Catabolism of heme to bile pigments and hyperbilirubinemia

Catabolism of heme to bile pigments and hyperbilirubinemia



       At the end of this lecture, student will be able to

      Explain Porphyrin

      Explain formation of bile pigments, Catabolism of heme to bile pigments

      Discuss hyperbilirubinemia


       Porphyrins are cyclic compounds composed of 4 pyrrole rings held together by methenyl (=CH-) bridges

       Metal ions can bind with nitrogen atoms of pyrrole rings to form complexes

       Eg: Heme is an iron-containing porphyrin while chlorophyll is a magnesium-containing porphyrin

       Heme and chlorophyll are the classical examples of metalloporphyrins

Structure of heme

       The characteristic red color of hemoglobin (ultimately blood) is due to heme

       Heme contains a porphyrin molecule namely protoporphyrin lX, with iron at its center

       Protoporphyrin lX consists of four pyrrole rings to which four methyl, two propionyl and two vinyl groups are attached

Structure of globin

       Globin consists of four polypeptide chains of two different primary structures( monomeric units)

       The common form of adult hemoglobin (HbA1) is made up of two α-chains and two β-chains(α2 β2)

       The four subunits of hemoglobin are held together by non-covalent interactions primarily hydrophobic, ionic and hydrogen bonds. Each subunit contains a heme group.

Degradation of heme to bile pigments

       Erythrocytes have a life span of 120 days

       At the end of this period, they are removed from the circulation

       Erythrocytes are taken up and degraded by the macrophages of the reticuloendothelial (R E) system in the spleen and liver

       Hemoglobin is cleaved to the protein part globin and non-protein heme

       About 6 g of hemoglobin per day is broken down, and resynthesized in an adult man (70 kg)

       Fate of globin: globin may be reutilized as such for the formation of hemoglobin or degraded to the individual amino acids

Formation of Bile Pigments

       Non protein heme: 80% of heme that is subjected for degradation comes from erythrocytes and 20% from immature RBC & cytochromes

       Normal concentration in male is 14-16 g/dl, and in female 13-15 g/dl

       Heme oxygenase is a complex microsomal enzyme utilize NADPH & O2 to cleaves the methenyl bridge between two pyrrole ring (A&B) to form biliverdin, simultaneously  ferrous ion (Fe2+) is oxidized to ferric form(Fe3+) and released in circulation

       The product of heme oxygenase is biliverdin, Fe3+ and carbon monoxide

       Biliverdin reductase reduce biliverdin to bilirubin (yellow pigment) by reducing methylene group

       1gm of hemoglobin on degradation finally yields about 35 mg bilirubin

        Approximately 250-350 mg of bilirubin is daily produced in human adults

Transport of Bilirubin in Plasma

•   Bilirubin on release from macrophages circulates as unconjugated bilirubin in plasma tightly bound to albumin.

•   Albumin + free Bilirubin ó Bilirubin ~ Albumin Complex à unconjugated bilirubin

Why bound to albumin?


Increase the solubility of whole molecule

Prevent unconjugated bilirubin freely come into other tissue, cause damage.

       Bilirubin is lipophilic and therefore insoluble in aqueous solution

       Bilirubin is transported in the plasma in a bound form to albumin

       Albumin has two binding sites for bilirubin- high-affinity site and a low affinity site

       Albumin-bilirubin complex enters the liver, bilirubin dissociates and is taken up by hepatocytes by a carrier-mediated active transport

       Conjugated bilirubin is excreted into the bile canaliculi against a concentration gradient which then enters the bile.

       The transport of bilirubin diglucuronide is an active, energy-dependent and rate limiting process

       Bilirubin glucuronides are hydrolysed in the intestine by specific bacterial enzymes namely B-glucuronidases to liberate bilirubin

       The latter is then converted to urobilinogen (colourles compound), a small part of which may reabsorbed into the circulation

       Urobilinogen can be converted to urobilin (an yellow colour compound) in the kidney and excreted

       The characteristic colour of urine is due to urobilin A major part of urobilinogen is converted to stercobilin which is excreted with feces The characteristic brown colour of feces is due to stercobilin

Formation of urobilins in the intestine

Catabolism of heme to bile pigments



       The normal serum total bilirubin concertration is in the range of 0.2 to 1.0 mg/dl.

       About 0.2-0.6 mg/dl is unconjugated whie 0.2 to 0.4 mg/dl is conjugated bilirubin

       Jaundice( French: Jaune-yellow) is a clinical condition characterized by yellow colour of the white of the eyes (sclerae) and skin, due to deposition of bilirubin and  its elevation levels in the serum

        The term hyperbilirubinemia is often used to represent the increase  concentration of serum bilirubin

       Classification of jaundice : Jaundice is classified into three major types- hemolytic, hepatic and obstructive

1.      Hemolytic jaundice: This condition is associated with increased hemolysis of erythrocytes (e.g. incompatible blood transfusion, malaria, sickle-cell anemia).

       This results in the overproduction of bilirubin beyond the ability of the  Liver to conjugate and excrete the same

       lt should, however be noted that liver possesseas large capacity to conjugate about 3.0 g of bilirubin per day against the normal bilirubin production is 0.3/day

       In hemolytic jaundice, more bilirubin is excreted into the bile leading to the increased formation of urobilinogen and stercobilinogen

       Hemolytic jaundice is characterized by Elevation in the serum unconjugated bilirubin

       Increased excretion of urobilinogen in urine

       Dark brown colour of feces due to high content of stercobilinogen

2. Hepatic (hepatocellular) jaundice:

       caused by dysfunction of the Iiver due to damage to the parenchymal cells

       This may be attributed to viral infection (viral infection, hepatic poisons and toxins (chloroform, carbon tetrachloride, phosphorus etc.) cirrhosis of liver, cardiac failure etc

       Damage to the liver adversely affects the bilirubin uptake and its conjugation by liver cells

       Hepatic jaundice is characterized by increased levels of conjugated and unconjugated bilirubin in the serum

       Dark coloured urine due to the excessive excretion of bilirubin and urobilinogen

       lncreased activities of alanine transaminase (SGPT) and aspartate transaminase (SCOT)

       Released into circulation due to damage to hepatocytes

       The patients pass pale, clay coloured stools due to the absence of stercobilinogen

       The affected individuals experience nausea and anorexia (loss of appetite)

3. Obstructive (regurgitation) jaundice:

       Due to an obstruction in the bile duct that prevents the passage of bile into the intestine

       The obstruction may be caused by gall stones, tumors etc

       Due to the blockage in bile duct, the conjugated bilirubin from the liver enters the circulation

       Obstructive jaundice is characterized by Increased concentration of conjugated bilirubin in serum

       Serum alkaline phosphatase is elevated as it is released from the cells of the damaged bile duct

       Dark coloured urine due to elevated excretion of bilirubin and clay coloured feces due to absence of stercobilinoge

       Feces contain excess fat indicating impairment in fat digestion and absorption in the absenceo f bile

       The patients experience nausea and gastrointestinal pain

Catabolism of heme to bile pigments and hyperbilirubinemia Summary

       Porphyrins are the cyclic compounds composed of 4 pyrrole ring held together by methlenyl (=CH-) bridges

        Biliverdin & Bilirubin are bile pigments

       Bile is secreted into intestine where glucuronic acid is removed and the resulting bilirubin is converted to urobilinogen

       Urobilinogen is oxidized by intestinal bacteria to the brown stercobilin

       Jaundice is a clinical condition characterized by yellow colour of the white of the eyes (sclerae) and skin, due to deposition of bilirubin

       The term hyperbilirubinemia is often used to represent the increase  concentration of serum bilirubin

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