1,720,982 research outputs found
Advances in the pathophysiology, diagnosis and management of chronic diarrhoea from bile acid malabsorption: a systematic review
No full text: Bile acid malabsorption (BAM) is an important disorder of digestive pathophysiology as it generates chronic diarrhoea. This condition originates from intricate pathways involving bile acid synthesis and metabolism in the liver and gut, the composition of gut microbiota, enterohepatic circulation and key receptors as farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and the G-protein bile acid receptor-1 (GPBAR-1). Although symptoms can resemble those related to disorders of gut brain interaction, accurate diagnosis of BAM may greatly benefit the patient. The empiric diagnosis of BAM is primarily based on the clinical response to bile acid sequestrants. Specific tests including the 48-hour fecal bile acid test, serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19), and the 75Selenium HomotauroCholic Acid Test (SeHCAT) are not widely available. Nevertheless, lack of diagnostic standardization of BAM may account for poor recognition and delayed management. Beyond bile acid sequestrants, therapeutic approaches include the use of FXR agonists, FGF19 analogues, glucagon-like peptide-1 (GLP-1) receptor agonists, and microbiota modulation. These novel agents can best make their foray into the therapeutic armamentarium if BAM does not remain a diagnosis of exclusion. Ignoring BAM as a specific condition may continue to contribute to increased healthcare costs and reduced quality of life. Here, we aim to provide a comprehensive review of the pathophysiology, diagnosis, and management of BAM
Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications
No full textNonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD
Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it?
No full textClinical and experimental advances related to the detection, magnitude and pathobiology of subclinical portal hypertension in non-alcoholic fatty liver disease (NAFLD), primarily observed in the presence of non-alcoholic steatohepatitis (NASH), prompt us to revisit current disease paradigms. Hepatic venous pressure gradient (HVPG) has been reported to underestimate portal pressure in NASH-related cirrhosis, while inaccuracy is more likely in non-cirrhotic livers, indicating a potential need for new and preferably non-invasive methods of measurement. Although clinically significant portal hypertension (HVPG ≥10 mmHg) retains its prognostic significance in NASH, subclinical portal hypertension (HVPG 6.0-9.5 mmHg) has been repeatedly detected in patients with NAFLD in the absence of cirrhosis or even significant fibrosis whereas the impact of these findings on disease outcomes remains unclear. Mechanocrine signalling pathways in various types of liver cell reveal a molecular basis for the adverse effects of subclinical portal hypertension and suggest a bidirectional relationship between portal pressure and fibrosis. These findings may guide efforts to improve risk assessment and identify novel therapeutic targets in NAFLD
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Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, and Prevention
No full textHepatocellular cancer (HCC) is the fifth most prevalent cancer worldwide and the third leading cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD), a spectrum of hepatic disorders associated with obesity and the metabolic syndrome, is a recognized risk factor for HCC. NAFLD that is advanced to cirrhosis carries the highest risk for HCC, but there is increasing concern that NAFLD-associated HCC may also occur in non-cirrhotic liver. As NAFLD is rapidly becoming the most common liver condition, it has been implicated in the worrisome trend of rising HCC incidence in a number of countries, which may offset successful measures in reducing the effect of virus-related liver cancer. Independently or in synergy with cirrhosis, NAFLD may provide a special oncogenic microenvironment through its pathogenic association with chronic nutrient excess and adipose tissue remodeling, characterized by pro-inflammatory adipokine profiles, lipotoxicity, altered hepatocellular bioenergetics, and insulin resistance. Better understanding of this complex process, and development of reliable biomarkers for HCC will be critical for early recognition and risk prediction. Moreover, correcting deranged lipid metabolism and restoring insulin sensitivity by lifestyle measures and targeted pharmacotherapy holds major promise for effective prevention of NAFLD-associated HCC.Version of Recor
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Uncoupling protein-2 and non-alcoholic fatty liver disease
No full textNon-alcoholic fatty liver disease (NAFLD) has become the most common form of hepatic disorders in the developed world. NAFLD is part of the metabolic syndrome with insulin resistance as a primary underlying derangement. The natural history of NAFLD may extend from simple steatosis over steatohepatitis into cirrhosis and hepatocellular carcinoma. Among numerous factors shaping these transitions, uncoupling protein-2 (UCP2) may theoretically contribute to every stage of this disease. UCP2 is a recently identified fatty acid-responsive mitochondrial inner membrane carrier protein showing wide tissue distribution with a substantially increased presence in fatty liver. The biological functions of UCP2 are not fully elucidated and the greater part of our current knowledge has been obtained from animal experiments. These data suggest a role for UCP2 in lipid metabolism, mitochondrial bioenergetics, oxidative stress, apoptosis, and even carcinogenesis. Available evidence is reviewed and new concepts are considered to appraise the potential role of UCP2 in the pathogenesis of NAFLD.Accepted Manuscrip
Mitochondrial uncoupling in cancer cells: Liabilities and opportunities
No full textAcquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochon- dria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the de- velopment of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the ‘contract of endosymbiosis’ represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This impor- tant property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Respiratory complex I, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.Version of Recor
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Novel strategies in the pharmacotherapy of nonalcoholic fatty liver disease
No full textNonalcoholic fatty liver disease (NAFLD) affects an estimated one billion people in the world. NAFLD is a spectrum of disease ranging from steatosis to steatohepatitis with variable outcomes that include cirrhosis and hepatocellular carcinoma. Lifestyle adjustment may be sufficient to manage steatosis, but success is difficult to achieve and sustain. In addition, patients with advanced forms of NAFLD or faster rates of progression need more efficient treatment. There is still no approved pharmacotherapy for NAFLD and current options have been limited to the secondary use of drugs developed for the treatment of obesity or diabetes and to hepatoprotective agents for the effect of which the strength of evidence is variable. However, recent advances in pharmaceutical research may soon change the landscape with several promising drug candidates in the pipeline designed to target specific molecular mechanisms implicated in the pathogenesis of NAFLD.Version of Recor
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Decoding multifocal hepatocellular carcinoma: an opportune pursuit
No full textHepatocellular carcinoma (HCC) is a malignancy with major worldwide prevalence and a poor overall prognosis. About 75% of all HCC cases are initially diagnosed as multiple tumors, presenting a particular challenge for aggressive surgical therapy. Multiple HCC may result from multicentric occurrence (MO-HCC) or intrahepatic metastases (IM-HCC), corresponding to highly dissimilar clinical outcomes. Reliable distinction of these two mechanisms is therefore paramount in optimizing the management of multiple HCC. In a recent work, Miao et al. adopted a multi-omics approach to find key parameters of different clonality in MO-HCC vs. IM-HCC and link these data to tumor behavior and prognosis in a cohort of patients with HBV-related HCC. The mitotic checkpoint regulator TTK has emerged from this analysis as a novel biomarker that may predict aggressive behavior and early postoperative recurrence of HCC.Accepted Manuscrip
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The Impact of Network Medicine in Gastroenterology and Hepatology
No full textIn the footsteps of groundbreaking achievements made by biomedical research, another scientific revolution is unfolding. Systems biology draws from the chaos and complexity theory and applies computational models to predict emerging behavior of the interactions between genes, gene products, and environmental factors. Adaptation of systems biology to translational and clinical sciences has been termed network medicine, and is likely to change the way we think about preventing, predicting, diagnosing, and treating complex human diseases. Network medicine finds gene-disease associations by analyzing the unparalleled digital information discovered and created by high-throughput technologies (dubbed as “omics” science) and links genetic variance to clinical disease phenotypes through intermediate organizational levels of life such as the epigenome, transcriptome, proteome, and metabolome. Supported by large reference databases, unprecedented data storage capacity, and innovative computational analysis, network medicine is poised to find links between conditions that were thought to be distinct, uncover shared disease mechanisms and key drivers of the pathogenesis, predict individual disease outcomes and trajectories, identify novel therapeutic applications, and help avoid off-target and undesirable drug effects. Recent advances indicate that these perspectives are increasingly within our reach for understanding and managing complex diseases of the digestive system.Accepted Manuscrip
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MicroRNAs in Nonalcoholic Fatty Liver Disease
Full text linkNonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD.Accepted Manuscrip
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