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

Because hypoglycemia can kill 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 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 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 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)

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

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 Salicylates Pentamidine Propronalol 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 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 Drugs Surgery 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