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Boon-yasidhi P, Karnsakul W. Non-Invasive Biomarkers and Breath Tests for Diagnosis and Monitoring of Chronic Liver Diseases. Diagnostics (Basel) 2024; 15:68. [PMID: 39795596 PMCID: PMC11720471 DOI: 10.3390/diagnostics15010068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Chronic liver disease (CLD) presents a significant global health burden, demanding effective tools for diagnosis and monitoring. Traditionally, liver biopsy has been the gold standard for evaluating liver fibrosis and other chronic liver conditions. However, biopsy's invasiveness, associated risks, and sampling variability indicate the need for reliable, noninvasive alternatives. This review examines the utility of noninvasive tests (NITs) in assessing liver disease severity, progression, and therapeutic response in patients with CLD. Result: Key modalities discussed include serum biomarker panels (e.g., FIB-4, APRI, ELF), imaging techniques like transient elastography, and magnetic resonance elastography, each offering unique benefits in fibrosis staging. Emerging biomarkers such as extracellular vesicles and circulating microRNAs show promise in early detection and personalized monitoring. Comparative studies indicate that while no single NIT matches biopsy precision, combinations of these modalities improve diagnostic accuracy and patient outcomes by reducing unnecessary biopsies. Moreover, NITs are instrumental in monitoring dynamic changes in liver health, allowing for more responsive and patient-centered care. Conclusions: Challenges remain, including standardization across tests, cost considerations, and the need for larger, diverse population studies to validate findings. Despite these limitations, NITs are increasingly integrated into clinical practice, fostering a paradigm shift toward noninvasive, accessible liver disease management. Continued advancements in NITs are essential for improved patient outcomes and will likely shape the future standard of care for CLD.
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Affiliation(s)
- Pasawat Boon-yasidhi
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Wikrom Karnsakul
- Pediatric Liver Center, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
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2
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Zhang H, Huang OY, Chen LL, Zhang N, Chen WY, Zheng W, Zhang XL, Jin XZ, Chen SD, Targher G, Byrne CD, Zheng MH. Diagnostic accuracy of exhaled nitric oxide for the non-invasive identification of patients with fibrotic metabolic dysfunction-associated steatohepatitis. Ann Med 2024; 56:2410408. [PMID: 39376063 PMCID: PMC11463020 DOI: 10.1080/07853890.2024.2410408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/12/2024] [Accepted: 08/19/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is a condition at risk of progressing to advanced liver disease. We examined whether an innovative exhaled nitric oxide (eNO) breath test (BT) can accurately diagnose fibrotic MASH without requiring blood tests. METHODS One hundred and forty-seven patients with MASH were recruited, and all tests were undertaken within 1 week of recruitment. With fibrotic MASH (NAS ≥ 4 and fibrosis stage ≥ 2) as the main outcome indicator, the diagnostic efficacy of eNO in identifying fibrotic MASH was compared to other validated models for advanced fibrosis requiring venesection, namely FAST, Agile 3+, and FIB-4 scores. RESULTS The mean age was 40.36 ± 12.28 years, 73.5% were men. Mean body mass index was 28.83 ± 4.31 kg/m2. The proportion of fibrotic MASH was 29.25%. The area under the receiver operating curve for eNO in diagnosing fibrotic MASH was 0.737 [95% CI 0.650-0.823], which was comparable to FAST (0.751 [0.656-0.846]), Agile 3+ (0.764 [0.670-0.858]), and FIB-4 (0.721 [0.620-0.821]) (all DeLong test p > 0.05). A cut-off of eNO <8.5 ppb gave a sensitivity of 86.0% and a negative predictive value of 88.5% for ruling-out fibrotic MASH. A cut-off of eNO >13.5 ppb provided a specificity of 91.3% and a positive predictive value of 65.4% for ruling-in fibrotic MASH. Sensitivity analyses demonstrated that the diagnostic efficacy of eNO was similar across characteristics such as age. Moreover, adding vibration-controlled transient elastography-LSM (liver stiffness measurement) reduced the uncertainty interval from 46.9% to 39.5%. CONCLUSIONS The eNO-BT is a promising simple test for non-invasively identifying fibrotic MASH, and its performance is further improved by adding LSM measurement.
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Affiliation(s)
- Huai Zhang
- Department of Biostatistics and Medical Record, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ou-Yang Huang
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li-Li Chen
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ni Zhang
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Ying Chen
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen Zheng
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin-Lei Zhang
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Zhi Jin
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sui-Dan Chen
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton and University of Southampton, Southampton General Hospital, Southampton, UK
| | - Ming-Hua Zheng
- MAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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3
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Zheng W, Pang K, Min Y, Wu D. Prospect and Challenges of Volatile Organic Compound Breath Testing in Non-Cancer Gastrointestinal Disorders. Biomedicines 2024; 12:1815. [PMID: 39200279 PMCID: PMC11351786 DOI: 10.3390/biomedicines12081815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/16/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Breath analysis, despite being an overlooked biomatrix, has a rich history in disease diagnosis. However, volatile organic compounds (VOCs) have yet to establish themselves as clinically validated biomarkers for specific diseases. As focusing solely on late-stage or malignant disease biomarkers may have limited relevance in clinical practice, the objective of this review is to explore the potential of VOC breath tests for the diagnosis of non-cancer diseases: (1) Precancerous conditions like gastro-esophageal reflux disease (GERD) and Barrett's esophagus (BE), where breath tests can complement endoscopic screening; (2) endoluminal diseases associated with autoinflammation and dysbiosis, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and coeliac disease, which currently rely on biopsy and symptom-based diagnosis; (3) chronic liver diseases like cirrhosis, hepatic encephalopathy, and non-alcoholic fatty liver disease, which lack non-invasive diagnostic tools for disease progression monitoring and prognostic assessment. A literature search was conducted through EMBASE, MEDLINE, and Cochrane databases, leading to an overview of 24 studies. The characteristics of these studies, including analytical platforms, disorder type and stage, group size, and performance evaluation parameters for diagnostic tests are discussed. Furthermore, how VOCs can be utilized as non-invasive diagnostic tools to complement existing gold standards is explored. By refining study designs, sampling procedures, and comparing VOCs in urine and blood, we can gain a deeper understanding of the metabolic pathways underlying VOCs. This will establish breath analysis as an effective non-invasive method for differential diagnosis and disease monitoring.
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Affiliation(s)
- Weiyang Zheng
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China;
| | - Ke Pang
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100006, China; (K.P.); (Y.M.)
| | - Yiyang Min
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100006, China; (K.P.); (Y.M.)
| | - Dong Wu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China;
- Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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4
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Wang D, Hua X, Hu G, Wang Z, Yan F, Zhang K, Cheng C, Li S, Wu X, Wang H. A compact breath breathalyzer for identifying the non-alcoholic fatty liver disease biomarker. JOURNAL OF INSTRUMENTATION 2024; 19:P06003. [DOI: 10.1088/1748-0221/19/06/p06003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent
chronic liver disease worldwide. Currently, its diagnosis relies
primarily on imaging and histological examinations, which are
invasive and prone to misdiagnosis in the early stage. To address
these limitations, detection and analysis of volatile organic
compounds (VOCs) in human breath can be a rapid and non-invasive
screening method for NAFLD. In this study, a compact breath
breathalyzer was developed, utilizing a miniaturized gas
chromatography chip with the STM32 microcontroller as the main
control chip to manage airflow, temperature, and receive terminal
signals from the photoionization detector. In the experiment, a gas
mixture comprising five VOCs (pentane, acetone, toluene, octane, and
decane) was selected as the simulated typical disease biomarkers in
human breath to investigate the breathalyzer's performance and
optimize testing conditions for multi-polar and wide-boiling-range
breath samples. Results show that the breathalyzer can detect
low-boiling components (< 100°C) such as the isoprene and
acetone, with a detection limit less than 50 ppb which are two
commonly biomarkers of NAFLD. Furthermore, breath samples were
collected from 35 non-diseased individuals, and NAFLD early-stage
patient samples were simulated by increasing the isoprene
concentration by 10 ppb. Convolutional neural network (CNN) were
used to identify the VOC signatures in gas chromatograms with
predictive accuracy of 85% for the classification model. Therefore,
the compact breath breathalyzer has potential application in the
rapid and early screening of NAFLD.
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5
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Moura PC, Raposo M, Vassilenko V. Breath biomarkers in Non-Carcinogenic diseases. Clin Chim Acta 2024; 552:117692. [PMID: 38065379 DOI: 10.1016/j.cca.2023.117692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/02/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023]
Abstract
The analysis of volatile organic compounds (VOCs) from human matrices like breath, perspiration, and urine has received increasing attention from academic and medical researchers worldwide. These biological-borne VOCs molecules have characteristics that can be directly related to physiologic and pathophysiologic metabolic processes. In this work, gathers a total of 292 analytes that have been identified as potential biomarkers for the diagnosis of various non-carcinogenic diseases. Herein we review the advances in VOCs with a focus on breath biomarkers and their potential role as minimally invasive tools to improve diagnosis prognosis and therapeutic monitoring.
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Affiliation(s)
- Pedro Catalão Moura
- Laboratory for Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, Campus FCT-UNL, 2829-516, Caparica, Portugal.
| | - Maria Raposo
- Laboratory for Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, Campus FCT-UNL, 2829-516, Caparica, Portugal.
| | - Valentina Vassilenko
- Laboratory for Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, Campus FCT-UNL, 2829-516, Caparica, Portugal.
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6
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De la Cruz-Ku G, Zevallos A, Rázuri-Bustamante CR, Kalipatnapu S, Príncipe-Meneses FS, Dongo P, Chambergo-Michilot D, Salinas-Sedo G, Valcarcel B. Predictors of Nonalcoholic Steatohepatitis Severity in Obese Patients Undergoing Bariatric Surgery: A Cross-Sectional Study. Bariatr Surg Pract Patient Care 2023; 18:218-224. [DOI: 10.1089/bari.2022.0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Affiliation(s)
- Gabriel De la Cruz-Ku
- General Surgery, University of Massachusetts, Worcester, Massachusetts, USA
- Universidad Científica del Sur, Lima, Perú
| | | | | | - Sasank Kalipatnapu
- General Surgery, University of Massachusetts, Worcester, Massachusetts, USA
| | | | | | - Diego Chambergo-Michilot
- Universidad Científica del Sur, Lima, Perú
- Tau-RELAPED Group, Trujillo, Perú
- Departamento de Investigación Cardiológica, Centro Nacional de Investigación Torres de Salud, Lima, Perú
| | | | - Bryan Valcarcel
- The George Washington University, Washington, District of Columbia, USA
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Walsh CM, Fadel MG, Jamel SH, Hanna GB. Breath Testing in the Surgical Setting: Applications, Challenges, and Future Perspectives. Eur Surg Res 2023; 64:315-322. [PMID: 37311421 PMCID: PMC10614239 DOI: 10.1159/000531504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 06/05/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND The potential for exhaled breath to be a valuable diagnostic tool is often overlooked as it can be difficult to imagine how a barely visible sample of breath could hold such a rich source of information about the state of our health. However, technological advances over the last 50 years have enabled us to detect volatile organic compounds (VOCs) present in exhaled breath, and this provides the key to understanding the wealth of information contained within these readily available samples. SUMMARY VOCs are produced as a by-product of metabolism; hence, changes in the underlying physiological processes will be reflected in the exact composition of VOCs in exhaled breath. It has been shown that characteristic changes occur in the breath VOC profile associated with certain diseases including cancer, which may enable the non-invasive detection of cancer at primary care level for patients with vague symptoms. The use of breath testing as a diagnostic tool has many advantages. It is non-invasive and quick, and the test is widely accepted by patients and clinicians. However, breath samples provide a snapshot of the VOCs present in a particular patient at a given point in time, so this can be heavily influenced by external factors such as diet, smoking, and the environment. These must all be accounted for when attempting to draw conclusions about disease status. This review focuses on the current applications for breath testing in the field of surgery, as well as discussing the challenges encountered with developing a breath test in a clinical environment. The future of breath testing in the surgical setting is also discussed, including the translation of breath research into clinical practice. KEY MESSAGES Analysis of VOCs in exhaled breath can identify the presence of underlying disease including cancer as well as other infectious or inflammatory conditions. Despite the patient factors, environmental factors, storage, and transport considerations that must be accounted for, breath testing demonstrates ideal characteristics for a triage test, being non-invasive, simple, and universally acceptable to patients and clinicians. Many novel biomarkers and diagnostic tests fail to translate into clinical practice because their potential clinical application does not align with the requirements and unmet needs of the healthcare sector. Non-invasive breath testing, however, has the great potential to revolutionise the early detection of diseases, such as cancer, in the surgical setting for patients with vague symptoms.
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Affiliation(s)
- Caoimhe M Walsh
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Michael G Fadel
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Sara H Jamel
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - George B Hanna
- Department of Surgery and Cancer, Imperial College London, London, UK
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9
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Westphal K, Dudzik D, Waszczuk-Jankowska M, Graff B, Narkiewicz K, Markuszewski MJ. Common Strategies and Factors Affecting Off-Line Breath Sampling and Volatile Organic Compounds Analysis Using Thermal Desorption-Gas Chromatography-Mass Spectrometry (TD-GC-MS). Metabolites 2022; 13:8. [PMID: 36676933 PMCID: PMC9866406 DOI: 10.3390/metabo13010008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
An analysis of exhaled breath enables specialists to noninvasively monitor biochemical processes and to determine any pathological state in the human body. Breath analysis holds the greatest potential to remold and personalize diagnostics; however, it requires a multidisciplinary approach and collaboration of many specialists. Despite the fact that breath is considered to be a less complex matrix than blood, it is not commonly used as a diagnostic and prognostic tool for early detection of disordered conditions due to its problematic sampling, analysis, and storage. This review is intended to determine, standardize, and marshal experimental strategies for successful, reliable, and especially, reproducible breath analysis.
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Affiliation(s)
- Kinga Westphal
- Department of Hypertension and Diabetology, Medical University of Gdansk, 80-214 Gdansk, Poland
| | - Danuta Dudzik
- Department of Biopharmaceutics and Pharmacodynamics, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland
| | - Małgorzata Waszczuk-Jankowska
- Department of Biopharmaceutics and Pharmacodynamics, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland
| | - Beata Graff
- Department of Hypertension and Diabetology, Medical University of Gdansk, 80-214 Gdansk, Poland
| | - Krzysztof Narkiewicz
- Department of Hypertension and Diabetology, Medical University of Gdansk, 80-214 Gdansk, Poland
| | - Michał Jan Markuszewski
- Department of Biopharmaceutics and Pharmacodynamics, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland
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10
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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11
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Liver Impairment-The Potential Application of Volatile Organic Compounds in Hepatology. Metabolites 2021; 11:metabo11090618. [PMID: 34564434 PMCID: PMC8471934 DOI: 10.3390/metabo11090618] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/20/2022] Open
Abstract
Liver diseases are currently diagnosed through liver biopsy. Its invasiveness, costs, and relatively low diagnostic accuracy require new techniques to be sought. Analysis of volatile organic compounds (VOCs) in human bio-matrices has received a lot of attention. It is known that a musty odour characterises liver impairment, resulting in the elucidation of volatile chemicals in the breath and other body fluids such as urine and stool, which may serve as biomarkers of a disease. Aims: This study aims to review all the studies found in the literature regarding VOCs in liver diseases, and to summarise all the identified compounds that could be used as diagnostic or prognostic biomarkers. The literature search was conducted on ScienceDirect and PubMed, and each eligible publication was qualitatively assessed by two independent evaluators using the SANRA critical appraisal tool. Results: In the search, 58 publications were found, and 28 were kept for inclusion: 23 were about VOCs in the breath, one in the bile, three in urine, and one in faeces. Each publication was graded from zero to ten. A graphical summary of the metabolic pathways showcasing the known liver disease-related VOCs and suggestions on how VOC analysis on liver impairment could be applied in clinical practice are given.
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12
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Wu X, Zhang J, Yan X, Zhu Y, Li W, Li P, Chen H, Zhang W, Cheng N, Xiang T. Characterization of Liver Failure by the Analysis of Exhaled Breath by Extractive Electrospray Ionization Mass Spectrometry (EESI-MS): A Pilot Study. ANAL LETT 2021. [DOI: 10.1080/00032719.2020.1793993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Xiaoping Wu
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianguo Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xingyan Yan
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ying Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wei Li
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Penghui Li
- Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, East China University of Technology, Nanchang, China
| | - Huanwen Chen
- Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, East China University of Technology, Nanchang, China
| | - Wei Zhang
- Department of Respiratory, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Na Cheng
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Tianxin Xiang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Liver Regeneration Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Chen T, Liu T, Li T, Zhao H, Chen Q. Exhaled breath analysis in disease detection. Clin Chim Acta 2021; 515:61-72. [PMID: 33387463 DOI: 10.1016/j.cca.2020.12.036] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 02/05/2023]
Abstract
Investigating the use of exhaled breath analysis to diagnose and monitor different diseases has attracted much interest in recent years. This review introduces conventionally used methods and some emerging technologies aimed at breath analysis and their relevance to lung disease, airway inflammation, gastrointestinal disorders, metabolic disorders and kidney diseases. One section correlates breath components and specific diseases, whereas the other discusses some unique ideas, strategies, and devices to analyze exhaled breath for the diagnosis of some common diseases. This review aims to briefly introduce the potential application of exhaled breath analysis for the diagnosis and screening of various diseases, thereby providing a new avenue for the detection of non-invasive diseases.
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Affiliation(s)
- Ting Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Tiannan Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ting Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China.
| | - Hang Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China
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Berardo C, Di Pasqua LG, Cagna M, Richelmi P, Vairetti M, Ferrigno A. Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research. Int J Mol Sci 2020; 21:ijms21249646. [PMID: 33348908 PMCID: PMC7766139 DOI: 10.3390/ijms21249646] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in parallel with a worldwide increase in the recurrence rate of diabetes and metabolic syndrome. It has been estimated that NASH cirrhosis may surpass viral hepatitis C and become the leading indication for liver transplantation in the next decades. The broadening of the knowledge about NASH pathogenesis and progression is of pivotal importance for the discovery of new targeted and more effective therapies; aim of this review is to offer a comprehensive and updated overview on NAFLD and NASH pathogenesis, the most recommended treatments, drugs under development and new drug targets. The most relevant in vitro and in vivo models of NAFLD and NASH will be also reviewed, as well as the main molecular pathways involved in NAFLD and NASH development.
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Affiliation(s)
| | | | | | | | | | - Andrea Ferrigno
- Correspondence: (L.G.D.P.); (A.F.); Tel.: +39-0382-986-451 (L.G.D.P.)
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Paul J. Recent advances in non-invasive diagnosis and medical management of non-alcoholic fatty liver disease in adult. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00043-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abstract
Background
Number of non-alcoholic fatty liver disease (NAFLD) cases is increasing over time due to alteration of food habit, increase incidence of metabolic syndrome, and lack of exercise. Liver biopsy is the test for diagnosis and staging of NAFLD, but nowadays several biochemical markers, scoring systems, and imaging studies are available to diagnose and stage NAFLD which is linked to end-stage liver disease, hepatocellular cancer, and elevated cardiovascular- and cancer-related morbidity and mortality. Therefore urgent diagnosis and management are required to avoid complications related to NAFLD. This review summarizes recent advances in diagnosis and medical management of non-alcoholic fatty liver disease.
Main text
Recently published studies from PubMed, Red Cross, Copernicus, and also various previous studies were reviewed. We have discussed various non-invasive methods for detection of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), and hepatic fibrosis. Non pharmacological therapies for NAFLD, indications, and approved medications for NAFLD and other commonly used non-approved medications have been discussed in this review article.
Conclusions
Multiple non-invasive tests are available for diagnosis of NAFLD, and its different stages however gold standard test is liver biopsy. NALFD without NASH and significant fibrosis is treated by lifestyle modifications which include moderate to vigorous exercise and diet modification. To improve hepatic steatosis, minimum of 3–5% of body weight loss is necessary, but > 7–10% weight reductions is required for histological improvement in NASH and fibrosis. Pharmacotherapy is indicated when patient is having NASH with significant fibrosis.
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Houben T, Bitorina AV, Oligschlaeger Y, Jeurissen ML, Rensen S, Köhler SE, Westerterp M, Lütjohann D, Theys J, Romano A, Plat J, Shiri-Sverdlov R. Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling. J Pathol 2020; 251:429-439. [PMID: 32472585 PMCID: PMC7497011 DOI: 10.1002/path.5477] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 04/28/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023]
Abstract
Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27‐hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non‐alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol‐induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex‐opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex‐opposed effects on inflammation, we injected 27HC into female and male Niemann–Pick disease type C1 mice (Npc1nih) that were used as an extreme model of cholesterol‐induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow‐derived macrophages (BMDMs) that were treated with 27HC and 17β‐estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty‐seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2‐enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex‐opposed inflammatory effects of 27HC are E2‐dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual’s sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Tom Houben
- Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Albert V Bitorina
- Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Yvonne Oligschlaeger
- Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Mike Lj Jeurissen
- Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Sander Rensen
- Department of Surgery, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - S Eleonore Köhler
- Department of Anatomy & Embryology, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Marit Westerterp
- Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Jan Theys
- Department of Precision Medicine, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Andrea Romano
- Department of Obstetrics & Gynaecology, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Jogchum Plat
- Department of Nutrition and Movement Sciences, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Ronit Shiri-Sverdlov
- Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
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Accuracy of proton magnetic resonance for diagnosing non-alcoholic steatohepatitis: a meta-analysis. Sci Rep 2019; 9:15002. [PMID: 31628409 PMCID: PMC6802098 DOI: 10.1038/s41598-019-51302-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 09/28/2019] [Indexed: 12/19/2022] Open
Abstract
Liver biopsy is the reference standard test to differentiate between non-alcoholic steatohepatitis (NASH) and simple steatosis (SS) in non-alcoholic fatty liver disease (NAFLD), but noninvasive diagnostics are warranted. The diagnostic accuracy in NASH using MR imaging modality have not yet been clearly identified. This study was assessed the accuracy of magnetic resonance imaging (MRI) method for diagnosing NASH. Data were extracted from research articles obtained after a literature search from multiple electronic databases. Random-effects meta-analyses were performed to obtain overall effect size of the area under the receiver operating characteristic(ROC) curve, sensitivity, specificity, likelihood ratios(LR), diagnostic odds ratio(DOR) of MRI method in detecting histopathologically-proven SS(or non-NASH) and NASH. Seven studies were analyzed 485 patients, which included 207 SS and 278 NASH. The pooled sensitivity was 87.4% (95% CI, 76.4–95.3) and specificity was 74.3% (95% CI, 62.4–84.6). Pooled positive LR was 2.59 (95% CI, 1.96–3.42) and negative LR was 0.17 (95% CI, 0.07–0.38). DOR was 21.57 (95% CI, 7.27–63.99). The area under the curve of summary ROC was 0.89. Our meta-analysis shows that the MRI-based diagnostic methods are valuable additions in detecting NASH.
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De Vincentis A, Vespasiani-Gentilucci U, Sabatini A, Antonelli-Incalzi R, Picardi A. Exhaled breath analysis in hepatology: State-of-the-art and perspectives. World J Gastroenterol 2019; 25:4043-4050. [PMID: 31435162 PMCID: PMC6700691 DOI: 10.3748/wjg.v25.i30.4043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 06/11/2019] [Accepted: 06/25/2019] [Indexed: 02/06/2023] Open
Abstract
Liver disease is characterized by breath exhalation of peculiar volatile organic compounds (VOCs). Thanks to the availability of sensitive technologies for breath analysis, this empiric approach has recently gained increasing attention in the context of hepatology, following the good results obtained in other fields of medicine. After the first studies that led to the identification of selected VOCs for pathophysiological purposes, subsequent research has progressively turned towards the comprehensive assessment of exhaled breath for potential clinical application. Specific VOC patterns were found to discriminate subjects with liver cirrhosis, to rate disease severity, and, eventually, to forecast adverse clinical outcomes even beyond existing scores. Preliminary results suggest that breath analysis could be useful also for detecting and staging hepatic encephalopathy and for predicting steatohepatitis in patients with nonalcoholic fatty liver disease. However, clinical translation is still hampered by a number of methodological limitations, including the lack of standardization and the consequent poor comparability between studies and the absence of external validation of obtained results. Given the low-cost and easy execution at bedside of the new technologies (e-nose), larger and well-structured studies are expected in order to provide the adequate level of evidence to support VOC analysis in clinical practice.
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Affiliation(s)
- Antonio De Vincentis
- Unit of Clinical Medicine and Hepatology, Unit of Geriatrics, Department of Medicine, Campus Bio-Medico University Hospital, Rome 00128, Italy
| | - Umberto Vespasiani-Gentilucci
- Unit of Clinical Medicine and Hepatology, Unit of Geriatrics, Department of Medicine, Campus Bio-Medico University Hospital, Rome 00128, Italy
| | - Anna Sabatini
- Unit of Electronics for sensor systems, Department of Engineering, University Campus Bio-Medico of Rome, Rome 00128, Italy
| | - Raffaele Antonelli-Incalzi
- Unit of Clinical Medicine and Hepatology, Unit of Geriatrics, Department of Medicine, Campus Bio-Medico University Hospital, Rome 00128, Italy
| | - Antonio Picardi
- Unit of Clinical Medicine and Hepatology, Unit of Geriatrics, Department of Medicine, Campus Bio-Medico University Hospital, Rome 00128, Italy
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Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World J Gastroenterol 2019; 25:1307-1326. [PMID: 30918425 PMCID: PMC6429343 DOI: 10.3748/wjg.v25.i11.1307] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/20/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023] Open
Abstract
With the increasing number of individuals with diabetes and obesity, nonalcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent, affecting one-quarter of adults worldwide. The spectrum of NAFLD ranges from simple steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD, especially NASH, may progress to fibrosis, leading to cirrhosis and hepatocellular carcinoma. NAFLD can impose a severe economic burden, and patients with NAFLD-related terminal or deteriorative liver diseases have become one of the main groups receiving liver transplantation. The increasing prevalence of NAFLD and the severe outcomes of NASH make it necessary to use effective methods to identify NAFLD. Although recognized as the gold standard, biopsy is limited by its sampling bias, poor acceptability, and severe complications, such as mortality, bleeding, and pain. Therefore, noninvasive methods are urgently needed to avoid biopsy for diagnosing NAFLD. This review discusses the current noninvasive methods for assessing NAFLD, including steatosis, NASH, and NAFLD-related fibrosis, and explores the advantages and disadvantages of measurement tools. In addition, we analyze potential noninvasive biomarkers for tracking disease processes and monitoring treatment effects, and explore effective algorithms consisting of imaging and nonimaging biomarkers for diagnosing advanced fibrosis and reducing unnecessary biopsies in clinical practice.
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Affiliation(s)
- Jiang-Hua Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jing-Jing Cai
- Department of Cardiology, The 3rd Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Hong-Liang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
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Abstract
Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global adult population and is the most common chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is the active form of NAFLD, with hepatic necroinflammation and faster fibrosis progression. With an increasing number of patients developing NASH-related end-stage liver disease and pharmacological treatments on the horizon, there is a pressing need to develop NAFLD and NASH biomarkers for prognostication, selection of patients for treatment and monitoring. This requirement is particularly true as liver biopsy utility is limited by its invasive nature, poor patient acceptability and sampling variability. This article reviews current and potential biomarkers for different features of NAFLD, namely, steatosis, necroinflammation and fibrosis. For each biomarker, we evaluate its accuracy, reproducibility, responsiveness, feasibility and limitations. We cover biochemical, imaging and genetic biomarkers and discuss biomarker discovery in the omics era.
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Hua Q, Zhu Y, Liu H. Detection of volatile organic compounds in exhaled breath to screen lung cancer: a systematic review. Future Oncol 2018; 14:1647-1662. [PMID: 29939068 DOI: 10.2217/fon-2017-0676] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/26/2018] [Indexed: 12/15/2022] Open
Abstract
To evaluate the clinical value of volatile organic compounds (VOCs) in exhaled breath for lung cancer (LC) screening, a systematic review was performed. Systematic search for studies about exhaled VOCs for LC screening was conducted according to PRISMA. Thirty eight studies with 4873 participants met the criteria for inclusion in this systematic review. Generally speaking, the results suggest that exhaled VOCs have potential to screen LC and more studies are needed in the future.
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Affiliation(s)
- Qingling Hua
- Department of Oncology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, PR China
| | - Yanzhe Zhu
- Department of Oncology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Hu Liu
- Department of Oncology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
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Verhaegh P, Bavalia R, Winkens B, Masclee A, Jonkers D, Koek G. Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018; 16:837-861. [PMID: 28838784 DOI: 10.1016/j.cgh.2017.08.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 08/15/2017] [Accepted: 08/16/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. METHODS We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sensp) and specificity (specp) values were determined using the Meta-Analysis Package for R (metafor). RESULTS In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sensp, 63.5% and specp, 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and specp, 75.7%) within inflammatory markers, CK18-M30 (sensp, 68.4% and specp, 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sensp, 69.0% and specp, 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sensp and 95.3% specp) and the GlycoNASH test (67.1% sensp and 63.8% specp). CONCLUSION In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (≥80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with ≥80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis.
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Affiliation(s)
- Pauline Verhaegh
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Roisin Bavalia
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Bjorn Winkens
- Department of Methodology and Statistic, School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, the Netherlands
| | - Ad Masclee
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Daisy Jonkers
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Ger Koek
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.
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Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers. J Hepatol 2018; 68:305-315. [PMID: 29154965 DOI: 10.1016/j.jhep.2017.11.013] [Citation(s) in RCA: 438] [Impact Index Per Article: 62.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 11/03/2017] [Accepted: 11/09/2017] [Indexed: 12/04/2022]
Abstract
The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease (NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest®, ELF™ or Pro-C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver-related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on "omics" approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes.
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Affiliation(s)
- Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, IN, USA.
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, IN, USA.
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Blanchet L, Smolinska A, Baranska A, Tigchelaar E, Swertz M, Zhernakova A, Dallinga JW, Wijmenga C, van Schooten FJ. Factors that influence the volatile organic compound content in human breath. J Breath Res 2017; 11:016013. [PMID: 28140379 DOI: 10.1088/1752-7163/aa5cc5] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thousands of endogenous and exogenous volatile organic compounds (VOCs) are excreted in each breath. Inflammatory and deviant metabolic processes affect the level of endogeneous VOCs, which can serve as specific biomarkers for clinical diagnosis and disease monitoring. Important issues that still need to be tackled are related to potential confounding factors like gender and age and endogenous and exogenous factors, like f.i. smoking. METHODS The aim of this study was to systematically access the effect of endogenous and exogenous factors on VOC composition of exhaled breath. In the current study breath samples from 1417 adult participants from the LifeLines cohort, a general population cohort in the Netherlands, were collected and the total content of VOCs was measured using gas chromatography-time-of-flight-mass spectrometry. Breath samples were collected in Groningen and transferred to carbon tubes immediately. These samples were then shipped to Maastricht and measured in batches. VOCs profiles were correlated to 14 relevant characteristics of all participants including age, BMI, smoking and blood cell counts and metabolic parameters as well as to 16 classes of medications. RESULTS VOCs profiles were shown to be significantly influenced by smoking behavior and to a lesser extent by age, BMI and gender. These factors need to be controlled for in breath analysis studies. We found no evidence whatsoever in this 1417 subjects' cohort that white blood cell counts, cholesterol or triglycerides levels have an influence on the VOC profile. Thus they may not have to be controlled for in exhaled breath studies. CONCLUSION The large cohort of volunteers used here represents a unique opportunity to gauge the factors influencing VOCs profiles in a general population i.e. the most clinically relevant population. Classical clinical parameters and smoking habits clearly influence breath content and should therefore be accounted for in future clinical studies involving breath analysis.
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Affiliation(s)
- L Blanchet
- Top Institute Food and Nutrition (TIFN), Wageningen, The Netherlands. Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands. Thayer school of engineering, Dartmouth College, Hanover, NH, United States of America
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Lawal O, Ahmed WM, Nijsen TME, Goodacre R, Fowler SJ. Exhaled breath analysis: a review of 'breath-taking' methods for off-line analysis. Metabolomics 2017; 13:110. [PMID: 28867989 PMCID: PMC5563344 DOI: 10.1007/s11306-017-1241-8] [Citation(s) in RCA: 161] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 07/24/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The potential of exhaled breath sampling and analysis has long attracted interest in the areas of medical diagnosis and disease monitoring. This interest is attributed to its non-invasive nature, access to an unlimited sample supply (i.e., breath), and the potential to facilitate a rapid at patient diagnosis. However, progress from laboratory setting to routine clinical practice has been slow. Different methodologies of breath sampling, and the consequent difficulty in comparing and combining data, are considered to be a major contributor to this. To fulfil the potential of breath analysis within clinical and pre-clinical medicine, standardisation of some approaches to breath sampling and analysis will be beneficial. OBJECTIVES The aim of this review is to investigate the heterogeneity of breath sampling methods by performing an in depth bibliometric search to identify the current state of art in the area. In addition, the review will discuss and critique various breath sampling methods for off-line breath analysis. METHODS Literature search was carried out in databases MEDLINE, BIOSIS, EMBASE, INSPEC, COMPENDEX, PQSCITECH, and SCISEARCH using the STN platform which delivers peer-reviewed articles. Keywords searched for include breath, sampling, collection, pre-concentration, volatile. Forward and reverse search was then performed on initially included articles. The breath collection methodologies of all included articles was subsequently reviewed. RESULTS Sampling methods differs between research groups, for example regarding the portion of breath being targeted. Definition of late expiratory breath varies between studies. CONCLUSIONS Breath analysis is an interdisciplinary field of study using clinical, analytical chemistry, data processing, and metabolomics expertise. A move towards standardisation in breath sampling is currently being promoted within the breath research community with a view to harmonising analysis and thereby increasing robustness and inter-laboratory comparisons.
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Affiliation(s)
- Oluwasola Lawal
- 0000000121662407grid.5379.8Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 0000 0004 0398 9387grid.417284.cPhilips Research, Royal Philips B.V., Eindhoven, The Netherlands
- 0000000121662407grid.5379.8School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Waqar M. Ahmed
- 0000000121662407grid.5379.8Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 0000 0004 0398 9387grid.417284.cPhilips Research, Royal Philips B.V., Eindhoven, The Netherlands
- 0000000121662407grid.5379.8School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Tamara M. E. Nijsen
- 0000 0004 0398 9387grid.417284.cPhilips Research, Royal Philips B.V., Eindhoven, The Netherlands
| | - Royston Goodacre
- 0000000121662407grid.5379.8School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Stephen J. Fowler
- 0000000121662407grid.5379.8Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 0000 0004 0430 9363grid.5465.2Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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Meng Q, Duan XP, Wang CY, Liu ZH, Sun PY, Huo XK, Sun HJ, Peng JY, Liu KX. Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation. Acta Pharmacol Sin 2017; 38:69-79. [PMID: 27773935 PMCID: PMC5220543 DOI: 10.1038/aps.2016.119] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 08/26/2016] [Indexed: 12/12/2022]
Abstract
Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from the traditional Chinese medicine rhizoma alismatis, which exhibits a number of pharmacological activities, including anti-hepatitis virus, anti-cancer and antibacterial effects. In this study we examined whether AB23A protected against non-alcoholic steatohepatitis (NASH) in mice, and the mechanisms underlying the protective effects. NASH was induced in mice fed a methionine and choline-deficient (MCD) diet for 4 weeks. The mice were simultaneously treated with AB23A (15, 30, and 60 mg·kg-1·d-1, ig) for 4 weeks. On the last day, blood samples and livers were collected. Serum liver functional enzymes, inflammatoru markers were assessed. The livers were histologically examined using H&E, Oil Red O, Masson's trichrome and Sirius Red staining. Mouse primary hepatocytes were used for in vitro experiments. The mechanisms underlying AB23A protection were analyzed using siRNA, qRT-PCR, and Western blot assays. AB23A treatment significantly and dose-dependently decreased the elevated levels of serum ALT and AST in MCD diet-fed mice. Furthermore, AB23A treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration and hepatic fibrosis in the mice. AB23A-induced decreases in serum and hepatic lipids were related to decreased hepatic lipogenesis through decreasing hepatic levels of SREBP-1c, FAS, ACC1 and SCD1 and increased lipid metabolism via inducing PPARα, CPT1α, ACADS and LPL. The reduction in inflammatory cell infiltration corresponded to deceased serum levels of mKC and MCP-1 and decreased hepatic gene expression of MCP-1 and VCAM-1. The reduction in hepatic fibrosis was correlated with decreased hepatic gene expression of fibrosis markers. The protective effects of AB23A were FXR-dependent, because treatment with the FXR agonist CDCA mimicked AB23A-induced hepato-protection in the mice, whereas co-administration of FXR antagonist guggulsterone abrogated AB23A-induced hepato-protection. In mouse primary hepatocytes, FXR gene silencing abrogated AB23A-induced changes in gene expression of Apo C-II, CPT1α, ACADS and LPL. AB23A produces protective effects against NASH in mice via FXR activation.
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Affiliation(s)
- Qiang Meng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
- Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China
| | - Xing-ping Duan
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Chang-yuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
- Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China
| | - Zhi-hao Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
- Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China
| | - Peng-yuan Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
- Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China
| | - Xiao-kui Huo
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Hui-jun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
- Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China
| | - Jin-yong Peng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Ke-xin Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
- Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China
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27
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Walenbergh SMA, Houben T, Rensen SS, Bieghs V, Hendrikx T, van Gorp PJ, Oligschlaeger Y, Jeurissen MLJ, Gijbels MJJ, Buurman WA, Vreugdenhil ACE, Greve JWM, Plat J, Hofker MH, Kalhan S, Pihlajamäki J, Lindsey P, Koek GH, Shiri-Sverdlov R. Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention. Sci Rep 2016; 6:38278. [PMID: 27922112 PMCID: PMC5138820 DOI: 10.1038/srep38278] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 10/25/2016] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver lipid accumulation and inflammation. The mechanisms that trigger hepatic inflammation are poorly understood and subsequently, no specific non-invasive markers exist. We previously demonstrated a reduction in the plasma lysosomal enzyme, cathepsin D (CatD), in children with NASH compared to children without NASH. Recent studies have raised the concept that non-alcoholic fatty liver disease (NAFLD) in adults is distinct from children due to a different histological pattern in the liver. Yet, the link between plasma CatD to adult NASH was not examined. In the current manuscript, we investigated whether plasma CatD in adults correlates with NASH development and regression. Biopsies were histologically evaluated for inflammation and NAFLD in three complementary cohorts of adults (total n = 248). CatD and alanine aminotransferase (ALT) were measured in plasma. Opposite to our previous observations with childhood NASH, we observed increased levels of plasma CatD in patients with NASH compared to adults without hepatic inflammation. Furthermore, after surgical intervention, we found a reduction of plasma CatD compared to baseline. Our observations highlight a distinct pathophysiology between NASH in children and adults. The observation that plasma CatD correlated with NASH development and regression is promising for NASH diagnosis.
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Affiliation(s)
- Sofie M A Walenbergh
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Tom Houben
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Sander S Rensen
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Veerle Bieghs
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Tim Hendrikx
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Patrick J van Gorp
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Yvonne Oligschlaeger
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Mike L J Jeurissen
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Marion J J Gijbels
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Wim A Buurman
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Anita C E Vreugdenhil
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Jan Willem M Greve
- Surgery, Atrium Medical Center Parkstad, 6419PC, Heerlen, The Netherlands
| | - Jogchum Plat
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Marten H Hofker
- Pathology and Medical Biology, Molecular Genetics, Medical Biology Section, University Medical Center Groningen, 9713GZ, Groningen, The Netherlands
| | - Satish Kalhan
- Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, USA
| | - Jussi Pihlajamäki
- Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, FI-70211 Kuopio, Finland
| | - Patrick Lindsey
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Ger H Koek
- Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Ronit Shiri-Sverdlov
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
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Golabi P, Sayiner M, Fazel Y, Koenig A, Henry L, Younossi ZM. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis. Expert Rev Gastroenterol Hepatol 2016; 10:63-71. [PMID: 26469309 DOI: 10.1586/17474124.2016.1099433] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) can lead to complications such as liver failure, cirrhosis and hepatocellular carcinoma. The diagnostic gold standard for NASH is liver biopsy; however, other noninvasive methods have been developed. In this article, the authors evaluate current methods in NASH screening and diagnosis. Routine radiologic modalities were found to detect hepatic steatosis accurately, but were unable to establish the diagnosis of NASH or stage of fibrosis. Newly developed elastography based techniques seem promising to estimate liver fibrosis. Other noninvasive tests such as FibroTest, ELF, Hepascore, FIB-4, NFS, FLI and ION (biochemical panels) have AUROCs ranging between 0.80-0.98 for detecting advanced fibrosis but lack specificity for detecting mild fibrosis. Noninvasive tools, especially elastography, identify NASH associated advanced fibrosis potentially reducing liver biopsies. More research is needed to validate the clinical utility of these tests.
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Affiliation(s)
- Pegah Golabi
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Mehmet Sayiner
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Yousef Fazel
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Aaron Koenig
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Linda Henry
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Zobair M Younossi
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA.,b Center for Liver Disease, Department of Medicine , Inova Fairfax Hospital , Falls Church , VA , USA
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29
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Alkhouri N, Feldstein AE. Noninvasive diagnosis of nonalcoholic fatty liver disease: Are we there yet? Metabolism 2016; 65:1087-95. [PMID: 26972222 PMCID: PMC4931968 DOI: 10.1016/j.metabol.2016.01.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 12/22/2015] [Accepted: 01/07/2016] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has rapidly become the most common form of chronic liver disease in the United States affecting approximately 80-100 million Americans. NAFLD includes a spectrum of diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to fibrosis and eventually cirrhosis. Patients with NASH and significant fibrosis on liver biopsy have an increased risk for liver-related morbidity and mortality compared to those with NAFL. Due to the high prevalence of NAFLD and its progressive nature, there has been an urgent need to develop reliable noninvasive tests that can accurately predict the presence of advanced disease without the need for liver biopsy. These tests can be divided into those that predict the presence of NASH and those that predict the presence of fibrosis. In this review, we provide a concise overview of different noninvasive methods for staging the severity of NAFLD.
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Affiliation(s)
- Naim Alkhouri
- Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA; Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ariel E Feldstein
- Department of Pediatrics, University of California San Diego (UCSD), CA, USA.
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30
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Boots AW, Bos LD, van der Schee MP, van Schooten FJ, Sterk PJ. Exhaled Molecular Fingerprinting in Diagnosis and Monitoring: Validating Volatile Promises. Trends Mol Med 2016; 21:633-644. [PMID: 26432020 DOI: 10.1016/j.molmed.2015.08.001] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/23/2015] [Accepted: 08/04/2015] [Indexed: 12/19/2022]
Abstract
Medical diagnosis and phenotyping increasingly incorporate information from complex biological samples. This has promoted the development and clinical application of non-invasive metabolomics in exhaled air (breathomics). In respiratory medicine, expired volatile organic compounds (VOCs) are associated with inflammatory, oxidative, microbial, and neoplastic processes. After recent proof of concept studies demonstrating moderate to good diagnostic accuracies, the latest efforts in breathomics are focused on optimization of sensor technologies and analytical algorithms, as well as on independent validation of clinical classification and prediction. Current research strategies are revealing the underlying pathophysiological pathways as well as clinically-acceptable levels of diagnostic accuracy. Implementing recent guidelines on validating molecular signatures in medicine will enhance the clinical potential of breathomics and the development of point-of-care technologies.
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Affiliation(s)
- Agnes W Boots
- Department of Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
| | - Lieuwe D Bos
- Department of Respiratory Medicine, Academic Medical Centre, University of Medical Centre Amsterdam, The Netherlands
| | - Marc P van der Schee
- Department of Respiratory Medicine, Academic Medical Centre, University of Medical Centre Amsterdam, The Netherlands; Department of Pediatric Pulmonology, Emma's Children's Hospital, Academic Medical Centre Amsterdam, The Netherlands
| | - Frederik-Jan van Schooten
- Department of Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Peter J Sterk
- Department of Respiratory Medicine, Academic Medical Centre, University of Medical Centre Amsterdam, The Netherlands
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De Vincentis A, Pennazza G, Santonico M, Vespasiani-Gentilucci U, Galati G, Gallo P, Vernile C, Pedone C, Antonelli Incalzi R, Picardi A. Breath-print analysis by e-nose for classifying and monitoring chronic liver disease: a proof-of-concept study. Sci Rep 2016; 6:25337. [PMID: 27145718 PMCID: PMC4857073 DOI: 10.1038/srep25337] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 04/06/2016] [Indexed: 12/19/2022] Open
Abstract
Since the liver plays a key metabolic role, volatile organic compounds in the exhaled breath might change with type and severity of chronic liver disease (CLD). In this study we analysed breath-prints (BPs) of 65 patients with liver cirrhosis (LC), 39 with non-cirrhotic CLD (NC-CLD) and 56 healthy controls by the e-nose. Distinctive BPs characterized LC, NC-CLD and healthy controls, and, among LC patients, the different Child-Pugh classes (sensitivity 86.2% and specificity 98.2% for CLD vs healthy controls, and 87.5% and 69.2% for LC vs NC-CLD). Moreover, the area under the BP profile, derived from radar-plot representation of BPs, showed an area under the ROC curve of 0.84 (95% CI 0.76-0.91) for CLD, of 0.76 (95% CI 0.66-0.85) for LC, and of 0.70 (95% CI 0.55-0.81) for decompensated LC. By applying the cut-off values of 862 and 812, LC and decompensated LC could be predicted with high accuracy (PPV 96.6% and 88.5%, respectively). These results are proof-of-concept that the e-nose could be a valid non-invasive instrument for characterizing CLD and monitoring hepatic function over time. The observed classificatory properties might be further improved by refining stage-specific breath-prints and considering the impact of comorbidities in a larger series of patients.
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Affiliation(s)
- Antonio De Vincentis
- Clinical Medicine and Hepatology Department, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Giorgio Pennazza
- Center for Integrated Research - CIR, Unit of Electronics for Sensor Systems, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Marco Santonico
- Center for Integrated Research - CIR, Unit of Electronics for Sensor Systems, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Umberto Vespasiani-Gentilucci
- Clinical Medicine and Hepatology Department, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Giovanni Galati
- Clinical Medicine and Hepatology Department, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Paolo Gallo
- Clinical Medicine and Hepatology Department, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Chiara Vernile
- Center for Integrated Research - CIR, Unit of Electronics for Sensor Systems, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Claudio Pedone
- Chair of Geriatrics, Unit of Respiratory Pathophysiology, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Raffaele Antonelli Incalzi
- Chair of Geriatrics, Unit of Respiratory Pathophysiology, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
- San Raffaele- Cittadella della Carità Foundation, Taranto, Italy
| | - Antonio Picardi
- Clinical Medicine and Hepatology Department, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy
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A profile of volatile organic compounds in exhaled air as a potential non-invasive biomarker for liver cirrhosis. Sci Rep 2016; 6:19903. [PMID: 26822454 PMCID: PMC4731784 DOI: 10.1038/srep19903] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 12/16/2015] [Indexed: 12/16/2022] Open
Abstract
Early diagnosis of liver cirrhosis may prevent progression and development of complications. Liver biopsy is the current standard, but is invasive and associated with morbidity. We aimed to identify exhaled volatiles within a heterogeneous group of chronic liver disease (CLD) patients that discriminates those with compensated cirrhosis (CIR) from those without cirrhosis, and compare this with serological markers. Breath samples were collected from 87 CLD and 34 CIR patients. Volatiles in exhaled air were measured by gas chromatography mass spectrometry. Discriminant Analysis was performed to identify the optimal panel of serological markers and VOCs for classifying our patients using a random training set of 27 CIR and 27 CLD patients. Two randomly selected independent internal validation sets and permutation test were used to validate the model. 5 serological markers were found to distinguish CIR and CLD patients with a sensitivity of 0.71 and specificity of 0.84. A set of 11 volatiles discriminated CIR from CLD patients with sensitivity of 0.83 and specificity of 0.87. Combining both did not further improve accuracy. A specific exhaled volatile profile can predict the presence of compensated cirrhosis among CLD patients with a higher accuracy than serological markers and can aid in reducing liver biopsies.
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Baranska A, Smolinska A, Boots AW, Dallinga JW, van Schooten FJ. Dynamic collection and analysis of volatile organic compounds from the headspace of cell cultures. J Breath Res 2015; 9:047102. [PMID: 26469548 DOI: 10.1088/1752-7155/9/4/047102] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Exhaled breath has proven to be a valuable source of information about human bodies. Subtle differences between volatile organic compounds (VOCs) formed endogenously can be detected and become a base for a potential monitoring tool for health and disease. Until now, there has been a lack of biological and mechanistic knowledge of the processes involved in the production of relevant VOCs. Among the possible sources of health-related and disease-related VOCs are microorganisms found in the respiratory tract and in the gut. Other VOCs in the body are produced by cells that are influenced by the disease, for instance, due to metabolic disorders and/or inflammation. To gain insight into the in vivo production of VOCs by human cells and thus the exhaled breath composition, in vitro experiments involving relevant cells should be studied because they may provide valuable information on the production of VOCs by the affected cells. To this aim we developed and validated a system for dynamically (continuously) collecting headspace air in vitro using a Caco-2 cell line. The system allows the application of different cell lines as well as different experimental setups, including varying exposure times and treatment options while preserving cell viability. Significant correlation (p ⩽ 0.0001) between collection outputs within each studied group confirmed high reproducibility of the collection system. An example of such an application is presented here. We studied the influence of oxidative stress on the VOC composition of the headspace air of Caco-2 cells. By comparing the VOC composition of air flushed through empty culture flasks (n = 35), flasks with culture medium (n = 35), flasks with medium and cells (n = 20), flasks with medium and an oxidative stressor (H2O2) (n = 20), and flasks with medium, stressor, and cells (n = 20), we were able to separate the effects from the stressor on the cells from all other interactions. Measurements were performed with gas chromatography time-of-flight mass spectrometry. Multivariate data analysis allowed detection of significant altered compounds in the compared groups. We found a significant change (p ⩽ 0.001) of the composition of VOCs due to the stressing of the Caco-2 cells by H2O2. A total of ten VOCs showed either increased or decreased abundance in the headspace of the cell cultures due to the presence of the H2O2 stressor.
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Affiliation(s)
- A Baranska
- Top Institute Food and Nutrition, Wageningen, The Netherlands. Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center (MUMC+), PO Box 616, 6200 MD, Maastricht, The Netherlands
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Volatile Organic Compounds in Exhaled Air as Novel Marker for Disease Activity in Crohn's Disease: A Metabolomic Approach. Inflamm Bowel Dis 2015. [PMID: 26199990 DOI: 10.1097/mib.0000000000000436] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Disappearance of macroscopic mucosal inflammation predicts long-term outcome in Crohn's disease (CD). It can be assessed by ileocolonoscopy, which is, however, an invasive and expensive procedure. Disease activity indices do not correlate well with endoscopic activity and noninvasive markers have a low sensitivity in subgroups of patients. Volatile organic compounds (VOCs) in breath are of increasing interest as noninvasive markers. The aim of this study was to investigate whether VOCs can accurately differentiate between active CD and remission. METHODS Patients participated in a 1-year follow-up study and Harvey-Bradshaw index, blood, fecal, and breath samples were collected at regular intervals. Patients were stratified into 2 groups: active (fecal calprotectin >250 µg/g) or inactive (Harvey-Bradshaw index <4, C-reactive protein <5 mg/L, and fecal calprotectin <100 µg/g) disease. Breath samples were analyzed by gas chromatography-time-of-flight mass spectrometry. Random forest analyses were used to find the most discriminatory VOCs. RESULTS Eight hundred thirty-five breath-o-grams were measured, 140 samples were assigned as active, 135 as inactive disease, and 110 samples of healthy controls. A set of 10 discriminatory VOCs correctly predicted active CD in 81.5% and remission in 86.4% (sensitivity 0.81, specificity 0.80, AUC 0.80). These VOCs were combined into a single disease activity score that classified disease activity in more than 60% of the previously undetermined individuals. CONCLUSIONS We showed that VOCs can separate healthy controls and patients with active CD and CD in remission in a real-life cohort. Analysis of exhaled air is an interesting new noninvasive application for monitoring mucosal inflammation in inflammatory bowel disease.
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Fernández Del Río R, O'Hara ME, Holt A, Pemberton P, Shah T, Whitehouse T, Mayhew CA. Volatile Biomarkers in Breath Associated With Liver Cirrhosis - Comparisons of Pre- and Post-liver Transplant Breath Samples. EBioMedicine 2015; 2:1243-50. [PMID: 26501124 PMCID: PMC4588000 DOI: 10.1016/j.ebiom.2015.07.027] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/17/2015] [Accepted: 07/20/2015] [Indexed: 12/15/2022] Open
Abstract
Background The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics. Aims To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful. Methods A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the post-transplant period. Results Seven volatiles were elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2-pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics. Conclusions Limonene, methanol and 2-pentanone are breath markers for a cirrhotic liver. This study raises the potential to investigate these volatiles as markers for early-stage liver disease. By monitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed.
Breath volatiles were compared for cirrhotic patients and controls and pre- and post-liver transplant. Three volatiles (limonene, methanol, 2-pentanone) have been found to have excellent diagnostic capabilities. Limonene shows washout characteristics following transplant supporting a hypothesis that it accumulates in fat. There are numerous previous studies investigating breath volatiles in patients with liver disease but with conflicting results. It is impossible to tell which volatiles from previous studies may be false discoveries, and which are actually associated with the disease. We measured breath samples in patients and controls and in patients after transplant. Methanol, 2-pentanone and limonene show differences not only between patients and controls but also in cases pre- and post-transplant and have excellent diagnostic capabilities. We show evidence that limonene accumulates in the body, probably because the cirrhotic liver fails to metabolise dietary limonene.
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Key Words
- AID, autoimmune liver disease
- ALD, alcoholic liver disease
- AUROC, area under receiver operator curve
- BMI, body mass index
- Breath analysis
- CD, cryptogenic disease
- Cirrhosis
- Diagnosis limonene
- GC, gas chromatography
- HBV, hepatitis B virus
- HCC, hepatocellular cancer
- HCV, hepatitis C virus
- ITU, intensive treatment unit
- LQ, lower quartile
- Liver transplant
- MS, mass spectrometry
- OPU, out-patient clinic
- PBC, primary biliary cirrhosis
- PSC, primary sclerosing cholangitis
- PTR-MS
- PTR-MS, proton transfer reaction mass spectrometry
- ROC, Receiver operating characteristics
- TAC, transplant assessment clinic
- TE, transient elastography
- UKELD, United Kingdom model for end-stage liver disease
- UQ, upper quartile
- VMR, volume mixing ratio
- VOC, volatile organic compounds
- Volatile organic compounds
- ppbv, parts per billion by volume
- ppmv, parts per million by volume
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Affiliation(s)
- R Fernández Del Río
- School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK
| | - M E O'Hara
- School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK
| | - A Holt
- Department of Hepatology, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK
| | - P Pemberton
- Critical Care and Anaesthesia, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK
| | - T Shah
- Department of Hepatology, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK
| | - T Whitehouse
- Critical Care and Anaesthesia, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK
| | - C A Mayhew
- School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent etiology of chronic liver disease in America. NAFLD can be broadly classified in two subtypes: nonalcoholic fatty liver (NAFL), which is generally considered a benign condition with negligible risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), which is generally considered to be progressive with substantial risk of progression to cirrhosis. Additionally, recent studies suggest the odds of liver mortality increases amongst NASH patients with advanced fibrosis (bridging fibrosis ± cirrhosis). Liver biopsy examination is the current gold standard to accurately discriminate between NAFL vs. NASH as well as diagnose advanced fibrosis. However, due to its invasive nature, risk of bleeding (and even rarely death), prohibitive cost, and sampling error, liver biopsies are imperfect for diagnosis and monitoring of NAFLD. As a result, noninvasive biomarkers that can accurately detect NASH and advanced fibrosis without biopsy are needed. This article will discuss the most novel noninvasive biomarkers in diagnosing NASH and advanced fibrosis.
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Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol 2014; 14:189. [PMID: 25407511 PMCID: PMC4253991 DOI: 10.1186/s12876-014-0189-7] [Citation(s) in RCA: 1208] [Impact Index Per Article: 109.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 10/17/2014] [Indexed: 02/06/2023] Open
Abstract
Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and--more recently recognized--obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
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Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28:637-53. [PMID: 25194181 DOI: 10.1016/j.bpg.2014.07.008] [Citation(s) in RCA: 316] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 06/25/2014] [Accepted: 07/05/2014] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. This article details the pathogenesis of NAFLD along with the current state of its diagnosis and treatment.
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Affiliation(s)
- Peter Dietrich
- Institute of Pathology, University Regensburg, 93053 Regensburg, Germany
| | - Claus Hellerbrand
- Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany.
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39
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Smolinska A, Klaassen EMM, Dallinga JW, van de Kant KDG, Jobsis Q, Moonen EJC, van Schayck OCP, Dompeling E, van Schooten FJ. Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children. PLoS One 2014; 9:e95668. [PMID: 24752575 PMCID: PMC3994075 DOI: 10.1371/journal.pone.0095668] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 03/28/2014] [Indexed: 01/16/2023] Open
Abstract
Wheezing is one of the most common respiratory symptoms in preschool children under six years old. Currently, no tests are available that predict at early stage who will develop asthma and who will be a transient wheezer. Diagnostic tests of asthma are reliable in adults but the same tests are difficult to use in children, because they are invasive and require active cooperation of the patient. A non-invasive alternative is needed for children. Volatile Organic Compounds (VOCs) excreted in breath could yield such non-invasive and patient-friendly diagnostic. The aim of this study was to identify VOCs in the breath of preschool children (inclusion at age 2-4 years) that indicate preclinical asthma. For that purpose we analyzed the total array of exhaled VOCs with Gas Chromatography time of flight Mass Spectrometry of 252 children between 2 and 6 years of age. Breath samples were collected at multiple time points of each child. Each breath-o-gram contained between 300 and 500 VOCs; in total 3256 different compounds were identified across all samples. Using two multivariate methods, Random Forests and dissimilarity Partial Least Squares Discriminant Analysis, we were able to select a set of 17 VOCs which discriminated preschool asthmatic children from transient wheezing children. The correct prediction rate was equal to 80% in an independent test set. These VOCs are related to oxidative stress caused by inflammation in the lungs and consequently lipid peroxidation. In conclusion, we showed that VOCs in the exhaled breath predict the subsequent development of asthma which might guide early treatment.
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Affiliation(s)
- Agnieszka Smolinska
- Department of Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Top Institute Food and Nutrition, Wageningen, The Netherlands
| | - Ester M. M. Klaassen
- Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Jan W. Dallinga
- Department of Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Kim D. G. van de Kant
- Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Quirijn Jobsis
- Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Edwin J. C. Moonen
- Department of Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Onno C. P. van Schayck
- Department of General Practice, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Edward Dompeling
- Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
| | - Frederik J. van Schooten
- Department of Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands
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Smolinska A, Hauschild AC, Fijten RRR, Dallinga JW, Baumbach J, van Schooten FJ. Current breathomics--a review on data pre-processing techniques and machine learning in metabolomics breath analysis. J Breath Res 2014; 8:027105. [PMID: 24713999 DOI: 10.1088/1752-7155/8/2/027105] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We define breathomics as the metabolomics study of exhaled air. It is a strongly emerging metabolomics research field that mainly focuses on health-related volatile organic compounds (VOCs). Since the amount of these compounds varies with health status, breathomics holds great promise to deliver non-invasive diagnostic tools. Thus, the main aim of breathomics is to find patterns of VOCs related to abnormal (for instance inflammatory) metabolic processes occurring in the human body. Recently, analytical methods for measuring VOCs in exhaled air with high resolution and high throughput have been extensively developed. Yet, the application of machine learning methods for fingerprinting VOC profiles in the breathomics is still in its infancy. Therefore, in this paper, we describe the current state of the art in data pre-processing and multivariate analysis of breathomics data. We start with the detailed pre-processing pipelines for breathomics data obtained from gas-chromatography mass spectrometry and an ion-mobility spectrometer coupled to multi-capillary columns. The outcome of data pre-processing is a matrix containing the relative abundances of a set of VOCs for a group of patients under different conditions (e.g. disease stage, treatment). Independently of the utilized analytical method, the most important question, 'which VOCs are discriminatory?', remains the same. Answers can be given by several modern machine learning techniques (multivariate statistics) and, therefore, are the focus of this paper. We demonstrate the advantages as well the drawbacks of such techniques. We aim to help the community to understand how to profit from a particular method. In parallel, we hope to make the community aware of the existing data fusion methods, as yet unresearched in breathomics.
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Affiliation(s)
- A Smolinska
- Department of Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. Top Institute Food and Nutrition, Wageningen, the Netherlands
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Khalid T, Richardson P, Probert CS. The liver breath! Breath volatile organic compounds for the diagnosis of liver disease. Clin Gastroenterol Hepatol 2014; 12:524-6. [PMID: 24211289 DOI: 10.1016/j.cgh.2013.10.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 10/29/2013] [Accepted: 10/29/2013] [Indexed: 02/07/2023]
Affiliation(s)
- Tanzeela Khalid
- Department of Gastroenterology, University of Liverpool, Liverpool, United Kingdom
| | - Paul Richardson
- Department of Gastroenterology, Royal Liverpool University Hospital NHS Trust, Liverpool, United Kingdom
| | - Chris S Probert
- Department of Gastroenterology, University of Liverpool, Liverpool, United Kingdom
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42
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Dallinga JW, Smolinska A, van Schooten FJ. Analysis of volatile organic compounds in exhaled breath by gas chromatography-mass spectrometry combined with chemometric analysis. Methods Mol Biol 2014; 1198:251-263. [PMID: 25270934 DOI: 10.1007/978-1-4939-1258-2_16] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Analysis of exhaled breath samples reveals the presence of many volatile organic compounds (VOCs). The VOC composition of the breath, the so-called breath profile, contains a variety of information including the health status and condition of the organism that produced the sample. Therefore, breath profiling can be used in diagnosing and monitoring disease and other characteristics of the organism, such as phenotype, diet, and exercise. Among various techniques available for breath analysis, GC-MS provides the most extensive information with regard to the qualitative and quantitative presence of VOCs in breath.
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Affiliation(s)
- Jan W Dallinga
- Department of Toxicology, Maastricht University, 616, Maastricht, MD, 6200, The Netherlands
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43
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Zhernakova A, Withoff S, Wijmenga C. Clinical implications of shared genetics and pathogenesis in autoimmune diseases. Nat Rev Endocrinol 2013; 9:646-59. [PMID: 23959365 DOI: 10.1038/nrendo.2013.161] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the presence of autoreactive T cells. They are caused by a complex genetic predisposition that is attributable to multiple genetic variants, each with a moderate-to-low effect size. Most of the genetic variants associated with a particular autoimmune endocrine disease are shared between other systemic and organ-specific autoimmune and inflammatory diseases, such as rheumatoid arthritis, coeliac disease, systemic lupus erythematosus and psoriasis. Here, we review the shared and specific genetic background of autoimmune diseases, summarize their treatment options and discuss how identifying the genetic and environmental factors that predispose patients to an autoimmune disease can help in the diagnosis and monitoring of patients, as well as the design of new treatments.
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Affiliation(s)
- Alexandra Zhernakova
- University of Groningen, University Medical Centre Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, Netherlands
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44
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Flores-Calderón J. [Pediatric hepatology]. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2013; 78 Suppl 1:117-9. [PMID: 24041081 DOI: 10.1016/j.rgmx.2013.06.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/28/2013] [Indexed: 11/17/2022]
Affiliation(s)
- J Flores-Calderón
- UMAE Hospital de Pediatría, Departamento de Gastroenterología, Centro Médico Nacional SXXI. Instituto Mexicano del Seguro Social.
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Dowlaty N, Yoon A, Galassetti P. Monitoring states of altered carbohydrate metabolism via breath analysis: are times ripe for transition from potential to reality? Curr Opin Clin Nutr Metab Care 2013; 16:466-72. [PMID: 23739629 PMCID: PMC4060961 DOI: 10.1097/mco.0b013e328361f91f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW To introduce the potential of breath analysis as a diagnostic or monitoring tool in diabetes. RECENT FINDINGS Blood testing for plasma glucose and other metabolic variables is the base for the diagnosis and management of diabetes, whose two main types (type 1 and type 2, T1DM, T2DM) are projected to affect 450 million by 2030. As blood testing is often uncomfortable, painful, costly, and in some situations unreliable, the quest for alternative, noninvasive methods has been ongoing for decades. Breath analysis has emerged as an ideal alternative as sample collection is easy, painless, flexible, noninvasive, practical, and inexpensive. No single exhaled gas can reflect systemic glucose concentrations. Multiple gases, however, have been linked to various aspects of glucose metabolism, and integrated analysis of their simultaneous profiles during prolonged glycemic fluctuations has yielded accurate predictions of plasma values, building expectation that a clinically usable breath-based glucometer may be developed within a few years. SUMMARY While prototypes of hand-held breath testing glucometers may still be several years away, current research shows the imminent promise of this methodology and the widening support for its development.
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Affiliation(s)
- Newsha Dowlaty
- Institute for Clinical and Translational Science, University of California, Irvine, California 92697, USA
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46
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Baranska A, Tigchelaar E, Smolinska A, Dallinga JW, Moonen EJC, Dekens JAM, Wijmenga C, Zhernakova A, van Schooten FJ. Profile of volatile organic compounds in exhaled breath changes as a result of gluten-free diet. J Breath Res 2013; 7:037104. [DOI: 10.1088/1752-7155/7/3/037104] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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47
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Diagnosis: new noninvasive test to diagnose NASH by analysing exhaled breath. Nat Rev Gastroenterol Hepatol 2013. [PMID: 23183787 DOI: 10.1038/nrgastro.2012.226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
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