Download Hypoglycemia - University of Yeditepe Faculty of Medicine, 2011

Hypoglycemia
Hasan AYDIN, MD
Yeditepe University Medical Faculty
Department of Endocrinology and Metabolism
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 < 45-50
mg/dL
Hypoglycemia: Cause
Imbalance between factors raising and lowering blood
glucose levels
 Blood Glucose
 Blood Glucose
Food
Insulin/Oral Meds
Counterregulatory Hormones
Physical Activity
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.
Definition
• An abnormality, not a disease
• Abnormally low blood glucose level
• Caused by
– Pathologic conditions or disease states
– Physiological conditions
Definition
Condition of patient
Glucose concenatration (mg/dL)
Fasted
Fed*
Plasma
< 60
< 50
Whole blood
< 50
< 40
* After ingestion of glucose or meal
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
Insulin is the “key” that allows special
“gates” for sugar transport across cell
membranes to be opened
Why do we care about it?
Because hypoglycemia can kill
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
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)
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
Hormonal Control
• Insulin- inhibits glycogenolysis and
gluconeogenesisdecreased serum glucose
• Glucagon- promotes glycogenolysis and
gluconeogenesis
• Epinephrine- limits utilization of glucose by insulinsensitive tissues
• Growth hormone and cortisol have a role during
prolonged hypoglycemia
Signs and Symptoms
•Adrenergic
–
–
–
–
–
–
–
–
–
–
–
Weakness
Sweating
Tachycardia
Palpitations
Tremor
Nervousness
Irritability
Tingling of mouth
Hunger
Nausea
Vomiting
•Neuroglucopenic
–
–
–
–
–
–
–
–
Headache
Hypothermia
Visual disturbances
Mental dullness
Confusion
Amnesia
Seizures
Coma
Response to Hypoglycemia
Blood Glucose
< 60 mg/dL
Symptoms
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
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
SEVERITY OF HYPOGLYCEMIA
MILD
Autonomic symptoms are present
Individual is able to self-treat
MODERATE
Autonomic and neuroglycopenic symptoms are present
Individual is able to self-treat
SEVERE
Individual requires assistance of another person
Unconsciousness may occur
Plasma glucose is typically < 50 mg/dL
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 overtreatment 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.
TREATMENT
Mild to moderate hypoglycemia
 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)
TREATMENT
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
Etiology
Classified into three groups:
1. Medications or toxins.
2. Disorders associated with fasting hypoglycemia.
3.Disorders associated postprandial hypoglycemia.
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
Fasting Hypoglycemia
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
Drugs
• Insulin
• Sulfonylurea agents
–
–
–
–
–
•
•
•
•
•
•
•
Sulfonamides
Chloramphenicol
Coumadin
Phenylbutazone
Clofibrate
Salicylates
Pentamidine
Propronalol
MAO inhibitors
Oxytetracycline
Disopyramide
Quinine
Potentiate
hypoglycemic effect
of sulfonylurea
agents
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
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
Low
High
High
High
Insulin
Low
High
Low
Normal
Sulfonylurea
Low
High
High
Normal
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
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
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
5-10 %
Gastrointestinal tumors
5-10 %
Lymphomas
5-10 %
Miscallenous (kindey, lung, anaplastic carcinoma, carcinoid)
Hepatic Failure
• Only when the liver severely compromised
• Hypoglycemia indicates worst prognosis
• Death due to hypoglyceamia very rare
• Treatment simple-with iv glucose
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
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
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
Treatment
• Surgery
• Oral diazoxide 100 mg every 6-8 hours
• Phenytoin, chlorpromazine, propronalol, verapamil
• Streptozocin in metastatic islet cell cancer
• L-asparaginase, doxorubicin, mithramycin
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
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
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
Fed (Reactive) Hypoglycemia
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
Hyperalimentation
Patient who has undergone gastric surgery
Rapid entrance of food to duedonum
Rapid absorbtion of food
Rapid hyperglycemia
Hyperinsulinism
Hypoglycemia
Impaired Glucose Tolerance
• Patient with impaired glucose tolerance test
• Late hypoglycemia after 3 hours
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
Management
Diet
–
–
–
–
Avoidance of simple or refined carbohydrates
Limitation of carbohydrate intake to 35-40 %
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