Gall Stones (Formation and types)

Gall Stones (Every 5th person of our society has this).

When you eat some real fatty foods, like say some delicious French fries, they make their way 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 concentrates bile until the time comes to send it to the small intestine. It’s not the most glamorous of jobs, but they got to 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 helps 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 are also bilirubin stones, which are sometimes called pigmented stones. The first type, as you might guess, is 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 anymore 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 are 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 number 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 bilirubin. Since they’re made partly of calcium, they’ll usually be radio-opaque, meaning you can see them on x-ray, here is an example showing pigmented gallstones on x-ray. Since it’s the bilirubin in the bile, we’d maybe assume that they’re made of conjugated bilirubin, well; actually pigmented gallstones are made of unconjugated bilirubin. 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 the bile, only about 1-2% of total bilirubin, which is only 1% of bile.

Although the exact mechanism is unclear, this tiny amount of unconjugated bilirubin is thought to form from nonbacterial and non-enzymatic 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 an 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 the 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 Ascaris lumbricoid and clonorchiasis 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 the use of oral contraceptive pills that contain estrogen increases the risk of cholesterol stones. Also though, obesity is often associated with increased levels of cholesterol, meaning that it’s also associated with an 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.