HYPOGLYCEMIA IN PAEDIATRIC PATIENTS.pptx

neonatal cholestasis explained in details

1. HYPOGLYCEMIA IN PAEDIATRIC PATIENTS GUIDE: DR. RUPALI MOHARKAR STUDENT: DR. SAKSHI VASANT

2. Hypoglycemia One of the major metabolic emergencies at any age Has potentially devastating consequences on brain Should always be excluded as the cause of initial episode of convulsions, coma or neurobehavioral alteration in children.

3. DEFINITON: Whipple’s triad: Plasma glucose <60 mg/dL, concurrent CNS or catecholamine based symptoms, and resolution of symptoms when glucose concentration is restored to normal by treatment with glucose. In neonates: 0-4 hours: 25-30 mg/dL, 4-24 hours: 45 mg/dL, > 24 hours: 50 mg/dL ( according to AAP, 2020) In children: Symptomatic hypoglycemia occurs when blood sugar falls below 45 mg/dL. Blood glucose value of 60 mg/dL is suggestive of hypoglycemia , less than 50 mg/dL is considered highly suspicious and 40 mg/dL or less is diagnostic of hypoglycemia . Serum or plasma glucose levels are 12-15 % higher than whole blood (finger prick collection)

4. GLUCOSE HOMEOSTASIS AND PATHOPHYSIOLOGY Plasma glucose concentration is normally maintained within a narrow range by complex interaction between Insulin & Counter-regulatory hormones Hypoglycemia indicates failure of this homeostatic mechanisms The physiologic process of glucose homeostasis is governed by: Endocrine factors Autonomic neuronal factors Substrate availability Fat & protein metabolism

5. Efficiency of this regulatory control is related to Chronologic age Recent feed Food intake As blood glucose level tends to decrease Insulin secretion decreases Counter regulatory hormones: Glucagon, Catecholamines, Growth hormones, Glucocorticoids, Thyroid hormones, ACTH come into action

6. GLUCOSE METABOLISM FED STATE: Within 2-4 hours of food intake, plasma levels of glucose, amino acids, and triacyl glycerol increase. Chylomicron which carry triacyl glycerol also increase. INSULIN SECRETION: Insulin starts to rise when blood glucose concentration is > 70 mg/dL.

7. POST ABSORPTIVE STAGE: Well fed state Early fasting Fasting Prolonged fasting ( starvation) Prolonged starvation 2-4 hours after food 4 -16 hours after food 16- 48 hours without food 2 -5 days without food 5 days without food

8. EARLY FASTING : i . Source of glucose is Glycogenolysis. ii. Glycogen stores are depleted in 16-18 hours FASTING: Source of glucose is Gluconeogenesis. TAG gets converted to FA and glycerol Fatty acid undergoes Beta oxidation providing ATP. Glycerol can be converted to glucose.

9. PROLONGED FASTING/STARVATION: Decreased gluconeogenesis Only source of glucose: TAG gets converted to FA + Glycerol Acetyl CoA TCA cycle Ketone body synthesis

10. PROLONGED STARVATION: TGA stores are depleted, FA low Ketone body synthesis: decreasing Muscle proteolysis occurs causing cachexia

11. METABOLIC FUELS OF FED FAST CYCLE: ORGAN FED EARLY FASTING/FASTING STARVATION LIVER Glucose> FFA FFA> Glucose AA/FFA ( KB not used) HEART FFA> Glucose FFA FFA/KB BRAIN Glucose Glucose Glucose/KB SKELETAL MUSCLE Glucose> FFA FFA>Glucose FFA/KB RBC Glucose Glucose Glucose ADIPOCYTES Glucose> FFA FFA>Glucose FFA

12. In cases of hypoglycemia Inhibition of insulin (1st line of defence ) Increase realease of glucagon (2nd line of defense) Realease of catecholamines , anterior pituitary hormones, ACTH.(3rd line of defence ) Thyroid hormones and growth hormones are not essential for maintenance of blood glucose concentration but have an impact on carbohydrate metabolism. Glucose homeostasis is maintained by glycogenolysis in the immediate post feeding period and by gluconeogenesis several hours after meals. Hepatic glycogen stores are sufficient to maintain plasma glucose for approximately 8 hours.

13. PATHOPHYSIOLOGY During fasting and postabsorptive phase, Plasma glucose is maintained in narrow normal range by adequate substrate ( amino acids, adipose tissue, and hepatic and muscle glycogen), intact enzymatic and metabolic pathways, hormonal regulation for transport and interconversion, and utilisation of metabolic fuels. Insulin enhances glycogen synthesis, inhibits gluconeogenesis and ketogenesis, and activates lipid synthesis, thus increasing peripheral uptake of glucose. Reduction in insulin occurs at a plasma level of < 85mg/dL glucose and reaches minimum at 55mg/dL. This leads to hepatic GLYCOGENOLYSIS.

14. Counter regulatory hormones increase at a glucose level of 68 mg/dL, initially glucagon followed by epinephrine. Glucagon stimulates release of stored hepatic glycogen, and epinephrine promotes glycogenolysis, adipose tissue lipolysis, and hepatic ketoneogenesis . GH and cortisol stimulate hepatic gluconeogenesis. Thus peripheral uptake of glucose is reduced and there is a continuous supply of glucose to the brain.

15. CAUSES OF HYPOGLYCEMIA IN AN OLDER CHILD

16. 1. Accelerated starvation ( ketotic hypoglycemia ) 2. Diabetes Mellitus a) Prodromal to diabetes mellitus b) Hypoglycemia in type 1 DM 3. Hyperinsulinism a)Insulinoma b) Factitious- exogenous insulin administration c) Sulfonylureas ingestion d) Insulin autoimmunity e) Insulin resistance Genetic forms of congenital hyperinsulnism Autosomal dominant form: GCK-HI GDH-HI

17. II. Autosomal recessive form: i . SCHAD-HI 4. Hormone deficiency: a) Hypopituitarism ( GH and ACTH) b) Isolated GH c) Isolated ACTH/Cortisol 5. Critical illness: Sepsis Hepatic failure Renal failure Cardiac failure

18. 6. Disorders of fatty acid oxidation and ketone synthesis i . Carnitine transport and metabolism ii. Hydroxymethylglutaryl CoA lyase deficiency iii. Hydroxymethylglutaryl synthase deficiency iv. Beta- oxidation cycle 7. Miscalleneous Non pancreatic tumour hypoglycemia Disorders of gluconeogenesis: Malnutrition Diarrhoea Malaria Salicylate intoxication Reye syndrome

19. Reactive hypoglycemia ( dumping syndrome) Jamaican vomiting sickness ( ingestion of unripe ackee)

20. Clinical Features: Mostly nonspecific. Symptoms in 2 categories: Due to Activation of ANS & epinephrine release Seen with rapid decline in blood glucose level Due to Decreased cerebral glucose utilization Seen with slow decline in glucose level or prolonged hypoglycemia The glycemic threshold for activation for activation of glucose counter-regulation is higher in children as compared to adults, while the threshold for initiation of symptoms is lower.

21. Autonomic manifestations: ANS symptoms: Anxiety Tremor Tachycardia Cholinergic symptoms: Hunger Sweating Paresthesias Hypothermia

22. Features due to Cerebral Glucopenia Headache Mental confusion Visual disturbances (decreased acuity, diplopia) Organic personality changes Inability to concentrate Dysarthria Paresthesias Dizziness Amnesia Lethargy, Somnolence Seizures Coma Stroke Decerebrate or Decorticate posture

23. Clinical Symptoms as a defence for Hypoglycemia : Plasma Glucose (mg/dL) Slowing of auditory response time 72 Autonomic symptoms 55 Subclinical EEG changes 55 Impaired cognition and judgement ( neuroglycopenic symptoms) 49 Coma and seizures 40

24. Ketotic Hypoglycemia Most common form of childhood hypoglycemia. Presents between the ages of 18 mo & 5 yr Remits spontaneously by the age of 8-9 yr. Represents abnormally shortened fasting tolerance. Hypoglycemic episodes typically occur during periods of intercurrent illness when food intake is limited. At the time of documented hypoglycemia, there is associated ketonuria, ketonemia & elevated FFA. Blood alanine level is low & is diagnostic.

25. Child appear lethargic, drowsy, dehydrated but seizures & coma are uncommon These children have lesser muscle mass, or had transient hypoglycemia in neonatal period or are SGA at birth. Cause of hypoglycemia is deficient alanine availability due to poor muscle bulk, leading to defect in gluconeogenesis. The levels of counterregulatory hormones are appropriately elevated, and insulin conc. are appropriately low, ≤5-10 μU /mL Plasma alanine concentrations are markedly reduced after an overnight fast and decline even further with prolonged fasting. Alanine is the only amino acid that is significantly lower in these children Infusions of alanine (250 mg/kg) produce a rapid rise in plasma glucose

26. Etiology: Defect in any of the complex steps -Oxidative deamination of amino acids -Transamination -Alanine synthesis -Alanine efflux from muscle. -Immaturity of ANS may have a role. Pt is smaller than age-matched controls History of transient neonatal hypoglycemia Spontaneous remission is explained by the increase in muscle bulk with its resultant increase in supply of endogenous substrate and the relative decrease in glucose requirement per unit of body mass with increasing age.

27. However, it is a diagnosis of exclusion as an episodic ketotic hypoglycemia can occur with GSDs, Fanconi-Bickel syndrome, disorders of gluconeogenesis, cortisol deficiency, GH deficiency, short chain fatt y acid oxidation disorders, and organic acidemias ( MSUD, methylmalonic acidemia) Treatment: frequent feedings of a high protein, high carbohydrate diet. During intercurrent illnesses, parents should be taught to test urine for ketones(precedes hypoglycemia by several hours) In the presence of ketonuria, liquids of high carbohydrate content should be given. If not tolerated, the child should be treated with intravenous glucose administration. Short course of steroids can be tried.

28. APPROACH TO A CASE OF HYPOGLYCEMIA Careful elicitation of clinical History Physical examination Critical sampling Investigations

29. HISTORY Age & Gender of patient Relations of symptoms to time & type of food intake. Nature of symptoms whether singular or recurrent. Short duration ( < 4 hrs) : Hyperinsulinism or defect in glycogenolysis Long duration (10-12 hrs): FAO defect or defect in gluconeogenesis Family h/o hypoglycemia in infants or sudden unexplained neonatal or infant death Potential drug exposure ( sulfonylureas, salicylates, insulin) Illness such as malaria, diarrhea Unusual odors , especially when sick History of consanguinity Family history of hypoglycemia

30. Sudden neonatal or infant death in siblings/family Gestational age, birth weight Symptoms of hypoglycemia during neonatal period.

31. Physical Examination Macrosomia or IUGR baby Plethoric appearance Infants, if awake, may be irritable, tremulous, and cranky. Inappropriate affect and mood, lethargy, seizure, or coma. Cataract: Galactosemia Decreased subcutaneous fat: inadequate glucose stores. Liver size: Glycogen-storage diseases. Hematologic manifestations: Organic acidurias

32. Periorificeal eczematous vesiculobullous eruption: Propionic acidurea , methylmalonic aciduria Characteristic odour: -Sweaty feet: isovaleric aciduria & glutaric aciduria -Maple syrup: MSUD Poor linear growth: GH deficiency

33. Hyperpigmentation of skin & mucosa: Adrenal failure. Genital ambiguity in females: CAH Midline facial and cranial abnormalities: Pituitary h ormone deficiencies, as does micropenis in a male. Hypotonia: Urea cycle defect, MSUD, Organic acidurias Myopathy: FAO, GSD I, III Short stature ( GH deficiency, hypopituitarism) Hyperventilation ( metabolic acidosis, hyperammonemia ) Heart: Gallop rhythm, murmur ( FAO defect)

34. HYPOGLYCEMIA WITH HEPATOMEGALY Glycogen storage disorders ( Type 1, 3, 4) Defect of gluconeogenesis ( Glucose 1, 6 bisphosphatase ) Galactosemia Fructose intolerance

35. Critical Samples Biochemical tests: Blood sugar CBC Electrolytes Blood gases Insulin C- peptide Cortisol GH Urine pH Ketones Reducing substances Organic acids Carnitine derivatives Dicarboxylic acid

36. Metabolites: Lactate Pyruvate Plasma amino acids Ammonia Free fatty acids Betahydroxybutyrate Acetoacetate Total and free carnitine Acyl carnitine Others: Plasma glucose Uric acid Serum electrolytes pH, bicarbonates ALT AST

37. Hormones and Metabolites

38. If a blood sample during spontaneous hypoglycemia is not available, fasting study is planned depending on age & suspected diagnosis; while monitoring blood sugar When blood glucose drops below 40mg/dl blood should be collected. Specific loading & challenge tests with Galactose or glycerol done in the past are not recommended

39. Temporal relation of hypoglycemia Within 1-2 hrs of feeding: IEM After 10-12 hrs after meal: impaired gluconeogenesis due to substrate deficiency or ketotic hypoglycemia After introduction of lactose: Galactosemia After introduction of proteins & weaning diet: (MSUD, Organic acidurias, urea cycle defect)

40. CLINICAL AND BIOCHEMICAL FEATURES OF INBORN ERRORS OF METABOLISM

41. GSD1a Von Gierke’s Disease: - Glucose 6 phosphate deficiency - Onset: Early neonatal to 3-4 months - FTT, growth retardation, doll’s facies, earlt morning hypoglycemia,hepatomegaly , xanthomas, recurrent diarrhea . - hypoglycemia with short fasting, Poor response to glucagon, Lactic acidosis, hyperuricemia, hyperlipidemia , Normal liver function, platelet aggregation & adhesion defect. GSD1b: - G-6 phosphatase tranlocase deficiency - All the above features plus - Neutropenia, recurrent infections, Inflammatory bowel disease

42. GSD III Cori’s or Forbes disease: -Onset: Infancy to childhood -Debrancher enzyme deficiency -Hepatomegaly, short stature, skeletal myopathy, cardiomyopathy, splenomegaly+/- - hypoglycemia with short fasting, ketosis, normal lactate & uric acid, hyperlipidemia , abnormal liver enzymes.

43. GSD IV Anderson’ Disease: - Branching enzyme deficiency. - Onset: First few months of life - Hepato-splenomegaly, progressive liver cirrhosis, ascites, portal HT. - Abnormal glycogen on liver biopsy. GSD VI Hers disease: -Liver phosphorylase deficiency -Onset: early childhood. -Hepatomegaly, short stature -Mild hypoglycemia & hyperlipidemia , ketosis, Normal uric acid & lactate

44. GSD IX Phosphorylase kinase deficiency: - Onset: Early childhood - Short stature, hepatomegaly - Mild hypoglycemia with ketosis, raised cholesterol, abnormal liver enzymes, normal response to glucagon • GSD XII Fanconi- Bickel Syndrome: - GLUT 2 defect - Onset: First year of life - FTT, short stature, rickets, hepato- Renomegaly , Proximal RTA - Mild fasting hypoglycemia , normal lactate & liver enzymes, abnormal bone markers, glycosuria, bicarbonate wasting, phosphaturia, aminoaciduria

45. GSD 0: -Misnomer as glycogen is not stored. -Glycogen synthase deficiency. -Onset: Early infancy. -Early morning drowsiness, seizures NO HEPATOMEGALY -Post feed hypoglycemia , hyperlactic acidemia , fasting hypoglycemia with poor response to glucagon

46. Galactosemia: -Galactose-1-phosphate uridyl transferase(GALT) - Onset: Neonatal period - Poor feeding, vomiting, FTT, jaundice, hepatomegaly, prolonged bleeding, hemolytic anemia , RTA, cataract, E.coli sepsis - Hypoglycemia , urine for reducing substances positive, Qualitative & quantitative estimation of GALT activity.

47. Medium chain acyl CoA deficiency(MCAD): - Onset 2-3 yrs - Vomiting lethargy, seizures, cardiorespiratory collapse, hepatomegaly, Reye’s-like illness - Hypoketotic hypoglycemia , abnormal liver enzymes, prolonged PT, raised urinary dicarboxylic acids, secondary carnitine deficiency •Long chain acyl CoA deficiency(LCAD): - Onset: newborn - Muscle weakness, rhabdomyolysis, cardiomyopathy, arrhythmia, sudden death - Hypoketotic hypoglycemia , dicarboxylic aciduria, abnormal acyl carnitine profile

48. MANAGEMENT Hypoglycemia is a medical emergency Goal: maintain RBS > 70 mg/dL Conscious child: 15 g (0.3 g/kg) of rapidly absorbed carbohydrate After 15 min If no improvement, Parenteral glucose should be administered ( 2ml/kg) (0.2g/kg) D10 IV over 1 minute After 15 min If RBS still < 70 mg/dL, then repeat bolus of 5 ml/kg of D10 given Continuous infusion of D10 at 6-8 mg/kg/min

49. Blood glucose monitoring every 30 – 60 min initially, later every 2-4 hours ( after achieving euglycemia) to modify the infusion If required higher concentration of glucose should be used, requiring a central line. In case of severe hypoglycemia , parenteral glucagon is effective ( hyperinsulinemia, sulfonylurea agent poisoning, difficult IV access) and given as 0.03 mg/kg upto a max of 1mg sc / im . Glucagon infusion can be given upto 20 mcg/kg/hr IV. After acute management it is important to delineate the cause and initiate specific therapy.

50. REFERENCES: Nelson textbook of paediatrics IAP textbook of endocrinology Paediatric Endocrinology and Inborn Errors of Metabolism- George Hoffman/ Karl Roth Paediatric Endocrine disorders- Meena Desai, PS Menon, Vijaylakshmi Bhatia

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