4. Sources of Bilirubin
͓ Mainly from catabolism of circulating
hemoglobin by the reticulo- endothelial
system.
͓ One gram of hemoglobin produces 35 mg of
bilirubin.
͓ Shunt bilirubin from breakdown of non- RBC
heme pigments and lysis of precursor cells in
bone marrow.
4
5. “
When red blood cells have lived out their lifespan and have
become too fragile to exist in the circulatory system, their
cell membranes rupture.
5
6. “
The released hemoglobin molecules are immediately
phagocytosed by tissue macrophages to produce heme and
globin.
6
7. “
The heme ring is split into free iron and a straight chain of 4
pyrrole nuclei.
The tetra pyrrole ring is the main substrate of bilirubin
formation.
7
9. “
The first substrate formed is biliverdin, but this is rapidly
reduced to free bilirubin, also called unconjugated bilirubin.
Unconjugated bilirubin immediately combines strongly with
plasma albumin.
9
10. “
In the liver, unconjugated bilirubin is released from the
albumin, and the enzyme glucuronosyltransferase
conjugates it with glucuronic acid to form conjugated
bilirubin.
10
11. “
This conjugated bilirubin to the intestine where most is
converted by bacterial action into urobilinogen, then
excreted in stool as stercobilinogen.
11
16. Unconjugated
‐ Indirect bilirubin
‐ Lipid soluble
‐ Safe only if bound to albumin in
plasma
‐ Free unconjugated bilirubin can
cross blood- brain barrier
‐ Beware of drugs, sepsis and
prematurity
Conjugated
‐ Direct bilirubin
‐ Water soluble
‐ Excreted by biliary system and
kidney
‐ Dangerous underlying causes if
elevated
16
18. ͓ Yellow discolouration of skin and mucous
membranes
͓ Occurs in a cephalo- caudal pattern
͓ Clinical jaundice indicates a total bilirubin
level of at least 5 mg/dL
͓ Transcutaneous bilirubinometer (tBR) used
if gestation > 35 weeks or if age > 24 hours
͓ If tBR not available, gestation < 35 weeks or
age < 24 hours, use serum measurement
͓ Perform serum bilirubin level if tBR elevated
18
22. Physiological Jaundice
͓ Also known as Icterus Neonatorum.
͓ Fetal bilirubin crosses placenta to be metabolized and excreted by maternal
system. After birth, the neonatal liver has an immature enzyme system and is
unable to conjugate enough bilirubin for excretion in bile.
͓ Only diagnosed after exclusion of other causes.
22
24. Physiological Jaundice
͓ Indirect hyperbilirubinemia with no underlying haemolytic pathology.
͓ Appears after first 24 hours of life.
͓ Indirect bilirubin levels maximally at 12 mg/dL on Day 3 in term infants, or 15
mg/dL on Day 5 in preterm infants.
͓ Slightly higher range accepted in breastfed babies.
24
25. Non- physiologic Jaundice
Onset within first
24 hours of life
Development of
jaundice beyond 2
weeks of life
Duration of
jaundice longer
than 14 days in
term, and 21 days
in preterm babies
Presence of
hepatosplenomeg
aly
25
Rate of bilirubin
rise faster than 0.5
mg/dL/ hour
Direct bilirubin
fraction greater
than 1.5 mg/dL
Peak bilirubin
level higher than
95th percentile for
age
Presence of
concurrent anemia
31. 31
Unconjugated Hyperbilirubinemia
Hemolysis Present Hemolysis Absent
Blood group incompatibility (ABO, Rh, Kell,
Duffy)
Physiological jaundice
Red blood cell enzyme defects (G6PD
Deficiency, PK Deficiency)
Breast milk jaundice
Red blood cell membrane disorders
(Spherocytosis, Ovalocytosis)
Internal hemorrhage
Hemoglobinopathies (Thalassemia) Polycythemia
Infant of diabetic mother
Mutations of Glucuronyltransferase enzyme
(Crigler- Najjar Syndrome, Gilbert Syndrome)
Pyloric Stenosis
Hypothyroidism
Immune thrombocytopenia
32. Blood Group Incompatibility
͓ ABO incompatibility occurs if the mother’s blood group is O, and her baby is A or
B. IgG anti- haemolysin A or B antibodies develop in the maternal circulation,
and cross the placenta to lyse fetal red blood cells.
͓ Rh incompatibility is usually diagnosed by antenatal screening. Occurs if mother
is Rh negative, and the baby is Rh positive. Leads to severe fetal anaemia,
hydrops, hepatosplenomegaly and ascites that can be fatal.
͓ Minor blood group incompatibilities may also cause jaundice.
32
33. Red Cell Membrane Defects
͓ Spherocytosis, Elliptocytosis and Pyropoikilocytosis are all autosomal dominant
defects involving the protein lattice of the red cell membrane, creating a shape
that is less deformable, and destroyed in splenic microvasculature.
͓ Stomatocytosis has an autosomal dominant inheritance. Defect in band 3
membrane protein increases cell permeability to monovalent cations and leads to
severe haemolysis in infancy. Strongly associated with biliary lithiasis and iron
overload.
33
35. Red Cell Enzyme Defects
͓ G6PD Deficiency is an X- linked recessive disorder of hexose monophosphate shunt
pathway that leads to oxidant- induced red cell haemolysis. Over 400 enzyme variants.
͓ Females may be affected either if homozygous, or by extreme Lyonization.
͓ Results in intra- vascular haemolysis causing rapid drop in hemoglobin, along with
fever, malaise and dark urine. Diagnosis is confirmed by measurement of G6PD
enzyme level (not during a haemolytic crisis).
͓ Pyruvate kinase deficiency results in ATP depletion with poor RBC survival.
Associated with severe reticulocytosis and aplastic crisis. Patients may have severe
persistent hyperbilirubinemia. Parvovirus B19 infection can cause aplastic crisis.
35
36. Hemoglobinopathies
͓ Thalassemia represents a diverse group of disorders that develop secondary to
abnormal/ defective rate of synthesis of globin portion of hemoglobin molecule.
͓ There is an excess build- up of unpaired globin chains (either alpha or beta), that
precipitate in red cells as inclusion bodies.
͓ These inclusion bodies are toxic to the cell, and are destroyed both in the bone
marrow, and also in the spleen.
36
38. Breast Milk Jaundice
͓ Breast milk contains glucuronidase which may increase entero- hepatic
recirculation of bilirubin.
͓ Certain enzymes that inhibit bilirubin conjugation may also be present.
͓ Develops in first to second week of life.
͓ Interruption of breast feeding for 1- 2 days leads to a significant decline in levels.
͓ There is no significant increase upon re- starting breast- feeding.
38
39. Polycythemia
͓ Infant of a diabetic mother will have high erythropoiesis due to chronic hypoxia
associated with hyperinsulinemia/ hyperglycaemia/ hyperketonaemia.
͓ Small for gestational age infant will also have high erythropoiesis after prolonged
hypoxia.
͓ Delayed cord clamping increases fetal haematocrit and may be dangerous.
͓ Twin to Twin Transfusion Syndrome: recipient baby develops polycythaemia.
͓ Neonatal hyperthyroidism, Trisomy 13, 18 and 21 are also causes.
39
41. Hemorrhage
͓ Isoimmune Thrombocytopenia occurs when
an HPLA- 1 negative mother is sensitized to a
paternal platelet antigen expressed by the
fetal platelets. Fetuses are at increased risk
of petechiae, purpura, and intra- cranial
haemorrhage before/ after birth.
͓ Cephalhematomas, liver or spleen
hematomas may occur after birth trauma.
41
42. Glucuronyl Transferase Enzyme Defects
͓ Crigler- Najjar Syndrome is a serious, rare, autosomal recessive condition with
permanent enzyme deficiency. Type II responds to enzyme induction by Phenobarbital.
Type I does not, and can result in severe indirect hyperbilirubinemia and Kernicterus.
͓ Gilbert disease involves enzyme mutation, and results in mild indirect jaundice.
͓ Pyloric stenosis with jaundice due to severe dehydration may be an early manifestation
of Gilbert disease.
͓ Neonatal hypothyroidism has generalized slow body metabolism, so poor enzyme
activity.
42
45. Infections
͓ Congenital infections with TORCH broadly present with hepatosplenomegaly,
petechiae, intra- uterine growth restriction and neonatal jaundice. Herpes simplex
infections affect the liver more.
͓ Sepsis, particularly with gram negative bacteria (E. coli in particular), leads to
inflammation- induced cholestasis. Urinary tract infections should always be
suspected.
͓ Clues on investigation are a highly elevated bilirubin level in comparison to
mildly deranged liver transaminases.
45
46. Biliary Atresia
͓ Most common cause of cholestasis in term infants, and also of childhood liver
transplantation.
͓ Idiopathic progressive inflammation of the intra- hepatic and extra- hepatic bile
ducts. There is chronic cholestasis, resulting in liver cirrhosis.
͓ Types: 80% acquired, 20% embryonic.
͓ Neonate presents with history of normal birth weight and passing of meconium,
followed by failure to thrive, mild jaundice, dark urine with fluctuant pale stools.
46
48. Biliary Atresia
͓ Gold standard of diagnosis is operative cholangiography. Radionucleotide
TIBIDA scan is also helpful (good hepatic uptake, but no excretion in bowel).
͓ Abdomen ultrasound, liver function tests and liver biopsy are less diagnostic.
͓ Diagnosis before 45- 60 days of age is crucial to improve patient outcomes post-
operatively.
͓ Kasai procedure is the treatment of choice, and resolution of jaundice is the main
prognostic factor.
48
50. Choledochal Cyst
͓ Cystic dilatation in the extra- hepatic biliary system
͓ Child presents with jaundice, abdominal pain, palpable mass or cholangitis
͓ Diagnosed by ultrasound abdomen
͓ Treatment is by excision of the cyst, with Roux- en- Y anastomosis with patent bile
ducts
50
52. Idiopathic Neonatal Hepatitis
͓ Diagnosis of exclusion. Biopsy will show
giant cell multi- nucleated hepatocytes.
͓ Baby has IUGR and hepatosplenomegaly at
birth.
͓ Prognosis is variable, but many children
recovery by one year of age.
52
53. Genetic Intra- Hepatic Cholestasis
͓ Alagille Syndrome: Syndromic paucity of intra- hepatic
bile ducts, also known as arteriohepatic dysplasia
͓ Autosomal dominant with variable expression. Mutation
of JAG 1 on chromosome 20p.
͓ Chronic cholestasis, peripheral pulmonic stenosis,
butterfly vertebrae, posterior embryotoxon, typical
facies, with renal tubular disorders.
͓ Diagnosed by liver biopsy
53
54. Genetic Intra- Hepatic Cholestasis
͓ Progressive Familial Intra- Hepatic Cholestasis (PFIC): Autosomal recessive
condition with three sub- types. Involves altered canalicular bile transport.
͓ Type 1, also known as Byler disease presents in the first 3 months of life with
jaundice, intense pruritus, failure to thrive, pancreatitis and deficiency of fat-
soluble vitamins. Children develop liver cirrhosis by first decade, and require
liver transplantation by second decade.
͓ Types 2 and 3 have similar presentations, but have normal and high GGT levels
respectively.
54
55. Inborn Errors of Metabolism
͓ Alpha- 1 antitrypsin deficiency is the most common cause of neonatal hepatitis.
The severest deficiency is PiZZ, causing neonatal liver disease and emphysema in
adulthood. Presents with prolonged jaundice and hepatosplenomegaly. Diagnosis
is confirmed by enzyme level.
͓ Other causes: Zellweger syndrome, Mitochondrial hepatopathies.
55
56. Inborn Errors of Metabolism
͓ Galactosemia: autosomal recessive condition with three subtypes (GALT, GALK
and GALE deficiencies). Type 1 is the most common, and severest. Present with
vomiting, diarrhoea, irritability and prolonged jaundice. Labs will show low
enzyme level with urine reducing substances positive.
͓ Tyrosinemia: autosomal recessive. Damages liver, kidney and brain. Classically
has very high alpha feto- protein levels. Can result in hepatocellular cancer.
56
57. Others
͓ Inspissated Bile Syndrome: Haemolysis due to ABO or Rh incompatibility,
causing direct hepatocyte damage from high unconjugated bilirubin levels. Has
good prognosis generally.
͓ TPN- related cholestasis: Lack of enteral feeding causes decreased gut hormone
secretion, and reduced bile flow. Hence bile stasis develops, and leads to
jaundice.
͓ Cystic Fibrosis: Thick biliary secretions cause obstruction, chronic cholestasis
and liver fibrosis.
57
65. Phototherapy
͓ Principle is to transform unconjugated
bilirubin into water soluble isomers that are
easily excreted in urine.
͓ Uses either blue or white light. Irradiance
wavelength of 425- 475 nm.
͓ Good hydration should be ensured as urine
is the route of bilirubin excretion.
65
67. Phototherapy
͓ Complications include dehydration (insensible water losses, diarrhoea),
maculopapular skin rash, nasal compression from eye cover, interruption in breast
feeding, masking of cyanosis, lethargy, possible retinal damage.
͓ Rebound hyperbilirubinemia defined as any increase in TB levels following
discontinuation of phototherapy, is typically lower than the TB value before the
initiation of phototherapy. Essentially, the rate of bilirubin rise is likely to continue
without phototherapy and exceeds the natural elimination process. Most likely, the
excessive bilirubin production is due to unabated hemolysis.
67
68. Phototherapy
͓ Although uncommon, clinically significant rebound hyperbilirubinemia reaching TB
levels to phototherapy initiation thresholds within 72 hours of phototherapy
termination can occur.
͓ Risk factors for this degree of rebound include GA less than 38 weeks, Asian ethnicity,
breastfeeding, a positive DAT test, and the use of early phototherapy (eg, initiated
within 72 hours after birth).
68
74. Exchange Transfusion
͓ Reserved for infants with dangerously high indirect bilirubin levels who are at risk for
Kernicterus.
͓ Blood is removed in aliquots from an arterial line/ umbilical venous catheter, and replaced
with donor blood. Twice the infant’s blood volume is replaced (2 x 80 ml/kg).
͓ Rule of thumb: A level of 20 mg/dL of indirect bilirubin is the exchange transfusion number
for infants with hemolysis who weigh more than 2,000 grams.
͓ Generally an indirect bilirubin level more than 10% of birth weight in grams needs
exchange transfusion.
74
77. Conjugated Jaundice
͓ Must diagnose underlying cause and treat accordingly
͓ General measures:
‐ Elemental formula/ breast milk with MCT
(medium chain triglyceride) supplementation:
Enfaport, Pregestimil
‐ Fat- soluble vitamin supplementation (Vitamin
A, D, E). May need Vitamin K if bleeding
tendency develops.
‐ Galactose/ Fructose dietary restriction as
needed. 77
78. Conjugated Jaundice
͓ Pharmacological measures:
‐ Ursodeoxycholic acid: substitutes bile acid pool and stimulates flow. Causes
dose- dependant diarrhoea.
‐ Phenobarbital: enhances bile acid synthesis, increases flow and induces
hepatic microsomal enzymes. Causes sedation and behavioural disturbance.
͓ Surgical measures depending on underlying diagnosis (biliary atresia or
choledochal cyst).
78
79. Conjugated Jaundice
͓ Other pharmacological measures:
‐ Cholestyramine: binds bile acids in gut lumen and causes excretion in faeces. Reduces
entero- hepatic circulation and increases liver bile synthesis from cholesterol. Causes
fat- soluble vitamin depletion, constipation and metabolic acidosis.
‐ Rifampin: helps reduce pruritus. Rarely used because of hepatotoxicity and
idiosyncratic hypersensitivity reactions (renal failure, haemolytic anaemia,
thrombocytopenia).
79
82. Kernicterus
͓ Unconjugated bilirubin encephalopathy that develops when indirect bilirubin concentration
in the blood exceeds the albumin binding capacity.
͓ Deposits in brain cells, especially basal ganglia, causing disruption of neuronal metabolism
and function.
͓ Usually develops if bilirubin levels exceed 25 mg/dL in term infants. If preterm and weight
less than 1,000 g, kernicterus can even occur at indirect bilirubin levels of < 10 mg/dL
because prematurity increases blood brain barrier permeability.
82
84. Kernicterus
͓ May also develop at lower bilirubin levels in cases with:
84
Sepsis, Meningitis Asphyxia
Hypothermia Prematurity
Hemolysis Sulfa drugs
Hypoglycemia Hypoxia
85. Kernicterus
͓ Early clinical features include lethargy, poor feeding, emesis, hypotonia, poor Moro
response, and high- pitched crying. Usually develop by fourth day of life.
͓ Late features (usually after which child will not survive) include fever, hypertonicity,
bulging anterior fontanelle, opisthotonic posturing, paralysis of upwards gaze, seizures and
pulmonary haemorrhage.
͓ If the child survives, residual features are nerve deafness, choreoathetoid cerebral palsy,
enamel dysplasia and discolouration of teeth.
85
87. References
͓ Illustrated Textbook of Paediatrics, Fourth Edition
͓ Nelson Essentials of Pediatrics, Seventh Edition
͓ Lange Neonatology, Seventh Edition
͓ Oxford Handbook of Paediatrics, Second Edition
͓ University of British Columbia: http://learn.pediatrics.ubc.ca/
͓ NICE Guideline for Neonatal Jaundice, May 2010
͓ Treatment of unconjugated hyperbilirubinemia in term and late preterm infants, UpToDate
87