Gender and liver: Is the liver stiffness weaker in weaker sex?

Abstract

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.

Liver stiffness values in apparently healthy subjects: Influence of gender and metabolic syndrome

“…This finding, which is consistent with the results of a previous study conducted on a small population of supposedly ''healthy subjects'' [12], indicates that gender should be taken into account when interpreting liver stiffness values. It also suggests the existence of intrinsic differences between men and women in the density of liver extracellular matrix [13], a hypothesis supported by previous studies showing that ovarian hormones inhibit extracellular matrix production by liver stellate cells [14].…”

Non-invasive evaluation of liver fibrosis using transient elastography

“…The mean liver stiffness value in these patients was 5.5 ± 1.6 kPa. Age had no influence but as suggested previously [27], liver stiffness values were higher in men than in women (5.8 + 1.5 vs. 5.2 + 1.6 kPa, respectively; p = 0.0002), and in subjects with BMI > 30 kg/m2 (6.3 + 1.9 vs. 5.4 + 1.5 kPa, respectively; p = 0.0003). However, even after adjustment for gender and BMI, liver stiffness values remained higher in subjects with metabolic syndrome (n = 59; 13.7%) than in those without (6.5 + 1.6 vs. 5.3 + 1.5 kPa, respectively; p < 0.0001) (Fig.…”

Transient elastography in patients with celiac disease: A noninvasive method to detect liver involvement associated with celiac disease

“…According to transaminase levels, 19 of 95 patients with CD (20%) showed an increase in ALT and/or AST values that could suggest a liver impairment, whereas an actual hepatic involvement, evaluated by TE, was detected in only 10 CD patients. According to our data, significant or severe liver fibrosis is not a common finding in CD, thus confirming previous studies [54,59,60]. Moreover, from this study, the absolute values of TE observed in patients with CD were within the reference range, considering the group of healthy subjects as controls.…”