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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
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Wolfram MathCore AB, Linköping, Sweden.ORCID iD: 0000-0003-4630-6550
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).ORCID iD: 0000-0002-4111-1693
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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. Vol. 153, no 1, p. 53-+
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-136544DOI: 10.1053/j.gastro.2017.03.005ISI: 000403918300022OAI: oai:DiVA.org:liu-136544DiVA, id: diva2:1089379
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
In thesis
1. 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. 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
2. Non-Alcoholic Fatty Liver Disease: Aspects on Diagnosis and Long-term Prognosis
Open this publication in new window or tab >>Non-Alcoholic Fatty Liver Disease: Aspects on Diagnosis and Long-term Prognosis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population and is commonly recognized as the hepatic manifestation of the metabolic syndrome. The histological spectrum of NAFLD ranges from isolated steatosis to non-alcoholic steatohepatitis (NASH), with risk of developing fibrosis and subsequent cirrhosis and hepatocellular carcinoma. The gold standard for diagnosing NAFLD is liver biopsy. However, because of its invasive nature, several non-invasive methods have been developed and validated in evaluating fat and fibrosis in patients with NAFLD.

Liver fat content can be assessed using various methods. The conventional histopathological method consists of a visual semiquantitative approach in which the pathologist uses a four-point scale: grade 0 corresponds to fat deposition in <5% of hepatocytes and grade 1−3 (which is needed for the diagnosis of NAFLD) corresponds to ≥5%. An alternate approach is to quantitatively assess steatosis using stereological point counting (SPC) – which rely on liver biopsy. However, in vivo proton magnetic resonance spectroscopy (1H-MRS) is a reliable noninvasive method that can be used to quantitatively assess total hepatic lipid content, or proton density fat fraction (PDFF).

In Paper I we compared the conventional semiquantitative histological method (grade 0-3) with SPC and 1H-MRS. We found a strong positive correlation between 1H-MRS and SPC, whereas the correlations between 1H-MRS or SPC and histopathological grading were substantially weaker. Using the widely used cut-off value of PDFF ≥5%, all participants were found to have steatosis (specificity 100%, sensitivity 53%). Reducing the cut-off value to 3% maintained 100% specificity while increasing sensitivity to 79%.

In Paper IV we evaluated quantitative steatosis, by SPC, in 106 biopsy-proven NAFLD patients during a 20-year follow-up. SPC was independently associated with an increased risk of all-cause mortality and development of T2DM. Moreover, in the 59 patients with sequential biopsies (approximately 10 years apart), a reduction of quantitative hepatic steatosis decreased the all-time risk of developing T2DM.

NASH is commonly seen as a histological feature portending a worse prognosis in NAFLD. Interestingly, no dual biopsy study has ever shown that NASH predicts fibrosis progression. Yet, NASH is seen as a surrogate marker in pharmaceutical trials – were resolution in NASH is equivalent to future resolution of fibrosis.

In Paper II we conducted a long-term follow-up study (20 years) in a large cohort of biopsy-proven NAFLD patients (n=646), in a collaboration with Karolinska Institute. We could not ascertain that NASH had any effect on all-cause, or disease-specific mortality. However, higher stages of fibrosis predicted all-cause and disease specific mortality. In Paper III, we present 129 biopsy-proven NAFLD patients, in which we had prospective, longitudinal data. They were included between 1988 and 1993. All patients alive, were re-invited 2003-2005 and 2013-2015. Dual biopsies were present in 68 patients, and three consecutive biopsies were available in 33 patients. Results showed that NAFLD is a highly heterogeneous disease, with 9.3% developing end-stage liver disease and 16% progressing to advanced stages of fibrosis without any clinically significant baseline data predicting disease progression. In summary, when using 1H-MRS as a diagnostic method for NAFLD, the diagnostic cut-off should be reduced from 5% to 3%. Furthermore, quantitative amount of hepatic steatosis could be used to stratify patients with NAFLD related to future risk of developing T2DM. Moreover, we have shown that NASH does not predict future all-cause or disease-specific mortality nor end-stage liver disease, therefore a different surrogate marker should be used in clinical trials when assessing NAFLD improvement, so to not imbue false reliance in new therapies. Lastly, we have shown that NAFLD has a more dismal prognosis than previously reported, and that it is unexpectedly difficult to predict fibrosis progression in individual NAFLD patients, emphasizing the need for robust non-invasive biomarkers suitable to monitor large number of patients.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 98
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1690
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-160523 (URN)10.3384/diss.diva-160523 (DOI)9789176850381 (ISBN)
Public defence
2019-10-25, Berzeliussalen, Building 463, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved

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Nasr, PatrikForsgren, Mikael F.Ignatova, SimoneLundberg, Peter

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Nasr, PatrikForsgren, Mikael F.Ignatova, SimoneDahlström, NilsCedersund, GunnarDahlqvist Leinhard, OlofNorén, BengtEkstedt, MattiasLundberg, PeterKechagias, Stergios
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Division of Cardiovascular MedicineFaculty of Medicine and Health SciencesDepartment of GastroentorologyDivision of Radiological SciencesDepartment of Radiation PhysicsCenter for Medical Image Science and Visualization (CMIV)Divison of NeurobiologyClinical pathologyDepartment of Radiology in LinköpingDivision of Biomedical EngineeringFaculty of Science & EngineeringDepartment of Clinical and Experimental Medicine
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