhood
Reactive Hypoglycemia
Congenital deficiencies of enzymes of carbohydrate metabolism
Alimentary hypoglycemia
Idiopathic(functional) postprandial hypoglycemia

24. Fasting Hypoglycemia

25. Fasting Hypoglycemia Gradual onset
Autonomic component of signs and symptoms absent
Persistent fasting hypoglycemia
Requires glucose administration for reversal
Can occur both in fasting state and after meals

26. Drugs Insulin Sulfonylurea agents Salicylates Pentamidine Propronalol
Sulfonamides
Chloramphenicol
Coumadin
Phenylbutazone
Clofibrate
Salicylates
Pentamidine
Propronalol
MAO inhibitors
Oxytetracycline
Disopyramide
Quinine
Potentiate hypoglycemic effect of sulfonylurea agents

27. Treatment Insulin induced hypoglycemia treated with iv glucose
Hypoglycemia often relapses and recovery takes time----- hospitalization
Discontinue offending agent
IV glucose can stimulate further insulin release
Octreaotide or oral diazoxide

28. Factitious Hypoglycemia
Emotionally disturbed patient surreptitiously taking insulin or occasionally sulfonylurea agents
Usually female in health related occupations
Female relatives of diabetic patients
Diagnosis
Low blood glucose with hyperinsulinemia
Low C-peptide level
Measurement of sulfonylurea in blood or urine
Condition Glucose Insulin C-peptide Proinsulin
Insulinoma
Insulin
Sulfonylurea
Low
High
Normal

29. Ethanol Inhibits gluconeogenesis in liver
Common in case of restricted food intake
Malnourished chronic alcoholics
Heavy weekend drinkers
Social drinker who miss meals
Children
Neuroglycopenic signs and symptoms predominate
Failure to recognition
Mortality 25% in children, 10 % in adults
Treatment
Glucagon not effective
Good response to iv glucose

30. Non-β-Cell Tumors Excess glucose consumption by tumor tissue
Secrete incompletely processed IGF-II
Normally IGF-II binds IGFBP-3 and acid-labile protein and mediates actions of GH
IGHBP-3 and IGF-1 levels decreased
Diagnosis
Other causes should be ruled out
Usually a late manifestation
Low IGF-1 diagnostic
DHEAS elevated in adrenal carcinoma
Treatment
Surgical removal of tumor
Effective radio or chemotherapy
Parenteral glucocorticoids can stimulate gluconeogenesis
Continuous iv glucoıse is not practical

31. Non-β-cell tumors associated with hypoglycemia
Large mesenchymal tumors 50 %
Mesothelioma, fibrosarcoma, neurofibroma, neurofibrosarcoma
Spindle cell sarcoma, leonyosarcoma, rhabdomyosarcoma
Hepatocellular carcinoma 25 %
Adrenal carcinoma %
Gastrointestinal tumors %
Lymphomas %
Miscallenous (kindey, lung, anaplastic carcinoma, carcinoid)

32. Hepatic Failure Only when the liver severely compromised
Hypoglycemia indicates worst prognosis
Death due to hypoglyceamia very rare
Treatment simple-with iv glucose

33. Adrenal Failure
In absence of cortisol hepatic glucose production decreases
Diagnosis
24-h urine cortisol
Cosynptropin stimulation test
Insulin tolerance test
Metyrapone stimulation test
Management
IV bolus glucose
Cortisol 100 mg every 8-hour period
Maintenant cortisol dose

34. β-Cell Tumors (Insulinoma)
Rare
Undiagnosis related to permanent neouropsycihiatric sequela
Slow progression of hypoglycemia
Autonomous signs and symptoms lacking
Present often with visual difficulties, transient neurologic syndromes, mental confusion, convulsions, personality changes
Weight gain is common

35. Diagnosis 72-hour fasting Insulin/glucose >0.3 abnormal
Proinsulin > 20 % of total insulin or high levels
Stimulatory tests
Tolbutamide, glucagon, calcium, leucine
OGTT worthless (normal, flat, impaired)
Preoperative localisation
Only after biochemical diagnosis
Pancreatic areteriography identifies 50 %
USG, CT, radionuclide scanning not helpfull (most<2 cm)
USG at surgery most sensitive method
Others
Endoscopic ultrasonography
Portal venous sampling with selective intraarteial calcium injection

36. Treatment Surgery Oral diazoxide 100 mg every 6-8 hours
Phenytoin, chlorpromazine, propronalol, verapamil
Streptozocin in metastatic islet cell cancer
L-asparaginase, doxorubicin, mithramycin

37. Renal Failure Poor dietary intake in some of them
Impaired gluconeogenesis
Enhanced glucose utilization
Takes a period of weeks or months and suddenly ceases
Frequent feeding or corticosteroid administration
Poor prognostic sign, most die within a year

38. Miscallaneous Causes Insulin Autoantibodies
Part of the autoimmune endocrine syndrome
Majorly Japon
Sulfhydryl compound use in many
Insulin Receptor Autoantibodies
A female with insulin resistance and acathosis nigricans
High ESR, ANA, Anti-DNA, hypergammaglbemia, decreased complement
Ab acts as insulin to cause hypoglycemia

39. Miscallaneous Causes Sepsis Falciparum malaria
Glucose utilization by parasite
Pregnant patients and cerebral-involved are prone
Quinine may contribute
Congestive Heart Failure
Secondary to decreased delivery of gluconeogenic substrates to liver
Wight loss, anoreksia, low cardiac output

40. Fed (Reactive) Hypoglycemia

41. Fed (Reactive) Hypoglycemia
Symptoms predominantly autonomic
Onset characteristically rapid
Neuroglycopenic component unusual
Transient and normalized by normal hormonal response
Exogenous glucose reverses condition rapidly
Three main causes
Hyperalimentation
Impaired glucose tolerance
Idiopathic reactive hypoglycemia

43. Hyperalimentation Patient who has undergone gastric surgery
Rapid entrance of food to duedonum
Rapid absorbtion of food
Rapid hyperglycemia
Hyperinsulinism
Hypoglycemia

44. Impaired Glucose Tolerance
Patient with impaired glucose tolerance test
Late hypoglycemia after 3 hours

45. Idiopathic Reactive Hypoglycemia
Definition
Normal glucose levels eraly
Late hypoglycemia
Controversies
Not repeatable
Large amount of glucose not physiologic
Disparity between result and symptoms
Most have psychologic basis

46. Management Diet Drugs Surgery
Avoidance of simple or refined carbohydrates
Limitation of carbohydrate intake to %
Multiple small feeding especially in hyperalimentation
Weight reduction in obese
Drugs
Propantheline bromide
Phenytoin
Propronalol
Calcium channel blockers
Alpha-glucosidase inhibitors
Surgery
In patients with hyperalimentation
Placement of a reversed jejunal segment near the gastric outlet