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Lithogenic bile formation

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Biology of bile acids

According to the hydrophilic-hydrophobic index, the bile acids are divided into hydrophilic and hydrophobic ones (table 1) (1-3).

If the hydrophobic index is less than that of cholic acid (CA), the bile acids are hydrophilic, if it is more than the hydrophobic index, they are hydrophobic (1-3). The primary bile acids are more hydrophilic than the secondary ones, but the taurine conjugates of the bile acids are more hydrophilic than the glycine ones (1-3). The hydrophilic bile acids have hepatoprotective properties [muricholic (MCA) > ursodeoxycholic (UDCA) > cholic (CA)] (4, 5). The hydrophobic bile acids are hepatotoxic [lithocholic (LCA) > deoxycholic (DCA) > chenodeoxycholic (CDCA) > CA] (1-7). Depending on the concentration, the hydrophobic bile acids cause cholestasis (LCA > DCA), necrosis (LCA > DCA) or apoptosis of hepatocytes (LCA > DCA > CDCA) (2-7).

Furthermore, DCA is cancerogenic (8). Experiments on animals showed that it causes cancer of the colon (9). The hydrophilic bile acids prevent the development of cholestasis or necrosis/apoptosis of hepatocytes (UDCA, MCA), as well as cancer of the colon (UDCA) (4-7, 9).

In serum up to 40% of bile acids are transported with HDL, up to 15% with LDL (10). The mechanism of binding of bile acids with lipoproteins depends on their hydrophobic index (CDCA > DCA > UDCA > CA > 7-epicholic acid) (10). In the liver, 60-80% of bile acids are uptake during one passage of portal blood (11). In earlier experiments on hamsters, it was demonstrated that the hepatic LDL uptake could influence the bile flow rate, the biliary secretion of bile acids and cholesterol (12, 13). The composition and concentration of bile acids participating in the enterohepatic circulation can modulate the LDL receptor activity and the receptor-dependent LDL uptake in the liver. More hydrophilic UDCA stimulates the receptor-dependent LDL uptake in the liver, but more hydrophobic CDCA decreases the LDL receptor activity (12, 13). It was also shown that the addition of hydrophobic CDCA to the hypercholesterolemic diet reduces the decrease of HDL concentration in serum, but the addition of hydrophilic UDCA causes the opposite effect (14, 15).

In hepatocytes, the bile acids may inhibit the activity of HMG-CoA reductase and cholesterol-7α-hydroxylase, depending on their concentration and hydrophobic index (DCA > CDCA > CA > UDCA) (2, 16-18). The hydrophilic bile acids stimulate the secretion of the hepatic bile (UDCA > CA), the hydrophobic ones lower it (LCA > DCA > CDCA) (19-21). UDCA and CDCA reduce the secretion of biliary cholesterol in the hepatic bile, but CA and DCA raise it (1, 19-21). In the gallbladder bile, the hydrophobic bile acids form mixed (bile acid-phospholipid-cholesterol) and simple (bile acid-cholesterol) micelles (DCA > CDCA > CA), but the hydrophilic bile acids form liquid crystalline lamellas (MCA > UDCA); that is, the lower the hydrophobic index of bile acids, the lower the ability to form micelles (22-25).

In the ileum, CA and CDCA raise the absorption of cholesterol, but UDCA and DCA reduce it (26-29). During the process of enterohepatic circulation, in the ileum and the colon, anaerobic bacteria promote 7α-dehydroxylation of the primary bile acids (hyocholic (HCA), MCA, CA, CDCA) and the formation of the secondary bile acids (hyodeoxycholic (HDCA), murideoxycholic (MDCA), DCA, LCA) (1, 2, 30, 31). The secondary bile acids are more hydrophobic than the primary ones (HDCA > HCA, MDCA > MCA, DCA > CA, LCA > CDCA) (1-3). The secondary bile acids are usually poorly absorbed in the ileum and the colon and are excreted with feces (1-3).

 

The mechanism of “lithogenic” bile formation

In patients with chronic calculous cholecystitis, there is a marked increase of the COX-2 expression. Previously, we had demonstrated the increased COX-2 expression in the gallbladder wall in the gallbladder specimens which were obtained from 21 patients with chronic calculous cholecystitis after cholecystectomy (32).

An increase of COX-2 expression in the gallbladder wall (n=21) was observed in 86% of the smooth muscle cells, in 81% of the epithelial cells, in 71% of the vascular smooth muscle cells, in 57% of the stromal cells and in 37% of the Rokitansky-Aschoff sinuses (32).

At mild degree of inflammation in the gallbladder wall (n=12),  the COX-2 expression was increased in 83% of the epithelial cells, in 78% of the vascular smooth muscle cells, in 75% of the smooth muscle cells, in 33% of the stromal cells and in 17% of the Rokitansky-Aschoff sinuses.

At moderate and severe degree of inflammation in the gallbladder wall (n=9),  the COX-2 expression was increased in 100% of the smooth muscle cells, in 89% of the vascular smooth muscle cells, in 78% of the epithelial cells, in 78% of the stromal cells and in 67% of the Rokitansky-Aschoff sinuses.

Positive correlations exist between the degree of inflammation in the gallbladder wall and the degree of COX-2 expression in the smooth muscle cells (r= +0.71, p<0.001) and in the vascular smooth muscle cells (r= +0.51, p<0.001).

In 8 gallbladder specimens with gastric metaplasia, an increase of COX-2 expression was seen in 100% of the epithelial cells, in 87% of the smooth muscle cells, in 75% of the vascular smooth muscle cells, in 63% of the stromal cells and in 37% of the Rokitansky-Aschoff sinuses. In this group, a positive correlation was seen between the degree of inflammation in the gallbladder wall and the degree of COX-2 expression in the stromal cells (r= +0.72, p<0.05).

In 13 gallbladder specimens without metaplasia, an increased COX-2 expression was determined in 85% of the smooth muscle cells, in 69% of the epithelial cells, in 69% of the vascular smooth muscle cells, in 54% of the stromal cells and in 38% of the Rokitansky-Aschoff sinuses. In this group, a positive correlation was revealed between the degree of inflammation in the gallbladder wall and the degree of COX-2 expression in the smooth muscle cells (r= +0.82, p<0.05).
In patients with chronic calculous cholecystitis, a negative correlation was revealed between the absorption function of gallbladder and the thickness of the gallbladder wall (r= -0.71, p<0.05) (33).

Obtained data demonstrate:

  1. The excessive COX-2 expression in the smooth muscle cells, in the vascular smooth muscle cells and in the epithelial cells of the gallbladder may be the cause of chronic aseptic inflammation, of the decrease of water absorption and of the decrease of hepatic bile “passage” into the gallbladder up to 35%.
  2. The excessive COX-2 expression in the smooth muscle cells may be the cause of gallbladder hypomotility and biliary pain.
  3. The excessive COX-2 expression in the smooth muscle cells, in the vascular smooth muscle cells and in the epithelial cells of the gallbladder may be the cause of increased thickness of the gallbladder wall.
  4. The excessive COX-2 expression in the epithelial cells of the gallbladder may be the cause of hypersecretion of the biliary glycoprotein mucin into the gallbladder lumen and of increase of the biliary glycoprotein mucin concentration in the gallbladder bile.

Taking account the fact that the excessive COX-2 expression in the smooth muscle cells, in the vascular smooth muscle cells and in the epithelial cells of the gallbladder may appear at the early stage of the development of cholecystolithiasis, then the excessive COX-2 expression in the smooth muscle cells, in the vascular smooth muscle cells and in the epithelial cells of the gallbladder may be the physical cause of appearance of the chronic intrahepatic “bland” cholestasis and the “lithogenic” gallbladder bile formation:
1) to decrease of water absorption by the epithelial cells of mucous gallbladder and to promote the reduce of the hepatic bile inflow into the gallbladder (the limitation of “passive” passage of the hepatic bile) and to promote the reduce of the total bile acids concentration in the gallbladder bile;
2) to decrease of vesicular cholesterol absorption by the epithelial cells of mucous gallbladder and to promote the increase of cholesterol concentration in the phospholipid vesicles in the gallbladder bile;
3) to decrease of hydrophilic proteins absorption by the epithelial cells of mucous gallbladder and to promote the increase of hydrophilic proteins concentration in the gallbladder bile.

This process is accompanied by the increase of the vesicular cholesterol/total bile acids ratio and by the increase of the total biliary proteins/total bile acids ratio and it promote the rise of the rate of cholesterol monohydrate crystals precipitation on the epithelial cells of mucous gallbladder.

Hence, than the less is the absorption of vesicular cholesterol by the epithelial cells of mucous gallbladder, then the higher is the cholesterol concentration in the gallbladder bile and the less is the nucleation time of cholesterol monohydrate crystals in the gallbladder bile, and vice versa. Hence, the excessive COX-2 expression in the epithelial cells of the gallbladder decreases the absorption and concentration functions of the gallbladder and promotes the “lithogenic” gallbladder bile formation. The decrease of the evacuation function of the gallbladder (the excessive COX-2 expression in the smooth muscle cells) is the predisposing factor for the precipitation of cholesterol monohydrate crystals and for the formation of cholesterol gallstones (fig. 5).

The decrease of hepatic bile “passage” into the gallbladder promote the hepatic bile “passage” into the duodenum and increase the frequency of the gallbladder-independent enterohepatic circulation of bile acids and stimulate the formation of the hydrophobic hepatotoxic deoxycholic bile acid (DCA) (10, 34, 35).

The increase of the frequency of the gallbladder-independent enterohepatic circulation of bile acids and the increase of hydrophobic hepatotoxic deoxycholic bile acid concentration in the hepatocytes reduce the bile-acid-independent secretion of hepatic bile and stimulate the chronic intrahepatic “bland” cholestasis formation (36, 37). Hence, the decrease of hepatic bile “passage” into the gallbladder and, respectively, the increase of hepatic bile “passage” into the duodenum is the cause of the increased frequency of the gallbladder-independent enterohepatic circulation of bile acids and of the appearance of the chronic intrahepatic “bland” cholestasis.

The chronic intrahepatic “bland” cholestasis is accompanied by the reduction of secretion volume of hepatic bile and by the rise of biliary cholesterol, total bile acids and total biliary protein concentration in the hepatic bile (fig. 6) (38, 39). The increase of biliary cholesterol concentration in the hepatic bile promote the rise of the biliary cholesterol concentration in phospholipid vesicles (r= +0.59, p<0.05) (40). The increase of total bile acids concentration in the hepatic bile reduces the stability of phospholipid vesicles and shortens the nucleation time of cholesterol monohydrate crystals (r= -0.53, p<0.05) (40).

We suppose that the chronic intrahepatic “bland” cholestasis, reducing the secretion rate and the hepatic bile volume, promotes the rise of biliary cholesterol, total bile acids and total biliary protein concentration in the hepatic bile, and shortens the nucleation time of cholesterol monohydrate crystals, what predispose to the “lithogenic” hepatic bile formation.

The decrease of absorption, concentration and evacuation functions of the gallbladder promote the “lithogenic” gallbladder bile formation, the chronic intrahepatic “bland” cholestasis promote the “lithogenic” hepatic bile formation (fig. 5, fig. 6). These two factors determine the cholesterol gallstones formation.

In patients with chronic acalculous cholecystitis with biliary sludge, the formation of cholesterol gallstones is promoted by the decrease of absorption (the decrease of the water and phospholipid vesicles absorption), concentration (the decrease of total bile acids concentration in gallbladder bile) and evacuation (the decrease of the gallbladder-dependent output of biliary cholesterol) functions and by the increase of secretion (hypersecretion of glycoprotein mucin by the gallbladder mucosa) function of the gallbladder (fig. 7) (41).

The decrease of the water absorption rate of in the gallbladder wall limits the “passive” passage of the hepatic bile into the gallbladder and increases the hepatic bile passage into the duodenum (fig. 8) (41-43).

The decrease of the evacuation function of the gallbladder reduces the “active” passage of the hepatic bile into the gallbladder (44, 45). This process is accompanied by the decrease of the total bile acids concentration and the increase of the biliary cholesterol concentration in phospholipid vesicles and it also promotes the increase of time for precipitation of cholesterol monohydrate crystals and the formation of cholesterol gallstones (fig. 9) (46-50).

The excessive hepatic bile passage from the liver into the duodenum increases the frequency of the gallbladder independent enterohepatic circulation of bile acids. The gallbladder-independent enterohepatic circulation of bile acids in patients with the cholesterol gallstone disease (CGD) or after cholecystectomy is raised (fig. 10).

It results in: 1) the increase of the hydrophobic hepatotoxic DCA formation (table 3) and its accumulation in hepatocytes (51), 2) the formation of morphological changes in the liver (nonspecific reactive hepatitis) (52) and 3) the appearance of cholestasis (53).
The risk of cancer of the liver, the pancreas, the small intestine, and the colon increases as well (54-62). The increases of DCA, participating in the enterohepatic circulation, and of other toxic agents in the hepatic bile can result in chronic pancreatitis and duodeno-gastral reflux (63-66).

 

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Hydrophilic-hydrophobic index of bile acids
Table 1


Lithogenic gallbladder bile formation
Fig. 5


Lithogenic hepatic bile formation
Fig. 6


Cholesterol and bile acids metabolism, chronic acalculous cholecystitis, chronic calculous cholecystitis
Fig. 7


Passive passage of hepatic bile, chronic acalculous cholecystitis, biliary sludge
Fig. 8


Cholesterol metabolism, chronic acalculous cholecystitis, chronic calculous cholecystitis
Fig. 9


Enterohepatic circulation of bile acids, chronic calculous cholecystitis, cholecystectomy
Fig. 10


Hydrophobic DCA
Table 3


 
 
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