What Is Kernicterus

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Overview

Kernicterus is a devastating condition primarily affecting infants with severe and long-term consequences. It is caused by the over-production and inadequate removal of a naturally occurring substance in the body called bilirubin.1 Bilirubin is the end product of the body’s natural metabolism of heme, a component of red blood cells which collect oxygen to transport throughout your body, and is yellow in colour.2 In infants, the build-up of this product results in a condition known as jaundice.2 Jaundice is extremely common in newborns, affecting around 20% in the first week of life, and is characterised by the yellow discolouration of the skin and eyes.3 Jaundice tends to resolve on its own, however, if it persists or worsens there are multiple therapies available depending on the severity, including phototherapy, warm baths or medication. Kernicterus is caused by untreated jaundice.3,4

There are two types of bilirubin; conjugated and unconjugated, the latter is what causes kernicterus.1 Unconjugated bilirubin can cross the blood-brain barrier and enter the brain. It is toxic to brain tissue, including the neurons, and mainly affects the globus pallidus, the subthalamic nucleus, and the hippocampus.1 Bilirubin binds to the outside of the cell and prevents the cell from producing energy through the mitochondria, as well as causing cell death via the release of calcium.1

If left untreated, kernicterus can cause a plethora of complications, including hearing loss and issues with sight.1 Due to the bilirubin damage to the brain, serious neurological damage may occur leading to more serious conditions such as cerebral palsy. Severe cases can lead to fatalities, which is reported to make up to 15% of newborn deaths in low to middle-income countries.1 This article will cover the causes, signs and symptoms of kernicterus in depth, and discuss the management of the disease, including its diagnosis, resulting complications and risk factors.

Causes of kernicterus

The causes of kernicterus can be broken down into two categories, the overproduction of bilirubin and the hindered excretion of bilirubin.1 If the body over-produces bilirubin, it’s concentration in the blood increases to dangerous levels with the body unable to efficiently remove it. Over time, this leads to unconjugated bilirubin entering the brain causing neurological damage. Similarly, if the body has issues removing bilirubin, it will build up, and over time lead to the same outcome.

 Increased production of bilirubin

  • Polycythemia: a rare blood disorder which is characterised by an increase in red blood cell production.5 The cause of polycythemia is currently unknown, however, there is a clear link between the onset of polycythemia in newborns and kernicterus.5 When the overproduced red blood cells break down, excess bilirubin is created, which can cause kernicterus
  • Hemolysis: the breakdown of red blood cells, which leads to the production of bilirubin. There are many diseases and genetic conditions which can cause excess hemolysis, including; spherocytosis, pyruvate kidney deficiency, or glucose-6-phosphate dehydrogenase deficiency6
  • Cephalohematoma and other birthing injuries: Cephalohematoma is the buildup of blood under the scalp due to the separation and breaking of blood vessels between the scalp and top of the skull. The accumulation of blood in the body leads to a higher risk of jaundice and kernicterus7

Impaired removal of bilirubin

  • Hypoalbuminemia: low levels of albumin, a molecule that attaches to unconjugated bilirubin, is caused by several different diseases, including; cirrhosis, nephrotic syndrome, and sepsis.8 Low levels of albumin mean more unbound unconjugated bilirubin in the blood that is able to cross the blood-brain barrier, causing kernicterus.1
  • Hereditary bilirubin conjugation defects: unconjugated bilirubin is transformed into conjugated bilirubin through an enzyme called uridine 5'-diphosphate-glucuronosyltransferase. Diseases that disrupt the function of that enzyme, including Crigler-Najjar syndrome and Gilbert syndrome, result in a greater concentration of unconjugated bilirubin in the blood, which can cause kernicterus1,9
  • Breast milk jaundice: certain enzymes present in some people's breast milk, including ß-glucuronidase, inhibits the conjugation of bilirubin. This increases unconjugated bilirubin levels in the blood and can lead to kernicterus10

Signs and symptoms of kernicterus

As kernicterus is closely linked with jaundice, looking out for symptoms such as the yellowing of the skin or eyes is key. Jaundice is extremely common in newborn babies, as their livers have not yet fully developed naturally have a high number of red blood cells. Other notable signs of jaundice include; sleepiness, rejecting food, dark yellow urine and pale faeces. Jaundice usually clears up within two weeks, but if it persists, it could be a sign of an underlying condition and lead to kernicterus.11

In addition to the symptoms above, a baby developing kernicterus will display other symptoms which can be used as an early warning sign. Irritability, a high-pitched cry, and no startle reflex are all signs of kernicterus. As the disease progresses, more severe symptoms such as seizures and muscle spasms may occur, this is due to the bilirubin in the brain causing brain damage.12

In extreme cases where the afflicted baby does not receive treatment quickly enough, permanent complications may occur, including hearing loss and cerebral palsy.12

Management and treatment for kernicterus

A new, key, treatment of kernicterus is exchange transfusion therapy. This method removes excess bilirubin from the newborn's blood, replacing it with donated blood that doesn't contain bilirubin.1 This method is currently recommended when traditional methods fail to lower bilirubin levels, or bilirubin levels are higher than 20-25 mg/dL.1 Whilst this is a very effective treatment there are some risks associated with it. The contraction of hepatitis C is a small risk, minimised due to the introduction of routine screening.1 Issues caused by the new blood, including hypoglycemia, thrombocytopenia, hyperkalemia, and hypocalcemia may manifest, and necessitate the continual monitoring of the infant's blood levels.13 Despite these risks,  exchange transfusion therapy remains a vital and life-saving intervention for the treatment of kernicterus.

Phototherapy is another key treatment for kernicterus. It works by exposing the newborn to a specific type of light, converting the bilirubin into a form that can dissolve in water and be excreted from the body.1 During this process the newborn’s temperature and hydration levels should be monitored, and an IV may need to be administered if the baby is becoming dehydrated.11 Bilirubin levels should be checked every 4-6 hours and if they do not lower, a higher intensity of light can be used.11

If kernicterus is caused by rhesus disease, and phototherapy alone has not worked, intravenous immunoglobulin may be administered.11

Diagnosis

Kernicterus is typically diagnosed through a combination of clinical evaluations, blood tests and scans. During this process, healthcare professionals will also try and gauge the progression of the disease.

Firstly, signs and symptoms of kernicterus will be assessed, including the presence of jaundice via the yellowing of the skin and eyes, alongside the presence of neurological symptoms such as seizures, spasms and loss of reflexes. If both of these symptoms are present, it will be considered a strong indicator of kernicterus.

Blood tests are the next step to officially diagnose kernicterus. All forms of bilirubin will be measured, with high bilirubin levels indicating the disease.1 A full blood count, specifically looking at immune red blood cells, is crucial for identifying haemolysis (a cause of kernicterus) and can help rule out blood infections such as sepsis.1 Furthermore a reading of blood electrolytes, such as potassium and sodium can help identify issues such as haemolysis and mental status changes.1

Whilst not routinely used in diagnosis, scans such as ultrasound and MRI’s can be used to rule out brain infections or issues caused by other toxins in the blood.1 Additionally, a test called brainstem evoked auditory response can be used to identify any hearing loss caused by kernicterus.1

Risk factors

Newborns are at the most risk of developing kernicterus, with adult-onset exceedingly rare and caused by Crigler-Najjar syndrome.14

In newborns, premature birth can lead to an increased risk of kernicterus, as the baby’s liver may be underdeveloped and cannot function well enough to properly process bilirubin.1 Additionally birthing injuries that cause the pooling of blood in the body can increase the baby’s risk of developing kernicterus.1 Blood pooling, particularly around the head region can lead to kernicterus through the breakdown of the blood into bilirubin.

Genetics plays a role in the development of kernicterus, with defects in certain enzymes that deal with bilirubin sometimes being the result of a genetic mutation. A baby may be at an increased risk of kernicterus if siblings have also developed the disease.1 There may also be an increased risk of kernicterus if there is a glucose-6-phosphate dehydrogenase deficiency known in the family lineage.

Complications

Kernicterus can carry with it some long-lasting and life-changing complications if not treated quickly enough. The most common complication is hearing loss, which can be permanent.1 The disease may also affect the eyes, causing gaze palsy which is where someone may not be able to move both eyes together or follow a singular moving object.1 The loss and impairment of senses can lead to intense social, emotional and physical isolation, and can really impact the child's mental health as they grow up.15 This exemplifies the importance of catching this disease early.

Additionally, kernicterus may leave the newborn with long-term motor-function issues such as cerebral palsy, and symptoms such as athetosis and chorea.1 This can cause delays in the child achieving certain milestones such as sitting up and standing and can go on to affect their day-to-day life during adulthood.

Kernicterus may also affect the newborn's teeth, causing stains to appear on the outermost layer.16

FAQs

How can I prevent kernicterus

The best way to prevent kernicterus is the early detection and treatment of jaundice. Whilst jaundice is extremely common in newborns, the persistence of the condition beyond two weeks is a sign that there may be an underlying condition. If kernicterus runs in the family, or the baby was injured during childbirth, extra precautions for kernicterus should be taken.

How common is kernicterus

Kernicterus is a very rare condition but can carry with it some very serious complications.12 A major symptom and precursor of kernicterus, jaundice, is very common, however. This means that if your newborn develops jaundice the chance of them also having kernicterus is low. 

What can I expect if I have kernicterus?

The chance of you having kernicterus is exceedingly rare. Adult onset kernicterus is mainly limited to a disease known as Crigler-Najjar syndrome.14 However, if your newborn develops kernicterus they will have yellowing of the skin and eyes, as well as a high-pitched scream, reluctance to feeding and no startle reflex. Once diagnosed, doctors will use a mixture of light therapy and exchange transfusion therapy to relieve the body of excess bilirubin. If caught early the likelihood of complication drastically increases, however, if left untreated, hearing loss, right impairment and cerebral palsy may arise.1

When should I see a doctor

If jaundice develops in your newborn it is always a good precaution to let your midwife know. The jaundice should be monitored but if it doesn’t go away after two weeks, or you notice signs and symptoms of kernicterus such as high-pitched screams, a reluctance to feed and no startle reflex, you should consult a doctor.

Summary

Kernicterus is a severe condition affecting newborns due to the accumulation of unconjugated bilirubin, a byproduct of red blood cell breakdown. It can lead to neurological damage, hearing loss, and even fatalities if untreated. Causes include overproduction or impaired excretion of bilirubin, with risk factors including prematurity and genetic factors. Diagnosis involves clinical assessments, blood tests, and scans, while treatment options include exchange transfusion therapy and phototherapy. Complications, such as permanent hearing loss, gaze palsy, and motor function issues like cerebral palsy, underscore the critical importance of early detection and intervention in managing kernicterus.

References

  1. Reddy DK, Pandey S. Kernicterus. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Dec 19]. Available from: https://europepmc.org/article/NBK/nbk559120
  2. Abbas M, Shamshad T, Ashraf M, Javaid R. Jaundice: a basic review. Int J Res Med Sci [Internet]. 2016 [cited 2023 Dec 19];1313–9. Available from: http://www.msjonline.org/index.php/ijrms/article/view/705
  3. Joseph A, Samant H. Jaundice. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Dec 19]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK544252/
  4. nhs.uk [Internet]. 2018 [cited 2023 Dec 19]. Newborn jaundice - Treatment. Available from: https://www.nhs.uk/conditions/jaundice-newborn/treatment/
  5. Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood [Internet]. 2002 Dec 15 [cited 2023 Dec 19];100(13):4272–90. Available from: https://ashpublications.org/blood/article/100/13/4272/106060/Polycythemia-vera-myths-mechanisms-and-management
  6. Christensen RD, Nussenzveig RH, Yaish HM, Henry E, Eggert LD, Agarwal AM. Causes of hemolysis in neonates with extreme hyperbilirubinemia. J Perinatol [Internet]. 2014 Aug [cited 2023 Dec 19];34(8):616–9. Available from: https://www.nature.com/articles/jp201468
  7. Raines DA, Krawiec C, Jain S. Cephalohematom. 2022 [cited 2023 Dec 19]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK470192
  8. Gatta A, Verardo A, Bolognesi M. Hypoalbuminemia. Intern Emerg Med [Internet]. 2012 Oct 1 [cited 2023 Dec 19];7(3):193–9. Available from: https://doi.org/10.1007/s11739-012-0802-0
  9. Cichoz-Lach H, Celiński K, Słomka M. Congenital nonhemolytic hyperbilirubinemias. Ann Univ Mariae Curie Sklodowska Med [Internet]. 2004 Jan 1 [cited 2023 Dec 19];59(1):449–52. Available from: https://europepmc.org/article/med/16146029
  10. Bratton S, Cantu RM, Stern M. Breast milk jaundice. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Dec 19]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK537334/
  11. nhs.uk [Internet]. 2018 [cited 2023 Dec 19]. Newborn jaundice - Symptoms. Available from: https://www.nhs.uk/conditions/jaundice-newborn/symptoms/
  12. nhs.uk [Internet]. 2018 [cited 2023 Dec 19]. Newborn jaundice - Kernicterus. Available from: https://www.nhs.uk/conditions/jaundice-newborn/complications/
  13. Badiee Z. Exchange transfusion in neonatal hyperbilirubinemia: experience in Isfahan, Iran. Singapore Med J [Internet]. 2007  [cited 2023 Dec 19];48(5):421. Available from: https://www.researchgate.net/profile/Zohreh-Badiee/publication/6376133_Exchange_transfusion_in_neonatal_hyperbilirubinaemia_Experience_in_Isfahan_Iran/links/00b7d518c8fb46df72000000/Exchange-transfusion-in-neonatal-hyperbilirubinaemia-Experience-in-Isfahan-Iran.pdf
  14. Jansen PLM. Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr [Internet]. 1999 Nov 1 [cited 2023 Dec 21];158(2):S089–94. Available from: https://doi.org/10.1007/PL00014330
  15. When sight and hearing loss affects your mental wellbeing | Deafblind UK [Internet]. 2020 [cited 2023 Dec 21]. Available from: https://deafblind.org.uk/when-sight-and-hearing-loss-affects-your-mental-wellbeing/

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Elijah Cacicedo-Hough

BS (Biological and Medicinal Chemistry), University of Exeter, United Kingdom

Elijah is a first class graduate from the University of Exeter, with a BSc in Biological and Medicinal Chemistry, earning multiple awards during their studies, including the Deans Award. Having developed a novel ionophore precursor for the sequestration of calcium, Elijah has both laboratory and research experience. With a specific interest in pharmacology, microbiology and disease, Elijah is a passionate medical writer who wants to help make science more accessible to everyone.

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