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[1-Methyl-C], [3-Methyl-C] and [7-Methyl-C] caffeine were used to investigate demethylation in control rats, and in rats pretreated with phenobarbital or 3-methylcholanthrene, by aCO-exhalation test. Compared to controls, pretreatment with phenobarbital did not enhance demethylation of any of the labelled caffeines. In contrast, induction by 3-methylcholanthrene, presumably of cytochrome P-448, resulted in highly significant increases in peakCO exhalation rates,CO disappearance constants and areas under the exhalation rate - time curves. Based on these results, [7-methyl-C] and [3-methyl-C] caffeine were chosen for assessing the feasibility of a caffeine breath test in man, using 5 normal volunteers and 2 patients with compensated liver cirrhosis.CO exhalation curves in cirrhotics were clearly different from those in normal volunteers, being characterised by a slower rise and a lower specific activity of exhaledCO. Since the variability of the levels of the specific activity in subjects with normal livers suggested the influence of extraneous factors, a second group of normal volunteers, smokers and nonsmokers, was investigated. With either labels, the averageCO exhalation rate was doubled in smokers. From these studies in rats and preliminary results in man it is concluded that specifically labelled caffeine is a suitable and promising substrate for studying demethylation by breath analysis. Presumably, caffeine represents a safe and sensitive indicator of the activity of the cytochrome P-448 system. [ABSTRACT FROM AUTHOR]

A provocation test with nicotinic acid (50 mg intravenously) was performed in 13 patients with Gilbert's syndrome and seven healthy volunteers to investigate the diagnostic value of several test parameters and to correlate them with the bilirubin clearance. The maximal increment of unconjugated serum bilirubin, the retention at four hours, and the area under the bilirubin concentration time curve. (AUC) were measured. Significant differences between patients and controls were found with regard to the AUC (7.95 +/- SD, 3.29 mmol/min/l vs. 3.08 +/- 0.57; P less than 0.001), the increment of unconjugated bilirubin (24.1 +/- 7.1 mumol/l vs. 10.2 +/- 3.2; P less than 0.001) and the retention (77.7 +/- 8.9% vs. 45.8 +/- 27.4%; P less than 0.02). Of those, the AUC discriminated best between patients and controls. Five patients with Gilbert's syndrome had normal serum bilirubin concentrations (less than 17.1 mumol/l = 1 mg%) at the time of the study, but abnormal AUC and bilirubin increment. A significant correlation was found between the bilirubin clearance and the retention (r = -0.96; P less than 0.001) as well as the AUC (r = -0.82; P less than 0.05) but not with the bilirubin increment. This simple test may be used to assess the disturbance of bilirubin clearance in Gilbert's syndrome. [ABSTRACT FROM PUBLISHER]

Excretion of the major urinary bile alcohol 27-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24,25- pentol, and of cholic, chenodeoxycholic, deoxycholic and lithocholic acid was measured in 24 h urine collections of 10 extensive and seven poor metabolizers of debrisoquine. There was no significant difference of the excretion of these cholesterol metabolites between the two groups, indicating that cholesterol hydroxylation to bile alcohols and bile acids is probably not controlled by the same genes responsible for the 'debrisoquine- type' hydroxylation polymorphism. [ABSTRACT FROM AUTHOR]

Despite standardization, marked interindividual variation in the severity of the disulfiram-alcohol reaction (DAR) has been observed. We studied the DAR in 51 consecutive alcoholics with (n = 16) and without (n = 35) significant alcoholic liver disease. Clinical signs of the DAR were much weaker in the patients with compared with those patients without liver disease. Because acetaldehyde is thought to be the main cause of the DAR, we studied ethanol and acetaldehyde kinetics in 13 patients (6 females, 7 males) with alcoholic liver disease (documented by biopsy, clinical and/or radiological findings, and by quantitative liver function) [galactose elimination capacity (GEC) 4.2 +/- SD 1.0 mg/min/kg; aminopyrine breath test (ABT) 0.14 +/- 0.10% dose x kg/mmol CO2] and 13 age- and sex-matched controls (alcoholics without significant liver disease, GEC 7.1 +/- 0.7; ABT 0.81 +/- 0.35). Clinical signs of acetaldehyde toxicity during the DAR (flush, nausea, tachycardia, and blood pressure drop) were absent in alcoholic liver disease, but clearly evident in controls. Blood ethanol kinetics were similar in both groups, Cmax and area under the concentration-time curve (AUC) being 6.27 +/- 1.82 and 368.9 +/- 72.9 mmol x min/liter in alcoholic liver disease, and 6.62 +/- 1.71 and 377.6 +/- 124.5 in controls, respectively. In contrast, there was a strong (p < 0.001) difference in Cmax and AUC of acetaldehyde, respective values being 33.46 +/- 21.52 and 1463.8 +/- 762.5 mumol x min/liter in alcoholic liver disease, and 110.87 +/- 56.00 and 4162.0 +/- 2424.6 in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Twenty-five large broad-breasted white turkeys were fed a 22% protein diet supplemented with 500 ppm furazolidone from day 1 to 3.5 weeks of age and the same diet supplemented with 700 ppm furazolidone until 9.5 weeks of age. Following the development of round heart disease as indicated by altered electrocardiograms the 25 turkeys were sacrificed. In the livers of turkeys with biventricular dilatation (72% of cases) there was bile duct hyperlasia, portal fibrosis and intracytoplasmic globules in the hepatocytes. Globules stained pink with hematoxylin-eosin, deep red with PAS and variable with Massons trichrome stains in paraffin-embedded liver sections. Clear intracytoplasmic vacuoles demonstrable in hepatocytes of PAS stained liver sections embedded in paraffin did not stain as lipid in frozen sections but did contain sparse flocculent material in 1 micrometer sections of liver embedded in epoxy resin and stained with toluidine blue. At the subcellular level, the intracytoplasmic globules in hepatocytes were surrounded by a single membrane, contained flocculent material and had enzymatic properties characteristic of lysosomes. Blood pressure, heart rate, dp/dt max, total plasma proteins and plasma trypsin inhibitory capacity of turkeys with round heart disease were lower than corresponding values for control turkeys. Control turkeys did not exhibit the characteristic gross or microscopic lesions of round heart disease.

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.

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.