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1.
Alpha-1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by Epigenetic Heterogeneity With Links to Obesity.
Wang, L, Marek, GW, Hlady, RA, Wagner, RT, Zhao, X, Clark, VC, Fan, AX, Liu, C, Brantly, M, Robertson, KD
Hepatology (Baltimore, Md.). 2019;(1):51-66
Abstract
Alpha-1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5-methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early-stage AATD and the ZZ genotype, genome-wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver-impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome-wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well-known sex-specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.
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2.
A Metabonomics Approach to Drug Toxicology in Liver Disease and its Application in Traditional Chinese Medicine.
Su, G, Wang, H, Bai, J, Chen, G, Pei, Y
Current drug metabolism. 2019;(4):292-300
Abstract
BACKGROUND The progression of liver disease causes metabolic transformation in vivo and thus affects corresponding endogenous small molecular compounds. Metabonomics is a powerful technology which is able to assess global low-molecular-weight endogenous metabolites in a biological system. This review is intended to provide an overview of a metabonomics approach to the drug toxicology of diseases of the liver. METHODS The regulation of, and relationship between, endogenous metabolites and diseases of the liver is discussed in detail. Furthermore, the metabolic pathways involved in drug interventions of liver diseases are reviewed. Evaluation of the protective mechanisms of traditional Chinese medicine in liver diseases using metabonomics is also reviewed. Examples of applications of metabolite profiling concerning biomarker discovery are highlighted. In addition, new developments and future prospects are described. RESULTS Metabonomics can measure changes in metabolism relating to different stages of liver disease, so metabolic differences can provide a basis for the diagnosis, treatment and prognosis of various diseases. CONCLUSION Metabonomics has great advantages in all aspects of the therapy of liver diseases, with good prospects for clinical application.
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3.
Liver R2* is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease.
Karlsson, M, Ekstedt, M, Dahlström, N, Forsgren, MF, Ignatova, S, Norén, B, Dahlqvist Leinhard, O, Kechagias, S, Lundberg, P
Journal of magnetic resonance imaging : JMRI. 2019;(1):325-333
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Abstract
BACKGROUND Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement. PURPOSE To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD. STUDY TYPE Prospective. POPULATION Eighty-one patients with suspected CLD. FIELD STRENGTH/SEQUENCE 1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF. ASSESSMENT Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated. STATISTICAL TESTS Pearson correlation, linear regression, and area under the receiver operating curve. RESULTS There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively. DATA CONCLUSION PDFF increases R2*. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.
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Challenges and future developments in liver transplantation.
Toniutto, P, Bitetto, D, Fornasiere, E, Fumolo, E
Minerva gastroenterologica e dietologica. 2019;(2):136-152
Abstract
Liver transplantation (LT) has become the treatment of choice for a wide range of liver diseases in both adult and pediatric patients. Until recently, the largest proportion of LT in adults, were performed in patients with hepatitis C (HCV) related cirrhosis. The recent availability of safe and effective direct antiviral agents to cure HCV infection in almost all patients whatever the HCV genotype and severity of liver disease, will reduce the need for LT in this category of recipients. Thus, it is presumed that in the next 1 to 2 decades HCV related liver disease will diminish substantially, whereas non-alcoholic steato-hepatitis (NASH) will correspondingly escalate as an indication for LT. The greatest challenges facing LT remain the limited supply of donor organs, and the need for chronic immunosuppression, which represent the true obstacles to the greater application and durable success of the LT procedure. This review aimed to highlight, in different sections, the main open issues and future developments in LT. These will be focused to explore current and future strategies to maximize the use of limited organs, to offer an update on potential new approaches to immunosuppression and to imagine new indications for LT when the number of patients awaiting transplants for HCV related liver disease is reduced.
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Contrast-Enhanced Ultrasound for the Characterization of Malignant versus Benign Focal Liver Lesions in a Prospective Multicenter Experience - The SRUMB Study.
Sporea, I, Săndulescu, DL, Şirli, R, Popescu, A, Danilă, M, Spârchez, Z, Mihai, C, Ioanițescu, S, Moga, T, Timar, B, et al
Journal of gastrointestinal and liver diseases : JGLD. 2019;:191-196
Abstract
AIM: This study evaluated the accuracy of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of benign vs. malignant focal liver lesions (FLL) in a real-life, multicenter experience. METHODS This prospective study, including 14 Romanian centers, was performed over a 6 year period (February 2011- April 2017) and included 2062 FLLs assessed by CEUS. Inclusion criteria were: newly diagnosed FLL on B-mode ultrasound, less than three lesions/patient, all FLLs evaluated by CEUS and by a second-line imaging technique (contrast enhanced CT or contrast enhanced MRI) or histology, considered as reference. The trial was registered in clinicaltrials.gov (Identifier NCT01329458). RESULTS From the 2062 FLLs included in the study, 57.2% (1179) were malignant and 42.8% (883) were benign. CEUS had 83.9% sensitivity (Se), 97.8% specificity (Sp), 98.1% positive predictive value (PPV), 82.2% negative predictive value (NPV) and a diagnostic accuracy (Ac) of 89.9% for the positive diagnosis of malignant lesions. For the benign lesions, CEUS had 97.8% Se, 83.9% Sp, 82.2% PPV, 98.1% NPV 89.9% Ac. The diagnostic performance of CEUS for hepatocellular carcinoma was 76.6% Se, 98.4% Sp, and 91.2% Ac; for hemangioma: 89.2% Se, 99% Sp, and 96.9% Ac and for metastases: 90.9% Se, 98.4% Sp, and 96.9% Ac. CONCLUSIONS CEUS proved a high accuracy in differentiating the malignant vs. benign character of a FLL. It can be confidently used as a first line imaging method in daily practice.
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Updates on hepatic homeostasis and the many tiers of hepatobiliary repair.
Monga, SP
Nature reviews. Gastroenterology & hepatology. 2019;(2):84-86
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The changing epidemiology of liver diseases in the Asia-Pacific region.
Wong, MCS, Huang, JLW, George, J, Huang, J, Leung, C, Eslam, M, Chan, HLY, Ng, SC
Nature reviews. Gastroenterology & hepatology. 2019;(1):57-73
Abstract
This Review presents current epidemiological trends of the most common liver diseases in Asia-Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia-Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.
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8.
Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment.
Ng, J, Duan, WR, Marbury, T, Schmidt, JM, Klein, CE
Clinical pharmacology in drug development. 2019;(8):1053-1061
Abstract
The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic). Intensive pharmacokinetic blood samples were collected. Elagolix exposures were comparable in women with normal renal function and those with moderate/severe renal impairment or end-stage renal disease. Elagolix exposures also appeared to be similar in women with normal hepatic function and women with mild hepatic impairment. Elagolix area under the curve in women with moderate hepatic impairment and with severe hepatic impairment was approximately 3-fold and 7-fold higher than in women with normal hepatic function. The adverse event incidence was low, with the main events being mild nausea and headache. No dosage adjustment was needed in women with renal impairment or women with mild hepatic impairment. Although an elagolix dose of 150 mg once daily may be used in women with moderate hepatic impairment for up to 6 months, this elagolix dose should not be used in women with severe hepatic impairment.
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REVIEW- Contemporary evidence on the dynamic role of probiotics in liver diseases.
Ahmed, B, Rasul, A, Tareen, KZ, Hamid Akash, MS, Muhammad, SA, Irfan, M, Abbas, K, Qadir, MI
Pakistan journal of pharmaceutical sciences. 2019;(6):2765-2770
Abstract
Currently probiotics are considered as an emerging therapeutic strategy in the treatment of many liver disorders. The use of probiotics beyond infection of intestinal flora is a very helpful approach. The optimistic effect of probiotics has been observed in treating the hepatic cirrhosis, hepatic encephalopathy, viral hepatitis, irritable bowel syndrome, non-alcoholic fatty liver and alcoholic liver disease. The characterize mechanisms of probiotics are still unknown but may involve in, maintaining a microbial barrier against potential pathogens, reducing the production of bacterial toxins, modulating the immune system, intestinal permeability, and the inflammatory response. Its safety issues, effectiveness, food supplements as its source are still to be studied. However, studies revealed that probiotic therapy in hepatocellular carcinoma and in portal hypertension are still weak. Larger clinical studies are required before probiotics can be recommended as a treatment modality in liver diseases.
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10.
Measurement of the enriched stable isotope 58Fe in iron related disorders- comparison of INAA and MC-ICP-MS.
Yagob, T, van de Wiel, A, Bode, P, Demir, A, van der Wagt, B, Krystek, P, Wolterbeek, B
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2019;:77-83
Abstract
As a safer alternative for the use of radioactive tracers, the enriched stable 58Fe isotope has been introduced in studies of iron metabolism. In this study this isotope is measured with instrumental neutron activation analysis (INAA) in blood samples of patients with iron related disorders and controls after oral ingestion of a 58Fe containing pharmaceutical. Results were compared with those derived from MC-ICP-MS, applied on the same samples, and analytical and practical aspects of the two techniques were compared. Both techniques showed an increased absorption and incorporation in red blood cells of the 58Fe isotope in iron deficient patients in contrast to the controls. In all individuals results of INAA measurements were in good agreement with those of MC-ICP-MS (|zeta| < 2). Uncertainties in INAA are substantially higher than those achievable by MC-ICP-MS but the INAA technique offers a high specificity and selectivity for iron close to 100%. In contrast to INAA, sample preparation before measurement is very critical in MC-ICP-MS and interferences with 58Ni and 54Cr may hamper the measurement of 58Fe and 54Fe respectively. Since it takes at least five days after irradiation to reduce the activity of interfering radionuclides (mainly 24Na), INAA is a more time consuming procedure; the need of a nuclear reactor facility makes it also less accessible than MC-ICP-MS. Costs are comparable. Both INAA and MC-ICP-MS are able to adequately measure changes in iron isotope composition in blood when an enriched stable iron isotope is applied in clinical research. Although MC-ICP-MS is more sensitive, is faster and has easier access, in INAA preparative steps before measurement are simpler and there are hardly demands on the kind and size of the samples. This may be relevant working with biomaterials in a clinical setting.