PubMed Health⌕ Search

Biomedical subjects

Christophe Corpechot

Publications and source records attributed to Christophe Corpechot.

13 recordsLinked to original sources
PubMed2006

Identification of a novel 974C-->G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.

Rifampicin (RIF) and ursodeoxycholic acid (UDCA) therapies have beneficial effects in chronic cholestatic diseases. These may result in part from the induction of multidrug-resistance protein 2 (MRP2/ABCC2) expression in the liver and kidney. However, the precise mechanisms by which RIF and UDCA act in cholestasis remain unclear. In the present study, we report the effects of chronic administration of both drugs in a patient with Dubin-Johnson syndrome (DJS), an inherited autosomal recessive disorder characterized by the absence of functional MRP2 protein at the canalicular hepatocyte membrane. A novel 974C-->G nonsense mutation was identified in the MRP2 gene sequence from this patient. RIF induced further increase in conjugated bilirubinemia, whereas concomitant administration of RIF and UDCA led to a dramatic rise in serum bile acid concentrations. These biochemical effects, which are in marked contrast to those observed in cholestatic settings, were concomitant with an increased MRP3, but not MRP4, expression on basolateral hepatocyte membrane. Such findings highlight the key role of MRP2 in the pharmacological properties of RIF and UDCA and suggest that both drugs should be used with caution in pathologic settings in which MRP2 expression may be downregulated, as in advanced stage of cholestatic diseases.

Adult↗
PubMed2006

Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P < .0001) and histological (0.79, P < .0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F) > or =2, 0.95 for F > or =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F > or =2, F > or =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.

Adolescent↗
PubMed2006

Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis.

Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is a clinical entity characterized by the occurrence of both conditions at the same time in the same patient. In addition to PBC-AIH overlap syndrome, transitions from one autoimmune disease to another have been reported, but no systematic series have been published. We report a series of 12 patients with consecutive occurrence of PBC and AIH (i.e., PBC followed by AIH). Among 282 PBC patients, 39 were identified who fulfilled criteria for probable or definitive AIH. AIH developed in 12 patients (4.3%). The baseline characteristics of the patients were similar to those of patients with classical PBC. Time elapsed between the diagnosis of PBC and the diagnosis of AIH varied from 6 months to 13 years. Patients with multiple flares of hepatitis at the time of diagnosis of AIH had cirrhosis on liver biopsy. Ten patients were given prednisone +/- azathioprine; short-term as well as sustained remissions were obtained in 8 of these, while two had multiple relapses and eventually died 8 and 7 years after diagnosis of AIH. In conclusion, the development of superimposed AIH could not be predicted from baseline characteristics and initial response to UDCA therapy. If not detected early, superimposed AIH can result in rapid progression toward cirrhosis and liver failure in PBC patients.

Adult↗
PubMed2005

The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.

BACKGROUND AND AIMS: We used a multistate modeling approach to assess the effect of ursodeoxycholic acid (UDCA) therapy on the natural course of primary biliary cirrhosis (PBC), which remains controversial. METHODS: Our population included 262 patients with PBC who had received 13-15 mg/kg UDCA daily for a mean of 8 years (range, 1-22 years). Data were analyzed using a multistate Markov model, with histologic stage progression, death, and orthotopic liver transplantation (OLT) as main end points. Survival without OLT was compared with that predicted by the updated Mayo model and with the expected survival in the control population. RESULTS: Forty-five patients developed cirrhosis, 20 underwent OLT, and 16 died by the censor date. Ten deaths were due to liver disease. The overall survival rates were 92% at 10 years and 82% at 20 years. Survival rates without OLT were 84% and 66% at 10 and 20 years, respectively, which were slightly lower than the survival rate of an age- and sex-matched control population (relative risk [RR], 1.4; P = .1) but better than the spontaneous survival rate as predicted by the updated Mayo model (RR, .5; P < .01). The survival rate of patients in stage 1 and 2 was similar to that in the control population (RR, .8; P = .5), whereas the probability of death or OLT remained significantly increased in treated patients in late histologic stages (RR, 2.2; P < .05). CONCLUSIONS: Treatment with UDCA alone normalizes the survival rate of patients with PBC when given at early stages. However, there is a continued need for new therapeutic options in patients with advanced disease.

Adult↗
PubMed2004

Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis.

BACKGROUND/AIM: We have previously shown that the histological stage and severity of lymphocytic piecemeal necrosis (LPN) are independent predictive factors of cirrhosis development in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cirrhosis (PBC). Our aim during this study was to determine whether biochemical parameters classically used in PBC management and measured under UDCA could be considered as reliable surrogate markers for these histological prognostic indices in clinical practice. METHOD: The study included 153 patients with PBC who had undergone a control liver biopsy after 2 years of UDCA therapy. The relationships between histological and biological features were assessed by variance analysis and logistic regression. The diagnostic value of independent markers was assessed in terms of their sensitivity, specificity, positive predictive value (PPV) and negative value (NPV) and receiver-operating characteristic curves. RESULTS: Two variables were independently associated with extensive fibrosis (i.e. advanced histological stages): serum levels of bilirubin and hyaluronic acid (HA). A fibrosis index ([bilirubin (micromol/l)/14]+[HA (microg/l)/143]) higher than 1.5 exhibited good PPV and specificity (>74%) but rather poor NPV and sensitivity (<64%) regarding a diagnosis of extensive fibrosis. The only independent marker of LPN was aspartate aminotransferase (AST) activity. AST activity of more than twice the upper limit of normal showed acceptable PPV (>70%) but very low sensitivity (<25%) for a diagnosis of LPN. CONCLUSIONS: Serum bilirubin and HA levels measured under UDCA therapy are of acceptable diagnostic value for extensive fibrosis, but none of the biochemical tests commonly employed in the management of PBC can be considered as surrogate markers of LPN. Taken together with our previous results, these findings suggest that liver biopsy may be necessary to screen UDCA-treated patients who might require additional therapies.

Aspartate Aminotransferases↗
PubMed2002

Hepatocyte growth factor and c-Met inhibition by hepatic cell hypoxia: a potential mechanism for liver regeneration failure in experimental cirrhosis.

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Animals↗
PubMed2002

Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis (PBC). However, some UDCA-treated patients escape and progress toward cirrhosis and end-stage disease. This study aimed to assess the incidence of cirrhosis in UDCA-treated patients with PBC and to determine the predictive factors of cirrhosis development under this treatment. METHODS: A Markov model was used to describe the progression toward cirrhosis in 183 UDCA-treated patients with PBC. A total of 254 pairs of liver biopsy specimens collected during 655 patient-years were studied. RESULTS: The incidence of cirrhosis after 5 years of UDCA treatment was 4%, 12%, and 59% among patients followed-up from stages I, II, and III, respectively. At 10 years, the incidence was 17%, 27%, and 76%, respectively. The median time for developing cirrhosis from stages I, II, and III was 25 years, 20 years, and 4 years, respectively. The independent predictive factors of cirrhosis development were serum bilirubin greater than 17 mumol/L, serum albumin less than 38 g/L, and moderate to severe lymphocytic piecemeal necrosis. CONCLUSIONS: This study provides new data about the time course of PBC under UDCA and constitutes a rationale for the design and evaluation of clinical trials aimed to assess the efficacy of drugs associated with UDCA.

Bilirubin↗
PubMed2002

Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.

Cirrhosis consists of hepatocyte nodules surrounded by a highly vascularized fibrous tissue. We previously showed that the development of biliary cirrhosis in the rat is associated with the occurrence of hepatocellular hypoxia and the induction of hepatic angiogenesis. We herein examined the occurrence of hypoxia in an experimental model of diethylnitrosamine (DEN)-induced cirrhosis. We also determined whether hypoxia directly affects the expression of vascular endothelial growth factor (VEGF), of VEGF receptors (Flt-1, Flk-1), and of type I and type IV collagens in activated hepatic stellate cells (HSCs) and the expression of VEGF in hepatocytes. Our results show that in DEN-treated rats, although the progression of liver fibrosis is associated with hepatocellular hypoxia and angiogenesis, VEGF and Flt-1 expressions in the liver are increased and correlated with the density of microvessels. In vitro, hypoxia induces the expression of VEGF, Flt-1, and type I collagen in activated HSCs and that of VEGF in hepatocytes. In addition, we show that hypoxia-induced type I collagen expression in HSCs may occur independently of transforming growth factor beta1 (TGF-beta1) overexpression. In conclusion, the present study provides further evidence that hepatocellular hypoxia and angiogenesis progress together with fibrogenesis after liver injury and that hypoxia directly contributes to the progression of liver fibrosis.

Alkylating Agents↗