Pekka Pikkarainen

Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three‐year randomized trial

Ursodeoxycholic acid (UDCA) is a safe medical therapy for primary biliary cirrhosis (PBC), but its effect on liver histology remains uncertain. Budesonide is a glucocorticoid with high receptor activity and high first‐pass metabolism in liver. We evaluated the combination of budesonide and UDCA on liver histology and compared this with UDCA alone in a 3‐year prospective, randomized, open multicenter study. Patients with PBC (n = 77), at stages I to III, were randomized into 2 treatment arms, A (n = 41): budesonide 6 mg/d and UDCA 15 mg/kg/d and B (n = 36): UDCA 15mg/kg/d. Liver histology was assessed at the beginning and at the end of the study. Liver function tests and glucose and cortisol values were determined every 4 months. Paired liver biopsy specimens were available from 69 patients (A = 37 and B = 32). Stage improved 22% in group A but deteriorated 20% in group B (P = .009). Fibrosis decreased 25% in group A but increased 70% in group B (P = .0009). S‐PIIINP decreased significantly in group A. Inflammation decreased in both groups, 34% in group A (P = .02), but only 10% in group B (P = NS). Serum liver enzymes decreased significantly in both treatment arms. Bilirubin values rose in group B but stayed stable in group A (A/B P = .002). A mild systemic glucocorticoid effect from budesonide was evident after 2 years. In conclusion, budesonide combined with UDCA improved liver histology, whereas the effect of UDCA alone was mainly on laboratory values. Studies with longer follow‐up using a combination of budesonide and UDCA are warranted to confirm safety and effects. (HEPATOLOGY 2005.)

Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: A randomized placebo‐controlled trial

No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC‐like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo‐controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases γ‐glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (−337 ± 54 U/L, P < .05) compared with the UDCA/placebo group. The New Mayo Risk Score decreased markedly only in the UDCA/MTZ group (−0.50 ± 0.13, P < .01). The number of patients with improvement of stage (P < .05) and grade (P < .05) was higher in the combination group. ERCP findings showed no progression or improvement in 77% and 68% of patients on UDCA/MTZ and UDCA/placebo, respectively. In conclusion, combining MTZ with UDCA in PSC improved serum ALP levels and New Mayo Risk Score, but no statistically significant effect on disease progression as assessed via liver histology or ERCP was seen. Long‐term studies using a higher dose of UDCA combined with MTZ in larger patient populations are indicated. (HEPATOLOGY 2004;40:1379–1386.)

Elevated blood acetaldehyde in alcoholics with accelerated ethanol elimination

Alcoholics and controls given ethanol (1.2 g/kg body weight) were analyzed for blood and breath acetaldehyde using the more sensitive and reliable semicarbazide method. The acetaldehyde levels in controls were almost undetectable (less than 2 microM), but were found to be elevated (10--10 microM) in 6 of 8 alcoholics. Breath acetaldehyde and blood acetaldehyde co-fluctuated during the experiments. Fructose infusion transiently increased blood acetaldehyde, but only in 4 of the alcoholics. The apparent discrepancy between our finding and the simultaneously reported low acetaldehyde level in alcoholics (Eriksson and Peachy, this volume) may be explained by the different status of the alcoholics tested. Our alcoholics were tested on the day after hospital admission and eliminated ethanol 5% faster than controls. It is suggested that elevated blood acetaldehyde occurs regularly after interrupted drinking in heavy alcohol abusers with fast ethanol elimination, possibly combined with reduced liver aldehyde dehydrogenase activity, but that the phenomenon may rapidly disappear upon abstinence and hospital treatment, which reduces disturbances in hepatic functions and the ethanol elimination rate.

Differences between the sexes in voluntary alcohol consumption and liver adh-activity in inbred strains of mice.

Abstract During a self-selection period of four weeks, tests were made of the voluntary alcohol consumption of 21 males and 20 females of an inbred CBA mouse strain, and 23 males and 19 females of a C57BL-strain. The difference in alcohol consumption between the strains proved to be highly significant. There was also apparent a highly significant difference in the alcohol consumption of different sexes of the C57BL-strain, a strain which evidences a high spontaneous alcohol preference. Statistically significant differences in the total fluid consumption and in the body weight were also discernible between the strains and the sexes. Strain differences in voluntary alcohol consumption explained 69.4 per cent of the total variance of the males, and 94.2 per cent of that of the females; this indicates that the genetic strain differences are more pronounced in females. The sex differences explained 53.3 per cent of the variance of the C57BL-strain, and 0 per cent of the variance of CBA. The liver ADH-activity was determined in respect of 20 subjects, representing equal numbers of strains and sexes. The difference in ADH-activity was in the same direction as voluntary alcohol consumption, although less in extent.

Ethanol-induced hypoglycaemia in man: its suppression by the alcohol dehydrogenase inhibitor 4-methylpyrazole.

Abstract. Infusion of ethanol (0.6 g/kg body wt) caused marked hypoglycaemia in subjects fasted for 36 h. Previous administration of the alcohol dehydrogenase (ADH) inhibitor 4‐methylpyrazole (4‐MP, 7 mg/kg body wt i.v.) strongly suppressed the ethanol‐induced hypoglycaemia. The rate of ethanol elimination was 84.6 mg/kg per hour. 4‐MP at the dose used caused a 21% reduction of ethanol elimination, but had no significant effect on blood acetaldehyde levels. 4‐MP also significantly suppressed the ethanol‐induced elevation of blood lactate and almost completely prevented the increase in the 3‐hydroxy‐butyrate/acetoacetate ratio, but had only a slight effect on the lactate/pyruvate ratio of venous blood. The results demonstrate that the hypoglycaemia and lactacidaemia produced by the oxidation of alcohol can be prevented by a dose of 4‐MP that diminishes or prevents the ethanol‐induced shift in the NAD‐coupled redox state of the liver.

Effect of 4-Methylpyrazole on ethanol elimination rate and hepatic redox changes in alcoholics with adequate or inadequate nutrition and in nonalcoholic controls☆

Abstract Ethanol elimination rates produced by chronic alcohol consumption were higher in chronic alcoholics with adequate nutrition than in alcoholics with inadequate nutrition. 4-Methylpyrazole (4-MP, an inhibitor of alcohol dehydrogenase, ADH) at a dose of 7 mg/kg body weight inhibited ethanol elimination by 29% in nonalcoholic controls and by 35% in alcoholics with adequate nutrition, but only by 19% in alcoholics with inadequate nutrition. Galactose elimination rate (which is inhibited by NADH during ethanol oxidation) appeared to be a more sensitive indicator of hepatic redox changes than the lactate/pyruvate ratio of the peripheral venous blood. Ethanol-induced inhibition of galactose elimination was reduced in alcoholics as compared to nonalcoholic controls, and it was more reduced in alcoholics with poor nutrition than in alcoholics with adequate nutrition. Both in controls and in alcoholics, 4-MP reduced the inhibitory effect of ethanol on galactose elimination. In alcoholics with inadequate adequate nutrition, however, the further effect of 4-MP in this respect was negligible. The results indicate that the NADH reoxidation rate in chronic alcoholics is increased and support the existence, in chronic alcoholics with inadequate nutrition, of a non-ADH pathway for ethanol that does not produce reducing equivalents. In alcoholics with inadequate nutrition the proportional contribution of the ADH pathway to total ethanol elimination appears to be more decreased, resulting in reduction of the redox-mediated acute metabolic effects of alcohol.

STUDIES ON THE ROLE OF THE ADH PATHWAY IN INCREASED ETHANOL ELIMINATION AFTER CHRONIC ALCOHOL INTAKE IN THE RAT AND MAN

Publisher Summary This chapter presents studies on the role of the alcohol dehydrogenase (ADH) pathway in increased ethanol elimination after chronic alcohol intake in the rat and man. Accelerated ethanol elimination after chronic alcohol intake is regularly seen in man and in experimental animals, both in vivo and in isolated liver tissue. It is widely accepted that the major part of ethanol elimination is mediated via the hepatic ADH pathway. However, increased ADH activity is probably not responsible for the increased elimination, as in most studies this enzyme is not induced by alcohol pre-treatment, and as it appears, that normally the rate of ethanol oxidation is governed mainly by factors other than the total activity of ADH. Galactose elimination is inhibited when the hepatic NAD/ NADH ratio is reduced. Therefore, galactose elimination has been used as a more specific indicator of changes in the hepatic NAD-coupled redox state than the blood lactate/pyruvate ratio.

OCCURRENCE OF ANTIBODIES TO TEICHOIC ACID IN PATIENTS WITH DISEASES OTHER THAN STAPHYLOCOCCAL INFECTION

To determine the usefulness of the teichoic acid antibody (TAA) test in conditions where unspecific viral and bacterial antibodies are often encountered, we measured TAA by the gel-diffusion method in 475 patients without known staphylococcal disease; they included 213 patients with arthritis, 108 with liver diseases, 100 with gastro-intestinal disorders and 54 with acute pharyngitis. Positive controls were 104 patients with Staphylococcus aureus bacteraemia and 203 healthy adults were negative controls. Thirteen (6%) of the healthy adults had positive TAA titres (greater than or equal to 4), and the highest titre was 8 in two people (1%). Positive titres were found in 38% of patients with S. aureus bacteraemia and high titres (greater than or equal to 8) were seen in 24%. Among the patients with arthritis, positive TAA titres were found significantly more often than in healthy controls in patients with Yersinia arthritis (p less than 0.01) and systemic lupus erythematosus (SLE; p less than 0.02). In other patient groups, the percentage of positive TAA titres did not differ significantly from that in healthy adults. Eight (2%) of the 475 patients without known staphylococcal infection had TAA titres greater than or equal to 8 but these high titres were not associated with any particular disease group. Only two of these eight patients had slightly raised antibody to staphylococcal alpha-haemolysin. We conclude that the TAA test cannot be used as a reliable indicator of septic staphylococcal disease in patients with Yersinia arthritis or SLE, but that in general, TAA titres greater than or equal to 8 point strongly to S. aureus infection even in patients with autoimmune or liver diseases.