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Biomedical subjects

R Poupon

Publications and source records attributed to R Poupon.

At least 19 recordsLinked to original sources
PubMed1992

Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes.

Cell-mediated immunity and macrophage activity, especially that of Kupffer cells, are impaired during cholestasis. Some evidence exists that bile acids play a role in these immune defects. The purpose of this study was to evaluate the effects of individual bile acids on immunity and to determine whether monocytes could be a target. We assessed the effects of chenodeoxycholic acid, an endogenous bile acid, ursodeoxycholic acid, which has been shown to partially correct the immunological abnormalities observed in primary biliary cirrhosis, and their tauroconjugates on the production of interleukin-1, interleukin-6 and tumor necrosis factor-alpha. Chenodeoxycholic acid had a dose-dependent inhibitory effect on interleukin-1 (inhibitory concentration 50% = 60 mumol/L), interleukin-6 (inhibitory concentration 50% = 80 mumol/L) and tumor necrosis factor-alpha (inhibitory concentration 50% = 80 mumol/L) production; inhibition was almost complete at 250 mumol/L. In contrast, ursodeoxycholic acid had lesser or minimal inhibitory effects (inhibitory concentration 50% = 100 mumol/L for interleukin-1 and above 200 mumol/L for interleukin-6 and tumor necrosis factor-alpha). The inhibitory effects of taurochenodeoxy-cholic acid and tauroursodeoxycholic acid were similar to those of chenodeoxycholic acid and ursodeoxycholic acid, respectively. Ursodeoxycholic acid did not reverse the chenodeoxycholic acid-induced inhibition of interleukin-6 or tumor necrosis factor-alpha production. In conclusion, chenodeoxycholic acid exerts strong inhibitory effects on monocyte activity in vitro, whereas the effects of ursodeoxycholic acid are minor.

Cell Survival↗
PubMed1992

Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic acids in the mouse.

Cell-mediated immunity is impaired during cholestasis, and there is evidence that bile acids play a role in this immune defect. Ursodeoxycholic acid (UDCA), which corrects the immunological abnormalities observed in primary biliary cirrhosis, could counter the detrimental effects of the endogenous bile acids. Accordingly, we assessed the respective effects of cholestasis, chenodeoxycholic acid (CDCA), and UDCA, using mixed lymphocyte culture as a model of allogeneic immune response. CDCA induced a dose-dependent inhibition of the proliferative response (0-150 mumol/L). Mononuclear cells obtained from bile duct-ligated mice had a normal immunostimulatory effect, whereas responder cells obtained from such animals showed a profoundly impaired proliferative response, suggesting that responder T cels are the main target of the cholestasis-induced immune defect. Supplementation of cultures with exogenous interleukins partially compensated for the inhibitory effect of 25 mumol/L CDCA, but not for that of 50 mumol/L CDCA, suggesting that impaired secretion of interleukins is not the only factor involved in the effect of bile acids. In contrast to CDCA, UDCA had no inhibitory effect on the allogenic immune response at concentrations of up to 50 mumol/L.

Animals↗
PubMed1992

Tumor necrosis factor-alpha in liver transplantation and resection. No evidence for a key role in ischemia-reperfusion injury.

Experimental studies have shown that liver ischemia-reperfusion induces Kupffer cell activation and tumor necrosis factor-alpha (TNF alpha) release. The aim of this work was to determine whether severe hepatic ischemia and subsequent reperfusion triggers TNF alpha release in man. Serum TNF alpha was measured before and 3, 10, 30, 60, 120 min after revascularization and postoperatively at day 1 and 2 in 11 patients with orthotopic liver transplantation (group 1) and 4 patients with liver resection with vascular occlusion (group 2). In group 1, TNF alpha levels decreased during the first few minutes of reperfusion, then increased slightly to peak at 120 min (40 +/- 13 pg/ml). Primary non-function occurred in 1 patient in whom low peroperative levels of TNF alpha levels were measured. In group 2, no significant changes in TNF alpha levels were observed. These data, in a small number of patients: (a) show that hepatic ischemia-reperfusion does not result in major TNF alpha production; (b) do not support a primary pathogenic role for TNF alpha in damage after ischemia-reperfusion in humans.

Humans↗
PubMed1992

[Effects of fatty acids on hepatic amino acid metabolism in isolated perfused liver in rats].

Large disparity in experimental conditions concerning the use of isolated perfused liver led us to investigate the effects of two free-fatty acids on amino acid metabolism in this model. Oleate uptake was 210 +/- 46 nmol/min.g and octanoate uptake 550 +/- 60 nmol/min.g. Fatty acid utilization led to an increase in ketogenesis, enhanced by octanoate in accordance with its known availability for beta-oxidation. In our experiments neither oleate nor octanoate modified hepatic amino acid exchange and metabolism as assessed by the measurements of amino acids fluxes and glucose and urea production.

Amino Acids↗
PubMed1992

Cholestasis induces major histocompatibility complex class I expression in hepatocytes.

The hepatic expression of major histocompatibility complex (MHC) antigens is normally limited. However, aberrant expression occurs in cholestatic diseases such as primary biliary cirrhosis. The aim of this work was to assess the effect of cholestasis itself on hepatocyte MHC expression and to determine if immunosuppressive drugs might modulate this expression. Liver fragments taken from six patients with extrahepatic cholestasis and eight control patients were analyzed for MHC expression by direct immunofluorescence. MHC class I expression by hepatocytes was present in six of six cholestatic patients and zero of eight control subjects. Hepatocytes did not express MHC class II in either group. In further studies, cholestasis was induced in rats by ligation-section of the bile duct. Five groups of rats were studied: control, 3-day cholestasis, 5-day cholestasis, 5-day cholestasis plus cyclosporine, and 5-day cholestasis plus corticosteroids. Hepatocyte MHC class I expression was detected by immunofluorescence in bile duct-ligated rats but not in control animals. Flow-cytofluorimetric analysis of isolated hepatocytes showed that the percentage of hepatocytes expressing MHC class I increased from day 0 (9.9%) to days 3 (50.2%) and 5 (82.9%); this hyperexpression was not modified by cyclosporine (79.7%) or corticosteroids (77.9%). The percentage of hepatocytes spontaneously expressing MHC class II was low (0.05%) and was not significantly modified by cholestasis or immunosuppressive drugs. Thus, a nonimmunological factor such as cholestasis is able to modulate MHC expression. The liver may become more vulnerable to immune destruction in the presence of cholestasis, and immunosuppressive treatment has no effect on this phenomenon.

Aged↗
PubMed1991

A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.

BACKGROUND: In primary biliary cirrhosis the hepatic lesions may result, at least in part, from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid), a hydrophilic bile acid without hepatotoxicity, leads to improvement in the condition of patients with primary biliary cirrhosis. METHODS: We conducted a two-year, multicenter, double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 mumol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction. RESULTS: Treatment failed in 6 patients in the ursodiol group, as compared with 13 in the placebo group (P less than 0.01 by Cox regression model). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (P less than 0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, cholesterol, and IgM (all P less than 0.001); the antimitochondrial-antibody titer (P less than 0.01); and the Mayo risk score (P less than 0.001). Follow-up analysis of 95 liver-biopsy specimens showed a significant improvement in the mean histologic score (P less than 0.002) and in all the characteristic histologic features except fibrosis only in the group given ursodiol. CONCLUSIONS: Ursodiol is a safe and effective treatment for primary biliary cirrhosis.

Alkaline Phosphatase↗
PubMed1991

[Primary biliary cirrhosis].

Primary biliary cirrhosis was described in detail by Popper et al. in 1965. Segmentary necrosis of the interlobular bile ducts leads to progressive cholestasis of the mechanical type. Three stages, asymptomatic, cholestatic and finally terminal, are well known. The disease appears to be induced by genetic as well as by infectious and immunologic factors. There is a higher incidence of some HLA groups and sulphoxidation is deficient. Viruses such as HCV and CMV have been shown to be capable of damaging bile duct epithelia. The group most prone to develop the disease are women aged 30-65 years. In 30-40% diagnosis is already possible in the asymptomatic stage. Three criteria are of importance: cholestasis, elevated IgM and/or antimitochondrial antibodies, and histologic evidence of chronic aggressive cholangitis. Antimitochondrial antibodies of the M2 and M9 type are characteristic features. Their titer must be above 1:100. The transaminases are only slightly pathologic. Signs of hepatocellular insufficiency or of portal hypertension occur only in the advanced stages of the disease. 2-5% of patients display auto-immune symptoms such as Sjögren syndrome, Raynaud phenomenon and Crest syndrome. Steatorrhea, osteoporosis, infections of the urogenital tract and some carcinomas, such as liver and breast cancer, are known complications. The most specific feature differentiating primary biliary cirrhosis from other causes of intrahepatic cholestasis is demonstration of antimitochondrial antibodies and the typical histology. Various therapies have been evaluated in double-blind studies. Fairly good results have been achieved with cyclosporin A, though side effects have been marked and treatment with cyclosporin is therefore not recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

[Primary biliary cirrhosis].

Primary biliary cirrhosis is a chronic cholestatic disease which usually affects middle-aged women and is characterized by portal vein inflammation and by segmental and focal necrosis of small intrahepatic bile ducts. The prevalence of the disease is estimated at 8 to 12 cases for 100,000 inhabitants. Genetic, infectious and/or immunological factors acting together may be responsible for small bile duct destruction. The main consequence of this destruction is cholestasis. As in all types of mechanical cholestasis, so-called lobular lesions such a fibrosis or even cirrhosis may then develop. Clinically, primary biliary cirrhosis evolves in three phases: (1) a preclinical asymptomatic phase where the disease is revealed by the accidental discovery of antimitochondrial antibodies or of a moderate rise in gammaglutamyltranspeptidase or serum alkaline phosphatase activity; (2) a clinical phase, usually lasting 5 to 10 years, characterized by fatigue, pruritus and later, clinical signs directly related to the hepatic lesions; (3) a terminal phase marked by major cholestasis with lesions of fibrosis or cirrhosis and sometimes ascites and portal hypertension responsible for gastrointestinal haemorrhages. In the last few years the prognosis of primary biliary cirrhosis has been considerably improved by the introduction and development of liver transplantation (the first choice treatment in the terminal phase) and by the introduction of ursodeoxycholic acid.

Humans↗
PubMed1991

Effect of bile acids on ischemia-reperfusion liver injury.

We investigated whether stimulation of bile flow by taurocholic acid (TCA), ursodeoxycholic acid (UDCA) or its taurine conjugate (TUDCA) could protect the liver from ischemia-reperfusion injury. The isolated perfused rat liver model was used. In livers perfused without bile acids (n = 8), 60 min of ischemia induced a significant reduction in bile flow and in portal flow, together with a marked increase in LDH, AST and uric acid release in the perfusate. These alterations were maximal at the beginning of reperfusion. In livers perfused with TCA (n = 6), UDCA (n = 7) or TUDCA (n = 6), bile flow was significantly increased as compared to controls during the pre-ischemic phase, as well as during the reperfusion phase. However, no significant improvement was observed in any of the biochemical, hemodynamic or histologic parameters studied. The results show that stimulation of bile flow either by TCA, UDCA or TUDCA does not reduce ischemia-reperfusion liver injury. Furthermore, the results do not provide evidence for a cytoprotective effect of UDCA or TUDCA in this model of liver injury.

Animals↗
PubMed1991

Ursodeoxycholic acid (UDCA) in the treatment of chronic cholestatic diseases.

Several studies suggest that UDCA treatment has beneficial effects in chronic cholestatic diseases. We designed a controlled trial to assess the efficacy and tolerance of UCDA in primary biliary cirrhosis (PBC): 73 patients received UDCA (13-15 mg/kg per day) and 73 a placebo. One side-effect required interruption of therapy in each group. The relative risk of treatment failure (doubling of the bilirubin level or occurrence of a severe complication of cirrhosis) was 3 times higher in the placebo group. Pruritus resolved in 40% of the patients of UDCA group vs 19% in placebo group. Biological and histological parameters significantly improved in the patients receiving UDCA. Unexpectedly, immune parameters, including IgM levels and anti-mitochondrial antibody titers, also improved. The Mayo risk score was significantly different between the two groups at one and two years, suggesting that UDCA could prolong survival in PBC. Recent studies suggest that UDCA could have immunoregulating properties. Abnormal MHC class I expression by hepatocytes, observed in PBC, was dramatically reduced by UDCA treatment. Cholestasis itself induces hepatic MHC expression: hepatocyte MHC class I expression was present in 6/6 cholestatic patients vs 0/8 control subjects. Experimental cholestasis in the rat induced MHC class I expression. Cyclosporin or corticosteroids had no effect on this overexpression, suggesting that an immune mechanism is not involved in this phenomenon. To assess the effect of bile acids on MHC expression, human hepatocytes were incubated with bile acids. Chenodeoxycholic acid (CDCA) (an endogenous bile acid) but not UDCA induced a dose-dependent MHC class I hyperexpression. UDCA suppressed the CDCA-induced MHC hyperexpression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Pregnancy-associated idiopathic intrahepatic cholestasis. Hypotheses of physiopathology: a therapeutic case report.

By modification of the circulating pool of biliary acids, the administration of ursodesoxycholic acid has permitted the restoration of normal maternal hepatic function during a triple pregnancy complicated by the precocious onset of an intrahepatic cholestasis. The marked regression in clinical and biological markers of the disease confirms the role of biliary acids in the aggravation of hepatic abnormalities.

Adult↗
PubMed1991

[Primary biliary cirrhosis and pregnancy. Apropos of a clinical case. Review of the literature].

The appearance of pruritus and abnormal liver function tests (cellular damage) during pregnancy should of course suggest the diagnosis of intrahepatic cholestasis of pregnancy. However, these signs must also be recognized as signs of other hepatic diseases, especially primary biliary cirrhosis. The diagnosis is based on the search for antimitochondrial antibodies. This mode of presentation must not be overlooked because of major therapeutic consequences. The disease course often stabilizes with ursodeoxycholic acid, if administrated early.

Adult↗
PubMed1991

Indocyanine green-sulfobromophthalein pharmacokinetics for diagnosing primary biliary cirrhosis and assessing histological severity.

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease in which there is a crucial need for quantitative liver-function tests. We have developed a mixed sulfobromophthalein (BSP)-indocyanine green (ICG) test and have applied it to 15 healthy subjects and 50 patients with PBC to determine its relevance to the histological severity of the disease. The two dyes were administered intravenously and sequentially as boluses. Plasma concentrations were measured over 60 min. Pharmacokinetic analysis of the plasma elimination curve permitted the calculation of clearance, constants k1 and k2, and the retention percentage at 45 min. In PBC patients, ICG kinetics were within the normal range except for those with stage IV disease (cirrhosis). BSP clearance and the k2 constant were reduced in all the patients, whereas the k1 constant was reduced only in stage III and IV disease. The BSP retention percentage at 45 min was highly correlated with histological stage (r = 0.89, P less than 0.001). The BSP-ICG mixed test may thus prove useful in the diagnosis and follow-up of patients with PBC.

Humans↗