When you eat some real fatty foods, like say some delicious french fries, they make their
way to through the stomach and into the small intestine.
At this point they aren’t really french fries anymore, but since they’re high in
fat, they’re still a little more difficult to absorb, and that’s where your gallbladder
comes in.
This high fat food stimulates the gallbladder to squeeze out some bile into the small intestine,
that bile emulsifies the fat, or basically mixes the fat up, and makes it easier to absorb.
This is pretty much your gallbladder’s job—store and concentrate bile until the time comes
to send it to the small intestine.
It’s not the most glamorous of jobs, but hey, gotta start somewhere.
If we take a closer look at this magical substance, we’d get a rough breakdown that’s something
like the following: ~70% bile salts and acids, ~10% cholesterol ~5% phospholipids, ~5% proteins,,
and 1% conjugated bilirubin, and the rest, small amounts of various other compounds like
water, electrolytes, and bicarbonate.
Bile salts and acids are mostly a product of cholesterol metabolism, so an acid might
look something like this and its salt is the anionic form, something like this (ROO-) group.
These acids and their salts have both hydrophobic and hydrophilic sides, making them amphiphilic,
which help them make cholesterol and fat in the gut more soluble in bile.
The phospholipids are mostly lecithin, also amphiphilic, and also help make cholesterol
and fats more soluble in bile.
Gall-stones are these round and solid stones you can find inside your gallbladder, and
they’re made from the components of bile, and so they’re categorized depending on
what they’re made of, the most common ones are cholesterol stones, but there’s also
bilirubin stones, which are sometimes called pigmented stones.
The first type, as you might guess, are made mostly of cholesterol that has precipitated
out of the bile as a solid and formed these solid stones.
These account for around 75 to 90% of cases.
This cholesterol precipitation can happen in a couple ways, first, the bile can become
supersaturated with cholesterol, meaning that the bile has so much cholesterol that the
bile salts and acids or phospholipids can’t hold any more in solution, because remember
that these all help make the cholesterol more soluble in bile, and so the cholesterol comes
out of solution as a solid.
Another, somewhat similar way, is if you don’t have enough of these bile salts or acids and
phospholipids to help keep the cholesterol in solution, so the less you have, the less
cholesterol can be in solution and the more precipitates out.
Gallbladder stasis, or inactivity, has also been linked to forming stones, if the bile
just sits there it can cause the solid to separate and precipitate out, kind of like
when the oil in your peanut butter jar separates from the peanuts if it just sits too long.
Stones that’re made of cholesterol can’t be seen on x-ray, but rarely are the stones
only cholesterol, and usually you’ll see a bit of a mixed composition; if they have
enough calcium carbonate they might be able to be seen on x-ray.
Remember that we said there’s a small amount of electrolytes and bicarbonate?
Well some of those electrolytes are calcium ions, and calcium ions tend to form insoluble
precipitates with bicarbonate as calcium carbonate, which would be radio-opaque, and visible on
x-ray, but usually there’s not enough calcium carbonate and the cholesterol stones will
be radiolucent on x-ray and you won’t be able to see them.
Alright, so the other type is bilirubin or pigmented gallstones.
These ones, again, are pretty self-explanatory and are made mostly of bilirubin and therefore
are pigmented.
These are made when there’s too much bilirubin in the bile and it has combined with calcium
to form the solid precipitate calcium bilirubinate.
Since they’re made partly of calcium, they’ll usually be radiopaque, meaning you can see
them on x-ray, here’s an example showing pigmented gallstones on x-ray.
Since it’s the bilirubin in bile, we’d maybe assume that they’re made of conjugated
bilirubin, right?
Well, actually pigmented gallstones are made of unconjugated bilirubin.
What?
I thought there was only conjugated bilirubin in bile?
Well the vast majority is conjugated, but there is a small amount of unconjugated bilirubin
in bile, only about 1-2% of total bilirubin, which is only 1% of bile.
Although the exact mechanism is unclear, this tiny tiny amount of unconjugated bilirubin
is thought to form from nonbacterial and nonenzymatic hydrolysis of conjugated bilirubin, so through
a reaction in the chemical environment of bile that doesn’t involve enzymes or bacteria.
K quick breakdown of the structure of conjugated vs. unconjugated bilirubin: the conjugated
form has this R-group, glucuronic acid, that makes it water soluble, unconjugated just
has this OH group, which at the pH of bile, is in anionic form that’d probably really
like to bind with calcium.
Usually though, bile salts bind up the calcium ions and keep them from binding with and precipitating
unconjugated bilirubin.
With extravascular hemolysis, we have macrophages eating up red blood cells more than normal
and unconjugated bilirubin production is ramped up, which is conjugated by the liver and sent
to the gallbladder.
These situations where there’s a lot of hemolysis and unconjugated bilirubin production,
there’s going to eventually be more conjugated bilirubin produced, and it’s thought that
when there’s more conjugated bilirubin in the bile, there’s also more unconjugated
bilirubin, to the point where it can now bind calcium instead of the bile salts, and precipitate
out to form black pigmented stones.
If the gallstone is brown pigmented, it’s often a sign of gallbladder or biliary tract
infection, and often the stones have even ventured outside gallbladder and into the
bile ducts.
These brown gallstones are also made of the calcium salts of unconjugated bilirubin, what’s
different, though, is how the unconjugated bilirubin forms: what happens is that a bacteria
that causes gallbladder infection, like E coli., for example, brings about hydrolytic
enzymes that hydrolyze both conjugated bilirubin and phospholipids, that again combine with
calcium ions, which then precipitates out to form stones.
The brownness is due to this mix of unconjugated or hydrolyzed bilirubin and phospholipids.
Some other common gallbladder infections are Ascitris lumbricoides and clonorchis sinesis—the
second of which is endemic to China, Korea, and Vietnam, so brown-pigmented stones are
commonly seen in Asian populations.
Women are typically more at risk than men, because estrogen increases cholesterol stone
formation, which is also why use of oral contraceptive pills that contain estrogen increase the risk
of cholesterol stones.
Also though, obesity is often associated with increased levels of cholesterol, meaning that
it’s also associated with increased risk of cholesterol stones.
Finally rapid weight-loss that decreases lipids can create an imbalance in bile composition
that increases the chances of calcium-bilirubin precipitation and gallstone formation.