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To assess the effects of experimental liver injury on caffeine metabolism, 1 muCi/kg b.w. of [3-methyl 14C]-caffeine (together with 5 mg/kg b.w. of the cold compound) was injected i.p. to four different experimental groups and respective controls of unanesthetized male Sprague-Dawley rats. Exhaled 14CO2 was completely collected during 4 h and peak exhalation rate and fraction of dose recovered were calculated. 1/3 hepatectomy affected 14CO2 exhalation to a limited extent, decreasing solely peak exhalation rate (p < 0.05 compared to sham-operated controls). 2/3 hepatectomy, on the other hand, resulted in significant reduction (p < 0.01) in both peak exhalation rate (by 59%) and fraction of dose recovered (by 47%), that were proportionate to the loss of liver mass (59%). End-to-side portocaval shunt led to the well-documented hepatic "atrophy", liver weight being diminished on average to 50% within 2 weeks of surgery; however, reductions in peak exhalation rate (by 75%) and fraction of dose recovered (by 64%) were even more pronounced. Finally, 48 h bile duct ligation was equivalent to "functional 2/3 hepatectomy", peak exhalation rate (by 65%) and fraction of dose recovered (by 56%) being markedly diminished despite increased liver weight. These results indicate that 14CO2 exhalation curves following administration of specifically labelled caffeine are quantitative indicators of acute or chronic loss of functioning liver mass. In addition, the 3-demethylation pathway appears to be particularly sensitive to the inhibitory effects of cholestasis on microsomal function.

We have previously shown that the functioning hepatocyte mass (galactose elimination capacity, GEC) and microsomal liver functions (non-renal clearances of unbound prednisolone and cyclosporin A) are impaired in renal allograft recipients (N = 28) one month and one year after successful transplantation. To assess the natural history of these hepatic functional derangements, we reinvestigated 21 patients with stable renal function three to five years following grafting. GEC remained with 6.07 +/- 0.86 mg/min x kg significantly (P less than 0.001) below that in healthy controls (7.52 +/- 0.78 mg/min x kg), but did not significantly change during follow-up (5.93 +/- 0.96 and 6.26 +/- 0.94 mg/min x kg at 1 year and 1 month, respectively). In contrast, the non-renal clearance of unbound prednisolone declined steadily during follow-up averaging 4.98 +/- 0.71 ml/min x kg at three to five (compared to 5.83 +/- 1.51 and 6.80 +/- 1.73 ml/min x kg at one year and one month, respectively). These values were lower (P less than 0.01) than those observed in healthy control subjects (7.56 +/- 1.59 ml/min x kg). The total body clearance of cyclosporin A decreased similarly with time averaging 4.5 +/- 1.2 ml/min x kg at three to five years (compared to 4.9 +/- 1.2 and 5.9 +/- 2.1 ml/min x kg at 1 year and 1 month, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

To establish the potential value of quantitative tests of liver function following orthotopic liver transplantation (OLT), a total of 100 determinations of caffeine clearance (CafCl) and galactose elimination capacity (GEC) were made in ten OLT recipients early in the post-operative course (days 2, 4, 6, 8 and 12) and later when clinically stable (3-12 months). Values were compared with a reference range in six normal volunteers in whom it was shown that the standard doses of caffeine (125 mg) and galactose (0.5 g per kg body weight) could be given together without interference. In orthotopic liver transplantation recipients initial GEC and CafCl measurements showed no correlation with peri-operative blood loss, donor ischaemia time, initial bile flow or survival. Throughout the early post-operative period, there were wide inter- and intra-individual variations in both CafCl (17-fold range from 0.16 to 2.7 ml.min-1.kg-1) and GEC (2.4-fold range from 5.1 to 12 mg.min-1.kg-1), but the only correlation of test values with standard liver function tests results was between GEC and gamma-glutamyltranspeptidase. However, GEC values fell by 19% during periods of acute rejection and there was an inverse correlation of GEC with white cell count probably related to sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to improve the clinical usefulness of the plasma disappearance curve of sulfobromophthalein (BSP), its components were analyzed in 26 control subjects, in 28 patients with cirrhosis, and in 13 cases of miscellaneous liver abnormalities. The uncorrected initial disappearance rate (ki) was found to discriminate best between the control and the patient groups. The second exponential component (k2) was linearly correlated with the transport maximum (Tm) on a double logarithmic plot, but appeared to be independent of the estimated hepatic plasma flow (EHPF). An interpretation of this relationship was possible, when based on a model having saturation kinetics for biliary excretion. The first exponential component (ki) appeared primarily determined by hepatic perfusion. These relationships may contribute to a better understanding and more rational use of dye excretion tests as measures of hepatic function. The data also add to our knowledge about the nature of the excretory defect in cirrhosis.

The bile alcohol glucuronides in urine of 12 patients with primary biliary cirrhosis (PBC), 10 patients with chronic active hepatitis (CAH), and 6 healthy volunteers were analyzed by capillary gas-liquid chromatography-mass spectrometry. In all subjects studied, the major urinary bile alcohol was found to be 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol (C26 pentol). In PBC patients, the excretion of C26 pentol (main isomer) was significantly increased above values observed in healthy volunteers (mean +/- SD = 5.2 +/- 3.5 mumol/24 h, range 1.0-13.4; versus 0.6 +/- 0.3, range 0.4-1.0). In addition, PBC patients excreted increased amounts of other bile alcohols such as isomers of C26 pentol, pentahydroxylated C27 bile alcohols (5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol) and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol) and a hexahydroxylated C26 bile alcohol (27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25,26-hexol). In CAH patients, the excretion of the C26 pentol main isomer ranged from 0.3 to 2.0 mumol/24 h (mean +/- SD = 0.7 +/- 0.5) and did not significantly differ from that in healthy volunteers. Moreover, the bile alcohol profile was comparable to those found in healthy volunteers and PBC patients. These findings show that total urinary bile alcohol glucuronide excretion is significantly increased in primary biliary cirrhosis. A PBC-specific urinary bile alcohol profile, however, does not exist.