Biliary lipid composition and bile acid profiles during and after enteral fast of total parenteral nutrition in the rabbit.

Feeding and fasting influence biliary lipid composition. With total parenteral nutrition (TPN), it is possible to study the effects of a long-term "enteral fast" on biliary lipid composition without the metabolic ill-effects of nutrient deprivation. We compared the lipid and bile acid (BA) contents of hepatic and gallbladder biles in rabbits on completion of a 14-day regimen of TPN with those in rabbits returned to oral feeds for 6 weeks after a similar spell of TPN. Chow-fed rabbits served as controls. With TPN, plasma phospholipid and cholesterol levels were elevated. Basal bile flow and the secretion of bile acids and phospholipids were decreased in the TPN and post-TPN groups, while the cholesterol secretion rate was essentially unchanged. During TPN, the molar percent of cholesterol (relative to bile acids and phospholipid) in hepatic bile was increased. Biliary glycolithocholic acid (GLCA; as a percent of total conjugated BA) in hepatic bile increased from 1.7% (0.9% SEM) in the chow-fed to 8.5% (1.5% SEM) during TPN. In TPN and post-TPN groups, the gallbladder was enlarged to more than twice normal (chow-fed) size, and contained a dark, mucoid bile (biliary sludge). In this bile, (a) there was a 2.5-fold increase in bile acid concentration; and (b) the molar percent of cholesterol decreased while that of bile acids increased. TPN produced a state of functional cholestasis, which extended into the post-TPN period. Gallbladder distension was the common denominator of the hepatobiliary dysfunction in the TPN and post-TPN rabbits. With sequestration of bile acids in the gallbladder during and after TPN, the circulating bile acid pool was constricted, and the enterohepatic circulation impaired. As cholesterol secretion was low at all times, cholesterol supersaturation did not occur. The molar percent of cholesterol in gallbladder bile decreased, while that of bile acids increased; this suggests absorption of cholesterol by gallbladder mucosa. The increase in biliary GLCA probably resulted from bacterial biotransformation of glycochenodeoxycholic acid to lithocholic acid and its increased absorption from the cecum during TPN.

Biliary lithocholate and cholestasis during and after total parenteral nutrition: an experimental study.

To evaluate the role of lithocholic acid (LCA) in the etiology of parenteral nutrition-associated cholestasis (PN-AC), we studied (i) the changes in the percentage of biliary LCA and (ii) the emergence and resolution of cholestatic changes in the liver after total parenteral nutrition (TPN) and after 6 weeks of oral feeding following the TPN. We compared these changes in rabbits on TPN support (via a central vein) for 14 days (TPN, n = 8) with those after 6 weeks of refeeding (Post-TPN, n = 8). Age-matched rabbits on lab chow served as controls (CHOW, n = 8). At the end of the diet regimens, the common bile duct was cannulated under anesthesia, and hepatic bile collected for measurements of bile flow and bile acid (BA) secretion rates, and BA profiles. The 60-min biliary excretion of sulfobromophthalein (BSP) after an intravenous bolus (5 mg/kg) was determined. A liver biopsy was taken for light microscopy. After 14 days of TPN, bile flow was reduced by 60%, bile acid secretion by 52%, and BSP excretion by 38%. On refeeding, only the BSP excretory rate recovered fully. In the TPN group, histology of the liver showed hepatocellular degeneration and portal tract inflammation; these resolved after refeeding leaving a mild portal fibrosis in 4/8 rabbits. Total colonic stasis occurred during TPN. With TPN, a decrease in the percentage of biliary glycochenodeoxycholate and an increase in LCA% were seen, whereas after refeeding the increase was in the percentage of glycoursodeoxycholate. An LCA% > or = 6 was associated with liver cell damage. After 6 weeks of refeeding, the structural cholestasis disappeared, but the decreases in basal bile flow and bile acid secretion (functional cholestasis) persisted. These data associate an increase in biliary LCA with the emergence of cholestasis during TPN in rabbits.

Early hepatobiliary dysfunction during total parenteral nutrition: an experimental study.

The etiology and pathophysiology of the liver disease associated with total parenteral nutrition (TPN) are unknown. In this study, we have attempted to define the early changes in hepatobiliary function during TPN in young rabbits nourished totally by the intravenous route for 3, 5, and 15 days, with age-matched rabbits on lab chow serving as controls. A decrease in basal bile flow along with elevations of serum bile acids and cholesterol was seen. The capacity for biliary secretion of sulfobromophthalein and of ursodeoxycholic acid was measured at the end of each diet regimen. Early impairment of biliary sulfobromophthalein (BSP) secretion was seen after 5 days of TPN, with no further deterioration after 15 days. Maximal bile acid secretory rate and bile flow, in response to the ursodeoxycholic acid load, were decreased after 15 days of TPN. Furthermore, after 15 days of TPN, both the volume of gallbladder bile and its bile acid content increased. The combined effects of the enteral fast and the intravenous administration of all nutrients were bile acid sequestration in an adynamic gallbladder with interruption of the enterohepatic circulation. In the parenterally fed rabbit, we have demonstrated bile secretory failure and gallbladder sludge, the two common complications of clinical TPN. These may be the early events that subsequently lead to cholestasis and liver damage in neonates maintained on prolonged TPN.

Hepatic organic anion transport kinetics and bile flow during short-term total parenteral nutrition in the rabbit.

Plasma disappearance of sulfobromophthalein (BSP) after an intravenous bolus (5 mg/kg) was determined in six lab chow-fed (LCF) rabbits and in six rabbits maintained on total parenteral nutrition (TPN) for 5 days. A common bile duct cannula enabled measurements of bile flow and biliary BSP excretion. Compartmental analysis of the biexponential plasma disappearance curve yielded three fractional transfer rates, plasma to liver (hepatic uptake), liver to plasma (reflux), and liver to bile (canalicular excretion). The transfer rates for hepatic uptake were 0.253 +/- 0.061/min for LCF and 0.147 +/- 0.040/min for TPN (P less than 0.01) and for the canalicular excretion of BSP were 0.038 +/- 0.019/min for LCF and 0.019 +/- 0.002/min for TPN (P less than 0.05). Model-computed rates for BSP excretion in bile over 60 min were lower with TPN (61%) than with LCF (80%); the measured excretory rates were 53% for TPN rabbits and 75% of injected dose for LCF animals. Basal biliary flow was reduced by 50% in the TPN group. With a two-compartmental model, assuming two pools and three transfer rates, we have demonstrated for the first time significant decreases in hepatic uptake and canalicular excretion of the organic anion BSP during TPN. A decrease in hepatic blood flow due to the enteral fast of TPN could have contributed in part to the decreased hepatic uptake. But, because the second exponent of the biexponential curve is independent of hepatic blood flow, the decrease in liver to bile transfer rate is a true approximation of a diminished canalicular excretory capacity during TPN. It is concluded that the movement of organic anions along the hepatic BSP/bilirubin transport system is impaired early during TPN.