Hypoglycemia

Hasan AYDIN, MDYeditepe 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 gluconeogenesisdecreased 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– 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 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 HypoglycemiaDrugs 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 HypoglycemiaCongenital deficiencies of enzymes of carbohydrate metabolismAlimentary hypoglycemiaIdiopathic(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

Insulin

Sulfonylurea

Low

Low

Low

High

High

High

High

Low

High

High

Normal

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

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)

Non-β-cell tumors associated with hypoglycemia

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

Rapid entrance of food to duedonum

Rapid absorbtion of food

Rapid hyperglycemia

Hyperinsulinism

Hypoglycemia

Patient who has undergone gastric surgery

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

ManagementDiet

– 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