METABOLISME BILIRUBIN dr I NJOMAN WIDAJADNJA, M.KES

Is a product of heme metabolism What is Bilirubin? (indirect= cunjugated . direct = unconjugated = free) Is a bile pigment Is lipid soluble Is a product of heme metabolism

Bilirubin bebas = bilirubin yang terlarut dalam albumin plasma darah (unconjugated) Dalam hepar bilirubin ini dilepaskan dari albuminnya, tapi diikatkan dg glukoronida / sulfat = bilirubin terkonyugasi(conjugated) Bentuk bilirubin yg terkonyugasi ini diekskresikan ke dalam kantong empedu usus, dan oleh bakteri usus  menjadi Urobilinogen (mudah larut)

Macrophage of the reticuloendothelial system at spleen Metabolisme Heme Fe3+ + CO NADP+ Hemoglobin – 80% Myoglobin Cytochrome P450s Hemoproteins O2 NADPH + H+ Heme Biliverdin Bilirubin Heme Oxygenase Biliverdin Reductase Hepar Macrophage of the reticuloendothelial system at spleen Blood Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).

HANCURNYA SEL DARAH MERAH (FATE OF RBCs)  Life span dlm aliran darah: 60-120 days  kematian RBCs : phagocytosis and/or lysis Normalnya: lysis terjadi sec. extravascular di dlm RE system (spleen)  RBC phagocytosis Lysis juga terjadi sec. intravascularly (in blood stream)

The Fate of Bilirubin… ? Alb B B B CB B + GST MRP2 :GST sER Plasma Hepatic Cell Bile Alb B ? B + GST MRP2 B CB + UDPGA :GST B UGT1A1 sER Alb = albumin B = bilirubin GST = glutathione-S-transferase UDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubin UGT1A1 = UDP-glucuronosyltransferase 1A1 MRP2 = Multi-drug Resistance Protein 2 Adapted from Harrison’s 15th Ed. “Principles of Internal Medicine”, 2001.

Bilirubin Excretion B CB B CB Liver Enterohepatic circulation Bile B-glucoronidase Bacteria B ox Urobilinogen Urobilin CB Stercobilinogen Stercobilin Bacteria usus Intestines feces

Bilirubin Excretion B CB B CB Liver Urobilin Kidney ox Urobilinogen Urine Enterohepatic circulation Bile B-glucoronidase bacteria B CB ox Urobilin Urobilinogen Stercobilin Stercobilingogen bacteria Intestines feces

NORMAL BILIRUBIN METABOLISM Uptake of bilirubin by the liver is mediated by a carrier protein (receptor) Uptake may be competitively inhibited by other organic anions On the smooth ER, bilirubin is conjugated with glucoronic acid, xylose, or ribose Glucoronic acid is the major conjugate - catalyzed by UDP glucuronyl tranferase “Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut Oxidized to stercobilin which is colored Excreted in feces Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney

Hyperbilirubinemia Interferences at any one of the points of bilirubin processing described above can lead to a condition known as HYPERBILIRUBINEMIA. As the name implies this disease is characterized by abnormally elevated levels of bilirubin in the blood.

HYPERBILIRUBINEMIA Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when there is an imbalance between its production and excretion Recognized clinically as jaundice

Prehepatic (hemolytic) jaundice Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis Excess RBC lysis is commonly the result of autoimmune disease; hemolytic disease of the newborn (Rh- or ABO- incompatibility); structurally abnormal RBCs (Sickle cell disease); or breakdown of extravasated blood High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

Intrahepatic jaundice Impaired uptake, conjugation, or secretion of bilirubin Reflects a generalized liver (hepatocyte) dysfunction In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

Posthepatic jaundice Caused by an obstruction of the biliary tree Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin) In a complete obstruction, urobilin is absent from the urine

Diagnoses of Jaundice

Neonatal Jaundice Common, particularly in premature infants Transient (resolves in the first 10 days) Due to immaturity of the enzymes involved in bilirubin conjugation High levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus

Neonatal Jaundice If bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form If necessary, exchange blood transfusion is used to remove excess bilirubin Phenobarbital is oftentimes administered to Mom prior to an induced labor of a premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl transferase Jaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is usually pathological and needs to be further investigated

Causes of Hyperbilirubinemia

SYMPTOMS Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice) Detectable when total plasma bilirubin levels exceed 2-3mg/100mL AHHH!!! I have symptoms of hyperbilirubinemia!!!

Causes: Increased bilirubin production Reduced bilirubin uptake by hepatic cells Disrupted intracellular conjugation Disrupted secretion of bilirubin into bile canaliculi Intra/extra-hepatic bile duct obstruction Lead to increases in free (unconj.) bilirubin Result in rise in conj. bilirubin levels

INCREASED BILIRUBIN PRODUCTION (unconj. Hyperbilirubinemia) Hemolysis Increased destruction of RBCs eg sickle cell anemia, thalassemia Drastic increase in the amount of bilirubin produced Unconj. bilirubin levels rise due to liver’s inability to catch up to the increased rate of RBC destruction Prolonged hemolysis may lead to precipitation of bilirubin salts in the gall bladder and biliary network result in formation of gallstones and conditions such as cholecystitis and biliary obstruction Other Degradation of Hb originating from areas of tissue infarctions and hematomas Ineffective erythropoiesis

DECREASED HEPATIC UPTAKE (unconj. Hyperbilirubinemia) Several drugs have been reported to inhibit bilirubin uptake by the liver e.g. novobiocin, flavopiridol Bile MRP2 B + GST CB Plasma Hepatic cell Alb :GST sER + UDPGA UGT1A1