• Physiology of bilirubin metabolism
  
• Clinical assessment of the jaundiced infant
  
• Unconjugated hyperbilirubinaemia
  
• Conjugated hyperbilirubinaemia

Introduction

Jaundice is a yellow discolouration of the skin, sclera and mucous membranes due to the deposition of bilirubin. Neonatal jaundice is the most common problem encountered in the newborn. About 50% of all full-term infants and 85% of preterm infants are visibly jaundiced within the first week of life. In most infants the jaundice is physiological as there is no underlying disease. Physiological jaundice results from increased bilirubin production (due to increased haemoglobin levels at birth and a shortened red cell lifespan), and decreased bilirubin excretion (due to low concentrations of the hepatocyte binding protein, low activity of glucuronosyl transferase, and increased enterohepatic circulation). Unconjugated bilirubin, which is elevated in the most common forms of neonatal jaundice, can pass through the blood–brain barrier and is neurotoxic. High levels in the brain can cause acute or chronic encephalopathy if not treated appropriately. Conjugated hyperbilirubinaemia is much less common than unconjugated jaundice in the newborn, but has a much more serious prognosis.

Physiology of Bilirubin Metabolism

Fetal

In the uterus, the fetal liver is relatively inactive. The placenta and maternal liver metabolize the bilirubin from worn-out red blood cells. The fetus is capable of conjugating bilirubin in small amounts and when haemolysis occurs in utero (as in severe rhesus isoimmunization), bilirubin conjugation increases and high levels may be measured in the umbilical cord blood.

Newborn

The metabolism of bilirubin in the newborn is summarized in Fig. 19.1. Each of the steps in the metabolism of bile will be discussed in turn.

Figure 19.1 Summary of neonatal bilirubin metabolism.

Bilirubin Production

Most of the daily bilirubin production comes from ageing red blood cells. The red cells are destroyed in the reticuloendothelial (RE) system and the haem is converted to unconjugated bilirubin. One gram of haemoglobin will produce 600 µmol (35 mg) of unconjugated bilirubin. Haemolysis may be increased by maternal drugs such as salicylates, sulphonamides, phenacetin and nitrofurantoin. Twenty-five per cent of the daily pro­duction of bilirubin comes from sources other than the red cells, such as haem protein and free (tissue) haem.

Transport and Liver Uptake

Most of the unconjugated bilirubin in the blood is bound to serum albumin and is transported to the liver as a bound complex. This binding is extremely important and may be altered by many factors. Factors that decrease albumin binding ability include low serum albumin, asphyxia, acidosis, infection, prematurity and hypoglycaemia. In addition, there are many competitors for bilirubin binding sites, and these include

• non-esterified (free) fatty acids produced by starvation, cold stress or intravenous fat emulsion
  
• drugs (sulphonamides, cephalosporins, sodium benzoate (present in diazepam), frusemide and thiazide diuretics).

When bilirubin is bound to albumin it is probably non-toxic, but free unbound unconjugated bilirubin is fat soluble and can be transported across the blood–brain barrier and be deposited in certain neurons causing damage. Hepatocytes lining the liver sinusoids are able to extract unconjugated bilirubin from the blood and this is then accepted in the liver cell by the Y and Z proteins (ligandins).

Conjugation and Excretion

The unconjugated bilirubin is conjugated in the liver and the reaction involves the conversion of insoluble unconjugated bilirubin to direct-reacting bilirubin (water soluble). Each molecule of bilirubin is conjugated with two molecules of glucuronic acid in a reaction catalysed by the enzyme glu­curonyl transferase. The conjugated bilirubin is excreted into the bile, and subsequently into the duodenum. In the older child the bilirubin is reduced to stercobilinogen by bacteria in the small bowel, but in the newborn with a relatively sterile bowel and poor peristalsis much of the conjugated bilirubin may be hydrolysed by glucuronidase back to unconjugated bilirubin. This is then absorbed in the bowel, re-entering the circulation for further liver metabolism, a process called enterohepatic circulation.

This may be important in pathological situations, and reinforcement of the enterohepatic circulation will increase unconjugated bilirubin levels in prematurity, small bowel obstruction, functional bowel obstruction and pyloric stenosis.

Clinical Assessment of the Jaundiced Infant

Jaundice can be detected clinically once the serum bilirubin result (SBR) is above 90 µmol/L. As jaundice is common it is essential to have a clinical method for determining its severity. Proper lighting (ideally daylight) is important for detecting subtle levels of jaundice.

An older method of assessing the degree of jaundice is the use of Kramer’s rule (Kramer 1969). This technique depends on the blanching of the infant’s skin with the examiner’s finger at standard zones (1–5) and observing the colour in the blanched area.

Management

The first investigation in any jaundiced newborn is to take a careful history. Important considerations in history taking are listed in Box 19.1. The next step is to perform a complete physical examination. Clinical findings that may help to delineate the cause are listed in Box 19.2.

In assessing the significance of jaundice in a newborn infant the following guidelines may be useful. Investigations should be carried out under the following circumstances:

• Any infant who is visibly jaundiced in the first 24 h of life.
  
• Any jaundiced infant whose mother has rhesus antibodies.
  
• A preterm infant whose estimated serum bilirubin is greater than 150 µmol/L.
  
• A term infant whose estimated serum bilirubin exceeds 200 µmol/L.
  
• Any infant who has the clinical signs of obstructive jaundice (dark urine, pale stools).
  
• Prolonged hyperbilirubinaemia beyond 1 week in term infants and beyond 2 weeks in preterm infants.

First line tests should include:

• unconjugated bilirubin
  
• direct antibody test
  
• blood group
  
• full blood count (FBC) and red cell morphology

Directed tests may include:

• infection screen (e.g. TORCH, septicaemia)
  
• glucose-6-phosphate dehydrogenase assay
  
• thyroid function
  
• conjugated bilirubin
  
• liver USS
  
• erythrocyte galactose uridyl transferase activity if considering galactosemia.

Once this basic information has been collected the possible aetiology, and therefore the investigations that should be collected, will often be obvious. Table 19.1 lists the common causes of jaundice and the timing of their presentation.

Table 19.1 Possible causes of jaundice presenting at different times in the neonatal period

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