Transcript The many faces of hypoglycaemia in the paediatric population

The many faces of
hypoglycaemia in the paediatric
population
Dr HC Yau
Prince of Wales Hospital
Case 1
• MHY
• Full term baby boy
• Birth weight 3.605 kg
• Uneventful antenatal course
• Third child of the family, healthy siblings
• No family history of note
• No consanguinity
• Presented with limbs twitching and startling response
since 17 days of life
• Increased in frequency
• Physical examination – hypotonia, liver 2-3 cm below
costal margin
• Plasma glucose 1.2 mmol/L
• Given bolus of dextrose, followed by dextrose infusion
with maximum glucose load at 12 mg/kg/min
Laboratory Results
Date
25/5/2005
31/5/2005
Glucose (mmol/L)
1.9
2.0
Insulin (mIU/L)
23.9
10.5
Growth Hormone
(mIU/L)
54
Cortisol (nmol/L)
311
Laboratory Results
• Urine metabolic screen and plasma amino acid profile
normal
• Lactate normal
• Ammonia – persistently high (253 – 334 umol/L) despite
normal glucose level and low protein diet
• Carnitine and acylcarnitine profile normal
• CT abdomen – apparent lobulation of body of pancreas
Treatment
• Initially started intravenous octreotide,
maximum at 26 mcg/kg/day
• Later switched to oral diazoxide 10
mg/kg/day and hydrochlorothiazide 2
mg/kg/day
Diagnosis
• Diagnosis – Hyperinsulinism
Hyperammonaemia Syndrome
• Genetic study – mutation detected in exon
10; Asn410Ile (N410I), represented by a
mutation of AAC to ATC at codon 410 in
GLUD1 gene
Congenital Hyperinsulinism
Introduction
• Heterogeneous disorder with respect to clinical
presentation, pancreatic histology and molecular biology
• Sporadic and familial
• Sporadic forms – relatively uncommon (incidence
1/40000 live births)
• Familial forms – common in communities with high rates
of consanguinity (incidence 1/2500 live births)
Clinical Presentation
• Typically present in first few days after birth
• Subtle forms may present later in infancy or
childhood
• Non-specific symptoms of hypoglycaemia such
as poor feeding, lethargy, irritability, seizures and
coma
• Macrosomia due to exposure to perinatal
hyperinsulinaemia
Diagnosis
• Hypoglycaemia (<2.6 mmol/L) with inappropriately raised
serum inuslin
• Low serum fatty acids levels and ketone bodies
• High intravenous glucose infusion rate, usually >8
mg/kg/min
• Serum lactate and ammonia may be elevated
• Urinary organic acid and acylcarnitine analysis (e.g. shortchain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD)
deficiency)
Role of KATP channels in linking glucose
metabolism to regulated insulin
Pathophysiology
• Channelopathies
– Defects in pancreatic β-cell KATP channels
lead to unregulated insulin secretion
• Metabolopathies
– Increased β-cell ATP formation or
accumulation of intermediary metabolites,
triggering insulin secretion
Channelopathies
• Mutations in genes ABCC8 and KCNJ11
(encoding two subunits SUR1 and Kir6.2) of
pancreatic KATP channels
• Autosomal recessive mutations – commonest
genetic causes of congenital hyperinsulinism
• Autosomal dominant mutations also described
Metabolopathies
• Glutamate dehydrogenase
• Glucokinase
• Short-chain L-3-hydroxyacyl-CoA
dehydrogenase (SCHAD) deficiency
GDH and Regulation of Insulin
Secretion and Hepatic Ureagenesis
Summary of the known genetic causes of
hyperinsulinaemic hypoglycaemia
Intramitochondrial enzyme
catalyze β-oxidation of fatty
acids
Histology
• Diffuse form
– Affects all β-cells
– Most commonly due to
recessive mutations in
genes encoding two
subunits of KATP
channel
• Focal form (40-50%)
– Localised to one
region of pancreas
– Germline mutation in
paternal allele of
ABCC8 & KCNJ11
genes on chromosome
11p15.1 and somatic
loss of part of
maternally inherited
chromosome 11p15.5
Differentiating Focal from Diffuse
Congenital Hyperinsulinism
• In the past, invasive methods such as
intrahepatic pancreatic portal venous sampling,
intra-arterial calcium stimulation/venous
sampling test, acute insulin response testing to
intravenous glucose, calcium, and tolbutamide
• Recently, 18F-L-dopa PET scan successfully
used to localize focal disease
• Islets take up L-dopa and convert it to dopamine
by dopa carboxylase
European Case Series
•
18F-Dopa
PET scan identified 5 focal pancreatic lesions
in 14 patients with congenital hyperinsulinism
• These 5 patients operated, lesions matching PET scan
removed, became normoglycaemia
• Remaining 9 patients had diffuse disease in PET scan, 4
verified by histology while 4 consistent with pancreatic
catheterization
Diabetes 2006;55(1):13-18.
American Case Series
• 24 infants with hyperinsulinism unresponsive to medical
treatment
• Diagnosis of focal or diffuse disease by 18F-Dopa PET
scan correct in 23 of the 24 cases (96%) and equivocal
in 1 case
• 11 focal diseases confirmed by pathology and location of
lesions matched with PET scan in all cases (100%)
J Pediatr 2007;150:140-150.
Diffuse Disease
Focal Disease
Management
Hyperinsulinism
NH3
Diazoxide
PET scan
Focal
Diffuse
Glutamate
dehydrogenase
mutation
(Hyperinsulinism
Hyperammonaemia
Syndrome)
Octreotide
Partial pancreatectomy
Near-total pancreatectomy
Follow-up
Follow-Up
• Growth
• Neuro-development
• Diabetes mellitus management
• Pancreatic exocrine function
• Genetic counseling
Case 2
• ITL
• Presented at 4 years of age with fasting
hypoglycaemia
• History of stage IV peripheral T-cell lymphoma
arising from anterior mediastinum with
metastases to bone marrow and multiple bone
sites (basal skull, ribs, right femoral head and
left sacrum) at 3 years of age
• Treated according to ALL IC BFM 2002
high risk protocol
• In complete remission
• In maintenance phase chemotherapy with
methotrexate and 6-mercaptopurine
• Presented with 2 episodes of
hypoglycaemic attacks (sweating, malaise
and weakness) after prolonged fasting in
the morning without breakfast
• Symptoms resolved after taking food
• No more hypoglycaemic attack after
resuming breakfast everyday
Laboratory Results
• Fasting test – took 14 hours before developing
hypoglycaemia
• Plasma glucose 2.0 mmol/L, paired insulin 0.9 mIU/L
• Growth hormone 9.8 mIU/L, cortisol 1250 nmol/L
• Beta-hydroxybutyrate 2.0 mmol/L
• Lack of response to glucagon stimulation test – preglucagon glucose 2.4 mmol/L, post-glucagon glucose 2.0
mmol/L
Laboratory Results
• Lactate and ammonia normal
• Urine metabolic screen unremarkable except
large amount of ketones and reducing
substances
• Plasma amino acid profile normal
• Carnitine and acylcarnitine profile normal
Diagnosis
• Diagnosis – fasting hypoglycaemia related
to maintenance therapy
• 6-mercaptopurine and methotrexate
potentially affected hepatic
gluconeogenesis and glycogenolysis
Case Series from Finland
• 19 of 35 patients (54%) developed hypoglycaemia after 11 to 16
hours of fasting
• 14 of the 19 patients with hypoglycaemia (74%) <6 years of age
• No significant difference with respect to sex, height, body mass
index, doses of 6-mercaptopurine and methotrexate, duration of
therapy, or ALL risk group
• 15 of the 19 patients with hypoglycaemia re-tested 3 to 4 months
after cesation of maintenance therapy, all had improved fasting
tolerance
J Pediatr 2001;138:428-431
Case Series from Italy
• 6 of 86 patients developed total of 18
episodes of spontaneous hypoglycaemia
during treatment
• 5 of 6 patients are male, none >5 years of
age, 4 being only 3 years old
Med Pediatr Oncol 2002;39:32-34.
Summary
• Hypoglycaemia: a challenge to diagnosis
and treatment
• Careful history and investigations: PET
scan
• Meticulous control and follow up to reduce
CNS damage associated with recurrent
hypoglycaemia