persistant hyperinsulinemic hypoglycemia in infant

+

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


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簡報者

簡報註解

Contribution of major fasting systems to brain metabolism over time in a typical normal infant. Note that glycogen stores are depleted by 8 to 12 hours and that ketogenesis becomes the major source of brain substrate by 24 hours.


12Metabolic systems regulate the physioloic response to fasting:

簡報者

簡報註解

Key metabolic pathways of intermediary metabolism. Disruption of the elements of these pathways may be pathogenetic in the development of hypoglycemia. Not shown is the hormonal control of these pathways. Indicated are (1) glucose 6-phosphatase, (2) glucokinase, (3) phosphorylase, (4) phosphoglucomutase, (5) glycogen synthetase, (6) phosphofructokinase, (7) fructose 1,6-diphosphatase, (8) fructose 1,6-diphosphate aldolase, (9) phosphoenolpyruvate carboxykinase, and (10) pyruvate carboxylase.

+ Counter-regulatory hormones13

+ Changes in plasma fuel concentrations in a normal child

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簡報者

簡報註解

In infants, a 24-hour fast is accompanied by a gradual fall in plasma glucose levels as hepatic glycogen stores are depleted, a progressive fall in concentrations of gluconeogenic substrate (e.g., lactate, alanine) as they are used for hepatic gluconeogenesis, a brisk rise in free fatty acids (FFA) as lipolysis is activated, and a dramatic rise in β-hydroxybutyrate (BOB) (the major ketone) as hepatic ketogenesis is turned on.

+ 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

+Algorithm for diagnosis of hypoglycemia

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簡報者

簡報註解

Algorithm for diagnosis of hypoglycemia based on “critical” blood tests obtained during a period of hypoglycemia. FFA, free fatty acids; FAO: fatty acid oxidation; GSD, glycogen storage disorder; SGA, small for gestational age.

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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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+ 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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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)

簡報者

簡報註解

Diazoxide: KATP channel agonosit

+ 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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+ 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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+ 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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+ 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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+ 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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+ 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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+ 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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+ 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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34Diagnostic and treatment approach in cases of hyperinsulinism.

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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

+ 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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+ 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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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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+ 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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+ Focal Lesion Distribution44


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.

簡報者

簡報註解

Near-total pancreatectomy: >95% of the pancreas removed Subtotal pancreatectomy: 80-94% of pancreas removed 10 patients (77%) had macrosomia 9 patients (69%) had seizures as their initial presentation. Pt 9 had focal adenomatous hyperplasia. Pt 3 had ectopic pancreas at the gastric pylorus, aside from the pancreatic lesion.

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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)

簡報者

簡報註解

CGMS of patient 1. Each curve color represents a separate day. A, Seventy-two-hour glucose profile under treatment with continuous sc octreotide infusion. B, Ninety-six-hour glucose profile under treatment with a monthly injection of lanreotide acetate. CGMS was done during the fourth week after injection, at the time lanreotide levels would be expected to be the lowest.

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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

persistant hyperinsulinemic hypoglycemia in infant

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