metabolic disorders causing hypoglycemia · 26/01/2016 1 metabolic disorders causing hypoglycemia...

26/01/2016

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Metabolic disorders causing hypoglycemia

Peter Witters

Centrum Metabole Ziekten en Pediatrie Leuven

www.metaboleziekten.be

26/01/2016

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http://sur1.congenitalhi.org/stories.htm

Hypoglycemia

°36w6/7, 3,6 kg day0: not feeding, pale, moaning: glc 22mg/dL

IV glc bolus, high glc need 16‐18 mg/kg/min

Not possible to wean

Clin Ex: No hepatomegaly

Bloods: low FFA, no lactate, no urinary ketones

High insulin 36,5mIU/L

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What is your diagnosis?

1. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)

2. Fatty acid oxidation disorder

3. Glycogen storage disease (GSD)

4. Other





4. Other

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4. Other





4. Other

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What is the diagnosis?




4. Other

Isn’t it just hormonal?

Pancreatic Beta-cell

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Isn’t it just hormonal?

Pancreatic Beta-cell

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Glucose → energy, work → food → glucose

Glucose is fuel

Hypoglycemia

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Why do we need glucose?

Basal glucose oxidation rate

• Neonate:4–6 mg/kg/min

• Infants & children: 3–5 mg/kg/min

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Paris, NEM, 1975–2005, n = 539

Hyperinsulinisms 363

FAO 65

Glycogenoses (I, III) 39

Fructose biphosphatase 7

Glycogen synthase 5

Respiratory chain 5

HMGCoA-lyase 3

Bickel-Fanconi (GLUT-2) 3

CDG syndrome 3

Growth hormone deficiency 11

Adrenal failure 3

Munchausen by proxy 2

Ketotic hypoglycemia 21

Unclassified 9

Hypoglycemia: a large series

SUBDIVISIONS 2015

A. Disorders of amino acid metabolism 150

B. Organic acidemias 31

C. Biotin‐responsive disorders 12

D. Disorders of carbohydrate metabolism and glycogen storage diseases 49

E. Hyperinsulinism 7

F. Disorders of mitochondrial energy metabolism 56

G. Mitochondrial beta oxidation defects 39

H. Disorders of ketone body metabolism 2

I. Disorders of sterol, bile acid, lipid and lipoprotein metabolism 24

J. Peroxisomal disorders 14

K. Lysosomal disorders 51

L. Disorders of purine and pyrimidine metabolism 2

M. Disorders of creatine metabolism 0

N. Disorders of neurotransmitter and small peptide metabolism 3

O. Congenital defects of glycosylation (CDG) 13

P. Porphyrias 39

Q. Disorders of copper metabolism 26

R. Other progressive neurodegenerative diseases 0

S. Connective tissue disorders 43

T. Extra 28

588

1/3

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Putting it all together….

Permanent Post-prandial Fasting

• According to its timing

PHHI, factitious HFI, Gal, PHHI

Short fasting: GSDILong fasting: FBP, FAO

Timing ?Hepatomegaly ?Lactate ?Ketones ?

I II III IV

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I II III IVPhase 1: Post-prandial <2.5 hours after meal

Hyperinsulinism Hereditary fructose intolerance

Phase 2: Short fast >2.5 hours to <12 hours after mealGlycogenosis, Glycogen synthase defect Gluconeogenesis defects

Phase 3: Medium to long fast >12 hours after mealGluconeogenesis defectsMostly fatty acid oxidation defects with hypoketosisKetotic hypoglycemia with major ketosis






• Hepatomegaly ?

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Hepatomegaly No hepatomegalyPHHI, factitious HFI, Gal, PHHI



• Hepatomegaly ?



Hepatomegaly No hepatomegaly

Postprandial lactate Fasting lactate




GSD III, VI, IX

• Lactate ?

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Ketones no ketonesPostprandial lactate Fasting lactate


GSD III, VI, IX Ketotic HypoglcKetolysis

FAOKetogenesisPHHI



• Ketonuria ?

Hypoglycemia samples

• Glucose

• Lactate

• Insulin + cortisol

• ACARP

• Urine Ketones + Organic acids

• (FFA, BHB = 2 ml heparin + freeze )


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Case: Hypoglycemia

°38w4/7, day0: glc 14mg/dL after 10h, over the following weeks repeatedly glc 30 mg/dL despite 3‐hourly feeding.

Seizures with hypoglycemia R/ luminal

Clin Ex(6w): 4.5kg ,normal tone, epicanthic fold, prominent cheecks, soft liver 2‐3 cm BCM

Bloods: Low insulin during hypo, normal cortisol, normal PAA, ACARP, UOA, no ketonuria, initially normal lactate?

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FAOKetogenesisPHHI

PHHI, factitious HFI, Gal, PHHI1

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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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Lactic acidosis in GSD type Ia

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Glycogen storage disease type I. Liver biopsy showing mosaic pattern, prominent cell membranes and rare nuclear hyperglycogenation (HE stain)

Hypoglycemia

1y‐old, vomiting after fruit mix, no appetite, went to sleep

Morning: Twitching of the arms

Hypoglycemia 4mg/dL

Clin Ex: Seizures, liver 1 cm

Bloods: hypoglc, appropiately low insulin, elevated FFA, no ketones, dicarboxyluria

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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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1st step = length specific!SCAD: 4 - 6CMCAD: 6 – 10CVLCAD: 12 – 18C

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Hypoglycemia & acidosis

2y‐old, Vomiting and diarrhea, Evolution to somnolence

Bloods: pH 6.95, bic 3.3mmol/l, pCO2 16mm Hg; No lactate, ketones ++ in urine, no glucosuria, hypoglycemia at admission

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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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MCT1 transporter

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Ketones are alternative fuel

Hypoglycemia?

A 9 year old male is brought to the emergency room due to vomiting and lethargy shortly after a birthday party. (glc 40mg/dL)

PMHx is significant for FTT in late infancy which resolved without determination of a diagnosis. He had had several bouts of vomiting in the past, usually after consuming candy or soft drinks. Labs reveal elevated AST and ALT.

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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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FAOKetogenesisPHHI


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Take home:






FAOKetogenesisPHHI



Or more easy to remember

• Hypoglycemia + Hepatomegaly= GSD

• Hypoglycemia + high Insulin= PHHI

• Hypoglycemia – ketones = PHHI or FAO» Measure insulin

• Postprandial hypoglycemia = HFI

• High ketones and acidosis = ketone metabolism

• Consider central hypo = GLUT1

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These samples are you friends

• Glucose

• Lactate

• Insulin + cortisol

• ACARP

• Urine Ketones+ Organic acids

• (FFA, BHB = 2 ml heparin + freeze)

These samples are you friends

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Peter Witters, Eva Morava, Wouter Meersseman and David Cassiman Metabolic Center Leuven-Genk-Kortrijk

www.metaboleziekten.be

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FFA glucose

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Metabolism

Fed state

High Insulin, Low Glucagon

High Glucose

• Use of glucose

• Buildup of glycogen (muscle and liver)

• Storage of fat

• Protein accretion

Fasted

Low Insuline, High Glucagon

Low Glucose

• Gluconeogenesis

• Glycogen breakdown

• Lipolysis

• Ketogenesis

• Protein catabolism

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metabolic disorders causing hypoglycemia · 26/01/2016 1 metabolic disorders causing hypoglycemia...

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