You are on page 1of 41

CASE PRESENTATION

Tad Miya
Case
• 18-month-old male with “recurrent hypoglycemia” and a 4-day
history of nausea, vomiting, diarrhea, fatigue and decreased
oral intake. His family has been attempting to hydrate him with
juice and Pedialyte. He has been given corn syrup to prevent
further “lows”. His urine output decreased. He became
lethargic, non-responsive followed by a 5-10 second
generalized tonic-clonic seizure and remained unresponsive
after. A neighbor with medical training couldn’t feel a pulse,
started CPR x 10sec and had one after.

• Blood Glucose:
• Home: 79mg/dL
• EMS: 50mg/dL
• OSH: 33mg/dL
Course to Floor:
• OSH: “Several D10 Boluses”
• Transfer: D5-containing fluids
• PCH ED:
• BG: 30-45mg/dL; D10-bolus x 3
• D10-1/2NS+20KCl @ 1.0 mIVF

Blood Glucose now normalizing.


Past Medical History:
• Born: 38wk6 via Home birth at 11 lb 6 oz. [5.16kg]
• DOL #1: Blue, “low oxygen” and BG: 60mg/dL
• ED: BG: 20mg/dL. Limp, Seizure
• NICU: Sz x 2. On dextrose-fluids x 13 days. PHB wean.
• MRI, EEG, TTE: wnl.
• Steroid wean and sent home
• 5mo’s: Odd eye movements at PCP’s (?Seizure).
• BG: 57mg/dL. Referred to Neurology
• Neuro: Voice-responsive seizure-like activity. Started AED (tapered off)
• 2wks post-taper. Unresponsive during viral illness.
• EMS: BG: 30mg/dL > OSH: 24hrs of D10 IVF > Home.
• Home>Now: Internet research, frequent BG checks.
• Formula: Rice milk (Rice cereal, Powdered formula, Corn Starch)
• +/- Juice
Histories:
• PSH: Neg
• Med/All: Neg
• FamHx:
• Dad: T2DM (neonatal hypoglycemia)
• Mom: Thyroid Dz.
• SOC: Mom, Dad, Two Sibs (Healthy).
• Imms: UTD
• Developmental: Mild speech delay; Normal development
Temp: 36.1, HR: 120, RR: 42, BP: 94/74.
WT: 14.4 kg
Physical Exam:

GEN: Crying, but consolable by mom. Vigorous.
• HEENT: Eyes without drainage, no nasal congestion, TMs normal, moist
mucus membranes without ulceration, no cervical adenopathy
• CARDIOVASCULAR: Regular rate and rhythm, no murmurs or gallops.
Central capillary refill of 2 seconds and peripheral pulses of 2+.
• RESPIRATORY: Clear to auscultation bilaterally without wheezing or
crackles. No work of breathing, no retractions, no nasal flaring or grunting.
Good air movement.
• MSK: No deformities of the extremities, no swollen or erythematous joints,
full range of motion of all joints. No clavicle abnormality
• GASTROINTESTINAL: Abdomen is soft, non-tender and not distended.
There are no masses. Normal bowel sounds, no hepatosplenomegaly
• GENITOURINARY: Normal genitals
• SKIN: No rashes, no jaundice
• NEUROLOGIC: Cranial nerve II to XII intact. There are no neurological
deficits. Pupils are equal and reactive to light bilaterally.
DIFFERENTIAL
DIAGNOSES
Intake/Production/Storage <> Blood Glucose <> Utilization
Differential Diagnoses
• CV:
• Metabolic: • Heart Failure, Shock
• Glycogen Storage Disease
• Glycogen Synthase def
• Glucose-6 Phos defi (VonGierke) • FEN:
• Debrancher def (Cori’s) • Hepatitis/Alpha-1-Anti-trypsin def
• …
• Reye’s Syndrome
• Gluconeogensis (Produce)
• Glucose-6 Phos
• Fructose 1,6 Deficiency / Hereditary • ENDO:
Fructose Intolerance
• Hyperinsulinism
• …
• GH deficiency
• Galactosemia
• Hypothyroidism
• Amino Acid D/o’s
• Propionic Acidemia • Adrenal Insufficiency
• Methylmalonic Aciduria
• … • MISC:
• Fatty Acid Oxidation: • Ketotic Hypoglycemia
• Medium-chain Acyl-Coa Dehydrogenase
def • Toxins:
• Insulin, Sulfonylurea
• Munchausen’s
• Ethanol
• Beta-blockers
Labs: On D10NS+20KCl

7.38/38/-/22 Base Def: 3

Triglycerides: 41
Uric Acid: 5.6 (1.8-4.9)

UA: Clean Catch.


500+ BG, Neg Ketones, Leuk/Nitr/WBC/RBC Pending Labs:
Urine Organic Acids
Plasma Amino Acids
RFA: Rhino/Corona/HMPV Acylcarnitine Profile
Biotinidase Activity
Consults:
• Genetics/Metabolics and Endocrinology:
Consults:
Consults:
Consults:
Consults:
• Genetics/Metabolic and Endocrinology:
Labs: On D10NS+20KCl

7.38/38/-/22 Base Def: 3

Triglycerides: 41
Uric Acid: 5.6 (1.8-4.9)

UA: Clean Catch.


500+ BG, Neg Ketones, Leuk/Nitr/WBC/RBC Pending Labs:
Urine Organic Acids
Plasma Amino Acids
RFA: Rhino/Corona/HMPV Acylcarnitine Profile
Biotinidase Activity
Labs: On D10NS+20KCl

7.38/38/-/22 Base Def: 3

Triglycerides: 41
Uric Acid: 5.6 (1.8-4.9)

UA: Clean Catch.


500+ BG, Neg Ketones, Leuk/Nitr/WBC/RBC Pending Labs:
Urine Organic Acids
Plasma Amino Acids
RFA: Rhino/Corona/HMPV Acylcarnitine Profile
Biotinidase Activity
Non-Ketotic Hypoglycemia
• CV:
• Metabolic: • Heart Failure, Shock
• Glycogen Storage Disease
• Glycogen Synthase def
• Glucose-6 Phos defi (VonGierke) • FEN:
• Debrancher def (Cori’s) • Hepatitis/Alpha-1-Anti-trypsin def
• … • Reye’s Syndrome
• Gluconeogensis (Release)
• Glucose-6 Phos • ENDO:
• Fructose 1,6 Deficiency / Hereditary • Hyperinsulinism
Fructose Intolerance
• GH deficiency
• …
• Hypothyroidism
• Galactosemia
• Adrenal Insufficiency
• Amino Acid D/o’s
• Propionic Acidemia
• Methylmalonic Aciduria • MISC:
• … • Ketotic Hypoglycemia
• Fatty Acid Oxidation: • Toxins:
• Medium-chain Acyl-Coa Dehydrogenase • Insulin, Sulfonylurea
def • Munchausen’s
• Ethanol
• Beta-blockers
• Beckwith-Wiedemann Syndrome
Non-Ketotic Hypoglycemia
• CV:
• Metabolic: • Heart Failure, Shock
• Glycogen Storage Disease
• Glycogen Synthase def
• Glucose-6 Phos defi (VonGierke) • FEN:
• Debrancher def (Cori’s) • Hepatitis/Alpha-1-Anti-trypsin def
• … • Reye’s Syndrome
• Gluconeogensis (Release)
• Glucose-6 Phos
• Fructose 1,6 Deficiency / Hereditary • ENDO:
Fructose Intolerance • Hyperinsulinism
• … • GH deficiency
• Galactosemia • Hypothyroidism
• Amino Acid D/o’s • Adrenal Insufficiency
• Propionic Acidemia
• Methylmalonic Aciduria
• …
• MISC:
• Fatty Acid Oxidation: • Ketotic Hypoglycemia
• Medium-chain Acyl-Coa Dehydrogenase • Toxins:
def • Insulin, Sulfonylurea
• Munchausen’s
• Ethanol
• Beta-blockers
Clinical Suspicion
• Birth weight: 5.16kg = 99%tile
• Admit weight:14.5kg = 99%tile. Height: 88cm (98%tile)
• No Hepatomegaly, Syndromic features

Working Diagnosis: Hyperinsulinemia


Re-test to confirm: Thorton et al, 2015
Re-test to confirm:
NonKetotic Hypoglycemia

Sensitivity: B-hydroxybutarate>Urinary Ketones

Fatty Acid Oxidation Defects:


• Inc’d FFA’s

Hyperinsulinemia:
• Dec’d FFA’s (Lipogenesis)
Re-test to confirm:

D10 D7.5…......D5.......D2.5.....
Re-test to confirm: Insulin: 6.2 (4-45)
FFAs: 0.26 (<1.0)
Lactate: 1
B-Hydroxy B: 0.1
Coritsol: 1 (5-10)
Growth Hormone: 0.71

BG: 47mg/dL
Re-test to confirm:

Insulin: <1.0 Insulin: 6.0


Re-test to confirm:

N= 90 Hyperinsulinemia w/ Hypoglycemia
~1/3 w/ Undetectable insulin levels
- No Statistical correlation

Al-Otaibi, et al 2013
Re-test to confirm:

Ferrara, et al 2016
Re-test to confirm: Insulin: 6.2 (4-45)
FFAs: 0.26 (<1.0)
Lactate: 1
B-Hydroxy B: 0.1
Coritsol: 1 (5-10)
Growth Hormone: 0.71

Hypoglycemia-associated autonomic
failure (HAAF)

-Blunted neurogenic response to


repeated episodes of hypoglycemia.
BG: 47mg/dL
Hussain, et al 2003, Thorton et al 2013.
Hyperinsulinemia “Hyperinsulinism”
• AKA:
• Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)
• Congenital Hyperinsulinism (CHI)
• Familial Hyperinsulinemic Hypoglycemia (FHH)
• Primary Islet Cell Hypertrophy

• Not including Insulinomas (MEN1), exogenous.

• Heterogeneous Disorder
• Birth-Childhood
• Degree of hypoglycemia/hyperinsulinemia
• Presenting symptoms
• Response to therapy
Hyperinsulinemia
• Epi: 1:30,000 births

• Pathophys:
• Many genetic mutations of the insulin regulation in the B-cells.
• Autosomal Recessive>>Dominant mutations
Hyperinsulinemia

• Insulin: Anabolic Hormone


• Promotes:
• Glucose transit into Muscle/Fat
• Glycogen Synthesis.
• Growth (IGF-1)

• Inhibits:
• Glycogenolysis, Lipolysis(FFO), Ketone production, Proteinolysis
Hyperinsulinemia
• Clinical Features:
• Infant:
• Poor feeding, Jitteriness, Lethargy
• LGA (1/3)
• Hypoglycemia despite oral feeds.

• Recurrent Hypoglycemia
• Neurologic Symptoms: Seizure, Coma
Hyperinsulinemia: Diagnosis
• Hypoglycemia, Non-ketotic, Non-acidotic.
• Short durations of euglycemia post feeds (< 1-2hr)
• Inappropriately elevated Insulin levels
• Normal levels support, undetectable cannot exclude

• Glucagon-Responsive (Excessive)
Hyperinsulinemia: Diagnosis
Glucagon: 30mcg/kg IM/IV
10,20,30-min post-
administration

(+) Response >30mg/dL rise


BG: 91mg/dL

Suggestive of insulin-driven
glycogenolysis/storage in
hepatocytes
BG: 47mg/dL
Hyperinsulinemia: Management
• Euglycemic (Neonate>50mg/dL, Child > 60-80mg/dL)
• GIR: 10-40mg/kg*min. May need >D10 (Central Line)
• Frequent BG monitoring

• Diet: Endocrinology/Metabolics Nutrition


• OraGel, Pixie Sticks
• Sick-day dosing
Hyperinsulinemia: Management
• Diazoxide: Inhibition of Sulfonylurea Receptors
• 8-10mg/kg/day div TID

• +Cholorothiazide (Diuril): 8-10mg/kg/day BID


• - Mitigates edema/fluid retention.

RESCUE:
• Glucagon Kits
Hyperinsulinemia: Management
• Alternatives:
• Octreotide
• Sirolimus
• Ca-Channel Blockers

• Surgical:
• Focal pancreatic hypertrophy
• Uniparental disomies
• Failed pharmacologic therapies
Hyperinsulinemia: Morbidity
• Neurological Sequelae
• Children/Neonates: Higher metabolic rates
• Head to body ratio
• Seizures

• Developmental
• Psychomotor Delay/Retardation (21-44%)
• Motor/Speech
• Cognitive Deficits (memory, arithmetic)
• Epilepsy (18-25%)
Summary:
• Hypoglycemia: Intake/Production/Storage/Utilization
• Clinical Examination>Laboratory Data

• Hyperinsulinemia:
• Variable Presentation/Pathology
• Non-Ketotic, Non-acidotic, Unremitting Hypoglycemia.
• Insulin Levels: “Abnormally Normal”
• Undetectable levels do NOT exclude diagnosis
• Glucagon Challenge. (+) > 30mg/dL rise.
• Treatment: Acute:
• Dextrose-containing fluids (GIR 10-40), Glucagon, OraGel
• Treatment: Maintenance:
• Diazoxide + Diuril.
• +/- Surgery
Summary:
References:
• Uptodate.com
• Ferrara, Christine, Payal Patel, Susan Becker, Charles A. Stanley, and Andrea Kelly.
“Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and
Children.” The Journal of Pediatrics 168 (January 2016): 212–19.
https://doi.org/10.1016/j.jpeds.2015.09.045.

• Hussain, K., P. Hindmarsh, and A. Aynsley-Green. “Neonates with Symptomatic


Hyperinsulinemic Hypoglycemia Generate Inappropriately Low Serum Cortisol
Counterregulatory Hormonal Responses.” The Journal of Clinical Endocrinology &
Metabolism 88, no. 9 (September 2003): 4342–47. https://doi.org/10.1210/jc.2003-030135.

• Lonlay, Pascale de, Jean-Christophe Fournet, Guy Touati, Marie-Sylvie Groos, Delphine
Martin, Caroline Sevin, Véronique Delagne, et al. “Heterogeneity of Persistent
Hyperinsulinaemic Hypoglycaemia. A Series of 175 Cases.” European Journal of Pediatrics
161, no. 1 (October 2002): 37–48. https://doi.org/10.1007/s004310100847.

• Thornton, Paul S., Charles A. Stanley, Diva D. De Leon, Deborah Harris, Morey W.
Haymond, Khalid Hussain, Lynne L. Levitsky, et al. “Recommendations from the Pediatric
Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates,
Infants, and Children.” The Journal of Pediatrics 167, no. 2 (August 2015): 238–45.
https://doi.org/10.1016/j.jpeds.2015.03.057.