Protoporphyn ׀׀׀ heme ferrochel atase Fe Pb inhibits ferrochelatase, ALA dehydratase
porphinogen Bili digluco Reduction, intestine orobillinogen intestine orobillin liver
Uncon, therapy phenobar bital,photo therapy
Uncon-billi; hemolytic anemia Neonatal physilogical jaundice, most common Crigler najjar syndrom (Phenobarbital has not effect) ׀ Billi more than 20mg/dl Crigler najjar syndrom glucoronidase active ׀ ׀ Billi not more than 20mg/dl Gilbert glucoronidase active 30%, harmless Toxic hyperbilli liver Damage liver parenchym Con billi; Obstruction of billiary no excretion of con-billi appear in serum, urine Dubin johnson no secretion Con billi to bile Rotor syndrom normal liver, abnormality in liver storage
Degradation of Haemglobin After approximately 120 days, red blood cells are degraded by reticuloendothelial (RE) system, particularly in the liver and spleen. 1) First haemoglobin is dissociated into haem and globin. 2) Globin is degraded to its constituent amino acids,which are reused. 3) The catabolism of haem is carried out in the microsomal fraction of cells by a complex enzyme system called haem oxygenase, in presence of NADPH,O2
Pathway for conversion of Hb to bilirubin Red Blood Cells Haemoglobin 120 days dissociation Globin Haem O2, NADPH + H+ Fe Haem Oxygenase Amino Acids NADP+, CO Biliverdin NADPH + H+ Biliverdin reductase Reutilized NADP+ Bilirubin
Metabolism and excretion of bilirubin occurs in the liver and intestine. It can be divided into four processes :- 1- Uptake of bilirubin by liver parenchymal cells. 2- Conjugation of bilirubin in the smooth endoplasmic reticulum in liver. 3- Secretion of conjugated bilirubin into the bile. 4- Excretion of bilirubin in the form of urobilinogen through faeces and urine.
1- Uptake of bilirubin by liver parenchymal cells a- Bilirubin formed in peripheral tissues is transported to the liver by binding to plasma albumin. b- In the liver bilirubin is removed from albumin and taken up by hepatocyte where it binds to intracellular proteins called ligandin. 2- Conjugation of Bilirubin a- Hepatocytes convert soluble bilirubin to a more soluble form by conjugation of two molecules of glucuronic acid. -This reaction is catalyzed by bilirubin glucuronyl transferase using UDP-glucuronate as a source of glucuronic acid.
b- Bilirubin monoglucuronide is an intermediate and is converted to the bilirubin diglucuronide as shown in figure (2). Bilirubin Bilirubin glucuronyl UDP-Glucuronate transferees UDP Bilirubin monoglucuronide UDP-Glucuronate Bilirubin glucuronyl transferase UDP Bilirubin diglucuronide Figure(2):- Conjugation of bilirubin with glucuronic acid in the liver.
Overview of heme degradation. Heme is degraded to bilirubin, carried in the blood by albumin, conjugated to form the diglucuronide in the liver, and excreted in the bile. The iron is returned to the body’s iron stores. RES = reticuloendothelial system: RBC = red blood cells.
3- Secreation of Bilirubin into Bile:- Most of the bilirubin secreted in the bile is in the form of bilirubin diglucuronide (conjugated form of bilirubin), Unconjugated bilirubin is not secreted into bile. 4- Excretion of Bilirubin in the form of Urobilinogen through Faeces and Urine:- a- After secretion into bile, the conjugated bilirubin passes through the hepatic and common bile ducts into the intestinal lumen. b- Bilirubin diglucuronide is hydrolyzed in the intestine by bacterial enzymes β-glucuronidase and the bilirubin portion is reduced by the faecal flora to colourless urobilinogens and excreted through faeces.
The normal concentration of serum bilirubin is :- Total bilirubin = mg/dl. Conjugated bilirubin = mg/dl. Unconjugated bilirubin = mg/dl. Hyperbilirubinemia exists when bilirubin in the blood exceeds 1mg/dl. Hyperbilirubinemia may be due to:- 1. Increased bilirubin production. 2. Decreased hepatic uptake. 3. Decreased hepatic conjugation 4. Decreased excretion of bilirubin into bile
In all these situations bilirubin accumulates in the blood and when it reaches a certain concentration ( mg/dl), it diffuses into the tissues. The skin and the sclera appear yellowish due to the deposition of bilirubin in the tissues. The condition is called Jaundice. Jaundice can be divided into four types:- 1. Haemolytic anemia un-billi or prehepatic jaundice. 2. Hepatocellular or intrahepatic jaundice. 3. Obstructive or posthepatic jaundice. 4. Neonatal or physiological jaundice. Hyperbiliubinemia may be acquired or inherited
cquried hyperbilirubinemia:- 1. Haemolytic Jaundice. 2. Hepatic Jaundice. 3. Obstructive Jaundice. 4. Neonatal Jaundice. 1. Haemolytic Jaundice:- In haemolytic jaundice, there is an increased in breakdown of haemoglobin to bilirubin at a rate in excess of the ability of the liver cell to conjugate and excrete it. Excess haemolysis may be due to:- a- Sickle haemoglobin. b- Deficiency of G-6-P dehydrogenase. c- Incompatible blood transfusion.
The main biochemical features of the haemolytic jaundice are: 1- Inreased plasma concentration of unconjugated bilirubin. 2- Increased amount of urobilinogen in urine and faeces. 3- Absence of bilirubin in the urine. 2- Hepatic jaundice:- In hepatic jaundice, there is some disorder of the liver cells or the bile passages within the liver. The hepatic parenchymal cell damage impairs conjugation of bilirubin and results in unconjugated hyperbilirubinemia. Hepatocellular damage is caused by :- a- Infections ( Viral Hepatitis). b-Toxic chemicals ( Alcohol,Chloroform,CCl4). c- Drugs. d- Cirrhosis.
Patients with hepatic jaundice have obstruction of the biliary tree within the liver that results in the presence of some conjugated hyperbilirubinemia. The main biochemical features of the hepatic jaundice:- 1- Increased plasma concentration of conjugated and unconjugated bilirubin. 2- Decreased amount of urobilinogen in urine and faeces 3- Presence of bilirubin in the urine. 4- Increased level of alanine transaminase (hepatic cell damageallows intracellular enzymes to leak into theblood).
3- Obstructive Jaundice:- This occurs when there is an obstruction in the passage of conjugated bilirubin from the liver cells to the intestine. This condition is also called Cholestasis, (the obstruction of biliary flow). The obstruction may be intrahepatic or extrahepatic. Extrahepatic cholestasis occurs due to :- 1- Blockage of the common bile duct by gallstones. 2- Carcinoma of the head of the pancrease. 3- Carcinoma of the bile duct.
The liver is deficient in UDP-glucuronyl transferase which is necessary for conjugation. The enzyme deficiency is more serious with increasing degree of prematurity. The increased in unconjugated bilirubin above mg/dl can cause mental retardation