How do gallstones form?

There are two types of gallstones: cholesterol stones and pigment stones. If you didn’t know anything about gallstones, you’d guess (rightly so) that cholesterol stones are made up of cholesterol. And you’d also probably guess that you get cholesterol stones when there’s too much cholesterol around. But how, exactly? And pigment stones – what are those made of? Pigment?

Turns out there are very good explanations for all of these questions. Let’s take a look.

Cholesterol gallstones

Cholesterol gallstones contain – not surprisingly – cholesterol. And they arise when there’s more cholesterol around than the gallbladder can handle. But what does this actually mean?

A tiny bit of basic science here. Under normal conditions, cholesterol is soluble in bile because it binds to bile salts (which are water-soluble) and lecithins (which are water-insoluble). These guys both act like detergents, and cholesterol is dispersed within the bile, and everything’s cool.

But what happens if there’s too much cholesterol around? If the concentration of cholesterol exceeds the solubilizing capacity of bile, then cholesterol will nucleate into solid cholesterol crystals, which can over time get big enough to form stones.

Pigment gallstones

These stones are made of unconjugated bilirubin (mixed with calcium salts). They’re called pigment gallstones because they’re dark brown to black in color (compared to cholesterol stones, which are usually pale yellowish-greenish in color).

The two main conditions in which you see pigment stones are chronic hemolytic anemia and infection of the biliary tract. Why would these conditions lead to an accumulation of unconjugated bilirubin in the bile? In order to answer that, let’s quickly review bilirubin metabolism in the bile itself.

Normally, the liver conjugates bilirubin and dumps it into the bile. So the bile contains just conjugated bilirubin, then, right? Wrong! About 1% of the bilirubin in bile undergoes deconjugation while it’s still in the biliary tree (betcha didn’t know that!). Bile is then dumped into the gut, where bacterial-glucuronidases convert most of the remaining conjugated bilirubin into its unconjugated form.

Back to the causes of pigmented stones. If you have an infection in the biliary tree, and the infectious agent makes glucuronidase, then you’ll end up deconjugating more bilirubin than normal…and over time, that unconjugated bilirubin can accumulate and form stones.

The other main cause of pigmented stones is chronic hemolysis. If you’re busting open lots of red cells, all that heme gets transformed into bilirubin, which the liver conjugates and dumps into the bile. So the bile contains a lot more bilirubin than usual. Most of that bilirubin remains conjugated – but around 1% is turned into unconjugated bilirubin right there in the biliary tree. If you’re making a lot more bilirubin than normal, that 1% is significant – and over time, that excess of unconjugated bilirubin can be enough to lead to pigment stones.

Four inherited hyperbilirubinemias: Crigler-Najjar, Gilbert, Dubin-Johnson and Rotor syndromes

Here are a few syndromes that are easy to mix up: Crigler-Najjar, Gilbert, Dubin-Johnson, and Rotor syndromes. All are inherited disorders in which there is a high bilirubin – but there are important differences. Pay attention to the inheritance pattern (hint: all are autosomal recessive except type II CN), the type of bilirubinemia (conjugated or unconjugated), the specific molecular defect, and the clinical picture (hint: all of them are innocuous except type I CN).

Crigler-Najjar syndrome

There are actually two types of Crigler-Najjar, and boy are they different clinically. Type I CN is a super rare, autosomal recessive disorder in which patients have no UGT1A1 activity. UGT1A1 is a liver enzyme that participates in bilirubin processing (it conjugates bilirubin with one or two molecules of glucuronic acid, if you must know). The bile is colorless, with only trace amounts of unconjugated bilirubin. So the unconjugated bilirubin backs up into the blood, producing severe jaundice and icterus. The liver, by the way, looks totally normal under the microscope. Type 1 CN is fatal in the neonatal period unless the baby gets a liver transplant.

Type II CN is an autosomal dominant disorder in which patients have some UGT1A1 activity, but it’s decreased (the enzyme is only capable of forming monoglucuronidated bilirubin). The disorder is not fatal; in fact, the major consequence is simply really really yellow skin.

Gilbert syndrome

This syndrome is common – it’s estimated that 5-10% of the population has it. Wow! In this disorder, patients have a decreased activity of UGT1A1. Wait a minute, that sounds just like type II CN!  Yes, that’s true – both have decreased UGT1A1 activity. However, Gilbert syndrome (which is an autosomal recessive syndrome) has a UGT1A1 activity level of about 30% of normal, which is quite a bit higher than the amount of activity you see in CN. Patients usually have only mild hyperbilirubinemia (unconjugated, of course), and there is no clinical consequence (other than an increased sensitivity to drugs that are metabolized by UGT1A1. Oh, and the anxiety that occurs when your skin turns yellow.).

Dubin-Johnson syndrome

This one is an autosomal recessive disorder in which patients have an increase in conjugated bilirubin in the blood. It’s caused by a defect in secretion of bilirubin glucuronides (already conjugated!) across the canalicular membrane (patients are missing a canalicular protein that transports bilirubin glucuronides into bile). The liver looks funny in this disorder: it is darkly pigmented because of coarse granules within the hepatocyte cytoplasm. Most patients are asymptomatic (other than some jaundice here and there).

Rotor syndrome

Here’s another autosomal recessive disorder in which patients have an increase in conjugated bilirubin in the blood. The exact molecular defect is unknown – but it seems these patients have multiple defects in hepatocyte uptake and excretion of bilirubin pigments. The liver looks normal, and as in Dubin-Johnson syndrome, most patients are asymptomatic (other than some jaundice).