Paediatrics JC113: A Jaundiced Child Flashcards
Clinical assessment of Neonatal jaundice (NNJ)
Neonate: First 28 days of life
Jaundice:
- result from Bilirubin accumulation in skin + sclera
- ***Yellow: Unconjugated bilirubin
- Yellow with green hue: Conjugated bilirubin
- Visible in neonates if 80-100 umol/L (4.5-6 mg/dL)
Physiologic NNJ: ***Unconjugated hyperbilirubinaemia
Epidemiology:
- ***>50% term infants
- 80% preterm infants
—> clinical jaundice within first few days of life
- more common in Asian population
Physiology of Bilirubin metabolism
Bilirubin: breakdown product of Heme
Reticuloendothelial system:
Heme
—> Biliverdin
—> **Unconjugated bilirubin —> bind to albumin + transport to liver
—> conjugated by **UDP-GT
—> **Conjugated bilirubin (Bilirubin diglucuronide)
—> excreted in bile into intestine
—> Intestinal **β-glucuronidase breakdown Conjugated bilirubin into Unconjugated
—> ***Urobilinogen
—> absorbed into bloodstream again (Enterohepatic circulation: recycling of bilirubin from gut to blood, esp. when feeding is minimal in first 2-3 days of life ∵ ↑ intestinal transit time)
Neonatal Physiologic Jaundice
Neonatal period:
- Very common to have jaundice during the first few days of life: called “Physiological” / “Non-specific” jaundice of neonates
- Level of bilirubin much higher c.f. adult
- Metabolic diseases, congenital hepatobiliary disease
***Causes of Neonatal Physiologic Jaundice
Unconjugated hyperbilirubinaemia
- Upstream
- **High Hb load in neonates at birth (mean 17-19 g/dL)
- **Short RBC lifespan (t1/2 80 days)
—> a lot of breakdown of heme —> a lot of bilirubin formation - Downstream
- **Immature liver metabolic function
—> **Low ligandin —> ↓ Uptake of bilirubin into liver cells
—> ***Low conjugation enzyme activity (UDP-GT) —> ↑ Unconjugated bilirubin
—> Low canalicular excretion of organic anions - ***↑ Enterohepatic circulation
- esp. when feeding is minimal in first 2-3 days of life (∵ ↑ intestinal transit time) - ***Transient ductus venosus patency (bypass liver)
- Breast milk / Breastfeeding jaundice
UDP-GT activity
Genetic variation (Polymorphism) common —> affects activity
Common: Gilbert syndrome
Uncommon: Criggler Najjar syndrome
Natural history of Physiologic jaundice
- Apparent from day ***2-3 of life (never within first 24 hours of life —> pathological)
- Peak at day ***4-5
- Subside by day ***7-14
Investigations:
1. **Unconjugated hyperbilirubinaemia (commonly >170 umol/L)
2. **Absent conjugated fraction
3. Normal hepatic ductal + parenchymal enzymes
4. Blood smear: No evidence of haemolysis
***Hazards of NNJ
Cross lipid layer + BBB (∵ unconjugated bilirubin is hydrophobic)
- damage to CNS / neural tissue
- luckily most unconjugated bilirubin is bound to **albumin
- risk ↑ when free bilirubin ↑
—> when albumin is **low
—> when there is ***competitive binding to albumin e.g. drugs
—> other adverse factors: prematurity, acidosis, hypoxia, hypoglycaemia, endotoxins and cytokines
Kernicterus (bilirubin-induced brain dysfunction):
- **Death
- Long term morbidity
—> **Dystonic cerebral palsy
—> ***Hearing loss
—> Upward gaze palsy
Clinical manifestation of bilirubin neurotoxicity —> Encephalopathy / Kernicterus
Early signs:
- **Hypotonia
- Poor feeding
- Lethargy
- **Hypertonia
- **Opisthotonus (arching of back)
- Fever
- **Convulsion
- Death
Late signs:
- **Extrapyramidal signs
- **Hearing loss
Postmortem:
- Yellow stain of brain esp. Basal ganglia
Risks of Kernicterus higher when
- ***Very high unconjugated bilirubin in blood for prolonged period
- ***High free bilirubin (∵ low albumin)
- ***Haemolysis (ongoing unconjugated bilirubin formation)
- ***Sepsis
- Acidosis
- Hypoglycaemia
- Prematurity
***Other causes of severe NNJ (Unconjugated hyperbilirubinaemia)
- Haemolysis
- Immune: **Rh incompatibility, **ABO incompatibility
- Non-immune: **G6PD deficiency
- **Extravasation of blood: Cephalhaematoma (blood between the skull and periosteum), Intraventricular haemorrhage
—> reabsorption of blood —> breakdown of heme —> unconjugated hyperbilirubinaemia
- ***Polycythaemia: ↑ RBC load at birth —> ↑ RBC breakdown - Inadequate feeding
—> ***↑ Enterohepatic circulation (∵ ↑ intestinal transit time) - Sepsis
- Prematurity
(5. Dehydration - Endocrine disorders (e.g. ***Hypothyroidism ∵ decreased rate of bilirubin conjugation, slows gut motility + impairs feeding)
- Intestinal obstruction)
Reduce bilirubin toxicity
- Intervene before plasma bilirubin reaches “risky” level —> regularly screen for NNJ (esp. in first 1-2 weeks of life)
- term < 340 umol/L (20 mg/dL)
- lower in preterm infants - ***Avoid risk factors for Kernicterus
- “Free” bilirubin not readily measurable
- take ***total bilirubin to assess severity of jaundice
History taking in NNJ
Prenatal:
1. Prenatal complications (e.g. GDM: **chronic in-utero hypoxia —> **polycythaemia at birth)
Perinatal:
2. Gestation at birth (Preterm: ↑ risk of early + severe NNJ)
3. Birth weight (compare with current weight: assess feeding)
Postnatal:
4. Age of life
5. **Feeding details (breast feeding / artificial formula, feeding intolerance, bowel opening, urine output)
6. **Blood groups (e.g. ABO incompatibility) / **G6PD status
7. **Postnatal complications (e.g. sepsis)
Need to ensure whether jaundice is physiological (compatible with natural course) or pathological (jaundice within first 24 hours of life)
Physical examination of NNJ
- Severity of jaundice
- observe skin + sclera
- using ***Transcutaneous bilirubinometer (aka Jaundice meter: more objective)
—> 2 readings: 1 forehead + 1 sternal area - Hydration status
- **Pallor (evidence of haemolysis) / **Plethora (deep red colour of skin: indicate polycythaemia)
- Cephalhaematoma / Bruises
- birth trauma - Neurologic state (i.e. ***signs of Kernicterus)
- ***Size of Liver + Spleen
- haemolysis
Investigations of NNJ
- Transcutaneous bilirubinometer / Jaundice meter
- measured by Jaundice meter —> photo level —> if above curve —> do blood test (Total serum bilirubin)
- NOT accurate for babies who received phototherapy in the past 12 -24 hours —> do blood test (Total serum bilirubin) - Total serum bilirubin
- more accurate than Jaundice meter —> if photo level still above curve —> treatment
***Treatment of NNJ
- Phototherapy
- photo-isomerisation of bilirubin to less toxic (hydrophilic) + readily excretable forms (in bile + urine)
- wavelength 460 uL (***Blue light spectrum)
- mild SE:
—> corneal / retinal damage (use eye shield)
—> dehydration
—> skin rash (transient)
—> loose stool (transient)
—> bronze baby syndrome (unknown mechanism) - Exchange transfusion (for severe NNJ)
- rapid way to remove plasma bilirubin by gradual exchange of patient’s blood
- indicated when plasma bilirubin reaches a **dangerous level (e.g. >380) or child already showing signs of **neurotoxicity
- require close monitoring + central line insertion —> done in ICU setting
- carries significant risk itself - IVIG
- for immune haemolytic jaundice (e.g. ABO / Rh incompatibility)
- bind Ab to ***prevent further haemolysis - Mesoporphyrins
- potent inhibitor of heme oxygenase —> ↓ degradation of heme
Breast milk jaundice vs Breastfeeding jaundice
Breast milk jaundice:
- Certain ingredients in breast milk ***slow down conjugation (5-β-pregnant-3α, 20-β-diol, nonesterified long chain fatty acids, glucuronidase)
—> delayed type of jaundice
- have genetic predisposition
Breastfeeding jaundice / No breastfeeding jaundice:
- Inadequate breast milk supply during first few days of life
—> **↑ Enterohepatic circulation / ↓ Bilirubin excretion in stool
—> ↑ Reabsorption of **unconjugated bilirubin (by intestinal β-glucuronidase deconjugation) into blood
Breast milk jaundice
Benign condition
- jaundice may be prolonged (i.e. beyond 14 days of life) —> even up to **2-3 months old
- ALL **Unconjugated hyperbilirubinaemia (do fractional bilirubin: direct + indirect)
- baby is otherwise healthy, well, thriving
- mothers should be advised to **continue breastfeeding because of other beneficial effect of breast milk —> Breast milk jaundice will **go away by itself
Conjugated hyperbilirubinaemia in baby
NOT cause Kernicterus, but can indicate ***sinister hepatobiliary diseases
Direct bilirubin **>35 umol/L (>2 mg/dL) or **>15% of Total serum bilirubin
Associated with:
1. **↑ Parenchymal / Ductal enzymes
2. Deranged synthetic functions (e.g. **↓ clotting factors, albumin)
3. Deranged detoxication functions (e.g. **hyperammonaemia)
4. Deranged metabolic function (e.g. **hypoglycaemia)
Need to identify if caused by obstruction —> ∵ amenable to surgery
—> need to rule out **Biliary atresia + **Choledochal cyst (2 most important DDx to rule out)
***Causes of Conjugated hyperbilirubinaemia
Neonatal period:
1. Neonatal hepatitis (etiological agents mostly unknown)
2. **Biliary atresia / **Choledochal cyst (obstructive cause)
3. Metabolic diseases (e.g. ***citrin deficiency, galactosaemia)
4. Parenteral nutrition associated cholestasis
5. Syndromal disorders
6. Neonatal haemochromatosis (accumulation of excess iron)
Beyond neonatal period:
1. **Viral hepatitis (A-E)
2. Drug-induced hepatotoxicity (e.g. paracetamol)
3. **Wilson’s disease
4. Haemochromatosis, other metabolic diseases
5. Choledochal cyst
6. Hereditary hyperbilirubinaemia
7. ***Cystic fibrosis
Biliary atresia
Progressive obliterative cholangiopathy due to ductal obstruction
Present during / beyond neonatal period with:
1. Prolonged jaundice
2. **Tea urine
3. **Clay stool
4. Poor growth
5. Enlarged (or shrunken) liver + spleen (∵ portal hypertension)
Lab result: Conjugated hyperbilirubinaemia
Diagnosis (From SC040):
- CBC
- LRFT (conjugated bilirubin)
- INR
- USG (absent / small gallbladder)
- Radioisotope scan (EHIDA scan: not confirmatory, skipped usually —> uptake in liver but no excretion)
- Laparoscopy +/- Cholangiogram +/- Liver biopsy (Gold standard)
Natural course:
**Continuous inflammation of duct epithelium ∵ atresia of biliary tract
—> **Hepatitis in acute setting
—> Progressive hepatic parenchymal damage
—> ***Liver failure / Cirrhosis if untreated
Management of Biliary atresia
Portoenterostomy (Kasai operation)
- ***before 12 weeks —> best result
- after 12 weeks —> poor result (∴ early diagnosis is important)
After operation
—> Jaundice clear
or
—> Jaundice recurred / reduced / persistent (∵ existing liver damage) —> Liver failure —> Liver transplant
Indications for liver transplant referral
- ***Progressive liver failure
- ***Growth retardation
- Recurrent cholangitis
- ***Portal hypertension
LDLT vs DDLT have similar 10-year survival
Extra: Citrin deficiency
Citrin:
- shuttles aspartate, glutamate in and out of mitochondria —> essential for urea cycle + involved in making proteins and nucleotides
Citrin deficiency:
- **inhibits the urea cycle + disrupts the production of proteins and nucleotides
—> buildup of **ammonia + other toxic substances
—> symptoms of type II citrullinemia
—> ***neonatal intrahepatic cholestasis
Citrullinemia:
- Too much ammonia + toxic substances accumulate in blood
Hyperbilirubinaemia (SpC Neonatal Teaching)
- Unconjugated fraction
- Increased level in blood when there is excessive heme breakdown
—> Bound to albumin
—> Unbound (free bilirubin) - Conjugated fraction
- Normally excreted in bile and absent in plasma
- Presence in blood —> Hepatobiliary disease - δ fraction (covalently bound to albumin)
- Associated with Hepatocellular disease
