Gallstone Genes

Key takeaways:
~ Gallstones are solid deposits that form in the gallbladder or bile ducts, primarily composed of cholesterol, bile pigments, and calcium salts.
~Gallstones typically form due to an imbalance in bile composition, where cholesterol levels exceed the capacity of bile salts and phospholipids to keep it dissolved.
~ Genetic variants increase the risk of gallstone in multiple ways. Understanding where your susceptibility lies can help you to find your right path for prevention.

Gallstones:

Your gallbladder is a small organ (~4 inches long) located on the upper right side of your abdomen, behind the liver. It stores bile, which your liver produces to break down fat in the foods you eat.

Gallstones (also called cholelithiasis) are hard ‘stones’ made of hardened bile. The composition of the stones can be either cholesterol or calcium bilirubinate. Cholesterol stones, the most common type, are thought to be formed if there is a lot of cholesterol in the bile. When the bile becomes supersaturated with cholesterol, the cholesterol can no longer be soluble in micelles (think oil droplets in water).[ref]

It is estimated that 10 – 40% of the population has gallstones, which are more common in women than in men. About 700,000 people each year in the US have their gallbladders removed.[ref]  That is a lot of people missing an organ…

Let’s dig into what happens to cause gallstones…

How gallstones form:

Gallstones are solid deposits that develop in the gallbladder or biliary ducts. They are primarily composed of cholesterol, bile pigments, and calcium salts, and they can be classified as cholesterol, pigmented, and mixed gallstones depending on their chemical composition.

Bile is a digestive fluid produced in the liver for breaking down fats from foods, and it is stored in the gallbladder until needed. Normally, bile contains cholesterol, bile salts, and phospholipids in balanced proportions.

After you eat a large amount of food containing fat and protein, a neuroenteropeptide hormone called cholecystokinin (CCK) is released in the intestines.  CCK then binds to the CCK1 receptor (CCK-1R) on the muscle cells of the gallbladder wall, triggering contraction of the gallbladder. When the gallbladder contracts, it pushes bile into the intestines.[ref]

Here’s how the gallstone formation process goes:

Supersaturation of Bile:
Gallstones often begin with bile that is supersaturated with cholesterol. When cholesterol levels exceed the capacity of bile salts and phospholipids to keep it dissolved, cholesterol crystallizes and forms the foundation for gallstones. The imbalance can come from too much cholesterol being produced or not enough bile acid being produced in the liver. Or it can be due to excess cholesterol absorption in the intestines.[ref]

Nucleation and crystals:
Mucins are glycoproteins secreted in the body to provide a thick, sticky, and protective layer, such as in the intestines, lungs, nose, and even the gallbladder.

Cholesterol crystals aggregate into larger structures when exposed to pronucleating factors, including mucin glycoproteins secreted by the gallbladder epithelium. Mucin acts as a scaffold for the formation of the gallstones.[ref]

Inflammatory changes in the gallbladder wall can further promote crystal growth by increasing mucin secretion.

Gallbladder Hypomotility:

Impaired gallbladder motility leads to bile stasis, providing more time for cholesterol crystals to grow into stones. Hypomotility can result from hormonal changes (e.g., pregnancy), rapid weight loss, or prolonged fasting.

Microbiome Influence:

Gut and biliary microbiota contribute to gallstone disease by altering bile composition and promoting biofilm formation around stones. Certain bacteria, such as Escherichia coli and Clostridium, produce enzymes like β-glucuronidase that enhance pigment stone formation or promote biofilm-mediated aggregation of cholesterol stones[ref][ref].

Lifehacks:

Plant Sterols:
Conflicting information exists for plant sterols from margarine or other foods labeled as “cholesterol-lowering plant sterols” in regards to gallstones and cardiovascular disease. The American Heart Association says plant sterols are good for reducing cardiovascular disease. But the ABCG8 variants that increase the risk of gallstones due to increased absorption of sterols also increase the risk of cardiovascular disease.

Related article: Plant sterols and your genes.

Estrogens (natural or environmental):
Environmental factors that increase gallstones include estrogens (women have more gallstones), oral contraceptives, and hormone replacement therapy.[ref]

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