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The Non-Invasive Liver Biopsy: Determining Hepatic Function in Diffuse and Focal LiverDisease
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.ORCID-id: 0000-0003-4630-6550
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2017. , s. 126
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1564
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-136545DOI: 10.3384/diss.diva-136545ISBN: 9789176855720 (tryckt)OAI: oai:DiVA.org:liu-136545DiVA, id: diva2:1089418
Disputas
2017-05-23, Eken, Campus US, Linköping, 13:15 (engelsk)
Opponent
Veileder
Merknad

The original title of Manuscript IV was Quantitative Assessment of Liver Functions by Gadoxetate-Enhanced MRI: a Prospective Study of Chronic Liver Disease.

Tilgjengelig fra: 2017-04-19 Laget: 2017-04-19 Sist oppdatert: 2020-08-14bibliografisk kontrollert
Delarbeid
1. Separation of advanced from mild hepatic fibrosis by quantification of the hepatobiliary uptake of Gd-EOB-DTPA
Åpne denne publikasjonen i ny fane eller vindu >>Separation of advanced from mild hepatic fibrosis by quantification of the hepatobiliary uptake of Gd-EOB-DTPA
Vise andre…
2013 (engelsk)Inngår i: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 23, nr 1, s. 174-181Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Springer, 2013
Emneord
Quantification, Gd-EOB-DTPA, Dynamic contrast-enhanced MRI, Pharmacokinetics, Liver
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-87242 (URN)10.1007/s00330-012-2583-2 (DOI)000312324500022 ()
Prosjekter
NILB
Merknad

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||

Tilgjengelig fra: 2013-01-14 Laget: 2013-01-14 Sist oppdatert: 2020-08-14
2. Physiologically Realistic and Validated Mathematical Liver Model Revels Hepatobiliary Transfer Rates for Gd-EOB-DTPA Using Human DCE-MRI Data
Åpne denne publikasjonen i ny fane eller vindu >>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 (engelsk)Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 4, s. 0095700-Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Public Library of Science, 2014
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-106962 (URN)10.1371/journal.pone.0095700 (DOI)000335226500139 ()
Tilgjengelig fra: 2014-06-04 Laget: 2014-06-02 Sist oppdatert: 2021-06-14
3. 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
Åpne denne publikasjonen i ny fane eller vindu >>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 (engelsk)Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, nr 1, s. 53-+Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Elsevier, 2017
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-136544 (URN)10.1053/j.gastro.2017.03.005 (DOI)000403918300022 ()
Merknad

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)

Tilgjengelig fra: 2017-04-19 Laget: 2017-04-19 Sist oppdatert: 2023-09-29bibliografisk kontrollert
4. Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort
Åpne denne publikasjonen i ny fane eller vindu >>Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort
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2019 (engelsk)Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 6, artikkel-id e1007157Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.

Author summary

Being able to accurately and reliably estimate liver function is important when monitoring the progression of patients with liver disease, as well as when identifying drug-induced liver injury during drug development. A promising method for quantifying liver function is to use magnetic resonance imaging combined with gadoxetate. Gadoxetate is a liver-specific contrast agent, which is taken up by the hepatocytes and excreted into the bile. We have previously developed a mechanistic model for gadoxetate dynamics using averaged data from healthy volunteers. In this work, we extended our model with a non-linear mixed-effects modeling framework to give patient-specific estimates of the gadoxetate transport-rates. We validated the model by recruiting 100 patients with liver disease, covering a range of severity and etiologies. All patients underwent an MRI-examination and provided both blood and liver biopsies. Our validated model provides a new and deeper look into how the mechanisms of liver function varies across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate.

sted, utgiver, år, opplag, sider
San Francisco, CA, United States: Public Library of Science, 2019
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-159165 (URN)10.1371/journal.pcbi.1007157 (DOI)000474703000068 ()31237870 (PubMedID)2-s2.0-85069296906 (Scopus ID)
Merknad

Funding Agencies|Swedish Research Council [2014-6157, 2007-2884]; Medical Research council of Southeast Sweden [12621]; Vinnova [2013-01314]; Linkoping University, CENIIT [15.09]; Swedish fund for research without animal experiments [Nytank2015]

Tilgjengelig fra: 2019-07-30 Laget: 2019-07-30 Sist oppdatert: 2023-09-29bibliografisk kontrollert
5. Biomarkers of liver fibrosis: prospective comparison of multimodal magnetic resonance, serum algorithms and transient elastography.
Åpne denne publikasjonen i ny fane eller vindu >>Biomarkers of liver fibrosis: prospective comparison of multimodal magnetic resonance, serum algorithms and transient elastography.
Vise andre…
2020 (engelsk)Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 55, nr 7, s. 848-859Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND AND AIMS: Accurate biomarkers for quantifying liver fibrosis are important for clinical practice and trial end-points. We compared the diagnostic performance of magnetic resonance imaging (MRI), including gadoxetate-enhanced MRI and 31P-MR spectroscopy, with fibrosis stage and serum fibrosis algorithms in a clinical setting. Also, in a subset of patients, MR- and transient elastography (MRE and TE) was evaluated when available.

METHODS: Patients were recruited prospectively if they were scheduled to undergo liver biopsy on a clinical indication due to elevated liver enzyme levels without decompensated cirrhosis. Within a month of the clinical work-up, an MR-examination and liver needle biopsy were performed on the same day. Based on late-phase gadoxetate-enhanced MRI, a mathematical model calculated hepatobiliary function (relating to OATP1 and MRP2). The hepatocyte gadoxetate uptake rate (KHep) and the normalised liver-to-spleen contrast ratio (LSC_N10) were also calculated. Nine serum fibrosis algorithms were investigated (GUCI, King's Score, APRI, FIB-4, Lok-Index, NIKEI, NASH-CRN regression score, Forns' score, and NAFLD-fibrosis score).

RESULTS: The diagnostic performance (AUROC) for identification of significant fibrosis (F2-4) was 0.78, 0.80, 0.69, and 0.78 for MRE, TE, LSC_N10, and GUCI, respectively. For the identification of advanced fibrosis (F3-4), the AUROCs were 0.93, 0.84, 0.81, and 0.82 respectively.

CONCLUSION: MRE and TE were superior for non-invasive identification of significant fibrosis. Serum fibrosis algorithms developed for specific liver diseases are applicable in this cohort of diverse liver diseases aetiologies. Gadoxetate-MRI was sufficiently sensitive to detect the low function losses associated with fibrosis. None was able to efficiently distinguish between stages within the low fibrosis stages.Lay summaryExcessive accumulation of scar tissue, fibrosis, in the liver is an important aspect in chronic liver disease. To replace the invasive needle biopsy, we have explored non-invasive methods to assess liver fibrosis. In our study we found that elastographic methods, which assess the mechanical properties of the liver, are superior in assessing fibrosis in a clinical setting. Of interest from a clinical trial point-of-view, none of the tested methods was sufficiently accurate to distinguish between adjacent moderate fibrosis stages.

sted, utgiver, år, opplag, sider
Taylor & Francis, 2020
Emneord
31P-MR spectroscopy, Elastography, Gadoxetate-enhanced MRI, MRE, liver fibrosis, serum fibrosis algorithms
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-168081 (URN)10.1080/00365521.2020.1786599 (DOI)32684060 (PubMedID)
Merknad

Funding agencies: Swedish Research Council (VR/MH, #2007- 2884 as well as VR/NT #2014-6157 both to P. L.), the Medical Research council of Southeast Sweden (FORSS #12621 to P. L.), Vinnova (#2013- 01314 to P. L.), the Linköping University, the Linköping University Hospital Research Foundations, and Region Ostergötland.

Tilgjengelig fra: 2020-08-14 Laget: 2020-08-14 Sist oppdatert: 2021-05-01

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