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Non-Invasive Assessment of Liver Fibrosis with 31P-Magnetic Resonance Spectroscopy and Dynamic Contrast Enhanced Magnetic Resonance Imaging
Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
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: urn:nbn:se:liu:diva-90154ISBN: 978-91-7519-705-0N (print) OAI: oai:DiVA.org:liu-90154DiVA: diva2:612205
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
List of papers
1. Absolute quantification of human liver metabolite concentrations by localized in vivo 31P NMR spectroscopy in diffuse liver disease
Open this publication in new window or tab >>Absolute quantification of human liver metabolite concentrations by localized in vivo 31P NMR spectroscopy in diffuse liver disease
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2005 (English)In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 15, no 1, 148-157 p.Article in journal (Refereed) Published
Abstract [en]

Phosphorus-31 NMR spectroscopy using slice selection (DRESS) was used to investigate the absolute concentrations of metabolites in the human liver. Absolute concentrations provide more specific biochemical information compared to spectrum integral ratios. Nine patients with histopathologically proven diffuse liver disease and 12 healthy individuals were examined in a 1.5-T MR scanner (GE Signa LX Echospeed plus). The metabolite concentration quantification procedures included: (1) determination of optimal depth for the in vivo measurements, (2) mapping the detection coil characteristics, (3) calculation of selected slice and liver volume ratios using simple segmentation procedures and (4) spectral analysis in the time domain. The patients had significantly lower concentrations of phosphodiesters (PDE), 6.3±3.9 mM, and ATP-β, 3.6±1.1 mM, (P<0.05) compared with the control group (10.0±4.2 mM and 4.2±0.3 mM, respectively). The concentrations of phosphomonoesters (PME) were higher in the patient group, although this was not significant. Constructing an anabolic charge (AC) based on absolute concentrations, [PME]/([PME] + [PDE]), the patients had a significantly larger AC than the control subjects, 0.29 vs. 0.16 (P<0.005). Absolute concentration measurements of phosphorus metabolites in the liver are feasible using a slice selective sequence, and the technique demonstrates significant differences between patients and healthy subjects.

Keyword
phosphorus MR spectroscopy, absolute concentrations, diffuse liver disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24421 (URN)10.1007/s00330-004-2434-x (DOI)000227354900022 ()6524 (Local ID)6524 (Archive number)6524 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
2. Separation of advanced from mild fibrosis in diffuse liver disease using 31P magnetic resonance spectroscopy
Open this publication in new window or tab >>Separation of advanced from mild fibrosis in diffuse liver disease using 31P magnetic resonance spectroscopy
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2008 (English)In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 66, no 2, 313-320 p.Article in journal (Refereed) Published
Abstract [en]

31P-MRS using DRESS was used to compare absolute liver metabolite concentrations (PME, Pi, PDE, γATP, αATP, βATP) in two distinct groups of patients with chronic diffuse liver disorders, one group with steatosis (NAFLD) and none to moderate inflammation (n = 13), and one group with severe fibrosis or cirrhosis (n = 16). All patients underwent liver biopsy and extensive biochemical evaluation. A control group (n = 13) was also included. Absolute concentrations and the anabolic charge, AC = {PME}/({PME} + {PDE}), were calculated.

Comparing the control and cirrhosis groups, lower concentrations of PDE (p = 0.025) and a higher AC (p < 0.001) were found in the cirrhosis group. Also compared to the NAFLD group, the cirrhosis group had lower concentrations of PDE (p = 0.01) and a higher AC (p = 0.009). No significant differences were found between the control and NAFLD group. When the MRS findings were related to the fibrosis stage obtained at biopsy, there were significant differences in PDE between stage F0–1 and stage F4 and in AC between stage F0–1 and stage F2–3.

Using a PDE concentration of 10.5 mM as a cut-off value to discriminate between mild, F0–2, and advanced, F3–4, fibrosis the sensitivity and specificity were 81% and 69%, respectively. An AC cut-off value of 0.27 showed a sensitivity of 93% and a specificity of 54%.

In conclusion, the results suggest that PDE is a marker of liver fibrosis, and that AC is a potentially clinically useful parameter in discriminating mild fibrosis from advanced.

Place, publisher, year, edition, pages
Elsevier, 2008
Keyword
Absolute quantification; Phosphorus; MRS; Steatosis; In vivo
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43125 (URN)10.1016/j.ejrad.2007.06.004 (DOI)000256140900026 ()17646074 (PubMedID)71944 (Local ID)71944 (Archive number)71944 (OAI)
Projects
NILB
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
3. Separation of advanced from mild hepatic fibrosis by quantification of the hepatobiliary uptake of Gd-EOB-DTPA
Open this publication in new window or tab >>Separation of advanced from mild hepatic fibrosis by quantification of the hepatobiliary uptake of Gd-EOB-DTPA
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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
Keyword
Quantification, Gd-EOB-DTPA, Dynamic contrast-enhanced MRI, Pharmacokinetics, Liver
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87242 (URN)10.1007/s00330-012-2583-2 (DOI)000312324500022 ()
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
4. Visual assessment of biliary excretion of Gd-EOB-DTPA in patients with suspected diffuse liver disease – a biopsy-controlled prospective study
Open this publication in new window or tab >>Visual assessment of biliary excretion of Gd-EOB-DTPA in patients with suspected diffuse liver disease – a biopsy-controlled prospective study
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2015 (English)In: European Journal of Radiology Open, ISSN 2352-0477, Vol. 2, 19-25 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: To qualitatively evaluate late dynamic contrast phases, 10, 20 and 30 min, after administration of Gd-EOB-DTPA with regard to biliary excretion in patients presenting with elevated liver enzymes without any clinical signs of cirrhosis or hepatic decompensation and to compare the visual assessment of contrast agent excretion with histo-pathological fibrosis stage, contrast uptake parameters and blood tests.

Methods: 29 patients were prospectively examined using 1.5-T MRI. The visually assessed presence (1) or absence (0) of contrast agent for each of five anatomical regions in randomly reviewed time-series was summarised on a four grade scale. The scores, including a total visual score, were related to the histo-pathological findings, the quantitative contrast agent uptake parameters and blood tests

Results: No relationship between the fibrosis grade or contrast uptake parameters expressed as KHep or LSC_N could be established. A negative correlation between the visual assessment and ALP was found. Comparing a sub-group of cholestatic patients with fibrosis score and Gd-EOB-DTPAdynamic parameters did not add any additional significant correlation.

Conclusions: In this prospective study with a limited number of patients we were not able to demonstrate a correlation between visually assessed biliary excretion of Gd-EOB-DTPA and  histo-pathological or contrast uptake parameters.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
Gd-EOB-­DTPA, Dynamic contrast enhanced MRI, Liver, Bile, Excretion
National Category
Radiology, Nuclear Medicine and Medical Imaging Physical Chemistry
Identifiers
urn:nbn:se:liu:diva-90159 (URN)10.1016/j.ejro.2014.12.004 (DOI)
Projects
NILB
Available from: 2013-03-20 Created: 2013-03-20 Last updated: 2016-03-23Bibliographically approved

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Norén, Bengt

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