Lithocholic acid liver disease

Although cholesterol is the major source of 5)9-bile acids, an unsaturated acid, 3)8-hydroxy-5-cholenic acid [174] has been found in meconium, mainly as the sulfate [175], in bile of a boy with a deficiency of 3)8-hydroxysteroid dehydrogenase [176], and in urine of healthy persons and individuals with liver disease [164]. The details of metabolism of 3)8-hydroxy-5-cholenic acid to lithocholate have not been entirely elucidated, but the mechanism for conversion of the 3/8-hydroxy-A to the 3-oxo-A derivative has been formulated in the C27 series (cf. Chapter 9). Briefly, the 3)8-ol is dehydrogenated by a microsomal enzyme fortified with NAD to provide the 3-oxo-A system [177,178]. Whether a A - A" isomerase is essential is not known, since there is no direct evidence for the formation of the intermediary 3-oxo-A system the rate-limiting step is the dehydrogenation of the 3)8-ol which may prevent accumulation of the 3-oxo-A system [177]. The reduction of the double bond at 4-5 to the 5)8- or 5a-bile acid is catalyzed by the respective A -3-oxosteroid 5)8- or 5 -reductase obtained from liver cytosol [170], and has been purified about 10-fold [178]. The formation of the 3-oxo-5/9 derivative requires the enzyme and NADPH the proton from the A side (4A-NADPH) appeared in the product as the 5)8-H, whereas the proton at C-4 is derived from the aqueous medium. Formation of the 5a derivative requires (4B-NADPH) in a similar mechanism (Fig. 4) [179], Reduction of the 3-0X0 product is then catalyzed by 3a-hydroxysteroid dehydrogenase as discussed above. 

Liver cirrhosis is known to markedly change bile acid metabolism. On the other hand, the role of bile acids as an etiological factor in liver cirrhosis has also been widely discussed (188), particularly because lithocholic acid feeding results in the development of experimental cirrhosis (189,190). Major changes of bile acid metabolism in liver diseases are presented in Table IV. 

The liver damage found frequently in association with inflammatory bowel disease, regional ileitis, and ulcerative colitis has also been postulated to be caused by lithocholic acid (212). The serum concentration of lithocholic acid appears to be, however, quite normal or zero in patients with these diseases (188,193) even if liver damage is present (193), indicating that the association, if any, is not a simple one. 

Additionally there are fused-silica columns with i.d. ca. 0.2 mm. Representing all other small-bore techniques, Fig. 22.1 illustrates the performance of micro-HPLC using this kind of column. Fifteen bile acids which are vital to any assessment of possible liver disease were identified in body fluids. The total solvent consumption of 210 pi, the ability to mix a gradient in this small volume and reproduce it and the refined reaction detector already described in Section 19.9 are special features of this particular system. The following abbreviations are used UDC = ursodeoxycholic acid C = cholic acid CDC = chenodeoxycholic acid DC = deoxycholic acid LC = lithocholic acid G (prefix) = glycine conjugate T (prefix) = faurine conjugate. 

King, J.E., Schoenfield, L.J. Lithocholic acid, cholestasis, and liver disease. Mayo Clin. Proc. 47, 725-730 (1972)... 

Lithocholic acid was first isolated from a gallstone by Fischer in 1911 (30). It was later isolated from ox bile (1 g from 100 kg of bile) (64) from rabbit bile (0.4 g from 900 ml) (65) and subsequently from monkey, human, pig, and guinea pig bile (2, 66, 67). Lithocholic acid has been identified as one of the bile acids in human blood (68) and as a principal fecal bile acid. Moset-tig et al. (69) isolated lithocholic acid from human stool and estimated its concentration to be 3 g/100 kg of fresh stool. Lithocholic acid is particularly insoluble, is not hydroxylated to an appreciable extent in man (70), and may be the cause of liver disease (4). In early studies lithocholic acid was not available in sufficient amounts from natural sources and was prepared from cholic acid. Lithocholic acid was particularly valuable in establishing the correspondence of the B/C ring structure between bile acids and cholesterol (71). 

In liver disease patients and in control subjects we evaluated fasting and postprandial serum levels of cholic, chenodeoxy-cholic and lithocholic acid conjugates and LFT. For the above mentioned problems, data were subjected to variance and discriminant analyses. 

Fasting and postprandial SBA were higher in patients when compared to controls and were significantly higher in severe than in mild liver disease. The statistical analyses of our data showed that SBA determination is more sensitive and discriminant when obtained fasting than postprandial, and that the most useful determination is the combination of a primary bile acid (cholic acid) with lithocholic acid. 

The liver, and also bacteria in the small and large intestine, can cause other structural modifications to bile acids as they undergo their entero-hepatic cycle. The formation of sulfate esters, already mentioned with respect to lithocholate in Section 4.2.1, is carried out primarily in the liver in man by a sulfotransferase (Lll). Other bile acids can also be sulfoconjugated to a small extent, mainly at the 3a-hydroxyl position. Bacteria, which have been isolated anaerobically from human feces, are known to possess bile acid sulfatase activity, which removes the 3a-sul te group of chenodeoxycholic and cholic acids (H24). The action of this bacterial enzyme probably explains why only trace amounts of sul ted bile acids, which are poorly absorbed in the intestine, are detected in the feces (12). Another type of bile acid conjugate, which has been identified in the urine of healthy subjects and patients with hepatobiliary disease, is the glucuronide (A7, S41). Both the liver and extrahepatic tissues, such as the kidney and small intestinal mucosa, are capable of glucuronidation of bile acids in man (M14). 

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