Discovery and Validation of Non-invasive Biomarkers of Non Alcoholic Fatty Liver Disease PDF Download

Author: Michael H. Miller
Publisher:
ISBN:
Category :
Languages : en
Pages :

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Author: Manuel Romero-Gomez
Publisher: Springer Nature
ISBN: 3030371735
Category : Medical
Languages : en
Pages : 239

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This book provides a comprehensive overview of the diagnosis and management of Non-alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatis (NASH). Basic principles of disease progression, the genetic and nutritional basis of NAFLD and NASH are explained along with the proteomic principles underlying biomarker development. Chapters cover both biochemical and imaging biomarkers used in elastrography and ultrasound and discuss how these are applicable to early diagnosis and monitoring of NASH and NAFLD. This is a useful resource for hepatologists, primary care providers with an interest in metabolic disease, diabetologists and endocrinologists in their daily clinical practice.

Author: Patrik Nasr
Publisher: Linköping University Electronic Press
ISBN: 9176850382
Category :
Languages : en
Pages : 98

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population and is commonly recognized as the hepatic manifestation of the metabolic syndrome. The histological spectrum of NAFLD ranges from isolated steatosis to non-alcoholic steatohepatitis (NASH), with risk of developing fibrosis and subsequent cirrhosis and hepatocellular carcinoma. The gold standard for diagnosing NAFLD is liver biopsy. However, because of its invasive nature, several non-invasive methods have been developed and validated in evaluating fat and fibrosis in patients with NAFLD. Liver fat content can be assessed using various methods. The conventional histopathological method consists of a visual semiquantitative approach in which the pathologist uses a four-point scale: grade 0 corresponds to fat deposition in <5% of hepatocytes and grade 1?3 (which is needed for the diagnosis of NAFLD) corresponds to ?5%. An alternate approach is to quantitatively assess steatosis using stereological point counting (SPC) – which rely on liver biopsy. However, in vivo proton magnetic resonance spectroscopy (1H-MRS) is a reliable noninvasive method that can be used to quantitatively assess total hepatic lipid content, or proton density fat fraction (PDFF). In Paper I we compared the conventional semiquantitative histological method (grade 0-3) with SPC and 1H-MRS. We found a strong positive correlation between 1H-MRS and SPC, whereas the correlations between 1H-MRS or SPC and histopathological grading were substantially weaker. Using the widely used cut-off value of PDFF ?5%, all participants were found to have steatosis (specificity 100%, sensitivity 53%). Reducing the cut-off value to 3% maintained 100% specificity while increasing sensitivity to 79%. In Paper IV we evaluated quantitative steatosis, by SPC, in 106 biopsy-proven NAFLD patients during a 20-year follow-up. SPC was independently associated with an increased risk of all-cause mortality and development of T2DM. Moreover, in the 59 patients with sequential biopsies (approximately 10 years apart), a reduction of quantitative hepatic steatosis decreased the all-time risk of developing T2DM. NASH is commonly seen as a histological feature portending a worse prognosis in NAFLD. Interestingly, no dual biopsy study has ever shown that NASH predicts fibrosis progression. Yet, NASH is seen as a surrogate marker in pharmaceutical trials – were resolution in NASH is equivalent to future resolution of fibrosis. In Paper II we conducted a long-term follow-up study (20 years) in a large cohort of biopsy-proven NAFLD patients (n=646), in a collaboration with Karolinska Institute. We could not ascertain that NASH had any effect on all-cause, or disease-specific mortality. However, higher stages of fibrosis predicted all-cause and disease specific mortality. In Paper III, we present 129 biopsy-proven NAFLD patients, in which we had prospective, longitudinal data. They were included between 1988 and 1993. All patients alive, were re-invited 2003-2005 and 2013-2015. Dual biopsies were present in 68 patients, and three consecutive biopsies were available in 33 patients. Results showed that NAFLD is a highly heterogeneous disease, with 9.3% developing end-stage liver disease and 16% progressing to advanced stages of fibrosis without any clinically significant baseline data predicting disease progression. In summary, when using 1H-MRS as a diagnostic method for NAFLD, the diagnostic cut-off should be reduced from 5% to 3%. Furthermore, quantitative amount of hepatic steatosis could be used to stratify patients with NAFLD related to future risk of developing T2DM. Moreover, we have shown that NASH does not predict future all-cause or disease-specific mortality nor end-stage liver disease, therefore a different surrogate marker should be used in clinical trials when assessing NAFLD improvement, so to not imbue false reliance in new therapies. Lastly, we have shown that NAFLD has a more dismal prognosis than previously reported, and that it is unexpectedly difficult to predict fibrosis progression in individual NAFLD patients, emphasizing the need for robust non-invasive biomarkers suitable to monitor large number of patients.

Author: Roger Williams
Publisher: John Wiley & Sons
ISBN: 1118924959
Category : Medical
Languages : en
Pages : 256

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Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease offers hepatologists practical, up-to-date and expert guidance on the most topical dilemmas, difficulties and areas of controversy/difficulty surrounding this ever-increasing area of liver disease they face in daily practice. Roger Williams and Simon Taylor-Robinson, two of Europe’s leading hepatologists, have recruited leading figures from across the world to assist them, resulting in a truly international approach. Each chapter covers a specific area of difficulty, containing clear learning points and providing evidence-based expert guidance on the latest hot topics in clinical management such as: Is NAFLD different in absence of Metabolic Syndrome? Are the pros outweighed by the cons of obtaining a liver biopsy? Is progression to cirrhosis more likely in children with NAFLD? What are the dangers as well as the true benefits of bariatric surgery? How is it best to use antifibrotic agents in clinical practice? Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease provides the answers to the questions and challenges that clinicians face every day in this area. It is essential reading for hepatologists of all levels and researchers in hepatology, as well as all those involved in the care of patients with NAFLD, including gastroenterologists, pathologists and specialist hepatology nurses.

Author: Markus Karlsson
Publisher: Linköping University Electronic Press
ISBN: 9179299423
Category :
Languages : en
Pages : 77

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There is a large and unmet need for diagnostic tool that can be used to characterize chronic liver diseases (CLD). In the earlier stages of CLD, much of the diagnostics involves performing biopsies, which are evaluated by a histopathologist for the presence of e.g. fat, iron, inflammation, and fibrosis. Performing biopsies, however, have two downsides: i) biopsies are invasive and carries a small but non-negligible risk for serious complications, ii) biopsies only represents a tiny portion of the liver and are thus prone to sampling error. Moreover, in the later stages of CLD, when the disease has progressed far enough, the ability of the liver to perform its basic function will be compromised. In this stage, there is a need for better methods for accurately measuring liver function. Additionally, measures of liver function can also be used when developing new drugs, as biomarkers for drug-induced liver injury (DILI), which is a serious drug-safety issue. Magnetic resonance imaging (MRI) is a non-invasive medical imaging modality, which have shown much promise with regards to characterizing liver disease in all of the abovementioned aspects. The aim of this PhD project was to develop and validate MR-based methods that can be used to non-invasively characterize liver disease. Paper I investigated if R2* mapping, a MR-method for measuring liver iron content, can be confounded by liver fat. The results show fat does affect R2*. The conclusion was therefore that fat must be taken into account when measuring small amounts of liver iron, as a small increase in R2* could be due to either small amounts of iron or large amounts of fat. Paper II examined whether T1 mapping, which is another MR-method, can be used for staging liver fibrosis. The results of previous research have been mixed; some studies have been very promising, whereas other studies have been less promising. Unfortunately, the results in Paper II belongs to the less promising studies. Paper III focused on measuring liver function by dynamic contrast-enhanced MRI (DCEMRI) using a liver specific contrast agent, which is taken up the hepatocytes and excreted to the bile. The purpose of the paper was to extend and validate a method for estimating uptake and efflux rates of the contrast agent. The method had previously only been applied in health volunteers. Paper II showed that the method can be applied to CLD patients and that the uptake of the contrast agent is lower in patients with advanced fibrosis. Paper IV also used studied liver function with DCE-MRI in patients with primary sclerosing cholangitis (PSC). PSC is a CLD where the bile ducts are attacked by the immune system. When diagnosing PSC patients, it is common to use magnetic resonance cholangiopancreatography (MRCP), which is a method for imaging the bile ducts. Paper IV examined if there was any correlation between number and severity of the morphological changes, seen on MRCP, and measures of liver function derived using DCE-MRI. However, the results showed no such correlation. The conclusion was that the results indicates that MRCP should not be used to predict parenchymal function. Paper V developed a method for translating DCE-MRI liver function parameters from rats to humans. This translation could be of value when developing new drugs, as a tool for predicting which drugs might cause drug-induced liver injury. In summary, this thesis has shown that multimodal quantitative MR has a bright future for characterizing liver disease from a range of different aspects.

Author: Sandra J. Page
Publisher:
ISBN:
Category : Biochemical markers
Languages : en
Pages : 0

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Obesity is on the rise in populations across the world, and represents a major health concern. It is a component of Metabolic Syndrome, a collection of risk factors that predispose to diabetes and cardiovascular disease. Metabolic Syndrome is often accompanied by non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disease ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Currently, the gold standard for NASH and liver fibrosis diagnostics is liver biopsy; thus, a non-invasive procedure for detecting and staging NAFLD is greatly needed. The research presented herein involves evaluating various kinds of soluble biomarkers and the development of a novel, serum-based biomarker panel for NASH and NASH-related fibrosis. The biomarker panel comprises proteins that reflect the disease process of NASH and NASH-related fibrosis, including hormones derived from adipose tissue (adipokines) and proteins involved in fibrogenesis and cell death. While the sample size in this study was small at 79 patients, it is anticipated that subsequent testing of the panel on larger populations of NAFLD patients will ultimately support its use in clinical settings. A second study was conducted with the goal of discovering novel, as-of-yet untested biomarkers of NASH and NASH-related fibrosis that may be tied to the deregulation of cell signaling pathways in adipose tissue. A previous study used a phosphoproteomic approach to discover that several kinase-driven pathways were deregulated in the adipose tissue of patients with NASH and NASH-related fibrosis; enrichment analysis showed that these pathways were linked to the regulation of cell functions by insulin, as well as signal transduction by AKT and PIP3. Subsequent pathway analyses were then conducted to identify a set of secreted, soluble proteins associated with these pathways. From this set two promising candidates were selected based on extensive literature searches; these were the chemokine CCL-2/MCP-1, and soluble Fas ligand. These candidates were then tested on a small cohort of patients with NASH and NASH-related fibrosis to determine if they had the potential to be diagnostically predictive, and it was discovered that both worked reasonably well as biomarkers of fibrosis. Consequently, these molecules may be released at abnormal levels by adipose tissue in patients with NAFLD and may in turn play a role in fibrogenesis associated with NASH; they would therefore be good candidates to test in future development of biomarker panels for NASH-related fibrosis. A third study was undertaken to evaluate the association between levels of various soluble molecules and fatigue in patients with NAFLD or hepatitis C. Specifically, I correlated self-reported assessments of fatigue dissecting this condition into fatigue associated with physical activity (peripheral fatigue) or more global lack of energy and motivation (central fatigue) with measures of inflammation, or with abnormalities of glucose and lipid metabolism. The study demonstrated that a substantial majority of patients with chronic liver disease report significant peripheral fatigue. This type of fatigue was linked to elevated serum levels of IL-6 and IL-8, linking it to an inflammatory component, which is not the case for central fatigue.

Author: Emad Hamdy Gad
Publisher: BoD – Books on Demand
ISBN: 1839628693
Category : Medical
Languages : en
Pages : 146

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Non-alcoholic fatty liver disease (NAFLD) is a major medical challenge because of its increasing prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. In the near future, it will become the major form of chronic liver disease in adults and children and the leading indication for liver transplantation. It can be detected by noninvasive and invasive tools, and its treatment depends mainly on lifestyle modification to prevent disease progression and its related sequelae. This book provides information on NAFLD prevalence, etiology, pathogenesis, pathology, diagnosis, and treatment. Chapters cover such topics as experimental work related to the disease, other diseases related to NAFLD, and noninvasive tools for diagnosis.

Author: Geoffrey C. Farrell
Publisher: John Wiley & Sons
ISBN: 1118556224
Category : Medical
Languages : en
Pages : 438

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Book Description
The sharp rise in cases of Non-alcoholic fatty liver disease is fast becoming one of the major concerns for hepatologists worldwide. This comprehensive clinical guide explains how to diagnose NAFLD and manage patients according to the best standards of care. Contributors from the world's leading institutions concentrate on patient care, drawing on their extensive experience.

Author: Catherine Emer Fitzpatrick
Publisher:
ISBN:
Category : Biochemical markers
Languages : en
Pages : 416

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Book Description
Prevalence of nonalcoholic fatty liver disease (NAFLD) in children is rising exponentially, mirroring the increase in paediatric obesity. The spectrum ranges from simple steatosis to inflammation and fibrosis (nonalcoholic steatohepatitis/NASH). A third of those with NASH may develop cirrhosis and/or hepatocellular carcinoma. Liver biopsy is the standard for establishing the diagnosis and assessing severity, but is limited by the potential risks. There is a real need for noninvasive methods of screening, stratifying disease severity and following disease progression over time. This thesis explores and evaluates noninvasive biomarkers of disease in children with NAFLD. -- An initial pilot study (n=45) evaluated serum markers of apoptosis, inflammation and fibrogenesis. CK18-M30 and leptin concentrations were found to be valuable markers of NAFLD activity. Following this, a panel of adipokines was investigated in a cohort of children with NAFLD (n=40). Plasminogen activator inhibitor, monocyte chemoattractant protein 1 and resistin were useful markers of disease. A prospective study (n=101) then combined transient elastography (TE) and blood biomarkers in children with various forms of chronic liver disease (including NAFLD). TE was the best predictor of fibrosis severity (AUROC 0.96 for cirrhosis). -- Proteomic studies suggest that the glycoprotein, lumican, may be a potential biomarker of NAFLD. Expression of lumican in liver tissue of children with NAFLD was quantified using histomorphometry and molecular biology. Lumican was found to be overexpressed at protein level (by 215%) and upregulated at pre-translational level (15x) with more severe disease. Finally, the role of glycosylation in NAFLD was evaluated by characterising the glycomic profile in serum of 51 paediatric patients. -- In conclusion, this thesis describes and evaluates a variety of noninvasive biomarkers of paediatric NAFLD.

Author: Naim Alkhouri
Publisher: CRC Press
ISBN: 1000928667
Category : Medical
Languages : en
Pages : 556

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Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity and metabolic syndrome epidemics, which this up-to-date book deals with comprehensively. The contents outline disease mechanisms, diagnostic tests, management, varying manifestations, and special populations. It covers the mechanistic pathways that contribute to NAFLD development, including the role of genetic variants and the gut microbiome. It elaborates on noninvasive diagnostic tests to screen for NAFLD, determine its severity, and monitor response to lifestyle intervention and pharmacologic treatment. This book helps clinicians diagnose and treat this common and potentially deadly disease. Key Features: Reviews current drugs in development and provides practical advice to clinicians on the diagnosis and management of fatty liver. Proves attractive to primary care providers who are on the front line of managing patients with NAFLD, to gastroenterologists and hepatologists who would benefit from updated data on how to risk-stratify patients and identify those who will be eligible for pharmacologic treatment, and other specialists such as cardiologists, endocrinologists, and nephrologists who will find this book to be a useful reference on the extrahepatic manifestations of NAFLD. Focuses on extrahepatic manifestations and new insights on the mechanistic drivers of the disease.