| 1. |
- Buch, S., et al.
(author)
-
Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
- 2023
-
In: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 72:2, s. 381-391
-
Journal article (peer-reviewed)abstract
- Objective Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41x10(-9), OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94x10(-5), OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12x10(-44)). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Krawczyk, M., et al.
(author)
-
Variant adiponutrin confers genetic protection against cholestatic itch
- 2014
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 4
-
Journal article (peer-reviewed)abstract
- Lysophosphatidic acid (LPA) mediates cholestatic pruritus. Recently the enzyme PNPLA3, expressed in liver and skin, was demonstrated to metabolise LPA. Here we assess the association of the PNPLA3 variant p.Ile148Met, known to be associated with (non-)alcoholic fatty liver disease (NAFLD) in genome-wide association studies, with cholestatic itch in 187 patients with primary biliary cirrhosis (PBC) and 250 PBC-free controls as well as 201 women with intrahepatic cholestasis of pregnancy (ICP) and 198 female controls without a history of ICP. Our hypothesis was that the intensity of cholestatic itch differs in carriers of distinct PNPLA3 p.Ile148Met genotypes. Patients with PBC carrying the allele p.148Met that confers an increased NAFLD risk reported less itching than carriers of the p.148Ile allele (ANOVA P = 0.048). The PNPLA3 p.148Ile allele increased the odds of requiring plasmapheresis for refractory pruritus (OR = 3.94, 95% CI = 0.91-17.00, P = 0.048). In line with these findings, the PNPLA3 p.148Met allele was underrepresented in the ICP cohort (OR = 0.66, 95% CI = 0.47-0.92, P = 0.013). Notwithstanding the need for further replication of these findings, we conclude that the PNPLA3 allele p.148Met might confer protection against cholestatic pruritus, possibly due to increased LPA-acyltransferase activity in liver and/or skin.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Friedrich, D., et al.
(author)
-
Response of fibroblast growth factor 19 and bile acid synthesis after a body weight-adjusted oral fat tolerance test in overweight and obese NAFLD patients: a non-randomized controlled pilot trial
- 2018
-
In: Bmc Gastroenterology. - : Springer Science and Business Media LLC. - 1471-230X. ; 18
-
Journal article (peer-reviewed)abstract
- Background: Non-alcoholic fatty liver disease (NAFLD) is common both in obese and overweight patients. Fibroblast growth factor 19 (FGF19), an intestinal hormone, could play a role in the complex pathogenesis of NAFLD. The aim of our study was to investigate responses of FGF19 and bile acid (BA) synthesis after a body weight-adjusted oral fat tolerance test (OFTT) in overweight and obese NAFLD patients. Methods: For this study, we recruited 26 NAFLD patients; 14 overweight (median BMI 28.3 kg/m(2)), 12 obese (35.3 kg/m(2)) and 16 healthy controls (24.2 kg/m(2)). All individuals received 1 g fat (Calogen (R)) per kg body weight orally. Serum concentrations of FGF19 were determined by ELISA. Concentrations of BAs and BA synthesis marker 7 alpha-hydroxy-4-cholesten-3-one (C4) were measured by gas chromatography-mass spectrometry and high-performance liquid chromatography, respectively; all at 0 (baseline), 2, 4 and 6 h during the OFTT. Results: BMI correlated negatively with fasting FGF19 concentrations (rho = - 0.439, p = 0.004). FGF19 levels of obese NAFLD patients were significantly (p = 0.01) lower in the fasting state (median 116.0 vs. 178.5 pg/ml), whereas overweight NAFLD patients had significantly (p = 0.004) lower FGF19 concentrations 2 h after the fat load (median 163.0 vs. 244.5 pg/ml), and lowest values at all postprandial time points as compared to controls. Baseline BA concentrations correlated positively with FGF19 values (rho = 0.306, p = 0.048). In all groups, we observed BA increases during the OFTT with a peak at 2 h but no change in C4 levels in overweight/obese NAFLD patients. Conclusions: Reduced basal gastrointestinal FGF19 secretion and decreased postprandial response to oral fat together with blunted effect on BA synthesis indicate alterations in intestinal or hepatic FXR signaling in overweight and obese NAFLD subjects. The precise mechanism of FGF19 signaling after oral fat load needs further evaluation.
|
|
| 18. |
- Glantz, Anna, 1959, et al.
(author)
-
Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid
- 2005
-
In: Hepatology. ; 42:6, s. 1399-405
-
Journal article (peer-reviewed)abstract
- Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (> or =10 micromol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, > or =40 micromol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P = .01) and bilirubin (P = .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids > or =40 micromol/L at inclusion (n = 34), UDCA had significant effects on pruritus (-75%), bile acids (-79%), ALT (-80%), and bilirubin (-50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Kuttner, C. S., et al.
(author)
-
Four-Week Omega-3 Supplementation in Carriers of the Prosteatotic PNPLA3 p.I148M Genetic Variant: An Open-Label Study
- 2019
-
In: Lifestyle Genomics. - : S. Karger AG. - 2504-3161 .- 2504-3188. ; 12:1-6, s. 10-17
-
Journal article (peer-reviewed)abstract
- Background/Aims: The PNPLA3 loss-of-function variant p.I148M is a strong genetic determinant of nonalcoholic fatty liver disease. The PNPLA3 protein functions as an intracellular lipase in the liver, with a greater activity on unsaturated fatty acids. This study aimed to determine whether short-term supplementation with omega-3 fatty acids impacts hepatic steatosis differently in PNPLA3 p.148I wild-type individuals as compared to homozygous carriers of the PNPLA3 p.148M variant. Methods: Twenty subjects with hepatic steatosis (50% women, age 18–77 years) were included. Ten subjects homozygous for the PNPLA3 148M variant were matched to 10 wild-type individuals. The subjects received 4 g omega-3 fatty acids (1,840 mg eicosapentaenoic acid and 1,520 mg docosahexaenoic acid) a day for 4 weeks. Transient elastography with a controlled attenuation parameter (CAP) was used to quantify liver fat before and after the intervention. Body composition, fibrosis, liver function tests, serum free fatty acids (FFA) and glucose markers were compared. Results: Patients homozygous for the PNPLA3 p.148M variant (risk group) demonstrated no significant changes in CAP compared to baseline (284 ± 55 vs. 287 ± 65 dB/m) as did the control group (256 ± 56 vs. 262 ± 55 dB/m). While serum liver enzyme activities remained unchanged in both groups, the risk group displayed significantly (p = 0.02) lower baseline FFA concentrations (334.5 [range 281.0–431.0] vs. 564.5 [range 509.0–682.0] μmol/L), which markedly increased by 9.1% after the intervention. In contrast, FFA concentrations decreased significantly (p = 0.01) by 28.3% in the wild-type group. Conclusions: Short-term omega-3 fatty acid supplementation did not significantly alter hepatic steatosis. The nutrigenomic and metabolic effects of omega-3 fatty acids should be investigated further in carriers of the PNPLA3 148M risk variant.
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
- Marschall, HU, et al.
(author)
-
Jaundice
- 2003
-
In: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 38:3, s. 233-234
-
Journal article (other academic/artistic)
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
- Valentine, W. J., et al.
(author)
-
Evaluating the cost-effectiveness of reduced mild hypoglycaemia in subjects with Type 1 diabetes treated with insulin detemir or NPH insulin in Denmark, Sweden, Finland and the Netherlands
- 2012
-
In: Diabetic Medicine. - : Wiley-Blackwell Publishing Inc.. - 0742-3071 .- 1464-5491. ; 29:3, s. 303-312
-
Journal article (peer-reviewed)abstract
- AIMS: To estimate short-term cost-effectiveness of insulin detemir vs. NPH insulin based on the incidence of mild hypoglycaemia in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands.METHODS: A model was developed to evaluate cost-effectiveness based on mild (self-treated) hypoglycaemia and pharmacy costs over 1 year. Published rates of mild hypoglycaemia were used for NPH insulin and insulin detemir. Effectiveness was calculated in terms of quality-adjusted life expectancy. Pharmacy costs were accounted using published prices and defined daily doses for both insulins. Costs were expressed in 2010 euros (€).RESULTS: Treatment with insulin detemir was associated with fewer mild hypoglycaemic events than NPH insulin (mean rates of 26.3 vs. 35.5 events per person-year), leading to an improvement in mean quality-adjusted life expectancy of approximately 0.019 (0.030) quality-adjusted life years (standard deviation). Annual costs were € 573.55 (110.42) vs. € 332.76 (62.18) in Denmark for insulin detemir and NPH insulin, respectively. These values were € 545.79 (106.54) vs. € 306.12 (57.78) in Sweden, € 720.10 (140.74) vs. € 408.73 (78.61) in Finland and € 584.01 (109.47) vs. € 359.60 (64.84) in the Netherlands. Incremental cost-effectiveness ratios were approximately € 12,644 (Denmark), € 12,612 (Sweden), € 16,568 (Finland) and € 12,216 (the Netherlands) per quality-adjusted life year gained for insulin detemir vs. NPH insulin.CONCLUSIONS: Insulin detemir is likely to be cost-effective vs. NPH insulin in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. Increased pharmacy costs with insulin detemir should not be a barrier to therapy based on these findings.
|
|
| 33. |
|
|
