Hypoglycemia is a potentially devastating metabolic emergency in children. It can cause cognitive impairment, seizures, cerebral palsy, and other neurological issues if severe and prolonged. The document discusses the various causes and classifications of hypoglycemia in infants and children, including transient neonatal hypoglycemia, persistent hypoglycemia due to conditions like hyperinsulinism, counterregulatory hormone deficiencies, and disorders of glycogenolysis and gluconeogenesis. Clinical features and key cases are also presented.

1. HYPOGLYCEMIA
-Sujay Bhirud

2. Hypoglycemia
• One of the major metabolic emergencies at any age
• Has potentially devastating consequences on brain
• Should always be excluded as the cause of initial episode of
convulsions, coma or neurobehavioral alternation in children.
• Incidence: 1-3/1000 live births.

3. Definition
• In Neonates: hypoglycemia is blood glucose value less than
40mg/dl(2.7mmol/L)[Plasma glucose level less than 45mg/dl]
• In infants & older children: a whole blood glucose
concentration less than 55mg/dl
• For children with Severe Acute Malnutrition(SAM), the cut-
off is taken as blood glucose value of less than 54mg/dl
The serum or plasma glucose levels are 12-15% higher than in
whole blood(finger prick collection)

4. Hypoglycemia & Brain damage
• The brain of infant grows most rapidly in 1st year of
life, it uses glucose at a rate of 3-5mg/kg/min which is
equal to almost all endogenous glucose production.
• The glucose is also a source of membrane lipids &
protein synthesis: Provides structural proteins &
myelination important for normal brain maturation.

5. Conditions of severe & sustained hypoglycemia
Cerebral structural substrates are degraded
Energy usable intermediates: lactate, pyruvate,
aminoacids, ketoacids
Supports brain metabolism
At the expense of brain growth

6. Major long term sequelae of severe
prolonged hypoglycemia
• Cognitive impairment
• Recurrent seizure activity
• Cerebral palsy
• Autonomic dysregulation
• Subtle effects on personality

7. Glucose homeostasis
• Plasma glucose concentration is normally maintained within a narrow
range by complex interaction between Insulin & Counter-regulatory
hormones
• Hypoglycemia indicates failure of this homeostatic mechanisms
The physiologic process of glucose homeostasis is governed by:
• Endocrine factors
• Autonomic neuronal factors
• Substrate availability
• Fat & protein metabolism
Efficiency of this regulatory control is related to
• Chronologic age
• Recent feed
• Food intake

8. As blood glucose level tends to decrease
Insulin secretion decreases
Counter regulatory hormones: Glucagon, Catecholamines, Growth hormones,
glucocorticoids, Thyroid hormones, ACTH come into action
In cases of hypoglycemia
• Inhibition of insulin (1st line of defence)
• Increase realease of glucagon (2nd line of defense)
• Realease of catecholamines , anteriour pituitary hormones, ACTH.(3rd line of
defence)
Thyroid hormones and growth hormones are not essential for maintanance of
blood glucose concetration but have an impact on carbohydrate metabolism

9. • Glucose homeostasis is maintained by glycogenolysis in the
immediate post feeding period and by gluconeogenesis several
hours after meals.
• Hepatic glycogen stores are sufficient to maintain plasma glucose
for approx. 8 hours

10. OVERVIEW
Blood
Glucose
(60mg-
100mg/dl)
Gluconeogenesis
DIET
Hepatic
glycogenolysis
Peripheral uptake
Utilization
GLUCOSE
OBTAINED
FROM OTHER
CARBOHYDRATES
Glycolysis
lipogenesis
Glycogenesis
Uronic acid
pathway
HMP pathway
Urine(glycosuria)
Other sugars

11. In Newborn
• Under non-stressed condition almost all fetal glucose is derived
from the maternal circulation by transplacental facilitated
diffusion that maintains fetal glucose at two-third of maternal
levels.
• At birth the acute interruption of maternal glucose transfer to
fetus imposes an immediate need to mobilize endogenous glucose.
• During this transition, newborn glucose levels fall to nadir in the
first 1-2 hrs of life, then increase & stabilize at mean levels of 65-
70 mg/dl by the age of 3 to 4 hours.

12. •Three related events facilitates this transition:
changes in hormones
changes in their receptors
changes in key enzymatic activity

13. Changes in hormones
• Glucagon increases abruptly within minutes to hours after
birth.
• Insulin level falls initially & remains in the basal range for
several days without response to physiologic stimuli like
glucose.
• Surge in Catecholamine secretion
• GH secretion which is elevated at birth is augmented by
epinephrine.
Results in glycogenolysis, gluconeogenesis, lipolysis &
ketogenesis stabilizes glucose level.

14. Adaptive changes in hormone receptors occurs.
Changes in enzymes:
• Rapid fall in glycogen synthase activity
• Rise in phosphorylase activity
• Rise in RLE of gluconeogenesis phosphooenolpyruvate
carboxykinase

15. Neonatal hypoglycemia
• During fetal life glucose, aminoacids & lactate are the principal
energy substrates.
• Insulin is the predominant anabolic hormone causing deposition of
glycogen in liver, muscle & brain.
• After birth,
fetal life with constant supply of glucose from mother
extrauterine life of intermittent supply with
feeding

16. • There occurs shift from glycogen formation to
breakdown & switch from fatty acid synthesis to FAO
triggered generation of ketone bodies.
• The immaturity cAMP generating system of B cells may
extend into newborn period resulting in limited ability to
alter insulin secretion in response to glucose.
• This transitional hypoglycemia in the first few hrs of life
signifies a period of metabolic adjustments.

17. Hormonal control on Blood Glucose
Insulin Glucagon Catecholamines Glucocorticoids Growth
hormone
Thyroid
hormones
Absorbtion of
glucose
Peripheral uptake
Glycolysis
Gluconeogenesis
glycogenesis
Glucogenolysis
Lipogenesis
Lipolysis
Protein catabolism
Net effect on
blood glucose

18. Tug of war between Insulin & other hormones
glucagon
glucocorticoids
G.H
Thyroid
hormones
epinephrine
catecholamine
s

19. Glucose 6
phosphate
SUR1
Sulfonylureas
KATP channel
GLUT2
Insulin
Independen
Voltage
Dependent
Ca channel
Insulin
Kir6.2
Glucokinase
Increased ATP
Decreased ADP
Increased
intracellular
Ca
Kir6.2
Membrane
depolarization
Kir6.2
Beta cell of pancreas
Glucose
metabolism
K+
Ca

20. Clinical Features
• Mostly nonspecific.
• Symptoms in 2 categories:
• The glycemic threshold for activation for activation of glucose
counter-regulation is higher in children as compared to adults,
while the threshold for initiation of symptoms is lower.
Due to Activation of ANS & epinephrine release
Seen with rapid decline in blood glucose level
Due to Decreased cerebral glucose utilization
Seen with slow decline in glucose level or
prolonged hypoglycemia

21. Features due to Activation of ANS
•Anxiety
•Perspiration
•Palpitation
•Pallor
•Tremulousness
•Weakness
•Hunger
•Nausea
•Emesis
Adrenergic symptoms are not prominent in newborns & infants

22. Features due to Cerebral Glucopenia
• Headache
• Mental confusion
• Visual disturbances
(decreased acuity, diplopia)
• Organic personality changes
• Inability to concentrate
• Dysarthria
• Paresthesias
• Dizziness
• Amnesia
• Lethargy, Somnolence
• Seizures
• Coma
• Stroke
• Decerebrate or Decorticate
posture

23. Symptoms in newborns
• Jitteriness/ tremors
• Apathy
• Episodes of cyanosis
• Convulsions
• Apneic spells
• Shrill cry
• Lethargy
• Poor feeding
• Eye rolling
• Episodes of sweating
• Sudden pallor
• Hypothermia
In approx. of frequency

24. Case 1
• 1.5 months, male, born of non consanguineous marriage, 1st by birth
order, BW 2.9kg
• h/o:•Yellowish discoloration of eyes and skin since 3days.
• Abdominal distension with increased frequency of stools since 2days.
• Fever since 1day
• GENERAL EXAMINATION:
Drowsy, afebrile; HR=124/min, pulses well felt; RR=58/min,
subcostal retractions+; SPO2=98 on room air BP= 74/46 mmHg,
Icterus+++, Pallor+,

25. • Liver 2cm, spleen 3cm, Ascitis +
• Drowsy, tone, reflexes normal
• Hypoglycemia noted RBS 30mg/dl.
• I.V glucose infusion started, management of fulminant
liver failure started
• Next day sensorium deteriorated with worsening LFTs,
Hypoglycemia persisted inspite of increasing glucose
infusion
• CRP: Negative, Blood Cultures: negative.
• TORCH Titres : Negative

26. Workup for IEM:
• Urine Thin Layer Chromatography: Galactose+,
• Total Galactose level: High,
• GALT Enzyme level: Low

27. Case: 2
•A 28 day old phenotypic female infant was
admitted for poor weight gain and lethargy.
•FT BW 3250 gm, length 51 cm, HC 34 cm
•Lethargic, depressed fontanele.
•mild dehydration and decreased skin turgor.
•mild hyperpigmentation, including oral cavity.
•External genitalia seemed normal female type with
no ambiguity.

28. • Her body weight, length & HC were 2900, 51 cm and
33.5 cm, all < 5th centiles.
• T: 37.1°C. BP 60/40 mmHg, RR 39/min, PR 112/min
• Patient hydrated with normal saline
• Laboratory findings
• S. Na 129 meq/lit, S. K 6.1 meq/lit
• RBS: 45 mg/dl; BUN: 73 mg/dl; s. creatinine, 0.5
mg/dL; CRP: negative;
• Blood culture: negative.

29. •ABG: pH: 7.3 HCO3=11.9 mmol/L, PCO2= 35 mmHg
s/o metabolic acidosis.
•Hormonal assay: Cortisol: 0.2 μg/dl, ACTH: >1000
pg/ml, 17 OHP: 0.3 ng/ml.
•USG: revealed small hypoplastic uterus (6X7X3
ml) & atretic ovaries and adrenal glands had
normal sizes

30. • Classification of Hypoglycemia
in Infants and Children

31. A.NEONATAL TRANSITIONAL (ADAPTIVE)
HYPOGLYCEMIA
• Associated with Inadequate
Substrate or Immature
Enzyme Function in
Otherwise Normal Neonates
1. Prematurity
2. Small for gestational age
3. Normal newborn
• Transient Neonatal
Hyperinsulinism
1. Infant of diabetic mother
2. Small for gestational age
3. Discordant twin
4. Birth asphyxia
5. Infant of toxemic mother

32. B. NEONATAL, INFANTILE, OR CHILDHOOD
PERSISTENT HYPOGLYCEMIAS
1. Hyperinsulinism
• Recessive KATP channel HI
• Recessive HADH (hydroxyl acyl-CoA dehydrogenase) mutation HI
• Recessive UCP2 (mitochondrial uncoupling protein 2) mutation HI
• Focal KATP channel HI
• Dominant KATP channel HI
• Atypical congenital hyperinsulinemia (no mutations in ABCC8 or
KCN11 genes)
• Dominant glucokinase HI
• Dominant glutamate dehydrogenase HI
(hyperinsulinism/hyperammonemia syndrome)

33. • Dominant mutations in HNF-4A and HNF-1A (hepatic
nuclear factors 4α and 1α) HI with monogenic diabetes
of youth later in life
• Dominant mutation in SLC16A1(the pyruvate
transporter)— exercise-induced hypoglycemia
• Acquired islet adenoma
• Beckwith-Wiedemann syndrome
• Insulin administration (Munchausen syndrome by proxy)
• Oral sulfonylurea drugs
• Congenital disorders of glycosylation

34. 2. Counterregulatory Hormone Deficiency
• Panhypopituitarism
• Isolated growth hormone deficiency
• Adrenocorticotropic hormone deficiency
• Addison disease
• Epinephrine deficiency

35. 3. Glycogenolysis and Gluconeogenesis Disorders
• Glucose-6-phosphatase deficiency (GSD 1a)
• Glucose-6-phosphate translocase deficiency (GSD 1b)
• Amylo-1,6-glucosidase (debranching enzyme) deficiency (GSD3)
• Liver phosphorylase deficiency (GSD 6)
• Phosphorylase kinase deficiency (GSD 9)
• Glycogen synthetase deficiency (GSD 0)
• Fructose-1,6-diphosphatase deficiency
• Pyruvate carboxylase deficiency
• Galactosemia
• Hereditary fructose intolerance

36. 4. Lipolysis Disorders or Fatty Acid Oxidation
Disorders
• Carnitine transporter deficiency (primary carnitine
deficiency)
• Carnitine palmitoyltransferase-1 deficiency
• Carnitine translocase deficiency
• Carnitine palmitoyltransferase-2 deficiency
• Secondary carnitine deficiencies
• Very-long-, long-, medium-, short-chain acyl-CoA
dehydrogenase deficiency

37. C. OTHER ETIOLOGIES
1. Substrate-Limited
• Ketotic hypoglycemia
• Poisoning—drugs
• Salicylates
• Alcohol
• Oral hypoglycemic agents
• Insulin
• Propranolol
• Pentamidine
• Quinine
• Disopyramide
• Ackee fruit (unripe)—hypoglycin
• Vacor (rat poison)
• Trimethoprim-sulfamethoxazole (with
renal failure)
2. Liver Disease
• Reye syndrome
• Hepatitis
• Cirrhosis

38. D. AMINO ACID AND ORGANIC ACID
DISORDERS
• Maple syrup urine disease
• Propionic acidemia
• Methylmalonic acidemia
• Tyrosinosis
• Glutaric aciduria
• 3-Hydroxy-3-methylglutaric aciduria

39. E. SYSTEMIC DISORDERS
• Sepsis
• Heart failure
• Malnutrition
• Malabsorption
• Antiinsulin receptor
antibodies
• Antiinsulin antibodies
• Neonatal hyperviscosity
• Renal failure
• Diarrhea
• Burns
• Shock
• Postsurgical
• Pseudohypoglycemia
(leukocytosis, polycythemia)
• Nissen fundoplication
(dumping syndrome)
• Falciparum malaria

40. Transient Neonatal Hypoglycemia
Transitional hypoglycemia:
• Refers to problems of glucose homeostatic mechanisms
in AGA infants adapting from intrauterine to
extrauterine life.
• Incidence: upto 30% of AGA babies.
• Occurs on 1st day of life, usually in first 12 hrs
• Resolves in next 12 hrs
• Managed by frequent feeding.
• Hypoglycemia occurring beyond 1st day of life is not
normal for AGA infants & needs appropriate
management.

41. Transient hypoglycemia of infancy:
• Subnormal blood glucose persists beyond 24 hrs of life.
• Most commonly seen in preterm infants who tend to have low
glycogen & fat reserve and delay in maturity of enzymes.
• Frequent feeds are essential.
• Also seen in infants of diabetic mothers.
• They have charactristic fat & plethoric appearance.
• resolves in 2-3 days.
• Transient perinatal stress hyperinsulinism: seen in IUGR
babies, mother with toxemia, perinatal asphyxia.
• Hypoglycemia persists beyond 3-4 days of life may upto 6
months
• T/t: Diazoxide 10-115mg/kg/day & frequent feeds

42. Hyperinsulinism
• Most common cause of persistent hypoglycemia in early
infancy.
• Onset of symptoms is from birth to 18 mo of age
• Macrosomic at birth, reflecting the anabolic effects of
insulin in utero.
• Increasing appetite & demands for feeding, wilting
spells, jitteriness, and frank seizures are the most
common presenting features.

43. Clues to suspect hyperinsulinism:
• Rapid development of fasting hypoglycemia within 4-8 hr of
food deprivation
• Need for high rates of glucose infusion to prevent
hypoglycemia, >10-15 mg/kg/min
• Absence of ketonemia or acidosis
• Elevated C-peptide or proinsulin levels at the time of
hypoglycemia
• The insulin (μU/mL):glucose (mg/dL) ratio is commonly >0.4
• Low levels of plasma insulin-like growth factor binding
protein-1 (IGFBP-1), β OH butyrate, and FFA

44. Criteria for Diagnosing Hyperinsulinism
Based on “Critical” Samples
1. Hyperinsulinemia (plasma insulin >2 μU/mL)
2. Hypofatty acidemia (plasma free fatty acids <1.5 mmol/L)
3. Hypoketonemia (plasma β-hydroxybutyrate: <2.0 mmol/L)
4. Inappropriate glycemic response to glucagon, 1 mg IV
(change in glucose >40 mg/dL)
Sample drawn at a time of Fasting Hypoglycemia: Plasma
glucose <50 mg/dL)

45. D/d of endogenous hyperinsulinism:
Diffuse β-cell hyperplasia or
Focal β-cell microadenoma.
• The former, if unresponsive to medical therapy, requires
near total pancreatectomy.
• Some may respond to sirolimus.
• Positron emission tomography using 18-fluoro-ldopa.
distinguish these 2 entities with an extremely high
degree of reliability, success, specificity, and sensitivity

46. PERSISTANT HYPERINSULINEMIC
HYPOGLYCEMIA IN INFANCY
• Nesidioblastosis
• Islet Cell Dysmaturation Syndrome(ICDS)
• Focal or Multiple Islet cell adenomatosis
• Most common & severe form of persistant hypoglycemia
• 2 major forms: Focal & Diffuse
• 4 genetic defects: SUR-1, Kir6.2, Glud-1,GK
• Most common form is caused by loss of function mutation in
two genes: SUR-1, Kir6.2

47. • AR form is most common
• Age of onset is variable: few hrs to few months
• Majority of infants are macrosomic at birth.
• Causes severe hypoglycemia
• Commonest presentation: recurrent generalized seizures.
• Somatostatin partially effective.
• Probability of devastating consequences causing severe brain
damage is high.

48. • Therapeutic approach to PHHI
IV D10 bolus 2ml/kg(0.2g/kg)
Infusion of D10 > 8mg/kg/min
If uncorrected in 15 min
Repeat bolus 2-5 ml/kg D10
D10 infusion can be increased 10-30mg/kg/min

49. • Glucagon (30μg/kg Ivor IM) only as an emergency measure.
• Hydrocortisone 5-10mg/kg in 3 divided doses.
• Trial of Diazoxide after confirmation of diagnosis 10-20
mg/kg/day in 3 divided doses.
• If no response add inj. Octrotide 5μg/kg every 6 hrly SC max
upto 40μg/kg/day.
• If no success then Pancreatectomy.

50. Case 3
• A female pt born of consanguineous marriage
• Wt & ht at birth were 1,590 g and 39.5 cm.
• presented at 1st week of life with respiratory distress,
physiologic jaundice, and hypoglycemia.
• latter was controlled with iv of glucose at 6 mg/kg/min.
• Discharged weighing 1,860 g.
• remained stable for 2 months.

51. • At 3.5 months of age patient
presented with 2-day history of
apathy & tonic-clonic seizures
with RBS of 16 mg/dl.
• Wt & ht 3,880 g and 49 cm,
both below the 3rd percentile
• IV glucose starting at 6
mg/kg/min increased upto 12.
• Hypoglycemia and seizures,
however, were still observed.
Lab results
TSH - 5.43 m UI/ml (nl)
T4 - 13.6 m g/dl (nl)
Growth hormone (GH) - 13 ng/ml
Cortisol - 278.3 ng/ml (nl)

52. • Glucagon infusion test: indicated baseline glycemia of 5
mg/dl with concomitant insulinemia of 39.5 mU/ml. The
insulin to glucose ratio was 8:1 characterizing
hyperinsulinism.*
• Pt was administered growth hormone subcutaneously at
2 U per day.
• less frequent seizures with hypoglycemia still persisted.
• Diazoxide at 10 mg/kg/day
• Prednisone at 1 mg/kg/day
• Discharged on fractionated hypercaloric diet,
prednisone and phenobarbital at 5 mg/kg/day.

53. Ketotic Hypoglycemia
• Most common form of childhood hypoglycemia.
• Presents between the ages of 18 mo & 5 yr
• Remits spontaneously by the age of 8-9 yr.
• Represents abnormally shortened fasting tolerance.
• Hypoglycemic episodes typically occur during periods of
intercurrent illness when food intake is limited.
• At the time of documented hypoglycemia, there is associated
ketonuria, ketonemia & elevated FFA.
• Blood alanine level is low & is diagnostic.

54. • Child appear lethargic, drowsy, dehydrated but seizures & coma
are uncommon
• The levels of counteregulatory hormones are appropriately
elevated, and insulin conc. are appropriately low, ≤5-10 μU/mL
• Plasma alanine concentrations are markedly reduced after an
overnight fast and decline even further with prolonged fasting.
• Alanine is the only amino acid that is significantly lower in these
children
• Infusions of alanine (250 mg/kg) produce a rapid rise in plasma
glucose

55. Etiology: Defect in any of the complex steps
-Oxidative deamination of amino acids
-Transamination
-Alanine synthesis
-Alanine efflux from muscle.
-Immaturity of ANS may have a role.
• Pt is smaller than age-matched controls
• History of transient neonatal hypoglycemia
• Spontaneous remission is explained by the increase in muscle
bulk with its resultant increase in supply of endogenous
substrate and the relative decrease in glucose requirement per
unit of body mass with increasing age.

56. • Treatment: frequent feedings of a high protein, high-
carbohydrate diet.
• During intercurrent illnesses, parents should be taught to test
urine for ketones(precedes hypoglycemia by several hours)
• In the presence of ketonuria, liquids of high carbohydrate
content should be given.
• If not tolerated, the child should be treated with intravenous
glucose administration.
• Short course of steroids can be tried.

57. Approach to a Case of Hypoglycemia
• Careful elicitation of clinical History
• Physical examination
• Critical sampling
• Investigations

58. History
• Age & Gender of patient
• Relations of symptoms to time & type of food intake.
• Nature of symptoms whether singular or recurrent.
• h/o caloric deprivation
• Family h/o hypoglycemia in infants or sudden
unexplained neonatal or infant death
• h/o in newborns antenatal, natal & immediate postnatal
history, h/o maternal diabetes

59. • Deliberate or accidental ingestion of drugs like sulfonylurea
or related compounds
• h/o anticonvulsant drugs- Valproate
• H/o parental consanguinity.
• Frequent infections: GSD Ib due to neutropenia.

60. Physical examination
• Macrosomia or IUGR baby
• Plethoric appearance
• Infants, if awake, may be irritable, tremulous, and cranky.
• Inappropriate affect and mood, lethargy, seizure, or coma.
• Cataract: Galactosemia
• Decreased subcutaneous fat: inadequate glucose stores.
• Liver size: Glycogen-storage diseases.
• Hematologic manifestations: Organic acidurias

61. •Periorificeal eczematous vesiculobullous eruption:
Propioonic acidurea, methylmalonic aciduria
•Characteristic odour:
-Sweaty feet: isovaleric aciduria & glutaric
aciduria
-Maple syrup: MSUD
-Boiled cabbage or Fishy: Tyrosinemia Type I
•Poor linear growth: GH deficiency

62. •Hyperpigmentation of skin & mucosa: Adrenal
failure.
•Genital ambiguity in females: CAH
•Midline facial and cranial abnormalities: Pituitary
hormone deficiencies, as does micropenis in a male.
•Hypotonia: Urea cycle defect, MSUD, Organic
acidurias
•Myopathy: FAO, GSD I, III

63. Critical samples
Biochemical tests:
Blood sugar
CBC
Electrolytes
Blood gases
Urine
• pH
• Ketones
• Reducing substances
• Organic acids
• Carnitine derivatives
• Dicarboxylic acid
• Glycemic conjugates

64. Hormones & Metabolites
sample
Insulin < 2μU/ml
C-peptide
Cortisol >20μg/dl
GH >7-10ng/ml
Lactate <2.5mmol/L
Pyruvate
Ammonia <35mmol/l
FFA >1.5mmol/L
B-hydroxybutyrate >2mmol/L
Alanine
Acylcarnitine

65. • If a blood sample during spontaneous hypoglycemia is not
available, fasting study is planned depending on age & suspected
diagnosis; while monitoring blood sugar
• When blood glucose drops below 40mg/dl blood should be
collected.
• Specific loading & challenge tests with Galactose or glycerol
done in the past are not recommended

66. Temporal relation of hypoglycemia
• Within 1-2 hrs of feeding: IEM
• After 10-12 hrs after meal: impaired gluconeogenesis due to
substrate deficiency or ketotic hypoglycemia
• After introduction of lactose: Galactosemia
• After introduction of proteins & weaning diet: (MSUD,
Organic acidureas, urea cycle defect)

67. HYPOGLYCEMIA
Ketosis +
Acidosis -
Ketosis -
Acidosis + Acidosis -Acidosis +
Lactate Lactate N Lactate
Negative Positive
Urine for reducing substance-Ketotic hypoglycemia
(Accelerated
starvation)
-Fasting/ Starving
-Catabolic state
-Ketogenic diet
-Adrenal insufficiency
-GSD I, GSD II,
-FDP def
-PC, PEPCK def
-Respiratory
chain disorder
-Normal neonate
-GSD III, IV,IX
-GLUT-2 defect
-Urea cycle
defect
-Organic acidurea
-MSUD
-Ketolysis defect
-FAO defect
-HMG CoA
Synthase
defect
-Hyperinsulinism
-FAO defect
-Fructosemia
Galactosemia

68. Case: 4
•2½-year-old male child born of consanguineous
marriage
•C/o: progressive abdominal distension,
hepatomegaly and failure to thrive
•h/o 2-3 attacks of afebrile seizures during 1st yr
•CT scan and EEG were normal and phenobarbitone
started.
•O/e: round face, his weight was 11 kg and height
was 80 cm, both <3rd centile.

69. • Liver:15 cm; spleen of 4 cm, no ascites.
• Lab tests:
- CBC: normal,
- total protein: 7 g/dl, s. albumin: 4.4 g/dl, ALP: 335 U/L,
- s. bilirubin 2 mg/dl, SGOT 587 U/L, SGPT 361 U/L
- Fasting blood sugar: 29 mg/dl, PPBS: 108 mg/dl,
- s. cholesterol 495 mg/dl, s. triglyceride 372 mg/dl,
- blood pyruvate 3.8 mg/dl, blood lactate 1 mM.

70. • Glucagon challenge test after overnight fast:
- FBS–39 mg/dl; 30 min–36 mg/dl and 60 min–41 mg/dl.
- After meals, blood sugar was 84 mg/dl and 1 hour after
glucagon administration blood sugar increased to 104
mg/dl
• Liver histology with H&E stain showed hepatocytes
with vacuolated cytoplasm and central nuclei.
• Hormonal assay: deficiency of amylo-1-6 glucosidase
activity in the leukocytes.

71. Case 5:
•A yr old male child with c/o unexplained weight loss
& fatigue since last 6months.
-h/o convulsions & syncope 4 months back with
documented hypoglycemia, for which he was
admitted & treated.
-h/o elder brother having repeated episodes of
convulsion & died at age of 3 yrs.

72. -O/e : vital parameters normal, motor & mental
development normal.
-Hyperpigmentation on all over body.
•Ix: hemogram – normal
•Hypoglycemia +
•Low sodium, normal potassium & calcium.
•Urine negative for sugar & ketones.

73. Clinical & Biochemical Features
of
Inborn Error of Metabolism

74. GSD1a Von Gierke’s Disease:
- Glucose 6 phosphate deficiency
- Onset: Early neonatal to 3-4 months
- FTT, growth retardation, doll’s facies, earlt morning hypoglycemia,
hepatomegaly, xanthomas, recurrent diarrhea.
- hypoglycemia with short fasting, Poor response to glucagon, Lactic
acidosis, hyperuricemia, hyperlipidemia, Normal liver function,
platelet aggregation & adhesion defect.
GSD1b:
- G-6 phosphatase tranlocase deficiency
- All the above features plus
- Neutropenia, recurrent infections, Inflammatory bowel disease

75. GSD III Cori’s or Forbes disease:
-Onset: Infancy to childhood
-Debrancher enzyme deficiency
-Hepatomegaly, short stature, skeletal myopathy,
cardiomyopathy, splenomegaly+/-
-hypoglycemia with short fasting, ketosis, normal
lactate & uric acid, hyperlipidemia, abnormal liver
enzymes.
-glycemic response to Glucagon giver 2 hrs post
carbohydrate meal.

76. •GSD IV Anderson’ Disease:
- Branching enzyme deficiency.
- Onset: First few months of life
- Hepato-splenomegaly, progressive liver cirrhosis, ascites, portal
HT.
- Abnormal glycogen on liver biopsy.
•GSD VI Hers disease:
-Liver phosphorylase deficiency
-Onset: early childhood.
-Hepatomegaly, short stature
-Mild hypoglycemia & hyperlipidemia, ketosis, Normal uric avid &
lactate

77. • GSD IX Phosphorylase kinase deficiency:
- Onset: Early childhood
- Short stature, hepatomegaly
- Mild hypoglycemia with ketosis, raised cholesterol, abnormal liver
enzymes, normal response to glucagon
• GSD XII Fanconi- Bickel Syndrome:
- GLUT 2 defect
- Onset: First year of life
- FTT, short stature, rickets, hepato-Renomegaly, Proximal RTA
- Mild fasting hypoglycemia, normal lactate & liver enzymes, abnormal
bone markers, glycosuria, bicarbonate wasting, phosphaturia,
aminoaciduria

78. •GSD 0:
-Misnomer as glycogen is not stored.
-Glycogen synthase deficiency.
-Onset: Early infancy.
-Early morning drowsiness, seizures, NO
HEPATOMEGALY
-Post feed hypoglycemia, hyperlactic acidemia,
fasting hypoglycemia with poor response to glucagon

79. •Galactosemia:
-Galactose-1-phosphate uridyl transferase(GALT)
- Onset: Neonatal period
- Poor feeding, vomiting, FTT, jaundice,
hepatomegaly, prolonged bleeding, hemolytic
anemia, RTA, cataract, E.coli sepsis
-Hypoglycemia, urine for reducing substances
positive, Qualitative & quantitative estimation of
GALT activity.

80. •Fructosemia:
- Fructose-1-phosphate aldolase B def.
-Onset: introduction of fructose in diet.
-Poor feeding, vomiting, FTT, hepatomegaly,
liver failure, RTA
-Hypoglycemia post ingestion of fructose in
diet

81. •Tyrosinemia type I: (Hepato- renal tyrosinemia)
-Fumaryl acetoacetate hydrolase(FAH):
-Onset: newborn to infancy
-Acute presentation: Hepatic crisis- jaundice, ascites,
hepatomegaly, boiled cabbage odour,
Neuronal crisis: convulsion, hypertonia, peripheral
neuropathy
- Increased plasma tyrosine, methionine

82. •Fructose 1-6 diphosphate deficiency:
- Onset: few days to few months
- Hyperventilation, apnoea, irritability, coma, moderate
hepatomegaly, hypotonia, FTT
- Hypoglycemia, increased ketones, lactate, uric acid, normal liver
funtions
-MSUD:
- Onset: first week
- Hypoglycemia, hypertonia, hypotonia, convulsions, coma,
vomiting, lethargy.

83. •Medium chain acyl CoA deficiency(MCAD):
- Onset 2-3 yrs
- Vomiting lethargy, seizures, cardiorespiratory collapse, hepatomegaly,
Reye’s-like illness
- Hypoketotic hypoglycemia, abnormal liver enzymes, prolonged PT,
raised urinary dicarboxylic acids, secondary carnitine deficiency
•Long chain acyl CoA deficiency(LCAD):
- Onset: newborn
- Muscle weakness, rhabdomyolysis, cardiomyopathy, arrhythmia,
sudden death
- Hypoketotic hypoglycemia, dicarboxylic aciduria, abnormal acyl
carnitine profile

84. Indication for routine blood glucose screening
1. infants <2000gms
2. Infants <= 35wks
3. small for gestational age infants: birth weight <10th percentile
4. Infants of diabetic mother
5. Large for gestational age infants: birth weight >90th Percentile
6. Infants with Rh-hemolytic disease
7. Infants born to mothers receiving terbutaline/ propranolol/ labetalol/OHA
8. Infants with morphological IUGR
9. Any sick neonate e.g. those with perinatal asphyxia, polycythemia, sepsis, shock.
10.Infants on parenteral nutrition

85. Management of Asymptomatic Hypoglycemia
• BGL 20-40mg/dl : Trial of oral feeds (EBM or Formula) & repeat
after 1 hr.
1. If repeat BGL is >40 mg/dl, two hrly feeds are
ensured with 6 hrly monitoring of BGL for 48 hrs.
2. If repeat blood sugar is <40mg/dl, IV dextrose is
started & further manage as symptomatic hypoglycemia.
• BGL < 20mg/dl : Start IV dextrose (6mg/kg/dl) & further manage
as symptomatic hypoglycemia.

86. Management of Symptomatic Hypoglycemia

87. Hypoglycemia BGL <40 mg/dl
Asymptomatic
20-<40 mg/dl <20 mg/dl
Trial of oral feeds
Monitor the BGL
After 1 hour
>40 mg/dl <40 mg/dl
Frequent feeding
Monitor BGL
Before discharge ,ensure
That there is no feeding difficulty
Stop after 48 hour
Symptomatic including seizure
Bolus of 2ml/kg of
10 ml glucose
IV glucose infusion@6ml/kg/min.
monitor hourly till euglycemic then 6 hourly
BGL>50 mg/dl
BGL <50mg/dl
Stable for 24 hours on
IV fluids;2 values of
BGL >50 mg/dl
increase glucose till
2mg/kg/min till euglycemic
Weaning @2mg/kg/min every
6 hrs; increase oral feeds 6 hrly
monitor
Stop IV fluid when rate is
4g/kg/min and infant is stable
Refer to specialist centre
for further investigation
Stop monitoring when 2 values are
more than 50 on full oral feed
Hydrocortisone Diazoxide (not
in SGA) Glucagone(not in SGA)
Octreotide
Increase till the glucose
infusion rate is 12mg/kg/min

88. Recurrent/ Resistant Hypoglycemia
• Consider when – recurrent episodes of hypoglycemia
- if fails to maintain normal BGL despite a
GIR of 12mg/kg/min
- requires IV glucose greater than 7 days.
• Causes: congenital hypopituitarism
Adrenal isufficiency
Hyperinsulinemic states
Galactosemia
Glycogen storage diseases
MSUD
Mitochondrial disorders
Fatty acid oxidation defects

89. Management
• Central venous catheter is necessary to give glucose greater than
12mg/kg/dl.
Hydrocortisone : ( 5mg/kg/day iv in 2 divided doses)
• Indication: as an acute treatment hypoglycemia when GIR
requirement is > 12 mg/kg/min.
• MOA: it reduces peripheral glucose utilization, increases
gluconeogenesis, increases the effect of glucagon.
•The hydrocortisone will usually result in stable and adequate glucose
levels, and it can then be rapidly tapered over the course of a few
days.
•Before administering hydrocortisone, obtain a blood sample for
measurements of glucose, insulin, and cortisol levels at a time when the
serum sugar is low.

90. Diazoxide:
•(5-8 mg/kg/day divided in two to three doses)
•Indication: infants who are persistently
hyperinsulinemic.
•It inhibits inulin release by acting as a ATP
sensitive K+ channel agonist in beta cells.
•It can take up to 5 days for its effects to be seen.
•Infants are more responsive than neonates.

91. Octreotride :
• ( 5-20 mcg/kg/day S.C or I.V. in 3 to 4 divided
doses)
• Indication: failure to respond to adequate treatment
with diazoxide.
• It’s a long acting somatostatin analog & inhibits
insulin secretion.
• Tachyphylaxis can develop.

92. •Glucagon :
• (0.025 to 0.2 mg/kg I.M, S.C, I.V max 1 mg)
• Acts by mobilizing hepatic glycogen stores , enhancing
gluconeogenesis & promoting ketoneogenesis.
• Given to a hypoglycemic infant with good glycogen stores
as a temporary measure.
• Used in combination with octreotride when there is no
response or incomplete response to octreotide alone.
•For infants of diabetic mothers, the dose is 0.3 mg/kg
(maximum dose is 1 mg)
• Diazoxide & glucagon should not be given SGA babies.

93. Schedule for blood glucose monitoring
CATEGORY OF INFANTS TIME SCHEDULE
At risk neonates 2,6,12,24,48 and 72hrs
Sick Infants
(infants with sepsis, asphyxia, shock)
Every 6-8hrs (individualize as needed)
Stable VLBW infants on parenteral
nutrition
Initial 72hrs:every 6-8hrs
After 72hrs:once a day

94. How to calculate desired GIR
• Formula for preparing 50ml of fluid with desired conc. of
glucose using D5/Isolyte P & D25.
X = desired GIR(in mg/kg/min) X 144
Rate of I.V. fluid(in ml/kg/day)
(25-X)
(25-5*)
* Amount of glucose in the IVF.
Amount of D25 = 50- 50

95. Follow-up & Outcome
• Factors determining outcome:
- degree & duration of hypoglycemia,
- rate of cerebral blood flow,
- cerebral utilization of blood glucose,
- co-morbidities.
• F/U at 1 month corrected age for vision.
• F/U at 3,6,9,12,&18 months corrected age for growth,
neurodevelopment, vision, hearing loss.

96. TAKE HOME MESSAGE

97. • On 1st day of life:
Transitional hypoglycemia.
- Early: LGA babies
- Secondary: AGA babaies
- Classical: SGA babies
Hypoglycemia is an emergency.
Persistent neonatal hypoglycemia:
doesn’t resolves within5-7 days
1. Hormone deficiency: GH def,
Cortisol def. (pri adrenal
or sec. pituitary)
2. Hormone excess:
hyperinsulinemia( beta cell
hyperplasia or adenoma),
3. Beckwith- Weidman
syndrome.
4. Metabolic diseases: IEM

98. • Age < 12-18 months:
-congenital pituitary or
adrenal defects.
-hyprinsulinemia
-Metabolic(IEM)
Age > 12-18 months:
-Acquired pituitary or adrenal
defects.
-Ketotic hypoglycemia
-Islet cell adenoma
- Metabolic(IEM)
• Symptoms devlop shortly after meal : Hyperinsulinism
• Within 1-2 hrs of feeding: IEM
• After 4-8 hrs after meal: impaired gluconeogenesis due to
substrate deficiency or ketotic hypoglycemia
• After 8-12hrs after meal: Fatty acid oxidation defect.
• After introduction of proteins & weaning diet: (MSUD, Organic
acidureas, urea cycle defect)

99. Clues:
• Hyperinsulinism may present from 3rd day of life to 18monts.
• Short stature, growth failure : GH deficiency.
• Disturbances in sr. electrolytes(hyponatremia, hyperkalemia) &
ambiguous genitalia: Adrenal cause.
• Hyperpigmentation, salt craving : Addison’s disease.
• Growth failure, micropenis, midline facial defects: Pituitary
defect.
• Cataract, presence of non-glucose reducing sugar :
Galactosemia.
• Hepatomegaly : Glycogen storage ds.
• Hematologic manifestations : Organic acidureas.

100. Thank You!