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Clinical Journal of the American... May 2019Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central... (Review)
Review
Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme kidney vasoconstriction leading to decreased GFR. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years. The mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal syndrome need to be clarified. Early diagnosis is central in the management and recent changes in the definition of hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option. Several controlled studies proved that terlipressin is effective at reversing hepatorenal syndrome and may improve short-term survival. Not all patients are responders, and even in responders, early mortality rates are very high in the absence of liver transplantation. Liver transplantation is the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) is often a challenging yet important step because vasoconstrictors are not justified for the treatment of ATN. Hepatorenal syndrome and ATN may be considered as a continuum rather than distinct entities. Emerging biomarkers may help differentiate these two conditions and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the decision for simultaneous liver-kidney transplantation.
Topics: Acute Kidney Injury; Biomarkers; Hepatorenal Syndrome; Humans; Kidney Transplantation; Liver Cirrhosis; Liver Transplantation
PubMed: 30996046
DOI: 10.2215/CJN.12451018 -
Annals of Hepatology Nov 2017The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile,... (Review)
Review
The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat, as well as bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolism by activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and glucose metabolism.
Topics: Animals; Bacteria; Bile Acids and Salts; Energy Metabolism; Enterohepatic Circulation; Feces; Gallbladder; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Intestines; Lipid Metabolism; Liver; Signal Transduction
PubMed: 29080336
DOI: 10.5604/01.3001.0010.5493 -
Journal of Hepatology Jul 2021Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acute-on-chronic liver failure, which is characterised by hepatic and... (Review)
Review
Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acute-on-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure(s). The pathomechanisms involved in decompensation and disease progression are still not well understood, and as specific disease-modifying treatments do not exist, research to identify novel therapeutic targets is of the utmost importance. This review amalgamates the latest knowledge on disease mechanisms that lead to tissue injury and extrahepatic organ failure - such as systemic inflammation, mitochondrial dysfunction, oxidative stress and metabolic changes - and marries these with the classical paradigms of acute decompensation to form a single paradigm. With this detailed breakdown of pathomechanisms, we identify areas for future research. Novel disease-modifying strategies that break the vicious cycle are urgently required to improve patient outcomes.
Topics: Acute-On-Chronic Liver Failure; Humans; Inflammation; Liver Circulation; Liver Cirrhosis; Oxidative Stress; Prognosis
PubMed: 34039492
DOI: 10.1016/j.jhep.2021.01.002 -
Journal of Cardiology Sep 2019The Fontan procedure has led to increased long-term survival of patients with single ventricle congenital heart disease. Hemodynamic changes associated with the Fontan... (Review)
Review
The Fontan procedure has led to increased long-term survival of patients with single ventricle congenital heart disease. Hemodynamic changes associated with the Fontan circulation, including elevated central venous pressure and diminished cardiac output are responsible for the development of Fontan-associated liver disease (FALD). Liver fibrosis is a universal feature following the Fontan operation. The incidence of both liver cirrhosis and hepatocellular carcinoma (HCC) increases with the duration of the Fontan circulation. The staging of liver fibrosis in FALD requires a multi-modality approach involving clinical assessment, biochemical/hematological parameters, non-invasive fibrosis scores, radiological imaging, elastography, and liver histology. Patients with a failing Fontan circulation who have evidence of significant hepatic congestion require careful hemodynamic assessment to optimize the Fontan pathway and physiology. This may necessitate percutaneous or surgical intervention, or heart transplantation. Combined heart-liver transplantation may be required in patients with clinical, imaging, or biopsy evidence of advanced liver cirrhosis, particularly if there is evidence of hepatic decompensation or localized HCC. Patients with suspected liver cirrhosis should be enrolled into HCC surveillance and require endoscopic variceal assessment. There is a clear need to establish local/national registries for Fontan patients with standardized guidelines for the management of FALD, bringing together the expertise of professional bodies representing both cardiologists and hepatologists.
Topics: Carcinoma, Hepatocellular; Cardiac Output, Low; Central Venous Pressure; Female; Fontan Procedure; Heart Transplantation; Humans; Incidence; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Male; Postoperative Complications; Registries; Time Factors; Univentricular Heart
PubMed: 30928109
DOI: 10.1016/j.jjcc.2019.02.016 -
International Journal of Molecular... Dec 2020Liver disease resulting from heart failure (HF) has generally been referred as "cardiac hepatopathy". One of its main forms is congestive hepatopathy (CH), which results... (Review)
Review
Liver disease resulting from heart failure (HF) has generally been referred as "cardiac hepatopathy". One of its main forms is congestive hepatopathy (CH), which results from passive venous congestion in the setting of chronic right-sided HF. The current spectrum of CH differs from earlier reports with HF, due to ischemic cardiomyopathy and congenital heart disease having surpassed rheumatic valvular disease. The chronic passive congestion leads to sinusoidal hypertension, centrilobular fibrosis, and ultimately, cirrhosis ("cardiac cirrhosis") and hepatocellular carcinoma after several decades of ongoing injury. Contrary to primary liver diseases, in CH, inflammation seems to play no role in the progression of liver fibrosis, bridging fibrosis occurs between central veins to produce a "reversed lobulation" pattern and the performance of non-invasive diagnostic tests of liver fibrosis is poor. Although the clinical picture and prognosis is usually dominated by the underlying heart condition, the improved long-term survival of cardiac patients due to advances in medical and surgical treatments are responsible for the increased number of liver complications in this setting. Eventually, liver disease could become as clinically relevant as cardiac disease and further complicate its management.
Topics: Heart Failure; Humans; Liver; Liver Circulation; Liver Diseases
PubMed: 33321947
DOI: 10.3390/ijms21249420 -
Cell Metabolism Jan 2018Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to... (Clinical Trial)
Clinical Trial
Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles. Pulse-chase and intravital imaging experiments suggested EVs liberated by exercise have a propensity to localize in the liver and can transfer their protein cargo. Moreover, by employing arteriovenous balance studies across the contracting human limb, we identified several novel candidate myokines, released into circulation independently of classical secretion. These data identify a new paradigm by which tissue crosstalk during exercise can exert systemic biological effects.
Topics: Adult; Animals; Chromatography, High Pressure Liquid; Cytokines; Endocytosis; Exercise; Exosomes; Extracellular Vesicles; Female; Glycolysis; Humans; Intravital Microscopy; Isotope Labeling; Liver; Male; Mice; Mice, Inbred C57BL; Nanotechnology; Organ Specificity; Proteome; Proteomics; Tandem Mass Spectrometry
PubMed: 29320704
DOI: 10.1016/j.cmet.2017.12.001 -
Gut Jan 2022Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are... (Review)
Review
Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.
Topics: Cholestasis; Gastrointestinal Agents; Humans; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear
PubMed: 34615727
DOI: 10.1136/gutjnl-2021-324305 -
Circulation Aug 2020Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An... (Review)
Review
Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.
Topics: Animals; Fontan Procedure; Heart Transplantation; Humans; Liver Diseases; Liver Transplantation; Postoperative Complications
PubMed: 32776846
DOI: 10.1161/CIRCULATIONAHA.120.045597