Bilirubin metabolism: How is bilirubin excreted by the body?
Are you wondering how bilirubin is metabolized and excreted by the body?
Well, that’s the focus of this Chalk Talk episode.
Bilirubin is produced during the breakdown of hemoglobin, the oxygen-carrying pigment
of erythrocytes, commonly termed red blood cells
It has no further benefit for the body and must be excreted, as high bilirubin levels
can be toxic.
In part one, we’ll go through the process of bilirubin metabolism.
In part two, we’ll look at how conjugated and unconjugated bilirubin is measured in
the lab.
Bilirubin is a metabolic end-product of heme, a component of hemoglobin.
In healthy individuals, approximately 80% of heme is produced during the breakdown of
aged erythrocytes in the spleen.
The remaining 20% accumulate during red blood cell formation in the bone marrow, also termed
erythropoiesis.
Heme is absorbed initially by the macrophages of the spleen, bone marrow, and liver.
In macrophages, the red heme is converted into orange-yellow bilirubin through several
intermediate steps.
Since bilirubin is initially water-insoluble, it can’t be excreted in the urine or bile.
The unconjugated bilirubin binds to serum albumin for its transport in the blood plasma
so that it can be made water-soluble, i.e., conjugated.
This conversion occurs in the liver and involves four steps:
First, there’s bilirubin uptake by the hepatocyte.
Second, it conjugates with glucuronic acid, making it soluble in water;
Third, the now water-soluble bilirubin is secreted into the bile canaliculi by a membrane
transporter.
In the final step, bilirubin is excreted via the bile ducts.
The third step, which involves bilirubin secretion into the bile canaliculi, is an active transport
mechanism, limiting the rate of bilirubin excretion.
This is important in cases of impaired hepatocyte function, where hepatocyte excretion of conjugated
bilirubin is usually more severely impaired than conjugation itself.
The conjugated bilirubin is excreted into the gut from the liver through bile.
The colonic bacteria deconjugate and metabolize the bilirubin into urobilinogen.
Urobilinogen is a colorless intermediate product and 80% of the urobilinogen remains in the
colon.
It can be further converted by bacteria initially into stercobilinogen and finally into stercobilin,
which gives feces its characteristic brown color.
The remaining 20% of urobilinogen is reabsorbed from the intestine and transported via the
blood to the liver.
Because urobilinogen is water-soluble, it can be re-excreted in bile.
This creates a circulatory process known as enterohepatic circulation.
Reabsorbed urobilinogen can also be excreted by the kidneys.
In fact, the term urobilinogen originates from the finding of small detectable amounts
in urine.
Urobilinogen is colorless.
Non-enzymatic oxidation of urobilinogen leads to its conversion to urobilin, which is responsible
for the yellow characteristic color of urine.
Now, back to the liver: The conjugated bilirubin in the liver not only exits the hepatocyte
through the bile ducts but it can also re-enter the bloodstream.
So, that’s why conjugated bilirubin can be detected in the plasma of healthy individuals.
However, only small amounts are usually present: Approximately 10 to 20% of plasma bilirubin
is conjugated, whereas the majority, the remaining 80 to 90%, is unconjugated and returned to
the liver.
Biliary obstruction, which refers to blockage of the bile ducts, can substantially increase
the reflux of conjugated bilirubin from the hepatocytes back into the plasma.
As a result, conjugated bilirubin levels in the blood increase and are detectable.
Bilirubin metabolism can also be measured in urine.
The urine dipstick test is used to detect two substances involved in bilirubin metabolism:
conjugated bilirubin and urobilinogen.
Although the urine dipstick test is labeled as only detecting bilirubin, it actually detects
conjugated bilirubin.
Unconjugated bilirubin is fat-soluble and bound to albumin in the blood.
It’s not excreted in the urine.
The amount of conjugated bilirubin in the plasma of healthy individuals is so small
that only a tiny amount is excreted in the urine.
These small amounts are usually not detectable using the urine dipstick test.
The detection of bilirubin in urine indicates a pathological process and is termed bilirubinuria.
Because bilirubin has a yellow-orange color, the urine in bilirubinuria is dark in color.
Bilirubinuria only occurs in conditions associated with increased levels of conjugated
bilirubin in the blood.
Conditions leading to elevated levels of unconjugated bilirubin don’t cause bilirubinuria.
In addition to bilirubin, urobilinogen can also be measured using the urine dipstick.
Under normal conditions, small quantities of up to 1 mg per decilitre may be found in
the urine.
Higher values are pathological and termed urobilinogenuria.
It’s usually observed in hemolytic diseases.
These conditions lead to the breakdown of erythrocytes and an increase in unconjugated
serum bilirubin levels.
There is higher bilirubin excretion via the liver into the colon, resulting in more urobilinogen
produced, which is eventually reabsorbed.
The reabsorbed urobilinogen can be excreted by the liver and in urine, resulting in elevated
urobilinogen levels.
Because urobilinogen is colorless, urine color isn’t changed in urobilinogenuria.
In addition to conditions associated with urobilinogenuria, there are diseases that
may lead to decreased urobilinogen in urine.
One of these conditions is biliary obstruction.
As a result, less bilirubin reaches the intestine and less urobilinogen is formed.
Decreased urobilinogen levels can’t be detected with the urine dipstick because the test strip
only measures semiquantitatively.
However, this isn’t usually necessary in a clinical setting, as cholestasis, in which
bile is congested, can be diagnosed using laboratory parameters of cholestasis and imaging.
Before we look at the laboratory measurement of bilirubin, we’ve prepared a quiz on bilirubin
metabolism.