Enterohepatic circulation of bile salts

Houten SM, Auwerx J (2004) The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann Med 36 482-491... 

Enterohepatic circulation of bile salts and bile acids. 

FIGURE 2.38 Enterohepatic circulation of bile salts. Bile salts from the liver enter the duodenum at the ampulla of Vater, the same opening through which material from the exocrine pancreas is released. Most of the gall bladder is hidden within the lobes of the liver. After varying degrees of utilization and reutilization for lipid absorption, the bile salts reach the distal ileum, where they are reabsorbed and returned to the liver via the portal vein. The portal vein is very important because it also carries water-soluble nutrients absorbed from the diet. 

Bile-acid-binding resin results in an interruption of the enterohepatic circulation of bile salts and in their increased excretion in the feces. This drug therapy can produce a 20-25% decrease in plasma LDL-cholesterol. A side effect of cholestyramine is constipation, but this problem can be relieved by a high fiber diet. 

BILE ACID SEQUESTRANTS Cholestyramine, colestipol, and colesevalam effectively bind bile acids and some bacterial toxins. Cholestyramine is useful in the treatment of bile salt-induced diarrhea, as in patients with resection of the distal Ueum. In these patients, there is partial interruption of the normal enterohepatic circulation of bile salts, resulting in excessive concentrations reaching the colon and stimulating water and electrolyte secretion (see below). Patients with extensive ileal resection (usually >100 cm) eventually develop net bile salt depletion, which can produce steatorrhea because of inadequate micellar formation required for fat absorption. In such patients, the use of cholestyramine will aggravate the diarrhea. 

EXAMPLE 12.10 About 20 g of bile salts are secreted by the liver into the duodenum each day. Only a small proportion (less than 2 g) enters the feces because the uptake from the intestine into the bloodstream and transport back to the liver are very efficient. This is called the enterohepatic circulation of bile salts. 

How might intermption of the enterohepatic circulation of bile salts lead to reduction of the total pool of cholesterol in the body ... 

The enterohepatic circulation of bile salts involves the cycling of fairly large quantities of material. It has been estimated that the human liver secretes some 30 g of bile salts per day. Of these 30 g, approximately 0.8 g per day is newly synthesized material (4). This emphasizes the efficiency of the intestinal reabsorptive processes. The liver also is remarkably efficient in extracting bile salts from portal blood, as evidenced by the fact that the concentration of bile salts in peripheral plasma is a small fraction of that of portal plasma (5-7). Direct determination of taurocholate and glycocholate extraction by the liver in the dog has been measured by O Maille et al. (8) and found to be 92%. 

Similar studies to those described have been performed in only a limited number of patients with ileal disease in the absence of resection or bypass (3,9-11) five with active regional ileitis and two with radiation damage. The results of isotope dilution studies (Table I, Fig. 2), fecal excretion measurements, and measurements of luminal bile salt concentration have thus far been similar to those reported in ileectomized patients, suggesting that inflammatory disease of the ileum per se results in a loss of enterohepatic circulation of bile salts. It is not known whether this absorptive defect is repaired in remission of regional enteritis. The course of this disease is characterized by variations in activity whether or not these defects in bile salt metabolism vary in accordance with this natural history of the disease is one of several questions requiring study. 

As already discussed, obesity is associated via augmented cholesterol synthesis with an increased bile acid production. Since obesity as such is a result of excessive consumption of calories, it is logical to infer that overeating stimulates cholesterol synthesis and secondarily bile acid production. An increased number and quantity of daily meals may, however, change under these conditions the metabolism of both cholesterol and bile acids in complicated ways which are not yet completely understood, by augmenting the number of enterohepatic circulations of bile salts. Increased intestinal contents and fecal mass may also interfere with reabsorption of bile acids. 

Bile acids are formed from cholesterol in the liver via a sequence of reactions initiated by 7a-hydroxylase. Two primary bile acids, cholic acid and chenodeoxycholic acid, are formed and secreted as glycine or taurine conjugates into the bile and intestine. Most of them are reabsorbed, taken up by the liver and resecreted, completing enterohepatic circulation of bile salts. During each cycle a small amount of bile acids escape into the colon and feces and is regenerated by new hepatic synthesis. 

Despite our increased knowledge of the synthesis, secretion and enterohepatic circulation of bile salts, several aspects of the effects of these sterol metabolites on the physiology of the intestine itself have not been emphasized and are poorly understood. This becomes of greater significance when we consider that bile acids, particularly chenodeoxycholic acid and ursodeoxycholic acids, are employed for gallstone therapy there are several dietary influences on the enterohepatic circulation of bile acids and on bile acid excretion (e.g. fats and dietary fibers) increased colonic bile acid concentrations have been implicated in the promotion of colorectal cancer and there appears to be an inverse relationship between cholesterolemia and colon cancer. 

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