Leukemia (Blood Cancer)

Jaundice

Jaundice, which doesn’t have the most intuitive name, comes from French jaundice, meaning yellowing. It’s also sometimes referred to as icterus though, the origin of which is even less intuitive, coming from the thought that jaundice could once be cured by looking at a yellow bird, the more you know!   Haha

Anyways, as you’ve probably gathered, jaundice involves someone taking on yellow pigments, specifically in the skin and eyes. The yellowing pigment is caused by a compound called bilirubin, a component of bile and the main cause of bruises being yellow, and after its metabolism, the yellowness of urine and brownness of feces. So since bilirubin is the main culprit of yellowness, it’s super important to know where it comes from. As red blood cells near the end of their lifespan—which is about 120 days—they’re eaten up or phagocytosed by macrophages in the reticuloendothelial system, aka the macrophage system, where the spleen plays the largest part, but it’s also made of parts of the lymph nodes.

So first the macrophage eats up the blood cell, and hemoglobin is broken up into heme and globin, the globin is further broken into amino acids. The heme on the other hand is split into iron and protoporphyrin; protoporphyrin is then converted into unconjugated bilirubin or UCB. Unconjugated bilirubin in the form of bilirubin that’s lipid-soluble, meaning it’s not water-soluble; sometimes it’s also known as indirect bilirubin. Albumin in the blood then binds to UCB and gives it a lift over to the liver where it’s taken up by hepatocytes, where it’s conjugated by an enzyme called uridine glucuronyl transferase (UGT), making it now water-soluble.

At this point, the conjugated bilirubin is secreted out the bile canaliculated where it drains into the bile ducts and is sent to the gallbladder for storage as bile. Now when you eat a donut or something, your gallbladder secretes the bile and CB, it moves through the common bile duct to the duodenum of the small intestine and is converted to urobilinogen, or UBG, by intestinal microbes in the gut. Now some of that urobilinogen is reduced to stercobilin which is excreted and responsible for the brown color of feces. Some of that UBG is actually recycled, though, and it gets reabsorbed into the blood and spontaneously oxidizes into urobilin, most of which is sent to the liver to the liver and some of which goes to the kidneys. It’s then excreted and is responsible for the yellowness of urine! And there you have it, bilirubin metabolism in a nutshell. Now if some point in this process is disrupted, for example, if your liver cells are damaged and can’t conjugate bilirubin anymore, or if they die and release their bilirubin, you can end up with increased bilirubin in the blood, which can be conjugated or unconjugated, or both! This is what accounts for the yellow color of the skin and eyes. Usually, it takes about 2.5mg/dL or greater of serum bilirubin to give the skin that Simpsons-Esque yellow skin tone.

The earliest sign of jaundice and increased bilirubin in the blood is by looking at the sclera of the eyes. Scleral tissue is high in elastin, which has a particular fondness for bilirubin and binds it with a high affinity, giving the Scleral tissue a yellow color often before the skin. Now as you might imagine after looking at this process, they're quite a few potential, pitfalls along the way that can lead to jaundice, and they’re lumped together depending on whether they have more UCB in the blood, more CB in the blood, or more of both in the blood. Two types of disorders that have increased UCB and similar presentation of jaundice are extra-vascular hemolytic anemia, where red blood cells are broken down earlier than they normally would, and ineffective hematopoiesis, where your blood cells don’t form quite right in your bone marrow, causing macrophages to break them down.

In both cases, the red blood cells are broken down, causing high levels of UCB. Since your hepatocytes can only work so hard converting UCB to CB, they can get overwhelmed. As an imaginary example, say that this liver cell can conjugate 10 molecules of UCB a minute, max, but normally they only see 5, so that’s easy. If all of a sudden your body starts breaking down more blood cells and the UCB molecules on this cell’s docket jump to 15/min, this liver cell can’t keep up, and that excess of 5 molecules of UCB stays in the blood, that’s the first issue. In addition, as the liver cells max out, now there’s all this CB that goes to the bile, which increases the risk for pigmented bilirubin gallstones. Not only that, once all that CB is sent to the duodenum, it’s converted to urobilinogen. Remember some of that urobilinogen is recycled back into the blood, oxidized to urobilin, and excreted in the urine, giving it a much darker color. The UCB is not excreted because it’s not water-soluble! In the previous two cases, too much UCB was created, but you can also have hepatocytes that just can’t work hard enough and keep up.

Physiologic jaundice of newborns is one of these cases; newborn livers have a lower amount of UGT in the liver to convert UCB, and after birth, UCB levels can be high due to the natural process of macrophages destroying fetal red blood cells. Typically this is normal, but can cause complications if UCB raises a LOT; since it’s fat-soluble, it can collect in the basal ganglia of the brain, which is called kernicterus, and cause damage to the brain or death. Treatment of this condition is usually phototherapy, which uses light to induce structural and configurationally changes in the bilirubin molecule, basically, it absorbs the energy from the light and changes shape. These new shapes are more soluble and can be excreted in the urine. This can be a super effective and non-invasive way to get excess UCB out of the blood. Another potential case where not enough UCB can be conjugated is through hereditary defects. One case is called Gilbert’s syndrome, where their UGT enzyme activity is low and has a hard time cranking up when needed, so maybe this liver cell can only pump through a max of 6 molecules/minute.

Unfortunately, if something comes along that increases hemolysis, like infection, stress, or starvation, the unconjugated bilirubin load will increase which can easily overwhelm these hepatocytes, causing a buildup of unconjugated bilirubin in the blood and leading to jaundice. Another genetic example is called Crigler Najjar syndrome, where Gilbert’s syndrome was a low amount of UGT, Crigler Najjar is where there’s pretty much no UGT and therefore no ability to conjugate UCB, this will lead to SUPER high levels of UCB, and likely UCB deposits in the brain and kernicterus; Crigler Najjar syndrome is usually fatal. A previous couple of examples focused on high levels of unconjugated bilirubin in the blood, but there are also examples of jaundice with high levels of conjugated bilirubin in the blood. Dubin-Johnson syndrome is an autosomal recessive disorder where there’s a deficiency in the protein that helps move CB from the liver cell to the bile ducts, called MRP2, so CB builds up in the hepatocytes. It’s thought that when the MRP2 transporter has defected, another transporter, MRP3 is up-regulated, though this transporter moves it into the interstitial space and blood flow, as opposed to the bile canaliculus, so in this case, you’ll have increased CB in the blood, which also gets excreted into the urine, giving it a darker color, this leakage also causes the liver itself to get super dark.

Another high-CB category of jaundice is called obstructive jaundice, and this is basically where something blocks the flow of bile, these blockages could be anything from gallstones, pancreatic carcinomas, and cholangiocarcinoma  (https://www.muhammadfahadhealthcare.blogspot.com/2022/03/cholangiocarcinoma.html), to parasites like the liver fluke. Remember that bile’s made up of conjugated bilirubin and this blockage basically causes pressure to rise in the bile duct, which literally causes bile to leak through the tight junctions between hepatocytes, but that’s not the only thing that leaks out though; bile salts, bile acids, and cholesterol all can get into the blood. If they deposit in the skin, it could lead to itchiness or pruritus, but also lead to things like hypercholesterolemia and xanthomas. The excess CB is excreted in the urine, leading again to dark urine.

Also, since you’re losing bile, you won’t be able to absorb fat as well, which (1) causes you to excrete a ton of fat, a condition called steatorrhea, and (2) causes you to not be able to absorb as many fat-soluble vitamins as you need. Finally, viral hepatitis leads to both conjugated and unconjugated bilirubin in the blood. When hepatocytes get infected and start to die off, they both lose the ability to conjugate bilirubin, leading to excess UCB in the blood, AND since they also line the bile ducts, when they die they let bile leak out into the blood, causing an increase in blood CB as well. Again, since CB is up, patients will have more CB excreted and darker urine.