Introduction

Bilirubin is a yellow pigment formed by the breakdown of a molecule called heme in red blood cells. Heme is the part of red blood cells which binds to oxygen, allowing oxygen transport around the body. There are two types of bilirubin: indirect (unconjugated) and direct (conjugated). Unconjugated bilirubin is formed when heme is broken down, while conjugated bilirubin is the form which is excreted from the body. 

In normal bilirubin metabolism (breakdown), haemoglobin (a complex made up of 4 heme molecules) is broken down to form unconjugated bilirubin or indirect bilirubin. The indirect bilirubin is transported to the liver, where it is metabolised into direct bilirubin. This process is driven by an enzyme (protein) called UDP-glucuronosyltransferase (UGT1A1), which binds a sugar molecule to the indirect bilirubin and forms direct bilirubin. The direct bilirubin is excreted into bile, then the intestines, before finally leaving the body. 

Bilirubin levels are typically higher in neonates due to immature liver function and a high red blood cell turnover. This causes neonatal jaundice, which can occur for physiological or pathological reasons.

Herein, we will discuss the major causes of elevated unconjugated bilirubin in newborns, their mechanisms, and the clinical importance.

Bilirubin metabolism in the newborn

Red blood cells in newborns differ slightly from those in adults; they’re known as fetal erythrocytes. They contain a different form of haemoglobin, which allows oxygen to be more efficiently transferred around the baby’s body within the womb. Once born, these erythrocytes are broken down into unconjugated bilirubin.

Unconjugated bilirubin is bound to another protein called albumin for transport in the bloodstream to the liver. This is a vital step in the bilirubin metabolism because unconjugated bilirubin is toxic. Once in the liver, the unconjugated form is conjugated using the UGT1A1 enzyme, and the conjugated bilirubin is then excreted. 

Newborns are less able to metabolise bilirubin properly because their livers are not fully mature for complete metabolic function. This makes it difficult to conjugate bilirubin in newborns, who have increased enterohepatic circulation. Substances like bilirubin are reabsorbed by the intestines and returned to the liver more frequently than usual.

Physiological jaundice

Physiological jaundice is a harmless rise in unconjugated bilirubin seen in most healthy newborns. It is noticed clinically from the yellowing of the skin and the whites of the eyes. In brown or black skin, the yellowing may be easier to see on the palms of the hands and soles of the feet. With physiological jaundice, there is no underlying systemic cause. 

This is caused by the high number of red blood cells as well as the high turnover of fetal erythrocytes into red blood cells.¹ Since the UGT1A1 enzyme doesn’t conjugate the bilirubin very well in the immature liver, it leaves a high concentration of unconjugated bilirubin within the body. This process is further enhanced by increased bilirubin circulation from the intestines back to the liver (enterhepatic circulation).

Physiological jaundice appears around 2–3 days after birth, peaks at day 4–5, but is usually fully resolved by 10–14 days.² Physiological jaundice is usually self-limiting, but it is important to differentiate it from pathological causes.

Pathological causes of elevated unconjugated bilirubin

Pathological causes of increased bilirubin indicate an underlying systemic condition. 

Hemolytic causes

Hemolytic causes refer to an excessive red blood cell breakdown, also known as hemolysis. 

• Hemolytic disease of the newborn:

Rhesus (Rh) and ABO incompatibility arise when the mother's blood type is different from the baby’s. This results in maternal antibodies attacking fetal erythrocytes, causing excessive hemolysis and hemolytic disease of the newborn. The increased red blood cell breakdown leads to rapid bilirubin production and puts the baby at risk of severe hyperbilirubinemia (excess bilirubin).

Rhesus (Rh) incompatibility occurs when the mother is Rh negative, whereas the baby is Rh positive. The mother will receive RhoGAM injections to prevent this from happening in the current and in any future pregnancies.

The effect of ABO incompatibility is typically milder and occurs when the mother has blood type O but the baby has blood type A, B, or AB. 

• Red blood cell enzyme defects:

Another pathological cause of increased bilirubin is red blood cell enzyme deficiency, such as Glucose-6-phosphate dehydrogenase (G6PD) deficiency. This is where red blood cells are broken down faster than they can be replaced, which then causes hemolytic anaemia and, in turn, hemolysis.

Another example of an enzyme defect is pyruvate kinase deficiency. This inherited deficiency causes red blood cells to be broken down prematurely. It also results in hemolytic anaemia and hemolysis.  

Both of these enzyme deficiencies cause elevated bilirubin levels due to the massive red blood cell breakdown.

Other red blood cell-related causes of increased bilirubin levels include:

• Ineffective erythropoiesis: Breakdown of immature erythroid cells before they reach circulation
• Polycythemia: Increased red cell mass leads to higher bilirubin production
• Cephalohematoma or bruising: Localised blood breakdown increases bilirubin concentrations within the body

Impaired hepatic uptake or conjugation

Increased hepatic activity in the liver can also lead to jaundice, and there are a couple of reasons the liver isn’t functioning as it should:

• Prematurity: Being born prematurely means the liver hasn’t fully developed yet. Enzyme systems are not working properly, resulting in reduced UGT1A1 activity
• Genetic enzyme deficiencies:
  • Crigler–Najjar syndrome types I and II: This is a genetic disorder which causes a severe UGT1A1 deficiency/absence, resulting in notable unconjugated hyperbilirubinemia
  • Gilbert’s syndrome: This disorder is usually mild and involves a reduction in bilirubin conjugation activity
• Drugs or competitive binding: Certain drugs like steroids, oral contraceptives and antibiotics can be toxic to the liver, resulting in high amounts of bilirubin

Increased enterohepatic circulation

Increased enterhepatic circulation occurs when the intestines circulate bilirubin back to the liver. This can occur in a few ways:

• Delayed meconium passage or intestinal obstruction: Conjugated bilirubin is hydrolysed (broken down) by an enzyme called β-glucuronidase back to unconjugated form and reabsorbed
• Breast milk jaundice: This is thought that substances in breast milk (e.g., β-glucuronidase, pregnane-3α, 20β-diol) enhance bilirubin reabsorption in the first week of life.³ However, the benefits of breastfeeding massively outweigh this potential risk
• Feeding failure jaundice: If the baby is not being fed enough, there is an inadequate milk intake. This leads to the baby becoming dehydrated, causing delayed meconium passage and increased enterohepatic circulation

Clinical implications and diagnosis

The effects of suspected pathological jaundice can be seen within the first 24 hours of life. There is a rapid rise in bilirubin, prolonged jaundice, or associated illness.
There are a few diagnostics which can be run to confirm jaundice:

• Total and direct bilirubin levels (to differentiate conjugated vs unconjugated) are measured
• Blood group typing to check for a mismatch between the mother and baby, as well as the Coombs test to test for hemolysis
• The doctor will perform a peripheral smear, take a reticulocyte count, test G6PD and carry out liver function tests

There is a neurotoxicity risk associated with high unconjugated bilirubin. Unconjugated bilirubin can cross the blood-brain barrier and cause permanent brain damage known as kernicterus.⁴ The symptoms to look out for are: lethargy, hypotonia, seizures, and long-term neurological impairment. However, the occurrence of kernicterus is very rare in the UK

Management overview

Once jaundice has been diagnosed, there are a few steps which clinicians will take to manage it.

The general aim is to reduce bilirubin levels and prevent neurotoxicity. This takes place through:

• Phototherapy: A specific type of light converts unconjugated bilirubin into water-soluble molecules so it can be excreted⁵
• Exchange transfusion: This approach is used in severe cases (e.g., hemolytic disease) to rapidly remove bilirubin and antibodies
• Addressing the underlying cause: This step is arguably the most important to prevent recurrent episodes of jaundice. Doctors will treat infections or hemolytic conditions where appropriate; if the jaundice is breastfeeding-related, feeding baby will be optimised

Prognosis and long-term outcomes

For physiological jaundice/high bilirubin, the prognosis outcomes are excellent as it is self-limiting and usually resolves spontaneously. As for pathological causes of elevated bilirubin, early recognition is vital to allow timely treatment to prevent complications.

Summary

Elevated unconjugated bilirubin in newborns arises from overproduction, decreased conjugation, or increased reabsorption. Distinguishing physiological from pathological causes is essential for safe management. With timely diagnosis and appropriate therapy, most cases resolve without long-term effects, emphasising the importance of vigilant neonatal monitoring.