پروفسور محمد حسین سلطان زاده       استاد دانشگاه علوم پزشکی شهید بهشتی      متخصص کودکان ونوزادان         طی دوره بالینی عفونی از میوکلینیک آمریکا دبیر برگزاری کنفرانس های ماهیانه گروه اطفال  دانشگاه علوم پزشکی شهید بهشتی	معرفی : دکتر شاداب  صالح پور فوق تخصص غدد اطفال به اتفاق اعضای هیئت علمی  گروه کودکان  بیمارستان مفید

تشخیص

Hypoglycemia

Definition of hypoglycemia

<36mg/dl in 2-3hr after birth

<47mg/dl

<40mg/dl on first day

<40-50mg/dl after 24hr

Signs and symptoms

Cyanosis

 respiratory distress

 apnea

 lethargy

 sweating

 hypothermia

 jitteriness

 irritability,

 poor feeding

 seizures,

 tachycardia

 vomiting.

Abnormal crying

Hypotonia

Limpness

Grunting

Blood sampling

Whole blood glucose <plasma glucose(14%)

Whole blood glucose in accordance with Hct

Room temperature :15-20mg/dl/hr

Test strip (more reliable at high glucose concentration 

Causes of hypoglycemia

Transient hypoglycemia

    -Change in maternal metabolism

    -Neonatal problems

Persistent or recurrent hypoglycemia

    -Hyperinsulinism

    -Endocrine disorders

    -Inborn errors of metabolism

Neurohypoglycemia due to defective glucose     transport

PATHOGENESIS

Diminished glucose production

Increased glucose utilization due to hyperinsulinism

Increased glucose utilization without hyperinsulinism

Diminished glucose production

Inadequate glycogen stores (prematurity, IUGR )

Metabolic disorders

Endocrine disorders

Maternal treatment with beta-adrenergic-blocking agents

Hypothermic

Endocrine disorders

Pituitary insufficiency

Cortisol deficiency

Congenital glucagon deficiency

Epinephrine deficiency

Inborn errors of metabolism

         Carbohydrate metabolism:

    -Galactosemia

    -GSD

    -Fructose intolerance 

         Amino acid metabolism:

    -MSUD

    -PPA

    -MMA

    -Tyrosinemia

    -3OH3metyl glutaric aciduria

    -glutaric academia type2

         Fatty acid metabolism:

    -Defect in carnitine metabolism

    -Acyl co dehydrogenage defect 

Increased glucose utilization due to hyperinsulinism

Infant of a diabetic mother

Beckwith-Wiedemann syndrome

Persistent hyperinsulinemic hypoglycemia of infancy

Exogenous insulin

Increased glucose utilization without hyperinsulinism

Decreased tissue perfusion or poor oxygenation

Sepsis

Polycythemia

Heart failure

Perinatal asphyxia

Persistent hypoglycemia

Hypoglycemia is profound

Glucose infusions >8 to 10 mg/kg -min are needed to maintain BS> 45 to 60 mg/dL>1wk

Should be evaluated for rare causes

Laboratory measurement

                Blood:

   (Should be obtained at the time of hypoglycemia hypoglycemia.)

 insulin

 cortisol

ACTH

growth hormone

 thyroxine

 amino acids

                        Urine:

Ketones

 reducing substances

 organic acids

glucose homeostasis

           Fasting state :

1-glycogenolysis in the liver

2-insulin levels fall increased lipolysis creates free fatty acids and glycerol

Differential diagnosis

Defective glycogenolysis: hypoglycemia within a few hours of fasting( low insulin levels )

Disorders of fat metabolism( unavailability of free fatty acids and ketones as alternative fuels : Hypoglycemia occurs after  several hours of fasting ( low insulin levels )

Growth hormone deficiency ,hypocortisolemia: decreased ketogenesis ( low insulin levels ) 

Hypoglycemia associated with elevated insulin

Defects in gluconeogenesis, free fatty acid synthesis, and ketogenesis; growth hormone deficiency; and cortisol deficiency: unlikely

Hypoglycemia +ketonuria :hyperinsulinism less likely. (Ketonuria does not rule out hyperinsulinemia. )

Hyperinsulinism

Persistent hypoglycemia

Inappropriately high concentrations of circulating insulin

Free fatty acids (FFAs) and ketones (ie, beta-hydroxybutyrate, acetoacetate) are low

Primary hyperinsulinism

It is the most common cause of neonatal hypoglycemia persisting beyond the first few hours of life.

 Early diagnosis and treatment are essential to prevent seizures and neurologic sequelae  

Classification of Hyperinsulinism

Transient

Persisten

Transient hyperinsulinism of infancy

Infant of a mother with diabetes

Infant small for gestational age (SGA)

Perinatal stress/asphyxia

Erythroblastosis fetalis

Sepsis

Beckwith-Wiedemann syndrome

Drug-induced hyperinsulinism

Surreptitious insulin administration

Oral hypoglycemic ingestion

Blood transfusion

Umbilical artery catheter placement  

Congenital causes of Hyperinsulinism

Beckwith-Wiedemann syndrome 

Focal causes (30-40%)

Genetic form (AR,AD)

Hyperinsulinism-hyperammonemia syndrome 

Frequency

In the US: 1 in 50,000 live births

Europe: 1 in 30,000 live births

Internationally: Autosomal recessive forms: Saudi Arabia1/2675 live births .

Clinical manifestation

30% :macrosomia

65%:newborn(AR)

28%:infancy

7%:childhood

Dysmorphic features 

Prenatal diagnosis

Amniotic fluid: Ûinsulin, C peptide

Amniotic fluid: glucoseÜ

Lab Studies

insulin > (2)5 mU/mL in serum glucose <60 mg/dL is diagnostic

glucose-to-insulin <3

insulin to glucose>0.4 

Lab Studies

Übeta-hydroxybutyrate (<1 mmol/L)Ü free fatty acids (<1 mmol/L)

Üinsulin-like growth factor binding protein-1 (IGFBP-1 <120 ng/mL). Insulin suppresses secretion of IGFBP-1, which normally is elevated in the fasting or hypoglycemic child

C-peptideÛ( ÜC-peptide +Ûinsulin :surreptitious insulin administration.)

Other Tests

A glycemic response: BS rises (more than 30 mg/dL above the basal level) immediately after administration of 1 mg of glucagon (IM or IV). indicates inappropriately conserved glycogen stores. ( observed in  hyperinsulinism.)

L-leucine stimulates the secretion of insulin  

           Imaging Studies:

Pancreatic ultrasonography, CT scan, MRI) generally are not very useful

Pancreatic angiography and pancreatic angiography and pancreatic venous sampling

Spiral CT scan in adults

Consultations:

Pediatric endocrinologist

Pediatric surgeon

Neonatologist

Geneticist (if family history is present or suspected)

Closest tertiary referral center children's hospital

TREATMENT

Medical Care  

Surgical Care

Medical Care

May require very high glucose infusion rates (20-30 mg/kg/min)

Frequent feedings by gastrostomy

Drug Category

   -Insulin secretion inhibiting agents

  -Dextrose and glucose release stimulators

  -Drugs inhibiting insulin effect

Insulin secretion inhibiting agents

Diazoxide: 5-15 mg/kg/d PO divided q8h

Octreotide (Sandostatin) :5-40 mcg/kg/d SC divided q4-6h or administered as continuous SC infusion; titrate to effect

Nifedipine (Adalat, Procardia): 0.25-0.7 mg/kg/d PO divided q8h

Dextrose and glucose release stimulators

Dextrose

Glucagon( 2-10 mcg/kg/h IV, alternatively, 0.2 mg/kg IV/IM/SC bolus; not to exceed 1 mg/dose )

Drugs inhibiting insulin effect

Hydrocortisone( 25-50 mg/m2/d PO divided q8h )

Growth hormone, human( 0.05-0.06 mg/kg/d SC as single daily injection)

Surgical Care:

Partial pancreatectomy (focal)

 

Near-total pancreatectomy (diffuse) 

        Prognosis:

Severity of the disease at presentation, duration of hypoglycemia

Etiology of hyperinsulinism

Presence of neurologic complications.

 Improving diagnostic techniques make earlier and more appropriate surgical intervention

Near-total pancreatectomy are at risk for developing exocrine pancreatic insufficiency and diabetes mellitus