Bilirubin Metabolism Flashcards
A metabolite of heme
Bilirubin
Very recently, bilirubin has been shown to possess important functions as an
Antioxidant
Also serves as a means to excrete unwanted, derived from various heme containing proteins such as hemoglobin, myoglobin, and various P450 enzymes
Bilirubin
Bilirubin and its metabolites are also notable for the fact that they provide color to the
Bile and stool (and to a lesser degree, urine)
Certain disease states that involve excessive levels of bilirubin in the bloodstream can lead to accumulation of bilirubin in the
Brain
Bilirubin can cross the
Blood-brain barrier
Certain disease states that involve excessive levels of bilirubin in the bloodstream can lead to accumulation of bilirubin in the brain due to its ability to cross the blood–brain barrier, a condition known as
Kernicterus (yellow stained nucleus)
Notable for its yellow coloration
Bilirubin
Accumulation of Bilirubin in the blood is the basis of
Jaundice
In a healthy individual, red blood cells, and their contents, are turned over after about
120 days
Broken down to its constituent amino acids, and the heme ring is released, degraded, and secreted
Hemoglobin
Take up aged RBCs and begin to degrade them into a heme iron-porphyrin complex and globin
Cells of the reticuloendothelial system (RES)
Heme is further degraded by macrophages using
Heme oxygenase
Heme is further degraded by macrophage using heme oxygenase. releasing green pigmented
Biliverdin, as well as Fe and CO
This reaction is the only endogenous source of
CO
Acts as an antioxidant
Biliverdin
Structurally resembles nitric oxide and acts as a signaling molecule and a vasodilator
CO
For example, CO has been shown to be beneficial in
Stroke Victims
Biliverdin is substrate for biliverdin reductase, producing the red-orange colored
Bilirubin
Bilirubin and its derivatives are known as
Bile pigments
The changing colors of a bruise mirror the evolution of different
Intermediates of heme degredation
Bilirubin is poorly soluble in the aqueous medium of the plasma, so it is transported to the liver bound to
Albumin
After entering the hepatocyte, unconjugated bilirubin is bound to the cytosolic protein
-prevents bilirubin from reentering plasma
Glutathione S transferase B
Concentrations are low at birth, but appear to reach adult values by 2 weeks of age
Glutathione S-transferase (GST-beta)
In the endoplasmic reticulum, bilirubin is solubilized by conjugation to glucuronic acid, which yields
Bilirubin monoglucuronide and diglucuronide
The conjugation of glucuronic acid to bilirubin is catalyzed by
Bilirubin uridine diphosphateglucuronosyl transferase (UDPGT)
The activity of this enzyme increases 100 fold after birth so that the % of conjugated bilirubin in the bile rises from
20% to 50% in adults
Bilirubin monoglucuronide and diglucuronide undergo unidirectional transport by
MRP2
The vast majority of bilirubin monoglucuronide and diglucuronide is eliminated in bile, but small amounts are transported at the sinusoidal membrane back into plasma, possibly via
MRP3
Intracellular bilirubin monoglucuronide and diglucuronide secreted by MRP3 to the blood can be taken up again into downstream hepatocytes via
OATP1B1 and OATP1B3
This secretion-and reuptake loop may prevent the saturation of biliary excretion in the upstream hepatocytes, thereby ensuring efficient
Biliary elimination
The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the
Proximal small bowel
Conjugated bilirubin is not taken up by the
Intestinal mucosa
When the conjugated bilirubin reaches the distal ileum and colon, it is hydrolyzed to unconjugated bilirubin by
Bacterial glucuronidases
The unconjugated bilirubin is reduced by normal gut bacteria to form a group of colorless tetrapyrroles called
Urobilinogens
About 80–90% of these products are excreted in feces, either unchanged or oxidized to orange derivatives called
Urobilins or stercobilins
The remaining 10% of the urobilinogens are passively absorbed, enter the portal venous blood, and are re-excreted by the
Liver
A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in
Urine
Results from the rupture or lysis of red blood cells within the circulation
Intravascular hemolysis
When the membrane of erythrocytes ruptures, they release their hemoglobin into the
Plasma
The hemoglobin breaks down into
Hemoglobin dimers
Binds the liberated free hemoglobin dimers
-an α-2 globulin produced in the liver
Haptoglobin
However, haptoglobin is readily
Saturated
If intravascular hemolysis continues, the hemoglobin dimers are in excess in plasma and are filtered readily through the glomerulus. This will cause
Hemoglobinuria
Hemoglobinuria is typically visible as
Pink to Red urine
The hemoglobin dimers that remain in circulation are oxidized to
Methemoglobin
The hemoglobin dimers that remain in circulation are oxidized to methemoglobin, which disassociates into a
Free heme and globin chains
The oxidized free heme (met-heme) binds to
Hemopexin (a β-globulin, Hpx)
Taken up by a receptor on hepatocytes and macrophages within the spleen, liver and bone marrow
The met-heme-hemopexin complex
Similarly, the hemoglobin/haptoglobin complex is taken up by
Hepatocytes and macrophages
The function of Hpx thus appears to be to prevent loss of free hemoglobin into the
Kidney
This is important because it conserves the valuable
Iron
Low levels of haptoglobin are found in patients with hemolytic anemias seen in
Sickle cell anemia, thalassemia, G6PDH and pyruvate kinase deficiency
The terms direct- and indirect-reacting bilirubin are based on the original
Van den Bergh reaction
This assay, or a variation of it, is still used in most clinical chemistry laboratories to determine the serum level of
Bilirubin
The direct fraction is that which reacts in the absence of an accelerator substance such as alcohol with
Diazotized sulfanilic acid
The direct fraction provides an approximate determination of the serum levels of
Conjugated Bilirubin
The total serum bilirubin is the amount that reacts after the addition of
Alcohol
The difference between the total and the direct bilirubin and provides an estimate of the unconjugated bilirubin in serum
Indirect fraction
What are the normal values of
- ) Direct bilirubin
- ) Total bilirubin
- ) 0-0.3 mg/dL
2. ) 0.3-1.9 mg/dL
Massive lysis of RBCs, precipitated by some other preexisting condition, releases heme in quantities that exceed the liver’s capacity to process it to bilirubin diglucuronide in the case of
Hemolytic jaundice
Bilirubin itself builds up in the blood and hence in peripheral tissue with
Hemolytic Jaundice
Stems from a mechanical obstruction of the bile duct, preventing the ‘draining’ of conjugated bilirubin into the intestines
Obstructive Jaundice
What is an indicator of obstructive jaundice?
Feces have pale clay color
In obstructive jaundice, feces have a characteristic pale clay color, due to the relative absence of the brown colored
Stercobilin
Occurs when damage to liver cells results in a decrement in normal biochemical functions of these cells for heme metabolism
Hepatocellular Jaundice
Hepatocytes cannot meet the loads presented even under otherwise normal circumstances with
Hepatocellular jaundice
Both liver uptake of bilirubin and the conjugation of bilirubin can be affected in
Hepatocellular jaundice
Results, particularly in premature infants, due to low levels of the hepatic enzyme UDP-glucuronyl transferase (UDP-GT) at birth
Neonatal Jaundice
Neonatal Jaundice results, particularly in premature infants, due to low levels of the hepatic enzyme
UDP-glucuronyl transferase (UDP-GT)
Adult levels of UDP-GT is achieved in about a
Month
To avoid the adverse neurologic outcomes of elevated circulating bilirubin levels, newborns receive phototherapy to
Convert bilirubin to a soluble derivative
