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Separation of advanced from mild hepatic fibrosis by quantification of the hepatobiliary uptake of Gd-EOB-DTPA
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.ORCID iD: 0000-0003-4630-6550
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.ORCID iD: 0000-0002-4111-1693
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2013 (English)In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 23, no 1, 174-181 p.Article in journal (Refereed) Published
Abstract [en]

Objectives

To apply dynamic contrast-enhanced (DCE) MRI on patients presenting with elevated liver enzymes without clinical signs of hepatic decompensation in order to quantitatively compare the hepatocyte-specific uptake of Gd-EOB-DTPA with histopathological fibrosis stage.

Methods

A total of 38 patients were prospectively examined using 1.5-T MRI. Data were acquired from regions of interest in the liver and spleen by using time series of single-breath-hold symmetrically sampled two-point Dixon 3D images (non-enhanced, arterial and venous portal phase; 3, 10, 20 and 30 min) following a bolus injection of Gd-EOB-DTPA (0.025 mmol/kg). The signal intensity (SI) values were reconstructed using a phase-sensitive technique and normalised using multiscale adaptive normalising averaging (MANA). Liver-to-spleen contrast ratios (LSC_N) and the contrast uptake rate (KHep) were calculated. Liver biopsy was performed and classified according to the Batts and Ludwig system.

Results

Area under the receiver-operating characteristic curve (AUROC) values of 0.71, 0.80 and 0.78, respectively, were found for KHep, LSC_N10 and LSC_N20 with regard to severe versus mild fibrosis. Significant group differences were found for KHep (borderline), LSC_N10 and LSC_N20.

Conclusions

Liver fibrosis stage strongly influences the hepatocyte-specific uptake of Gd-EOB-DTPA. Potentially the normalisation technique and KHep will reduce patient and system bias, yielding a robust approach to non-invasive liver function determination.

Place, publisher, year, edition, pages
Springer, 2013. Vol. 23, no 1, 174-181 p.
Keyword [en]
Quantification, Gd-EOB-DTPA, Dynamic contrast-enhanced MRI, Pharmacokinetics, Liver
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-87242DOI: 10.1007/s00330-012-2583-2ISI: 000312324500022OAI: oai:DiVA.org:liu-87242DiVA: diva2:587224
Projects
NILB
Note

Funding Agencies|Swedish Research Council|VR/M 2007-2884|Medical Research Council of South-east Sweden|FORSS 12621|Linkoping University, Linkoping University Hospital Research Foundations||County Council of Ostergotland||

Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06
In thesis
1. Non-Invasive Assessment of Liver Fibrosis with 31P-Magnetic Resonance Spectroscopy and Dynamic Contrast Enhanced Magnetic Resonance Imaging
Open this publication in new window or tab >>Non-Invasive Assessment of Liver Fibrosis with 31P-Magnetic Resonance Spectroscopy and Dynamic Contrast Enhanced Magnetic Resonance Imaging
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present study aims at demonstrating phosphorus metabolite concentration changes and alterations in uptake/excretion of a hepatocyte specific contrast agent in patients with diffuse - or suspected diffuse - liver disease by applying two non-invasive quantitative MR techniques and to compare the results with histo-pathological findings, with focus on liver fibrosis.

In the first study phosphorus-31 MR spectroscopy using slice selection (DRESS) was implemented. Patients with histopathologically proven diffuse liver disease (n = 9) and healthy individuals (n = 12) were examined. The patients had significantly lower concentrations of phosphodiesters (PDE) and ATP compared with controls. Constructing an ‘anabolic charge’ (AC) based on absolute concentrations, [PME] / ([PME] + [PDE]), the patients had a significant larger AC than the control subjects.

The MRS technique was then, in a second study, applied on two distinct groups of patients, one group with steatosis and none-to-moderate inflammation (n = 13) and one group with severe fibrosis or cirrhosis (n = 16). A control group (n = 13) was also included. Lower concentrations of PDE and a higher AC were found in the cirrhosis group compared to the control group. Also compared to the steatosis group, the cirrhosis group had lower concentrations of PDE and a higher AC.  A significant correlation between fibrosis stage and PDE and fibrosis stage and AC was found. Using an AC cut-off value of 0.27 to discriminate between mild (stage 0-2) and advanced (stage 3-4) fibrosis yielded an AUROC value of 0.78, similar as for discriminating between F0-1 vs. F2-4.

Dynamic contrast enhanced MRI (DCE-MRI) was performed prospectively in a third study on 38 patients referred for evaluation of elevated serum alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) levels. Data were acquired from regions of interest in the liver and spleen by using single-breath-hold symmetrically sampled two-point Dixon 3D images time-series (non-enhanced, arterial and venous portal phase; 3, 10, 20 and 30 min) following a bolus injection of Gd-EOB-DTPA (0.025 mmol/kg). A new quantification procedure for calculation of the ‘hepatocyte specific uptake rate’, KHep, was applied on a two-compartment pharmacokinetic model. Liver-to-spleen contrast ratios (LSC_N) were also calculated. AUROC values of 0.71, 0.80 and 0.78, respectively, were found for KHep, LSC_N10 and LSC_N20 with regard to severe versus mild fibrosis. Significant group differences were found for KHep (borderline), LSC_N10 and LSC_N20.

In study four no significant correlation between visual assessments of bile ducts excretion of Gd-EOB-DTPA and histo-pathological grading of fibrosis or the quantified uptake of Gd-EOB-DTPA defined as KHep and LSC_N.

In conclusion 31P-MRS and DCE-MRI show promising results for achieving a non-invasive approach in discriminating different levels of fibrosis from each other.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1351
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90154 (URN)978-91-7519-705-0N (print) (ISBN)
Public defence
2013-03-15, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2013-06-04 Created: 2013-03-20 Last updated: 2014-10-02Bibliographically approved
2. The Non-Invasive Liver Biopsy: Determining Hepatic Function in Diffuse and Focal LiverDisease
Open this publication in new window or tab >>The Non-Invasive Liver Biopsy: Determining Hepatic Function in Diffuse and Focal LiverDisease
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The liver is one of the largest organs within the human body and it handles many vital tasks such as nutrient processing, toxin removal, and synthesis of important proteins. The number of people suffering from chronic liver disease is on the rise, likely due to the present ‘western’ lifestyle. As disease develops in the liver there are pathophysiological manifestations within the liver parenchyma that are both common and important to monitor. These manifestations include inflammation, fatty infiltration (steatosis), excessive scar tissue formation (fibrosis and cirrhosis), and iron loading. Importantly, as the disease progresses there is concurrent loss of liver function. Furthermore, postoperative liver function insufficiency is an important concern when planning surgical treatment of the liver, because it is associated with both morbidity and mortality. Liver function can also be hampered due to drug-induced injuries, an important aspect to consider in drug-development.

Currently, an invasive liver needle biopsy is required to determine the aetiology and to stage or grade the pathophysiological manifestations. There are important limitations with the biopsy, which include, risk of serious complications, mortality, morbidity, inter- and intra-observer variability, sampling error, and sampling variability. Cleary, it would be beneficial to be able investigate the pathophysiological manifestations accurately, non-invasively, and on regional level.

Current available laboratory liver function blood panels are typically insufficient and often only indicate damage at a late stage. Thus, it would be beneficial to have access to biomarkers that are both sensitive and responds to early changes in liver function in both clinical settings and for the pharmaceutical industry and regulatory agencies.

The main aim of this thesis was to develop and evaluate methods that can be used for a ‘non-invasive liver biopsy’ using magnetic resonance (MR). We also aimed to develop sensitive methods for measure liver function based on gadoxetate-enhanced MR imaging (MRI).

The presented work is primarily based on a prospective study on c. 100 patients suffering from chronic liver disease of varying aetiologies recruited due to elevated liver enzyme levels, without clear signs of decompensated cirrhosis. Our results show that the commonly used liver fat cut-off for diagnosing steatosis should be lowered from 5% to 3% when using MR proton-density fat fraction (PDFF). We also show that MR elastography (MRE) is superior in staging fibrosis.

Finally we presented a framework for quantifying liver function based on gadoxetate-enhanced MRI. The method is based on clinical images and a clinical approved contrast agent (gadoxetate). The framework consists of; state-of the-art image reconstruction and correction methods, a mathematical model, and a precise model parametrization method. The model was developed and validated on healthy subjects. Thereafter the model was found applicable on the chronic liver disease cohort as well as validated using gadoxetate levels in biopsy samples and blood samples. The liver function parameters correlated with clinical markers for liver function and liver fibrosis (used as a surrogate marker for liver function).

In summary, it should be possible to perform a non-invasive liver biopsy using: MRI-PDFF for liver fat and iron loading, MRE for liver fibrosis and possibly also inflammation, and measure liver function using the presented framework for analysing gadoxetate-enhanced MRI. With the exception of an MREtransducer no additional hardware is required on the MR scanner. The liver function method is likely to be useful both in a clinical setting and in pharmaceutical trials.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 126 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1564
National Category
Radiology, Nuclear Medicine and Medical Imaging Gastroenterology and Hepatology Biomedical Laboratory Science/Technology Neurology Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:liu:diva-136545 (URN)10.3384/diss.diva-136545 (DOI)9789176855720 (ISBN)
Public defence
2017-05-23, Eken, Campus US, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-04-30Bibliographically approved

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Norén, BengtForsgren, Mikael FredrikDahlqvist Leinhard, OlofDahlström, NilsKihlberg, JohanRomu, ThobiasKechagias, StergiosAlmer, SvenSmedby, ÖrjanLundberg, Peter

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Norén, BengtForsgren, Mikael FredrikDahlqvist Leinhard, OlofDahlström, NilsKihlberg, JohanRomu, ThobiasKechagias, StergiosAlmer, SvenSmedby, ÖrjanLundberg, Peter
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Center for Medical Image Science and Visualization (CMIV)RadiologyFaculty of Health SciencesDepartment of Radiology in LinköpingDivision of Radiological SciencesDepartment of Radiation PhysicsMedical InformaticsThe Institute of TechnologyInternal MedicineDepartment of GastroentorologyGastroenterology and Hepatology
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