Pediatric Hypoglycemia
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A 2 year old boy was admitted multiple times with vomiting, loose stool, lethargy and severe dehydration and hypoglycemia. Critical sample and tests showed lactic acidosis, ketones in urine and normal hormone and acylcarnitine levels, consistent with a diagnosis of ketotic hypoglycemia. Differential diagnoses included inborn errors of metabolism like fatty acid oxidation defects or gluconeogenesis defects based on the recurrent presentation and metabolic profile.
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Pediatric Hypoglycemia
- 1. CASE PRESENTATION Dr. Fahad Fayyaz Butt Pediatric Resident 2
- 2. CASE: 2y, boy Complaints: Vomiting 2days Loose stools-2days lethargic 1 day
- 3. EXAMINATION: General Condition: Lethargic and sick looking, deep rapid breathing, delayed capillary refill >3secs, severely dehydrated Vital signs: HR: Tachycardic RR: Tachypneic Temp : afebrile Spo2: 99% saturation B.P: Normal B.P.
- 4. SYSTEMIC EXAM: CNS: Drowsy and lethargic otherwise unremarkable CVS: S1+S2+No murmur GIT: Soft, No organomegaly, non-tender Chest: Bilateral equal air entry, no adventitious sounds ENT: Normal
- 5. CBG : Hypocount: 60 mg/dl pH: 7.03 PCO2: 6.5 HCO3: 1.6 Base Excess: -28 Glu: 60 Lactate: 13.9 Electrolytes: normal
- 6. TREATMENT GIVEN IN EMERGENCY : IV 0.9% NaCl Boluses IV D10% Bolus Provisional Diagnosis: •Gastroenteritis and Severe Dehydration
- 7. Past medical history: No prior hospitalization or a severe presentation in ER Birth History: Term , NVD, Admitted in NICU after birth due to hypoglycemia for few hours , Birth Weight: 3.5kg (mother has no reports) Vaccination: Current Nutritional: On regular family diet, high amount of milk intake. Development: Age -appropriate Family history: one of two siblings. Consanguineous No history of miscarriage, still born or developmental delay, significant Metabolic disorder in family
- 8. SUMMARY: 2 year old boy Vomiting/loose stool and lethargy for 2 days Severe dehydration with hypoglycemia CBG with Metabolic acidosis No significant past medical/family history. Patient sometime looks sweaty at night and wakes up hungry.
- 9. Differential Diagnosis: Gastroenteritis with severe dehydration Septic Shock Inborn Error of Metabolism
- 10. INVESTIGATIONS: Labs: Patient value CBC WBC 33.1 x 10^3 ABN:22.9 HGB 9.3 g/dl PLT 587 x 10^3 CRP <5 mg/L LFTs Albumin 4.9 g/dL ALP 283U/L ALAT 181 U/L T. Bil 0.1 mg/dL Total Protein 8.3 g/dL PT 12.5 secs APTT 32.4 secs INR 1.39
- 11. Labs: Patient value Urea and electrolytes Sodium 135 Potassium 4.1 Chloride 106 HCO3 5 Urea 31 creatinine 0.3
- 12. Labs: Patient value Blood Culture No growth Urine Routine WBC: 0-3 RBC: Nil Culture No growth Stool Routine No Pus Cells No RBCs No Ova And Parasites Culture No Growth Rota & Adenovirus Negative Ammonia 43 umol/L , 17-68 INVESTIGATIONS:
- 13. COURSE IN THE HOSPITAL: Day 1: •Admitted to ICU •IV NaHCO3 •IV D10% +0.45%NaCl •IV Ceftriaxone •Clinical Status: Markedly Improved • After 24hours in ICU: • CBG: pH: 7.4, pCO2: 32, HCO3: 20.1 • Lac:2.7 Glu: 85mg/dl
- 14. Day 2 & 3 : Shifted to ward Full Oral ,Vitally stable, had no episode of fever Discharged with instructions
- 15. Since then Child was admitted in Hospital for a total of five times in one year with Identical picture: Chief complaints Blood gas picture : Low blood glucose and metabolic acidosis Course in hospital
- 16. 2ND EPISODE: Complaints: runny nose and cough ,fever and vomiting. hypocount: 35mg/dl in ER CBG showed severe Metabolic Acidosis Critical Sample was taken
- 17. Indications for critical Sample : 1. Recurrent hypoglycemia 2. Not explained by history and physical examination
- 18. HOW TO COLLECT THE SAMPLE: 1. gray-top tube :Glucose, lactate, 2. red tiger-top tube : Insulin, GH, cortisol, 3. Filter Paper: Acylcarnitine profile 4. dark green-top tube : FFA, 5. lavender-top tube : C-peptide from 2 mL in a lavender-top tube (0.5 mL minimum). 6. Send next voided urine for quantitative determination of organic acids, reducing substances and ketones
- 19. CRITICAL SAMPLE IN LH Blood FFA Insulin C-peptide Growth Hormone Cortisol Lactate Acylcarnitine on filter paper Urine Urinary Ketones Urinary Organic acids Urinary Reducing Substances
- 20. HYPOGLYCEMIA • Definition • Clinical Features • Pathophysiology • Differential diagnosis • History and PE • LH approach • Management
- 21. DEFINITION OF HYPOGLYCEMIA : Laboratory Serum: less than 50mg/dl Whipple’s triad
- 24. Excessive Utilization of Glucose: Hyperinsulinism Defect in Ketogenesis Defect in Ketolysis Fatty acid Oxidation Defects Under Production of Glucose: Glycogen storage disease Gluconeogenesis defect Hormonal Defects: Cortisol or growth hormone deficiency
- 25. HYPERINSULINISM Insulin Glucagon Gluconeogenesis Glycogenesis Lipogenesis Hypoglycemia Pathogenesis FFA Low Insulin High C-peptide High Growth Hormone High Cortisol High Lactate Normal AcylCarnitine Low Urinary Ketones Low Urinary Organic Acids Absent
- 26. CORTISOL DEFICIENCY Cortisol Reduced protein Breakdown Gluconeogenesis Hypoglycemia Pathogenesis FFA Raised Insulin Low C-peptide low Growth Hormone High Cortisol Low Lactate Normal Acylcarnitine Normal Urinary Ketones Raised Urinary Organic Acids Absent
- 27. GROWTH HORMONE DEFICIENCY Growth Hormone Insulin sensitivity Peripheral glucose Uptake Hypoglycemia Pathogenesis FFA Raised Insulin Low C-peptide low Growth Hormone Low Cortisol High Lactate Normal Acylcarnitine Normal Urinary Ketones Raised Urinary Organic Acids Absent
- 28. GLUCONEOGENESIS DEFECTS 1. Glu. 6 Phosphatase 2. Fru. 1.6 Diphoshaphatase 3. PEP Cabroxykinase Gluconeogenesis Hypoglycemia Pathogenesis FFA Raised Insulin Low C-peptide Low Growth Hormone High Cortisol High Lactate High Acylcarnitine Normal Urinary Ketones High Urinary Organic Acids Absent Lactate Alanine Glycerol 3 P
- 29. GLYCOGENOLYSIS DEFECT 0, Gly. Synthase 3, Debranching Enzy. 6, Liver Phophorylase Enzy. 9, Phosphorylase kinase Glucose Release Hypoglycemia Pathogenesis FFA Raised Insulin Low C-peptide low Growth Hormone High Cortisol High Lactate Normal to High Acylcarnitine Normal Urinary Ketones high Urinary Organic Acids Absent Ketone production
- 30. FATTY ACID OXIDATION DEFECTS Acyl CoA Dehydrogenase Beta oxidation of FA Hypoglycemia Pathogenesis FFA High Insulin Low C-peptide low Growth Hormone High Cortisol High Lactate Normal to High Total carnitines and acylcarnitines Total Acylcarnitine Urinary Ketones Low Urinary Organic Acids Dicarboxylic acids Ketone production
- 31. KETOGENESIS DEFECTS HMG CoA Lyase HMG CoA synthase Ketone production Hypoglycemia Pathogenesis FFA High Insulin Low C-peptide low Growth Hormone High Cortisol High Lactate Normal to High acylcarnitines Acylcarnitine Urinary Ketones Low Urinary Organic Acids Dicarboxylic acids
- 32. KETOLYSIS DEFECTS SCOT def. Beta Ketothiolase deficiency Ketone utilization Hypoglycemia Pathogenesis FFA High Insulin Low C-peptide low Growth Hormone High Cortisol High Lactate Normal acylcarnitines - Urinary Ketones High Urinary Organic Acids -
- 33. Excessive Utilization of Glucose: Hyperinsulinism Defect in Ketogenesis Defect in Ketolysis Fatty acid Oxidation Defects Under Production of Glucose: Glycogen storage disease Gluconeogenesis defect Hormonal Defects: Cortisol or growth hormone deficiency
- 34. HISTORY: History Of presenting Illness Age: • Neonate to 2 years of life: MC age of Presentation • Toddlers or older children: Toxin intake Trigger: • Period Fasting Specific Foods • Milk products • fruit juices Past Medical History • Prior ER visit or Hospitalizations: labelled as seizure disorders or other disorders. Birth History • Antenatal Preeclampsia , GDM • Natal LGA • Postnatal Hypoxic injury at birth Family history • Unexplained deaths in family • Affected members in family Developmental Milestones • Appropriate for age
- 35. PHYSICAL EXAM: General Examination: Dysmorphic features: Mid facial defects Growth Charts : Failure to thrive Short stature Underweight Neonate: Macrosomia Vital Signs RR: Deep rapid breathing Temperature: Hypothermia or fever Systemic Examination: GIT: Hepatomegaly Umbilical hernia or omhpalocele Skin : Hyperpigmentation Eye: Cataract Genitalia Ambiguous genitalia
- 37. APPROACH
- 38. Hypoglycemia Urine Ketones Non-glucose Reducing substances Galactosemia H. Fructose Intolerance Tyrosinemia Approach Continued…
- 39. Ketones Positive Negative Hyperinsulinemia + Low FFA + High Insulin And C-peptide FA Oxidation Defects +High FFA +Undetectable Insulin & C- Peptide Approach Continued…
- 40. Ketones Positive Serum Lactate High Normal 1. Growth Hormone 2. Adrenal Insufficiency 3. Idiopathic Ketotic Hypoglycemia Approach Continued…
- 41. High Serum Lactate Hepatomegaly Glycogen storage disease GSD1 Gluconeogenesis defects No Hepatomegaly Organic Acidopathy Ketolysis Defect Approach Continued…
- 42. TREATMENT
- 43. Glucose <50mg/dl Conscious Oral trial Recheck Drowsy IV access IV D10% Commence IV infusion <50mg/dl: adjust infusion >50mg/dl: Introduce oral feeds No IV access IM Glucagon Target: 60- 140mg/dl
- 44. HYPOGLYCEMIA • Definition • Clinical Features • Pathophysiology • Differential diagnosis • History and PE • Critical sample • LH approach • Management
- 45. CRITICAL SAMPLE OF THE PATIENT Blood Patient values Normal range FFA - - Insulin 3.2 4.0-16 C-peptide 1.8 1.8-4.7 Growth Hormone 5.2 0-3 Cortisol 1681 69-328 Lactate 11.4 0.5-2.2 Acylcarnitine on filter paper Increased Level of all Acylcarnitine
- 46. CRITICAL SAMPLE IN LH Urine Patient Values Urinary Ketones 3+ Urinary Organic acids Lactic Acids Urinary Reducing Substances +Glucose (taken after glucose infusion) Urinary Amino Acids All in normal range except borderline increased levels of Alanine, Valine , Phenylalanine and Leucine
- 47. OTHER TESTS Tests Values Normal Range TSH 1.37 0.80-6.26 T3 4.7 3.96-8.14 T4 13.8 10.45-22.35 CPK levels 123 0-228 Total and Free Carnitines 70.4 39.4 35.0-84.0 24.0-63.0
- 48. 2 year old boy Vomiting/loose stool and lethargy for 2 days Admitted 5 times with Severe dehydration & hypoglycemia No significant past medical/family history. Patient sometime looks sweaty at night and wakes up hungry. Labs: 1. CBG: Metabolic acidosis with hypoglycemia 2. Critical Sample: Lactic acidosis , rest of profile normal 3. Urinary tests done: Ketone 3+ 4. Other tests: CPK: Normal , TFTs: Normal Case : Ketotic Hypoglycemia for evaluation
- 49. Glucose Acidosis Lactic acid Ketones Hepatomegaly Others tests Patient Low Present Present Present Absent Normal, mild deranged LFTs Hyperinsulinism Low Absent Absent Absent Absent Insulin and C- peptide FA Oxidation defects Low Absent Absent Absent Present Acylcarnitine profile Elevated dicarboxylic acids Hormone deficiency Low Present Absent Present Absent Hormone levels P.E. Gluconeogenesis Low Present Present Present Present Hyperuricemia Hyperlipidemia Glycogen storage Disease Low Present +/- Present Present Present Deranged LFTs Ketogenesis defects Low Present Absent Absent Present Elevated acetoacetate levels Ketolysis Defects Low Present +/- Present Present Absent Elevated dicarboxylic acids
Editor's Notes
- Vomiting: Several times a day , normal amount, non bilious, non bloody. Not associated with coughing or food intake Loose stools: several times a day, watery, normal amount, non bloody Lethargic: Since morning of the presentation to ER. CNS: Meningitis , encephalitis ( fever, irritability, petechial rash, convulsions or abnormal movements) GIT: Intussception ( bouts of abdominal pain or irritability), appendicitis( fever) Respiratory: pneumonia ( cough or difficulty breathing) Kidney ,Circulation: UTI (fever , no irritability on passing urine, no abdominal pain ), Urinary output Viral : (URTI , rash, anyone else is sick at home, Day care ) Ingestions: No observed toxin ingestion Chronicity : was he well before this event ( IBD) Travel History: non regional microbes etiology ( Hep A , amoeba ) No history of : Fever ,Rash ,Irritability , abdominal pain ,Cough or Breathing difficulty, Convulsions or Abnormal Movements urinary habits (past 2 days urine reduced) circulation, perfusion status Was completely well prior to this episode Came Back from Pakistan 2 days ago.
- respiratory distress vs shock
- Vitals and general Examination Respiratory distress vs failure Compensated shock
- Summarize CNS: reduced cerebral perfusion or hypoglycemia CVS: no signs of congestive heart failure Chest: no pulmonary edema GIT: soft, no hepatomegaly, non tender ( ?no hepatitis,? no appendicitis? No pyelonephritis ) ENT: no focus of infection ( otitis media or tonsillitis) Skin: no rash of sepsis or viral exanthem,
- Acidosis , low co2 and low HCO3 =Metabolic Acidosis Lactic Acidosis Hypoglycemia: Mention hypocount and emphasize on hypoglycemia Partially compensated metabolic acidosis
- The causes of anion Gap acidosis most relevant here are
- IV antibiotics?????? Emphasoze low glu
- Birth history: GDM??? Birthweight??? Developmental : Gross Motor: He is able to run and walk well, Fine motor: Likes to scribble, Social and Language: Very playful and interactive with other kids with able to say few words Revised History: Mother reveals its common for him to have profuse sweating overnight.
- FBC: WBC: Raised ( infection or ? dehydration ) PLT: thrombocytosis ( DIC would low plt) ( high may be dehydration) LFTs: normal , ALAT raised Coagulation Profile: normal Highlight positive finding
- Blood Culture: Remained no growth Differential Diagnosis: Support for Infection being the sole cause of the presentation became weaker and idea of IEM became more valid.
- Admitted to ICU in view of low GCS and clinical signs and symptoms Clinical Status: Markedly Improved in 24hours with improvement in vitals, consciousness & activity levels CBG: showed marked improvement in pH , HCO3 .
- Discharged: With instructions on when to come to ER , diagnosis : gastroenteritis and severe dehydration and avoid fasting for more than 4-5 hours , have complex carbohydrate overnight and come back for follow up in clinic.
- With an average gap of 1-2 months Chief complaints: history of flu like symptoms, vomiting , reduced oral intake, Blood Gas Picture: Metabolic acidosis, remarkable Lactic Acidosis Course In Hospital : Rapid improvement with correction of dehydration , hypoglycemia, HCO3. with no residual symptoms at time of discharge.
- 2nd episode: 4 months later with complaints of: Runny nose, cough, vomiting and fever 1 day CBG: was very similar to the one on first presentation with severe metabolic acidosis and lactic acidosis. Recurrent Hypoglycemic Episode: with presentation not explaining the extent of lab abnormalities: critical sample was taken in ER prior to glucose infusion
- History: septic shock, burns, Liver disease, malnutrition, Drugs/ Toxin ingestion: Salicylates, Beta-blockers, quinines,
- With Some Individual variation this is the general Hierarchy of clinical signs and symptoms 70-50: Counter regulatory hormones starts acting (catecholamine, glucagon , cortisol and Growth Hormones) 55-35: Autonomic Symptoms: Tachycardia, Tremulousness, Brisk moro reflex 50-25: Neuroglycopenic symptoms: (this is when brain starts receiving less supply) poor feeding , apneic episodes, seizures 40-20 : lethargy 35-5 : Coma and death Surprisingly children especially young children: May remain asymptomatic until glucose falls very low Whipple triad: Low blood sugar, presence of symptoms and resolution of symptoms with administration of glucose.
- Hypoglycemia inhibits insulin which automatically promotes glycogenolysis and gluconeogenesis Activates Counter-regulatory Enzymes: Glucagon and epinephrine: Glycogenolysis in liver and Muscle Epinephrine: Induces Lipolysis thereby providing glycerol for gluconeogenesis and FFA for ketongenesis , sparing glucose for brain utilization Growth hormone: Decreases peripheral sensitivity of insulin receptors , sparing peripheral glucose utilization, increasing blood glucose Cortisol: Mobilizes amino acids namely alanine from muscle for gluconeogenesis
- Infants: don’t have enough glycogen stores in liver ,lipid stores in fat and muscle mass ,their hormonal and enzymatic activity favors constant glucose formation. Older infants and children: Post feeding (6-12 hours) : Glucose is maintained by glycogenolysis (glucagon and epinephrine) which raise blood glucose to be used by RBCS and Brain cells. Beyond 6-12hours gluconeogenesis (glucagon and cortisol) must be activated, the source of carbon which is mainly alanine from muscle cells (followed by Glycerol and lactate) gluconeogenesis can be primary pathway for several day depending on (muscle mass) beyond which lipolysis must be induced ( glucagon, epinephrine and cortisol ) and body reduces gluconeogenesis and uses fatty acid derived products such as Ketone bodies for use. At this point brain adopts to use ketone bodies and spares glucose for RBCs
- Pathology other than IEM causing excessive utilization is : IODM, sepsis and hypoglycemia cases in LH examples…, Post surgical dumping syndrome Underproduction: Inadequate stores: SGA, LBW, IUGR babies ( no glycogen stores , no fat stores) Hormonal Defects: Pan-hypopituitarism , Hypocortisolemia: CAH 21BOH Def. cases in LH examples ,Primary adrenal insufficiency: eg addisons disease cases in LH examples , Growth hormone deficiency
- High level of insulin due to insulinomas, can be iatrogenic cause
- Lactate: depending on liver damage
- Most common MCAD Lactate: Normal to high (depending on liver damage and extent of body needs) Urinary Organic acid: Dicarboxylic acids (medium chain) As acylcarnitines are not being recycled total carnitine decrease, acylcarnitine accumulates C8-C10
- Reduced production results in increase utilization of glucose results in hypoglycemia FFA: back up of cycle results in spilling of FFA in blood Lactate: Normal to high depending on extent of liver damage and its ability to clear it and body needs Carnitine: backing up of the entire cycle reduces the recycling of carnitine results in low total carnitines and raised acylcarnitines Urine organic Acids: backing up of substrated FA accumulates appears as raised dicarboxylic acids in urine
- Reduced peripheral utilization results in increase glucose utilization even though ketones are high . SCOT : succinyl CoA Transferase deficiency Beta-Ketothiolase deficiency: Normal Ammonia levels
- Pathology other than IEM causing excessive utilization is : IODM, sepsis, Post surgical dumping syndrome Underproduction: Inadequate stores: SGA, LBW, IUGR babies Hormonal Defects: Pan-hypopituitarism , Hypocortisolemia: CAH 21BOH Def. ,Primary adrenal insufficiency, Growth hormone deficiency
- A) HOPI 1. Neonate to 2 years of life: Most common presentation age for IEM 2. Toddlers or older children: Toxin intake, Such as Ackee fruit , Aspirin, Beta blockers, quinines, Sulfonylureas 3. Period of Fasting: which may have precipitated the attack , most neonatal period if symptoms occur shortly after meal then hyperinsulinemia? If 6hours or so consider gluconeogenesis, the period may vary between children depending on severity and the presence of disease status. 4. a. Since Ingestion of Milk products: galactosemias b. Since ingestion of fruit juices: Fructose Intolerance B) Past Medical History : which can be attributed to hypoglycemia C) Birth History: D) Pre-eclampsia : IUGR less fat stores, GDM: neonate with transient hyperinsulinemia , LGA: is retrospectively telling you it is IODM, All of these tend to be transient. HIE: panhypopituitarism hypoglycemia and other symptoms. E) Family history : Affected members in family such as: developmental delay, mental retardation, movement disorder, seizure disorder. F) Developmenatal Milestones: significant failure in attaining motor, language and cognitive milestones is feature of several IEM. Which may not be as much apparent if hypoglycemia due to hormonal insufficiencies
- General Examination: Midline facial Defects: Single central incisor, cleft lip and palate,holoprosencephayl, micro-phallus, undescended testicles Growth Charts: FTT: Organic Acidemia, GSD, Gluconeogenesis defects, Short stature: Panhypopituitarism, GH deficiency. Underweight: Idiopathic Ketotic hypoglycemia Neonate: Macrosomia Hyperinsulinism Vital Signs: look for all signs RR: Deep rapid breathing: Acidosis, Temperature: Low sign of hypoglycemia, High may actually be the Infectious trigger rather than simple infection. Systemic Examination: GIT: hepatomegaly GSD, Gluconeogenesis defects, if we are talking about a macrosomic neonate then Umbilical hernia: may point towards Beckwith wiedieman Syndrome along with other abnormalities such macroglossia , hemihypertrophy, ear crease Skin: Hyperpigmentation of gums, lips, crease of hand, sun exposed area, Primary adrenal Insufficiency or Cotisol Insufficiency: Addison’s disease EYE: cataract: galactosemia Genitalia: ambiguous genitalia in Female along with characteristic electrolyte abnormalities the possibility of CAH 21BOH Def.
- Galactosemia: Age of onset of symptoms is since neonatal period with hepatomegaly Fructose Intolerance: With addition of fructose in diet this would be a baby usually during weaning period Tyrosinemia:
- Hyperinsulinemia: Such as IODM, LGA, Beckwith wiedieman Syndrome , Dumping syndrome, Insulinomas FA Oxidation Defects:
- Growth hormone Deficiency: Isolated : young child probably hypoglycemia will be the only symptom and only later/ Older child: Short stature on P.E Pan hypopituitarism: Microphallus, Midline facial defects, later short stature Idiopathic Ketotic Hypoglycemia: is diagnosis of exclusion and has all the normal physiologic findings. He just doesn’t have the capacity to fast to duration that’s considered normal for his age.
- GSD: 0,1,3,6,9 Gluconeogenesis defects: , Phosphoenolpyruvate carboxykinase, Fructose 1,6 diphosphatase For GSD and GNG , you must see the LFTs, CBC, UA, Cholesterol levels, TGL, Creatinine Kinase Organic acidemia: MSUD, Propionic acidemia, Methylmalonic acidemia Ketolysis Defect: SCOT deficiency, Urinary Organicemia and acylcarnitine profile
- Oral Trial: 100ml juice IV D10%: 2ml/kg IM Glucagon: <25kg: 0.5 mg >25kg: 1mg Conscious and recheck in 15mins Commence infusion: requirement varies by age : between 4-8mg/kg/min <50: adjust infusion and consider steroids >50: Introduce oral
- Thyrotoxicosis related lactic acidosis Hypothyroidism in newborns and neonates
- Patient sometimes look sweaty at night and wakes up hungry which shows that he seems to have hypoglycemia after certain duration of fasting without any active disease process