Ciin. Biochem. 9, (3) 149-152 (1976)

Bile.Acid Metabolism and the Liver C. N. W I L L I A M S D e p a r t l a c a t of M e d i c i n e , D a l h o u s i e U n i v e r s i t y , H a l i f a x , N o v a S c o t i a B 3 H 4H7

PRIMARY BILE ACIDS

CLBIA 9, (3) 149-152 (1976)

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Williams, C. N. Department of Medicine, Dalho,sie Halifax, Nova Scotia, B3H ~H7.

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Primary bile acids are exclusively synthesized, and all bile acids are conjugated, in the liver. When hepatic function is altered by disease, not surprisingly the bile-acid metabolism reflects this change. 1. In chronic liver disorders the glycine:taurine ratio of serum and bile is reduced. 2. In cases of relapsing acute hepatitis and relapsing chronic active hepatitis the serum bile acids are increased, providing ~tn aid to early diagnosis. Their pattern often distinguishes chronic cholestatic conditions from Laennec's cirrhosis. 3. In chronic liver disease, the concentration of intraduodenal bile acids is reduced; when the reduction is severe, this probably accounts for coexistent steatorrhoea. 4. In Laennec's cirrhosis, both the synthesis and pool size of cholic acid are markedly depressed; in primary biliary cirrhosis, however, preliminary data indicate a decrease in the chenodeoxycholic acid component.

PRIMARY BILE ACIDS are made exclusively in the liver as oxidative degradation products of cholesterol. Conj u g a t i o n with glycine and taurine, in a normal ratio of 3:1, precedes secretior~ into bile. Bile acids a g g r e g a t e into micelles at the concentrations normally found in bile. They solubilise non-polar lipids and facilitate the absorption of d i e t a r y f a t in the upper small bowel, and then are mainly absorbed in the distal ileum by an active process and returned to the liver for recycling. Bacterial enzymes are necessary for conversion of p r i m a r y to secondary bile acid, by loss of the hydroxyl group at the 7 position (Fig. 1). Anaerobic bacteria, resident in the human colon, contain these dehydroxylating enzymes and also enzymes for deconjugation of bile acids (Fig. 2). Some unconjugated (free) bile acid is passively absorbed, but most is excreted in the stools. Consequently, a complex mixture of conjugated and unconjugated p r i m a r y and secondary bile acids r e t u r n s to the liver for reconjugation (accomplished in one passage) and secretion into bile. This constitutes the enteropatic circulation of bile acids. The normal total pool of bile acids is 2---4 g, of which more than 99% is confined to the enterohepatic circulation and circulates twice per average meal. Thus, up to 24 g bile acid is secreted daily into bile: because of efficient ileal absorption, only 0.5 g is lost in the stools, all of which is normally

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BILE ACID METABOLISM AND THE LIVER

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secondary free bile acid. The normal liver synthesises 0.5 g bile acid per day to make good this loss. When chronic parenchymal liver disease is present, changes occur in bile-acid metabolism"): the bile-acid pool is redistributed, a g r e a t e r percentage being sequestered to plasma, tissues, and, when present, ascitic fluid, with decreased amounts in the enterohepatic circulation; the bile-acid loss in the stools diminishes and u r i n a r y loss becomes significant. In cirrhosis of non-alcoholic type, the secretion of conj u g a t e d bile acids into bile may be so reduced t h a t the concentrations in the duodenal a s p i r a t e fall below ' the critical micellar concentration (2 raM), with r e s u l t a n t steatorrhoea. Impaired hepatocyte function results in inefficient conjugation of bile acids and thereby increased levels of unconjugated bile acids in the serum. In cirrhosis complicated by portal hypertension, this effect is a g g r a v a t e d by the porto-systemic

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WILLIAMS

s h u n t i n g o f blood c o n t a i n i n g a h i g h p e r c e n t a g e of free bile acid. T a u r i n e c o n j u g a t e s p r e d o m i n a t e in t h e blood and bile. There is d i u r n a l v a r i a t i o n in the c o n c e n t r a t i o n of t o t a l c o n j u g a t e d bile acids in bile-rich duodenal a s p i r a t e s in L a e n n e c ' s c i r r h o s i s and in o t h e r f o r m s of c h r o n i c liver disease, i n c l u d i n g prirrrary b i l i a r y c i r r h o s i s and the c i r r h o s i s a s s o c i a t e d w i t h a , - a n t i trypsin deficiency (unpublished observations*). In g e n e r a l , bile-acid a b n o r m a l i t i e s help to c h a r a c t e r i s e d i f f e r e n t t y p e s of liver d i s o r d e r : the r a t i o of t r i h y d r o x y bile acids (cholic acid and c o n j u g a t e s ) to d i h y d r o x y bile acids (chenodeoxycholic and deoxycholic acid and c o n j u g a t e s ) exceeds u n i t y in cholestatic liver diseases, w h e r e a s the r a t i o is < 1 in non-cholestatic forms. The r a i s e d c o n c e n t r a t i o n of t o t a l bile acids in the s e r u m m a y bo the most s e n s i t i v e index of rel a p s i n g acute v i r a l h e p a t i t i s , b e i n g r e p o r t e d to precede the i n c r e a s e in s e r u m a s p a r t a t e t r a n s a m i n a s e ( S G O T ) and the r e t u r n of j a u n d i c e "). S i m i l a r l y , a c o n t i n u i n g controlled s t u d y a t t h e Mayo Clinic (5) has shown t h h t i n c r e a s e in the t o t a l s e r u m bile acid s t u d y of p a t i e n t s w i t h L a e n n e c ' s c i r r h o s i s t h e t o t a l precedes r e l a p s e s of chronic active h e p a t i t i s . I n one c o n c e n t r a t i o n was a b o u t f i f t y - f o l d increased, w i t h ' r e v e r s a l of the g l y c i n e : t a u r i n e r a t i o ( T a b l e 1). Bile acids not n o r m a l l y p r e s e n t a r e f o u n d in t h e p l a s m a in some unusual f o r m s of chronic liver disease"'~J; f o r example, lithocholic acid and its c o n j u g a t e s a r e p r e s e n t in one of the r a r e f a m i l i a l cholestatic syndromes p r o g r e s s i n g to c i r r h o s i s ~6) (Table 2). L i t h o cholic acid is an active h a e m o l y s i n ; i t causes f e v e r and inflammatory change when injected subcutaneously in man, c i r r h o s i s when fed to r a b b i t s , and d u c t u l a r cell h y p e r p l a s i a , l e a d i n g to t h i c k e n e d bile ducts, when fed to v a r i o u s species of p r i m a t e s , rodents, and reptiles. I n j e c t i o n of a bolus into an isolated p e r f u s e d liver produces cholestasis in h a m s t e r s and d i s r u p t s m e m b r a n e s of t h e cells l i n i n g the bile canaliculi in rats. The e f f e c t s a s s o c i a t e d w i t h a b n o r m a l bile-acid m e t a b o l i s m in liver d i s e a s e include p r u r i t i s , s t e a t o r rhoea, h a e m o l y t i c a n a e m i a , a g g r a v a t i o n or i n i t i a t i o n of liver disease, and p o s s i b l y r e n a l f a i l u r e . T h e severi t y of p r u r i t i s c o r r e l a t e s w i t h t h e levels of bile acids e x t r a c t e d f r o m t h e s k i n (8) b u t not w i t h s e r u m levels. T h e bile acids p a r t i c u l a r l y r e s p o n s i b l e a p p e a r to be u n c o n j u g a t e d d i h y d r o x y bile acids. P r u r i t i s is a m a j o r p r e s e n t i n g s y m p t o m of p r i m a r y b i l i a r y c i r r h o s i s and f a m i l i a l cholestatic c i r r h o s i s ; s t e a t o r r h o e a occurs in a s s o c i a t i o n w i t h a l a r g e v a r i e t y of acute and chronic l i v e r d i s e a s e s (~) ( T a b l e 3), i n c l u d i n g h a e m o c h r o m a tosis and o~,-antitrypsin-associated c i r r h o s i s . The s t e a t o r r h o e a t h a t occurs in m a n y cases m a y r e l a t e to d i u r n a l c h a n g e s in the c o n c e n t r a t i o n of c o n j u g a t e d bile acids in t h e d u o d e n u m : c o n c e n t r a t i o n s a r e lowest in t h e evening, w h e n m a n y p e r s o n s have j u s t consumed t h e i r l a r g e s t meal. U n c o n j u g a t e d s e c o n d a r y bile acids can d i s r u p t m e m b r a n e s and m a y p l a y a role in t h e complex s i t u a *Presented at Workshop on Bile-acid Metabolism, Canadian Hepatic Foundation, J a n u a r y 1974.

TABLE 1 MEAN PLASMA BILE-ACID VALUES IN NORMAL SUBJECTS AND IN PATIENTS WITH LAENNEC'S CIRRHOSIS* Laerlnec's

Normal (n = 5) Glycocholate (nmoles/ml) . . . . . . . Taurocholate (nmoles/ml) . . . . . . Total bile acids (nmoles/ml) . . . . . Glycine :taurine ratio . . . . . . . . . . . . Unconjugated bile acids (%) . . . . . Trihydroxy :dihydroxy ratio . . . . . . Cholic acid (%) . . . . . . . . . . . . . . . .

0.58 0.16 2.81 1.25 16.4 1.20 26.9

cirrhosis (n -- 8) 38.1 78.9 237 0.79 19.2 1.68 45.4

*Unpublished observations (C.N. Williams and J. R. Senior). TABLE 2 PLASMA BILE ACIDS IN FAMILIAL CHOLESTATIC CIRRHOSIS6

Normal Patient (nmoles per ml) Glycolitnocholic. . . . . . . . Taurolithocholic . . . . . . . . Lithocholic . . . . . . . . . . . . . Total bile acids . . . . . . . . .

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Bile-acid metabolism and the liver.

Primary bile acids are exclusively synthesize, and all bile acids are conjugated, in the liver. When hepatic function is altered by disease, not surpr...
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