Faculty Bibliography

Serum bile acid patterns were determined in 31 infants ranging in age from 4 days to 24 weeks. Fifteen infants with extrahepatic biliary atresia had a mean concentration of serum bile acids of 90 microng/ml +/- 47 SD;; 16 infants with neonatal hepatitis had a mean concentration of 60 +/- 35.5 SD. The chenodeoxycholate/cholate ratio was greater than one in 13 infants (87%) with atresia and in 10 infants (66%) with neonatal hepatitis. Except for the tendency of a higher total concentration of serum bile acids in infants with atresia, a single serum bile acid value does not differentiate neonatal hepatitis from extrahepatic biliary atresia. The high proportion of chenodeoxycholate in extrahepatic atresia is different from the pattern in other types of cholestatic disease and may reflect an underlying hepatitis

7 alpha-Hydroxycholesterol, (22R)-22-hydroxycholesterol and 26-hydroxycholesterol have been quantitated in human meconium. The method used tetrahydrofuran for extraction and solvolysis of the sulfate esters, liquid partition chromatography for the separation of the hydroxysterols, gas-liquid chromatography for quantitation, gas-liquid chromatography-mass spectrometry for identification, and tritiated and 14C-labeled tracers for overall recovery standards. (22R)-22-Hydroxycholesterol and 26-hydroxycholesterol were present almost entirely, ( greater than 93%) in the sulfate fraction at concentrations of 3.8-6.4 and 0.4-0.8 mg per 100 g meconium, respectively. Since free tritiated (22R)-22-hydroxycholesterol was used as the tracer to assess recovery of this hydroxysterol, the concentrations found for this compound may be minimal. Tritiated 26-hydroxycholesterol 3,26-disulfate was used as tracer to determine the levels of this compound, and the solvolysis procedure was optimized for recovery of 26-hydroxycholesterol and least decomposition of 7 alpha-hydroxycholesterol. No significant amounts of 7 alpha-hydroxycholesterol were found based on the tracer-free hydroxysterol as recovery standard

Cholestasis or choleresis was induced in the rat by intravenous infusion (0.05 to 0.2 mumole per minute per 100 grams of body weight) of sodium taurolithocholate, 3beta-hydroxy-5-cholenoate, taurocholate, and dehydrocholate either singly or in combination after or without cannulation of the common bile duct. Bile flow was monitored and ultrastructural changes were examined by scanning and transmission electron microscopy up to 3 hours after bile salt administration. Taurolithocholate induced acute cholestasis and ultrastructural alterations consisting primarily of dilation of bile canaliculi, loss of canalicular microvilli, and lamellar transformation of the canalicular membrane. Occasionally, crystalline precipitates were present within the canalicular lumen and in the pericanalicular region of hepatocytes. 3beta-Hydroxy-5-cholenoate caused similar but less severe ultrastructural changes than those induced by taurolithocholate. Dehydrocholate had a greater choleretic effect than taurocholate, but neither induced noteworthy ultrastructural change. When infused simultaneously with taurolithocholate, taurocholate reversed cholestasis and largely prevented development of the ultrastructural changes induced by taurolithocholate. In contrast, simultaneous infusion of dehydrocholate prevented neither cholestasis nor development of the ultrastructural changes induced by taurolithocholate, which were more striking than those caused by taurolithocholate or 3beta-hydroxy-5-cholenoate alone. In addition, structural changes associated with cholestasis induced by these bile salts either singly or in combination were more pronounced and frequent in the periportal zone than elsewhere in the hepatic lobule. These results suggest that both taurolithocholate and 3beta-hydroxy-5-cholenoate induce cholestasis by affecting the structural and functional integrity of the bile canalicular membrane and also, in part, by forming untransportable precipitates. The contrasting effects of taurocholate and dehydrocholate on taurolithocholate-induced changes suggest that taurocholate overcomes the effect of taurolithocholate by solubilizing it into mixed micelles, but dehydrocholate and its metabolites have little or no such effect. The intralobular variation in severity of ultrastructural changes probably reflects the accumulation of bile salts in greater concentrations in hepatocytes near the portal triads

With the development of simplified methods of bile acid analysis, a new era has drawned in the evaluation of hepatobiliary disease. 1. A total serum bile acid particularly in the postprandial periods is more sensitive than either BSP or ICG for the detection of minimal liver disease and will become a useful screening method. 2. The ratio of chenodeoxycholate to cholate in serum together with the total concentration can often distinguish hepatitis and cirrhosis from intrahepatic and extrahepatic cholestasis with normal liver cell parenchyma. However, in practice this is usually of less value than the total serum bile acid level. 3. Changes in serum bile acids throughout a 24 hour cycle reflect the enterohepatic circulation of bile acids and the capacity of the liver to transport them. These patterns are most useful in judging the severity of cholestasis and response to resin therapy. They also provide new insights into the pathophysiology of bile acid metabolism and excretion in different diseases of the liver

Since 1974, 16 consecutive infants with biliary atresia have been treated by hepatic portoenterostomy employing an exteriorized Roux-en-Y intestinal segment (Miluliez). Simultaneous, sequential analyses of bile pigments and lipids in serum and biliary drainage were performed. In the 11 patients with sustained bile drainage, progressive increases in bile volume, bilirubin and biliary lipid concentrations correlated well with their subsequent return toward normal in the serum. Despite relief of biliary obstruction, four patients have had progressive liver cirrhosis. The other 7 have residual liver damage which has been stable, or in two instances, improved, at late biopsy. The clinical and biochemical results suggest that both obstructive and parenchymal factors are operative in infants with biliary atresia