黃疸手作坊

影片連結：https://en.wikipedia.org/wiki/File:Jaundice-video-osmosis.webm

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• Jaundice, which doesn’t have the most intuitive
• name, comes from the french jaunice, meaning
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• yellowing. It’s also sometimes referred
• to as icterus though, the origin of which
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• is even less intuitive, coming from the thought
• that jaundice could once be cured by looking
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• at a yellow bird, the more you know! Anyways,
• as you’ve probably gathered, jaundice involves
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• someone taking on yellow pigments, specifically
• in the skin and eyes. The yellowing pigment
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• is caused by a compound called bilirubin,
• a component of bile and the main cause of
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• bruises being yellow, and after its metabolism,
• the yellow-ness of urine and brown-ness of
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• feces. So since bilirubin’s our main culprit
• of yellow-ness, it’s super important to
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• know where it comes from. As red blood cells
• near the end of their lifespan—which is
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• about 120 days—they’re eaten up or phagocytosed
• by macrophages in the reticuloendothelial
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• system, aka the macrophage system, where the
• spleen plays the largest part, but it’s
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• also made of parts of the lymph nodes. K so
• first the macrophage eats up the blood cell,
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• and hemoglobin is broken up into heme and
• globin, the globin is further broken into
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• amino acids. The heme on the other hand is
• split into iron and protoporphyrin, protoporphyrin
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• is then converted into unconjugated bilirubin,
• or UCB. Unconjugated bilirubin is the form
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• of bilirubin that’s lipid-soluble, meaning
• it’s not water-soluble, sometimes it’s
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• also known as indirect bilirubin. Albumin
• in the blood then binds to UCB and gives it
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• a lift over to the liver where it’s taken
• up by hepatocytes, where it’s conjugated
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• by an enzyme called uridine glucuronyl transferase
• (UGT), making it now water soluble. At this
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• point the conjugated bilrubin is secreted
• out the bile canaliculi where it drains into
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• the bile ducts and sent to the gallbladder
• for storage as bile. Now when you eat a donut
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• or something, your gallbladder secretes the
• bile and CB, it moves through the common bile
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• duct to the duodenum of the small intestine
• and is converted to urobilinogen, or UBG,
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• by intestinal microbes in the gut. Now it
• undergoes spontaneous oxidation, turning it
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• into urobilin, which is excreted and responsible
• for the brown color of feces. About 20% of
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• that UBG is actually recycled, though, in
• other words it doesn’t get oxidized and
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• instead gets reabsorbed into the blood and
• gets sent to the liver and kidneys, about
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• 90% going to the liver and 10% going to the
• kidneys. The 10% that goes to the kidneys
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• and is excreted causes the yellow-ness of
• urine! And there you have it, bilirubin metabolism
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• in a nutshell.
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• Now if some point in this process is disrupted,
• for example if your liver cells are damaged
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• and can’t conjugate bilirubin anymore, or
• if they die and release their bilirubin, you
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• can end up with increased bilirubin in the
• blood, which can be conjugated or unconjugated,
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• or both! This is what accounts for the yellow
• color in the skin and eyes. Usually it takes
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• about 2.5 mg/dL or greater of serum bilirubin
• to give the skin that Simpsons-esque yellow
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• skin tone. The earliest sign of jaundice and
• increased bilirubin in the blood is by looking
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• at the sclera of the eyes. Scleral tissue
• is high in elastin, which has a particular
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• fondness for bilirubin and binds it with a
• high affinity, giving the scleral tissue a
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• yellow color often before the skin. Now as
• you might imagine after looking at this process,
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• there’re quite a few potential pitfalls
• along the way that can lead to jaundice, and
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• they’re lumped together depending on whether
• they have more UCB in the blood, more CB in
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• the blood, or more of both in the blood.
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• Two types of disorders that have increased
• UCB and similar presentation of jaundice are
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• extravascular hemolytic anemias, where red
• blood cells are broken down earlier than they
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• normally would, and ineffective hematopoesis,
• where your blood cells don’t form quite
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• right in your bone marrow, causing macrophages
• to break them down. In both cases, the red
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• blood cells are broken down, causing high
• levels of UCB. Since your hepatocytes can
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• only work so hard converting UCB to CB, they
• can get overwhelmed. As an imaginary example,
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• say that this liver cell can conjugate 10
• molecules of UCB a minute, max, but normally
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• they only see 5, so that’s easy. If all
• the sudden your body starts breaking down
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• more blood cells and the UCB molecules on
• this cell’s docket jumps to 15/min, this
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• liver cell can’t keep up, and that excess
• of 5 molecules of UCB stays in the blood,
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• that’s the first issue. In addition, as
• the liver cells max out, now there’s all
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• this CB that goes to the bile, which increases
• the risk for pigmented bilirubin gallstones.
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• Not only that, once all that CB is sent to
• the duodenum, it’s converted to urobilinogen.
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• Remember 20% of that urobilinogen is recycled
• back into the blood and some of it is excreted
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• in the urine, giving it a much darker color.
• The UCB is not excreted because it’s not
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• water soluble!
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• In the previous two cases, too much UCB was
• created, but you can also have hepatocytes
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• that just can’t work hard enough and keep
• up. Physiologic jaundice of newborn is one
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• of these cases; newborn livers having a lower
• amount of UGT in the liver to convert UCB,
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• and after birth, UCB levels can be high due
• to the natural process of macrophages destroying
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• fetal red blood cells. Typically this is normal,
• but can cause complications if UCB rises a
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• LOT; since it’s fat soluble, it can collect
• in the basal ganglia of the brain, which is
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• called kernicterus, and cause damage to the
• brain or death. Treatment of this condition
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• is usually phototherapy, which uses light
• to induce structural and configurational changes
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• in the bilirubin molecule, basically it absorbs
• the energy from the light and changes shape.
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• These new shapes are more soluble, and can
• be excreted in the urine. This can be a super
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• effective and non-invasive way to get excess
• UCB out of the blood.
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• Another potential case where not enough UCB
• can be conjugated is through hereditary defects.
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• One case is called Gilbert’s syndrome, where
• their UGT enzyme activity is low and has a
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• hard time cranking up when needed, so maybe
• this liver cell can only pump through a max
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• of 6 molecules/minute. Unfortunately, if something
• comes along that increases hemolysis, like
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• infection, stress, or starvation, the unconjugated
• bilirubin load will increase which can easily
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• overwhelm these hepatocytes, cause buildup
• of unconjugated bilirubin in the blood and
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• lead to jaundice.
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• Another genetic example is called Crigler
• Najjar syndrome, where gilbert’s syndrome
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• was a low amount of UGT, Crigler Najjar is
• where there’s pretty much no UGT and therefore
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• no ability to conjugate UCB, this will lead
• to SUPER high levels of UCB, and likely UCB
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• deposits in the brain and kernicterus; Crigler
• Najjar syndrome is usually fatal.
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• The previous couple examples focused on high
• levels of unconjugated bilirubin in the blood,
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• but there are also examples of jaundice with
• high levels of conjugated bilirubin in the
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• blood.
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• Dubin-Johnson syndrome is an autosomal recessive
• disorder where there’s a deficiency in the
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• protein that helps move CB from the liver
• cell to the bile ducts, called MRP2, so CB
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• builds up in the hepatocyte. It’s thought
• that when the MRP2 transporter is defected,
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• another transporter, MRP3 is upregulated,
• though this transporter moves it into the
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• interstitial space and blood flow, as opposed
• to the bile canaliculus, so in this case you’ll
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• have increased CB in the blood, which also
• gets excreted into the urine, giving it a
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• darker color, this leakage also causes the
• liver itself to get super dark.
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• Another high-CB category of jaundice is called
• obstructive jaundice, and this is basically
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• where something blocks the flow of bile, these
• blockages could be anything from gallstones,
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• pancreatic carcinomas and cholangiocarcinomas,
• to parasites like the liver fluke. Remember
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• that bile’s made up of conjugated bilirubin
• and this blockage basically causes pressure
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• to rise in the bile duct, which literally
• causes bile to leak through the tight junctions
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• between hepatocytes, but that’s not the
• only thing that leaks out though; bile salts,
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• bile acids, and cholesterol all can can get
• into the blood. If they deposit in the skin,
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• it could lead to itchiness or pruritus, but
• also lead to things like hypercholesterolemia
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• and xanthomas. The excess CB is excreted in
• the urine, leading again to dark urine. Also,
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• since you’re losing bile, you won’t be
• able to absorb fat as well, which (1) causes
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• you to excrete a ton of fat, a condition called
• steatorrhea, and (2) causes you to not be
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• able to absorb as many fat-soluble vitamins
• as you need.
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• Finally, viral hepatitis leads to both conjugated
• and unconjugated bilirubin in the blood. When
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• hepatocytes get infected and start to die
• off, they both lose the ability to conjugate
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• bilirubin, leading to excess UCB in the blood,
• AND since they also line the bile ducts, when
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• they die they let bile leak out into the blood,
• causing an increase in blood CB as well. Again,
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• since CB is up, patients will have more CB
• excreted and darker urine.