Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules ...with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.
The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver ...disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease.
Physical activity and liver diseases Berzigotti, Annalisa; Saran, Uttara; Dufour, Jean‐François
Hepatology,
March 2016, Letnik:
63, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Regular physical activity beneficially impacts the risk of onset and progression of several chronic diseases. However, research regarding the effects of exercising on chronic liver diseases is ...relatively recent. Most researchers focused on nonalcoholic fatty liver disease (NAFLD), in which increasing clinical and experimental data indicate that skeletal muscle crosstalking to the adipose tissue and the liver regulates intrahepatic fat storage. In this setting, physical activity is considered to be required in combination with calories restriction to allow an effective decrease of intrahepatic lipid component, and despite that evidence is not conclusive, some studies suggest that vigorous activity might be more beneficial than moderate activity to improve NAFLD/nonalcoholic steatohepatitis. Evidence regarding the effects of exercise on the risk of hepatocellular carcinoma is scarce; some epidemiological studies indicate a lower risk in patients regularly and vigorously exercising. In compensated cirrhosis, exercise acutely increases portal pressure, but in the longer term it has been proved safe and probably beneficial. Decreased aerobic capacity (VO2) correlates with mortality in patients with decompensated cirrhosis, who are almost invariably sarcopenic. In these patients, VO2 is improved by physical activity, which might also reduce the risk of hepatic encephalopathy through an increase in skeletal muscle mass. In solid organ transplantation recipients, exercise is able to improve lean mass, muscle strength, and, as a consequence, aerobic capacity. Few data exist in liver transplant recipients, in whom exercise should be an object of future studies given its high potential of providing long‐term beneficial effects. Conclusions: Despite that evidence is far from complete, physical activity should be seen as an important part of the management of patients with liver disease in order to improve their clinical outcome. (Hepatology 2016;63:1026–1040)
In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive ...strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.
Knowledge on SARS-CoV-2 infection and its resultant COVID-19 in liver diseases has rapidly increased during the pandemic. Hereby, we review COVID-19 liver manifestations and pathophysiological ...aspects related to SARS-CoV-2 infection in patients without liver disease as well as the impact of COVID-19 in patients with chronic liver disease (CLD), particularly cirrhosis and liver transplantation (LT). SARS-CoV-2 infection has been associated with overt proinflammatory cytokine profile, which probably contributes substantially to the observed early and late liver abnormalities. CLD, particularly decompensated cirrhosis, should be regarded as a risk factor for severe COVID-19 and death. LT was impacted during the pandemic, mainly due to concerns regarding donation and infection in recipients. However, LT did not represent a risk factor per se of worse outcome. Even though scarce, data regarding COVID-19 specific therapy in special populations such as LT recipients seem promising. COVID-19 vaccine-induced immunity seems impaired in CLD and LT recipients, advocating for a revised schedule of vaccine administration in this population.
Hepatocellular carcinoma (HCC) ranks number three among the most frequent causes of death from solid tumors worldwide. With obesity and fatty liver diseases as risk factors on the rise, HCC ...represents an ever increasing challenge. While there is still no curative treatment for most patients numerous novel drugs have been proposed, but most ultimately failed in phase III trials. This manuscript targets therapeutic advances and most burning issues. Expert key point summaries and urgent research agenda are provided regarding risk factors, including microbiota, need for prognostic and predictive biomarkers and the equivocal role of liver biopsy. Therapeutic topics highlighted are locoregional techniques, combination therapies and the potential of immunotherapy. Finally the manuscript provides a critical evaluation of novel targets and strategies for personalized treatment of HCC.
The selection of liver transplantation (LT) candidates with hepatocellular carcinoma (HCC) is currently validated based on Milan criteria. The use of extended criteria has remained a matter of ...debate, mainly because of the absence of prospective validation. The present prospective study recruited patients according to the previously proposed total tumor volume (TTV; ≤115 cm3)/alpha‐fetoprotein (AFP; ≤400 ng/mL) score. Patients with AFP >400 ng/mL were excluded, and, as such, the Milan group was modified to include only patients with AFP <400 ng/mL; these patients were compared to patients beyond Milan, but within TTV/AFP. From January 2007 to March 2013, 233 patients with HCC were listed for LT. Of them, 195 patients were within Milan and 38 beyond Milan, but within TTV/AFP. The average follow‐up from listing was 33.9 ± 24.9 months. Risk of dropout was higher for patients beyond Milan, but within TTV/AFP (16 of 38; 42.1%), than for those within Milan (49 of 195 25.1%; P = 0.033). In parallel, intent‐to‐treat survival from listing was lower in patients beyond Milan (53.8% vs. 71.6% at 4 years; P < 0.001). After a median waiting time of 8 months, 166 patients were transplanted, 134 within Milan criteria, and 32 beyond Milan but within TTV/AFP. They demonstrated acceptable and similar recurrence rates (4.5% vs. 9.4%; P = 0.138) and post‐transplant survivals (78.7% vs. 74.6% at 4 years; P = 0.932). Conclusion: Based on the present prospective study, HCC LT candidate selection could be expanded to the TTV (≤115 cm3)/AFP (≤400 ng/mL) criteria in centers with at least 8‐month waiting time. An increased risk of dropout on the waiting list can be expected, but with equivalent and satisfactory post‐transplant survival. (Hepatology 2015;62:158‐165)
Hepatocellular carcinoma (HCC) is one of the commonest causes of death from cancer. A plethora of metabolomic investigations of HCC have yielded molecules in biofluids that are both up‐ and ...down‐regulated but no real consensus has emerged regarding exploitable biomarkers for early detection of HCC. We report here a different approach, a combined transcriptomics and metabolomics study of energy metabolism in HCC. A panel of 31 pairs of HCC tumors and corresponding nontumor liver tissues from the same patients was investigated by gas chromatography‐mass spectrometry (GCMS)‐based metabolomics. HCC was characterized by ∼2‐fold depletion of glucose, glycerol 3‐ and 2‐phosphate, malate, alanine, myo‐inositol, and linoleic acid. Data are consistent with a metabolic remodeling involving a 4‐fold increase in glycolysis over mitochondrial oxidative phosphorylation. A second panel of 59 HCC that had been typed by transcriptomics and classified in G1 to G6 subgroups was also subjected to GCMS tissue metabolomics. No differences in glucose, lactate, alanine, glycerol 3‐phosphate, malate, myo‐inositol, or stearic acid tissue concentrations were found, suggesting that the Wnt/β‐catenin pathway activated by CTNNB1 mutation in subgroups G5 and G6 did not exhibit specific metabolic remodeling. However, subgroup G1 had markedly reduced tissue concentrations of 1‐stearoylglycerol, 1‐palmitoylglycerol, and palmitic acid, suggesting that the high serum α‐fetoprotein phenotype of G1, associated with the known overexpression of lipid catabolic enzymes, could be detected through metabolomics as increased lipid catabolism. Conclusion: Tissue metabolomics yielded precise biochemical information regarding HCC tumor metabolic remodeling from mitochondrial oxidation to aerobic glycolysis and the impact of molecular subtypes on this process. (HEPATOLOGY 2013)
mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, ...has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.
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