+ Persistent Hyperinsulinemic Hypoglycemia in Infant 邱巧凡 2015.10.22
+
Persistent Hyperinsulinemic Hypoglycemia in Infant
邱巧凡2015.10.22
+ Review of the case A full term baby, appropriate for gestational age, without prenatal or
perinatal insults, presented with symptomatic hypoglycemia since 2 days after birth. (GA 38+3 weeks, BBW 3260g)
No dysmorphism, no hepatomegaly, no liver function impairment.
Critical sample showed hyperinsulinism, I/G ratio> 0.3; nonketotichypoglycemia, adequate response of GH, cortisol; normal thyroid function test.
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+ Critical samples of this patient7/31 (D 7)
Sugar 46mg/dL
hGH 18.8ng/mL
11:58am Cortisol 16.39 ug/dL
Insulin 15.3uU/mL
C-peptide 2.38ng/mL
I/G ratio: 0.33
Lactate 40 mg/dL
Blood ketone 0 mmol/L
Ammonia 50 ug/dL
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8/11 (D 18)
Sugar 33 mg/dL
Insulin 19.5uU/mL
I/G ratio: 0.59
8/29 (D 36)
Sugar 28 mg/dL
Insulin 42.9uU/mL
I/G ratio: 1.53
C-peptide 6.65ng/mL
Blood ketone 0 mmol/L
+ Critical samples of this patient4
Requirement of glucose infusion, up to GIR 13.4 mg/kg/min.
Poor response to diazoxide 15mg/kg/day for 4 days.
Stable under Octreotide 15mg/kg/day q8h sc
+ Background
In normal humans, plasma glucose concentration range from 70-128mg/dL; and in the brain the range is from 14-41mg/dL.
Brain glucose consumption will outstrip glucose transport at plasma glucose concentration< 36mg/dL (brain glucose will approach 0 mmol/L)
Normal regulation range of glucose concentration: >70mg/dL during fasting <140mg/dL during feeding
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+ Glucose Metabolism in the Fetus Fetal energy 80% from glucose and 20% from metabolism of lactate
and amino acid.
Fetal glucose is derived entirely from mother through the placenta transfer(main GLUT1), with no endogenous glucose production in the fetus.
Mean fetal glucose concentration: 79mg/dL
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Int. J. Mol. Sci. 2014, 15(9), 16153-16185
+ Glucose Metabolism in the Fetus Maternal insulin dose not significantly cross the placenta unless it is
bound to antibody.
In utero, the raised insulin-to-glucagon ratio drives metabolism towards anabolism rapid rate of fetal growth.
Throughout gestation, the balance of glycogen metabolism is toward anabolism and the building of glycogen stores.
By 120 days, fetal glycogen 24,6mg/g liver
At 36 weeks gestation, there is a steep increase in accumulation of glycogen, with level raising to 50mg/g liver at term.
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+ Change at Birth: Transition Phase Constant supply of glucose and amino acid from mother
variable and intermittent oral intake.
At birth, the epinephrine and norepinephrine rise 3-10 times, may response to the change in the insulin-to-glucagon ratio(high to low).
Glucagon rise: 2hrs after birth 3 days after birth
Insulin: falls initially and remains in the basal range for several days.
By 8-12 hrs, gluconeogenesis becomes fully effective.
Ketone utilization can provide 25% of the energy food after the first 12 hrs of life.
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+ Change at Birth: Transition Phase Glycogen decline from peak 50mg/g liver to <10mg/g liver in the first
24 hrs of life.
Glycogen contributes 50% of the NB’s glucose requirements. Gluconeogenesis from pyruvate: 20-30%.Glycerol produced by lipolysis: 20%.
Transitional hypoglycemia (physiologic drop) 30% of normal NB: glucose <50mg/dL in the first 24hrs. In NBs>24hrs of age, glucose <50mg/dL accounts for <0.5%
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Intrauterine 2hrs 2-24hrsglucose >70 56 63
10Symptoms of hypoglycemia in infancy
Mark A. Sperling, Pediatric Endocrinology, 4th edition, 2014
Mark A. Sperling, Pediatric Endocrinology, 4th edition, 2014
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Mark A. Sperling, Pediatric Endocrinology, 4th edition, 2014
12Metabolic systems regulate the physioloic response to fasting:
+ Counter-regulatory hormones13
+ Changes in plasma fuel concentrations in a normal child
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+ Critical samples
Plasma glucose
Lactate
Free fatty acid
β-Hydroxybutyrate (Ketone)
Insulin
Cortisol
Growth hormone
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When plasma glucose is below 50mg/dL
16Differential Diagnosis of Hypoglycemia in Neonates and Infants
17Differential Diagnosis of Hypoglycemia in Neonates and Infants
18Differential Diagnosis of Hypoglycemia in Neonates and Infants
+Algorithm for diagnosis of hypoglycemia
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A glycemic response of greater than 30 mg/dL following injection of 0.03 mg/kg glucagon excludes a primary hepatic or metabolic defect.
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Children’s Hospital of Philadelphia (CHOP) Hyperinsulinism Center
+ Establishing the diagnosis of hyperinsulinism Evidence of increased insulin secretion/effects: Increased glucose utilization (GIR > 10mg/kg/min) Hyperinsulinemia (plasma insulin > 2uU/mL) Hypofattyacidemia (plasma FFA < 1.5 mmol/L) Hypoketonemia (plasma BOHB < 2 mmol/L) Glycemic response to glucagon (delta glucose > 30 mg/dL)
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Perinatal Stress-Induced Hyperinsulinism Poorly understood form of hypoglycemia in high-risk neonates
Associated with IUGR, birth asphyxia, maternal pre-eclampsia
Not uncommon: 10% of SGA
Presentation overlaps with monogenic forms but history of perinatal stress and responsiveness to diazoxide are clues to the diagnosis
May persist for several weeks-months
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Monogenic Hyperinsulinism
KATP HI (SUR1/Kir6.2) Diffuse (recessive dominant) Focal (LOH and paternal mutation)
Dominant GDH-HI (glutamate dehydrogenase)
Dominant GCK-HI (glucokinase)
Recessive SCHAD-HI(short-chain 3-OH-acy-CoA dehydrogenase)
Dominant exercise induced HI(MCT1)
Dominant HNF4alpha and HNF1 alpha HI (MODY 1 and 3)
Dominant UCP2 HI)
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
25Current model of mechanisms of insulin secretion by the beta cell of the pancreas.
KATP channel
Activating mutationInactivating mutation
HNF4a
HNF1a
ABCC8 SUR1: 146(119 recessive and 27 dominent)KCNJ11 Kir6.2: 22(18 recessive and 4 dominent)
+ KATP Hyperinsulinism
Most common and severe form of congenital hyperinsulinism
Inactivating mutations of SUR1(ABCC8) and Kir6.2 (KCNJ11) Recessive diazoxide-unresponsive Dominant diazoxide-unresponsive Dominant diazoxide-responsive
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Focal KATP HI
40-60% of severe form of conhenital HI
Clinical overlap with diffuse hyperinsulinism
Diazoxide unresponsive
Surgical pancreatectomy required
Cured by surgery
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ GDH-HyperinsulinismHyperinsulinism/Hyperammonemia syndrome
GLUD1 mutations impair GTP inhibition of GDH
Activating mutation
Autosomal dominant (30%) or sporadic (80%)
Mild, late onset, normal birth weight
Fasting and protein-induced hypoglycemia
Asymptomatic hyperammonemia
Diazoxide responsive
Seizure are common
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ HNF4alpha-Hyperinsulinism Frequent cause of diazoxide-responsive hyperinsulinism(5%)
Clinical presentation: Early presentation: DOL 1 Macrosomia: +2.4 SDS
Variable phenotype: Macrosomia only Transient hypoglycemia: 1-9 days Prolonged hypoglycemia: 3m-8years
Bi-phasic phenotype: Neonatal hypoglycemia diabetes
Dominant mutations: 64% no family history of diabetes Incomplete penetrance
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Glucokinase-Hyperinsulinism
Glucokinase: glucose sensor of the beta cell
Autosomal dominant mutations lower glucose threshold for insulin release.
Fasting hypoglycemia
Severity variable
Response to diazoxide < 1/3 cases
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ SCHAD-Hyperinsulinism
Rare cause of hyperinsulinism
Recessive mutations of short-chain 3-hydroxy-acyl-Co dehydrogenase(SCHAD—HADH)
Mechanism: loss of negative regulation of GDH
Fasting and protein-induced hypoglycemia
Metabolic markers: serum 3-OH-butyryl-carnitine; urine 3-OH-glutarate
Diazoxide-responsive
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ UCP2-Hyperinsulinism
UCP2: inhibitor of insulin secretion
Autosomal dominant mutations
Neonatal or later presentation
Responsive to diazoxide
Resolves in 1-2 years
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ MCT1-Hyperinsulinism
MCT1(SLC16A1): transporter of pyruvate and lactate
Autosomal dominant mutations failure of transcriptional silencing of MCT-1 in beta cells
Exercise-induced hypoglycemia
Some response to diazoxide
Carbohydrate loading before exercise
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
34Diagnostic and treatment approach in cases of hyperinsulinism.
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
Diagnosis of HI 5 days trial of Diazoxide
Safety Fast with BS > 70mg/dL
Diazoxideresponsive
Continue Diazoxide DiazoxideUnresponsive
Stop Diazoxide Initiate glucagon infusion 1mg/day if unable to maintain
BS > 70mg/dL with dextrose IV
18F-DOPAPET scanFocal Diffuse
Limited resection Aggrasive medical therapy with octrotide + G-tube Dextrose
Send genetic testing
Suggests KATP HI
Refer to center with 18F-DOPA PET scan
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18Fluoro-L-DOPA PET scan
The gold standard technique to localize the focal lesion is:
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A requirement of greater than 15 mg/kg/min is highly suggestive of HI. Normal requirements:
Neonate: 5-8 mg/kg/minOlder infant or child: 3-5 mg/kg/min
Calculate glucose requirement.
Glucagon stimulation test
When glucose <50 mg/dL , give glucagon 1 mg IV/IMMonitor blood sugar every 10 minutes for 40 minutes; if there is no increase in blood sugar by 20 minutes, terminate test and rescue with IV dextroseA positive response is a rise of more than 30 mg/dL and indicates that the hypoglycemia is due to increased insulin action
The Children’s Hospital of Philadelphia
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+ Current therapies: Pharmacological
Diazoxide: 5-15 mg/kg/day PO Activates the KATP channel via the SUR Effective for GDH-HI and GK-HI Side effects: fluid retention, hypertrichosis
Octreotide: 5-20 ug/kg/day SQ Activates KATP channel, affects intracellular translocation of Ca. direct inhibition
of insulin secretion Tachyphylaxis common Side effects: suppression of GH, TSH, ACTH; GI side effect, NEC
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Current therapies: Pharmacological
Long-acting somatostatin analogs: once a month Long-acting octreotide Lanreotide
Glucagon: 1mg/day IV/SQ Increase glycogenolysis/gluconeogenesis Side effects: nausea, vomiting
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
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1st line therapy- 5 day trial of Diazoxide 15 mg/kg/day (dosed 5-15 mg/kg/day)
Wean GIR as tolerated to maintain BS >70 mg/dLAfter 5 days, attempt 8-18 hour (depending on the age of the child) safety fast off of IV dextrose ► if unable to fast, considered medical failure and should refer to CHOP (suggests KATP-HI)Side effects: fluid retention, hypertrichosis. Young infants, especially if receiving fluids, may need diuretics for fluid retention.If diazoxide failure, stop diazoxide and initiate glucagon infusion 1 mg/day if unable to maintain BS >70 mg/dL with IV dextrose
Other considerations
Octreotide, which has been 2nd-line therapy for congenital HI has been associated with NEC; for this reason we do NOT recommend its usage prior to surgeryDouble-lumen PICC would be helpful prior to transferHypertrophic cardiomyopathy is common in infants with congenital HI- consider ECHO +/- Cardiology consult prior to transfer
The Children’s Hospital of Philadelphia
+ Current therapies: Surgery
Usually required for KATP-HI
May be curative for focal KATP-HI
Goal is to distinguish between diffuse and focal HI and to localize the focal lesion
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Focal vs. Diffuse Clinical presentation Subtle difference: focal vs diffuse: lower birth weight, later presentation,
lower GIR requirement
Mutation analysis: Monoallelic recessive KATP mutation: 97% sensitivity and 90% specificity If mutation is paternal: 94% PPV for focal HI
Imaging: US, CT, MRI: not useful ASVS, THVS: invasive, poor accuracy 18F-DOPA PET: not FDA approved, good sensitivity(85%) and specificity (96%).
Almost 100% accurate for localization.
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Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
+ Focal Lesion Distribution44
Diva D. De Leon-Crutchlow, MD, MSCECHOP, Congenital Hyperinsulinism Center
Head/Body 12%
Tail/Body 3%
Tail 20%
Body 20%
Head 44%
Ectopic 1%
+ Treatment of PHHI
First line: diazoxide acts as KATP opener, most KATP HI do not response to diazoxide 5-15mg/kg/day, orally, QD or BID Major AE: fluid retention, hypertrichosis The response should be evaluated after at least 5 days of therapy. Successful response: plasma glucose> 70mg/dL after fasting.
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+ Treatment of PHHI
Second line: octreotide Somatostatin analog, induce hyperpolarization of β cell, direct
inhibit votage-dependent calcium channels, and more distal events in the insulin secretory pathway.
5-20mcg/kg/day, q6h-q8h, SC or continuous infusion. AE: NEC
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39851NT/PC 53420NT/PC
+ Treatment of PHHI
Glucagon 1mg/day continuous intravenous infusion Help maintain euglycemia in infant waiting for surgery Long-term use as SC infusion is limited by crystalization of the
glucagon and clogging in the tubing.
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+ Outcomes
The prevalence of developmental delay in patients with congenital hyperinsulinism is approximately 30%.
Patients with KATP HI requiring surgical therapy have a higher incidence of neurodevelopmental problems than diazoxide responsive patients.
Children’s Hospital of Philadelphia
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• 5 patients (include pt 9) became euglycemic after pancreatectomy.• 1 (pt 2) patient develop DM immediately after surgery.• 7 pts still had hypoglycemia after pancreatectomy and were treated with diazoxide. (4/3)
• 2 had poor response to diazoxide and were shifted to octreotide.• 3 achieved long-term stable glycemic control by diazoxide alone.• 2 were treated with diazoxide + octreotide for a period after pancreatectomy.• 1 of them (pt 7) still had recurrent episodes of hypoglycemia until 10 months after surgery.
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Patient 1
ABCC8 mutation Hyperinsulinemic hypoglycemia• Hypoglycemia since 30 mins after birth• Tx with diazoxide, hydrochlorothiazide, frequent feeding with carbohydrate-enriched formula• At 4m/o, add sc octreotide due to recurrent hypoglycemia• Normoglycemia, normal weight gain and good growth rate, exellent neurodevelopment.• One month later, tx with octreotide via an insulin pump• At 4.5y/o, LAR 30mg/month sc (=55mcg/kg/day)
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Asymptomatic cholelithiasis A mild transient growth deceleration during the first 2 years of
treatment, with a shift of height from 50th to 35th percentile, but subsequently catch-up growth occurred.
Lanreotide 30mg once a month sc (=55mcg/kg/day) 20mg/month (=18mcg/kg/day) Patient 1
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Patient 1
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Patient 2
+ Our group introduced in 1986 the use of octreotide as a conservative
management option for CH in conjunction with frequent oral or gastrostomy feedings, diazoxide, and in some patients, glucagon.
To date, we have treated about 40 patients, achieving euglycemia, normal growth, and normal neurodevelopment; school-aged children were all enrolled in regular education, and some excelled in their studies.
Side effects of octreotide were minimal and included transient vomiting, diarrhea, abdominal distention, and steatorrhea during the first weeks of treatment, biliary sludge, asymptomatic cholelithiasis, and transient growth deceleration.
Clinical remission occurred in all patients, and they could be weaned off somatostatin analog therapy at a mean age of 5 yr (range, 1.5–12 yr)
Glucose intolerance has been described in some of these patients; however, only one of them developed overt diabetes mellitus during follow-up of up to 23 yr, and this patient is managed with diet alone.
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+ What we need to do in this patient
Cardiac evaluation
Glucagon stimulation test if hypoglycemia again
Mutation analysis for KATP channel ABCC8, KCNJ11, etc.
18F-DOPA PET for localization of the lesion Long acting octreotide Pancreatectomy
Frequent feeding
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60Beckwith-Wiedermann syndrome• Macroglossia• Macrosomia• Midline abdominal wall defects• Ear creases or ear pits• Neonatal hypoglycemia