The term jaundice comes from the French word jaundice, which literally translates as "yellowing." However, it is also known as icterus, which has an even more obscure origin, stemming from the belief that jaundice could once be cured by looking at a yellow bird.
As you might imagine, jaundice is caused by the body producing yellow pigments, most notably in the skin and eyes. The yellowing pigment is caused by bilirubin, a component of bile that is responsible for the yellowing of bruises, as well as the yellowing of urine and browning of feces following its metabolism.
Due to the fact that bilirubin is the primary cause of yellowing in our bodies, it is critical to understand where it originates. When red blood cells reach the end of their lifespan—approximately 120 days—they are consumed or phagocytosed by macrophages in the reticuloendothelial system, also known as the macrophage system, which is primarily composed of the spleen but also includes lymph node components.
Thus, the macrophage consumes the blood cell and breaks down hemoglobin into heme and globin, which are then further broken down into amino acids. On the other hand, heme is converted to iron and protoporphyrin, which is then converted to unconjugated bilirubin, or UCB. Unconjugated bilirubin is a water-insoluble lipid-soluble form of bilirubin; it is also referred to as indirect bilirubin.
The blood albumin then binds to UCB and transports it to the liver, where it is taken up by hepatocytes and conjugated by the enzyme uridine glucuronyl transferase (UGT), rendering it water soluble. Conjugated bilirubin is then secreted from the bile canaliculi and drains into the bile ducts, where it is transported to the gallbladder for storage as bile.
When you eat, your gallbladder secretes bile and CB, which travels through the common bile duct to the duodenum of the small intestine, where intestinal microbes convert it to urobilinogen, or UBG. A portion of that urobilinogen is now converted to stercobilin, which is excreted and contributes to the brown color of feces.
However, some of that UBG is recycled; it is reabsorbed into the bloodstream and spontaneously oxidizes to form urobilin, the majority of which is transported to the liver and some to the kidneys. It is then excreted and is responsible for the yellow color of urine! That concludes our discussion of bilirubin metabolism.
If any step in this process is disrupted, for example, if your liver cells become damaged and are unable to conjugate bilirubin, or if they die and release bilirubin, you can end up with increased bilirubin levels in the blood, which can be conjugated, unconjugated, or both! This is what gives the skin and eyes their yellow hue.
To achieve the Simpsons-like yellow skin tone, serum bilirubin levels of 2. 5 mg/dL or greater are typically required. The first sign of jaundice and elevated bilirubin levels in the blood is the yellowing of the sclera of the eyes. Scleral tissue contains a high concentration of elastin, which has a special affinity for bilirubin and binds it tightly, giving the scleral tissue a yellow color that appears prior to the skin.
As you might expect after reviewing this process, there are several potential pitfalls along the way that can result in jaundice. They are classified according to whether they have a higher level of UCB, CB, or both in their blood.
Extravascular hemolytic anemias, in which red blood cells are destroyed earlier than normal, and ineffective hematopoiesis, in which blood cells do not form properly in the bone marrow, resulting in their destruction by macrophages, are two conditions associated with increased UCB and a similar presentation of jaundice.
Both cases result in the breakdown of red blood cells, resulting in elevated levels of UCB. Due to the fact that your hepatocytes can only convert UCB to CB at a certain rate, they can become overworked. As an example, suppose this liver cell can conjugate no more than ten molecules of UCB per minute, but they only see five.
If your body suddenly begins breaking down more blood cells and the number of UCB molecules on this cell's docket increases to 15 molecules per minute, this liver cell cannot keep up and the extra 5 UCB molecules remain in the blood, which is the first issue. Additionally, as the liver cells degrade, all of this CB is excreted into the bile, increasing the risk of pigmented bilirubin gallstones.
Additionally, once the CB is delivered to the duodenum in its entirety, it is converted to urobilinogen. Bear in mind that some urobilinogen is recycled into the bloodstream, where it is oxidized to urobilin and excreted in the urine, giving it a much darker hue. The UCB is not excreted because it is not water soluble! Although excess UCB was produced in the previous two cases, it is also possible to have hepatocytes that cannot work fast enough to keep up.
One of these instances is newborn physiologic jaundice; newborn livers lack sufficient UGT to convert UCB, and UCB levels can be elevated following birth as a result of macrophages naturally destroying fetal red blood cells.
This is normal in the majority of cases, but it can result in complications if UCB levels rise significantly; because it is fat soluble, it can accumulate in the brain's basal ganglia, causing kernicterus and resulting in brain damage or death.
The most frequently used treatment for this condition is phototherapy, which utilizes light to induce structural and configurational changes in the bilirubin molecule; essentially, the bilirubin molecule absorbs the light's energy and changes shape. These new shapes are more soluble and are excreted via the urine.
This can be an extremely effective and non-invasive method of eliminating excess UCB from the blood. Inadequate UCB conjugation can also be caused by hereditary defects. Gilbert's syndrome is a condition in which their UGT enzyme activity is low and has difficulty ramping up when required, resulting in this liver cell pumping out a maximum of six molecules per minute.
Unfortunately, anything that increases hemolysis, such as infection, stress, or starvation, increases the unconjugated bilirubin load, which can easily overwhelm these hepatocytes, resulting in an accumulation of unconjugated bilirubin in the blood and jaundice.
Another genetic example is Crigler Najjar syndrome; unlike Gilbert's syndrome, Crigler Najjar has almost no UGT and thus no ability to conjugate UCB, resulting in EXTREMELY high levels of UCB and likely UCB deposits in the brain and kernicterus; Crigler Najjar syndrome is usually fatal.
Although the preceding two examples focused on elevated levels of unconjugated bilirubin in the blood, jaundice can also be caused by elevated levels of conjugated bilirubin in the blood. Dubin-Johnson syndrome is an autosomal recessive disorder caused by a deficiency in MRP2, a protein involved in the transport of CB from the liver cell to the bile ducts, resulting in CB accumulation in the hepatocyte.
When the MRP2 transporter is defective, another transporter, MRP3, is upregulated; however, this transporter transports it into the interstitial space and blood flow, rather than the bile canaliculus, resulting in increased CB in the blood, which is also excreted into the urine, darkening its color; this leakage also causes the liver to become extremely dark.
Obstructive jaundice is another type of high-CB jaundice that occurs when something obstructs the flow of bile. These obstructions can be caused by gallstones, pancreatic carcinomas, or cholangiocarcinomas, as well as parasites such as the liver fluke.
Bear in mind that bile is composed of conjugated bilirubin, and this blockage results in an increase in bile duct pressure, allowing bile to leak through the tight junctions between hepatocytes; however, bile salts, bile acids, and cholesterol can all leak into the blood.
They can cause itchiness or pruritus if they deposit on the skin, but they can also cause hypercholesterolemia and xanthomas. Excess CB is excreted in the urine, once again resulting in dark urine. Additionally, because you're losing bile, you'll be unable to absorb fat as well, which (1) results in excessive fat excretion, a condition known as steatorrhea, and (2) prevents you from absorbing as many fat-soluble vitamins as you need.
Finally, viral hepatitis results in the presence of both conjugated and unconjugated bilirubin in the blood. When hepatocytes become infected and die, they lose their ability to conjugate bilirubin, resulting in an excess of UCB in the blood, and because they also line the bile ducts, they allow bile to leak into the blood, increasing blood CB. Again, because CB levels are elevated, patients will have increased CB excretion and darker urine.