Notes
by doctor Claudio Italiano
The gallbladder stones is a very frequent pathology in western countries. In Italy the prevalence is between 7% and 10% of the general population, a rate comparable to what is observed for example in Germany, France or the United States. It has been calculated that the number of new cases each year in the USA is around 800,000. About 400,000 of these undergo surgical treatment. The frequency of the disease grows with age in a linear manner; it is rare in the pediatric age, progressively increasing until reaching the maximum over 80 years. The incidence is greater in the female sex, but this difference, which is maximum around the fourth decade (M / F = 1/2), tends to cancel after seventy years. As far as cholesterol calculations are concerned, environmental risk factors are represented as well as by diet, for ex. patients who always eat meat, fatty foods, sweets, etc., from the use of estrogens (contraceptives), from drugs that increase biliary excretion of cholesterol such as clofibrate and from obesity or rapid weight loss. Inheritance risk factors are instead represented by various metabolic defects that cause changes in the synthesis of bile salts or increase in blood and / or biliary levels of cholesterol. Bilirubin stones are particularly common in the Far East and are associated with excessive bilirubin levels in bile (hemolytic syndromes, ileal bypass, biliary tract infections).
The factors involved in the formation of gallstones are generally of three types: • thermodynamic: supersaturation of the bile with consequent tendency to precipitate the bile salts; • kinetics: presence of substances capable of accelerating or starting the crystallization process; • thunderstorms: slowing of the biliary flow with a consequent increase in the so-called "residence time", reaction time.
Biliary cholesterol is only partly (about 50%) of food origin, the rest
comes from plasma lipoproteins (LDL <IDL <HDL <"Remnants" of chylomicrons) or is
synthesized ex novo by hepatocytes. The control of its synthesis takes place at
the level of the enzyme HMG-CoA-reductase. In the hepatocyte, cholesterol is in
free or esterified form. The free fraction is largely used for bile acid
synthesis or excreted as such in the bile. Cholesterol, which is hydrophobic, is
secreted in the biliary canaliculus mixed with phospholipids (particularly
lecithins) in the form of "unilamellar vesicles"; the bile acids are in turn
independently secreted and mixed with cholesterol forming the so-called "simple
micelles" which subsequently also accommodate phospholipids giving rise to the
so-called "mixed micelles", in which the solubility of cholesterol is 2-3 times
greater. In the latter, the polar "heads" of the phospholipids and the polar
ends of the bile acids are turned outwards, while the apolar "tails" are turned
inward; among the "tails" are the cholesterol molecules. The micelles are stable
from the thermodynamic point of view and therefore do not tend to precipitate.
If the biliary concentration of cholesterol increases (due to increased
secretion of cholesterol, but also due to decreased production of fatty acids),
the excess does not dissolve in micelles, but remains in the state of "unilamellar
vesicles" which subsequently tend to merge and originate the "vesicles"
multilamellar "which are also called" liquid crystals ". The latter give rise
through the nucleation process to the crystals of cholesterol monohydrate. It is
important to note that the sole oversaturation of cholesterol is not sufficient
for the genesis of lithiasis. It is in fact known for at least thirty years that
bile is supersaturated in a high percentage of people who do not amalgamate with
lithiasis. Nucleation is defined as the spontaneous aggregation in a
supersaturated solution of complexes of a few hundred molecules that dissolve or
crystallize in relation to the thermodynamic conditions. The subsequent growth
by apposition determines the formation of cholesterol stones. In the formation
of calculations in humans, only one so-called "heterologous nucleation" is
observed, ie due to the combined action of several substances other than
cholesterol itself; in pathological conditions the balance between "pro-nucleation"
and "anti-nucleation" factors is obviously shifted in favor of the former.
They are represented by:
• Bile mucins. Under certain conditions of concentration, ionic strength and pH
the bile mucins form a gel within the molecular lattice of which the entire
crystallization process takes place.
• Bile proteins other than mucins. Several substances have been identified,
including: aminopeptidase, phospholipase C, alpha acid glycoprotein,
immunoglobulin. It should be noted that the protein content of the bile as well
as the mucin content can be modified by the presence of bacterial and / or
inflammatory infections.
• "Sludge" biliary, ie aggregation of bile mucins, granules of calcium
bilirubinate, cholesterol crystals.
• Increased concentration of hydrophobic bile acids.
• Increased bile acid / lecithin ratio.
• Increase in the cholesterol / lecithin ratio.
• Increase of Ca + + concentration.
• Hypomotility of the gallbladder with slow emptying.
Antinucleation factors
• Apolipoproteins Al and Al;
• 120 kd glycoprotein;
• 15 kd glycoprotein.
• "Black" or "furious" calculations. Composed of unbound conjugated bilirubin
and calcium bilirubinated polymers. They are formed in the absence of infection
and are generally associated with conditions that cause increased production of
bilirubin, such as hemolysis ooilidie, or reduction in the capacity for
conjugation of the liver (cirrhosis of the liver) or in the case of ileal
bypass. The increase in unconjugated bilirubin within the bile beyond the 200
mmol / 1 concentration leads to the precipitation of calcium bilirubinate, which
is practically insoluble and therefore to the crystallization and formation of
the calculations.
• "Brown" calculations: consisting of bilirubinate, palmite and calcium stearate.
They are formed after anaerobic infections (Enterococcos, Klebsiella,
Pseudomonas, Enterobacter, Proteus), of the biliary tract and are frequent
mainly in the Far East where they are mainly located in the common bile duct. In
the West they also give rise to cholecystolithiasis.
Morphology:
• Cholesterol calculations. They are found exclusively in the gallbladder and
are composed of cholesterol for at least 50%. The calculations of pure
cholesterol are pale yellow in color, round or oval in shape with a finely
granular outer surface. When cut, they have a radial crystalline appearance. As
the proportion of bilirubinate, phosphate and / or calcium carbonate increases,
the color tends to become greyish-white. A calcium content of at least 10% makes
radiopaque calculations.
• Pigment calculations.
• "Black" calculations. They are rarely greater than 1, 5 cm and present in
large numbers in the gallbladder, brittle and irregularly shaped. They are
radiopaque in most cases.
• "Brown" calculations. Small, of greyish color, soft. Radiotransparent.
The alterations of the gallbladder and of the liver
they observe in the lithiasis are secondary to the action calculations
The gallbladder, in the grip of lithiasis problems, can meet:
• cholecystitis, chronic. In general, inflammation and fibrosis of the
gallbladder depend on the size and / or number of calculations. However, there
are exceptions as in the case of a single gallbladder where 23530 calculi were
found without cholecystitis, preserved in the Thomas'Hospital Anatomical Museum
in London. The mechanical action of the calculations with the formation of
granulation tissue can lead to the incorporation of the calculations in the
gallbladder wall;
• hypertrophy of the muscular tunic; beyond a certain volume of calculations (about
4 ml.) the gallbladder loses its ability to concentrate the bile and
consequently compensates for the muscular tone and the glands. The picture of
adenomyosis of the gallbladder is therefore observed.
Hepatic lesions in the course of lithiasis
The inflammatory changes can be traced along the biliary tract up to the liver,
causing cholangitis with cholestasis, portal fibrosis periductal, progressing in
severe cases to biliary obstruction up to secondary biliary cirrhosis. The
severity of liver involvement depends on the age of the patients, the duration
of the obstruction and the location of the calculations (the most serious
pictures are observed in case of choledocholithiasis).
Clinic and complications
A large part of patients is asymptomatic and the finding of occasional calculations. Vague symptoms such as dyspepsia, flatulence, postprandial epigastric pain can be referred to the presence of calculations. The classic symptom is biliary colic due to obstruction. Cholecystitis also causes colonic pain (see below). Calculus migration into the cystic can result in gallbladder empyema or hydrops. Migration with wedging in the common bile duct causes acute cholestasis with possible pancreatitis. Other complications are free perforation in the abdomen with consequent coleperitoneum or the formation of fistulas (biliocutaneous, biliobiliary, biliodigestive, biliovascular and rarely biliobronchial and biliovescical). Rarely, a bilio-digestive fistula can cause the direct exit of a calculation in the intestine with consequent ileus. Finally, patients with lithiasis present a higher risk of the general population for gallbladder carcinoma.
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