Congenital Hyperinsulinism

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Congenital Hyperinsulinism

• Melissa Woythaler, DO
• January 24, 2005

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Introduction

• Hyperinsulinism is the most common cause of
  hypoglycemia in the newborn period
• It can be transient or persistent
• Uncontrolled hypoglycemia may lead to seizures or
  permanent brain damage
• Developmental delay or retardation has been
  reported to occur in 25-50 of affected children

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Introduction

• Hypoglycemia due to HI is dangerous because the
  brain is deprived of its alternative fuels
  (ketones and lactate)
• Affected children can be deceptively asymptomatic
• A study by Koh revealed that although a child
  clinically appears asymptomatic at the time of
  hypoglycemia, neurologic changes could be
  detected.1

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Definition

• The definition of neonatal hypoglycemia is
  heavily debated
• For our purposes, we will define it as
• Serum glucose less than 50 mg/dL beyond day of
  life one and recurrent

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Symptoms

• Lethargy
• Tremulousness
• Apnea / Respiratory distress
• Cyanosis
• Seizures
• Coma
• Weak, high-pitched cry
• Sweating

• Irritability
• Poor feeding
• Hunger
• Some infants may be asymptomatic
• Hypothermia
• Vomiting
• Tachycardia

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Differential Diagnosis

• PERSISTENT
• Congenital Hyperinsulinism
• Hypopituitarism
• Growth hormone deficiency
• Disorders of glyco-genoloysis and gluconeogenesis
• Fatty acid oxidation disorders

• TRANSIENT
• Maternal Diabetes
• Perinatal Stress
• Birth asphyxia
• Maternal toxemia
• IUGR
• Beckwith Wiedemann Syndrome

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Transient Hyperinsulinism
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Infant of a Diabetic Mother

• Macrosomia
• Metabolic Disorders
• Hypoglycemia
• Hypocalcemia
• Hypomagnesemia
• Immature lungs
• Transient tachypnea
• Hypertrophic cardiomyopathy

• Polycythemia and hyperviscosity
• Hyperbilirubinemia
• Congenital malformations
• Cardiac defects
• GI defects
• Skeletal defects

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Perinatal Stress 2,3

• Less well known, but probably even more common
• Associated with various perinatal stresses such
  as birth asphyxia, maternal toxemia, or IUGR
• Hypoglycemia can persist for several weeks to
  several months after delivery and then
  spontaneously remit
• Up to 10 of SGA infants may have this

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Beckwith Wiedemann Syndrome

• Congenital overgrowth syndrome associated with
  clinical features that include hyperinsulinism.
• Frequency 1 in 14,000 births
• 80 of these children show an abnormality in
  chromosome 11, but the cause of hyperinsulinism
  is unclear.
• Inappropriate and sustained insulin
  release/hypoglycemia has been reported in 50 of
  patients.

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Persistent Hyperinsulinism
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History

• Was first described in 1954 by McQuarrie.4 At
  that time was called idiopathic hypoglycemia of
  infancy.
• The name changed to nesidioblastosis later to
  describe the histologic features that showed
  persistence of a diffuse proliferation of islet
  cells budding from ducts in infants with HI.

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History

• Later protein-induced hypoglycemia was discovered
  in one family by Cochrane5 in 1956.
• Later, it was discovered that the cause of this
  protein-induced hypoglycemia was
  hyperinsulinism6,7
• In 1994, a linkage was found of some familial
  cases of HI to chromosome 118

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F L A S H B A C K

• TO
• MEDICAL SCHOOL
• PHYSIOLOGY

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Physiology

• Insulin secretion can be accomplished through two
  pathways
• Potassium dependent
• Potassium independent

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Physiology

• In the normal resting state of the B-cell, open
  ATP-sensitive postassium channels (KATP
  channnels) and the Na-K ATPase maintain the
  B-cell plasma membrane in a hyperpolarized state
  to suppress insulin secretion.

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Physiology

• Once glucose enters the cell, it is
  phosphorylated by glucokinase (GK).
• Further metabolism of glucose through glycolysis
  generates ATP, increasing the ATPADP ratio.

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Physiology

• After uptake and metabolism of glucose, closure
  of the KATP channels raises intracellular
  potassium to cause depolarization of the B-cell
  plasma membrane.
• Voltage-dependent calcium channels then open,
  calcium influx occurs, and intracellular calcium
  concentration rises.
• Insulin release is then initiated by the process
  of Ca-dependent exocytosis.

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Physiology

• This KATP dependent pathway is regulated by the
  phosphorylated energy state of the B-cell.
• The ATPADP ratio works on the sulfonylurea
  receptor (SUR1) to close the potassium channel.

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Physiology

• Glutamate dehydrogenase, another enzyme within
  the mitochondria of the B-cell, changes glutamate
  to a-ketoglutarate.
• This activity also generates ATP to decrease
  potassium efflux which turns on insulin secretion.

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Physiology

• The KATP channel-independent pathway is not
  completely understood.
• It has been demonstrated by glucose-stimulated
  insulin secretion above and beyond that induced
  by depolarization of the B-cell membrane and
  increased intracellular calcium concentrations.

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Now back to the show. .
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Persistent HI

• There are five identified genetic defects that
  cause mutations to the aforementioned insulin
  pathway via different mechanisms. They are
  divided into
• . KATP - HI
• . GDH - HI
• . GK HI
• 4 . Short-chain L-3-hydroxyacyl-CoA
  dehydrogenase HI
• 5 . Exercise-induced HI

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KATP HI9

• Change of KATP channel formation or activity
  allows the B-cell membrane to be continually
  depolarized.
• Due to mutation of chromosome 11p
• There are 2 mechanisms with 2 different
  inheritance patterns for this defect
• 1. Diffuse disease
• 2. Focal disease

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KATP - HI

• FOCAL DISEASE (40-65)
• - Focal cluster of B-cells with abnormal
  channels
• - Inherited by paternal abnormal allele that
  affects all cells, but there is loss of maternal
  tumor suppressor gene (H19).10

• DIFFUSE DISEASE (35 - 60)
• - All the B-cells of the pancrease abnormally
  secrete insulin
• - Autosomal recessive
• - Heterozygous family members are unaffected

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KATP - HI

• Affected infants are generally
• Large for gestational age
• Hypoglycemic within the first few days of life
• Diazoxide-unresponsive
• Octreotide can sometimes slow insulin secretion
• Most of these infants require pancreatectomy

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GDH-HI11

• Also known as hyperinsulinism/ hyperammonium
  syndrome
• The enzyme converts glutamate to a-ketoglutarate.
  It is allosterically activated by leucine and
  allosterically inhibited by GTP
• Autosomal dominant or sporadic
• Chromosome 11 mutation which causes a gain in
  function of the enzyme.

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GDH-HI

• Affected newborns are
• Normal birth weight
• Present with hypoglycemia later in infancy
• Hypoglycemia is subtle with fasting but
  potentially severe with protein ingestion
• Persistent hyperammonemia
• Diazoxide responsive

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GK HI12

• Glucokinase (GK) is considered the glucose sensor
  of the B-cell.
• This enzyme is the initial step in the pathway
  which is necessary for glucose-mediated insulin
  secretion.
• GK - HI is due to a gain of function mutation to
  GK.

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GK - HI

• One family with GK-HI has been reported in the
  literature
• Autosomal dominant
• They had a lower threshold for insulin secretion
• Fasting blood glucose stabilized at 40mg/dL
• Diazoxide responsive

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GK - HI

• This is a mild form of HI and the family did
  rather well
• Three members were not diagnosed until adulthood
• Two had symptoms starting in adolescence
• Two children suffered hypoglycemic seizures

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Short chain fatty acid HI

• Chromosome 4 defect
• There are only 2 reports in the literature of
  this kind of hyperinsulinism.
• Not well understood or studied as of yet

37
Exercise-Induced HI

• Strenuous physical exercise causes
  hyperinsulinemia in patients who do not normally
  experience fasting hypoglycemia.
• Autosomal dominant
• Reported in 10 people in 2 different families
• Also, not well understood or studied to date.

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Diagnosis

• Depends on demonstrating increased insulin
  concentrations at the time of hypoglycemia.

NOT AS EASY AS IT SOUNDS!!
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Diagnosis

• Serum insulin concentrations are not consistently
  elevated and cannot be relied upon to make the
  diagnosis.
• The work-up is further complicated because the
  recognition of signs of excess insulin may be
  subtle, particularly in GDH-HI
• You must demonstrate increased insulin action
  with suppressed free fatty acids, ketones, and
  IGFBP-1 and a glycemic response to glucagon at
  the time of hypoglycemia

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Diagnosis

• The serum insulin concentration may not be
  elevated
• IGFBP-1 suppressed (lt120 ng/mL)
• Free fatty acids suppressed (lt1.5 mmol/L)
• Suppressed ketones (B-hydroxybutyrate lt
  1.5mmol/L)
• Glycemic response to glucagon (gt 30 mg/dL
  increase in serum glucose with injection of 1 mg
  glucagon)

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Diagnosis

• GDH-HI will have elevated ammonium levels.
• Tests of leucine-sensitivity and oral protein
  challenges will be abnormal in GDH-HI
  (unpublished data).

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Diagnosis

• KATP HI can have severe hypoglycemia
• You must differentiate between the diffuse and
  focal forms.
• Transhepatic portal venous sampling
• Calcium and Tolbutamide challenges17
• Arterial stimulation venous sampling

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Treatment

• AIM to prevent hypoglycemia in the context of a
  normal feeding regimen

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Treatment

• Pharmacological interventions
• Diazoxide
• Somatostatin analogs Octreotide / Sandostatin
• Calcium-channel blockers
• Glucagon
• Corticosteroids
• Surgery
• G-tube and continuous feeds
• Pancreatectomy

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Medical Treatment
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Surgical Treatment

• Pancreatectomy
• Indicated for children who fail medical therapy
• Focal KATP HI can be cured with focal resection,
  however, it needs to be localized first
• Intraoperative venous sampling
• Intraoperative frozen section evaluation
• Diffuse KATP HI often necessitates 95-99
  subtotal pancreatectomy

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Surgical Treatment

• Many times this is undertaken to allow for more
  effective medical management
• Frequently, they are necessary to control
  hypoglycemia and are complicated by DM

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Complications

• Neurologic sequelae of hypoglycemia
• Seizures
• Permanent brain damage
• Prolonged hospitalization
• Impaired bonding and socialization
• Developmental delay
• Feeding issues
• NG feeds interfere with an infant learning to
  feed
• Meds suppress appetite

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Complications

• Post-op complications
• Pancreatitis
• Pseudocyst formation
• Duodenal hematoma
• Transient hyperglycemia
• Diabetes mellitus
• Pancreatic exocrine insufficiency
• Family problems
• Any chronic disease is emotionally burdensome
• Parental guilt

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References

• 1. Koh T, Aynsley-Green A, Tarbit M, Eyre J.
  Neural dysfunction during hypoglycemia. Arch Dis
  Child 1988 63 1353-8.
• 2. Collins JE, Leonard JV. Hyperinsulinism in
  asphyxiated and small-for-dates infants with
  hypoglycemia. Lancet 1984 2311-313.
• 3. Collins JE, Leonard JV, et al.
  Hyperinsulinemic hypoglycemia in small for dates
  babies. Arch Dis Child 1990 65 1118-20.
• 4. Mquarrie I. Idiopathic spontaneously
  occurring hypoglycemia in infants. Clinical
  significance of problem and treatment. Am J
  Pathol 1954 87 399-428.
• Cochrane WA, Payne WW, Simpkiss MJ, Woolf LI.
  Familial hypoglycemia prefcipitated by amino
  acids. J Clin Invest 1955 35 411-22.
• Fajans SS, Floyd FC, Knopf RF, et al. A
  differenfce in the mechanism by which leucine and
  other amino acids induce insulin release. J Clin
  Endocr Metab 1967 27 1600-6.
• Grumbach M, Kaplan S. Amino acid and alpha keto
  acid induced hyperinsulinism in the
  leucine-sensitive type of infantile and childhood
  hypoglycemia. J Pediatr 1960 57346-62.

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References

• Glaser B, Chiu KC, Anker R, et al. Familial
  hyperinsulinism maps to chromosome 11p14-15.1, 30
  cM centromeric to the insulin gene. Nat Genet
  1994 7 185-8.
• Glaser B, Thornton P, Otonkoski T, et al.
  Genetics of neonatal hyperinsulinism. Arch Dis
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• De Lonlay P, Fournet JC, Rahier J, et al.
  Somatic deletion of the imprinted 11p15 region in
  sporadic persistent hyperinsulinemic hypoglycemia
  of infancy is specific of focal adenomatous
  hyperplasia and endorses partial pancreatectomy.
  J Clin Invest 1997 100802-7.
• Bryla J, Michalik M, Nelson J, ERecinksa M.
  Regulation of the glutamate dehydrogenase
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• Glaser B, Kesavan P, Heyman M, et al. Familial
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References

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  interpretation can direct the extent of
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