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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.

Chronic alcoholics are all too often not recognized in general practice. Diagnosis is only possible if the doctor assumes potential alcoholism in all his patients. Because of the tendency of the patient and often his family to deny alcohol dependence, diagnosis is only possible by taking psychiatric, somatic and psychosocial aspects into consideration in addition to an independent history. Questionnaires may be helpful. The severity of the dependence on alcohol is not a predictor of success in therapy. In practice, three types of alcoholics may be distinguished: (1) patients with stable social relationships; (2) patients with stable social relationships and severe anxiety or depression with alcohol abuse as an inadequate self medication; (3) patients who are not able to maintain stable relationships. The latter are unlikely to be successfully treated by a family physician. A careful classification of patients according to these simple criteria may reduce the rate of treatment failures. Therapy by the family physician is initiated with an extensive somatic, psychiatric and psychosocial work-up, and maintained by counseling and care. An important factor is close collaboration between physician and social worker. Disulfiram may be a powerful adjunct to the therapy of the family physician if supervised by a trustee. In our departments we work with alcoholics in a joint consultation service involving an internist and a psychiatrist. Two thirds of the patients who consent to supervised disulfiram remain in the program for a year. 3 months after initiation of the treatment, gamma-glutamyltransferase, ASAT, ALAT and MCV are normalized. A follow-up 5 years after treatment indicated the efficacy of this treatment.

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)

A case of delayed biliary obstruction and cholangitis, occurring in the setting of chronic allograft rejection, 8 years after liver transplantation using the gallbladder-conduit, is presented. Extrahepatic biliary obstruction may be seen in the late follow-up of liver grafting and rejection phenomena may play a significant role in the development of such obstruction.

The treatment of patients suffering from alcoholism is notoriously difficult. Ambulatory supportive therapy using disulfiram and supervised by the practicing physician has many advantages. Foremost among these is the maintenance of the patient within his working and social environment. For achievement of longterm abstinence, psychological aspects (patients motivation and agreement, understanding care by the physician) may be more important than the aversive effects of disulfiram. Although disulfiram is generally a safe drug, careful preliminary work-up represents the key to proper assessment of risk versus benefit.

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)

Of 739 cholecystectomies carried out from 1971 to 1978, 40 cases revealed intraoperatively a hydrops of the gallbladder. This hydrops was caused in all cases by a stone located in the gallbladder neck or the cystic duct. In 37 cases, the gallbladder contents were examined: clear "white bile" was present in 29 (78%); this was always very viscous. With one exception, all biles were found to be sterile. The pressure in the gallbladder averaged 61.5 cm saline, ranging from 15 to 115 cm. The osmolality of bile was on the average 295 mosmol/kg, thus being roughly isotonic with blood. In three cases, where chemical analysis of the bile was perfomed, bilirubin-, bile salts, cholesterol-, phospholipids, and protein-content were reduced to non-measurable amounts or to concentrations below 1 mg%. It is suggested that the mucosal inflammation following the obstruction to bile flow leads to disturbances in reabsorptive processes, secretion of mucous and a subsequent increase in intraluminal pressure.

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.

The concentrations of bile acids in serum determined by a relatively simple enzymatic method ranged between 1.6 and 9.2 mumol/l in 60 normal volunteers and between 2.1 and 7.7. mumol/l in 14 patients with Gilbert's syndrome. In contrast, 48 patients with various liver diseases had - with 2 exceptions - markedly elevated serum bile acids (up to 140 mumol/l). Together with BSP retention, BSP disappearance and SGOT, the bile acid level in serum represented one of the most sensitive indices for detection of liver disease. The sensitivity of this test can be further increased by bile acid determination 2 h after a meal. Since this test is both simple and harmless its broader clinical use appears attractive.

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.

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.

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.

The quantification of liver function is possible using the approach of salivary caffeine clearance. Hepatopathy sometimes complicates cystic fibrosis (CF), thus suggesting the use of this diagnostic tool in CF as well. Since in CF some compounds are poorly absorbed or abnormally metabolized, and the function of salivary glands or renal tubuli partly impaired, caffeine was measured in urine, blood, and saliva after a single oral dose of 3 mg/kg in CF patients. The urinary excretion rate of caffeine was normal in five CF patients. The caffeine levels in plasma or saliva, measured 4 to 5 h and 16 to 17 h after caffeine intake, were normal in 34 nonhepatopatic CF patients. The calculated salivary caffeine clearance was comparable in the 34 nonhepatopatic CF patients (1.88 +/- 0.46 ml/min/kg) and in the control group (1.88 +/- 0.44 ml/min/kg). In CF patients, no correlation was found between caffeine clearance and body weight, height, relative underweight, dosage of pancreatic enzymes, or Chrispin-Norman x-ray score. The salivary caffeine clearance was reduced in seven hepatopathic CF patients (1.32 +/- 0.63 ml/min/kg, p less than 0.01); nevertheless, the salivary caffeine clearance was reduced (boundary line at 1.1 ml/min/kg) in three CF patients with proven liver cirrhosis but not in four with hepatosplenomegaly and altered liver tests. These data indicate an unaltered caffeine metabolism in CF and open the way for the use of this diagnostic procedure in CF as well. This test might be valuable in CF patients with clinical or laboratory findings suggesting liver involvement.

Microsomal demethylation, a partial function of the liver, can be estimated by the aminopyrine breath test. Both the determination of specific activity and the disappearance rate constant for 14CO2 in breath demand the assumption of rapid formaldehyde oxidation to CO2. Conversely, the disappearance of aminopyrine from plasma reflects microsomal aminopyrine metabolism only. Ethanol is known to affect both microsomal demethylation and formaldehyde metabolism. If in the presence of ethanol the latter process should become rate-limiting, a discrepancy between the data obtained in breath and in plasma could be expected. In order to investigate this possibility 10 fasting healthy male volunteers received 9 mg/kg (dimethylamine-14C)-aminopyrine (2 muCi) orally and, 3 hs later, 0.7 g/kg ethanol. Immediately following ethanol the specific activity of 14CO2 in breath decreased by 25% (p less than 0.005) and the disappearance of 14CO2 from breath was 31% lower than in 17 matched controls (p less than 0.005). The aminopyrine plasma disappearance rate, determined by GLC, decreased by 30% after ethanol (p less than 0.05). Since the decrease in aminopyrine plasma disappearance rate seems to account for the proportional decreases obtained by breath analysis, it is concluded that the aminopyrine breath test expresses the rate of microsomal demethylation even during altered formaldehyde metabolism, e.g. in acute ethanol intoxication.

The metabolic activity of the hepatic cytochrome P450 system was studied in 53 ambulatory subjects. 18 of these were cirrhotics and 23 had non-cirrhotic liver disease, documented by biopsy, serologic, ultrasound or computerized tomography findings, and characterized by quantitative liver function tests, such as galactose elimination capacity and indocyanine green fractional clearance. For comparison, 12 normal control subjects were also included. All subjects were given 10 mg/kg body weight antipyrine and saliva concentrations determined with an HPLC-method at 24 and 48 hours after dosing. Antipyrine saliva clearance (ASC) was calculated according to a two-point method (Cl1), and compared with a one-point method (Cl2) using the 24 h sample only. These subjects also underwent an aminopyrine breath test (ABT), breath samples being collected at regular intervals during 60 minutes following injection of a tracer dose of 1.5 muCi (14C-dimethylamino)antipyrine. Cl1 and Cl2 correlated strongly (r = 0.93). On the basis of smaller variations (particularly in control subjects), better definition of disease severity and convenience and time saving, Cl2 is to be preferred. Comparison of Cl2 with ABT showed that both procedures apparently quantify overlapping enzymatic activities. However, the relationship between Cl2 and ABT values, albeit highly significant (r = 0.72), suggests that only about half of the variables are subject to the same determinant. In addition, a positive intercept of the regression line extrapolated to the Cl2 axis points to quantitatively important extrahepatic breakdown of antipyrine. The results suggest that, in view of the wide variation in normal values (presumably in part influenced by exogenous pollutants), ASC only provides an approximation of hepatic metabolic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

The paper describes a modification of the galactose breath test (GBT) for assessing liver function. Following iv injection of 0.5 g galactose per kg body weight, together with 2 mu Ci generally 14C-labelled galactose, 14CO2 is collected in regular intervals during one hour. Since 14C-activity in breath exhibits a linear rise during 70--100 minutes, the curve obtained permits calculation of an initial slope, as well as the "standardized specific activity" after 45 min GBT was performed in 8 liver normals, 8 alcoholic cirrhotics, 4 patients with chronic active hepatitis (CAH) and 6 with primary biliary cirrhosis (PBC). The results were compared with the simultaneously measured galactose elimination capacity (GEC) and the initial plasma disappearance (ki) of bromsulphthalein (BSP). In the liver normals, the values for initial slope and standardized specific activity were 1.08 +/- S.D. 0.3 and 0.42 +/- S.D. 0.1, respectively. In comparison, the values obtained in all patients groups were markedly reduced. CAH patients exhibited the most severe decrease; the reduction was smallest in PBC patients. The GBT discriminated well between liver normals and patients with liver disease (p less than 0.001, t-test). The results of the GBT correlated linearly with GEC (r = 0.86 and 0.87, respectively) and with BSP-ki (r = 0.9 and 0.92, respectively). These results suggest that the GBT may be regarded as a quantitative measure of a cystosolic hepatic function.

Using quasi-elastic light scattering ( QLS ), we have characterized the macromolecular components in hepatic bile obtained from the dog and compared these results with data from model bile solutions containing the bile salt (BS) sodium taurocholate (TC), egg lecithin (L), and cholesterol (Ch). Native bile samples were obtained by direct catheterization of the common bile duct in a previously cholecystectomized dog fitted with a Thomas duodenal cannula. Hepatic bile was sampled during three secretory states: (A) unstimulated "fasting" bile, (B) "stimulated" secretion during an intravenous TC infusion, and (C) "secretin-stimulated" secretion. All three samples had comparable molar ratios of L/BS (0.21 +/- 0.03) and Ch/L (0.027 +/- 0.006) but differed in the total lipid concentration (BS + L + Ch): (A) 13.1 +/- 0.8, (B) 6.7 +/- 0.8, and (C) 3.0 +/- 0.4 g/dL. From the QLS autocorrelation functions measured on samples B and C, three macromolecular components (denoted 1 alpha, 1 beta, and 2) were resolved. Component 1 alpha (hydrodynamic radius R1 alpha = 10 +/- 2 A) is comparable in size to the micellar aggregates of model systems. Component 1 beta (R1 beta = 67 +/- 7 A) appears to reflect an average of biliary proteins. Component 2 (R2 = 650 +/- 15 A) is a trace component whose size and sedimentation behavior are compatible with those of the canalicular membrane vesicles postulated to be present in bile [ Godfrey , P. P., Warner, M. J., & Coleman , R. (1981) Biochem. J. 196, 11]. Serial dilution of the B and C bile samples with Tris buffer (0.15 M NaCl, pH 8.0) showed a remarkable similarity in the behavior of the 1 alpha component as compared to the mean hydrodynamic radius Rh of similarly diluted model bile solutions. When a critical dilution factor, d gamma, is reached, Rh increases abruptly from approximately 30 to approximately 400 A. Above a second dilution factor, d alpha, it then decreases to a value of approximately 150 A. Similar results were obtained on sample A but were shifted to higher dilutions. Such behavior is consistent with the presence of "mixed disk" micelles [ Mazer , N. A., Benedek , G. B., & Carey, M. C. (1980) Biochemistry 19, 601] in native bile which undergo a micelle-to-vesicle transition upon dilution. From the d gamma and d alpha values, estimates of the intermicellar bile salt concentrations were made for all three samples (range 1.4-6.2 mM) which agree well with previous experimental results on model and native bile. These studies offer compelling evidence for the existence of micellar aggregates in native bile whose size, structure, and equilibria are similar to those found in model bile solutions.

Bile acids are increasingly used as test substances for the estimation of liver function and it has been postulated that radioactive labeled bile acids have advantages over indocyanine green (ICG) for measurement of hepatic blood flow. Therefore, the hepatic extractions of 14C-taurocholate and ICG were compared in 23 patients with liver disease and correlated with various parameters of hepatic function. The hepatic extractions of 14C-taurocholate (mean: 42 +/- SD 17%) and ICG (mean: 35 +/- SD 18%) were similar. The correlations with galactose elimination capacity and BSP plasma disappearance were closer for ICG than for 14C-taurocholate extraction. Hepatic blood flow measured with 14C-taurocholate (mean: 1.45 +/- SD 0.51 l/min) correlated well (r = 0.81) with the respective values obtained with ICG (mean: 1.17 +/- SD 0.49 l/min), but was about 22% larger. This study does not provide evidence that 14C-taurocholate is superior to ICG as an intravenous test substance for measurement of hepatic function or blood flow.

The effects of liver disease on caffeine plasma clearance (Cl) and on exhalation of 14CO2 following i.v. injection of 2 mu Ci of [3-methyl-14C]caffeine together with 125 mg of the unlabeled compound were measured in 15 patients with cirrhosis, 11 subjects with miscellaneous liver disease, and 10 normal volunteers. Compared to mean values for Cl (2.02 +/- S.D. 0.68 ml per min per kg) and t1/2 (3.8 +/- 0.9 hr) in normal volunteers, cirrhotics were characterized by highly significant reductions in Cl (to 0.76 +/- 0.40) and prolongation in t1/2 (to 13.7 +/- 13.0), whereas the volume of distribution (VD) remained relatively unchanged (0.57 +/- 0.16 vs. 0.64 +/- 0.13 liter per kg in normals). Cumulative 14CO2 production and specific activity of 14CO2 in breath decreased in parallel (r = 0.83) with Cl. Patients with miscellaneous liver disease exhibited only small changes in Cl and t1/2; however, 14CO2 parameters in breath appeared more sensitive in indicating the slight functional derangement. In view of the correlation (Rs = 0.83) of cumulative 14CO2 excretion with the initial disappearance constant for bromosulfophthalein, the caffeine breath test may be considered as a quantitative measure of hepatic microsomal activity; based on a surprisingly close, hyperbolic relationship between Cl and fasting caffeine plasma concentrations, the latter might serve as a simple guide to severity of liver disease.

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.

The consequences of a portacaval shunt on liver function were studied in male Sprague-Dawley rats. Fourteen days after an end-to-side portacaval anastomosis the galactose elimination capacity and the plasma clearance of indocyanine green were reduced in proportion to the approximately 50% loss in liver mass. The biliary transport maximum for sulfobromophthalein, on the other hand, decreased by almost 70% from 153 to 52 nmoles per min per min per 100 g after portacaval anastomosis. This reduction of sulfobromophthalein excretion was accompained by a significant decrease in the hepatic conjugation of the dye to glutathione. Our findings demonstrate that a quantitative and qualitative functional deterioration of previously normal livers results from portal blood deprivation.

Inherited deficiency in mephenytoin hydroxylation was observed in a family study. It is important that the propositus was of the extensive metabolizer phenotype for the genetically controlled hydroxylation of debrisoquine. Thus, a genetic polymorphism of drug hydroxylation was suspected for mephenytoin. A population study of mephenytoin hydroxylation, combined with identification of extensive and poor debrisoquine hydroxylation phenotypes, was carried out in 221 unrelated normal volunteers. Twelve of them (5%) exhibited defective aromatic hydroxylation of mephenytoin, and 23 (10%) could be identified as poor metabolizers of debrisoquine. Amongst these 35 subjects with a drug hydroxylation deficiency, 3 (or 0.5%; 1 female, 2 males) displayed both defects simultaneously. A panel study of 10 extensive and 10 poor metabolizers of mephenytoin showed that the ability to perform aromatic hydroxylation of the demethylated mephenytoin metabolite nirvanol (5-phenyl-5-ethylhydantoin) was co-inherited with the mephenytoin hydroxylation polymorphism. Family studies suggested that poor metabolizer phenotypes of nirvanol and mephenytoin were most likely to have the homozygous genotype for an autosomal recessive allele of deficient aromatic drug hydroxylation. Intra-subject comparison of the debrisoquine and mephenytoin hydroxylation phenotypes in these subjects indicated that deficiency in the two drug hydroxylations occurred independently. Consequently, the co-inheritance of extensive and poor hydroxylation of mephenytoin and nirvanol, respectively, represents a new drug hydroxylation polymorphism in man.

The biologic effects of sulfation of tauro-3 beta-hydroxy-5-cholenoate and of taurolithocholate were compared. Equimolar amounts (100 nmol/min X 100 g body wt) of the following were administered intravenously to male Sprague-Dawley rats over a 180-min period: taurolithocholate, [14C]taurolithocholate-3-sulfate, tauro-3 beta-hydroxy-5-cholenoate, [14C]tauro-3 beta-hydroxy-5-cholenoate-3-sulfate, its combination with taurocholate, and a saline-albumin solution (control). Sulfation of taurolithocholate and of tauro-3 beta-hydroxy-5-cholenoate only prevented the cholestatic effect of the former. Bile flow during infusion of [14C]tauro-3 beta-hydroxy-5-cholenoate-3-sulfate was reduced by 80% at the end of the experiment. A dose-dependent bile flow reduction was demonstrated. Recovery of the administered bile acid was 3% in urine, 13% in serum, 23% in the liver tissue, and 52% in bile, respectively. Excretion of biliary cholesterol and phospholipids was significantly reduced during the first hour of infusion. Coadministration of taurocholate abolished the cholestatic effect and enhanced the renal excretion of the sulfated bile salt. These data suggest that (a) the cholestatic effect of tauro-3 beta-hydroxy-5-cholenoate-3-sulfate is comparable with or may even exceed the effect of taurolithocholate and (b) although sulfation renders some bile salts more water soluble, it does not prevent the cholestatic effect of all monohydroxy bile salts.

Thirty patients with jaundice and serum bilirubins above 4 mg.% were examined by slow infusion cholangiography (40 ml. (20 g.) Ioglycamid in 500 ml. 0.9% NaC1 in ten hours). Diagnostic results were achieved in 38%; in 15 patients with extra-hepatic obstruction, the success rate was 13%, whereas in disease of the liver parenchyma, the success rate was 60%.

13 ambulatory alcoholics (3 women, 10 men) who consented to alcohol-aversive treatment with disulfiram were subjected to detailed investigations before, during, and after the disulfiram-alcohol reaction (DAR). The studies included quantitative estimation of liver function (aminopyrine breath test, ABT; galactose elimination capacity, GEC) prior to the DAR, measurement of alcohol and acetaldehyde plasma levels together with pulse rate and blood pressure during the DAR, and the effects of disulfiram on erythrocyte acetaldehyde-oxidizing capacity (AOC). As expected, the severity of the DAR showed considerable interindividual variation. However, the maximal fall in diastolic blood pressure was closely (r = 0.83; p less than 0.001; n = 13) related to peak acetaldehyde plasma level (AAPL). The decrease in systolic blood pressure was age dependent, individuals greater than 40 years exhibiting a larger drop for a given AAPL. The dependence of acetaldehyde formation on liver function was suggested by a significant correlation (r = 0.88; p less than 0.01; n = 8) between ABT and AAPL; this relationship was influenced by the prior intake of enzyme-inducing drugs. Measurements of AOC indicated that a disulfiram-induced maximal suppression is achieved already after 6 days of treatment reaching levels of 0.7 +/- 0.6 nmol/ml/min (SD) (compared to pretreatment values of 4.1 +/- 0.9). Mean values in untreated alcoholics and in subjects with alcoholic or nonalcoholic liver disease were not significantly different from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The feasibility of measuring caffeine clearance from saliva (SCl) was assessed in ambulatory patients with liver disease and in a control group, and the results were compared with quantitative liver function tests. For this purpose, the subjects were given 280 mg caffeine p.o. in decaffeinated coffee powder between noon and 4 p.m., and caffeine concentrations were measured in saliva (using an enzyme immunoassay) before bedtime and upon arising. In the cirrhotics (n = 29), SCl was 0.58 +/- S.D. 0.45 ml per min X kg, thus being reduced to approximately one-third of drug-free, nonsmoking controls (1.53 +/- 0.46, n = 18); although patients with noncirrhotic liver disease showed intermediate values (0.95 +/- 0.47), their reduction in SCl was significant (p less than 0.001). SCl was correlated with indocyanine green fractional clearance, galactose elimination capacity and aminopyrine breath test; however, the closest relationship (Rs = 0.80) was observed with the aminopyrine breath test. It is suggested that the measurement of SCl represents a noninvasive and innocuous procedure for quantifying hepatic microsomal function, and is suitable for routine use. Since a.m. saliva concentrations of caffeine are highly correlated (Rs = -0.94) with SCl, further simplification of the test to a single-point measurement appears possible.

The clinical symptoms and signs, certain metabolic aspects (including ethanol, acetaldehyde and glucose concentrations in plasma) and hemodynamic parameters (cardiac rate, blood pressure and cardiac output) were assessed in 16 ambulatory alcoholics (3 female, 13 male, average age 46 years) following pretreatment with disulfiram (total dose 1.2 to 2.4 g) and oral administration of 0.2 g ethanol 94% per kg body weight. Since the only selection criterion for inclusion was a diagnosis of alcohol dependence (DSM III, 303.9), the group was heterogeneous and exhibited a variety of concomitant diseases such as alcoholic liver disease in 9, chronic bronchitis in 5 and arterial hypertension in 3. Whereas peak plasma alcohol concentrations were comparable (median: 0.33 mg/ml; range: 0.19 to 0.40) in all subjects, peak acetaldehyde levels varied over 40-fold (median 5.1 micrograms/ml; range: 0.2 to 8.8). In consequence, there were marked interindividual differences in cardiovascular reaction, in contrast to the virtually constant finding of flush, palpitations and dyspnoea. Since the decrease in peripheral vascular resistance (to a median of 46% of control) was only in part compensated by increased cardiac output (median: 161%), both systolic and diastolic blood pressures were reduced by 30 and 45 mm Hg respectively. In 4 patients systolic pressure fell to shock levels (less than 70 mm Hg). The presumed toxic effect of acetaldehyde is again supported by close correlations between acetaldehyde plasma concentrations and the changes in blood pressures and peripheral resistances. We were able to demonstrate that disulfiram-induced inhibition of hepatic microsomal function - measured with the aminopyrine breath test - predicts the expected acetaldehyde peak levels following ethanol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

During the period 1967 to 1971 an increase in the incidence of pulmonary hypertension of vascular origin (PHVO) was observed in Austria, Federal Republic of Germany, and Switzerland. Most patients had been given aminorex fumarate and a possible link was suspected. We therefore investigated the possibility of genetically-determined drug hydroxylation deficiencies (debrisoquine or mephenytoin type) in these patients as an explanation for the development of PHVO. Seventeen patients took 10 mg debrisoquine and 100 mg mephenytoin orally. Sixteen PHVO patients were classified as extensive metabolizers of debrisoquine with logarithmic metabolic ratios of -0.35 +/- 0.11 (mean +/- SEM), whereas one patient was a poor metabolizer with a logarithmic metabolic ratio of 1.82. For the mephenytoin hydroxylation sixteen patients with PHVO were extensive metabolizers, with logarithmic hydroxylation indices of 0.27 +/- 0.05. One poor metabolizer of mephenytoin had a logarithmic hydroxylation index of 1.59. Deficient hydroxylation of debrisoquine and mephenytoin was found in two different patients. The prevalence of poor metabolizers among patients with PHVO after aminorex fumarate was therefore approximately 9% for both debrisoquine and mephenytoin. This corresponds closely to the data of our reference population study where genetic debrisoquine and mephenytoin hydroxylation deficiencies occurred independently, with a prevalence of 10% and 5% respectively. Thus, the normal prevalence of extensive drug hydroxylation phenotypes in patients with PHVO is not consistent with the hypothesis that the development of PHVO after aminorex fumarate might be related to a pharmacogenetically determined impairment of polymorphic drug oxidation.

Following the occurrence of 3 cases of icteric hepatitis in the period August 1980 to January 1981 in a closed male ward for mentally retarded patients in a psychiatric institution, the present study was undertaken to determine the type, investigate the source and reconstruct the sequence of viral infection, and to make recommendations for its containment. For this purpose, serologic markers for HAV and HBV (including anti HBcIgM) were determined and serum transaminase (AST) measured in March 1981 in all 24 patients (mean age 40) and in the 39 members of the medical, nursing and housekeeping staff (mean age 39). Subsequently, HAV and HBV serologies were repeated after 6 and 9 months respectively. The propositus (B.F.) and the two subsequent cases with overt hepatitis (F.P. and K.E.) showed the serologic constellation of positive HBs, HBe and anti HBcIgM, together with elevated AST levels (600, 800 and 200 I.U. respectively) at the time of clinical illness, consistent with an acute HBV infection. Since 7 (18%) among the staff members were immune to HBV (positive anti HBs and anti HBc) and the remainder sero-negative; the remaining 6, however, showed evidence of active viral replication (S. P. and K. E.), viral infection (F. P. and J. L.) or incomplete immune response (B.F. and G.H.). During the 9 months' follow-up their serologic status did not change, with the exception of 2 (F.P. and B.F.), in whom HBs disappeared. The incidence of anti HAV in patients was 42% and in the staff 44%.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of ethanol on the fate of orally administered drugs which normally undergo a high presystemic elimination is as yet ill-defined. Experiments, therefore, were designed in four nonanesthetized dogs with mephenytoin as model compound. The drug was administered p.o. or i.v., and throughout an 8-hr period ethanol (100 mg kg-1 hr-1) or saline was infused according to a cross-over design. Concentrations of mephenytoin and its main metabolites, nirvanol and p-hydroxymephenytoin, were determined by gas-liquid chromatography. In experiments with oral mephenytoin administration and ethanol infusion, mephenytoin peak plasma concentrations were elevated by 87.0 +/- 15.2% (S.E.M.) (P less than .005, n = 4). Correspondingly, the average area under the plasma concentration time curve was increased to 229% of control (P less than .005). Ethanol also reduced metabolite formation; the area under the plasma concentration time curve for nirvanol was reduced by 40% (P less than .005). Urinary output of nirvanol was diminished to 51% and of p-hydroxymephenytoin to 73% (P less than .05, n = 12). It is concluded that drug ethanol interactions may be particularly prominent for orally administered drugs which normally are subject to a high presystemic elimination. This mechanism might be a clinically relevant cause for ethanol related drug toxicity.

The hydroxylation phenotype was determined in a sample of the Swiss population consisting of 222 normal unrelated subjects (131 women, 91 men). Following oral administration of a single dose of 19 mg debrisoquine, urine was collected for 8 hours. Urinary concentrations of parent compound and its major metabolite (4-hydroxydebrisoquine) were measured with GLC and their molar ratio ("metabolic ratio", MR) was calculated and plotted as a frequency distribution histogram. The frequency distribution of the MR was clearly bimodal, exhibiting two clusters of MR's of 0.1 to 1.0 and 20 to 100, respectively. Using probit analysis, the antimode was found at an MR of 12.6 Consequently, 22 subjects (16 women, 6 men), representing 10% of the population studied, were, with an MR of greater than 12.6, considered to be poor hydroxylators (PM). The families of two subjects, established as PMs in the population study, were also investigated. One family was found to be the first known pairing of homozygous PM parents with all 6 offspring exhibiting the PM phenotype. In both families the pattern was consistent with an autosomal recessive mode of inheritance for the two alleles E (extensive) and N (none) respectively. Clinical consequences of the PM phenotype known to date are summarized. Since some drugs typically used for longterm treatment (such as perhexiline, phenytoin, nortriptyline, guanoxan) are subject to the same hydroxylation pathway, PM patients are likely to be at higher risk of drug toxicity. This relationship has been well documented for perhexiline-induced neuropathy. Conversely, it is conceivable that with the use of prodrugs which have to be hydroxylated to the active compound, PM subjects might turn out to be "non-responders".

A new enzyme immunoassay (EMIT) for the measurement of levels of caffeine in plasma was adapted to an automated centrifugal analyzer (Cobas Bio) and compared with a high-performance liquid chromatographic (HPLC) method. Precision of the EMIT test was similar to that of the HPLC method with intraassay coefficients of variation in the range of 2.0-4.1% (EMIT) and 1.5-3.3% (HPLC), respectively, depending on the concentration range tested. Day-to-day precision ranged from 2.7 to 5.6% for EMIT and was 3% for HPLC. Comparison of 69 patient samples assayed with both methods yielded the following equation: y = 1.06x + 1.25 mumol/L, r = 0.994 (X = HPLC, y = EMIT). Evaluation of the cross-reactivity of the three main human caffeine metabolites revealed no significant interference from theobromine and theophylline; however, there was significant interference (28%) by paraxanthine at a concentration range from 2.5 to 80 mumol/L. At low caffeine concentrations, up to 10 mumol/L, the level of this metabolite may be more than twice the corresponding caffeine concentration; therefore, the latter may be falsely elevated in the EMIT test. Despite this cross-reactivity, the new EMIT test proved to be suitable for use in a drug assay laboratory, as well as in the routine screening of outpatients for liver disease.

The need to use xenobiotics to quantify liver function is based on the fact that the serum levels of endogenous tracers (such as transaminases, alkaline phosphatase, bilirubin and bile acids) cannot be interpreted in pharmacokinetic terms, since information is lacking on volume of distribution and on rate of synthesis and of disposition. Methods are now available which allow practically non-invasive estimation of (minimal) hepatic perfusion by indocyanine green fractional clearance, of portosystemic shunt flow by finger pulse photometry following nitroglycerin administration, of microsomal capacity by the aminopyrine breath test (ABT) or caffeine clearance, and of cytosolic function by galactose elimination capacity (GEC). Assessment of inherited hydroxylation deficiency of the debrisoquine type is best performed with dextromethorphan, and of the acetylator phenotype with sulfadimidine. Recently, caffeine clearance in saliva has been studied extensively in this laboratory, and, on the basis of a constant relationship between caffeine concentrations in serum and saliva, overnight clearance measurements (requiring a saliva sample at bedtime and upon arising following a single oral dose of caffeine) have been shown to be closely related to ABT or GEC. This approach, which has been successfully used in children, may represent the first simple and innocuous test for quantifying of hepatic function in the pediatric age group. The clinical utility of these clearance tests is to assess severity of disease (or genetically determined impairment of function), thus yielding important clues to prognosis.