Tetrapyrrole pigment- a breakdown product of heme

About 250-300 mg is produced per day primarily in R.E cells of Spleen and Liver

Sources- Breakdown of Hb in senescent R.B.C Prematurely destroyed erythroid cells Turnover of Hemoproteins Unconjugated Bilirubin is insoluble in water

due to tight internal hydrogen bonding

Hepatocellular uptake-Albumin bound unconjugated bilirubin is taken up by Hepatocytes mediated by Bilirubin transporter protein

Intracellular binding-Bilirubin is kept in solution by binding to Glutathione-S-transferases

Bilirubin conjugation is catalysed by the enzyme UDP-glucuronosyl transferase resulting in formation of mono and diglucuronides

These molecules are highly soluble in water facilitating their excretion through bile

In distal ileum and colon hydrolysis Conj Bilirubin Unconj Bilirubin gut bact reduction

Urobilinogen

80-90% 10-20%

Unchanged urobilin portal blood

faeces liver kidney

Excessive production of bilirubin Reduced hepatocyte uptake Impaired conjugation Decreased hepatocellular excretion Impaired bile flow

The first three mechanisms lead to unconjugated hyperbilirubinemia and the latter two produce conjugated hyper bilirubinemia

UNCONJUGATED HYPERBILIRUBINEMIA Hemolytic disorders Ineffective Erythropoiesis Drugs Inherited conditionsCONJUGATED HYPERBILIRUBINEMIA Inherited conditions

Inherited conditions like Spherocytosis,elliptocytosis,G6PD and pyruvate kinase deficiencies

Acquired conditions like Microangiopathic hemolytic anemias,PNH,Spur cell anemia,Immune hemolysis

Excessive hemolysis Inc Bilirubin turnover

Unconjugated Hyperbilirubinemia

In Thalassemia major,Megaloblastic anemia,Porphyrias,Lead poisoning abnormal R.B.C’ are produced and are destroyed in bone marrow

Excessive unconjugated Bilirubin(70% of total ) is formed resulting in Unconjugated hyper Bilirubinemia

Rifampicin, probenecid, ribavirin cause decreased uptake of Unconjugated Bilirubin by hepatocytes

Gentamicin, Pregnanediol, Chloramphenicol inhibit UGT1A1

Autosomal recessive Liver incapable of synthesising Functional

enzyme UGT1A1 Colorless Bile containing trace amount of

unconjugated bilirubin Serum Bilirubin can reach very high levels

producing severe Jaundice and Icterus Death within 18 months after birth is

common if no Liver transplantation is done

Autosomal dominant Mutation in UDPGT gene causes reduced

activity and affinity but not complete absence of enzyme

Capable of forming only Monoglucoronide Bilirubin

TREATMENT: Phenobarbitone-improves Bilirubin Glucuronidation by inducing hypertrophy of the hepatocellular E.R. Liver Transplantation

Reduction in Hepatic glucuronidating activity.

In most cases two extra bases(TA) are found in TATAA element of 5’Promotor region

Reduced expression of UGT1A1 It is found in association with

stress,severe exercise and fasting

Autosomal recessive Hereditary defect in Hepatocellular

excretion of Bilirubin Glucuronide across canalicular membrane

It is due to absence of canalicular protein,Multi-drug resistance protein2.

Asymptomatic apart from chronic or recurrent Jaundice of fluctuating intensity

Autosomal dominant Decreased Bilirubin uptake Decreased biliary excretion Patients exhibit Jaundice but otherwise

lead normal lives

Almost every newborn develops transient andmild unconjugated hyperbilirubinemia

Bilirubin conjugating and excreting machinery is not fully mature until about 2 weeks of age

Breast milk contains Beta glucuronidase

Deconjugation of bilirubin glucuronide

Increases intestinal reabsorption of unconjugated bilirubin