Author: Valeria Cassiano
Date: 02/07/2009



Jaundice is a clinical manifestation of hiperbilirubinemia, characterized by the yellowish staining of the skin, mucous membrane and sclera.
So that the jaundice is visible, the bilirubin level must exceed 3-5 mg / dL.

DatabaseGenetic Jaundice


Pre-hepatic or hemolytic jaundice: is caused by anything which causes an increased rate of hemolysis (breakdown of red blood cells). In tropical countries, malaria can cause jaundice in this manner.Certain genetic diseases, such as sickle cell anemia and glucose 6-phosphate dehydrogenase deficiency (favism) can lead to increased red cell lysis and therefore hemolytic jaundice.
The laboratory findings include - Urine: no bilirubin present, urobilirubin > 2 units,- Serum: increased unconjugated bilirubin.
# Hepatic jaundice:Hepatic causes include acute hepatitis, hepatotoxicity and alcoholic liver disease, whereby cell necrosis reduces the liver's ability to metabolise and excrete bilirubin leading to a buildup in the blood.Less common causes include primary biliary cirrhosis, Gilbert's syndrome and metastatic carcinoma.
The laboratory findings include - Urine: bilirubin present, Urobilirubin > 2 units but variable (Except in children)
# Post-hepatic (or obstructive) jaundice:also called cholestasis, is caused by an interruption to the drainage of bile in the biliary system.The most common causes are gallstones in the common bile duct, and pancreatic cancer in the head of the pancreas.Other causes include strictures of the common bile duct, biliary atresia, ductal carcinoma, pancreatitis and pancreatic pseudocysts. A rare cause of obstructive jaundice is Mirizzi's syndrome.


Bilirubin is an end product of heme metabolism, coming mainly, 70 ~ 80 %, from hemoglobin of senescent red blood cells and the others from other hemeproteins.
The daily amount of bilirubin originated from destruction of red blood cells is around 250 ~ 300 mg.

Bilirubin split to heme and globin at first, then further split to iron and biliverdin, and the biliverdin converts to bilirubin finally. Bilirubin circulates bound to albumin and then in rapidly transferred from plasma into liver by a carrier called ligandina. After uptake from plasma, bilirubin binds to cytosolic binding protein, glutatione s-transferase (GST) and then is transported by these soluble protein to intracellular site of metabolism: the endoplasmatic reticulum. The original bilirubin from hemoglobin is free unconjugated bilirubin in the blood stream and is not soluble in water.


After being taken into hepatocytes, it is converted to soluble conjugated. Conjugation of bilirubin is catalyzed by a liver enzyme called bilirubin-uridinediphosphate-glucuronosyltransferase UGT1A1. The first step entails binding of one molecule of glucuronic acid, resulting in a monoglucuronide; takes place in the endoplasmic reticulum of the microsomes. Binding of a second molecule off glucuronic acid results
in a bilirubin diglucuronide.


[Some substrates are specific for UGT1A1 (bilirubin), whereas others can be glucuronidated by several UGT1A enzymes (1-naphthol). Table lists some of the relevant pharmacologic substrates, inhibitors, and inducers for UGT1A1.The UGT1A1 isoform is primarily responsible for the conjugation of bilirubin, as well as glucuronidation of drugs (ethinylestradiol), xenobiotics (phenols, anthraquinonones), and endogenous steroids (hormones).]

Bilirubin conjugates are either secreted into bile or stored in the liver bound to GST. Biliary excretion of bilirubin conjugates are mediated by canalicular membrane protein, a multispecific organic anion transporter called MRP3.


The conjugated bilirubin is not absorbed in the bile ducts and intestinal tract, and is absorbed in the distal portion of the ileum after being hydrolyzed and converted to urobilinogen by the intestinal pathogens.

Mutations in glucuronyl transferase are responsible for genetic errors in bilirubin conjugation that cause:

  • Gilbert's disease. In patients with Gilbert's syndrome, hepatic glucuronidation by UGT1A1 is reduced to about 30% of normal
  • Crigler-Najjar syndrome types 1 and 2. Crigler-Najjar types I and II are autosomal recessive disorders associated with near (type II) or complete absence (type I) of UGT1A1 enzyme activity. There is a persistent unconjugated hyperbilirubinemia (range 300-850 mumol/l) with the plasma concentrations being higher in type I than in type II. Genetic mutations in exon 1-5 cause both Crigler-Najjar type I and type II. The urobilinogen is then oxidized to orange-color urobilin (stercobilin) and excreted in the stool out of the body. The yellowish color of stool is the color of the sterocobilin. Therefore, the clay color stool means that there is no bilirubin coming from biliary ducts owing to the obstruction of the bile ducts.

About 15 ~ 20 of the urobilinogen is reabsorbed from the intestine into portal veins and finally 90 of them return to the liver and is re-excreted in the bile, it is called entero-hepatic circulation of bilirubin. The remainding 10 % gets into the systemic circulation and finally excreted in the urine through kidney. Thus the urine urobilinogen increases in the case of hemolytic disease, hepatocellular disease and porto-systemic shunt.


The balance of the bilirubin between production from the hemoglobin and excretion from the bile duct is kept well in normal condition;jaundice occurs when the bilirubin balance between production and excretion breaks.
The possible causes of hyperbilirubinemia:

  1. Over production of bilirubin caused by hemolysis
  2. The impairment in bilirubin uptake by the liver, conjugation in the liver, and excretion from the liver cells
  3. The unconjugated and conjugated bilirubin is obstructed or leak back into the blood stream in the liver cells or from bile ducts.


Neonatal jaundice is usually harmless: this condition is often seen in infants around the second day after birth, lasting until day 8 in normal births, or to around day 14 in premature births. Serum bilirubin normally drops to a low level without any intervention required: the jaundice is presumably a consequence of metabolic and physiological adjustments after birth. In extreme cases, a brain-damaging condition known as kernicterus can occur; there are concerns that this condition has been rising in recent years due to inadequate detection and treatment of neonatal hyperbilirubinemia. Neonatal jaundice is a risk factor for hearing loss.

NICE - National Institute for Health and Clinical Excellence

Neonatal Jaundice
- Neonatal Jaundice (Draft For Consultation)
- Appendix A - Search Strategies
- Appnedix B - Economic Evalutation of Alternative Testing Strategies in the
Detection of Hyperbilirubinaemia
- Appendix C - Excluded Studies
- Appendix D - Evidence Tables
- Appendix E - Clinical Questions
- Give Information to Parents or Carers Regarding Jaundice and Care Pathway
- NICE Guideline - Draft for Consultation - August 2009
PDF File = 3.6 MB - Pages = 684

Guido Greogori,Valeria Cassiano

2012-07-16T16:16:00 - Davide Para


Kernicterus, also called Chronic Bilirubin Encephalopaty, is a rare condition with several neural symptoms associated with high levels of unconiugated Bilirubin in the blood and can be diagnosed with neurological examination and laboratory findings including auditory brainstem responses and magnetic resonance imaging. The term kernicterus literally means "yellow kern," with kern indicating the most commonly afflicted region of the brain ( the nuclear region).
Hervieux first described the condition in 1847, and Schmorl first used the term kernicterus as early as 1903. Around 70% of children with kernicterus die within seven days, while the 30% survivors usually suffer irreversible sequels, including hearing loss, paralysis of upward gaze and mental disorder.


Kernicterus is nowadays an unfamiliar condition to most pediatrician practicing, but during the 1940s and 1950s this severe disease was a common condition associated with hemolytic disease of the fetus. With the introduction of exchange transfusion and phototherapy , kernicterus became much less common but it has not been eliminated. This phenomenon occurs not only in developing countries with emerging medical systems, but in Westernized countries as well.(Neonatal Jaundice and Kernicterus)


Unconjugated bilirubin (UCB) is the product of Heme catabolism, it is produced in the Slpeen and it is carried by albumin to the liver, where it is converted or conjugated whit glucuronic acid and made water soluble. Normally, a small amount of bilirubin circulates in the blood (total bilirubin 0,3-1,0 mg/dl). Serum bilirubin is considered a true test of liver function, as it reflects the liver's ability to take up, process, and secrete bilirubin into the bile. Enzyme, glucuronyl transferase, is necessary for the conjugation of bilirubin. Either a lack of this enzyme impairs the liver's ability to conjugate bilirubin as occurs in Gilbert and Crigler-Najiar syndromes.
Hyperbilirubinemia means there is a high level of bilirubin in the blood. This condition is particularly common in newborn infants and it is called as Neonatal Jaundice or Icterus, if this condition persists beyond 14 days, it is called prolonged or protracted neonatal icterus. Before birth, an infant gets rid of bilirubin through the mother's blood and liver systems. After birth, the baby's liver has to take over processing bilirubin on its own because, especially in premature newborn, liver has Glucuronyl-transferase deficiency and it is unable to conjugate bilirubin into its water-soluble form. Almost all newborns have higher than normal levels of bilirubin and some infants may need medical treatment to prevent serious complications (Kernicterus and Newborn Jaundice). When unconjugated bilirubin gets too high, it can be treated. Norms exist for bilirubin in term and nearly term babies based on the age in hours after birth. Other factors, such as prematurity, blood group incompatibilities between infant and mother including Rh and ABO blood types (for example mother Rh- and fetus Rh+ during the second pregnancy) can increase bilirubin production and lead to excessive jaundice.
Kernicterus can result from high levels of bilirubin in a baby’s blood due to massive intravascular hemolysis, in this particular situation the hemolysis is due to reaction of mother's IgG with newborn's Erythrocytes Rh+, this massive hemolysis causes an extreme increase of UCb levels that aren't eliminated by newborn's immature liver and because of its lipide-soluble structure unconjugated bilirubin can easily cross the blood-brain barrier and accumulate in gray matter of Nervous Central System, especially in the Basial Ganglia of the Telencephalon. Unconjugated Bilirubin (UCB) was shown to be within neurons, neuronal processes, and microglia, and to produce loss of neurons, demyelination, and gliosis.In isolated cell cultures, Unconjugated Bilirubin was shown to impair neuronal arborization and to induce the release of pro-inflammatory cytokines from microglia and astrocytes; its accumulation in the CNS will depend on the total amount of unconjugated bilirubin in the systemic circulation, on the efficacy of Blood-Brain-Barrier transporters, and on the presence of acidosis, which increases binding of bilirubin to the brain parenchyma and the risk of kernicterus, increase of Unconjugated Bilirubin especially occurs with respiratory acidosis (The evolving landscape of neurotoxicity by unconjugated bilirubin: role of glial cells and inflammation, 2012).
Kernicterus occurs when Unconiugated Bilirubin levels reach approximately 20 mg/dL (340 mmol/L) the fat soluble unconjugated bilirubin deposits in the fat-rich brain cells causing brain cell damage.
Neurotoxicity of bilirubin is associated with many biochemical mechanism:

  • Unconjugated bilirubin increases reactive oxygen species (ROS) production and it is associated with protein oxidation and lipid peroxidation.
  • Excess of bilirubin in synaptic spaces increses opening of Ca2+channels and the activation of NMDA receptors and because of this bilirubin increases glutammate release which causes important damage to post-synaptic membrane and to nearby neuronal cells.
  • Bilirubin induces apoptosis in nerve cells by activating caspases 3 and 9 (intrinsic apoptotic cascade) as well as caspase-8 (extrinsic apoptotic cascade).
  • Oxidation of GSH to GSSG and inability to be restored is associated with the increased ROS generation, which may determine DNA damage. GSSG is an important anti-oxidation factor and a GSSG deficiency may cause several oxidative damages of the DNA structure that lead neuronal cell to apoptosis.

  • Bilirubin causes synaptotoxicity that has been related with potentiation of inhibitory synaptic transmission.
  • Unconjugated bilirubin,in NCS, decreases the expression of synaptophysin and SNAP-25 which are important in neurotransmitters relasing.
  • Excess of bilirubin decreases NADPH concentration, it means that cells are unable to continue aerobic glycolysis , there is an increae of Acid Lattic production, an increase of Astrocytes metabolic work. (http://themedicalbiochemistrypage.org/pentose-phosphate-pathway.php)
    ROS generation, and activation of caspases are key players in the induction of genes involved in UCB-induced neuronal demise by necrosis and apoptosis.


Acute bilirubin toxicity appears to occur in the first few days of life of the term infant, diagnosis of Kernicterus requests hystorical, phisical and neurological exams and it has to be done during the first days of newborn's life, in order to treat hyperbilirubinemia before the outcoming of organic brain damages. The first symptom that has to be verified is icterus, blood tests are necessary to examinate bilirubin levels in newborn's blood, Kernicterus occurs when bilirubin levels reach 20 mg/dl. Neurological symptoms are unregular movements and muscular tone, convulsions, deficit in ocular an auditory systems.
This symptoms are associated with brain damage of Basal Ganglia, but thanks to MRI it has been possible to discover that excess of bilirubin alterate also brainstem cranial nerves nuclei.
Magnetic resonance imaging of the brain in this condition has specfic findings which aid in the accurate diagnosis of the condition but in humans when lesions are visible with MRI, brain damage has already occured.


Nowdays treatments for full-blown disease do not exist, however newborns with high unconjugated bilirubin levels who may develop Kernicterus can be treated with blood transfusion to help remove extra bilirubin mother's IgG against erythrocytes from baby's blood if there is the suspect of hemolytic disease of the fetus (exchange transfusion) and phototherapy which uses UV radiation which are able to alterate bilirubin structure in way to make bilirubin photoisomers more watersoluble and easly eliminated with urine.

Prevention and especially screening for Rh incompatibility are the most succesfull treatments in order to avoid the outspread of Kernicterus.



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