Hypoglycemia in Infants and Children

Interesting Case Conference Pam Hildebrand, MD 21 April 2005

Normal Glucose Homeostasis

Requires
A normal endocrine system Intact, functional enzymes Adequate supply of endogenous fat, glycogen, and gluconeogenic substrates

Glucose use in Infants and Children

Unable to maintain normal plasma glucose levels after even a short fast (24-36 hrs). The brain uses glucose 20x the rate of other tissues; cant use FFA. Ketone bodies do pass the BBB and can be metabolized by the brain. Children have a higher rate of glucose turnover/kg body wt; have a greater proportion of brain mass:body size.

Insulin: A Key Player

Increased plasma gluc> into beta-cell via GLUT2> glycolysis> incr ATP> K+ channels close and membrane depolarizes> opens Ca2+ channels> fusion of insulin granule with plasma membrane Insulin receptor a tetramer with tyrosine kinase activity

Insulin Action
hormone of abundance- stores excess nutrients
Decreases blood glucose Decreases blood AA Decreases blood FA Decreases blood ketoacids Decreases blood K+

Hypoglycemia: definition
Exact number controversial Glucose <40-45 mg/dL commonly accepted Physiologic nadir in the first 2-4 hrs of life

Clinical Features
Nonspecific in infants: irritability, jitteriness, difficulty feeding, lethargy, cyanosis, tachypnea, hypothermia 2 groups:
Autonomic response (gluc 40-70 mg/dL): sweating, weakness, tachycardia, tremor, feeling of nervousness. Warning system Neuroglycopenia (gluc 10-50 mg/dL): lethargy, irritability, confusion, behavior changes, seizure and coma

Management of Hypoglycemia
Blood work (5-10 mL of blood prior to correction of glucose)
Substrates: FFA, beta-hydroxybutyrate, lactate, total and free carnitine, and acylcarnitines Regulatory hormones: insulin, C-peptide, cortisol, GH BMP, LFTs, ammonia, tox screen

Management cont.
First voided urine should be collected and tested for ketones and reducing substances. Remainder can be saved for tox studies, organic acids, etc. Glucagon challenge
0.03 mg/kg IV glucagon. Measure glucose at 10, 20, 30 minutes. > 20-30 mg/dL increase in plasma glucose in the first 10-20 min suggests inappropriate sequestration of hepatic glycogen.

Management cont.
Glucose therapy
2-2.5 cc/kg of 10% dextrose solution Glucose infusion at 6-9 mg/kg/min Monitor glucose frequently with goal 70120 mg/dL Suspect hyperinsulinemia when excessive glucose infusion rate needed to maintain plasma glucose (>10 mg/kg/min)

Interpreting the Tests

Look at the degree of ketosis (amt of beta-hydroxybutyrate in serum) at the time of hypoglycemia Inappropriate ketosis (<2.5 mEq/L)
Fats are not being mobilized= hyperinsulinism. Fats cant be used to make ketone bodies= FA oxidation defect.

Interpreting cont
Inappropriate ketosis
Glycogen storage diseases also have low ketosis, hepatomegaly, hypertriglyceridemia, no glycemia response to glucagon.

Interpreting cont.
Appropriate ketosis (>2.5 mEq/L)
Normal fasting response Ketotic hypoglycemia GH, cortisol deficiency Disorders of amino, organic acids

Etiology of Hypoglycemia
Glucose used faster than it appears in the serum- defective production, increased utilization, or combination Includes defects in enzymes needed for carbohydrate, amino acid, and fat metabolism

Disorders of Carbohydrate Metabolism

Disorders of glycogenolysis
Glycogen storage diseases Many enzymes: glycogen synthetase, gluc6-phosphatase deficiency Mild-mod ketosis, lactic acidosis, hypertriglyceridemia, clinical features such as hepatomegaly

Disorders of Carbohydrate Metabolism

Disorders of gluconeogenesis
Ketosis, lactic acidosis after glycogen stores depleted Hepatic enzyme defects Alcohol intoxication, salicylate poisoning Lack of substrate (lactose, fructose, AA)

Disorders of Carbohydrate Metabolism

Galactosemia
Hypoglycemia, vomiting, diarrhea with lactose-based milk/formula FTT, sepsis picture Low to absent urine ketones Accumulation of gal-1-phosphate: heptomegaly, cataracts, MR

Disorders of Carbohydrate Metabolism

Hereditary fructose intolerance
Hypoglycemia, vomiting following fructose, sucrose (gluc-fruc) ingestion Fructosuria, hepatomegaly, aminoaciduria, lactic acidosis, low/absent urine ketones, FTT.

Disorders of AA Metabolism (organic acidemias)

Present in newborn or early infancy Life-threatening episode of increased anion gap metabolic acidosis, hypoglycemia Also assoc with FTT, DD. Decompensate during times of increased catabolism: illness, trauma, surgery

Disorders of AA Metabolism
Tyrosinemia: hypoglycemia due to liver disease Maple Syrup Urine Disease: hypoglycemia due to protein malnutrition Methylmalonic, Proprionic, Isovaleric Acidemia: hypoglycemia due to carnitine deficiency from renal losses

Disorders of FA Metabolism
Hypoglycemia and hypoketonemia during periods of fasting FFA can be used by heart, skeletal muscle, gut. Converted to ketone bodies for the brain Usually mobilization of FFA occurs when plasma glucose <60 mg/dL (approx 12 hr fast in infants/young kids)

Disorders of FA Metabolism
Fatty acid oxidation disorders
Carnitine deficiency FA transportation defects Defects of beta-oxidation enzymes

Pathophysiology of hypoglycemia
Decreased hepatic glucose production Increased glucose utilization due to lack of ketone bodies and FFA.

Disorders of FA Metabolism
Clinical features
Hypoglycemia Decreased plasma free/total carnitine Low plasma ketones Elevated FFA Disturbance of consciousness that doesnt improve with glucose correction Hypotonia, hepatomegaly, CHF, rhabdo, cerebral edema

Disorders of Increased Glucose Utilization

Hyperinsulinemia: endogenous, exogenous administration of insulin or oral hypoglycemic agents Increased metabolic rates: sepsis, burns, hyperthyroidism

Hyperinsulinism
Plasma insulin inappropriately elevated for the level of hypoglycemia Plasma ketones and FFA are inappropriately depressed
Insulin secreting tumor of islet cells (insulinoma) Primary hyperinsulinemic hypoglycemia of infancy

PHHI
Primary islet cell hypertrophy = nesidioblastosis Most common cause of persistent hypoglycemia in infancy Can be sporadic or familial Focal islet cell hyperplasia (30-40%) vs Diffuse hyperplasia

PHHI
Presentation: 65% neonates, 28% infants, 7% childhood 1/3 of neonates will be macrosomic Diagnosed based on clinical and lab findings:
Inappropriately elevated insulin Inappropriately low FFA, ketone bodies Glycemic response to glucagon Decreased IGFBP-1, elevated C-peptide

PHHI: Focal vs. Diffuse

Unable to distinguish clinically Different surgical approaches if medical tx fails Focal lesions can be so small, even MRI, CT, celiac arteriography are limited
Pancreatic arterial calcium stimulation of insulin secretion Percutaneous transhepatic pancreatic venous sampling of insulin

PHHI: Treatment
Goal is to prevent neurologic sequelae Pharmacotherapy
Diazoxide (5-15 mg/kg/d): blocks receptors on beta-cell, inhibits insulin release Octreotide (5-20 mcg/kg/d) Nifedipine (0.5-2 mg/kg/d): no controlled trials More effective in those who present as infants/childhood vs neonates

PPHI: Treatment
Surgical
If pharmacological treatment fails Focal lesions hard to identify Focal resection vs subtotal pancreatectomy

PHHI: Complications
Neurologic sequelae from repeated/prolonged hypoglycemia
Psychomotor retardation Cognitive deficits Seizures

One review of 114 patients:

44% psychomotor or mental retardation 25% epilepsy

Misc Causes of Hypoglycemia

Ketotic hypoglycemia
Children age 18 mos-5yrs, usually remits by age 8-9 yrs Decreased availability or impaired mobilization of muscle AA and other substrates for gluconeogenesis Diagnosis of exclusion

Hormone deficiencies: GH, cortisol

Miscellaneous Causes
Ingestions
Oral hypoglycemics Ethanol: mouthwash Salicylates: hypoglycemia and ketosis Beta-blockers: blunt autonomic response to hypoglycemia Ackee fruit: hypoglycin impairs FA oxidation

Sources
Costanzo, L.S. Physiology. W.B Saunders Company, Philadelphia: 376-381. www.uptodate.com. Sunehag and Haymond. Approach to hypoglycemia in infants and children. www.uptodate.com. Sunehag and Haymond. Etiology of hypoglycemia in infants and children. www.uptodate.com. Sunehag and Haymond. Persistent hyperinsulinemic hypoglycemia of infancy.