Hypoglycemia Sylwia Murawska-Izdebska Department of Pediatrics, Pediatric Endocrinology, Diabetology and Neurology Provincial Polyclinical Hospital in Torun
Definition symptom not a disease too low glucose concetration for tisseu needs glucose concetration < 40mg% (<2,2 mmol/l) neonatal– 1 day of life: <30 mg % – >1 day of life: <40 mg% (<2,2mmol/l) diabetic patient: <70 mg% hiperinsulinism: <60 mg%
A little physiology – glucose suorce digestive tract glycogenolisis gluconeogenesis i lipolisis t minits 3-4 hours 6-12 hours
A little physiology – glucose suorce digestive tract glycogenolisis gluconeogenesis i lipolisis t minits 3-4 hours 6-12 hours
A little physiology – glucose suorce digestive tract glycogenolisis gluconeogenesis i lipolisis t minits 3-4 hours 6-12 hours
A little physiology – glucose suorce digestive tract glycogenolisis gluconeogenesis i lipolisis t minits 3-4 hours 6-12 hours
Normoglycemia hyperglycemics mechanisms hypoglycemics mechanisms intestinal absorption glucose rilease from glycogen saving in insulin-dependet tissues (liver, muscless, blood cells) gluconeogenesis increased use of glucose rebuilding glucose stores Hormony działające hiperglikemizująco: glukagon, GKS (kortyzol), adrenalina, hormon wzrostu Hipoglikemizuąco: insulina, IGF1
Hypoglycaemia etiology hormonal disorders excess hormones insulin hormonal deficiency growth hormone cortisol adrenaline glucagon metabolic disorders carbohydrates galactosemia fructosemia glikogenosis lipids fatty acids 𝜷-oxydation disorders proteins tyrosinemia zaburzona równowaga między mechanizmami hiperglikemizującymi i hipoglikemizującymi
Hormones - insulin allows to enter glucose into cells ↓ gluconeogenesis i glicogenolisis ↓ release of substrates to gluconegonesis (protein, fats) glucogose-independent: brain, nerve fibres, retina, kidney, adrenal glands, erythrocytes, blood vessels
2-4h „after” – glucagon, adrenaline glycogenolisis, protein gluconeogenesis, ↑ ketones production the effect is maintained for 30-60‘ action reduced/abolished when: glycogen storages reduced through exercise, recetn hypoglycemia, less food intake, eg during infection alcohol was consumed (!) High dose of insulin was given adrenaline: ↑ glicogenolisis ↑ protein gluconeogenesis ↓ glucose uptake by pripheral tissues ↓ insulin production
5-12h „after” – cortisol, growth hormone ↑ hepatic gluconeogenesis ↑ liver response to glucagon ↑ release of substrates for gluconeogenesis from peripheral tissues (muscle, fat tissue) ↓ glucose uptake by muscle, fat tissue, lymphatic system ↑ glycogen synthesis growth hormone: ↑ release of substrates for gluconeogenesis (proteins, fats) ↑ glycogenolysis and gluconeogenesis ↓ glucose uptake by peripheral tissues
Clinical symptoms hypoglycemia direct effect central nervous system defense mechanisms sympathetic nervous system
Clinical symptomes – – central nervous systme (neuroglycopenia) weakness, dizziness trouble with concentration and short-term memory visual disturbances (double, blurry, difficulty in color distinguishing) hearing impairment headache unusual behavior, bad judgment of the situation blurred speech, unstable gait, motor coordination disorder drowsiness, loss of consciousness convulsions coma Zaburzenia śwaidomości, dziwne zachowanie się, podobne do upojenia alkoholowego lub choroby psychicznej, „endokrynny zespół psychotyczny” (depresja, dysforia, splątanie, zaburzenia koncentracji)
Clinical signs – autonomic nervous system irritability, anxiety hunger nausea, vomiting trembling pale, cold sweat dilated pupils tachycardia, palpitations ripple in the chest and abdomen Objawy ze strony OUN - sedacja, która stopniowo się pogłębia, aż Stopniowo dochodzi do całkowitej utraty przytomności i głębokiej śpiączki z przyśpieszonym, lecz płytkim oddechem, zwolnienia czynności serca, zniesienia odruchów źreniczych na światło, zniesienia odruchu rogówkowego, •obniżenia temperatury ciała. wystąpienie prymitywnych automatyzmów
Clinical symptoms - age dependence the younger the child the less characteristic symptoms of hypoglycaemia newborns - often lack symptoms (90%!) infant - most often lost of contact, drowsiness, convulsions older children - symptoms are more characteristic, as in adults
Clinical symptoms - newborn thermoregulation disorders (cold) muscular tremors, convulsions apnea cyanosis lowering muscle tension unwillingness to suck apathy, pathological cry heart failure cardiac arrest
Newborn – risk groups premature babies the baby is too small or too high in weight compared to the gestational age infection perinatal hypoxia chilling defects in organs or systems serological conflict diabetic mother abuse of alcohol by the mother
Neonatal hypoglycaemia transitional: up to 12h after childbirth it usually gives up to 5 days of life cause: insufficient glycogen stores / feeding premature babies: 15:1000 survived: about 5% transitional over 5 days of life cause: hormonal disorders, metabolic defects
Why are we afraid of hypoglycemia ?? glucose - the main source of energy for the central nervous system safe for the brain is glycemia greater than 60-65 mg% permanent damage to the central nervous system (epilepsy, learning disabilities, epilepsy) particularly dangerous in the newborns and infants when the brain is developing rapidly Istnieje zależność między zdolnością do produkcji glukozy a szacowaną objętością mózgu w każdym wieku. Mózg rośnie najintensywniej w pierwszym roku życia, dlatego hipoglikemia przewlekła bądź nawracająca może prowadzić do upośledzonego rozwoju i czynności. Mózg noworodka ma pięciokrotnie większą zdolność do wykorzystania ciał ketonowych w porównaniu do mózgu osoby dorosłej. Chociaż zdolność do produkcji ciał ketonowych przez wątrobę noworodka może być pośledzona, szczególnie w przypadku hiperinsulinizmu, który hamuje uwalnianie glukozy z wątroby, lipolizę i ketogenezę. Pomimo możliwości metabolizowania ketonó∑, nie mogą one całkowicie zastąpić glukozy jako źródła energii dal mózgu.
Hyperinsulinism causes: hypersensitivity to leucine hyperplasia of pancreatic β cells disseminated (formerly: nesidoblastosis) focal (formerly: insulinoma) hypersensitivity to leucine syndromes related to hyperinsulinism (hyperinsulinism is only one of many disorders): Beckwith-Wiedemann Syndrome Perlman Syndrome, Simpson-Golabi-Behmel Syndrome Kabuki Syndrome, Costello Syndrome, Ondine Syndrome, Usher Ic Syndrome Glycosylation disorders Ia and Ib
Galactosemia fast growing intoxication after the introduction of milk (3-4 day of life) damage to the liver, kidneys, lenses, nervous system symptoms: hypoglycaemia, diarrhea, vomiting jaundice septicemia (E. coli) death with signs of liver and kidney failure diagnostics: reducing substances in the urine galactose-1-uridyltransferase deficiency In erythrocytes Mowa o klasycznej postaci galaktozemii
Fructosemia a clinical manifestation similar to galactosemia, but later (rarely before 3month of life) - a relationship with the introduction of fruit, sugar symptoms: hypoglycaemia, vomiting reluctance of a child to fructose inhibiting psychomotor development hepatopathy, tubulopathy acidosis frequent urinary tract infections diagnostics: fructose test (hypoglycaemia + lactic acidosis) DNA analysis Test obciążenia fruktozą jest niebezpieczny, może być wykonany tylko w szpitalu
Glycogenosis defect of glucose release from hepatic glycogen liver types: Ia, Ib, IIIb, IV, VI, IX inheritance mainly AR (exception type IX - conjugate to X) cumulative incidence 1: 20,000 (most common type I) type-dependent symptoms (heaviest type I) inhibiting physical development, doll face hepatomegaly with hepatopathy, hypoglycaemia, lactic acidosis, ketonuria, diagnostics: tests, liver biopsy, enzymes, DNA Typ I – von Gierke – Choroby spichrzania glikogenu Częstość ok. 1:40000 Dziedziczenie AR Wyjątek GDS VI a recesywne sprzężone z chromosomem X Glikogenozy Wątrobowe Hipoglikemia (pomiędzy posiłkami) z wyjątkiem GDS II, powiększenie wątroby, kwasica, hiperlipemia Mięśniowe Bez hipoglikemii objawy dotyczą tylko mięśni
Glycogenosis treatment: glucose infusion, maize starch, regular meals, symptomatic complications: liver failure, liver tumors, osteoporosis, renal failure, infections ...
Tyrosinemia fumaryloacetone hydrolase deficiency / defect (type1) succinicacetone toxicity the first months of life symptoms: severe liver and kidney damage hypoglycemia 30% of liver neoplasia (carcinoma hepatocellulare) diagnostics: slight increase in serum and urine tyrosine levels succinacetone in serum or in urine - basis of diagnosis (GC-MS) ↑ AFP (acute phase of the disease) Niedobór/defekt hydrolazy fumaryloacetonu Zaburzenia krzepnięcia, żółtaczka, wodobrzusze, hepatomegalia Białkomocz, hiperfosfatura, glukozuria, aminoacyduria Tubulopatia z krzywica witamino D-oporną Może ujawnić się jako ostra neuropatia obwodowa, może przypominać porfirię Chromatografia gazowa połączona ze spektrometrią masową tyrozynemia noworodkowa przejściowe zaburzenie związane z niedojrzałością oksydazy p-hydroksyfenylopirogronowego wcześniaki i niektóre młodsze niemowlęta karmione sztucznie Nie stwierdza się obecności bursztynyloacetonu, podwyższone stężenie tyrozyny i kwasu p-hydroksyfenylopirogronowego Mija w ciągu kilku tygodiu, czasami pozostawia niewielkie upośledzenie umysłowe
Fatty acids β-oxidation disorders fatty acid oxidation defect - 13 different diseases depending on the enzymatic defect most common in Poland: LCHAD (Kashubian) disclosure when starvation occurs, increased catabolism symptoms: general, independent of hypoglycaemia: disturbances of consciousness, hepatic encephalopathy cardiomyopathy, myopathy, conduction disorders laboratory results: increased concentration of free fatty acids without ketosis ↑ ALT, ↑ CPK, reduced carnitine concentration abnormal profile of acylcarnitine in MS / MS dicarboxylic acidosis in GC-MS profile
Ketotic hypoglycaemia cyclic vomiting syndrome the most common form of hypoglycemia in children (90% of cases of hypoglycaemia in children after 2 years) usually between 1.5-5 years old more often boys the sick children are usually slimmer and lower than their peers (less muscle mass) frequent transient neonatal hypoglycaemia in medical history it usually resolves spontaneously before 8-9 years of age 8-9 rż przyrost masy mięśniowej Contention - twierdzenie
Ketotic hypoglycaemia etiology - unknown (low availability of alanine for gluconeogenesis - adrenergic system immaturity?) clinical symptoms: hypoglycaemia within 12-18 h from the onset of starvation (after 36 h starvation ketotonic hypoglycaemia may occur even in a healthy child) laboratory tests: ketones in urine and blood insulin in the standard for hypoglycemia, ie very low concentration reduced alanine concentration diagnosis: from exclusion (glycogenosis I, III, deficiency of GH) treatment: regular meals prognosis: no permanent breakdown of development Alanina produkowana w mięśniach jest podstawowym substratem do glukoneogenezy. U dzieci z hipoglikemią ketotyczną dożylny wlew alaniny powoduje gwałtowny wzrost glikemii bez wpływu na stężenie pirogronianu oraz mleczanów . Pyruvate – pirogronian, Są też argumenty przemawiające za udziałem niedojrzałosci układu andrenergicznego, a co za tym idzie upośledzeniem sekrecji epinefryny Posiłki bogatobiałkowe, bogatowęglowodanowe. W przypadku choroby prowadzącej do upośledzonego przyjmowania pokarmów –> ocena stężenia ketonów w moczu –> gdy obecne propozycja przyjmowania płynów bogatych w węglowodan, gdy dziecko odmawia picia -> przyjęcie do szpitala i wlew z glukozy.
Trying to starve the planned duration depends on age it is important to exclude β-oxidation disorders of fatty acids - this defect threatens to disturb the heart, to stop including hypoglycaemia: insulin, glucose, free fatty acids, lactic acid, cortisol, growth hormone, protect the dry drop of blood and urine finish with glucagon
Diagnostyka różnicowa trying to starve hypoglicemia No hepatomegaly (glucose, insulin, cortisol, GH, LA, FFA, 𝛃OH-butyrate) norm ketotic hypoglicemia ⇑ insulin hyperinsulinism ⇓ butyrate fatty acids 𝝱-oxidation defect ⇓ hormones deficyt hormo-nalny hepatomegaly ⇑LA defect of gluconeo-genesis ⇓ or norm LA glycogenolysis defect no hypoglicemia mild
Reactive hypoglycemia usually 2-4 hours after a meal symptoms of sympathetic nervous system stimulation dominate symptoms resolves spontaneously or after eating sweet food possible causes: typically, in patients after gastrectomy with impaired bowel motility after drinking alcohol without food (especially in the case of liver damage) reactive idiopathic hypoglycaemia: no obvious disease that may be the cause it is believed that this is an inadequate response of pancreatic β cells to food, especially rich in carbohydrate diagnostics: extended glucose test
Treatment glucose supply: orally when the patient is conscious, cooperative Intravenously when oral supply is not possible hyperinsulinemia caused by hyperplasia of pancreatic 𝜷 cells- surgery glycogenose types III and IV - low carbohydrate diet, rich in protein diazoxide (closure of Ca-dependent channel voltages) somatostatin (disables the action of insulin) substitution of growth hormone or cortisol
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