Cholestatic liver disease

For healthy humans, bile usually flows from the liver and into the small intestine, and this is a super important part of digestion and absorption of nutrients.

When there isn’t enough bile flowing between these two, we can say that there’s some sort of cholestasis going on, because chole- means bile and -stasis means inactivity.

This reduction in bile flow can basically be split into two types, hepatocellular cholestasis, where for some reason the hepatocytes aren’t making enough bile, and obstructive cholestasis, where something’s physically blocking bile flow.

For hepatocellular cholestasis, which would be considered a form of intra-hepatic cholestasis since it’s happening inside the liver, a really important culprit is the hormone estrogen.

Estrogen is thought to basically cause the hepatocytes to not be able to pump out bile acids, usually in the form of cholic acid, which is produced when hepatocytes break down cholesterol.

And in this case, hepatocytes literally can’t pump out the cholic acid, because it’s been found that estrogen inhibits the export pump that usually moves the bile acid from the hepatocyte to the bile canaliculi, which leads to the bile ductules and eventually the common hepatic duct.

But bile acids are just one component of bile, right? Wouldn’t the bile still be made, just without the bile acids?

Well, production and secretion of bile acids is a major driving force for the synthesis of bile in the hepatocytes, so when the cells can’t transport the bile acids and so they build up inside the cells, and this is basically a signal to down-regulate bile acid synthesis and excretion of bile altogether, which decreases the total amount of bile production.

When excretion of bile components like conjugated bilirubin are down, but they’re still being conjugated, they also build up along with the bile acids, and eventually, it’s thought that they diffuse or are exocytosed into the interstitial space, where it can access the blood supply.

Since estrogen’s been linked as a primary suspect here, it makes sense that we see hepatocellular cholestasis in situations where estrogen levels might be higher.

Since oral contraceptive pills, or birth control pills, use estrogen and progesterone to stop ovulation, it makes sense that they’ve been linked to developing cholestasis.

Similarly, during pregnancy, estrogen levels can increase A LOT, which can lead to pregnancy-induced cholestasis.

Unfortunately, this can be a dangerous situation for the fetus because maternal bile acids can cross the placenta and buildup in the fetal compartment.

This can lead to an increased risk of stillbirth after 37 weeks of gestation.

Anabolic steroids, like those used by athletes or body-builders, have also been linked to cholestasis, it’s thought because they’re similar in structure to estrogen, though the mechanisms aren’t very well-known.

Another hepatocellular mechanism for cholestasis is related to newborns and is associated with neonatal hepatitis.

In newborns, it’s thought that several of the important mechanisms that help produce bile in hepatocytes are relatively immature, leading to an overall decreased ability to produce bile, and this, in combination with the developing liver being more sensitive to injury, can lead to a reduction in bile synthesis and bile flow.

The other major type of cholestasis is obstructive, which usually happens outside the liver, so we can call it extrahepatic cholestasis.

Now this is usually a physical blockage of the common bile duct, and there are some common causes.

It could be like a gallstone that came from the gallbladder, or it could be from a disease called primary sclerosing cholangitis, where the body’s immune system attacks the bile ducts causing inflammation and scar tissue buildup, which can make it more difficult for bile to flow through them.

Biliary atresia is another condition just like sclerosing cholangitis, but this one specifically affects newborns.

Finally, pancreatic carcinomas that grow at the head of the pancreas may also physically block flow of bile, since the common bile duct moves through the head of the pancreas.

This buildup of bile will be pretty obvious on histology of the liver, and will look like these “bile lakes” or “bile infarcts”, which are these pools of yellowish-green bile that has made their way into the interstitial space.