Diagnosis & Management of Hypoglycemia in Children

1. azad82d@gmail.com
azad.haleem@uod.ac
Dr.Azad A Haleem AL.Mezori
FRCPCH,DCH, FIBMS
Assistant Professor & Pediatric consultant
Pediatric Endocrinologist
University Of Duhok, College of Medicine
Pediatrics Department
Post Neonatal Hypoglycemia

2. Thank You

3. Introduction
• Glucose is the most commonly used readily available source of energy.
• It, along with ketones and fatty acids provide energy for important pathways.
• Highest energy requirements in the body are of the brain, red blood cells and
muscles.
• Hypoglycemia beyond the neonatal period is rare but indicative of an underlying
disease.
• Timely evaluation is mandatory to achieve good outcome.
glucose Glucose + ketone
Glucose + ketone + fatty acids

4. • Defense against hypoglycemia & Endocrine regulation:
• The immediate defense from hypoglycemia is nutrient intake.
• Liver is the main source of glucose production with endogenous glucose
production rate of 4-6 mg/kg/minute.
• The first metabolically regulated defense against hypoglycemia is glycogenolysis
that converts hepatic and muscle glycogen into glucose; first 6-12 hours of fasting.
• Fasting beyond this period stimulates gluconeogenesis that converts glycerol and
amino acids to glucose to provide glucose for 12-18 hours.
• During the latter part of this period, fatty acid oxidation takes over with the
production of ketones.

5. Effects of hypoglycemia
• Hypoglycemia leads to impaired central nervous system function
(Neurogenic & Neuroglycopenic) symptoms

6. • Hypoglycemia should be considered in a wide variety of clinical settings
including lethargy, seizures, encephalopathy and headache.
• Hypoglycemia is diagnosed by the demonstration of Whipple's triad. This
includes symptoms of hypoglycemia with low blood sugar levels (60
mg/dL, 3.3 mol/L) that improve with dextrose administration.
• Fallacies in glucose measurements
• Glucometer measures whole blood glucose of which levels are generally
15% lower than plasma glucose.
• Glucose levels can be erroneously low in the setting of polycythemia (due
to increased red blood cell consumption of glucose) and stored samples.
Criteria
All sick children

7. • Hypoglycemia is caused by:
• Decreased production (reduced stores, carbohydrate
metabolic defect, counter regulatory hormone deficiency) or
• Increased utilization (hyperinsulinism) of glucose
• Accelerated starvation is the commonest form of
childhood hypoglycemia.
Etiology

8. Glycogen disorders
• Glycogen synthesis disorders- Decreased glycogen synthesis causes prandial
hyperglycemia due to reduced glycogen deposition in liver and fasting
hypoglycemia.
• In contradistinction to other forms of glycogen storage disease hepatomegaly is
absent.
• Glycogen synthase deficiency (GSD 0) presents with ketotic hypoglycemia with
prandial hyperglycemia.
• Glucose transporter 2 (GLUT2) defect result in decreased glucose transfer to
liver along with renal tubular acidosis and rickets (Fanconi Bickel Syndrome).

9. • Glycogenolytic defects- These disorders have normal glycogen synthesis but
impaired release of glucose during hypoglycemia.
• Ketotic hypoglycemia with hepatomegaly is characteristic.
• The severity and clinical pictures are dependent on the site of defect.
• Glucose 6 phosphatase (GSD 1)- Glucose 6 phosphate is the most important
enzyme of the glycogenolytic pathway converting glucose 6 phosphate to glucose.
It is the link point of the major carbohydrate metabolic pathways (glycogenolysis,
gluconeogenesis and galactose metabolism).
• Debrancher deficiency (GSD III)-
• Phosphorylase and phosphorylase kinase deficiency (GSD 6 and 9)
Glycogen disorders

10. Gluconeogenic defects
• Gluconeogenesis- Gluconeogenesis involves production of glucose from non-
carbohydrate sources.
• This occurs at the cost of protein loss resulting in reduced muscle mass and growth
failure.
• Hypoglycemia develops after a fast of 12 hours as glycogenolysis is intact.
• The substrates for gluconeogenesis include protein (alanine), non-glucose
carbohydrate (fructose), lipid (glycerol) and intermediary pathways (lactate and
pyruvate).
• The key enzymes include pyruvate carboxylase, PEP carboxykinase, Fructose 1, 6
bisphosphatase and glucose 6, phosphatase.

11. • Galactosemia
• Galactosemia is caused by deficiency in galactose 1 phosphate uridyl transferase
(GALT) with impaired conversion of galactose1 phosphate to glucose1 phosphate.
• Hereditary fructose intolerance (Aldolase B deficiency)
• Aldolase deficiency is associated with abnormal fructose metabolism and accumulation
of toxic metabolites.
• Presentation is in late infancy with gastrointestinal symptoms after initiation of fructose.
• The condition presents like galactosemia with hepatomegaly, cataract, hypoketotic
hypoglycemia and renal tubular abnormalities.
• Diagnosis is established by demonstration of non-glucose reducing substance and low
aldolase B levels.

12. Fatty acid oxidation
• Fatty acid oxidation is an important factor maintaining glucose levels at advanced
stages of fasting.
• Lipid catabolism results in lipolysis with conversion of triglyceride to free fatty acids
and glycerol.
• Glycerol is taken up by the gluconeogenic pathway to produce glucose while fatty acids
are oxidized to ketones.
• Fatty acid oxidation defects are characterized by decreased ketone production due to
defects of transfer of fatty acids to cells (CPT), carnitine deficiency or fatty acid
oxidation abnormalities.
• Episodic non ketotic hypoglycemia with encephalopathy, myopathy, cardiac failure and
raised transaminases are characteristic.
• The diagnosis is established with acyl carnitine profile.

13. Accelerated starvation
• Accelerated starvation represents maladaptive response to fasting.
• The condition is associated with hypoglycemia at earlier than other children of the
age.
• Physiological response to hypoglycemia is intact.
• Low muscle and adipose mass is common.
• The presentation is of an infant unable to wake up in the morning followed by
seizures.
• This is often associated with an inter-current illness.
• Accelerated starvation is a diagnosis of exclusion.

14. Endocrine regulation of glucose
homeostasis.
• Blood glucose levels are maintained by hypoglycemic (insulin) and hyperglycemic
(growth hormone, glucagon, cortisol and epinephrine) hormones.
• Insulin: Insulin is the most hypoglycemic hormone.
• Action- Insulin acts through the insulin receptor to trigger the anabolic pathway
enhancing glycogen synthesis, protein formation and adipogenesis.
• Hyperinsulinism is an important and severe form of childhood hypoglycemia with
increased glucose requirement and low ketone production.
• The important causes include milder genetic forms (glucokinase defect),
insulinoma, wrong administration.

15. Glucose enters the
beta cell though
GLUT2 receptor and
is phosphorylated by
glucokinase to
glucose 6 phosphate.
increase ATP levels in the beta cell to close
the potassium ATP channel (KATP).
Calcium enter cell
Calcium pushes
the preformed
insulin vesicles
to the
membrane
allowing insulin
release.
Protein metabolism is
linked to insulin
secretion with the
glutamate
dehydrogenase
pathway along with
ammonia production.
Short-chain 3-hydroxyacyl-CoA
dehydrogenase

16. Assessment- History
• History-
• Key points to be assessed on
history include
• Age of onset,
• Relationship of hypoglycemia
with meals and
• Course of disease.
Age at onset
Relation to meal
Clinical course

17. Assessment- Examination
• Examination- Careful examination for pointers of hypoglycemia should be done.
Low weight and muscle mass points to accelerated starvation
GNG, galactosemia or fructose intolerance

18. • Diagnostic work-up- The most important part of work-up is to obtain critical samples
before correction of hypoglycaemia as interpretation is done in the light of blood glucose
levels.
• Urine, plasma and serum samples should be collected and stored.
• Insulin has a short half-life and a labile assay making it difficult to assess.
• C peptide is released in equimolar amount as insulin. It has a longer half-life than insulin
with more stable plasma levels.
• Ketone: The most important test in a neonate with hypoglycemia is measurement of
blood ketone (beta hydroxybutyrate).
• Electrolytes and blood gas, Urine for reducing substance.
• Growth hormone, cortisol, lactate
• Intermediary metabolites (acyl carnitine and organic acids).
• Genetic studies
• DOPA PET scan.
Assessment-Investigations

19. Approach
• Ketotic hypoglycemia-
• The causes of ketotic hypoglycemia
include
• GSD or gluconeogenic defect.
• Hypopituitarism,
• Accelerated starvation.
• Non ketotic Hypoglycemia-
• Key considerations in a neonate with
non ketotic hypoglycemia are
• Hyperinsulinism,
• Accumulation of intermediary
metabolites (fructose intolerance and
galactosemia).
• Fatty acid oxidation defects.

20. Case 1-
GSD I

21. Case 2-
GSD III

22. Case 3-
Accelerated starvation

23. Case 4-

24. Case 5-
FAO Defect

25. Management
• Key aspects of management of hypoglycemia include correction of symptomatic
hypoglycaemia, maintenance of euglycemia, correction of underlying cause.
• Symptomatic hypoglycemia should be managed with a bolus of 200 mg/kg
dextrose (2 ml/kg of 10% dextrose intravenously) followed by dextrose
infusion at a rate of 6 mg/kg/min. The infusion should be tapered after initiation
of specific treatment.
• Specific management
• Specific management is directed by the underlying cause.
• Galactosemia- Neonates with galactosemia require life-long lactose free diet.
• Fructose intolerance must avoid fruits, sweets and even medicines with added
sugar.

26. • Specific management
• Hypopituitarism- Life-long supplementation of cortisol (8-10 mg/m/day) is
required. Growth hormone therapy may be needed in refractory cases.
• Fatty acid oxidation defects - Neonates with fatty acid oxidation defects
should avoid fasting with increased intake during inter-current illnesses.
Specific treatment includes carnitine supplementation (100 mg/kg/day in
three doses), riboflavin (100-200 mg/day once daily) and medium chain
triglycerides.
• Glycogen storage disease- Regular feeds of uncooked cornstarch (1-2
g/kg every four hours) is effective. Overnight nasogastric feeds have
improved the outcome of GSD I with reduction in long term complications.
• Accelerated starvation- Regular feeds and night time protein snacks.
Special care should be taken during intercurrent illness with regular fluid
and glucose intake. Nutritional intervention aims at increasing muscle mass
and includes increased protein intake. The condition is self-limiting and
improves with increase in body weight and substrate levels.

27. • Hyperinsulinism- Hyperinsulinism is a challenging condition with very high
glucose requirements (16-18 mg/kg/minute).
• Treatment options include mediations and surgery.
• Medical treatment-
• KATP channel defects are unlikely to respond to medical therapy but should
be given a trial of treatment.
• The treatment options include potassium channel opener (diazoxide),
calcium channel blocker (nifedipine), inhibitors of insulin release (octreotide)
and insulin antagonist (glucagon)
• Surgery- Surgical treatment is indicated in most neonates with severe
forms of hyperinsulinism and insulinoma.

28. THANKS FOR YOUR
Attention