Causes of Jaundice ✅ Flashcards
What can the causes of hyperbilirubinaemia be divided into?
- Increased bilirubin production due to high red cell turnover
- Delayed bilirubin clearance
- Conjugated hyperbilirubinaemia
What forms of bilirubin clearance can be delayed?
- Conjugation
- Biliary excretion
- Faecal/urinary elimination
What are the causes of high red cell turnover?
- Physiological
- Polycythaemia
- Immune haemolysis
- RBC enyzme defects
- RBC membrane abnormalities
- Other causes of haemolysis
- Haematomas
- Maternal diabetes
Why might red cell turnover be high physiologically in a neonate?
High haemoglobin and red cell mass at birth and short RBC lifespan
What might cause immune haemolysis in a neonate?
Rb/ABO/other isoimmunisation
Give 2 examples of RBC enzyme defects
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Pyruvate kinase deficiency
Give 2 examples of RBC membrane abnormalities?
- Hereditary spherocytosis
- Hereditary elliptocytosis
Give 2 examples of causes of haematoma that can lead to jaundice in neonates
- Extensive bruising
- Cephalohaematoma
Give an example of another cause of haemolysis that can cause jaundice in neonates?
Sepsis
What are the causes of delayed bilirubin clearance?
- Gilbert’s syndrome
- Decreased activity of glucuronyltransferase enzyme
- Drugs needing conjugation for excretion
- Increased enterohepatic circulation
What happens in Gilbert’s syndrome?
There is a poor uptake of bilirubin by hepatocytes
What can cause decreased activity of glucuronyltransferase enzyme?
- Genetic
- Hypoxia
- Infection
- Thyroid deficiency
- Hypothermia
- Prematurity
Give a genetic cause of decreased activity of glucuronyltransferase enzyme
Crigler-Najjar syndrome
Why might drugs needing conjugation for excretion cause delayed bilirubin excretion?
They compete for transferase enzymes
What can cause increased enterohepatic circulation?
- Prolonged gut transit time
- Delayed passage of meconium
- Poor enteral feeding
- Prematurity
- Antibiotic treatment
What can cause conjugated hyperbilirubinaemia in neonates?
- Congenital infections
- Neonatal hepatitis
- Obstructive
- Parenteral nutrition induced cholestasis
What are the obstructive causes of conjugated hyperbilirubinaemia in neonates?
- Biliary atresia
- Choledochal cyst
What is physiological jaundice?
Common, generally harmless jaundice occurring a high proportion of newborn babies in the first weeks of life for which there is no underlying cause
What kind of hyperbilirubinaemia is seen in physiological jaundice?
Unconjugated
What is the normal cord blood level of unconjugated bilirubin?
20-35µmol/L
What usually happens to levels of bilirubin in the first few days of life?
They rise by less than 85µmol/L/day
When does jaundice become clinically apparent?
When serum bilirubin is 80-90µmol/L
When do bilirubin levels peak after birth in term infants?
Day 4-5
When do bilirubin levels peak after birth in preterm infants?
Day 7-8
Who is more likely to develop physiological jaundice?
Breastfed babies
Why are breastfed babies more likely to develop physiological jaundice than formula fed babies?
Pathogenesis unclear, but proposed mechanisms;
- Increased ß-glucuronidase in breast milk
- High free fatty acid in breast milk
- Certain factors in breast milk may inhibit the enzyme responsible for conjugation the liver
- Inadequate milk intake
Why does the increased beta-glucuronidase in breast milk increase the risk of jaundice?
It can increase enteric absorption of bilirubin and hence the hepatic bilirubin load
Why does the high free fatty acid in breast milk increase the risk of jaundice?
It may compete for albumin binding sites for transport to the liver
How does inadequate milk intake lead to jaundice in breastfed babies?
Leads to sluggish gut action which increases enterohepatic circulation of bilirubin
Why do formula-fed babies have lower bilirubin levels?
Due to increased clearance of bilirubin from the gut
When does jaundice in term infants resolve?
Usually by 2 weeks of age
When does jaundice in preterm infants resolve?
Usually by 3 weeks
How long might jaundice persist in breastfed infants?
4-10 weeks
Should breastfeeding be continued in jaundiced infants?
Yes
What are the types of haemolytic disease of the newborn?
- Rh incompatibility
- ABO incompatibility
What is rhesus haemolytic disease?
When there is incompatibility of the Rh blood group between the mother and fetus
What are the potential antigens in the Rh blood group?
- D
- C
- Kell
When can rhesus haemolytic disease occur, in terms of the blood groups of the mother and fetus?
If the mother is rhesus negative and the baby is rhesus positive
Why might a rhesus negative mother have a rhesus positive child?
If the child inherited the antigen from it’s father
What kind of antibodies can the mother generate against the baby in rhesus haemolytic disease?
IgG
Where are antigens generated in rhesus haemolytic disease?
In the mothers bloodstream
How does IgG generated in the mothers bloodstream get to the baby in rhesus haemolytic disease?
It crosses the placenta
What happens when maternal IgG against crosses the placenta in rhesus haemolytic disease?
It causes fetal red cell haemolysis
What can fetal red cell haemolysis lead to in rhesus haemolytic disease?
- Jaundice
- Anaemia
- Hydrops
- Hepatosplenomegaly
Can rhesus haemolytic disease occur in the first pregnancy?
Occasionally
Why does rhesus haemolytic disease not usually occur in the first pregnancy?
As the mother needs to be sensitised to the rhesus-positive antigen, which usually occurs during the first pregnancy
What causes sensitisation of the mother to rhesus-positive antigen in rhesus haemolytic disease?
Feto-maternal haemorrhage
When does feto-maternal haemorrhage most commonly occur?
During delivery
Other than delivery, when might feto-maternal haemorrhage occur?
- Miscarriage
- Placental abruption
- Amniocentesis
- Chorionic villus sampling
When can rhesus haemolytic disease occur in a first pregnancy?
If the mother has been sensitised, e.g. from blood transfusion
What does the prenatal management of rhesus haemolytic disease involve?
- Monitoring of antibody levels
- Referral to specialist centre if indicated
How can fetal rhesus genotype be determined?
Non-invasively by cell free fetal DNA analysis in maternal serum
How can fetal anaemia be monitored?
- Serial ultrasound scanning of middle cerebral artery Doppler waveform
- Measurement of fetal haematocrit from cordocentesis
What may be necessary in the prenatal management of rhesus haemolytic disease?
Intrauterine blood transfusion
What is required after birth in rhesus haemolytic disease?
Close bilirubin and haemoglobin monitoring
Why is close bilirubin monitoring required after birth in rhesus haemolytic disease?
Bilirubin level may rise very rapidly to dangerously high levels
Why has rhesus D alloimmunisation become rare?
As maternal blood group and antibody status is routinely tested, and if rhesus negative mothers are given anti-D IgG immunoglobulin
What does anti-D IgG immunoglobulin do?
Clears any felt red blood cells that may have leaked into the maternal circulation
How has the use of anti-D immunoglobulin changed the type of rhesus haemolytic disease that occurs?
Most cases are now anti-cell and anti-c
What is the difference between rhesus haemolytic disease caused by anti-Kell and anti-c compared to anti-D?
Anti-Kell and anti-c lead to much less severe fetal anaemia and hyperbilirubinaemia
What are the types of haemolytic disease of the newborn?
- Rh incompatibility
- ABO incompatibility
When does ABO incompatibility arise, in terms of the blood group of the mother and fetus?
When a mother with blood type O has a fetus with a different blood type (A, B, or AB)
What kind of antibodies are the anti-A/anti-B produced in ABO incompatibility?
IgG
Is hyperbilirubineamia more severe in ABO incompatibility or rhesus haemolytic disease?
Rhesus haemolytic disease
Why is hyperbilirubinaemia less severe in ABO incompatibility?
As fetal RBCs express low ABO blood group antigens compared with adult levels
When is the onset of haemolysis and jaundice in ABO incompatibility?
After birth
How is ABO incompatibility diagnosed?
Direct antibody test is positive
What is the most common cause of severe neonatal jaundice and kernicterus worldwide?
G6PD deficiency
What is G6PD deficiency?
An X-linked recessive disorder characterised by low levels of glucose-6-phosphate dehydrogenase
What is the function of G6PD?
It is involved in red blood cell metabolism
Is G6PD deficiency more common in males or females?
Male s
Why is G6PD deficiency more common in males?
Due to it’s X-linked inheritance
How might carrier females be affected with G6PD deficiency?
They may have a milder form
Why might carrier females have a milder form of G6PD deficiency?
As a result of lyonization
What ethnicity is G6PD more common in?
- Mediterranean
- Middle or Far Eastern
- African
What might trigger patients with G6PD deficiency to haemolyse?
A number of stressors, e.g.;
- Infection
- Certain medications
- Fava beans
How is G6PD deficiency diagnosed?
By measuring G6PD activity in RBCs
What causes Crigler-Najjar syndrome?
Deficiency of the enzyme uridine diphosphate glucuronyl-transferase (UGT)
What is the inheritance of Crigler-Najjar syndrome?
Autosome recessive
When does Crigler-Najjar syndrome present?
In the early neonatal period
How does Crigler-Najjar syndrome present?
Rapid rise in serum bilirubin to very high levels despite phototherapy
What can develop as a result of the jaundice in Crigler-Najjar syndrome?
Kernicterus
Is type 1 or type 2 Crigler-Najjar syndrome more severe?
Type 1
What are the peak bilirubin levels in type 1 Crigler-Najjar syndrome?
Up to 850µmol/L
Can Gilbert’s syndrome cause severe unconjugated hyperbilirubinaemia?
It can contribute
What % of the population is homozygous for Gilbert’s syndrome?
5-10%
What % of the population is heterozygous for Gilbert’s syndrome?
40%
