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.
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.
METABOLISM OF BILIRUBIN
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.
PHATOGENESIS OF HYPERBILIRUBINEMIA
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:
- Over production of bilirubin caused by hemolysis
- The impairment in bilirubin uptake by the liver, conjugation in the liver, and excretion from the liver cells
- 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 (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