Increased Susceptibility to Liver Disease in Relation to Alcohol Consumption in Women

Sex-related differences were prospectively studied in patients with the first presentation of alcoholic liver disease. Among 42 patients the diagnosis was cirrhosis in 8 women and 15 men, alcoholic hepatitis in 4 women and 1 man, steatosis in 6 women and 6 men, and no histologic changes were found in the liver biopsy specimens from 2 men (p > 0.1). The median (range) antipyrine clearance was 14.6 (1.0–64) versus 17.2 (3.0–83) ml/min and the clinical score in accordance with the Pugh modification of the Child-Turcotte classification was 8 (5–13) versus 8 (5–11) in the women and men, respectively (p > 0.05). In 5 women and only 1 man the antipyrine clearance was less than 5 ml/min, indicating an almost total loss of functional liver mass (p < 0.05), whereas the Pugh score was above 11 in 6 women, but not in any of the men (p < 0.05). On an average, the men estimated their total lifetime consumption of alcohol to be 2.1 times greater and the number of days they had consumed more than 5 drinks 2.9 times higher than the women (p < 0.05). These ratios are reduced to 1.4 and 1.7, respectively (p > 0.05), if the female alcohol intake is adjusted to the average male volume of distribution. The results support the concept that women may develop similar, and sometimes even more severe, liver disease after consumption of less alcohol than men. The apparent difference in susceptibility to alcohol may be partly explained by differences in volume of distribution.     

Hemodynamic and liver function predictors of serum hyaluronan in alcoholic liver disease.

To define hepatic predictors of serum hyaluronan in patients with chronic liver disease, 62 patients with alcoholic liver disease were evaluated. In group 1, 30 patients had concurrent assessment of serum hyaluronan, liver function tests, Pugh grade and hemodynamic indices. A second, overlapping group of 42 patients (group 2) also had antipyrine clearance measured but without hemodynamic assessment. All but six patients had elevated serum hyaluronan levels. In both groups, serum hyaluronan levels differed between Pugh grades and, in each group, was significantly greater in Pugh grade C compared with those in Pugh grade A (p less than 0.05, Kruskal-Wallis test). When analyzed by correlation, serum hyaluronan was significantly associated with several indices in group 1, but on multivariate linear regression only three statistically independent predictors of serum hyaluronan were identified: serum albumin (p = 0.008), indocyanine green clearance (p = 0.024) and indocyanine green extraction (p = 0.036). The overall R2 for these correlates was 65%. In the second group, antipyrine clearance was not significantly associated with serum hyaluronan (r = 0.29, p = 0.06), but other associations were similar to the first group. On multivariate analysis, only serum albumin predicted serum hyaluronan (p less than 0.001; R2 = 43%). In conclusion, indices of hepatocyte synthetic function, sinusoidal blood flow and degree of intrahepatic shunting are independent predictors of serum hyaluronan in alcoholic liver disease. These data show the unique nature of serum hyaluronan and suggest its potential application to the assessment of acute hemodynamic changes in patients with liver disease.     

Antipyrine elimination as a dynamic test of hepatic functional integrity in obstructive jaundice.

Antipyrine elimination was studied in 29 patients with obstructive jaundice Antipyrine half-lives calculated using plasma concentrations at four and 24 hours ('short antipyrine test') were significantly correlated with those calculated using six time points (p less than 0.001). Mean antipyrine half-life was 28.3 +/- 8 hours (standard error) and was significantly longer than in normal subjects (p less than 0.001). Antipyrine half-life did not correlate with standard biochemical liver function tests, but correlated positively with the postoperative half-time for clearance of endogenous bilirubin (p less than 0.05), and negatively with hepatic cytochrome P-450 content measured in peroperative liver biopsies (p less than 0.05). Of six patients with antipyrine half-life greater than 20 hours, four died, one preoperatively of gastrointestinal haemorrhage and three postoperatively of sepsis. Serial short antipyrine tests were performed in 13 patients before and after biliary drainage. Those with an initial antipyrine half-life greater than 15 hours showed significant changes after drainage, while those with an antipyrine half-life less than 15 hours did not. The test of antipyrine half-life may aid in selecting high risk patients with obstructive jaundice for percutaneous biliary drainage before definitive surgery, and in determining the optimal time for such preliminary biliary decompression.     

Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis.

Midazolam kinetics and psychomotor function were studied after an intravenous dose of 0.075 mg/kg body weight in seven patients with alcoholic cirrhosis and eight control patients. Four of the seven cirrhotics died of complications of their liver disease within six months of the study. The metabolism of midazolam was significantly impaired in the cirrhotic patients (p less than 0.025). These patients also had evidence of greater sedation than the control group for up to six hours after the dose was administered (p less than 0.05). The clearance of midazolam did not correlate significantly with the serum albumin, or bilirubin, or with the kinetics of antipyrine, or indocyanine green. This study shows significant delay in the elimination of midazolam and decreased psychomotor function in patients with severe alcoholic liver disease. Caution is needed in using this drug for premedication in such patients before endoscopy.     

Hepatic metabolic function in patients receiving long-term methotrexate therapy: comparison with topically treated psoriatics, patient controls and cirrhotics

Standard biochemical liver function tests and the clearances of antipyrine and indocyanine green have been compared in psoriatic patients taking methotrexate, psoriatic patients on topical treatment, patient controls and patients with hepatic cirrhosis. The methotrexate-treated patients showed significant elevations in alkaline phosphatase (p less than 0.025) and gamma glutamyl transpeptidase activities (p less than 0.05) compared to topically treated psoriatics and patient controls. The clearance of antipyrine was reduced in the methotrexate treated group but not significantly (p less than 0.1 greater than 0.05). In contradistinction, the weight-adjusted clearance of indocyanine green was significantly impaired in the methotrexate group in comparison with the topically treated psoriatics (p less than 0.01). The clearance of both antipyrine and indocyanine green were markedly lowered in the cirrhotics (p less than 0.001 against all other groups). These data suggest that the serial measurement of alkaline phosphatase and indocyanine green clearance may provide a non-invasive indicator of the development and progression of methotrexate-related liver injury.     

Renal sodium retention in cirrhosis: tubular site and relation to hepatic dysfunction

Renal sodium handling, assessed by the response to acute saline loading, was investigated in 14 well-compensated, nonascitic alcoholic cirrhotics and six normal controls. Urinary sodium excretion in cirrhotic patients (199 +/- 141 mumoles per min) was significantly lower than in controls (387 +/- 104 mumoles per min; p less than 0.01) at 3 hr postinfusion. In contrast to controls, renal plasma flow and glomerular filtration rate did not increase in the cirrhotics in response to acute saline loading. Proximal fractional reabsorption of sodium was estimated by clearance techniques in the presence of a hypotonic diuresis. Cirrhotic subjects with impaired functional liver cell mass as assessed by antipyrine clearance were unable to decrease proximal fractional reabsorption of sodium significantly in response to saline loading. Assessment in the cirrhotics included measurement of hepatic vein pressure gradient, indocyanine green extraction ratio, indocyanine green clearance, and antipyrine clearance as indices of portal pressure, intrahepatic shunting, hepatic blood flow and functional hepatocellular mass, respectively. Urinary sodium excretion in the cirrhotics correlated strongly with antipyrine clearance (r = 0.839, p less than 0.0001) and weakly with portal pressure (r = 0.562, p = 0.037). No correlation was seen with the other indices of hepatic blood flow and shunting. The findings of this study suggest that alcoholic cirrhosis is associated with a decline in hepatocellular function which results in either a decreased clearance of a salt-retaining hormone or decreased synthesis of a natriuretic hormone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of smoking on caffeine elimination in healthy volunteers and in patients with alcoholic liver cirrhosis

The effect of smoking on caffeine elimination was measured in 7 healthy volunteers and in 18 smoking and in 30 nonsmoking patients with alcoholic liver cirrhosis following oral application of 366 mg caffeine. In an intraindividual experiment in smoking health probands, caffeine clearance decreased from 118 +/- 33 to 77 +/- 22 ml per min (p less than 0.05) after abstaining cigarette smoking for 3 weeks. In a control group without liver disease (8 smokers, 15 nonsmokers), we found a caffeine clearance of 114 +/- 40 ml per min in smokers and 64 +/- 20 in nonsmokers (p less than 0.05). Smoking and nonsmoking patients with alcoholic liver cirrhosis did not differ with respect to clinical and laboratory data and hexobarbitone elimination. However, caffeine clearance was 63 +/- 63 ml per min in smoking patients compared to 34 +/- 49 ml per min in nonsmokers (p less than 0.05). Fasting plasma concentrations of caffeine were higher in nonsmokers (5.1 +/- 6.2 micrograms per ml) than in smokers (2.1 +/- 4.5 micrograms per ml, p less than 0.05). We conclude that smoking habits have to be taken into account if caffeine is used as a model compound for measuring quantitative liver function.     

Menopausal age and sex hormones in postmenopausal women with alcoholic and non-alcoholic liver disease.

In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were significantly (p less than 0.05) younger at the time of natural menopause than controls. Compared to controls, non-cirrhotic alcoholic women had significantly (p less than 0.05) reduced levels of DHAS, significantly (p less than 0.05) more alcoholic cirrhotic women had detectable oestradiol concentrations, elevated concentrations of oestrone and sex hormone binding globulin (SHBG) and reduced levels of 5 alpha-dihydrotestosterone (DHT), while women with non-alcoholic cirrhosis had significantly elevated concentrations of SHBG and reduced levels of oestrone sulphate, DHT, androstenedione and dehydroepiandrosterone sulphate (DHAS) (p less than 0.05). The observed changes may be a consequence of liver disease since similar changes were observed in patients with alcoholic and non-alcoholic liver disease, but an additional effect of alcohol cannot be excluded.     

The relationship of insulin sensitivity and metabolic clearance of insulin to adiposity and sex hormone binding globulin

Previous studies have shown that sex hormone binding globulin (SHBG) is negatively associated with insulin concentrations in premenopausal women. We determined insulin sensitivity (SI) and clearance (KI) in 8 non-obese men and 13 nonobese premenopausal women using the minimal model of Bergman and colleagues. Insulin clearance and insulin sensitivity were strongly correlated (p less than 0.05). SHBG was positively correlated with SI (i.e., individuals with high levels of SHBG had greater insulin sensitivity) in both men (r = .738, p less than 0.05) and women (r = .577, p less than 0.06). Insulin clearance was also positively correlated with SHBG in men (r = .619) and in women (r = .476) (0.05 less than p less than 0.10). Since obese subjects have both lower SHBG concentrations and decreased insulin sensitivity, we examined the effect of correcting for adiposity by partial correlation analyses. SHBG was not associated with KI after adjustment for BMI. SHBG was still positively correlated with SI in both men (r = .708) (p less than 0.06) and women (r = 0.541) (p less than 0.06), suggesting that the relationship between SHBG and insulin sensitivity is not confounded by obesity. Thus, the relationship of androgenicity with insulin sensitivity (but not insulin clearance) was independent of adiposity.     

Activities of ethanol-metabolizing enzymes in liver diseases

The activities of hepatic alcohol (ADH), aldehyde (ALDH), and lactate dehydrogenases were measured in 69 patients with various liver diseases (15 controls, 20 with alcoholic and 8 with non-alcoholic fatty liver, 13 with alcoholic cirrhosis, 2 with alcoholic hepatitis, 3 with cryptogenic and 3 with primary biliary cirrhosis, and 5 with acute or chronic hepatitis). The specific activities of all these enzymes were decreased in both alcoholic and non-alcoholic liver diseases. The activities of ADH and low-Km ALDH were significantly decreased both in alcoholic (ADH, 7.22 mU/mg protein, p less than 0.001; low-Km ALDH, 5.00 mU/mg protein, p less than 0.001) and in other liver diseases (ADH, 10.70 mU/mg protein, p less than 0.001; low-Km ALDH, 6.80 mU/mg protein, p less than 0.005) when compared with controls (ADH, 20.87 mU/mg protein; low-Km ALDH, 14.41 mU/mg protein). The hepatic protein content was significantly (p less than 0.001) increased in alcoholic fatty degeneration but not in alcoholic cirrhosis or other liver diseases. The results suggest that in man alcohol- and acetaldehyde-metabolizing enzymes are not induced by chronic alcohol consumption. On the contrary, the hepatic activities of these enzymes appeared to be lower in alcoholic than in non-alcoholic liver diseases. Consequently, in addition to liver injury alcohol may also directly affect the synthesis or breakdown of alcohol-metabolizing enzymes.     

Comparison of the cardiotoxicity of ethanol in women versus men.

Subclinical left ventricular (LV) dysfunction is a common occurrence in alcoholic men but has been claimed to be absent or very rare in alcoholic women. M-mode echocardiography was performed to study LV size, mass and systolic function, and Doppler ultrasound to study LV filling in 14 chronic female alcoholics aged 24 to 48 years and in 2 age-matched control groups consisting of 17 healthy women and 22 alcoholic men. Compared with healthy women, female alcoholics had no differences in heart rate or blood pressure but a shorter LV end-diastolic diameter (mean +/- standard deviation, 46 +/- 4 vs 48 +/- 3 mm, p less than 0.05), lower fractional shortening (31 +/- 6 vs 34 +/- 3%, p less than 0.05), increased wall thickness to radius ratio (0.43 +/- 0.08 vs 0.37 +/- 0.05, p less than 0.05), reduced peak early diastolic transmitral velocity (45 +/- 11 vs 68 +/- 7 cm/s, p less than 0.001), reduced deceleration of the early diastolic velocity (-274 +/- 69 vs -572 +/- 107 cm/s2, p less than 0.001), and an increased atrial filling fraction (35 +/- 12 vs 27 +/- 5%, p less than 0.05). Although alcoholic men had a longer duration of heavy drinking than alcoholic women (median 19 vs 5 years, p less than 0.001), and a higher systolic blood pressure (140 +/- 17 vs 120 +/- 17 mm Hg, p less than 0.001), there were no statistically significant differences between the sexes either in LV diameters, wall thickness or mass normalized to body area, or in indexes of systolic or diastolic LV function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glycerol clearance in alcoholic liver disease.

Glycerol clearance was studied by a primed dose-constant infusion technique in 14 patients with alcoholic liver disease and six normal control subjects. Fasting blood glycerol concentrations were raised in the alcoholic subjects (0.09 +/- 0.01 vs 0.06 +/- 0.01 mumol/l, p less than 0.05) and glycerol clearance was impaired (24.5 +/- 1.9 vs 37.5 +/- 3.2 ml/kg/min, p less than 0.005). Endogenous production rate of glycerol and distribution space at steady state were similar in alcoholic and control subjects. The metabolic clearance rate of glycerol correlated negatively with basal glycerol concentrations. Thus tissue uptake of glycerol is impaired in liver disease. As glycerol is metabolised primarily in the liver by conversion to glucose, these data suggest a defect of gluconeogenesis in alcoholic liver disease.     

A comparison between antipyrine and aminopyrine blood clearances.

The purpose of this study was to investigate the relationship between two quantitative liver functions, that is, antipyrine blood clearance and aminopyrine blood clearance, in normal subjects and in patients with liver cirrhosis. The mean blood clearances of antipyrine and aminopyrine in cirrhotic patients (0.220 +/- 0.085 ml/min/kg and 1.13 +/- 0.56 ml/min/kg; n = 64) was 50% and 38% of that of normal subjects (0.440 +/- 0.110 ml/min/kg and 2.95 +/- 0.59 ml/min/kg; n = 11). While no significant correlation was demonstrated between these two values in normal subjects (n = 11, r = -0.107, p greater than 0.10), a strong positive correlation was observed between antipyrine and aminopyrine blood clearances in cirrhotic patients (n = 64, r = 0.846, p less than 0.001). These results suggest that both antipyrine and aminopyrine blood clearances may be valuable indicators for assessing the total hepatic functioning mass in cirrhotics.     

Total and renal sympathetic nervous system activity in alcoholic cirrhosis

Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.     

Women produce fewer but triglyceride-richer very low-density lipoproteins than men

CONTEXT: Very low-density lipoproteins (VLDL) are a major risk factor for cardiovascular disease. The concentrations of VLDL particles and VLDL-triglyceride (TG) in plasma are lower in women than men, but the mechanisms responsible for these differences are unclear. OBJECTIVE: The objective of the study was to investigate the effects of sex on VLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) metabolism. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We measured basal VLDL-TG and VLDL-apoB-100 kinetics by using stable isotope labeled tracers. SETTING/PARTICIPANTS: Twenty-six healthy, lean subjects (13 men, aged 29+/-5 yr; 13 women, aged 28+/-6 yr) were studied in the General Clinical Research Center at Washington University School of Medicine. RESULTS: VLDL-TG and VLDL-apoB-100 concentrations were less in women than men (P<0.05). The secretion rate of VLDL-TG was approximately 70% greater (P<0.05), whereas the secretion rate of VLDL-apoB-100 (i.e. VLDL particles) was approximately 20% less (P<0.05) in women than men. The molar ratio of VLDL-TG and VLDL-apoB-100 secretion rates was therefore more than double (P<0.05) in women than men. VLDL-TG plasma clearance rate was approximately 70% greater in women than men (P<0.05), whereas VLDL-apoB-100 plasma clearance rate was not different between sexes. However, VLDL-TG and VLDL-apoB-100 mean residence times in plasma were both shorter (by 45 and 25%, respectively; P<0.05) in women than men. CONCLUSIONS: Increased VLDL-TG plasma clearance is responsible for lower VLDL-TG concentration, whereas decreased VLDL-apoB-100 secretion rate, combined with shorter VLDL-apoB-100 residence time in plasma, is responsible for lower VLDL-apoB-100 concentration in women than men. The greater molar ratio of VLDL-TG and VLDL-apoB-100 secretion rates suggests that the liver in women secretes fewer but TG-richer VLDL particles than the liver in men.     

Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay

Plasma endotoxin concentration was measured in 85 patients with alcoholic liver disease (alcoholic cirrhosis (n = 64), alcoholic hepatitis without cirrhosis (n = 11), fatty liver (n = 10), and in patients with non-alcoholic cirrhosis (n = 15]. Endotoxin concentration was determined with an improved chromogenic substrate assay, using individual standard curves for each plasma sample. In patients with alcoholic cirrhosis the mean endotoxin concentration was significantly higher than in patients with non-alcoholic cirrhosis (p less than 0.05). In addition, distinctly higher endotoxin concentrations (greater than 20 pg/ml) were more frequently observed in patients with alcoholic cirrhosis than in non-alcoholic cirrhosis (34.4 vs. 14.3%, p less than 0.05). Mean endotoxin concentration was not significantly higher in cirrhotics with ascites or esophageal varices as compared with the subgroup without ascites or esophageal varices. The endotoxin concentration did not correlate with serum bilirubin, prothrombin concentration or serum enzyme activities. In patients with alcoholic liver disease, however, endotoxin concentration revealed a negative correlation (p less than 0.05) with the concentration of high density lipoprotein cholesterol. On admission endotoxin concentrations in alcoholics with fatty liver were similarly elevated as observed in alcoholic cirrhosis. In six out of 12 patients with fatty liver or alcoholic hepatitis, in whom a second sample of plasma was investigated after 6 to 8 days, endotoxemia was no longer detectable; in the remaining patients, the endotoxin concentration decreased markedly. The results indicate that, irrespective of the stage of liver disease, alcohol abuse favours the development of endotoxemia. They support the hypothesis that gut-derived endotoxins might play a role in the initiation and aggravation of alcohol-induced liver disease.     

Pulmonary function responses of older men and women to ozone exposure

The pulmonary function of 8 men and 8 women (51 to 76 years of age), all nonsmokers, was measured before and after 2-h exposures to filtered air (FA) and 0.45 ppm ozone (O3). The subjects alternated 20-min periods of rest and 20-min periods of cycle ergometer exercise at a workload predetermined to elicit a ventilatory minute ventilation (VE) of approximately 25 L/min (BTPS). Functional residual capacity (FRC) was determined pre- and post-exposure. Forced vital capacity (FVC) was determined before and after exposure, and 5 min after each exercise period. Ventilatory minute volume (VE) was measured during the last 2 min of each exercise period, and heart rate was monitored throughout each exposure. The pulmonary function data were evaluated as the percentage change from pre- to post-exposure to partially remove the effect of differences between men and women in absolute lung volume. There were no statistically significant (p greater than 0.05) differences between the responses of men and women to FA or O3 exposure. There were no significant (p greater than 0.05) changes in any variable consequent to FA exposure. Exposure to O3 induced significant (p less than 0.01) decrements in FVC, FEV1.0, and FEV3.0 at post-exposure compared to pre-exposure. Ozone exposure induced no significant (p greater than 0.05) effect on FEF25-75% or FEF75%. Men had a significantly (p less than 0.05) higher mean exercise VE than women (27.9 +/- 0.29 L vs. 25.4 +/- 0.8 L; mean +/- SD). Since the men and women had similar decrements in pulmonary function, even though the women inhaled less O3, the data suggest that women may be somewhat more responsive to O3 than men. We also compared the responses of our older subjects with those of young men and women that we studied with the same protocol, and with published results of other investigators who have studied young men and women. This comparison suggests that older individuals may be less responsive to O3 than young individuals.     

Gender differences in medium-chain dicarboxylic aciduria in alcoholic men and women.

PURPOSE: Women appear to be more vulnerable to developing alcoholic liver disease than men. In rats, we previously found that the response of certain pathways of fatty acid metabolism to alcohol feeding was less efficient in females than in males, resulting in striking accumulation of fatty acids in the liver of the female rats. We sought to determine whether similar differences occurred in humans. PATIENTS AND METHODS: Urinary excretion of medium chain (C6-C10) dicarboxylic acids (final products of fatty acid omega-oxidation) was determined in 40 recently drinking alcoholic subjects (24 men and 16 women) and 21 nonalcoholic subjects (12 men and nine women). Sebacic (C10), suberic (C8), and adipic (C6) acids were measured in urine by gas chromatography/mass spectrometry, and their excretion was expressed per mg of creatinine. RESULTS: In nonalcoholic subjects, there was no gender difference in dicarboxylic aciduria. By contrast, alcoholic men (but not alcoholic women) developed dicarboxylic hyperaciduria. Alcoholic men had a marked increase in adipic acid excretion and in the adipic/sebacic (C6/C10) ratio (an index of peroxisomal beta-oxidation), whereas the values in alcoholic women did not differ from those in nonalcoholic women. CONCLUSIONS: The lack of response in alcoholic women could contribute to an aggravation of liver injury by promoting deleterious accumulation of fatty acids.     

Escherichia coli antibodies in alcoholic liver disease. Correlation to alcohol consumption, alcoholic hepatitis, and serum IgA

In 41 patients with alcoholic liver disease, antibodies to 12 common Escherichia coli O antigens (expressed as number of O antibody reactions with an agglutination titre of greater than or equal to 40) and to immunoglobulins IgG, IgA, and IgM were studied for 8 weeks. In 18 patients (8 with cirrhosis, 10 with fatty liver) who continued drinking during this period no significant changes were found. In 23 patients (11 with cirrhosis, 12 with fatty liver) who stopped or reduced drinking, a significant decrease in the levels of E. coli O antibodies and IgA was found (p less than 0.05 and p less than 0.01, respectively). In these 41 patients and in an additional 43 patients with alcoholic liver disease the amount of E. coli O antibodies was compared with type of histological lesion. The levels of E. coli O antibodies were significantly higher in cirrhosis with alcoholic hepatitis (22 cases) than in cirrhosis without alcoholic hepatitis (17 cases) (p less than 0.05). In these 17 patients antibody levels were significantly higher than in 41 patients with fatty liver without alcoholic hepatitis (p less than 0.02). In all patients a significant correlation between the number of positive reactions to E. coli O antigens and serum IgA concentration was found (p less than 0.01). No microbes were cultured from the liver biopsies, and no E. coli O antigens were demonstrated in the liver tissue by immunohistochemistry. Our results support the hypothesis that the high levels of E. coli O antibodies in alcoholic liver diseases are due to failure of the liver to extract circulating antigens and gut-derived endotoxins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of benzodiazepine antagonist Ro 15-1788 in cirrhotic patients with moderate or severe liver dysfunction

Ro 15-1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15-1788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score less than 10, Group II) and eight patients with severe liver dysfunction (Pugh score greater than 10, Group III). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15-1788 over 5 min, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15-1788 had a high plasma clearance [16.3 +/- 2.6 ml per min per kg (mean +/- S.D.)], a short half-life (45.7 +/- 8.5 min), a large volume of distribution (0.62 +/- 0.09 liter per kg) and a low plasma protein binding (45 +/- 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (-57 and -74%, respectively); the volume of distribution was unchanged in Group II and moderately increased in Group III (+37%). The elimination half-life was markedly prolonged in Groups II and III (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p less than 0.001). The plasma protein binding of Ro 15-1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group II; +44% in Group III).(ABSTRACT TRUNCATED AT 250 WORDS)