Bile salt accumulation

B. Clinical Use The resins are used in patients with hypercholesterolemia (Table 35-2). They have also been used to reduce pruritus in patients with cholestasis and bile salt accumulation. 

Pharmacokinetics Phytonadione is only absorbed from the Gl tract via intestinal lymphatics in the presence of bile salts. Although initially concentrated in the liver, vitamin K is rapidly metabolized, and very little tissue accumulation occurs. Parenteral phytonadione is generally detectable within 1 to 2 hours. Phytonadione usually controls hemorrhage within 3 to 6 hours. A normal prothrombin level may be obtained in 12 to 14 hours. Oral phytonadione exerts its effect in 6 to 10 hours. 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

The bile acids produced by the liver accumulate in the gall bladder in the form of bile salts they are bile acids in which the carboxylic acid group is conjugated with glycine or taurine. 

PFIC 2 This gene mutation, which is located on chromosome 2q24, impairs the canalicular bile salt export pump (BSEP), resulting in the accumulation of bile acids in hepatocytes. Laboratory tests show an increase in bile acid, AP and LAP levels with lowered gamma GT and cholesterol levels. Pruritus is common. There is histological evidence of neonatal giant cell hepatitis. Prognosis is poor. 

These data suggest that bosentan causes cholestatic liver injury due to inhibition of bile-salt efflux and damage due to intracellular accumulation of bile salts. 

Etiology of generalized itching Increased serum bile salts and accumulation of bile salts in the dermis of the skin. 

Intrahepatic cholestasis of pregnancy is a syndrome of unknown etiology characterized by a 100-fold increase in maternal and fetal blood bile salt levels. Bile salts are produced in both the fetal and maternal liver. The fetus transfers the bile salts across the placenta for disposal. When the function of the maternal gallbladder is slowed, bile salts can accumulate in the liver and bloodstream, ultimately resulting in the classical pruritus symptom. It is believed that pregnancy-related hormones may slow bile salt excretion from the gallbladder. 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

In 1980, Kibe et al. found considerable amounts of bile alcohol sulfates in the bile of a patient with cholestasis [81]. Solvolysis of the bile salts gave 3 different bile alcohols which were identified as 24-nor-5/3-cholestane-3a,7a,12 ,25-tetrol, 26,27-di-nor-5 -cholestane-3a,7a,12a,24,25-pentol, and 3a,7a,12a-trihydroxy-26,27-dinor-5 -cholestan-24-one, by comparison with synthetic standards [81]. Nothing is known about the biosynthesis of these C25 and 2 bile alcohols. Since the accumulation of bile alcohols has not been found in other cases with cholestasis, it seems unlikely that cholestasis is the primary cause of the formation of bile alcohols with unusual side chains. 

Bile has long been attributed an important role in medicine [1]. The effect of an impaired bile flow to the intestine has been known to result in steatorrhea — fat malabsorption — and defective absorption of fat-soluble vitamins, notably vitamin K [2], Thus, it is obvious that bile is important for fat assimilation from the intestine. However, it is equally apparent that when fat absorption after bile obstruction or diversion could be studied by quantitative methods, the malabsorption was found to be only partial [3]. In fact, it has seemed surprising that some 60-70% of a normal fat load is absorbed in man and the experimental animal in the absence of bile in the intestine. The absorption of nonpolar lipids, however, is much less efficient, and cholesterol absorption has been reported to have an absolute requirement for the presence of bile salts [4]. Of the bile components important for fat absorption bile salts have been ascribed the main role although experimental results are accumulating regarding the role of bile phospholipids in the specific uptake of sterols by the intestine [5]. 

At present the use of activity measurements to quantitate plasma, serum, or urinary levels of the GST are inadequate. With CDNB it is difficult to obtain sufficient sensitivity to allow the measurement of the levels in normal subjects (A4). In addition many drugs and endogenous substances may inhibit the activity to values that lie within the reference range. For example bile salts and bilirubin inhibit GST activity (H17) and since both of these nonsubstrate ligands are increased in liver disease their accumulation in plasma could theoretically suppress GST activity to within the reference range. An important problem with GST activity measurements concerns the ubiquitous nature of the GST since poor organ specificity will result unless specific isoenzymes are measured. For example, platelets, erythrocytes, and white cells contain high levels of the isoenzyme and these cells may release their GST into plasma prior to separation of the blood sample (G4, H52, L12, M8, Rll, S43). With the substrates that are available to date, the activity measurements are inadequate for clinical use. 

Unregulated cholesterol production can lead to serious human disease. When the sum of cholesterol synthesized and cholesterol obtained in the diet exceeds the amount required for the synthesis of membranes, bile salts, and steroids, pathological accumulations of cholesterol in blood vessels (atherosclerotic plaques) can develop, resulting in obstruction of blood vessels (atherosclerosis). Heart failure due to occluded coronary arteries is a leading cause of death in industrialized societies. Atherosclerosis is linked to high levels of cholesterol in the blood, and particularly to high levels of LDL-bound cholesterol there is negative correlation between HDL levels and arterial disease. 

Cholestasis is a condition characterized by impaired flow of bile, due to physical obstruction of the biliary tree or decreased bile secretion by the liver. Cholestasis produces alterations of enzyme activity in the liver (cytochrome P450) as well as altered transporter expression, with associated effects on drug clearance. As discussed previously, cholestasis can occur through inhibition of the canalicular membrane transporter, BSEP. In response to cholestasis, however, the liver has adaptive mechanisms to minimize cellular accumulation of toxic bile salts. These include upregulation of MRP3 to increase sinusoidal efflux, and downregulation of Na -taurocholate cotransporting polypeptide (NTCP), which mediates bile salt uptake from the blood to the liver. 

The mechanism of intestinal absorption of compounds with vitamin K activity varies with their solubility. In the presence of bile salts, phylloquinone and the menaquinones are adequately absorbed from the intestine, almost entirely by way of the lymph. Phylloquinone is absorbed by an energy-dependent, saturable process in proximal portions of the small intestine menaquinones are absorbed by diffusion in the distal portions of the small intestine and in the colon. Following absorption, phylloquinone is incorporated into chylomicrons in close association with triglycerides and lipoproteins. The extremely low phylloquinone levels in newborns may be partly related to very low plasma lipoprotein concentrations at birth and may lead to an underestimation of vitamin K tissue stores. Absorbed phylloquinone and menaquinones are concentrated in the liver, but the concentration of phylloquinone declines rapidly. Menaquinones, produced in the lower bowel, are less biologically active than phylloquinone due to their long side chain. Very little vitamin K accumulates in other tissues. 

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