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Forsgren, M. (2017). The Non-Invasive Liver Biopsy: Determining Hepatic Function in Diffuse and Focal LiverDisease. (Doctoral dissertation). Linköping: Linköping University Electronic Press
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. p. 126
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: 2019-06-14Bibliographically approved
Nasr, P., Forsgren, M. F., Ignatova, S., Dahlström, N., Cedersund, G., Dahlqvist Leinhard, O., . . . Kechagias, S. (2017). Using a 3% Proton Density Fat Fraction as a Cut-off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results from Histopathology Analysis. Gastroenterology, 153(1), 53-+
Open this publication in new window or tab >>Using a 3% Proton Density Fat Fraction as a Cut-off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results from Histopathology Analysis
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2017 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, no 1, p. 53-+Article in journal (Refereed) Published
Abstract [en]

It is possible to estimate hepatic triglyceride content by calculating the proton density fat fraction (PDFF), using proton magnetic resonance spectroscopy (less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS), instead of collecting and analyzing liver biopsies to detect steatosis. However, the current PDFF cut-off value (5%) used to define steatosis by magnetic resonance was derived from studies that did not use histopathology as the reference standard. We performed a prospective study to determine the accuracy of less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF in measurement of steatosis using histopathology analysis as the standard. We collected clinical, serologic, less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF, and liver biopsy data from 94 adult patients with increased levels of liver enzymes (6 months or more) referred to the Department of Gastroenterology and Hepatology at Linköping University Hospital in Sweden from 2007 through 2014. Steatosis was graded using the conventional histopathology method and fat content was quantified in biopsy samples using stereological point counts (SPCs). We correlated less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF findings with SPCs (r = 0.92; P less than.001). less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF results correlated with histopathology results (ρ = 0.87; P less than.001), and SPCs correlated with histopathology results (ρ = 0.88; P less than.001). All 25 subjects with PDFF values of 5.0% or more had steatosis based on histopathology findings (100% specificity for PDFF). However, of 69 subjects with PDFF values below 5.0% (negative result), 22 were determined to have steatosis based on histopathology findings (53% sensitivity for PDFF). Reducing the PDFF cut-off value to 3.0% identified patients with steatosis with 100% specificity and 79% sensitivity; a PDFF cut-off value of 2.0% identified patients with steatosis with 94% specificity and 87% sensitivity. These findings might be used to improve non-invasive detection of steatosis.

Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-136544 (URN)10.1053/j.gastro.2017.03.005 (DOI)000403918300022 ()
Note

Funding agencies: Swedish Research Council/Medicine and Health [VR/M 2007-2884, VR/M 2012-3199]; Swedish Research Council/Natural and Engineering Sciences [VR/NT 2014-6157]; Swedish Innovation Agency VINNOVA [2013-01314]; Region Ostergotland (ALF)

Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2019-09-25Bibliographically approved
Walter, S. A., Forsgren, M., Lundengård, K., Simon, R., Torkildsen Nilsson, M., Söderfeldt, B., . . . Engström, M. (2016). Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex. PLoS ONE, 11(3)
Open this publication in new window or tab >>Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3Article in journal (Refereed) Published
Abstract [en]

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

Place, publisher, year, edition, pages
San Francisco, CA, United States: Public Library of Science, 2016
Keywords
quantitative magnetic resonance imaging; brain tissue modeling; myelin; edema; T-1 relaxation; T-2 relaxation; proton density
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-126192 (URN)10.1371/journal.pone.0148737 (DOI)000371434500011 ()26930498 (PubMedID)
Note

Funding agencies: Linkoping University; County Council of Ostergotland

Available from: 2016-03-18 Created: 2016-03-18 Last updated: 2018-01-10Bibliographically approved
Forsgren, M., Norén, B., Kihlberg, J., Dahlqvist Leinhard, O., Kechagias, S. & Lundberg, P. (2015). Comparing hepatic 2D and 3D magnetic resonance elastography methods in a clinical setting – Initial experiences. European Journal of Radiology Open, 2, 66-70
Open this publication in new window or tab >>Comparing hepatic 2D and 3D magnetic resonance elastography methods in a clinical setting – Initial experiences
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2015 (English)In: European Journal of Radiology Open, E-ISSN 2352-0477, Vol. 2, p. 66-70Article in journal (Refereed) Published
Abstract [en]

Purpose

Continuous monitoring of liver fibrosis progression in patients is not feasible with the current diagnostic golden standard (needle biopsy). Recently, magnetic resonance elastography (MRE) has emerged as a promising method for such continuous monitoring. Since there are different MRE methods that could be used in a clinical setting there is a need to investigate whether measurements produced by these MRE methods are comparable. Hence, the purpose of this pilot study was to evaluate whether the measurements of the viscoelastic properties produced by 2D (stiffness) and 3D (elasticity and ‘Gabs,Elastic’) MRE are comparable.

Materials and methods

Seven patients with diffuse or suspect diffuse liver disease were examined in the same day with the two MRE methods. 2D MRE was performed using an acoustic passive transducer, with a 1.5 T GE 450 W MR system. 3D MRE was performed using an electromagnetic active transducer, with a 1.5 T Philips Achieva MR system. Finally, mean viscoelastic values were extracted from the same anatomical region for both methods by an experienced radiologist.

Results

Stiffness correlated well with the elasticity, R2 = 0.96 (P < 0.001; slope = 1.08, intercept = 0.61 kPa), as well as with ‘Gabs,ElasticR2 = 0.96 (P < 0.001; slope = 0.95, intercept = 0.28 kPa).

Conclusion

This pilot study shows that different MRE methods can produce comparable measurements of the viscoelastic properties of the liver. The existence of such comparable measurements is important, both from a clinical as well as a research perspective, since it allows for equipment-independent monitoring of disease progression.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Liver; Rheology; Elastography; Fibrosis; MRE; MRI
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-119848 (URN)10.1016/j.ejro.2015.04.001 (DOI)
Available from: 2015-06-26 Created: 2015-06-26 Last updated: 2019-06-14Bibliographically approved
Andersson, T., Romu, T., Karlsson, A., Norén, B., Forsgren, M., Smedby, Ö., . . . Dahlqvist Leinhard, O. (2015). Consistent intensity inhomogeneity correction in water–fat MRI. Journal of Magnetic Resonance Imaging, 42(2), 468-476
Open this publication in new window or tab >>Consistent intensity inhomogeneity correction in water–fat MRI
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2015 (English)In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 42, no 2, p. 468-476Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

To quantitatively and qualitatively evaluate the water-signal performance of the consistent intensity inhomogeneity correction (CIIC) method to correct for intensity inhomogeneities METHODS: Water-fat volumes were acquired using 1.5 Tesla (T) and 3.0T symmetrically sampled 2-point Dixon three-dimensional MRI. Two datasets: (i) 10 muscle tissue regions of interest (ROIs) from 10 subjects acquired with both 1.5T and 3.0T whole-body MRI. (ii) Seven liver tissue ROIs from 36 patients imaged using 1.5T MRI at six time points after Gd-EOB-DTPA injection. The performance of CIIC was evaluated quantitatively by analyzing its impact on the dispersion and bias of the water image ROI intensities, and qualitatively using side-by-side image comparisons.

RESULTS:

CIIC significantly ( P1.5T≤2.3×10-4,P3.0T≤1.0×10-6) decreased the nonphysiological intensity variance while preserving the average intensity levels. The side-by-side comparisons showed improved intensity consistency ( Pint⁡≤10-6) while not introducing artifacts ( Part=0.024) nor changed appearances ( Papp≤10-6).

CONCLUSION:

CIIC improves the spatiotemporal intensity consistency in regions of a homogenous tissue type. J. Magn. Reson. Imaging 2014.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
Keywords
water–fat imaging;Dixon imaging;inhomogeneity correction;intensity correction;water;fat quantification
National Category
Medical Image Processing Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-112129 (URN)10.1002/jmri.24778 (DOI)000358258600026 ()25355066 (PubMedID)
Note

Funding:

Financial support from the Swedish Research Council (VR/M 2007-2884), the Research Council of Southeast Sweden (FORSS 12621), Linkoping University, Lions Research Foundation in Linkoping, Linkoping University Hospital Research Foundations and the County Council of Ostergotland is gratefully acknowledged.

Available from: 2014-11-16 Created: 2014-11-16 Last updated: 2019-06-14
Norén, B., Dahlström, N., Forsgren, M., Dahlqvist Leinhard, O., Kechagias, S., Almer, S., . . . Lundberg, P. (2015). Visual assessment of biliary excretion of Gd-EOB-DTPA in patients with suspected diffuse liver disease – a biopsy-controlled prospective study. European Journal of Radiology Open, 2, 19-25
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, p. 19-25Article 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
Keywords
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: 2019-06-14Bibliographically approved
Forsgren, M., Norén, B., Kihlberg, J., Dahlqvist Leinhard, O., Kechagias, S. & Lundberg, P. (2014). Comparing 2D and 3D Magnetic Resonance Elastography Techniques in a Clinical Setting: Initial Experiences. In: : . Paper presented at ISMRM 2014, International Society for Magnetic Resonance in Medicine, 10-16 May 2014, Milan, Italy.
Open this publication in new window or tab >>Comparing 2D and 3D Magnetic Resonance Elastography Techniques in a Clinical Setting: Initial Experiences
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2014 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Purpose: It has been shown that liver fibrosis, and even cirrhosis, may be reversible in humans. For this reason there is a great need for the imminent introduction of non-invasive and clinically useful methods in order to monitor fibrosis in patients [1, 2]. A body of evidence points to the fact that MRE is a highly useful candidate towards this end [3]. However, before using such techniques more widely, it is important to verify that comparable physical measures are provided by alternative and clinically relevant MRE approaches. The aim of this pilot study was to compare 2D and 3D MRE, also known as MR Rheology, using a commercially available 2D system, with an acoustic transducer, and 3D MRE research system, with an electromagnetic transducer, with respect to liver stiffness and elasticity in patients with diffuse or suspected diffuse liver disease. Materials and Methods: Seven patients, referred to our hospital for evaluation of elevated serum alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) levels but without signs of cirrhosis on physical examination, were recruited from a previous study [4], and examined in the course of one day. Fibrosis staging from prior biopsy were gained from [4], see Table 1. The 3D MRE method included an active electromagnetic transducer generating waves at 56 Hz, and a 1.5 T Philips Achieva MR-scanner, with a phased array body coil (Sense TorsoXL, all 16 coil elements), GRE sequence parameters include; FOV = 320x256 mm2, matrix = 80x38, slice thickness = 4 mm, # slices = 9, FA = 15°, TR = 112 ms, TE = 9.21 ms, SENSE = 2. The 2D MRE method included a passive acoustic transducer generating waves at 60 Hz, and a 1.5 T GE 450W MR-scanner, with a phased array body coil (HD8 Torso, all 8 coil elements), GRE sequence parameters include; FOV = 440x440 mm2, matrix = 256x64, slice thickness = 10 mm, # slices = 4, FA = 30°, TR = 50 ms, TE = 21.7 ms, ASSET = 2. The transducers were on both systems placed on the anterior chest wall to the right of xiphoid process (patient in a supine position), the time between each MRE acquisition was dependent on how long it took to transfer the patient between the two MR systems in the hospital (<10 min) A region of interest (ROI) was placed in an appropriate single 10 mm slice acquired using the GE MR-scanner. A corresponding ROI for the Philips system, covering the same anatomical region, was placed over three slices (4 mm thickness each). This yielded a total cranio-caudal coverage of the ROIs equal to 10 mm (on the GE data) and 12 mm (on the Philips data). The mean and standard deviations of the stiffness (GE), elasticity (Philips) and Gabs,Elastic (Philips) were calculated. Gabs,Elastic is the absolute value of the shear modulus, which in principle is equivalent to the viscoelastic property, shear stiffness. In the 3D method the shear waves were obtained by applying the curl operator and using the Voigt rheological model to obtain shear elasticity maps [5, 6]. In the 2D method the GE system provided the stiffness maps. Statistics was performed using Mathematica 9. ROI drawing and quantification of the data from the GE system was performed using Sectra PACS IDS7, and ROI drawing and quantification of the data from the Philips system was performed using a custom software package implemented in ROOT, generously provided by R. Sinkus (Kings College, London, UK). Results: The measured values are presented in Table 1. Both elasticity and Gabs,Elastic correlates well with the stiffness measurement carried out in the GE system (Fig. 1), as was shown by the elasticity and stiffness correlation R2 = 0.96 (P < 0.001) slope = 1.08 (P < 0.001), intercept = 0.61 kPa (P = 0.08), Gabs,Elastic and stiffness correlation R2 = 0.96 (P < 0.001), slope = 0.95 (P< 0.001) intercept = 0.28 kPa (P = 0.43)

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-109079 (URN)
Conference
ISMRM 2014, International Society for Magnetic Resonance in Medicine, 10-16 May 2014, Milan, Italy
Available from: 2014-08-05 Created: 2014-08-05 Last updated: 2019-06-14
Forsgren, M., Dahlqvist Leinhard, O., Dahlström, N., Cedersund, G. & Lundberg, P. (2014). Physiologically Realistic and Validated Mathematical Liver Model Revels Hepatobiliary Transfer Rates for Gd-EOB-DTPA Using Human DCE-MRI Data. PLoS ONE, 9(4), 0095700
Open this publication in new window or tab >>Physiologically Realistic and Validated Mathematical Liver Model Revels Hepatobiliary Transfer Rates for Gd-EOB-DTPA Using Human DCE-MRI Data
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. 0095700-Article in journal (Refereed) Published
Abstract [en]

Objectives: Diffuse liver disease (DLD), such as non-alcoholic fatty liver disease (NASH) and cirrhosis, is a rapidly growing problem throughout the Westernized world. Magnetic resonance imaging (MRI), based on uptake of the hepatocyte-specific contrast agent (CA) Gd-EOB-DTPA, is a promising non-invasive approach for diagnosing DLD. However, to fully utilize the potential of such dynamic measurements for clinical or research purposes, more advanced methods for data analysis are required. Methods: A mathematical model that can be used for such data-analysis was developed. Data was obtained from healthy human subjects using a clinical protocol with high spatial resolution. The model is based on ordinary differential equations and goes beyond local diffusion modeling, taking into account the complete system accessible to the CA. Results: The presented model can describe the data accurately, which was confirmed using chi-square statistics. Furthermore, the model is minimal and identifiable, meaning that all parameters were determined with small degree of uncertainty. The model was also validated using independent data. Conclusions: We have developed a novel approach for determining previously undescribed physiological hepatic parameters in humans, associated with CA transport across the liver. The method has a potential for assessing regional liver function in clinical examinations of patients that are suffering of DLD and compromised hepatic function.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-106962 (URN)10.1371/journal.pone.0095700 (DOI)000335226500139 ()
Available from: 2014-06-04 Created: 2014-06-02 Last updated: 2019-06-14
Forsgren, M., Dahlström, N., Karlsson, M., Dahlqvist Leinhard, O., Smedby, Ö., Cedersund, G. & Lundberg, P. (2014). Whole Body Mechanistic Minimal Model for Gd-EOB-DTPA Contrast Agent Pharmacokinetics in Evaluation of Diffuse Liver Disease. In: : . Paper presented at Society of Abdominal Radiology (SAR) 2014 Boca Raton, Florida, USA.
Open this publication in new window or tab >>Whole Body Mechanistic Minimal Model for Gd-EOB-DTPA Contrast Agent Pharmacokinetics in Evaluation of Diffuse Liver Disease
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2014 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Purpose: Aiming for non-invasive diagnostic tools to decrease the need for biopsy in diffuse liver disease and to quantitatively describe liver function, we applied a mechanistic pharmacokinetic modelling analysis of liver MRI with Gd-EOB-DTPA. This modelling method yields physiologically relevant parameters and was compared to previously developed methods in a patient group with diffuse liver disease. Materials and Methods: Using data from healthy volunteers undergoing liver MRI, an identifiable mechanistic model was developed, based on compartments described by ordinary differential equations and kinetic expressions, and validated with independent data including Gd-EOB-DTPA concentration measurements in blood samples. Patients (n=37) with diffuse liver disease underwent liver biopsy and MRI with Gd-EOB-DTPA. The model was used to derive pharmacokinetic parameters which were then compared with other quantitative estimates in their ability to separate mild from severe liver fibrosis. Results: The estimations produced by the mechanistic model allowed better separation between mild and severe fibrosis than previously described methods for quantifying hepatic Gd-EOB-DTPA uptake. Conclusions: With a mechanistic pharmacokinetic modelling approach, the estimation of liver uptake function and its diagnostic information can be improved compared to current methods.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114363 (URN)
Conference
Society of Abdominal Radiology (SAR) 2014 Boca Raton, Florida, USA
Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2019-06-14
Gerdle, B., Forsgren, M., Bengtsson, A., Dahlqvist Leinhard, O., Sören, B., Karlsson, A., . . . Lundberg, P. (2013). Decreased muscle concentrations of ATP and PCR in the quadriceps muscle of fibromyalgia patients – A 31P-MRS study. European Journal of Pain, 17(8), 1205-1215
Open this publication in new window or tab >>Decreased muscle concentrations of ATP and PCR in the quadriceps muscle of fibromyalgia patients – A 31P-MRS study
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2013 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 17, no 8, p. 1205-1215Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND METHODS:

Fibromyalgia (FMS) has a prevalence of approximately 2% in the population. Central alterations have been described in FMS, but there is not consensus with respect to the role of peripheral factors for the maintenance of FMS. 31P magnetic resonance spectroscopy (31P-MRS) has been used to investigate the metabolism of phosphagens in muscles of FMS patients, but the results in the literature are not in consensus. The aim was to investigate the quantitative content of phosphagens and pH in resting quadriceps muscle of patients with FMS (n = 19) and in healthy controls (Controls; n = 14) using (31) P-MRS. It was also investigated whether the concentrations of these substances correlated with measures of pain and/or physical capacity.

RESULTS:

Significantly lower concentrations of adenosine triphosphate (ATP) and phosphocreatinine (PCr; 28-29% lower) were found in FMS. No significant group differences existed with respect to inorganic phosphate (Pi), Pi/PCr and pH. The quadriceps muscle fat content was significantly higher in FMS than in Controls [FMS: 9.0 ± 0.5% vs. Controls: 6.6 ± 0.6%; (mean ± standard error); P = 0.005]. FMS had significantly lower hand and leg capacity according to specific physical test, but there were no group differences in body mass index, subjective activity level and in aerobic fitness. In FMS, the specific physical capacity in the leg and the hand correlated positively with the concentrations of ATP and PCr; no significant correlations were found with pain intensities.

CONCLUSIONS:

Alterations in intramuscular ATP, PCr and fat content in FMS probably reflect a combination of inactivity related to pain and dysfunction of muscle mitochondria.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90364 (URN)10.1002/j.1532-2149.2013.00284.x (DOI)000322723600012 ()23364928 (PubMedID)
Available from: 2013-03-25 Created: 2013-03-25 Last updated: 2019-06-14Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4630-6550

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