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Trends in Pharmacological Sciences Nov 2020Metformin can improve patients' hyperglycemia through significant suppression of hepatic glucose production. However, up to 300 times higher concentrations of metformin... (Review)
Review
Metformin can improve patients' hyperglycemia through significant suppression of hepatic glucose production. However, up to 300 times higher concentrations of metformin accumulate in the intestine than in the circulation, where it alters nutrient metabolism in intestinal epithelial cells and microbiome, leading to increased lactate production. Hepatocytes use lactate to make glucose at the cost of energy expenditure, creating a futile intestine-liver cycle. Furthermore, metformin reduces blood lipopolysaccharides and its initiated low-grade inflammation and increased oxidative phosphorylation in liver and adipose tissues. These metformin effects result in the improvement of insulin sensitivity and glucose utilization in extrahepatic tissues. In this review, I discuss the current understanding of the impact of metformin on systemic metabolism and its molecular mechanisms of action in various tissues.
Topics: Animals; Glucose; Glycolysis; Humans; Hyperglycemia; Intestinal Mucosa; Intestines; Lipid Metabolism; Liver; Metabolism; Metformin; Microbiota
PubMed: 32994049
DOI: 10.1016/j.tips.2020.09.001 -
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 -
Circulation Aug 2019It has been 50 years since Francis Fontan pioneered the operation that today bears his name. Initially designed for patients with tricuspid atresia, this procedure is... (Review)
Review
It has been 50 years since Francis Fontan pioneered the operation that today bears his name. Initially designed for patients with tricuspid atresia, this procedure is now offered for a vast array of congenital cardiac lesions when a circulation with 2 ventricles cannot be achieved. As a result of technical advances and improvements in patient selection and perioperative management, survival has steadily increased, and it is estimated that patients operated on today may hope for a 30-year survival of >80%. Up to 70 000 patients may be alive worldwide today with Fontan circulation, and this population is expected to double in the next 20 years. In the absence of a subpulmonary ventricle, Fontan circulation is characterized by chronically elevated systemic venous pressures and decreased cardiac output. The addition of this acquired abnormal circulation to innate abnormalities associated with single-ventricle congenital heart disease exposes these patients to a variety of complications. Circulatory failure, ventricular dysfunction, atrioventricular valve regurgitation, arrhythmia, protein-losing enteropathy, and plastic bronchitis are potential complications of the Fontan circulation. Abnormalities in body composition, bone structure, and growth have been detected. Liver fibrosis and renal dysfunction are common and may progress over time. Cognitive, neuropsychological, and behavioral deficits are highly prevalent. As a testimony to the success of the current strategy of care, the proportion of adults with Fontan circulation is increasing. Healthcare providers are ill-prepared to tackle these challenges, as well as specific needs such as contraception and pregnancy in female patients. The role of therapies such as cardiovascular drugs to prevent and treat complications, heart transplantation, and mechanical circulatory support remains undetermined. There is a clear need for consensus on how best to follow up patients with Fontan circulation and to treat their complications. This American Heart Association statement summarizes the current state of knowledge on the Fontan circulation and its consequences. A proposed surveillance testing toolkit provides recommendations for a range of acceptable approaches to follow-up care for the patient with Fontan circulation. Gaps in knowledge and areas for future focus of investigation are highlighted, with the objective of laying the groundwork for creating a normal quality and duration of life for these unique individuals.
PubMed: 31256636
DOI: 10.1161/CIR.0000000000000696 -
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 -
Annals of Hepatology 2019Acute liver failure (ALF) is a severe condition secondary to a myriad of causes associated with poor outcomes. The prompt diagnosis and identification of the aetiology... (Review)
Review
Acute liver failure (ALF) is a severe condition secondary to a myriad of causes associated with poor outcomes. The prompt diagnosis and identification of the aetiology allow the administration of specific treatments plus supportive strategies and to define the overall prognosis, the probability of developing complications and the need for liver transplantation. Pivotal issues are adequate monitoring and the institution of prophylactic strategies to reduce the risk of complications, such as progressive liver failure, cerebral oedema, renal failure, coagulopathies or infections. In this article, we review the main aspects of ALF, including the definition, diagnosis and complications. Also, we describe the standard-of-care strategies and recent advances in the treatment of ALF. Finally, we include our experience of care patients with ALF.
Topics: Acetaminophen; Acute Kidney Injury; Amanita; Analgesics, Non-Narcotic; Biopsy; Blood Coagulation Disorders; Brain Edema; Chemical and Drug Induced Liver Injury; Extracorporeal Circulation; Female; Hemorrhage; Hepatitis B; Hepatitis, Autoimmune; Humans; Intracranial Hypertension; Liver; Liver Failure, Acute; Liver Transplantation; Mushroom Poisoning; Plasma Exchange; Pregnancy; Pregnancy Complications; Renal Replacement Therapy; Respiration, Artificial; Risk Assessment; Sepsis; Sorption Detoxification; Thrombelastography
PubMed: 31126880
DOI: 10.1016/j.aohep.2019.04.008 -
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 -
International Journal of Molecular... May 2022Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation,... (Review)
Review
Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.
Topics: Bile Acids and Salts; Cholesterol; Fibroblast Growth Factors; Liver; Receptors, Cytoplasmic and Nuclear; Signal Transduction
PubMed: 35682726
DOI: 10.3390/ijms23116046