HYPOGLYCEMIA

-Sujay Bhirud

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.

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)

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.

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

Major long term sequelae of severe prolonged hypoglycemia

•Cognitive impairment•Recurrent seizure activity•Cerebral palsy•Autonomic dysregulation•Subtle effects on personality

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 metabolismEfficiency of this regulatory control is related to • Chronologic age• Recent feed• Food intake

As blood glucose level tends to decreaseInsulin 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

• 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

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

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.

•Three related events facilitates this transition: changes in hormones

changes in their receptors

changes in key enzymatic activity

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.

Adaptive changes in hormone receptors occurs.

Changes in enzymes: • Rapid fall in glycogen synthase activity

• Rise in phosphorylase activity

• Rise in RLE of gluconeogenesis phosphooenolpyruvatecarboxykinase

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

• 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.

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

Tug of war between Insulin & other hormones

glucagon

glucocorticoids

G.H

Thyroid hormones

epinephrine

catecholamines

Glucose 6 phosphate

SUR1

Sulfonylureas

KATP channel

GLUT2Insulin

Independen

VoltageDependentCa channel

Insulin

Kir6.2

Glucokinase

Increased ATPDecreased ADP

Increased intracellular

Ca

Kir6.2

Membrane depolarization

Kir6.2

Beta cell of pancreas

Glucose

metabolism

K+

Ca

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 releaseSeen with rapid decline in blood glucose level

Due to Decreased cerebral glucose utilizationSeen with slow decline in glucose level or prolonged hypoglycemia

Features due to Activation of ANS

•Anxiety•Perspiration•Palpitation•Pallor•Tremulousness

•Weakness •Hunger•Nausea•Emesis

Adrenergic symptoms are not prominent in newborns & infants

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

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

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+,

• 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

Workup for IEM:

• Urine Thin Layer Chromatography: Galactose+,

• Total Galactose level: High,

• GALT Enzyme level: Low

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.

•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.

•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

• Classification of Hypoglycemia in Infants and Children

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

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)

•Dominant mutations in HNF-4A and HNF-1A (hepaticnuclear factors 4α and 1α) HI with monogenic diabetesof youth later in life

•Dominant mutation in SLC16A1(the pyruvatetransporter)— exercise-induced hypoglycemia

•Acquired islet adenoma

• Beckwith-Wiedemann syndrome

• Insulin administration (Munchausen syndrome by proxy)

•Oral sulfonylurea drugs

• Congenital disorders of glycosylation

2. Counterregulatory Hormone Deficiency

• Panhypopituitarism

• Isolated growth hormone deficiency

• Adrenocorticotropic hormone deficiency

•Addison disease

• Epinephrine deficiency

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

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

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

D. AMINO ACID AND ORGANIC ACID DISORDERS

• Maple syrup urine disease

• Propionic acidemia

• Methylmalonic acidemia

• Tyrosinosis

• Glutaric aciduria

• 3-Hydroxy-3-methylglutaric aciduria

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

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.

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

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.

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

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)

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

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

• 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.

• 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

• 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.

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.

• 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)

• 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.

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.

• 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

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.

• 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.

Approach to a Case of Hypoglycemia

•Careful elicitation of clinical History •Physical examination•Critical sampling•Investigations

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

• 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.

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

•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

•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

Critical samples

Biochemical tests:

Blood sugar

CBC

Electrolytes

Blood gases

Urine

• pH

• Ketones

• Reducing substances

• Organic acids

• Carnitine derivatives

• Dicarboxylic acid

• Glycemic conjugates

Hormones & Metabolitessample

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

• 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

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)

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

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 phenobarbitonestarted.•O/e: round face, his weight was 11 kg and height was 80 cm, both <3rd centile.

• 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.

• 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.

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.

-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.

Clinical & Biochemical Features of

Inborn Error of Metabolism

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

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.

•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

•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

•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

•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.

•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

•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

•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.

•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

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

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.

Management of Symptomatic Hypoglycemia

Hypoglycemia BGL <40 mg/dl

Asymptomatic

20-<40 mg/dl <20 mg/dl

Trial of oral feeds

Monitor the BGLAfter 1 hour

>40 mg/dl <40 mg/dl

Frequent feeding

Monitor BGL

Before discharge ,ensureThat there is no feeding difficulty

Stop after 48 hour

Symptomatic including seizure

Bolus of 2ml/kg of10 ml glucose

IV glucose infusion@6ml/kg/min. monitor hourly till euglycemic then 6 hourly

BGL>50 mg/dlBGL <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 every6 hrs; increase oral feeds 6 hrly

monitor

Stop IV fluid when rate is 4g/kg/min and infant is stable

Refer to specialist centrefor 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

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 hypopituitarismAdrenal isufficiencyHyperinsulinemic statesGalactosemiaGlycogen storage diseasesMSUDMitochondrial disordersFatty acid oxidation defects

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.

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.

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.

•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.

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 6-8hrsAfter 72hrs:once a day

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

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.

TAKE HOME MESSAGE

• 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 days1. 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

• 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)

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.

Thank You!