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Li J, Li Y, Lin X, Lv C, Zhang X, Chen J. Evaluation of Aortic Hemodynamics Using Four-Dimensional Flow of Magnetic Resonance Imaging in Rabbits with Liver Fibrosis. J Magn Reson Imaging 2024; 60:2604-2612. [PMID: 38520716 DOI: 10.1002/jmri.29363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Liver fibrosis (LF) precipitates systemic hemodynamic alterations, however, its impact on the aorta remaining undefined. PURPOSE To assess aorta hemodynamics changes during LF development in a rabbit model. STUDY TYPE Prospective, experimental. ANIMAL MODEL Thirty 7-month-old male rabbits underwent bile duct ligation (BDL) to induce LF. FIELD STRENGTH/SEQUENCE Biweekly four-dimensional (4D) flow imaging incorporating a 3D gradient-echo at 3.0 T scanner for 14 weeks post-BDL. ASSESSMENT Histopathological exams for 2-5 rabbits were performed at each time point, following each MRI scan. LF was graded using the Metavir scale by a pathologist. 4D flow was analyzed by two radiologists using dedicated postprocessing software. They recorded 4D flow parameters at four aorta sections (aortic sinus, before and after bifurcation of aortic arch, and descending aorta). STATISTICAL TESTS The linear mixed model; Bonferroni correction; Pearson correlation coefficient (r); receiver operating characteristic (ROC) curve; Delong test. The level of significance was set at P < 0.05. RESULTS Following BDL, the wall shear stress (WSS) (0.23-0.32 Pa), energy loss (EL) (0.27-1.55 mW) of aorta significantly increased at the second week for each plane, peaking at the sixth week (WSS: 0.35-0.49 Pa, EL: 0.57-2.0 mW). So did the relative pressure difference (RPD) (second week: 1.67 ± 1.63 mmHg, sixth week: 2.43 ± 0.63 mmHg) in plane 2. Notably, the RPD in plane 2 at the second week displayed the highest area under ROC curve of 0.998 (specificity: 1, sensitivity: 0.967). LF were found at the second, fourth, and sixth week after BDL, with grade F2, F3, and F4, respectively. The RPD in plane 2 was most strongly correlated with the severity of LF (r = 0.86). DATA CONCLUSIONS The occurrence of LF could increase WSS, EL, and RPD of aorta as early as the second week following BDL. LEVEL OF EVIDENCE 1 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Jiali Li
- Department of Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yuansheng Li
- School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Xin Lin
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Cheng Lv
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xiaoyong Zhang
- Clinical Science, Philips Healthcare, Chengdu, Sichuan, China
| | - Jing Chen
- Department of Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Huang ZH, Deng MQ, Lin Y, Ye CH, Zheng MH, Zheng YP. Body posture can modulate liver stiffness measured by transient elastography: a prospective observational study. BMC Gastroenterol 2024; 24:386. [PMID: 39482593 PMCID: PMC11526721 DOI: 10.1186/s12876-024-03473-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 10/21/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Non-invasive measurement of liver stiffness (LS), traditionally performed in the supine position, has been established to assess liver fibrosis. However, fibrosis degree is not the sole determinant of LS, necessitating the identification of relevant confounders. One often-overlooked factor is body posture, and it remains unclear whether normal daily postures interfere with LS irrespective of fibrosis. A prospective two-group comparison study was conducted to investigate the relationship between posture and LS. METHODS Sixty-two adults participated, divided into two groups: patients with chronic liver disease and healthy controls. Both groups were assessed using transient elastography (TE) under the supine, seated, and standing postures. Randomization was applied to the order of the two upright postures. A two-way mixed ANOVA was conducted to assess the posture-dependence of LS and its variations between two groups. RESULTS Results showed that posture differentially affected LS depending on the presence of liver fibrosis. In 31 healthy individuals (baseline LS range: 3.5-6.8 kPa), a transition from the supine (5.0 ± 1.0 kPa) to seated (5.7 ± 1.4 kPa; p = 0.036) or standing (6.2 ± 1.7 kPa; p = 0.002) positions increased LS, indicating liver stiffening. Conversely, in 31 patients with varying fibrosis stages (baseline LS range: 8.8-38.2 kPa), posture decreased LS from the supine (15.9 ± 7.3 kPa) to seated (13.8 ± 6.2 kPa; p < 0.001) or standing (13.9 ± 6.2 kPa; p = 0.001) positions. No significant difference in LS was observed between the seated and standing positions in both groups (control group: 5.7 vs. 6.2 kPa, p = 0.305; patient group: 13.8 vs. 13.9 kPa, p = 1). Additionally, different postures did not elicit significant changes in the success rate (supine, 98.6 ± 4%; seated, 97.6 ± 6%; standing, 99.1 ± 3%; p = 0.258) and IQR/median value (supine, 25 ± 8%; seated, 29 ± 15%; standing, 29 ± 12%; p = 0.117), implying no impact on both measurement feasibility and reliability. CONCLUSIONS We demonstrated, for the first time, the feasibility of utilizing upright postures as an alternative measurement protocol for TE. We further unravel a previously unrecognized role of transitioning between different postures to assist the diagnosis of cirrhosis. The findings suggested that daily physiological activity of postural changes suffices to alter LS. Therefore, body positioning should be standardized and carefully considered when interpreting LS.
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Affiliation(s)
- Zi-Hao Huang
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Miao-Qin Deng
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Yangmin Lin
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China
| | - Chen-Hui Ye
- MAFLD Research Center, 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
| | - Ming-Hua Zheng
- MAFLD Research Center, 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
| | - Yong-Ping Zheng
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China.
- Research Institute for Smart Ageing, The Hong Kong Polytechnic University, Hong Kong, China.
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Safraou Y, Krehl K, Meyer T, Mehrgan S, Jordan JEL, Tzschätzsch H, Fischer T, Asbach P, Braun J, Sack I, Guo J. The influence of static portal pressure on liver biophysical properties. Acta Biomater 2023; 169:118-129. [PMID: 37507032 DOI: 10.1016/j.actbio.2023.07.033] [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: 03/28/2023] [Revised: 07/03/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023]
Abstract
The liver is a highly vascularized organ where fluid properties, including vascular pressure, vessel integrity and fluid viscosity, play a critical role in gross mechanical properties. To study the effects of portal pressure, liver confinement, fluid viscosity, and tissue crosslinking on liver stiffness, water diffusion, and vessel size, we applied multiparametric magnetic resonance imaging (mpMRI), including multifrequency magnetic resonance elastography (MRE) and apparent diffusion coefficient (ADC) measurements, to ex vivo livers from healthy male rats (13.6±1.6 weeks) at room temperature. Four scenarios including altered liver confinement, tissue crosslinking, and vascular fluid viscosity were investigated with mpMRI at different portal pressure levels (0-17.5 cmH2O). Our experiments demonstrated that, with increasing portal pressure, rat livers showed higher water content, water diffusivity, and increased vessel sizes quantified by the vessel tissue volume fraction (VTVF). These effects were most pronounced in native, unconfined livers (VTVF: 300±120%, p<0.05, ADC: 88±29%, p<0.01), while still significant under confinement (confined: VTVF: 53±32%, p<0.01, ADC: 28±19%, p<0.05; confined-fixed: VTVF: 52±20%, p<0.001, ADC: 11±2%, p<0.01; confined-viscous: VTVF: 210±110%, p<0.01, ADC: 26±9%, p<0.001). Softening with elevated portal pressure (-12±5, p<0.05) occurred regardless of confinement and fixation. However, the liver stiffened when exposed to a more viscous inflow fluid (11±4%, p<0.001). Taken together, our results elucidate the complex relationship between macroscopic-biophysical parameters of liver tissue measured by mpMRI and vascular-fluid properties. Influenced by portal pressure, vascular permeability, and matrix crosslinking, liver stiffness is sensitive to intrinsic poroelastic properties, which, alongside vascular architecture and water diffusivity, may aid in the differential diagnosis of liver disease. STATEMENT OF SIGNIFICANCE: Using highly controllable ex vivo rat liver phantoms, hepatic biophysical properties such as tissue-vascular structure, stiffness, and water diffusivity were investigated using multiparametric MRI including multifrequency magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI). Through elaborate tuning of the experimental conditions such as the static portal pressure, flow viscosity, amount and distribution of fluid content in the liver, we identified the contributions of the fluid component to the overall imaging-based biophysical properties of the liver. Our finding demonstrated the sensitivity of liver stiffness to the hepatic poroelastic properties, which may aid in the differential diagnosis of liver diseases.
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Affiliation(s)
- Yasmine Safraou
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Karolina Krehl
- Department of Veterinary Medicine, Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Freie Universität Berlin
| | - Tom Meyer
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Shahryari Mehrgan
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jakob Ernst Luis Jordan
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Heiko Tzschätzsch
- Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Thomas Fischer
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Patrick Asbach
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jürgen Braun
- Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ingolf Sack
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jing Guo
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
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Kaur S, Kidambi S, Ortega-Ribera M, Thuy LTT, Nieto N, Cogger VC, Xie WF, Tacke F, Gracia-Sancho J. In Vitro Models for the Study of Liver Biology and Diseases: Advances and Limitations. Cell Mol Gastroenterol Hepatol 2022; 15:559-571. [PMID: 36442812 PMCID: PMC9868680 DOI: 10.1016/j.jcmgh.2022.11.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022]
Abstract
In vitro models of liver (patho)physiology, new technologies, and experimental approaches are progressing rapidly. Based on cell lines, induced pluripotent stem cells or primary cells derived from mouse or human liver as well as whole tissue (slices), such in vitro single- and multicellular models, including complex microfluidic organ-on-a-chip systems, provide tools to functionally understand mechanisms of liver health and disease. The International Society of Hepatic Sinusoidal Research (ISHSR) commissioned this working group to review the currently available in vitro liver models and describe the advantages and disadvantages of each in the context of evaluating their use for the study of liver functionality, disease modeling, therapeutic discovery, and clinical applicability.
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Affiliation(s)
- Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Srivatsan Kidambi
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, Nebraska
| | - Martí Ortega-Ribera
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Victoria C Cogger
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Wei-Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jordi Gracia-Sancho
- Liver Vascular Biology, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.
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5
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Czernuszewicz TJ, Aji AM, Moore CJ, Montgomery SA, Velasco B, Torres G, Anand KS, Johnson KA, Deal AM, Zukić D, McCormick M, Schnabl B, Gallippi CM, Dayton PA, Gessner RC. Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models. Hepatol Commun 2022; 6:1827-1839. [PMID: 35202510 PMCID: PMC9234684 DOI: 10.1002/hep4.1912] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Shear wave elastography (SWE) is an ultrasound-based stiffness quantification technology that is used for noninvasive liver fibrosis assessment. However, despite widescale clinical adoption, SWE is largely unused by preclinical researchers and drug developers for studies of liver disease progression in small animal models due to significant experimental, technical, and reproducibility challenges. Therefore, the aim of this work was to develop a tool designed specifically for assessing liver stiffness and echogenicity in small animals to better enable longitudinal preclinical studies. A high-frequency linear array transducer (12-24 MHz) was integrated into a robotic small animal ultrasound system (Vega; SonoVol, Inc., Durham, NC) to perform liver stiffness and echogenicity measurements in three dimensions. The instrument was validated with tissue-mimicking phantoms and a mouse model of nonalcoholic steatohepatitis. Female C57BL/6J mice (n = 40) were placed on choline-deficient, L-amino acid-defined, high-fat diet and imaged longitudinally for 15 weeks. A subset was sacrificed after each imaging timepoint (n = 5) for histological validation, and analyses of receiver operating characteristic (ROC) curves were performed. Results demonstrated that robotic measurements of echogenicity and stiffness were most strongly correlated with macrovesicular steatosis (R2 = 0.891) and fibrosis (R2 = 0.839), respectively. For diagnostic classification of fibrosis (Ishak score), areas under ROC (AUROCs) curves were 0.969 for ≥Ishak1, 0.984 for ≥Ishak2, 0.980 for ≥Ishak3, and 0.969 for ≥Ishak4. For classification of macrovesicular steatosis (S-score), AUROCs were 1.00 for ≥S2 and 0.997 for ≥S3. Average scanning and analysis time was <5 minutes/liver. Conclusion: Robotic SWE in small animals is feasible and sensitive to small changes in liver disease state, facilitating in vivo staging of rodent liver disease with minimal sonographic expertise.
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Affiliation(s)
- Tomasz J Czernuszewicz
- SonoVol, Inc.DurhamNCUSA.,Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | | | | | - Stephanie A Montgomery
- Department of Pathology and Laboratory MedicineUniversity of North CarolinaChapel HillNCUSA
| | - Brian Velasco
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Gabriela Torres
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Keerthi S Anand
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Kennita A Johnson
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Allison M Deal
- Biostatistics CoreLineberger Cancer CenterUniversity of North CarolinaChapel HillNCUSA
| | | | | | - Bernd Schnabl
- 19979Department of MedicineUniversity of California San DiegoLa JollaCAUSA.,19979Department of MedicineVA San Diego Healthcare SystemSan DiegoCAUSA
| | - Caterina M Gallippi
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Paul A Dayton
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
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Neuman MG, Mueller J, Mueller S. Non-invasive Biomarkers of Liver Inflammation and Cell Death in Response to Alcohol Detoxification. Front Physiol 2021; 12:678118. [PMID: 34305638 PMCID: PMC8292967 DOI: 10.3389/fphys.2021.678118] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction Alcohol-related liver disease (ALD) represents the most common liver disease worldwide, however, the underlying molecular mechanisms are still poorly understood. Namely centrilobular inflammation and programmed cell death are characteristic to ALD and it remains to be elucidated why they persist despite the absence of alcohol. Aims To study the effects of alcohol withdrawal in a cohort of heavy drinkers and the role of cirrhosis by using non-invasive biomarkers such as cytokines, apoptotic and angiogenic markers. Methods Caspase 3-cleaved M30, M65, cytokines (IL-6, IL-8), tumor necrosis factor alpha (TNF-α), transforming growth factor (TGF-β) and vascular endothelial growth factor (VEGF) were measured in 114 heavy drinkers. The role of alcohol detoxification was investigated in 45 patients. The liver histology was available in 23 patients. Fibrosis stage and steatosis were assessed by measuring liver stiffness (LS) and controlled attenuation parameter (CAP) in all patients using transient elastography (FibroScan, Echosens, Paris). Mean observation interval between the measurements was 5.7 ± 1.4 days (mean + -SD). Results Patients consumed a mean of 204 ± 148 g/day alcohol with a heavy drinking duration of 15.3 ± 11.0 years. Mean LS was 20.7 ± 24.4 kPa and mean CAP was 303 ± 51 dB/m. Fibrosis distribution was F0-38.1%, F1-2-31%, F3-7.1 and F4-23.9%. Apoptotic markers M30 and M65 were almost five times above normal. In contrast, TNF- α a, IL-8 and VEGF were only slightly elevated. Patients with manifest liver cirrhosis (F4) had significantly higher levels of M30, M65, IL-6 and IL-8. Histology features such as hepatocyte ballooning, Mallory-Denk bodies, inflammation and fibrosis were all significantly associated with elevated LS, and serum levels of TNF-alpha, M30 and M65 but not with CAP and other cytokines. During alcohol detoxification, LS, transaminases, TGF- β, IL-6, IL-8 and VEGF decreased significantly. In contrast, no significant changes were observed for M30, M65 and TNF- α and M30 even increased during detoxification in non-cirrhotic patients. Profibrogenic cytokine TGF-beta and pro-angiogenic cytokine VEGF showed a delayed decrease in patients with manifest cirrhosis. Conclusion Patients with alcohol-related cirrhosis have a pronounced apoptotic activity and a distinct inflammatory response that only partly improves after 1 week of alcohol detoxification. Alcohol withdrawal may represent an important approach to better dissect the underlying mechanisms in the setting of alcohol metabolism.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, Temerity Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Johannes Mueller
- Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Sebastian Mueller
- Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany.,Department of Internal Medicine, Salem Medical Center, Heidelberg, Germany
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Piecha F, Gänßler JM, Ozga AK, Wehmeyer MH, Kluwe J, Lampalzer S, Creutzfeldt AM, Buescher G, Horvatits T, Sterneck M, Pischke S, Lohse AW, Schulze Zur Wiesch J. Evolution of liver stiffness and post-treatment surveillance by liver elastography for HCV patients in the DAA era. Scand J Gastroenterol 2021; 56:840-848. [PMID: 34010581 DOI: 10.1080/00365521.2021.1915374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Baseline liver stiffness (LS) is prognostically relevant in patients with chronic hepatitis C virus (HCV) infection but may change after successful HCV eradication. Data on post-treatment LS for a further risk stratification remain scarce. Here, we study the kinetics of LS and laboratory parameters in patients undergoing HCV treatment and analyze the association of post-treatment LS with outcome parameters. METHODS In a cohort of 1011 chronic HCV patients undergoing DAA treatment, we identified 404 patients with sequential LS and laboratory assessments with or without viral eradication. Additionally, outcome parameters were correlated with post-treatment LS after successful HCV therapy. RESULTS LS significantly decreased from a median of 8.8 to 6.1 kPa in 346 patients after HCV eradication, but significantly increased from a median of 10.5 to 11.9 kPa in 58 patients without viral clearance. In 78 patients with two sequential post-treatment measurements, LS decreased from 12.6 to 8.7 kPa after a median 344 d, with a further decrease to 7.0 kPa after a median of 986 d after end of treatment (EoT). In 400 patients with a post-treatment LS assessment after viral eradication, only 9 liver-related events occurred over a median follow-up (FU) of 23 months. All events were observed in patients with a post-treatment LS >20 kPa. CONCLUSIONS After successful HCV eradication, LS improves sequentially, suggesting an initial phase of necroinflammation regression followed by a second phase of true fibrosis regression. Overall, liver-related events were rarely observed and seem to be limited to patients with a post-treatment LS >20 kPa, so that these patients require a closer clinical monitoring.
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Affiliation(s)
- Felix Piecha
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Jan-Michael Gänßler
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ann-Kathrin Ozga
- Center for Experimental Medicine, Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malte H Wehmeyer
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Kluwe
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sibylle Lampalzer
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Maria Creutzfeldt
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gustav Buescher
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Horvatits
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Martina Sterneck
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Pischke
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
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8
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Garczyńska K, Tzschätzsch H, Kühl AA, Morr AS, Lilaj L, Häckel A, Schellenberger E, Berndt N, Holzhütter HG, Braun J, Sack I, Guo J. Changes in Liver Mechanical Properties and Water Diffusivity During Normal Pregnancy Are Driven by Cellular Hypertrophy. Front Physiol 2020; 11:605205. [PMID: 33329058 PMCID: PMC7719759 DOI: 10.3389/fphys.2020.605205] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/29/2020] [Indexed: 12/27/2022] Open
Abstract
During pregnancy, the body’s hyperestrogenic state alters hepatic metabolism and synthesis. While biochemical changes related to liver function during normal pregnancy are well understood, pregnancy-associated alterations in biophysical properties of the liver remain elusive. In this study, we investigated 26 ex vivo fresh liver specimens harvested from pregnant and non-pregnant rats by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) in a 0.5-Tesla compact magnetic resonance imaging (MRI) scanner. Water diffusivity and viscoelastic parameters were compared with histological data and blood markers. We found livers from pregnant rats to have (i) significantly enlarged hepatocytes (26 ± 15%, p < 0.001), (ii) increased liver stiffness (12 ± 15%, p = 0.012), (iii) decreased viscosity (−23 ± 14%, p < 0.001), and (iv) increased water diffusivity (12 ± 11%, p < 0.001). In conclusion, increased stiffness and reduced viscosity of the liver during pregnancy are mainly attributable to hepatocyte enlargement. Hypertrophy of liver cells imposes fewer restrictions on intracellular water mobility, resulting in a higher hepatic water diffusion coefficient. Collectively, MRE and DWI have the potential to inform on structural liver changes associated with pregnancy in a clinical context.
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Affiliation(s)
- Karolina Garczyńska
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Heiko Tzschätzsch
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anja A Kühl
- iPATH.Berlin Core Unit, Charitá - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anna Sophie Morr
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ledia Lilaj
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Akvile Häckel
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Eyk Schellenberger
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Nikolaus Berndt
- Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Computational Systems Biochemistry Group, Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Hermann-Georg Holzhütter
- Computational Systems Biochemistry Group, Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jürgen Braun
- Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ingolf Sack
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jing Guo
- Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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9
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Hepatic Arterial Blood Flow Index Is Associated with the Degree of Liver Fibrosis in Patients with Chronic Hepatitis B Virus Infection. HEPATITIS MONTHLY 2020. [DOI: 10.5812/hepatmon.98323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Liver fibrosis due to Hepatitis B Virus (HBV) infection is an important public health concern worldwide. An accurate assessment of liver fibrosis is crucial for the identification of susceptible patients to severe clinical conditions and selection of treatment for patients with Chronic Hepatitis B (CHB) infection. Today, the development of simple, accurate, cost-effective, and non-invasive liver fibrosis tests is essential in clinical practice. Methods: According to liver biopsy as the reference standard, we compared the efficacy of hepatic arterial blood flow index (HBI) versus liver stiffness measurement (LSM), aspartate aminotransferase-to-platelet count ratio index (APRI), and fibrosis index based on 4 factors (FIB-4) to predict various degrees of liver fibrosis among 87 patients with CHB infection. Results: Spearman’s rank correlation coefficient of HBI versus the degree of liver fibrosis, according to the METAVIR scoring system, was 0.672 (P < 0.001). The area under the receiver operating characteristic curve (AUROC) of HBI (0.884; 95% CI: 0.806 - 0.961; P = 0.000) was greater than that of LSM (0.807; 95% CI: 0.703 - 0.912; P = 0.00), APRI (0.684; 95% CI: 0.556 - 0.812; P = 0.009), and FIB-4 (0.757; 95% CI: 0.641 - 0.873; P = 0.000) for the diagnostic analysis of significant liver fibrosis (≥ F2); similar results were obtained for the prediction of other liver fibrosis stages. Conclusions: The present findings shed new light on the association of HBI with the degree of liver fibrosis in patients with CHB infection. Hepatic Arterial Perfusion Scintigraphy (HAPS) with the measurement of HBI is a promising diagnostic method of liver fibrosis stage, which can guide therapy in CHB patients, although further large-scale studies are needed.
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10
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Mandorfer M, Hernández-Gea V, García-Pagán JC, Reiberger T. Noninvasive Diagnostics for Portal Hypertension: A Comprehensive Review. Semin Liver Dis 2020; 40:240-255. [PMID: 32557480 DOI: 10.1055/s-0040-1708806] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Noninvasive diagnostics for portal hypertension include imaging and functional tests, as well as blood-based biomarkers, and capture different features of the portal hypertensive syndrome. Definitive conclusions regarding their clinical utility require assessment of their diagnostic value in specific clinical settings (i.e., diagnosing a particular hemodynamic condition within a well-defined target population). Several noninvasive methods are predictive of clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥ 10 mm Hg; the threshold for complications of portal hypertension); however, only a minority of them have been evaluated in compensated advanced chronic liver disease (i.e., the target population). Importantly, most methods correlate only weakly with HVPG at high values (i.e., in patients with CSPH). Nevertheless, selected methods show promise for diagnosing HVPG ≥ 16 mm Hg (the cut-off for increased risks of hepatic decompensation and mortality) and monitoring HVPG changes in response to nonselective beta-blockers or etiological treatments. Finally, we review established and potential future clinical applications of noninvasive methods.
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Affiliation(s)
- Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Thomas Reiberger
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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11
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Mueller S, Piecha F, Elshaarawy O. Liver Stiffness and Nutrition. LIVER ELASTOGRAPHY 2020:271-276. [DOI: 10.1007/978-3-030-40542-7_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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12
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Zjacic Puljiz D, Mestrovic A, Zaja I, Tonkic A, Grgurevic I, Duplancic D, Delic Jukic IK, Ljutic D, Puljiz Z. Impact of hemodialysis on liver stiffness measured with real-time two-dimensional shear wave elastography. Wien Klin Wochenschr 2019; 133:96-101. [PMID: 31781940 DOI: 10.1007/s00508-019-01577-w] [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: 12/18/2018] [Accepted: 10/30/2019] [Indexed: 11/26/2022]
Abstract
BACKGROUND AND AIMS The impact of hemodialysis on liver stiffness is still unclear. The aim of the study was to assess liver fibrosis by real-time two-dimensional shear wave elastography (RT 2D-SWE) and to quantify the influence of net fluid withdrawal on liver stiffness during one hemodialysis session. The second aim was to investigate the influence of systolic blood pressure and time spent on dialysis (in years) on liver stiffness measurements. METHODS This before/after hemodialysis (HD) study in a group of end stage renal disease (ESRD) patients was carried out with patients on regular HD. Measurements of liver stiffness were done using RT 2D-SWE directly before and after a hemodialysis session. RESULTS In this study 27 patients with mean age 69.4 ± 14.75 years were included. Mean net fluid withdrawal volume per session was 2874.07 ± 778.35 ml. Mean pre-HD and post-HD liver stiffness measurements were 8.15 kPa (95% confidence interval, CI 7.61-8.68) and 6.70 kPa (95% CI 6.10-7.30 kPa), respectively. Mean liver stiffness reduction was 1.448 ± 1.14 kPa. The amount of fluid removed correlated with the decline in liver stiffness values after HD (ρ = 0.523, P = 0.003). There was a positive but statistically not significant correlation between time spent in HD and liver stiffness (ρ = 0.151, P = 0.623) CONCLUSION: Liver stiffness significantly declined after one session of HD. The change in liver stiffness was strongly correlated with the amount of net fluid withdrawal. Random liver stiffness measurements (LSM) by RT 2D-SWE does not precisely show the degree of fibrosis, Furthermore, it is presumed that postdialysis liver stiffness values likely reflect the real degree of liver fibrosis.
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Affiliation(s)
| | - Antonio Mestrovic
- Department of Gastroenterology, University Hospital Split, 21 000, Split, Croatia
| | - Ivan Zaja
- Department of Gastroenterology, University Hospital Split, 21 000, Split, Croatia
| | - Ante Tonkic
- Department of Gastroenterology, University Hospital Split, 21 000, Split, Croatia.
| | - Ivica Grgurevic
- Department of Gastroenterology, University Hospital Dubrava, Zagreb, Croatia
| | - Darko Duplancic
- Department of Cardiology, University Hospital Split, Split, Croatia
| | | | - Dragan Ljutic
- Department of Nephrology and Dialysis, University Hospital Split, Split, Croatia
| | - Zeljko Puljiz
- Department of Gastroenterology, University Hospital Split, 21 000, Split, Croatia
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13
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Winters AC, Mittal R, Schiano TD. A review of the use of transient elastography in the assessment of fibrosis and steatosis in the post-liver transplant patient. Clin Transplant 2019; 33:e13700. [PMID: 31441967 DOI: 10.1111/ctr.13700] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 07/21/2019] [Accepted: 08/18/2019] [Indexed: 12/13/2022]
Abstract
Liver biopsy is considered the gold standard method for diagnosing and staging liver disease, particularly in the post-liver transplant setting. Given the invasive nature of biopsy, alternate means for accurately assessing liver fibrosis and steatosis are preferred especially as the number of patients with fatty liver disease is increasing. Transient elastography has been validated as a useful tool for evaluation of liver fibrosis, as has controlled attenuation parameter index as a tool for assessing steatosis. It is a non-invasive, rapid, and highly reproducible approach to demonstrate the presence of fibrosis among non-transplant patients with chronic liver disease of various etiologies. However, it has not yet found wide acceptance in liver transplant recipients. There are few published studies evaluating the merits and applicability of transient elastography to assess allografts after liver transplantation. We review the published data on the use of transient elastography with concurrent controlled attenuation parameter in liver transplant recipients and recommend its greater use to follow allograft function over time.
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Affiliation(s)
- Adam C Winters
- Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA
| | - Rasham Mittal
- Transplant Hepatology, Southern California Permanente Medical Group, Kaiser Permanente, Los Angeles, CA, USA
| | - Thomas D Schiano
- Department of Medicine, Division of Liver Diseases, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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14
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Hsu TH, Tsui PH, Yu WT, Huang SF, Tai J, Wan YL, Tai DI. Cutoff Values of Acoustic Radiation Force Impulse Two-Location Measurements in Different Etiologies of Liver Fibrosis. J Med Ultrasound 2019; 27:130-134. [PMID: 31867175 PMCID: PMC6905267 DOI: 10.4103/jmu.jmu_7_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 01/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acoustic radiation force impulse (ARFI) imaging is a popular modality to measure liver fibrosis. ARFI selects optimal locations for measurement under imaging guiding. However, there are concerns on study locations and observers bias. To decrease the variations, ARFI at two locations was measured with standardized protocol. This study attempted to establish its cutoff values according to Metavir fibrosis score in different etiologies. METHODS A consecutive series of patients who received liver histology study were prospectively enrolled. All cases had hemogram, liver biochemistry, viral markers, and ARFI two-location measurements within 4 weeks of histology study. A standardized protocol was performed by single technologist. We excluded patients with alanine aminotransferase >5x upper limit normal. RESULTS Five hundred and ten patients that included 153 seronegative for both HBsAg and anti-HCV Non-B non-C (NBNC), 33 autoimmune liver diseases (AILD), 261 chronic hepatitis B (CHB), and 63 chronic hepatitis C (CHC) were enrolled. About 83% of NBNC patients had fat cell >5%. For diagnosis of liver cirrhosis, the area under receiver operating characteristic curve of NBNC, AILD, CHB, and CHC groups was 0.937, 0.929, 0.784, and 0.937; the cutoff values for mean ARFI were 1.788, 2.095, 1.455, and 1.710 m/s, respectively. The sensitivity and specificity are both over 0.818 for patients with nonalcoholic fatty liver diseases, CHC, and AILD, but the corresponding data are only 0.727-0.756 in CHB. The Fibrosis-4 Score is as good as ARFI on fibrosis assessment in NBNC. CONCLUSION The performance of ARFI two-location measurement is excellent in NBNC, AILD, and CHC, but is only satisfactory in CHB.
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Affiliation(s)
- Tse-Hwa Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Po-Hsiang Tsui
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan
| | - Wan-Ting Yu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Shiu-Feng Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan
| | - Jennifer Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yung-Liang Wan
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan
| | - Dar-In Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
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15
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Stenberg Ribeiro M, Hagström H, Stål P, Ajne G. Transient liver elastography in normal pregnancy - a longitudinal cohort study. Scand J Gastroenterol 2019; 54:761-765. [PMID: 31272248 DOI: 10.1080/00365521.2019.1629007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background and aim: Transient elastography can detect liver fibrosis by estimation of liver stiffness. Results may be falsely high when blood flow to the liver is increased, such as during late stages of pregnancy. The aim of the present study was to longitudinally evaluate transient elastography in healthy pregnant women. Methods: We recruited 24 healthy women with normal singleton pregnancies in a longitudinal cohort study. All women underwent transient elastography at gestational week 18-20, week 26-28 and week 36-38, as well as after a minimum of 8 weeks postpartum. Results: Mean age at baseline was 30.6 years ± 4.1, and mean BMI was 22.3 kg/m2±1.9. 14 women (58%) were nulliparous. The pregnancy outcomes were normal, with no cases of preeclampsia or gestational diabetes. Mean gestational length was 284 days ± 7. Mean liver stiffness increased from 3.8 kPa during the second trimester to 5.9 kPa during the third trimester (p = .002). At the third trimester, 2 women (8%) had an elastography measurement of >7.9 kPa. Postpartum, liver stiffness decreased to early second trimester levels (5.9 to 3.8 kPa, p = .002), and no woman had liver stiffness values above 7.9 kPa. Likewise, the mean Controlled Attenuation Parameter (CAP) increased from 186 dB/m in the second trimester to 215 dB/m in the third trimester (p = .01) and reversed postpartum (215 to 193 dB/m, p = .03). Conclusion: Liver stiffness and CAP increase reversibly during normal pregnancies, and slightly elevated levels in the third trimester can be considered a normal finding. Lay summary An ultrasound-based method called transient elastography can be used to measure fat content and estimate fibrosis in the liver. In this study, we examined healthy women three times during their pregnancy and once after labor to evaluate the effects of a normal pregnancy on a healthy liver. The ultrasound-estimation of fibrosis and fat content increased during pregnancy and reversed afterwards, without any other signs of disease in the liver.
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Affiliation(s)
| | - Hannes Hagström
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital , Stockholm , Sweden.,Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet , Stockholm , Sweden
| | - Per Stål
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital , Stockholm , Sweden
| | - Gunilla Ajne
- Pregnancy Care and Delivery, Karolinska University Hospital , Stockholm , Sweden
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16
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Piecha F, Radunski UK, Ozga AK, Steins D, Drolz A, Horvatits T, Spink C, Ittrich H, Benten D, Lohse AW, Sinning C, Kluwe J. Ascites control by TIPS is more successful in patients with a lower paracentesis frequency and is associated with improved survival. JHEP Rep 2019; 1:90-98. [PMID: 32039356 PMCID: PMC7001550 DOI: 10.1016/j.jhepr.2019.04.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/18/2019] [Accepted: 04/09/2019] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Refractory ascites is the main reason for the implantation of a transjugular intrahepatic portosystemic shunt (TIPS) in liver cirrhosis, but ascites control by TIPS fails in a relevant proportion of cases. Here, we investigated whether routine parameters pre-TIPS can predict persistent ascites after TIPS implantation and whether persistent ascites predicts long-term clinical outcome. Methods A detailed retrospective analysis of 128 patients receiving expanded polytetrafluoroethylene-covered stents for the treatment of refractory ascites was performed. Persistent ascites post-TIPS was defined as the prolonged need for paracentesis >3 months after TIPS. The influence of demographics, laboratory results, pre-TIPS heart and liver ultrasound results, and invasive hemodynamic parameters on persistent ascites was evaluated by univariable and multivariable logistic regression. Predictors of the composite endpoint liver transplantation/death were analyzed using a multivariable Cox regression. Results Ascites control post-TIPS was achieved in 95/128 patients (74%), whereas ascites remained persistent in 33/128 cases (26%). On multivariable analysis, a lower paracentesis frequency pre-TIPS (odds ratio 1.672; 95% CI 1.253–2.355) and lower baseline creatinine levels (odds ratio 2.640; CI 1.201–6.607) were associated with ascites control. Patients with persistent ascites post-TIPS had and impaired transplant-free survival (median 10.0 vs. 25.8 months), for which persistent ascites was the only independent predictor (hazard ratio 5.654; CI 3.019–10.59). Conclusion TIPS-placement in patients with lower paracentesis frequency and creatinine levels is associated with superior ascites control. Thus, TIPS implantation should be considered in moderate decompensation and not as a last resort. Persistent ascites post-TIPS seems to be the only predictor of liver transplantation and death. Lay summary The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) in patients with refractory ascites should be considered in patients with moderate decompensation and not as a last resort, as lower paracentesis frequency and creatinine levels pre-TIPS are associated with superior ascites control. In turn, failure to control ascites seems to be the only predictor of liver transplantation and death.
Ascites control post-TIPS is superior if the TIPS is placed at lower paracentesis frequency and creatinine levels. Transplant-free survival is decreased in patients with a failed ascites control post-TIPS. TIPS-placement should be considered “early” in ascitic decompensation. Close monitoring and prioritized organ allocation should be considered in patients with failed ascites control post-TIPS.
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Affiliation(s)
- Felix Piecha
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulf K Radunski
- Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ann-Kathrin Ozga
- Center for Experimental Medicine, Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Steins
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Drolz
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Horvatits
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Clemens Spink
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Harald Ittrich
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Benten
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Gastroenterology, Helios Klinikum Duisburg, Duisburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Sinning
- Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Kluwe
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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17
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Mandorfer M, Hernández-Gea V, Reiberger T, García-Pagán JC. Hepatic Venous Pressure Gradient Response in Non-Selective Beta-Blocker Treatment—Is It Worth Measuring? ACTA ACUST UNITED AC 2019. [DOI: 10.1007/s11901-019-00469-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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18
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Moreno C, Mueller S, Szabo G. Non-invasive diagnosis and biomarkers in alcohol-related liver disease. J Hepatol 2019; 70:273-283. [PMID: 30658728 DOI: 10.1016/j.jhep.2018.11.025] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/29/2018] [Accepted: 11/29/2018] [Indexed: 12/14/2022]
Abstract
Even though alcohol-related liver disease (ALD) is a major cause of severe liver disease worldwide, most patients with ALD are diagnosed at the decompensation stage. Liver biopsy is still considered the gold standard for establishing a definite diagnosis and assessing the fibrosis stage of ALD, but it is an invasive procedure, associated with significant morbidity. During the last decade, non-invasive tests have been developed to estimate the severity of liver fibrosis and steatosis. Measurement of liver stiffness by transient elastography has become the most commonly used non-invasive parameter to evaluate fibrosis. In ALD, transient elastography has been demonstrated to have an excellent performance to detect advanced fibrosis and cirrhosis. However, aspartate aminotransferase levels must be considered when interpreting liver stiffness cut-offs. Non-invasive biological tests have also been evaluated to assess liver fibrosis in ALD. The commercially available Enhanced Liver Fibrosis test and FibroTest have comparable performance for the diagnosis of advanced fibrosis in ALD, with studies suggesting that they are better than other biological tests (i.e. FIB-4 and APRI). Although ultrasound is still accepted as an initial screen for fatty liver diagnosis, new methods have recently been developed to detect steatosis. Magnetic resonance spectroscopy and magnetic resonance imaging techniques are highly accurate and reproducible, with superior sensitivities and specificities for detecting histological steatosis than ultrasound. However, low availability and high cost limit the use of magnetic resonance techniques in routine clinical practice. More recently, controlled attenuation parameter was developed as a novel tool to non-invasively assess liver steatosis; performed in combination with transient elastography, it was suggested to be superior to regular ultrasound for detecting steatosis and was shown to have acceptable diagnostic accuracy. New serum biomarkers are under investigation to non-invasively diagnose more severe forms of ALD and to predict prognosis of patients.
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Affiliation(s)
- Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
| | - Sebastian Mueller
- Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
| | - Gyongyi Szabo
- Department of Medicine, LRB-208, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
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19
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Ammon FJ, Kohlhaas A, Elshaarawy O, Mueller J, Bruckner T, Sohn C, Fluhr G, Fluhr H, Mueller S. Liver stiffness reversibly increases during pregnancy and independently predicts preeclampsia. World J Gastroenterol 2018; 24:4393-4402. [PMID: 30344423 PMCID: PMC6189842 DOI: 10.3748/wjg.v24.i38.4393] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/20/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To study liver stiffness (LS) during pregnancy and its association with complications during pregnancy.
METHODS In this observational, diagnostic study, 537 pregnant women were prospectively enrolled at the Department of Obstetrics and Gynecology, University hospital Heidelberg and Salem Medical Center. LS was measured using the Fibroscan device (Echosens, Paris) in all women and in 41 cases 24 h after delivery. Clinical and morphological data were recorded and abdominal ultrasound and standard laboratory tests were performed. No complications were observed in 475 women (controls) while preeclampsia and intrahepatic cholestasis of pregnancy (ICP) developed in 22 and 40 women, respectively.
RESULTS In controls, LS increased significantly from initially 4.5 ± 1.2 kPa in the second trimester to 6.0 ± 2.3 kPa (P < 0.001) in the third trimester. In the third trimester, 41% of women had a LS higher than 6 kPa. Elevated LS in controls was significantly correlated with alkaline phosphatase, leukocytes, gestational age and an increase in body weight and body mass index (BMI). In women with pregnancy complications, LS was significantly higher as compared to controls (P < 0.0001). Moreover, in multivariate analysis, LS was an independent predictor for preeclampsia with an odds ratio of 2.05 (1.27-3.31) and a cut-off value of 7.6 kPa. In contrast, ICP could not be predicted by LS. Finally, LS rapidly decreased in all women within 24 h after delivery from 7.2 ± 3.3 kPa down to 4.9 ± 2.2 kPa (P < 0.001).
CONCLUSION During pregnancy, LS significantly and reversibly increases in the final trimester of pregnant women without complications. In women with preeclampsia, LS is significantly elevated and an independent non-invasive predictor.
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Affiliation(s)
- Franziska J Ammon
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany
| | - Anna Kohlhaas
- Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Omar Elshaarawy
- Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Johannes Mueller
- Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry und Informatics, University of Heidelberg, Heidelberg 69121, Germany
| | - Christof Sohn
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany
| | - Gabriele Fluhr
- Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
| | - Herbert Fluhr
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany
| | - Sebastian Mueller
- Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg 69121, Germany
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20
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Piecha F, Mandorfer M, Peccerella T, Ozga AK, Poth T, Vonbank A, Seitz HK, Rausch V, Reiberger T, Mueller S. Pharmacological decrease of liver stiffness is pressure-related and predicts long-term clinical outcome. Am J Physiol Gastrointest Liver Physiol 2018; 315:G484-G494. [PMID: 29746172 DOI: 10.1152/ajpgi.00392.2017] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver stiffness (LS) as measured by transient elastography is increasingly used to noninvasively assess liver fibrosis. However, LS is efficiently modulated by confounders like arterial and portal pressure (PP). We here study the effect of acute hemodynamic changes on LS (measured by µFibroscan) in a rodent model of cirrhosis in response to pharmacological modulation of PP by losartan, nitric oxide donors, and propranolol. Additionally, changes of LS and the hepatic venous pressure gradient (HVPG) under propranolol therapy were assessed with regard to clinical outcomes in a human cohort of n = 38 cirrhotic patients. In the animal model, cirrhosis induction resulted in a significant increase of LS and PP. After losartan or NO application, a LS decrease of 25% was strongly correlated with a concomitant decrease of mean arterial pressure (MAP) and PP. In contrast, acute propranolol administration decreased heart rate but not MAP resulting in stable LS. In the human cohort, most patients ( n = 25, 66%) showed a LS decrease after propranolol treatment initiation which significantly correlated to HVPG ( r = 0.518, P < 0.01) but was not accompanied by statistically significant changes in transaminases or model of end-stage liver disease (MELD). On multivariate analysis, patients with decreasing LS on propranolol had a decreased risk for experiencing a transplantation or death than patients with increasing LS irrespective of HVPG. In conclusion, LS changes after pharmacological interventions are influenced by hemodynamic effects on arterial and portal pressure. In humans, a LS decrease may be predictive of improved outcome irrespective of MELD scores and may serve as an additional follow-up tool in the future. NEW & NOTEWORTHY Liver stiffness (LS) is efficiently modulated by changes in portal venous and systemic pressures in an animal model of liver cirrhosis irrespective of baseline LS and portal pressure values. In humans, most patients show a decrease in LS after propranolol treatment initiation without statistically significant changes in transaminases or model of end-stage liver disease (MELD) scores. A decrease in LS may be associated with improved outcome and thus another valuable tool in the follow-up of patients after propranolol treatment initiation.
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Affiliation(s)
- Felix Piecha
- Department of Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg , Heidelberg , Germany
| | - Mattias Mandorfer
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna , Vienna , Austria
| | - Teresa Peccerella
- Department of Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg , Heidelberg , Germany
| | - Ann-Kathrin Ozga
- Center for Experimental Medicine, Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany
| | - Tanja Poth
- Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg , Germany
| | - Anna Vonbank
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna , Vienna , Austria
| | - Helmut Karl Seitz
- Department of Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg , Heidelberg , Germany
| | - Vanessa Rausch
- Department of Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg , Heidelberg , Germany
| | - Thomas Reiberger
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna , Vienna , Austria
| | - Sebastian Mueller
- Department of Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg , Heidelberg , Germany
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21
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Liver stiffness and arterial stiffness/abnormal central hemodynamics in the early stage of heart failure. IJC HEART & VASCULATURE 2018; 20:32-37. [PMID: 30094333 PMCID: PMC6076211 DOI: 10.1016/j.ijcha.2018.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 07/09/2018] [Accepted: 07/18/2018] [Indexed: 12/20/2022]
Abstract
Background It remains to be clarified whether liver stiffness is a direct risk factor for heart failure (HF) or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether fibrosis 4 score (FIB-4 score) is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics. Methods and results In 3040 health Japanese subjects with serum NT-pro-BNP levels < 125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity and radial augmentation index (rAI) were measured. These parameters were measured again after a 3-year interval in 2135 subjects. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p < 0.01), but not with the baPWV or rAI. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2 ± 22.5 pg/ml) than that in those with decrease/no change (5.4 ± 22.3 pg/ml) (p < 0.05). Conclusion Liver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.
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22
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Jansen C, Möller P, Meyer C, Kolbe CC, Bogs C, Pohlmann A, Schierwagen R, Praktiknjo M, Abdullah Z, Lehmann J, Thomas D, Strassburg CP, Latz E, Mueller S, Rössle M, Trebicka J. Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality. Hepatology 2018; 67:1472-1484. [PMID: 29059466 DOI: 10.1002/hep.29612] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 09/05/2017] [Accepted: 10/18/2017] [Indexed: 12/15/2022]
Abstract
UNLABELLED Transjugular intrahepatic portosystemic shunt (TIPS) efficiently treats complications of portal hypertension. Liver and spleen stiffness might predict clinically significant portal hypertension. This prospective study investigated liver stiffness in patients receiving TIPS regardless of indication. Of 83 included patients, 16 underwent transient elastography immediately before and 30 minutes after TIPS (acute group), while 67 received shear wave elastography of liver and spleen 1 day before and 7 days after TIPS (chronic group) and were followed further. In blood samples obtained before TIPS from cubital, portal, and hepatic veins, levels of several interleukins (IL1b, IL6, IL8, IL10, IL18) and interferon-gamma were analyzed. In 27 patients (5 acute, 22 chronic), it resulted in an increase in liver stiffness of >10%. In 56 patients, liver stiffness decreased or remained unchanged (<10%). Importantly, spleen stiffness measured by shear wave elastography decreased in all patients (chronic group). None of the clinical or laboratory parameters differed between patients with increase in liver stiffness and those without. Of note, patients with increased liver stiffness showed higher overall and/or hepatic venous levels of proinflammatory cytokines at TIPS and higher incidence of organ failure and worse survival after TIPS. C-reactive protein values and increase of >10% in liver stiffness after TIPS were the only independent predictors of mortality in these patients. CONCLUSION This study demonstrates that the presence of systemic inflammation predisposes patients to develop increased liver stiffness after TIPS, a predictor of organ failure and death. (NCT03072615) (Hepatology 2018;67:1472-1484).
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Affiliation(s)
- Christian Jansen
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Philipp Möller
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Carsten Meyer
- Department of Radiology, University of Bonn, Bonn, Germany
| | | | - Christopher Bogs
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | | | | | - Zeinab Abdullah
- Institute of Experimental Immunology, University of Bonn, Bonn, Germany
| | - Jennifer Lehmann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Daniel Thomas
- Department of Radiology, University of Bonn, Bonn, Germany
| | | | - Eicke Latz
- Institute of Innate Immunity, University of Bonn, Bonn, Germany.,University of Massachusetts Medical School, Worcester, MA
| | - Sebastian Mueller
- Center for Alcohol Research, University of Heidelberg and Salem Medical Center, Heidelberg, Germany
| | - Martin Rössle
- Department of Gastroenterology, University Hospital Freiburg, Freiburg, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.,Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.,Institute for Bioengineering of Catalonia, Barcelona, Spain
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23
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Piecha F, Paech D, Sollors J, Seitz HK, Rössle M, Rausch V, Mueller S. Rapid change of liver stiffness after variceal ligation and TIPS implantation. Am J Physiol Gastrointest Liver Physiol 2018; 314:G179-G187. [PMID: 29051188 DOI: 10.1152/ajpgi.00239.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Liver stiffness (LS) as measured by transient elastography is widely used to screen for liver fibrosis. However, LS also increases in response to pressure changes like congestion but no data on portal pressure are available. We study here the effect of rapid portal pressure changes on LS. Therefore, LS was assessed directly prior and after ligation of esophageal varices ( n = 11) as well as transjugular intrahepatic portosystemic shunt (TIPS) implantation in patients with established cirrhosis ( n = 14). Additionally, we retrospectively analyzed changes in LS and variceal size in patients with sequential gastroscopic monitoring and LS measurements ( n = 14). To study LS and portal pressure in healthy livers, LS (µFibroscan; Echosens, Paris, France) and invasive pressures (Powerlab, AD Instruments, New Zealand) were assessed in male Wistar rats after ligation of single liver lobes. Ligation of esophageal varices caused an immediate and significant increase of LS from 40.3 ± 19.0 to 56.1 ± 21.5 kPa. Likewise, LS decreased significantly from 53.1 ± 16.6 to 43.8 ± 17.3 kPa after TIPS placement, which correlated significantly with portal pressure ( r = 0.558). In the retrospective cohort, the significant LS decrease from 54.9 ± 23.5 to 47.9 ± 23.8 kPa over a mean observation interval of 4.3 ± 3 mo was significantly correlated with a concomitant increase of variceal size ( r = -0.605). In the animal model, LS and portal pressure increased significantly after single lobe ligation without changes of arterial or central venous pressure. In conclusion, rapid changes of portal pressure are a strong modulator of LS in healthy and cirrhotic organs. In patients with stable cirrhosis according to the model for end-stage liver disease (MELD), a decrease of LS may be indicative for enlarging varices. NEW & NOTEWORTHY Liver stiffness (LS) immediately increases after variceal ligation while it decreases after transjugular intrahepatic portosystemic shunt (TIPS) implantation due to portal pressure changes. LS and portal pressure rapidly increase after single lobe ligation in Wistar rats without changes of arterial or central venous pressure. Collateral formation may be one cause for a transient decrease in LS in the absence of other confounders. Such pressure changes should be considered when interpreting LS in clinical practice.
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Affiliation(s)
- Felix Piecha
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg , Heidelberg , Germany
| | - Daniel Paech
- Department of Radiology, German Cancer Research Center , Heidelberg , Germany
| | - Janina Sollors
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg , Heidelberg , Germany
| | - Helmut-Karl Seitz
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg , Heidelberg , Germany
| | - Martin Rössle
- Department of Gatroenterology, University Hospital Freiburg , Freiburg , Germany
| | - Vanessa Rausch
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg , Heidelberg , Germany
| | - Sebastian Mueller
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg , Heidelberg , Germany
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24
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Mueller S. Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis. World J Gastroenterol 2016; 22:10482-10501. [PMID: 28082801 PMCID: PMC5192260 DOI: 10.3748/wjg.v22.i48.10482] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 10/10/2016] [Accepted: 11/28/2016] [Indexed: 02/06/2023] Open
Abstract
Independent of their etiology, all chronic liver diseases ultimately lead to liver cirrhosis, which is a major health problem worldwide. The underlying molecular mechanisms are still poorly understood and no efficient treatment strategies are available. This paper introduces the sinusoidal pressure hypothesis (SPH), which identifies an elevated sinusoidal pressure (SP) as cause of fibrosis. SPH has been mainly derived from recent studies on liver stiffness. So far, pressure changes have been exclusively seen as a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosis via biomechanic signaling by stretching of perisinusoidal cells such as hepatic stellate cells or fibroblasts (SPH part I: initiation). Fibrosis progression is determined by the degree and time of elevated SP. The SPH predicts that the degree of extracellular matrix eventually matches SP with critical thresholds > 12 mmHg and > 4 wk. Elevated arterial flow and final arterialization of the cirrhotic liver represents the self-perpetuating key event exposing the low-pressure-organ to pathologically high pressures (SPH part II: perpetuation). It also defines the “point of no return” where fibrosis progression becomes irreversible. The SPH is able to explain the macroscopic changes of cirrhotic livers and the uniform fibrotic response to various etiologies. It also opens up new views on the role of fat and disease mechanisms in other organs. The novel concept will hopefully stimulate the search for new treatment strategies.
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25
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Rausch V, Peccerella T, Lackner C, Yagmur E, Seitz HK, Longerich T, Mueller S. Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M. World J Hepatol 2016; 8:1547-1556. [PMID: 28050235 PMCID: PMC5165268 DOI: 10.4254/wjh.v8.i35.1547] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 07/15/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.
METHODS Caucasian heavy drinkers (n = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients.
RESULTS The PNPLA3 rs738409 genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005) and less with steatosis (r = 0.264, P < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r = 0.828, P < 0.005), ballooning (r = 0.516, P < 0.005), steatohepatitis (r = 0.319, P < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% vs 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3 G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers.
CONCLUSION In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers.
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26
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Ratziu V, Valla D, Rautou PE. Arterial hypertension as an uninvited player in hepatic stiffness? Am J Physiol Gastrointest Liver Physiol 2016; 311:G942-G944. [PMID: 27765758 DOI: 10.1152/ajpgi.00276.2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- Vlad Ratziu
- Service d'hépatogastroentérologie, Institute for Cardiometabolism and Nutrition, Hospital Pitié Salpêtrière, INSERM UMR S_938, Université Pierre et Marie Curie, Paris, France;
| | - Dominique Valla
- INSERM, UMR-970, Paris Cardiovascular Research Center-PARCC, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and.,Service d'hépatologie, DHU Unity Hôpital Beaujon, APHP, Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Clichy, France
| | - Pierre-Emmanuel Rautou
- INSERM, UMR-970, Paris Cardiovascular Research Center-PARCC, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and.,Service d'hépatologie, DHU Unity Hôpital Beaujon, APHP, Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Clichy, France
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