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 insulin-

sensitive tissues

• Growth hormone and cortisol have a role during

prolonged hypoglycemia
 Signs and Symptoms
•Adrenergic •Neuroglucopenic
– Weakness – Headache
– Sweating – Hypothermia
– Tachycardia – Visual disturbances
– Palpitations – Mental dullness
– Tremor – Confusion
– Nervousness – Amnesia
– Irritability – Seizures
– Tingling of mouth – Coma
– Hunger
– Nausea
– Vomiting
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
 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 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.
 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 Non-beta cell tumors
Drugs Endogenous hyperisulinism
Insulin,sulfonylureas,alcohol, Pancreatic beta cell disorders
Tumor(insulinoma)
Pentamidine, quinine
Nontumor Beta cell secretagogue
Salicylates, sulfonamides Autoimmune hypoglycemia
Critical illnesses Insulin antibodies
Hepatic failure Insulin receptor antibodies
Cardiac failure ？ Bate cell antibodies
Renal failure ？ Ectopic Insulin secretion
Sepsis Hypoglycemias of infancy and
childhood
Hormonal deficiencies
Reactive Hypoglycemia
Cortisol or growth hormone, or both Congenital deficiencies of enzymes of
Glucagon and epinephrine 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 Potentiate
– hypoglycemic effect
Coumadin
of sulfonylurea
– Phenylbutazone agents
– Clofibrate
• Salicylates
• Pentamidine
• Propronalol
• MAO inhibitors
• Oxytetracycline
• Disopyramide
• Quinine
 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