Epigenetic silencing is a prominent feature of cancer. Here, we investigated the expression of DNA demethylase and three DNA methyltransferases during colorectal tumorigenesis comparing the genes encoding DNA methyltransferases 1 (DNMT1), 3A, and 3B (DNMT3A and DNMT3B) with methyl-CpG binding domain protein 2 (MBD2), recently described as the only active DNA demethylase. Total RNA isolated from normal colonic mucosa (n = 24), benign adenomas (n = 18), and malignant colorectal carcinomas (n = 32) was analyzed by reverse transcriptase-PCR with subsequent quantification by capillary gel electrophoresis. In contrast to MBD2, expression of DNMT1 and DNMT3A increased in parallel to the degree of dysplasia, with significant overexpression in the malignant lesion when compared with mucosa or with benign lesions (DNMT1). Pairwise comparisons between tumors and matched, adjacent healthy mucosa tissue (n = 13) revealed that expression of all three genes encoding DNA methyltransferases increased by two- to three-fold. Our data suggest a relevant role of the DNA methyltransferases during colorectal tumorigenesis. This increase is not counterbalanced by enhanced expression of the demethylating component MBD2. As a consequence, epigenetic regulation in the adenoma-carcinoma sequence may be driven by increased methylating activity rather than suppressed demethylation.

SummaryBackgroundLiver disease impacts on hepatic synthesis of lipoproteins and lipogenesis but data on dyslipidemia during disease progression are limited. We assessed the patterns of dyslipidemia in (i) different liver disease etiologies and discriminated (ii) non-advanced (non-ACLD) from advanced chronic liver disease (ACLD) as it is unclear how progression to ACLD impacts on dyslipidemia-associated cardiovascular risk.MethodsPatients with alcoholic liver disease (n = 121), hepatitis C (n = 1438), hepatitis B (n = 384), metabolic/fatty liver disease (n = 532), cholestatic liver disease (n = 119), and autoimmune hepatitis (n = 114) were included. Liver stiffness ≥15 kPa defined ACLD. Dyslipidemia was defined as total cholesterol >200 mg/dL, low-density lipoprotein (LDL)-cholesterol >130 mg/dL and triglycerides >200 mg/dL.ResultsAcross all etiologies, total cholesterol levels were significantly lower in ACLD, when compared to non-ACLD. Accordingly, LDL-cholesterol levels were significantly lower in ACLD due to hepatitis C, hepatitis B, metabolic/fatty liver disease and autoimmune hepatitis. Triglyceride levels did not differ due to disease severity in any etiology. Despite lower total and LDL cholesterol levels in ACLD, etiology-specific dyslipidemia patterns remained similar to non-ACLD. Contrary to this “improved” lipid status in ACLD, cardiovascular comorbidities were more prevalent in ACLD: arterial hypertension was present in 26.6% of non-ACLD and in 55.4% of ACLD patients (p < 0.001), and diabetes was present in 8.1% of non-ACLD and 25.6% of ACLD patients (p < 0.001).ConclusionLiver disease etiology is a major determinant of dyslipidemia patterns and prevalence. Progression to ACLD “improves” serum lipid levels while arterial hypertension and diabetes mellitus are more prevalent. Future studies should evaluate cardiovascular events after ACLD-induced “improvement” of dyslipidemia.Electronic supplementary materialThe online version of this article (10.1007/s00508-019-01544-5) contains supplementary material, which is available to authorized users.

Statins reduce cardiovascular risk. However, “real-life” data on statin use in patients with chronic liver disease and its impact on overall and liver-related survival are limited. Therefore, we assessed 1265 CLD patients stratified as advanced (ACLD) or non-advanced (non-ACLD) stage. Statin indication was evaluated according to the 2013 ACC/AHA guidelines and survival-status was verified by national death registry data. Overall, 122 (9.6%) patients had an indication for statin therapy but did not receive statins, 178 (14.1%) patients were on statins and 965 (76.3%) patients had no indication for statins. Statin underutilization was 34.2% in non-ACLD and 48.2% in ACLD patients. In non-ACLD patients, survival was worse without a statin despite indication as compared to patients on statin or without indication (log-rank p = 0.018). In ACLD patients, statin use did not significantly impact on survival (log-rank p = 0.264). Multivariate cox regression analysis confirmed improved overall survival in patients with statin as compared to patients with indication but no statin (HR 0.225; 95%CI 0.053–0.959; p = 0.044) and a trend towards reduced liver-related mortality (HR 0.088; 95%CI 0.006–1.200; p = 0.068). This was not observed in ACLD patients. In conclusion, guideline-confirm statin use is often withhold from  patients with liver disease and this underutilization is associated with impaired survival in non-ACLD patients.

Background The prognostic impact of liver steatosis in obese patients is well established. Limited data on the risk factors for and impact of hepatic steatosis in lean patients are available. Aims Assess risk factors for liver steatosis in lean patients and investigate its impact on survival. Methods Patients without viral hepatitis and with a BMI ≤ 25 kg/m 2 undergoing liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) by transient elastography were retrospectively identified. Clinical characteristics and laboratory test results were obtained at the time of LSM/CAP measurement. National death registry data were obtained in order to assess survival. Results Among n = 218 lean patients, n = 97 (34.5%) showed significant liver steatosis (CAP ≥ 268 dB/m), while n = 184 (65.5%) had no or just mild steatosis (CAP < 268 dB/m). Patients with steatosis had higher GGT (238.0(± 450.3) vs. 112.1(± 180.0) IU/mL; p = 0.013), AST (63(± 67.4) vs. 38.5(± 32.9) IU/mL; p = 0.001), ALT (59.1(± 58.8) vs. 44.3(± 52.7) IU/mL; p = 0.048) and triglyceride levels (120.1(± 80.3) vs. 96.1(± 58.2) mg/dL; p = 0.014), and showed a trend toward more severe fibrosis (LSM 15.6(± 19.5) vs. 12.0(± 15.7) kPa; p = 0.115). In multivariate binary logistic regression analysis, only serum uric acid levels were independently associated with liver steatosis (odds ratio 1.43 per unit mg/dL; 95% CI 1.001-2.054; p = 0.049). During a mean follow-up of 38.9(± 10.6) months, n = 14 patients (5.0%) died. In the absence of advanced fibrosis, survival after 1 year was similar in patients without (98.7%) and with (98.6%) significant steatosis. Patients with advanced fibrosis had worse 1-year survival without concomitant significant steatosis (84.8%) than patients with steatosis (95.8%; log-rank p < 0.001). Conclusions High serum uric acid levels increase the risk of liver steatosis in lean patients. Liver fibrosis but not hepatic steatosis is a risk factor for impaired survival in lean patients.

Background: A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. Based on preclinical studies, this synergism has been attributed to an up-regulation of the enzyme thymidine phosphorylase (TP). Beside tumour tissue, TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. So far, this hypothesis has not been investigated in humans.

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