The burden of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. We performed a meta-analysis to determine the effectiveness of exercise-based lifestyle interventions on liver-specific ...end points in populations with NAFLD and underlying metabolic disorders such as obesity, type 2 diabetes, or metabolic syndrome.
We searched PubMed-MEDLINE, Embase, and the Cochrane Central register through October 21, 2015 for randomized trials of exercise-based lifestyle interventions on end points such as intrahepatic lipid content and blood levels of alanine and aspartate aminotransferases. Effect sizes are reported as standardized mean difference and weighted mean difference values. To investigate heterogeneity, we performed sensitivity and meta-regression analyses. Results were reported according to the PRISMA statement.
We analyzed data from 28 trials. Physical activity, independently from diet change, was associated with a significant reduction in intrahepatic lipid content (standardized mean difference, -0.69; 95% confidence interval CI, -0.90 to -0.48) and with reductions in alanine aminotransferase (weighted mean difference, -3.30 IU/L; 95% CI, 5.57 to -1.04) and aspartate aminotransferase (weighted mean difference, -4.85 IU/L; 95% CI, -8.68 to -1.02). By meta-regression, we found individuals with increasing body mass index to be increasingly more likely to benefit from the intervention (beta coefficient = -0.10; P = .037). We recorded no effect modification by variables related to the intensity of the intervention.
In a meta-analysis of randomized trials, we found strong evidence that physical activity reduces intrahepatic lipid content and markers of hepatocellular injury in patients with NAFLD. This effect correlated with baseline body mass index.
Non-alcoholic fatty liver disease (NAFLD) is one of the leading cause of hepatocellular carcinoma (HCC). This association is supported by the translocation of bacteria products into the portal ...system, which acts on the liver through the gut-liver axis. We hypothesize that portosystemic shunting can disrupt this relationship, and prevent NAFLD-associated HCC.
HCC carcinogenesis was tested in C57BL/6 mice fed a high-fat high-sucrose diet (HFD) and injected with diethylnitrosamine (DEN) at two weeks of age, and in double transgenic LAP-tTA and TRE-MYC (LAP-Myc) mice fed a methionine-choline-deficient diet. Portosystemic shunts were established by transposing the spleen to the sub-cutaneous tissue at eight weeks of age.
Spleen transposition led to a consistent deviation of part of the portal flow and a significant decrease in portal pressure. It was associated with a decrease in the number of HCC in both models. This effect was supported by the presence of less severe liver steatosis after 40 weeks, and lower expression levels of liver fatty acid synthase. Also, shunted mice exhibited lower liver oxygen levels, a key factor in preventing HCC as confirmed by the development of less HCCs in mice with hepatic artery ligation.
The present data show that portosystemic shunting prevents NAFLD-associated HCC, utilizing two independent mouse models. This effect is supported by the development of less steatosis, and a restored liver oxygen level. Portal pressure modulation and shunting deserve further exploration as potential prevention/treatment options for NAFLD and HCC.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Liver transplantation is widely indicated as a curative treatment for selected patients with hepatocellular carcinoma. However, with recent therapeutic advances, as well as efforts to increase the ...donor pool, liver transplantation has been carefully expanded to patients with other primary or secondary malignancies in the liver. Cholangiocarcinoma, colorectal and neuroendocrine liver metastases, and hepatic epithelioid haemangioendothelioma are amongst the most relevant new indications. In this review we discuss the fundamental concepts of this ambitious undertaking, as well as the newest indications for liver transplantation, with a special focus on future perspectives within the recently established concept of transplant oncology.
Hypothermic and normothermic ex vivo liver perfusions promote organ recovery after donation after circulatory death (DCD). We tested whether these perfusions can reduce the risk of hepatocellular ...carcinoma (HCC) recurrence in a 1h-DCD syngeneic transplantation model, using Fischer F344 rats. DCD grafts were machine perfused for 2h with hypothermic perfusion (HOPE) or normothermic perfusion (NORMO), and transplanted. After reperfusion, we injected HCC cells into the vena porta. On day 28 after transplantation, we assessed tumour volumes by MRI. Control rats included transplantations with Fresh and non-perfused DCD livers. We observed apoptotic-necrotic hepatocyte foci in all DCD grafts, which were more visible than in the Fresh liver grafts. Normothermic perfusion allowed a faster post-transplant recovery, with lower day 1 levels of transaminases compared with the other DCD. Overall, survival was similar in all four groups and all animals developed HCCs. Total tumor volume was lower in the Fresh liver recipients compared to the DCD and DCD+HOPE recipients. Volumes in DCD+NORMO recipients were not significantly different from those in the Fresh group. This experiment confirms that ischemia/reperfusion injury promotes HCC cell engraftment/growth after DCD liver transplantation. Using the present extreme 1h ischemia model, both hypothermic and normothermic perfusions were not effective in reducing this risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Blastocyst complementation refers to the injection of cells into a blastocyst. The technology allows for the creation of chimeric animals, which have the potential to be used as an unlimited source ...of organ donors. Pluripotent stem cells could be generated from a patient in need of a transplantation and injected into a large animal blastocyst (potentially of a pig), leading to the creation of organ(s) allowing immunosuppression‐free transplantation. Various chimera combinations have already been generated, but one of the most recent steps leads to the creation of human‐pig chimeras, which could be studied at an embryo stage. Although still far from clinical reality, the potential application is almost unlimited. The present review illustrates the historical steps of intra‐ and interspecific blastocyst complementation in rodents and large animals, specifically looking at its potential for generation of organ grafts. We also speculate on how it could change transplant indications, on its economic impact, and on the linked ethical concerns.
C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy ((1)H MRS), we have repeatedly observed an abnormal neurochemical profile in the ...brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical "phenotype" resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Because of the wide availability of genetically modified animals, mouse orthotopic liver transplantation is often preferred over rat liver transplantation. We present a simplified mouse liver ...transplantation technique and compare transplantation outcomes with versus without hepatic artery anastomosis. Instruments for liver implantation were designed and printed with a 3‐dimensional (3D) printer. The suprahepatic vena cava anastomosis was performed with a 10‐0 running suture. The vena porta and infrahepatic vena cava were joined on extraluminal cuffs, using the 3D‐printed device for spatial alignment and stabilization. The hepatic artery was reconstructed in half of the recipients using intraluminal stents. Liver function tests (3, 7, and 28 days) and histology (7 and 28 days) were assessed after transplantation. We performed 22 consecutive syngeneic C57BL/6 mouse orthotopic liver transplantations. The median portal clamping time was 12.5 ± 1.5 minutes. The survival rate at 4 weeks was 100% for both arterialized and nonarterialized recipients (n = 7, 4 recipients of each group being killed for early histology at day 7). Liver function tests at 3, 7, and 28 days were similar between arterialized versus nonarterialized groups. Liver parenchyma demonstrated only irrelevant abnormalities in both groups. The proposed device allows for a shorter clamping time compared with the published literature. Using this technique, the artery does not need to be anastomosed, with no impact on graft and recipient outcomes. The device is available for 3D printing. Liver Transplantation 22 1688–1696 2016 AASLD.
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