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Hyperbilirubinemia is defined as serum bilirubin concentration > 25 μmol/l. However, clinical presentation (jaundice (icterus) – yellowish colouring of the skin, sclera and mucosa) is apparent in newborns usually around hyperbilirubinemia of 80-100 μmol/l. It is one of the most common clinical and laboratory findings in both term and preterm infants (antenatally, placenta is responsible for the clearance of unconjugated bilirubin – see below). 

Neonatal jaundice reflects adaptive changes with increased red blood cells destruction, increasing bilirubin load and reduced hepatic capabilities to clear the excessive bilirubin load. The most common forms are physiologic unconjugated (indirect) hyperbilirubinemia and breast milk jaundice (see division).

Bilirubin metabolism starts with the degradation of hemoglobin from the red blood cells (turns into heme and globin). Heme is converted to biliverdin (and free Fe2+) and then to unconjugated (indirect) bilirubin, which is then swiftly bound to albumin and transported to liver.

Following transmembrane transport into the hepatocytes, bilirubin is conjugated with glucuronic acid (enzyme glucuronyltransferase) to form conjugated (direct) bilirubin (bilirubin mono/diglucuronide; water-soluble), which is then excreted into the bile (bile ducts empty into the small intestine).

Bile acids are reabsorbed in the terminal ileum, while conjugated bilirubin continues to the colon, where the bacteria perform deconjugation (reduction) into urobilinogen (colorless), which can be oxidized into urobilin (yellow) and stercobilin (brown). Urobilin is excreted by the kidneys (urine = yellow color), stercobilin is excreted in the feces (stool = brown color).

Around 1% of urobilinogen is reabsorbed into the enterohepatic circulation to be re-excreted in the bile. The portion of conjugated bilirubin that was not deconjugated is hydrolyzed (enzyme glucuronidase) into unconjugated bilirubin and re-absorbed (enterohepatic circulation).

It is essential to distinguish between 2 types of hyperbilirubinemia:

  • unconjugated hyperbilirubinemia
    → indirect; can be both physiologic and pathologic)
    → non-hemolytic (dysfunctional transport and conjugation)
    → hemolytic (increased red blood cells destruction)
  • conjugated hyperbilirubinemia
    → direct; always pathologic (direct bilirubin > 15 % of total bilirubin)
    → liver dysfunction
    → biliary atresia or hypoplasia

Unconjugated hyperbilirubinemia

A. NON-HEMOLYTIC unconjugated hyperbilirubinemia

Physiologic unconjugated jaundice

  • postnatal adaptive changes
  • end of placental bilirubin clearance
  • increased initial bilirubin load (increased destruction of red blood cells due to shorter half-life; secondary sources => myoglobin, cytochromes; more active enterohepatic circulation due to increased activity of intestinal glucuronidase)
  • decreased initial hepatic clearance (glucuronyltransferase activity 1% in the third trimester, while 100% active by the day of life 14)
  • typical after 24 hours, does not reach critical levels, disappears by the first week of life

Breast milk jaundice

  • inhibition of glucuronyltransferase by the breast milk molecules
  • later peak then physiologic jaundice, disappears over 2-3 months of life
  • no hearing deficits or adverse neurodevelopment

Infants of diabetic mothers


  • decreased uptake of unconjugated bilirubin by hepatocytes (defect transport proteins)

Congenital defects of bilirubin conjugation

  • Crigler-Najjar syndrome = rare autosomal recessive disorder with defect glucuronyltransferase gene
    → type I (severe form) = no enzyme in the liver => high risk of kernikterus (see below)
    → type II (mild form) = reduced enzyme activity in the liver => low risk of kernikterus
  • Gilbert syndrome = reduced glucuronyltransferase activity (at later age can be a cause of mild, intermittent jaundice)

Kernikterus (bilirubin encephalopathy)

Neuronal damage caused by significant unconjugated (indirect) hyperbilirubinemia (toxic levels of indirect bilirubin for prolonged amount of time, immaturity of blood-brain barrier and neuronal protection – low expression of membrane glycoprotein-P (capillaries, astrocytes) that inhibits bilirubin entry into the cerebral tissue).

  • Acute symptoms: apathy, apnea, poor suck reflex => later hypertonia, opisthotonus, seizures
  • Chronic symptoms: delayed neurodevelopment, mental retardation, extra-pyramid symptomatology, dental dysplasia, hearing deficits

B. HEMOLYTIC unconjugated hyperbilirubinemia

Corpuscular (Congenital) hemolytic anemia (congenital red blood cells defects)

  • erythrocyte membrane defects
  • enzymatic deficits
  • hemoglobinopathy

Extra-corpuscular (Acquired) hemolytic anemia

  • hemolytic disease of newborn (see below for more details)
  • extravasated blood (suffusion, hematoma)
  • sepsis


  • medical history (hemolytic anemia; bilirubin metabolism defects; jaundice occurence in the family members; previous pregnancy – anti-D antibodies, infectious diseases, medication)
  • clinical findings (birth injury; signs of infection; liver and spleen size; urine and stool color)
  • laboratory findings (blood group of mother and newborn; Coombs test; full blood count with reticulocytes; peripheral blood film; bilirubin – total and direct; liver function tests – ALT, AST; alkaline phosphatase – ALP; CRP; blood gas for acid-base homeostasis; glycemia; urine analysis)
  • imaging (ultrasound of liver, suprarenal glands; cranial ultrasound)


  • fluid management (enteral and parenteral fluids)
  • phototherapy (consensus-based bilirubin charts – can vary significantly among the countries and within the same country (however, one hospital should have unified graphs for the management of neonatal hyperbilirubinemia)
  • immunoglobulins (slows down massive breakdown of sensitized red blood cells)
  • exchange transfusion


Mainstay treatment for indirect (unconjugated) hyperbilirubinemia (use your local guidelines or recommended bilirubin charts; e.g. by the American Academy of Pediatrics – AAP). The principle behind phototherapy is the ability of bilirubin to accept photons and induce isomerization (structural and configurational isomers; the most important one is lumirubin).

The isomers are water-soluble and can be excreted by urine and bile, without the need for glucuronyltransferase conjugation. The efficiency of phototherapy relies on the light intensity and used wavelength – the most significant photon absorption happens at the blue light spectrum. The newborn’s eyes have to be protected (risk of retinopathy) and the babies need to be well hydrated.


As stated above, this type belongs to extra-corpuscular, acquired forms of unconjugated hyperbilirubinemia with resultant hemolytic anemia, significant levels of bilirubin that endanger the infants with kernikterus.

Mother is sensitized during the pregnancy and birth by the fetal erythrocyte antigens (most commonly Rh (D antigen) and AB0 systems) that pass into the maternal bloodstream and IgG antibodies are produced. Subsequently, they pass via placenta into the fetal bloodstream, bind to the fetal red blood cells which are then up-taken and destroyed in the fetal spleen.

Therefore, fetal red blood cell production (erythropoiesis) is maximized (medullary and extra-medullary), however, the overall balance is tilted toward anemia. Severe anemia can lead to chronic tissue hypoxia, hypoproteinemia, cardiac failure and fetal hydrops, there is a possibility of fetal demise.

  • Rh system (antigen D)
    → second and subsequent pregnancy
    → endangers fetus during the second half of the pregnancy => severe anemia => hydrops fetalis
  • AB0 system
    → can appear during the first pregnancy
    → does not usually endanger the fetus


  • Prenatal: maternal blood group; anti-D antibodies in Rh-negative mothers
    → in case of increasing antibodies titre => cordocentesis (hemoglobin, blood group, Coombs test)
  • Postnatal: cord blood of newborn born to Rh-negative mother => hemoglobin, blood group, Coombs test, bilirubin
  • Clinical findings:
  • Hemolytic anemia causing paleness (severe forms)
  • Hepatosplenomegaly (extra-medullary erythropoiesis)
  • Hydrops (severe forms)
  • Jaundice (the most common clinical finding)
    → rapid course during the first hours of life
    → hemoglobin can be normal or slightly lower
    → raised umbilical bilirubin
    → bilirubin levels escalated quickly during the first 24 hours
    → newborn is endangered by kernikterus if no treatment is given


  • depends on the dynamics of bilirubin escalation and severity of anemia
  • fluid management (enteral and parenteral fluids)
  • phototherapy
  • immunoglobulins (slows down massive breakdown of sensitized red blood cells)
  • exchange transfusion


  • Anti-D immunoglobulin to neutralise any Rh-D positive antigens that may have entered the mother’s blood (Rh-negative) during pregnancy (ceasing production of maternal antibodies)
  • Antenatal:
    → in case of risk factors (bleeding, invasive procedure – amniocentesis, abdominal injury)
    → routinely during the third trimester (28-30 weeks) (routine antenatal anti-D prophylaxis = RAADP)
  • Postnatal:
    → within 72 hours after birth to Rh-negative mother who gave birth to Rh-positive child

Conjugated hyperbilirubinemia

Direct hyperbilirubinemia is significantly rarer (but always pathologic) than the indirect one (incidence of 1:2500). It is characterized by elevated conjugated bilirubin fraction (forming > 15% of total bilirubin) and typically accompanies neonatal cholestasis of various origins.

Clinical examination reveals dark urine and pale stools. Furthermore, extensive laboratory and imaging testing may be required (blood tests, endocrinology, serology, ultrasound, liver biopsy). In terms of treatment, surgery is an option for certain cases (biliary atresia, choledochal cyst), while other forms can be treated only with conservative management (ursodeoxycholic acid – UDCA, vitamins, enteral nutrition)

A common feature is defective transport mechanism at the canalicular (bile) membrane of the hepatocytes (acquired or congenital).

A. LIVER dysfunction

Inherited metabolic disorders

  • galactosemia
  • tyrosinemia
  • fructose intolerance
  • alpha-1-antitrypsine
  • cystic fibrosis
  • hemochromatosis

Defects of liver transport mechanisms

  • inherited autosomal recessive genetic disorders (transport protein on the “bile” membrane of the hepatocytes)
  • Dubin-Johnson syndrome
  • Rotor syndrome
  • progressive familial intrahepatic cholestasis (PFIC)

Infection affecting liver

  • hepatitis B, C
  • cytomegalovirus (CMV)
  • toxoplasmosis
  • syphilis
  • general sepsis

Idiopathic neonatal hepatitis

  • complication of pregnancy and postnatal adaptation (inflammatory response syndrome, medication, parenteral nutrition)

B. BILIARY atresia

Biliary atresia

  • the most common indication for liver transplantation in children
  • should be diagnosed and treated up to 2 months of life for the best outcome
  • examples: extrahepatic atresia, hypoplasia of intrahepatic bile ducts
  • surgery: hepatoportoenterostomy or Kasai portoenterostomy

Choledochal cyst

  • the second most common operable cause of neonatal cholestasis
  • good prognosis

Alagille syndrome

  • autosomal dominant genetic disorder
  • affects the liver (hypoplastic bile ducts), heart, and other organs


① Amos RC, Jacob H, Leith W. Jaundice in newborn babies under 28 days: NICE guideline 2016 (CG98). Arch Dis Child Educ Pract Ed. 2017;102(4):207-209. doi:10.1136/archdischild-2016-311556

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