How is gallstone formed: The formation of gallstones – PubMed
Gallstones – PMC
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How do gallstones form?
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By Dr. Liji Thomas, MDOct 9 2019
The human body is known to produce stones in various locations, most commonly in the kidneys, the bladder, the gallbladder and the appendix. Many of these stones appear without any obvious reason. However, a new study published in the journal Immunity shows the whole storyline for the first time: how gallstones are formed.
Gallstones: what are they?
Gallstones are stones that form within the gallbladder, affecting about 25 million Americans and in Germany, about 6 million. In the USA, about 100,000 people die each year of gallstones and associated complications, and this disease is among the top causes for hospitalization.
Gallstone / Gall bladder stone. Image Credit: eleonimages / Shutterstock
Gallstones are typically composed of cholesterol and calcium crystals. The gallbladder epithelium concentrates bile and increases its acidity, so that cholesterol and calcium salts can dissolve in it to saturation levels and beyond. At such a point, supersaturation and precipitation occurs, leading to the crystallization of cholesterol and calcium salts. However, this is not just a physicochemical process. There is also an unknown aggregating agent that causes gallstones to form first, and then grow. The present study throws light on this factor.
The problem with gallstones is that while most are asymptomatic, some cause extreme colic, or waves of spasmodic pain in the abdomen.
More serious if not more painful complications may also arise, including perforation of the gallbladder, peritonitis or infection of the general abdominal cavity, and even death. Surgery is the way out in such a case. Most gallstones are cholesterol crystals, and are more frequent in people who have high cholesterol levels. However, how the microscopic crystals of cholesterol build up into stones as large as several centimeters across is a surprisingly under-researched topic – until now.
The search
The current study used a nontraditional approach to their investigation into how gallstones occur – one which took them on a tour of museums, butcher houses and modern operation rooms. They looked at human gallstones kept on display at the Charité hospital museum in Berlin and did their own tests. They examined pig bile from an abattoir. They even analyzed bile and gallstones from patients who had surgical procedures for gallstone disease.
The first step was taken when they successfully analyzed the composition of biliary sludge, the granular concentrated material within gallbladders containing gallstones.
The sludge came from patients on hepatobiliary stents. Fluorescence microscopy was carried out on this material, and the researchers found large clumps of extracellular DNA (ecDNA), and high levels of neutrophil elastase activity.
Secondly, they found that ecDNA was also seen in pig biliary sludge, and in human gallstones. Moreover, they found that ecDNA, neutrophil elastase and histone h4 ( a DNA-associated protein) were all found on the surface of gallstones, indicating the role played by NET in the formation of gallstones. Almost 90% of gallstones also showed evidence of neutrophil elastase activity at the surface, the actively growing part, whether or not active inflammation was present. Thus neutrophil deposition of ecDNA is a key event in gallstone formation.
The discovery
Subjecting these varied materials to modern investigative techniques, the team found one common factor: all gallstones are covered with traces of a white cell type called neutrophils, part of the granulocyte population in the blood.
These immune cells form part of the first frontier against invading bacteria and other harmful particles, including crystals which are not normally found in the blood.
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When they encounter cholesterol crystals in the gallbladder, they go into their usual act, attempting to engulf the crystals and dispose of them. However, in the process they undergo severe damage, with lysosomal disruption. The digestive lysosomal enzyme granular cathepsin G enters the cytoplasm, binds to DNA and causes the strands to spread out like a network, and finally extrudes them from the cell. this lysosomal leakage causes the formation of a sticky network of chromatin strands over the surface of the crystals.
This is called a neutrophil extracellular trap (NET). The NET wraps around multiple crystals to form clumps, forming increasingly large stones.
To prove this, the team found that when cholesterol and calcium crystals in solution were added to a neutrophil culture and incubated, small crystals were quickly precipitated, and gallstones began to form and grow. Both calcium and cholesterol crystals are found in gallstones, because of the effect of NET on crystals clustered together by the sticky tide of bile within the gallbladder.
The way out
The researchers also tested the effects of temporarily incapacitating neutrophils in vivo, or of NET inhibitors, and found that both reduced gallstone growth. The striking discovery is that “The production of gallstones can be greatly reduced or even stopped if the formation of these nets is inhibited using drugs,” according to researcher Luis Munoz. Using drugs to treat gallstones in this way is a previously unexplored option.
For instance, the drug Metoprolol could be used in this way.
This is a simple beta-blocker, so called because it blocks the beta-adrenergic receptors that mediate some effects of chemicals like adrenaline on various body organs and tissues. This drug has thus been in use for many years to treat high blood pressure. However, when used in patients with gallstones, metoprolol inhibits the entry of neutrophils into the circulation from the tissues. This automatically reduces NET formation and thus brings down the chances of gallstone formation. There are also other drugs called PAD inhibitors, which selectively prevent NET formation from neutrophils in experimental setups. These validate the role ascribed to the immune system in gallstone formation in the current study.
The importance of this process is that it applies not only to gallstone formation but also to kidney and salivary gland stones, among others. This means that these can also be prevented by the same drugs, which will provide relief to many sufferers without the need for surgery.
Journal reference:
Neutrophil extracellular traps initiate gallstone formation. Luis E. Muñoz, Sebastian Boeltz, Rostyslav Bilyy, Christine Schauer, Aparna Mahajan, Navena Widulin, Anika Grüneboom, Irmgard Herrmann, Edgyda Boada, Manfred Rauh, Veit Krenn, Mona H.C. Biermann, Malgorzata J. Podolska, Jonas Hahn, Jasmin Knopf, Christian Maueröder, Solomiya Paryzhak, Tetiana Dumych, Yi Zhao, Markus F. Neurath, Markus H. Hoffmann, Tobias A. Fuchs, Moritz Leppkes, Georg Schett, & Martin Herrmann. August 15, 2019. DOI:https://doi.org/10.1016/j.immuni.2019.07.002. https://www.cell.com/immunity/fulltext/S1074-7613(19)30318-8
Posted in: Medical Research News | Medical Condition News
Tags: Adrenaline, Appendix, B Cell, Bacteria, Beta Blocker, Bile, Bladder, Blood, Blood Pressure, Calcium, Cell, Chemicals, Cholesterol, Chromatin, Colic, Cytoplasm, DNA, Drugs, Enzyme, Fluorescence, Fluorescence Microscopy, Gallstones, High Blood Pressure, High Cholesterol, Hospital, Immune System, in vivo, Inflammation, Kidney, Microscopy, Nephrology, Neutrophils, Pain, Peritonitis, Protein, Salivary Gland, Surgery, T-Cell
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Thomas, Liji. 2019. How do gallstones form?. News-Medical, viewed 29 June 2023, https://www.news-medical.net/news/20191009/How-do-gallstones-form.aspx.
(2019, October 09). How do gallstones form?. News-Medical. Retrieved on June 29, 2023 from https://www.news-medical.net/news/20191009/How-do-gallstones-form.aspx.
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Gallbladder stones – causes of formation
Why is bile needed? It creates an environment in the intestines that is conducive to digestion.
“Turns on” the work of enzymes that are necessary for the digestion of the protein contained in food. Its constituent acids break down fats. With its help, cholesterol, bilirubin and a number of other substances that are not filtered by the kidneys are excreted from the body …
The liver produces bile constantly (total volume – from 600 ml to 1.5 liters per day), although the need to enter it into the intestine occurs only after eating. The rest of the time, the “surplus” must be stored somewhere. This is the purpose of the gallbladder. In addition, excess fluid and certain substances (for example, sodium and chlorine) are removed from bile in this organ. When needed, bile is supplied to the intestines.
But sometimes this well-established mechanism fails. And one of the possible consequences is the formation of calculi, stones in the gallbladder.
Main causes of cholelithiasis
Violation of the exchange mechanism of cholesterol and bilirubin.
If the ratio between bile acids and cholesterol changes, it precipitates and crystallizes.Dyscholia (change in the composition of bile) is caused by a metabolic disorder. Bile stagnates, thickens, bile acids precipitate and form solid dense formations – stones.
Dyskinesia (violation of the contractile function of the gallbladder) causes stagnation of bile – cholestasis. As a result, the gallbladder becomes inflamed – primary cholecystitis develops. Inflammation disrupts the acid-base balance of bile, which causes bile crystallization.
If the ratio between bile acids and cholesterol changes, it precipitates and crystallizes. Such situations can be provoked by malnutrition (excessive consumption of animal fats and insufficient consumption of vegetables and fruits), diabetes mellitus, hepatitis, infectious diseases. Both fasting and overeating can increase lithogenicity – that is, the ability to form stones – bile. A serious risk factor is the regular use of certain drugs, primarily hormonal contraceptives.
The factor of heredity is also important.
Types and composition of gallstones
Cholesterol . Formed in violation of cholesterol metabolism in overweight people. The disease often proceeds without inflammation, and such stones are accidentally detected during ultrasound. At the initial stage of the development of the disease, it lends itself well to conservative treatment.
Bilirubin (pigmented). They can be formed as a result of changes in the composition of the blood. As a rule, they are single rounded formations, but they can also be multiple, small in size.
Limestones . Formed as a result of primary cholecystitis – inflammation of the gallbladder. They contain calcium, the composition also includes cholesterol and dead epithelial cells.
Mixed . Most of the stones in the gallbladder belong to this type.
They may include cholesterol, bilirubin, various salts, bile acids, glycoproteins, proteins … They are a common cause of acute inflammation of the gallbladder, cause colic.
They may include cholesterol, bilirubin, various salts, bile acids, glycoproteins, proteins … They are a common cause of acute inflammation of the gallbladder, cause colic.It is important to understand that all types of stones pose a potential health hazard. Therefore, even if cholelithiasis is asymptomatic, and stones are found only during ultrasound, you should definitely consult a gastroenterologist to determine the necessary treatment.
Non-precious stones or “the secret of the complete blonde” – Gastroenterology – Departments bile. Accordingly, the stones are cholesterol, bilirubin or interspersed with calcium carbonate. Such an interesting pattern. Stones found among Europeans, including Russians, in 95-97 cases out of 100 are cholesterol, in Asians, for example, the Japanese, mostly bilirubin. Apparently, this is due to the peculiarities of the national cuisine. We eat more animal fats containing cholesterol, and the Japanese give the palm in their diet to fish and other seafood, which not only have little cholesterol, but also contain substances that remove it from the body.
However, the traditional food of the inhabitants of the Land of the Rising Sun in recent years has been increasingly Europeanized: chips, hamburgers, full-fat yogurts and many other cholesterol-containing dishes have appeared. And now the Japanese, suffering from gallstone disease, are more likely to find cholesterol stones. But still, no matter how people eat, gallstones are not formed in everyone. So what is the power to shape?
The secret of the full blonde
In the 30s, the English scientist Deaver proposed the “rule of five F” to determine the risk group for gallstone disease: femina (woman), fertaie (pregnant), forty (forty), fat (full) , fair (blonde). Of course, from the point of view of modern gastroenterology, Dr. Deaver’s classification is not complete. But it is very figurative and generally correct and understandable. Let’s take a closer look at each of the five F’s.
And so femina. Observations have shown that in women, gallstone disease occurs more than 2 times more often than in men, because, firstly, they have a specific hormonal background, and secondly, during pregnancy (here is the second F – fertaie) in the result of additional hormonal adjustment increases the cholesterol content in the body.
In those over forty (forty), contractions of the smooth muscles of the internal organs, including the walls of the gallbladder, become more sluggish. The secretion of bile is difficult, and it stagnates. In full (fat), as a rule, the content of cholesterol in the body is increased, since overweight is most often the result of overeating, including animal fats. Due to the abundance of cholesterol in the diet, the normal ratio in bile between it and bile acids is disturbed. Cholesterol crystals precipitate. And on them, as on a grain of sand in a pearl shell, new crystals settle in layers, forming stones. As for the blondes (fair), either the Englishman had an increased sympathy for them, or he did not share the reason for his conclusion, intriguing us with a “secret”. My many years of clinical practice does not allow me to draw such a conclusion: the disease is “favorable” to blondes, brunettes, and brown-haired women.
I would like to supplement my colleague and name a few more causes of cholelithiasis.
First of all, this is a violation of the diet: in a person who eats 1-2 times a day, bile stagnates in the gallbladder, since it is released only in response to food intake. And stagnation of bile, as already mentioned, to a large extent contributes to the formation of stones.
Physical inactivity also predisposes to the development of the disease: lack of movement causes a lack of contractions of the abdominal muscles and muscles of the abdominal organs, including the gallbladder, which inevitably leads to stagnation of bile with all the ensuing consequences.
Simulant stones
The process of stone formation is usually long. Years pass before they make themselves felt with bouts of biliary colic.
In some patients, gallstones lie quietly, without causing any disturbance. They are discovered by chance during the examination, when the patient undergoes an ultrasound examination (ultrasound). But this does not mean that such patients are lucky. “Silent” large stones can cause bedsores, and small ones can block the bile duct and then “talk” and even “shout” so that the patient will have to be operated on urgently.
Cutting? Don’t cut?
What to do if stones are found? In modern gastroenterology, there are several methods for the treatment of gallstone disease – both conservative and surgical.
I want to warn patients against home-grown methods of treatment, including the so-called “liver cleansing”. Squeezed lemon juice, along with a large dose of vegetable oil, is the strongest irritant of the gallbladder. Under the influence of the “cocktail”, it begins to actively contract. Disturbed stones, if any, can block the bile duct and block the exit of bile: hepatic colic, obstructive jaundice will develop, and urgent surgery will be required.
Conservative treatment consists of following a diet and diet, taking antispasmodic and enzyme preparations.
An endo-surgical or laparoscopic method, increasingly used instead of traditional abdominal surgery, allows 4 small holes to be made in the abdominal wall. Through them, a laparoscope is inserted, with the help of which stones are first removed from the gallbladder, and then the bladder itself is removed.
The operation takes much less time than the abdominal one. It is less traumatic, and the recovery period after it is much shorter. As a rule, already on the 3-4th day the patient is discharged.
But still there are “lucky ones” who are not suitable for any of the most modern methods. It is necessary to extract the stones (especially if they are very large) in the old way – to go for an abdominal operation.
On the “three pillars”
It is known that the earlier the disease is diagnosed, the easier it is to fight it. In the case of cholelithiasis, you cannot cope without the active help of the patient himself, because the basis for the prevention of exacerbations is your lifestyle.
Here are the “three pillars” on which it is desirable to rely: a normal diet, diet and physical activity.
To prevent exacerbations, frequent meals are needed – 5, and preferably 6 times a day in small portions.
Exclusion from the diet of foods containing a lot of animal fat (lard, fatty butter and poultry, cream, sour cream, cheese), rich broths, mushrooms, ice cream, fried dough dishes: pies, pasties, whites, doughnuts – everything that causes active separation of bile and a sharp contraction of the gallbladder.