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 ؍ 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) >2, 0.95 for F > 3 and 0.96 for F ؍ 4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F > 2, F > 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. (HEPATOLOGY 2006;43:1118-1124
dition, several statements purely reflect the authors' opinion without giving reference to published literature data.We agree that the mechanisms by which -catenin signaling might influence GS expression are not fully understood. However, in contrast to the statement that GS expression "is somehow dependent on -catenin signaling", a fundamental role of -catenin in regulation of GS expression has been clearly established by several groups: (i) GS is expressed in all hepatocytes of mice carrying an activated -catenin transgene 2 or a hepatocyte-targeted knockout of the -catenin antagonist APC. 3 (ii) By contrast, mice with hepatocyte-specific knockout of -catenin or overexpression of the Wnt/-catenin-signaling inhibitor DKK1 lack GS expression in liver. 3,4 Notably, livers of -catenin knockout mice also lack expression of several cytochrome P450 isozymes, 4 which are, like GS, overexpressed in liver tumors with mutated -catenin. 5 The fact that the Wnt antagonist DKK1 blocks expression of GS and other perivenous markers in mouse liver 3 indicates that Wnt molecules are indeed involved in regulation of several perivenous markers as suggested in our hypothesis. 1 Gebhardt and Ueberham criticize that only perivenous hepatocytes might have responded to -catenin activation by Wnt or a GSK3 inhibitor. 1 Earlier studies by Gebhardt's group have shown, however, that GS can be induced in periportal hepatocytes by co-cultivation with endothelial-like cells, 6 demonstrating that periportal hepatocytes are capable of responding to external stimuli that induce "perivenous" mRNAs. In addition, preferential localization of activated -catenin in perivenous hepatocytes has been demonstrated recently. 3 Regarding Ras activation in periportal hepatocytes, we agree that no experimental data directly supporting this hypothesis are presented, but relevant indirect evidence has been cited in our recent paper. 1 The statement that "many liver tumors with activated -catenin do not express GS" is made without giving any references and does not reflect previous results showing an almost 100% congruity between mutational activation of -catenin and GS expression, both in mouse and human liver tumors. 2,5,7,8 The notion that "hepatocellular tumors develop rarely in response to -catenin mutation alone" does not apply to initiation/promotion experiments with phenobarbital which strongly selects for -catenin, but not Ha-ras mutated liver tumors in mice. 9 We routinely screen liver tumors for mutations in both genes and can exclude a coincidental occurrence of -catenin and Ha-ras mutations, as suspected by Gebhardt and Ueberham.Following appearance of our paper, 1 other studies have been published, 3,4 supporting important parts of our hypothesis. We have also obtained new results, including serum effects on gene expression, which favor our original hypothesis. These data are described in a manuscript submitted for publication, which cannot be cited because it is presently undergoing the review process.
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