A recent article published in Immunity discovered the mechanism of how gallstones form.
Perhaps you know someone that has suffered from the presence of gallstones (cholelithiasis), since it is one of the leading causes of hospital admissions worldwide. Or perhaps you have heard of gallstones but can’t exactly recall what they are. Although it has been known for decades that cholesterol and calcium crystals are involved in gallstone formation, not much was known about their biological mechanism of action. Recently this changed when a team of researchers from Universitätsklinikum Erlangen (Germany) discovered how they form and grow. These insights published in Immunity provide new treatment opportunities to prevent gallstones in patients at risk.
What are gallstones?
Gallstones are similar to pebbles inside the gallbladder that range in size from as tiny as a grain of sand to as large as a golf ball. Bile, a greenish-yellow fluid, important for the digestion of fats is made in the liver but stored in the gallbladder. During digestion, the gallbladder delivers bile to the small intestine through a tube called the bile duct. Bile mainly consists of water with dissolved cholesterol, calcium, other salts, and bilirubin. When there is more cholesterol and calcium in the bile that can be dissolved, it becomes super-saturated and solid cholesterol and calcium crystals begin to form which is a prerequisite of gallstone formation. This is similar to what happens when too much salt is added to water in a glass. At a certain point, the salt becomes visible in the glass as the solution becomes super-saturated. The presence of cholesterol and calcium salt crystals initiate the process of gallstone formation; but what causes these crystals to aggregate and form pebble-like structures?
Aggregates of crystals form into gallstones
To determine how gallstones form Universitätsklinikum Erlangen researchers investigated gallstones obtained from adult surgery patients, human gallstones kept at the Charité hospital in Berlin and bile and gallstones obtained from six healthy pigs. Advanced imaging techniques and further studies that induced gallstone formation in mice revealed that all gallstones contain neutrophils with extracellular DNA. Neutrophils are white blood cells that are triggered by the body’s innate immune system to attack foreign objects or invaders, such as crystals. A neutrophil cell dies while attempting to ingest the crystals (known as micropinocytosis) and its DNA material leaks out of the cell and wraps around the crystals, similar to a net. These nets called neutrophil extracellular traps (NETs) function as the ‘glue’ that allows assembly of crystals into larger aggregates known as gallstones. Further tests demonstrated that PADI4 and NOX2 activity are necessary for the immune response of neutrophil NET formation.
Understanding how gallstones form provides strategy for prevention
Knowing the mechanism of action can lead to new pharmacological treatment options for gallstones. These new treatment possibilities can target gallstone formation at different stages that don’t involve surgery. For example, the activity of neutrophil and therefore NET formation has already been successfully reduced with an existing drug called Metoprolol, commonly used for the treatment of high blood pressure. Now of particular interest are approaches that prevent NET formation through the inhibition of PAD14 or NOX2 activity. According to the research team, this discovery may also have implications for kidney stones or salivary stones.
Written by Maria-Elena B.Sc. (Hons)
Muñoz, L. E., Boeltz, S., Bilyy, R., Schauer, C., Mahajan, A., Widulin, N., … Herrmann, M. (2019). Neutrophil Extracellular Traps Initiate Gallstone Formation. Immunity, 51(3). doi: 10.1016/j.immuni.2019.07.002
Unlocking the Secrets Of Gallstones. FAU_Germany – https://www.eurekalert.org/pub_releases/2019-10/uoe-uts100819.php