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  • 1.
    Boström, E A
    et al.
    University of Gothenburg.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Bokarewa, M I
    University of Gothenburg.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Resistin is Associated with Breach of Tolerance and Anti-nuclear Antibodies in Patients with Hepatobiliary Inflammation2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, no 5, p. 463-470Article in journal (Refereed)
    Abstract [en]

    Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohns disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P andlt; 0.001) and PSC (P andlt; 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P andlt; 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody-mediated gastrointestinal inflammatory diseases.

  • 2.
    Buzzetti, Elena
    et al.
    Royal Free Hosp, England; UCL, England.
    Hall, Andrew
    Royal Free Hosp, England; Royal Free Hosp, England.
    Ekstedt, Mattias
    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.
    Manuguerra, Roberta
    Royal Free Hosp, England.
    Misas, Marta Guerrero
    Royal Free Hosp, England; UCL, England.
    Covelli, Claudia
    Royal Free Hosp, England.
    Leandro, Gioacchino
    S de Bellis Res Hosp, Italy.
    Luong, TuVinh
    Royal Free Hosp, England.
    Kechagias, Stergios
    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.
    Manesis, Emanuel K.
    Hippokrateion Hosp, Greece.
    Pinzani, Massimo
    Royal Free Hosp, England; UCL, England.
    Dhillon, Amar P.
    Royal Free Hosp, England.
    Tsochatzis, Emmanuel A.
    Royal Free Hosp, England; UCL, England.
    Collagen proportionate area is an independent predictor of long-term outcome in patients with non-alcoholic fatty liver disease2019In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 49, no 9, p. 1214-1222Article in journal (Refereed)
    Abstract [en]

    Background Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies by measuring the amount of collagen deposition as a proportion of the total biopsy area. CPA predicts clinical outcomes in patients with HCV and can sub-classify cirrhosis. Aim To test the ability of CPA to quantify fibrosis and predict clinical outcomes in patients with NAFLD. Methods We assessed consecutive patients with biopsy-proven NAFLD from three European centres. Clinical and laboratory data were collected at baseline and at the time of the last clinical follow-up or death. CPA was performed at two different objective magnifications, whole biopsy macro and x4 objective magnification, named standard (SM) and high (HM) magnification respectively. The correlation between CPA and liver stiffness was assessed in a sub-group of patients. Results Of 437 patients, 32 (7.3%) decompensated and/or died from liver-related causes during a median follow-up of 103 months. CPA correlated with liver stiffness and liver fibrosis stage across the whole spectrum of fibrosis. HM CPA was significantly higher than SM CPA in stages F0-F3 but similar in cirrhosis, reflecting a higher ability to capture pericellular/perisinusoidal fibrosis at early stages. Age at baseline (HR: 1.04, 95% CI: 1.01-1.08), HM CPA (HR: 1.04 per 1% increase, 95% CI: 1.01-1.08) and presence of advanced fibrosis (HR: 15.4, 95% CI: 5.02-47.84) were independent predictors of liver-related clinical outcomes at standard and competing risk multivariate Cox-regression analysis. Conclusions CPA accurately measures fibrosis and is an independent predictor of clinical outcomes in NAFLD; hence it merits further evaluation as a surrogate endpoint in clinical trials.

  • 3.
    Dulai, Parambir S
    et al.
    University of California at San Diego, La Jolla, CA..
    Singh, Siddharth
    University of California at San Diego, La Jolla, CA.
    Patel, Janki
    University of California at San Diego, La Jolla, CA.
    Soni, Meera
    University of California at San Diego, La Jolla, CA.
    Prokop, Larry J
    Mayo Clinic, Rochester, Minnesota.
    Younossi, Zobair
    Department of Medicine, Inova Fairfax Hospital, Falls Church, VA.
    Sebastiani, Giada
    McGill University Health Centre, Montreal, Quebec, Canada.
    Ekstedt, Mattias
    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 Cardiovascular Medicine.
    Hagstrom, Hannes
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nasr, Patrik
    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.
    Stal, Per
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wong, Vincent Wai-Sun
    Chinese University of Hong Kong, Hong Kong.
    Kechagias, Stergios
    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 Cardiovascular Medicine.
    Hultcrantz, Rolf
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Loomba, Rohit
    University of California at San Diego, La Jolla, CA.
    Increased risk of mortality by fibrosis stage in non-alcoholic fatty liver disease: Systematic Review and Meta-analysis.2017In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 65, no 5, p. 1557-1565Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage-specific risk of all-cause and liver-related mortality in NAFLD.

    METHODS: Through a systematic review and meta-analysis, we identified 5 adult NAFLD cohort studies reporting fibrosis stage specific mortality (0-4). Using fibrosis stage 0 as a reference population, fibrosis stage-specific mortality rate ratios (MRR) with 95% confidence intervals (CI), for all-cause and liver-related mortality, were estimated. The study is reported according to the PRISMA statement.

    RESULTS: 1,495 NAFLD patients with 17,452 patient years of follow-up were included. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality and this risk increased with increase in the stage of fibrosis: stage 1, MRR, 1.58 (95% CI 1.19-2.11); stage 2, MRR, 2.52 (95% CI 1.85-3.42); stage 3, MRR, 3.48 (95% CI 2.51-4.83), and stage 4, MRR, 6.40 (95% CI 4.11-9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with increase in the stage of fibrosis: stage 1, MRR, 1.41 (95% CI 0.17-11.95); stage 2, MRR, 9.57 (95% CI 1.67-54.93); stage 3, MRR, 16.69 (95% CI 2.92-95.36); and stage 4, MRR, 42.30 (95% CI 3.51-510.34).

    LIMITATIONS: Inability to adjust for co-morbid conditions or demographics known to impact fibrosis progression in NAFLD, and the inclusion of patients with simple steatosis and NASH without fibrosis in the reference comparison group.

    CONCLUSION: The risk of liver-related mortality increases exponentially with increase in fibrosis stage. These data have important implications in assessing utility of each stage and benefits of regression of fibrosis from one stage to another. This article is protected by copyright. All rights reserved.

  • 4.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
    Non-Alcoholic Fatty Liver Disease: A clinical and histopathological study2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fatty liver has previously often been associated with excessive alcohol consumption. During the last two decades, the interest in fatty liver occurring in non-drinkers i.e. non-alcoholic fatty liver disease (NAFLD) has increased dramatically. Today, NAFLD is considered as the most common liver disease in the developed world. It is strongly associated with obesity, insulin resistance, and hypertension. Thus, NAFLD is considered as the hepatic manifestation of the metabolic syndrome.

    The spectrum of NAFLD includes: simple fatty liver without necroinflammatory activity; non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocellular injury, inflammation, and fibrosis; cirrhosis; and in some individuals hepatocellular carcinoma.

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the pathologist uses a four-graded scale: 0–3 or none, slight, moderate and severe. In this thesis we show that there is a considerable inter- and intraindividual variation in such scoring methods and that a more standardised and quantitative approach is preferable. The area/volume of fat in liver biopsies is greatly overestimated when assessed semiquantitatively. Moreover, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis.

    The long-term clinical and histopathological course of 129 consecutively enrolled NAFLD patients was studied. Mean follow-up (SD) was 13.7 (1.3) years. Survival of NASH patients was reduced compared with a matched reference population. These subjects more often died from cardiovascular and liver-related causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

    During follow-up, 17 patients had been prescribed a statin. At follow-up, patients on medication with statins had significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Although patients under statin treatment exhibited a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. It is concluded that statins can be prescribed safely in patients with elevated liver enzymes because of NAFLD.

    Alcohol consumption was evaluated with a validated questionnaire combined with an oral interview. In a multivariate analysis moderate alcohol consumption, particularly when frequency of heavy episodic drinking was analysed, consistent with the diagnosis of NAFLD to be set, was independently associated with fibrosis progression in NAFLD.

    The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. We evaluated the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in our cohort of NAFLD patients. Although the NAS was independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score was limited due to significant overlap in clinical development between NAS-score groups.

    List of papers
    1. Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
    Open this publication in new window or tab >>Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
    2005 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 18, no 7, p. 912-916Article in journal (Refereed) Published
    Abstract [en]

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.

    Keywords
    Liver, quantification, steatosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17322 (URN)10.1038/modpathol.3800370 (DOI)15920560 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    2. Long-term follow-up of patients with NAFLD and elevated liver enzymes.
    Open this publication in new window or tab >>Long-term follow-up of patients with NAFLD and elevated liver enzymes.
    Show others...
    2006 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 44, no 4, p. 865-873Article in journal (Refereed) Published
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

    Keywords
    Liver, quantification, steatosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17323 (URN)10.1002/hep.21327 (DOI)17006923 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    3. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
    Open this publication in new window or tab >>Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
    Show others...
    2007 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 1, p. 135-141Article in journal (Refereed) Published
    Abstract [en]

    Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins.

    Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up.

    Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage.

    Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.

    Keywords
    Non-alcoholic fatty liver disease, Histology, Statin, Metabolic syndrome
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17324 (URN)10.1016/j.jhep.2007.02.013 (DOI)17400325 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    4. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease
    Open this publication in new window or tab >>Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease
    Show others...
    2009 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 44, no 3, p. 366-374Article in journal (Refereed) Published
    Abstract [en]

    Objective: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD.

    Material and methods: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up.

    Results: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p0.001) and insulin resistance (p0.01) were independently associated with significant fibrosis progression.

    Conclusions: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.

    Keywords
    Alcoholic liver disease, fatty liver, histopathology, liver fibrosis, non-alcoholic fatty liver disease
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17133 (URN)10.1080/00365520802555991 (DOI)
    Available from: 2009-03-07 Created: 2009-03-07 Last updated: 2017-12-13Bibliographically approved
    5. The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression
    Open this publication in new window or tab >>The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression
    Show others...
    2008 (English)Article in journal (Other academic) Submitted
    Abstract [en]

    Objective: The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD.

    Methods: One hundred and twenty-nine patients with biopsy proven NAFLD were included in a long-term histological follow-up study. Clinical and histological course were compared between NASH, “borderline NASH”, and “not NASH” patients. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up.

    Results: Eighty-eight patients accepted re-evaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend towards higher baseline NAS was seen in patients (n = 7) that developed end-stage liver disease (3.1 ± 0.9 vs. 2.4 ± 1.0; P = 0.062). Baseline NAS was significantly higher in patients with progressive fibrosis (2.9 ± 0.9 vs. 2.2 ± 0.9; P = 0.017), and NAS was independently associated with significant fibrosis progression tested in a multivariate analysis (P = 0.023). However, 18% of patients without NASH progressed significantly in fibrosis stage.

    Conclusion: Although the NAS is independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS-score groups.

    Keywords
    Steatohepatitis, Fatty liver, Fibrosis progression, Clinical follow-up, Histopathology
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17325 (URN)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2009-08-17Bibliographically approved
  • 5.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Department of Histopathology and Cytology, Aleris Medilab, Täby, Sweden.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bendtsen, Preben
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland, Department of Medical Specialist.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease2009In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 44, no 3, p. 366-374Article in journal (Refereed)
    Abstract [en]

    Objective: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD.

    Material and methods: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up.

    Results: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p0.001) and insulin resistance (p0.01) were independently associated with significant fibrosis progression.

    Conclusions: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.

  • 6.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L.
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression2008Article in journal (Other academic)
    Abstract [en]

    Objective: The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD.

    Methods: One hundred and twenty-nine patients with biopsy proven NAFLD were included in a long-term histological follow-up study. Clinical and histological course were compared between NASH, “borderline NASH”, and “not NASH” patients. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up.

    Results: Eighty-eight patients accepted re-evaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend towards higher baseline NAS was seen in patients (n = 7) that developed end-stage liver disease (3.1 ± 0.9 vs. 2.4 ± 1.0; P = 0.062). Baseline NAS was significantly higher in patients with progressive fibrosis (2.9 ± 0.9 vs. 2.2 ± 0.9; P = 0.017), and NAS was independently associated with significant fibrosis progression tested in a multivariate analysis (P = 0.023). However, 18% of patients without NASH progressed significantly in fibrosis stage.

    Conclusion: Although the NAS is independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS-score groups.

  • 7.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.2007In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 1, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins.

    Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up.

    Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage.

    Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.

  • 8.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Aleris Medilab, Täby.
    Mathiesen, Ulrik L
    County Hospital, Oskarshamn.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL. Linköping University, Faculty of Health Sciences.
    Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 47, no 1, p. 108-115Article in journal (Refereed)
    Abstract [en]

    Background/Aims. The nonalcoholic fatty liver disease (NAFLD) activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD. Methods. One hundred and twenty-nine patients with biopsy-proven NAFLD were included in a long-term histological follow-up study. Clinical course and change in fibrosis stage were compared between nonalcoholic steatohepatitis (NASH), “borderline NASH,” and “not NASH” patients. Significant fibrosis progression was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up. Results. Eighty-eight patients accepted reevaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3–16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend toward higher baseline NAS was seen in patients (n = 7) who developed end-stage liver disease (3.1 ± 0.9 vs. 2.2 ± 1.0; p = 0.050). Baseline NAS was associated with progressive disease in a univariate binary logistic regression analysis (p = 0.024), but no difference was seen in the multivariate analysis including the NAS, portal inflammation, and perisinusoidal fibrosis. Moreover, 18% of patients without NASH progressed significantly in fibrosis stage. Conclusions. The ability of the NAS to predict progression of NAFLD is poor. The clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS score groups. To use the NAS as endpoint in treatment trial is not justified.

  • 9.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden;.
    Thorelius, Lars
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Long-term follow-up of patients with NAFLD and elevated liver enzymes.2006In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 44, no 4, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

  • 10.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Hagström, Hannes
    Unit of Gastroenterology and Hepatology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm .
    Nasr, Patrik
    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 Cardiovascular Medicine.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Stal, Per
    Unit of Gastroenterology and Hepatology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm .
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Hultcrantz, Rolf
    Unit of Gastroenterology and Hepatology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm.
    Nonalcoholic Fatty Liver Disease Activity Score and Mortality: Imperfect But Not Insignificant REPLY2016In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 64, no 1, p. 310-311Article in journal (Refereed)
  • 11.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Hagström, Hannes
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nasr, Patrik
    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.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Per
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Hultcrantz, Rolf
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up2015In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 61, no 5, p. 1547-1554Article in journal (Refereed)
    Abstract [en]

    Background and rationale for the study: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e. fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease-specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease-specific mortality. Methods: In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (± 5.6, range 6-33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. Main results: NAFLD patients had an increased mortality compared with the reference population (HR 1.29, CI 1.04-1.59, p=0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11-2.15, p=0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, p=0.001), infectious disease (HR 2.71, CI 1.02-7.26, p=0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, p=0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, p=0.07), whereas patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27-4.76, p<0.001). Conclusions: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality.

  • 12.
    Forsgren, Mikael
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Andregård, O.
    Dahlström, Nils
    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.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Smedby, Örjan
    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.
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Kihlberg, Johan
    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.
    Prospective evaluation of liver steatosis comparing stereological point-counting biopsy analysis and 1H MRS2012Conference paper (Other academic)
  • 13.
    Forsgren, Mikael
    et al.
    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).
    Karlsson, Markus
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    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).
    Dahlström, Nils
    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).
    Norén, Bengt
    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).
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ignatova, Simone
    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.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Lundberg, Peter
    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, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort2019In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, PLOS COMPUTATIONAL BIOLOGY, Vol. 15, no 6, article id e1007157Article in journal (Refereed)
    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.

  • 14.
    Franzen, L.
    et al.
    Department of Pathology, Clinical Research Centre, University Hospital Örebro, Örebro, Sweden.
    Ekstedt, Mattias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bodin, L.
    Unit of Biostatistics and Epidemiology, Clinical Research Centre, University Hospital, Örebro, Sweden.
    Fiorini, R.N.
    Fiorini, R.N..
    Kirtz, J.
    Kirtz, J..
    Periyasamy, B.
    Periyasamy, B..
    Evans, Z.
    Evans, Z..
    Haines, J.
    Haines, J..
    Cheng, G.
    Cheng, G..
    Polito, C.
    Polito, C..
    Rodwell, D.
    Rodwell, D..
    Zhou, X.
    Zhou, X..
    Campbell, C.
    Campbell, C..
    Birsner, J.
    Birsner, J..
    Schmidt, M.G.
    Schmidt, M.G..
    Lewin, D.
    Lewin, D..
    Chavin, K.D.
    Chavin, K.D..
    Letter to the editor (multiple letter)2005In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 19, no 4, p. 571-572p. 571-Article in journal (Other academic)
    Abstract [en]

    [No abstract available]

  • 15.
    Franzén, Lennart E
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bodin, Lennart
    Unit of Biostatistics and Epidemiology, Clinical Research Centre, University Hospital, Örebro, Sweden.
    Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.2005In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 18, no 7, p. 912-916Article in journal (Refereed)
    Abstract [en]

    The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.

  • 16.
    Hagstrom, Hannes
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Nasr, Patrik
    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.
    Ekstedt, Mattias
    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.
    Hammar, Ulf
    Karolinska Inst, Sweden.
    Stal, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden.
    Hultcrantz, Rolf
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kechagias, Stergios
    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.
    Cardiovascular risk factors in non-alcoholic fatty liver disease2019In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 39, no 1, p. 197-204Article in journal (Refereed)
    Abstract [en]

    Background amp; Aims Patients with non-alcoholic fatty liver disease (NAFLD) are at an increased risk for cardiovascular disease (CVD). It is unclear whether histological variables may help predict CVD risk. We evaluated histology and traditional CV risk factors as predictors of CVD outcomes in a large NAFLD cohort. Methods We included 603 biopsy-proven NAFLD patients free of baseline CVD and matched these (1:10, by age, sex and municipality) to 6269 population controls. All individuals were cross-linked to national registries to ascertain incident CVD events, defined as acute ischaemic heart disease or stroke. The presence of CV risk factors and liver histology were available in NAFLD patients only. Cox regression models were used to estimate hazard ratios (HR) for incident CVD. Results During a mean follow-up of 18.6 years, 168 (28%) of NAFLD patients and 1325 (21%) of controls experienced a CVD event (HR 1.54, 95%CI 1.30-1.83). Within the NAFLD cohort, age, male sex, type 2 diabetes, smoking and triglycerides were associated with risk of CVD. Taking these CV risk factors into account, no histological parameter, including presence of NASH and fibrosis stage, were associated with incident CVD. Conclusions Patients with NAFLD are at an increased risk for CVD compared to matched controls, but histological parameters do not seem to independently predict this risk.

  • 17.
    Hagstrom, Hannes
    et al.
    Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
    Nasr, Patrik
    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.
    Ekstedt, Mattias
    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.
    Stål, Per
    Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Hultcrantz, Rolf
    Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
    Kechagias, Stergios
    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.
    Accuracy of Noninvasive Scoring Systems in Assessing Risk of Death and Liver-Related Endpoints in Patients With Nonalcoholic Fatty Liver Disease2019In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 17, no 6, p. 1148-1156.e4Article in journal (Refereed)
    Abstract [en]

    Background and Aims

    Several non-invasive scoring systems have been developed to determine risk of advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). We examined the association between 4 scoring systems and incident severe liver disease and overall mortality in a large cohort of patients with biopsy-proven NAFLD.

    Methods

    We performed a retrospective analysis of data from 646 patients with biopsy-proven NAFLD, recruited from 2 hospitals in Sweden, from 1971 through 2009. The NAFLD fibrosis score (NFS), FIB-4, APRI, and BARD scores were calculated at the time of the liver biopsy. Based on each score, patients were assigned to categories of low, intermediate, or high risk for advanced fibrosis. Overall mortality and severe liver disease (cirrhosis, decompensated liver disease, liver failure, or hepatocellular carcinoma) were ascertained through linkage with national registers until the end of 2014. Cox regression, area under the receiver operating characteristic (AUROC) curve, and C-statistic analyses were used to study the predictive capacity of each scoring system.

    Results

    During a mean follow-up time of 19.9±8.7 years, there were 214 deaths and 76 cases of severe liver disease. For overall mortality, AUROC curve values were: NFS, 0.72 (95% CI, 0.68–0.76); FIB-4, 0.72 (95% CI, 0.68–0.76); BARD, 0.62 (95% CI, 0.58–0.66); and APRI, 0.52 (95% CI, 0.47–0.57). For severe liver disease, AUROC curve values were: NFS, 0.72 (95% CI, 0.66–0.78); FIB-4, 0.72 (95% CI, 0.66–0.79); BARD, 0.62 (95% CI, 0.55–0.69); APRI, 0.69 (95% CI, 0.63–0.76). C-statistics for all scores were of moderate capacity to predict outcomes.

    Conclusions

    In a retrospective analysis of data from 646 patients with biopsy-proven NAFLD, we found the NFS and the FIB-4 scores to most accurately determine risk of overall death or severe liver disease. However, the AUROC values for these scoring systems are not high enough for use in the clinic; new systems are needed to determine prognoses of patients with NAFLD.

  • 18.
    Hagström, Hannes
    et al.
    Center for Digestive Diseases, Unit of Hepatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Nasr, Patrik
    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.
    Bottai, Matteo
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Hultcrantz, Rolf
    Center for Digestive Diseases, Unit of Hepatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Stål, Per
    Center for Digestive Diseases, Unit of Hepatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Elevated serum ferritin is associated with increased mortality in non-alcoholic fatty liver disease after 16 years of follow-up2016In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 36, no 11, p. 1688-1695Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: High levels of ferritin in patients with non-alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD.

    METHODS: We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into "high" (n = 89) and "normal" (n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality was obtained from a national, population based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy.

    RESULTS: The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin (p < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, p < 0.05). There was no difference in mortality between patients with different iron overload patterns.

    CONCLUSIONS: High levels of ferritin are associated with a long-term increased risk of death. This article is protected by copyright. All rights reserved.

  • 19.
    Hagström, Hannes
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Nasr, Patrik
    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.
    Ekstedt, Mattias
    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.
    Hammar, Ulf
    Karolinska Institute, Sweden.
    Stal, Per
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Hultcrantz, Rolf
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Kechagias, Stergios
    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.
    Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD2017In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 67, no 6, p. 1265-1273Article in journal (Refereed)
    Abstract [en]

    Background amp; Aims: Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. Methods: We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. Results: During a follow-up of mean 20 years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p amp;lt; 0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test amp;gt; 0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26 years in F0-1, 9.3 years in F2, 2.3 years in F3, and 0.9 years to liver decompensation in F4. Conclusions: In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  • 20.
    Hagström, Hannes
    et al.
    Center for Digestive Diseases, Division of Hepatology Karolinska University HospitalStockholm Sweden. Department of Medicine, Huddinge Karolinska Institute Stockholm Sweden. Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institute Stockholm Sweden.
    Nasr, Patrik
    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.
    Ekstedt, Mattias
    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.
    Hammar, Ulf
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institute Stockholm Sweden.
    Stål, Per
    Center for Digestive Diseases, Division of Hepatology Karolinska University Hospital Stockholm Sweden. Department of Medicine and Huddinge Karolinska Institute Stockholm Sweden..
    Hultcrantz, Rolf
    Center for Digestive Diseases, Division of Hepatology Karolinska University Hospital Stockholm Sweden. Department of Medicine and Huddinge Karolinska Institute Stockholm Sweden..
    Kechagias, Stergios
    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.
    Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study.2018In: Hepatology communications, ISSN 2471-254X, Vol. 2, no 1, p. 48-57Article in journal (Refereed)
    Abstract [en]

    Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long-term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy-proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0-29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population-based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long-term risk of mortality and liver-related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow-up of 19.9 years (range 0.4-40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P =  0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P =  0.007). Conclusion: Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. (Hepatology Communications 2018;2:48-57).

  • 21.
    Hagström, Hannes
    et al.
    Karolinska Institute, Sweden.
    Nasr, Patrik
    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.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Onnerhag, Kristina
    Skåne University Hospital, Sweden.
    Nilsson, Emma
    Skåne University Hospital, Sweden.
    Rorsman, Fredrik
    University of Uppsala Hospital, Sweden.
    Sheikhi, Reza
    University of Uppsala Hospital, Sweden.
    Marschall, Hanns-Ulrich
    University of Gothenburg, Sweden.
    Hultcrantz, Rolf
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stal, Per
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 2, p. 159-165Article in journal (Refereed)
    Abstract [en]

    Background and aim: Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD. Methods: We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled. Results: An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76-0.97; p = .017). The lowest risk for fibrosis was found with the lowest odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08-0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth amp;gt;= 0.3 mu mol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01-7.59; p = .047). Conclusion: Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.

  • 22.
    Hagström, Hannes
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Nasr, Patrik
    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.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Stal, Per
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bedossa, Pierre
    University of Paris Diderot, France.
    Hultcrantz, Rolf
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    SAF score and mortality in NAFLD after up to 41 years of follow-up2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 1, p. 87-91Article in journal (Refereed)
    Abstract [en]

    Background and aims: A new score for the histological severity of nonalcoholic fatty liver disease (NAFLD), called SAF (Steatosis, Activity and Fibrosis) has been developed. We aimed to evaluate the impact of this score on overall mortality. Methods: We used data from 139 patients with biopsy-proven NAFLD. All biopsies were graded according to the SAF scoring system and disease severity was classified as mild, moderate or severe. Causes of death were extracted from a national, population-based register. A Cox regression model, adjusted for sex, body mass index (BMI) and diabetes mellitus type 2, was applied. Results: At baseline 35 patients presented with mild or moderate disease respectively, and 69 patients with severe disease. During follow-up (median 25.3 years, range 1.7-40.8) 74 patients died, 11 in the mild group (31%), 18 in the moderate group (51%) and 45 in the severe group (65%), p=.002. Compared to patients with mild disease, patients with moderate disease did not have a significant increase in overall mortality (HR 1.83, 95% CI 0.89-3.77, p=.10). Patients with severe disease had a significant increase in mortality (HR 2.65, 95% CI 1.19-5.93, p=.017). However, when adjusting for fibrosis stage, significance was lost (HR 1.85, 95% CI 0.76-4.54, p=.18). NASH, defined as per the FLIP algorithm, was not associated with mortality compared to not having NASH (HR 1.46, 95% CI 0.74-2.90, p=.28). Conclusions: After adjustment for fibrosis, the SAF score was not associated with increased mortality in NAFLD. This finding should be corroborated in larger cohorts with similar follow-up time.

  • 23.
    Holm, Anna
    et al.
    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 Cardiology in Linköping.
    Sederholm Lawesson, Sofia
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Zolfagharian, Shima
    Orebro Univ Hosp, Sweden.
    Swahn, Eva
    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 Cardiology in Linköping.
    Ekstedt, Mattias
    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.
    Alfredsson, Joakim
    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 Cardiology in Linköping.
    Bleeding complications after myocardial infarction in a real world population - An observational retrospective study with a sex perspective2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 167, p. 156-163Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the current study was to assess bleeding events, including severity, localisation and prognostic impact, in a real world population of men and women with myocardial infarction (MI). Methods and results: In total 850 consecutive patients were included during 2010 and followed for one year. Bleeding complications were identified by searching of each patients medical records and characterised according to the TIMI criteria. For this analysis, only the first event was calculated. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all inhospital bleeding events was 13.2%, with no sex difference. Women had significantly more minor non-surgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women had also more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p=0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008). Conclusions: Almost one in four patients experienced a bleeding complication through 12 months follow-up after a myocardial infarction. Women experienced more non-surgery related minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome. In contrast men with non-surgery related bleeding complications had higher mortality. Improved bleeding prevention strategies are warranted for both men and women.

  • 24.
    Homeyer, Andre
    et al.
    Fraunhofer MEVIS, Germany.
    Nasr, Patrik
    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.
    Engel, Christiane
    Fraunhofer MEVIS, Germany.
    Kechagias, Stergios
    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.
    Lundberg, Peter
    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).
    Ekstedt, Mattias
    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.
    Kost, Henning
    Fraunhofer MEVIS, Germany.
    Weiss, Nick
    Fraunhofer MEVIS, Germany.
    Palmer, Tim
    University of Leeds, England.
    Karl Hahn, Horst
    Fraunhofer MEVIS, Germany.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. University of Leeds, England; Leeds Teaching Hospital NHS Trust, England.
    Lundström, Claes
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Automated quantification of steatosis: agreement with stereological point counting2017In: Diagnostic Pathology, ISSN 1746-1596, E-ISSN 1746-1596, Vol. 12, article id 80Article in journal (Refereed)
    Abstract [en]

    Background: Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist. Methods: The evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability. Results: The new method showed the strongest agreement with the expert. At 20x resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10x resolution, it was more accurate than and twice as fast as all other methods at 20x resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer. Conclusions: The results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers.

  • 25.
    Johansson, Joel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Littoral cell angioma in a patient with Crohn's disease.2015In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2015, p. 1-4, article id 474969Article in journal (Refereed)
    Abstract [en]

    Littoral cell angioma is a rare vascular tumor of the spleen. The pathogenesis is unknown but the lesion is associated with several malignancies and immunological disorders. The diagnosis requires histopathological examination. The malignant potential of this lesion is unknown, which is why splenectomy is recommend for all cases. Symptomatic cases generally suffer from hypersplenism and pyrexia. A previously healthy 20-year-old female was diagnosed with colonic Crohn's disease; as part of the work-up a magnetic resonance enterography was performed which showed multiple signal changes of the spleen. The patient reported chronic abdominal pain in the left upper quadrant, malaise, and fever. The unknown splenic lesions prompted a laparoscopic splenectomy; pathology revealed a littoral cell angioma. The abdominal pain and malaise remitted but the fever persisted one year despite adequate treatment of the patient's Crohn's disease. Littoral cell angioma is associated with immune-dysregulation including Crohn's disease with several reported cases. Signs and symptoms of hypersplenism and splenic lesions on imaging should raise suspicion of littoral cell angioma in patients with Crohn's disease. Magnetic resonance enterography to assess disease severity in Crohn's disease may provide an opportunity to study the prevalence and natural history of this rare splenic tumor.

  • 26.
    Johansson, Joel
    et al.
    Linköping University, Faculty of Health Sciences, Faculty of Health Sciences, Medical Programme.
    Ignatova, Simone
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ekstedt, Mattias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Pinworm infestation mimicking crohns' disease2013In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2013, article id 706197Article in journal (Refereed)
    Abstract [en]

    We here report a case of a young man who presented to his general practitioner with diarrhea. Inflammatory bowel disease was suspected and a colonoscopy showed aphthous lesions suggestive of Crohns' disease but biopsies revealed eggs of Enterobius vermicularis. When treated for this parasite, his symptoms were alleviated and a followup colonoscopy revealed a normal colon and distal ileum. Enterobius vermicularis is the most common parasite worldwide and has been attributed with many different presentations and pathologies. It is therefore necessary to maintain vigilance, even in high-income countries, in order to diagnose patients with one of the many atypical presentations of pinworms.

  • 27.
    Johansson, Joel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Sahin, Christofer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Pestoff, Rebecka
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Edsjö, Anders
    Sahlgrenska University Hospital Göteborg .
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia.2015In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2015, p. 1-5, article id 140616Article in journal (Refereed)
    Abstract [en]

    Juvenile polyposis syndrome (JPS) is a rare genetic disorder characterized by juvenile polyps of the gastrointestinal tract. We present a new pathogenic mutation of the SMAD4 gene and illustrate the need for a multidisciplinary health care approach to facilitate the correct diagnosis. The patient, a 47-year-old Caucasian woman, was diagnosed with anaemia at the age of 12. During the following 30 years, she developed numerous gastrointestinal polyps. The patient underwent several operations, and suffered chronic abdominal pain, malnutrition, and multiple infections. Screening of the SMAD4 gene revealed a novel, disease-causing mutation. In 2012, the patient suffered hypoalbuminemia and a large polyp in the small bowel was found. Gamma globulin was given but the patient responded with fever and influenza-like symptoms and refused more treatment. The patient underwent surgery in 2014 and made an uneventful recovery. At follow-up two months later albumin was 38 g/L and IgG was 6.9 g/L. Accurate diagnosis is essential for medical care. For patients with complex symptomatology, often with rare diseases, this is best provided by multidisciplinary teams including representatives from clinical genetics. Patients with a SMAD4 mutation should be followed up both for JPS and haemorrhagic hereditary telangiectasia and may develop protein loosing enteropathy and immunodeficiency.

  • 28.
    Karlsson, Markus
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    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.
    Dahlström, Nils
    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).
    Forsgren, Mikael
    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).
    Ignatova, Simone
    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.
    Norén, Bengt
    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).
    Dahlqvist Leinhard, Olof
    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).
    Kechagias, Stergios
    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.
    Lundberg, Peter
    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, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Liver R2*is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease2019In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 50, no 1, p. 325-333Article in journal (Refereed)
    Abstract [en]

    Background Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement. Purpose To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD. Study Type Prospective. Population Eighty-one patients with suspected CLD. Field Strength/Sequence 1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF. Assessment Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated. Statistical Tests Pearson correlation, linear regression, and area under the receiver operating curve. Results There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively. Data Conclusion PDFF increases R2*. Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.

  • 29.
    Karlsson, Markus
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Leinhard Dahlqvist, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Norén, Bengt
    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.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Diffuse Liver Disease: Measurements of Liver Trace Metal Concentrations and R2* Relaxation Rates2016Conference paper (Refereed)
    Abstract [en]

    Introduction

    Over the past decade, several methods for measuring of liver iron content (LIC) non-invasively with MRI have been developed and verified. The most promising methods uses relaxometry, measuring either R2- or R2* relaxation rate in the liver1,2. For instance, several studies have shown that there seems to be a linear relationship between R2* and LIC1. However, few of these studies have measured the liver content of other metals, which could also affect the relaxation rates. The goal of this study was to investigate if any trace metals, other than iron could affect the R2* relaxation rate in liver tissue in a patients with diffuse liver disease.

    Subjects and methods

    75 patients with suspected diffuse liver disease underwent an MRI examination followed by a liver biopsy the same day. The R2* relaxation rate of the water protons in the liver was measured using an axial 3D multi-slice fat-saturated multi-echo turbo field echo sequence (TE=4.60/9.20/13.80/18.40/23.00ms). Regions of interest (ROI) were drawn and R2* was estimated by fitting the mean signal intensity from the ROIs to a mono-exponential decay model. The biopsies were freeze dried and the concentrations of iron, manganese, copper, cobalt and gadolinium were measured using Inductively Coupled Plasma Sector Field Mass Spectrometry (ICP-SFMS). A multiple linear regression analysis was applied to determine which of the measured metals significantly affected the relaxation rate.

    Results

    A linear regression with the LIC and R2* showed a reasonable fit (Figure 1). The multiple linear regression analysis (Table 1) showed that iron as well as manganese had a significant affect on R2*. Unlike iron however, the regression coefficient of manganese was negative, meaning that an increasing manganese concentration gave a shorter R2* relaxation rate. The same trend can be seen when plotting the manganese concentration against R2* (Figure 2).

  • 30.
    Kechagias, Stergios
    et al.
    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.
    Blomdahl, Julia
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    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.
    Alcohol consumption in non-alcoholic fatty liver disease-harmful or beneficial?2019In: Hepatobiliary surgery and nutrition, ISSN 2304-3881, E-ISSN 2304-389X, Vol. 8, no 3, p. 311-313Article in journal (Other academic)
    Abstract [en]

    n/a

  • 31.
    Kechagias, Stergios
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Ekstedt, Mattias
    Linköping University, Department of Molecular and Clinical Medicine.
    Mathiesen, UL
    Franzen, L
    New reference interval for ALAT does not identify subclinical liver disease. Lower limit than the proposed should be used for medical considerations!2004In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 101, p. 2884-2887Article in journal (Other academic)
  • 32.
    Lindh Falk, Annika
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlberg, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    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.
    Heslyk, Annika
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Creating spaces for interprofessional learning: Strategic revision of a common IPL curriculum in undergraduate programs2015In: Interprofessional Education in Europe: Policy and Practice / [ed] Andre Vyt, Majda Pahor, Tiina Tervaskanto-Maentausta, Antwerpen: Garant Publishers Limited , 2015, p. 49-66Chapter in book (Refereed)
  • 33.
    Lundberg, Peter
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Nasr, Patrik
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Leinhard Dahlqvist, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Kvantifiering av leversteatos: diagnostisk utvärdering av protonmagnetresonansspektroskopi jämfört med histologiska metoder2016Conference paper (Refereed)
    Abstract [sv]

    Bakgrund

    Leversteatos är den vanligaste manifestationen av leversjukdom i västvärlden. Leverbiopsi med semikvantitativ histologisk gradering är referensmetod vid gradering av leversteatos. Med protonmagnetsresonansspektroskopi (1H-MRS), en metod som föreslagits ersätta leverbiopsi för värdering av steatos, kan leverns innehåll av triglycerider mätas icke-invasivt. Triglyceridinnehåll >5,00 % används ofta som ett diagnostiskt kriterium för leversteatos vid undersökning med 1H-MRS. Syftet med studien var att jämföra 1H-MRS med semikvantitativ histologisk steatosgradering och kvantitativ histologisk steatosmätning.

    Metod

    Patienter remitterade för utredning av förhöjda leverenzymer in-kluderades i studien. Samtliga patienter genomgick klinisk undersökning, laboratorieprovtagning samt 1H-MRS direkt följd av leverbiopsi. För konventionell histologisk semikvantitativ gradering av steatos användes kriterierna utarbetade av Brunt och medarbetare. Kvantitativ mätning av fett i biopsierna utfördes genom att med hjälp av stereologisk punkträkning (SPC) mäta andelen av ytan som innehöll fettvakuoler.

    Resultat

    I studien inkluderades 94 patienter, varav 37 hade icke-alkoholor-sakad fettleversjukdom (NAFLD), 49 hade andra leversjukdomar och 8 hade normal leverbiopsi. En stark korrelation noterades mel-lan 1H-MRS och SPC (r=0,92, p<0,0001; к=0.82). Korrelationen mellan 1H-MRS och Brunts kriterier (к=0.26) samt mellan SPC och Brunts kriterier (к=0.38) var betydligt sämre. När patologens gradering (Brunts kriterier) användes som referensmetod för diag-nos av leversteatos så hade alla patienter med triglyceridinnehåll >5,00 % mätt med 1H-MRS steatos (specificitet 100 %). Emellertid hade 22 av 69 patienter med triglyceridinnehåll ≤5,00 % också le-versteatos enligt Brunts kriterier (sensitivitet 53 %). Motsvarande siffror när man använde gränsvärdet 3,02 % var sensitivitet 79 % och specificitet 100 %. Vid ytterligare reduktion av gränsvärdet för triglyceridinnehåll till 2,00 % ökade sensitiviteten till 87 % med upprätthållande av hög specificitet (94 %).

    Slutsats

    1H-MRS och SPC uppvisade en mycket hög korrelation vid kvantifiering av leversteatos. SPC borde därför föredras framför Brunts kriterier när noggrann histologisk kvantifiering av leversteatos är önskvärd. Många patienter kan ha histologisk leversteatos trots triglyceridinnehåll ≤5,00 % mätt med 1H-MRS. Gränsvärdet för diagnostisering av leversteatos med 1H-MRS bör därför reduceras.

  • 34.
    Lundberg, Peter
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Karlsson, Markus
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Leinhard Dahlqvist, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Norén, Bengt
    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.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Mechanistic modeling of qDCE-MRI data reveals increased bile excretion of Gd-EOB-DTPA in diffuse liver disease patients with severe fibrosis2016Conference paper (Refereed)
    Abstract [en]

    Introduction

    Over the past decades, several different non-invasive methods for staging hepatic fibrosis have been proposed. One such method is dynamic contrast enhanced MRI (DCE-MRI) using the contrast agent (CA) Gd-EOB-DTPA. Gd-EOB-DTPA is liver specific, which means that it is taken up specifically by the hepatocytes via the OATP3B1/B3 transporters and excreted into the bile via the MRP2 transporter. Several studies have shown that DCE-MRI and Gd-EOBDTPA can separate patients with advanced (F3-F4) from mild (F0-F2) hepatic fibrosis by measuring the signal intensity, where patients with advanced fibrosis have a lower signal intensity than the mild fibrosis cases.1 However, none of the studies up to date have been able to differentiate if the reduced signal intensity in the liver is because of an decreased uptake of CA or an increased excretion. Analyzing the DCE-MRI data with mechanistic mathematical modelling has the possibility of investigating such a differentiation.

    Subjects and methods

    88 patients with diffuse liver disease were examined using DCE-MRI (1.5 T Philips Achieva, two-point Dixon, TR=6.5 ms, TE=2.3/4.6 ms, FA=13) after a bolus injection of Gd-EOB-DTPA, followed by a liver biopsy. Regions of interest were placed within the liver, spleen and veins and a whole-body mechanistic pharmacokinetic model2 was fitted to the data. The fitted parameters in the model correspond to the rate of CA transport between different compartments, e.g. hepatocytes, blood plasma, and bile (Fig. 1).

    Results

    As can be seen in Fig. 2, the parameter corresponding to the transport of CA from the blood plasma to the hepatocytes, kph, is lower for patients with advanced fibrosis (p=0.01). Fig. 3 shows that the parameter corresponding to the CA excretion into the bile, khb, is higher for patients with advanced fibrosis (p<0.01).

    Discussion/Conclusion

    This work shows that the decreased signal intensity in DCE-MRI images in patients with advanced fibrosis depends on both a decreased uptake of CA in the hepatocytes and an increased excretion into the bile. Similar results have also been observed in a rat study3. In that study, rats with induced cirrhosis had a higher MRP2-activity than the healthy control rats.

    References

    1Norén et al: Eur. Radiol, 23(1), 174-181, 2013.

    2Forsgren et al: PloS One, 9(4): e95700, 2014.

    3Tsuda & Matsui: Radiol, 256(3): 767-773, 2010.

  • 35.
    Lykiardopoulos, Byron
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hagström, Hannes
    Karolinska Institute, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Stal, Per
    Karolinska Institute, Sweden.
    Hultcrantz, Rolf
    Karolinska Institute, Sweden.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Development of Serum Marker Models to Increase Diagnostic Accuracy of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: The New LINKI Algorithm Compared with Established Algorithms2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0167776Article in journal (Refereed)
    Abstract [en]

    Background and Aim Detection of advanced fibrosis (F3-F4) in nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis. Serum markers have been proposed as alternatives to biopsy. We attempted to develop a novel algorithm for detection of advanced fibrosis based on a more efficient combination of serological markers and to compare this with established algorithms. Methods We included 158 patients with biopsy-proven NAFLD. Of these, 38 had advanced fibrosis. The following fibrosis algorithms were calculated: NAFLD fibrosis score, BARD, NIKEI, NASH-CRN regression score, APRI, FIB-4, Kings score, GUCI, Lok index, Forns score, and ELF. Study population was randomly divided in a training and a validation group. A multiple logistic regression analysis using bootstrapping methods was applied to the training group. Among many variables analyzed age, fasting glucose, hyaluronic acid and AST were included, and a model (LINKI-1) for predicting advanced fibrosis was created. Moreover, these variables were combined with platelet count in a mathematical way exaggerating the opposing effects, and alternative models (LINKI-2) were also created. Models were compared using area under the receiver operator characteristic curves (AUROC). Results Of established algorithms FIB-4 and Kings score had the best diagnostic accuracy with AUROCs 0.84 and 0.83, respectively. Higher accuracy was achieved with the novel LINKI algorithms. AUROCs in the total cohort for LINKI-1 was 0.91 and for LINKI-2 models 0.89. Conclusion The LINKI algorithms for detection of advanced fibrosis in NAFLD showed better accuracy than established algorithms and should be validated in further studies including larger cohorts.

  • 36.
    Musso, G.
    et al.
    Gradenigo Hospital, University of Turin, Turin, Italy.
    Gambino, R.
    Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy.
    Tabibian, J.H.
    Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN, United States.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Hamaguchi, M.
    Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
    Hultcrantz, R.
    Departments of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Hagstrom, H.
    Departments of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Yoon, S.K.
    Division of Hepato-Gastroenterology, Department of Internal Medicine, Kangnam St. Mary Hospital, Catholic University Medical College, Seoul, South Korea.
    Charatcharoenwitthaya, P.
    Division of Gastroenterology, Medicine Department, Siriraj Hospital, Mahidol University, Bangkoknoi, Bangkok, Thailand.
    George, J.
    Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW, Australia.
    Barrera, F.
    Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW, Australia.
    Haflidadottir, S.
    Dept of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbrau, Reykjavik, Iceland.
    Bjornsson, E.S.
    Dept of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbrau, Reykjavik, Iceland.
    Armstrong, M.J.
    Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom.
    Hopkins, L.J.
    Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom.
    Gao, X.
    Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
    Francque, S.
    Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
    Verrijken, A.
    Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
    Yilmaz, Y.
    Department of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey.
    Lindor, K.D.
    Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN, United States.
    Charlton, M.
    Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN, United States.
    Haring, R.
    Institute of Clinical Chemistry and Laboratory Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
    Lerch, M.M.
    Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
    Rettig, R.
    Institute of Physiology, Ernst-Moritz-Arndt-University Medicine Greifswald, Karlsburg, Germany.
    Volzke, H.
    Institute for Community Medicine, Ernst-Moritz-Arndt University Medicine Greifswald, Greifswald, Germany.
    Ryu, S.
    Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, South Korea.
    Li, G.
    College of Life Sciences, Hunan Normal University, Changsha, China.
    Wong, L.L.
    John A. Burns School of Medicine at University of Hawaii, Transplant Institute, Hawaii Medical Center, Honolulu, HI, United States.
    Machado, M.
    Department of Gastroenterology, University Hospital of Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal.
    Cortez-Pinto, H.
    Department of Gastroenterology, University Hospital of Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal.
    Yasui, K.
    Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Japan.
    Cassader, M.
    Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy.
    Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 7, p. e1001680-Article in journal (Refereed)
    Abstract [en]

    Background:Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.Methods and Findings:English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) andlt;60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.Conclusion:The presence and severity of NAFLD are associated with an increased risk and severity of CKD.Please see later in the article for the Editors Summary. © 2014 Musso et al.

  • 37.
    Nasr, Patrik
    et al.
    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.
    Forsgren, Mikael F.
    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.
    Ignatova, Simone
    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.
    Dahlström, Nils
    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).
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlqvist Leinhard, Olof
    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).
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    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.
    Lundberg, Peter
    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).
    Kechagias, Stergios
    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.
    Using a 3% Proton Density Fat Fraction as a Cut-off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results from Histopathology Analysis2017In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, no 1, p. 53-+Article in journal (Refereed)
    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.

  • 38.
    Nasr, Patrik
    et al.
    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.
    Hilliges, Annette
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Thorelius, Lars
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kechagias, Stergios
    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.
    Ekstedt, Mattias
    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.
    Contrast-enhanced ultrasonography could be a non-invasive method for differentiating none or mild from severe fibrosis in patients with biopsy proven non-alcoholic fatty liver disease2016In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 51, no 9, p. 1126-1132Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The gold standard for diagnosing fibrosis stage in non-alcoholic fatty liver disease (NAFLD) is liver biopsy. The aim of this study was to determine whether contrast-enhanced ultrasonography (CEUS) with transit time measurements could be a non-invasive alternative for differentiating none or mild from severe fibrosis in NAFLD patients. Various serum markers and clinical variables were also evaluated.

    MATERIALS AND METHODS: Fifty-eight patients with NAFLD underwent CEUS prior to liver biopsy. All patients were also evaluated according to the Göteborg University Cirrhosis Index (GUCI), the AST-Platelet Ratio Index (APRI), the NAFLD fibrosis score, and the FIB-4 and BARD score.

    RESULTS: The hepatic vein arrival time (HV) was shorter in patients with severe fibrosis (25.9 ± 4.8 vs 29.5 ± 4.7 s, p = 0.023), and the difference between the hepatic and portal vein (ΔHV-PV) was shorter (2.3 ± 2.8 vs 6.4 ± 2.8 s, p < 0.0001) while the difference in arrival time between the portal vein and hepatic artery (ΔPV-HA) arrival time was significantly longer (6.0 ± 2.2 vs 3.6 ± 1.6 s, p < 0.0001). The area under receiver operating characteristics curve values for HV, ΔHV-PV and ΔPV-HA to separate none or mild from severe fibrosis was 0.71, 0.83 and 0.84, respectively. The corresponding figures for GUCI, APRI, NAFLD fibrosis score, FIB-4 and BARD score were 0.93, 0.92, 0.86, 0.90 and 0.77, respectively.

    CONCLUSIONS: CEUS and non-invasive scoring systems could exclude severe fibrosis in NAFLD patients.

  • 39.
    Nasr, Patrik
    et al.
    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.
    Ignatova, Simone
    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.
    Kechagias, Stergios
    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.
    Ekstedt, Mattias
    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.
    Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies.2018In: Hepatology communications, ISSN 2471-254X, Vol. 2, no 2, p. 199-210Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high-quality follow-up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow-up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow-up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end-stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty-six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy-proven fibrosis stage F3-F4 and 2 patients with end-stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end-stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end-stage liver disease. (Hepatology Communications 2018;2:199-210).

  • 40.
    Negoita, Florentina
    et al.
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    Blomdahl, Julia
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Wasserstrom, Sebastian
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    Winberg, Martin
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Osmark, Peter
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    Larsson, Sara
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    Stenkula, Karin G.
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    Ekstedt, Mattias
    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.
    Kechagias, Stergios
    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.
    Holm, Cecilia
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    Jones, Helena A.
    Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
    PNPLA3 variant M148 causes resistance to starvation-mediated lipid droplet autophagy in human hepatocytes2019In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 120, no 1, p. 343-356Article in journal (Refereed)
    Abstract [en]

    The mechanism of how patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant M148 is associated with increased risk of development of hepatic steatosis is still debated. Here, we propose a novel role of PNPLA3 as a key player during autophagosome formation in the process of lipophagy. A human hepatocyte cell line, HepG2 cells, expressing recombinant I148 or 148M, was used to study lipophagy under energy deprived conditions, and lipid droplet morphology was investigated using florescence microscopy, image analysis and biochemical assays. Autophagic flux was studied using the golden-standard of LC3-II turnover in combination with the well characterized GFP-RFP-LC3 vector. To discriminate between, perturbed autophagic initiation and lysosome functionality, lysosomes were characterized by Lysotracker staining and LAMP1 protein levels as well as activity and activation of cathepsin B. For validation, human liver biopsies genotyped for I148 and 148M were analyzed for the presence of LC3-II and PNPLA3 on lipid droplets. We show that the M148-PNPLA3 variant is associated with lipid droplets that are resistant to starvation-mediated degradation. M148 expressing hepatocytes reveal decreased autophagic flux and reduced lipophagy. Both I148-PNPLA3 and M148-PNPLA3 colocalize and interact with LC3-II, but the M148-PNPLA3 variant has lower ability to bind LC3-II. Together, our data indicate that PNPLA3 might play an essential role in lipophagy in hepatocytes and furthermore that the M148-PNPLA3 variant appears to display a loss in this activity, leading to decreased lipophagy.

  • 41.
    Norén, Bengt
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Lundberg, Peter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Radiation Physics.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart
    Medilab, Täby, Sweden.
    Wirell, Staffan
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Smedby, Örjan
    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.
    Separation of advanced from mild fibrosis in diffuse liver disease using 31P magnetic resonance spectroscopy2008In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 66, no 2, p. 313-320Article in journal (Refereed)
    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.

  • 42.
    Ratziu, V
    et al.
    Université Pierre et Marie Curie.
    Bugianesi, E
    University of Torino.
    Dixon, J
    Alfred Hospital.
    Fassio, E
    Hospital Nacional Profesor Alejandro Posadas.
    Ekstedt, Mattias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Charlotte, F
    Université Pierre et Marie Curie.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Poynard, T
    Université Pierre et Marie Curie.
    Olsson, R
    Sahlgrenska University Hospital.
    Histological progress of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.2007In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 26, p. 821-830Article in journal (Refereed)
    Abstract [en]

      Background: In non-alcoholic fatty liver disease, histological lesions display a significant sampling variability that is ignored when interpreting histological progression during natural history or therapeutic interventions. Aim: To provide a method taking into account sampling variability when interpreting crude histological data, and to investigate how this alters the conclusions of available studies. Methods: Natural history studies detailing histological progression and therapeutic trials were compared with the results of a previously published sampling variability study. Results: Natural history studies showed an improvement in steatosis, which was significantly higher than expected from sampling variability (47% vs. 8%, P < 0.0001). In contrast, no study showed a change in activity grade or ballooning higher than that of sampling variability. There was only a marginal effect on fibrosis with no convincing demonstration of a worsening of fibrosis, a conclusion contrary to what individual studies have claimed. Some insulin sensitizing drugs and anti-obesity surgery significantly improved steatosis, while most did not significantly impact on fibrosis or activity. Conclusions: Sampling variability of liver biopsy is an overlooked confounding factor that should be considered systematically when interpreting histological progression in patients with non-alcoholic fatty liver disease.

  • 43.
    Schattenberg, Joern M.
    et al.
    Johannes Gutenberg Univ Mainz, Germany.
    Ekstedt, Mattias
    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.
    Assessing the disease burden of non-alcoholic fatty liver disease in the real world - big data and big numbers2019In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 17, article id 123Article in journal (Refereed)
    Abstract [en]

    n/a

  • 44.
    Sjöwall, Christoffer
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Cardell, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Bokarewa, Maria I
    University of Gothenburg.
    Enocsson, Helena
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Lindvall, Liselott
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Frydén, Aril
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Infectious Diseases in Östergötland.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    High prevalence of autoantibodies to C-reactive protein in patients with chronic hepatitis C infection: association with liver fibrosis and portal inflammation2012In: Human Immunology, ISSN 0198-8859, E-ISSN 1879-1166, Vol. 73, no 4, p. 382-388Article in journal (Refereed)
    Abstract [en]

    The presence of autoantibodies against C-reactive protein (anti-CRP) has been reported in association with autoimmunity and histopathology in chronic hepatitis C virus (HCV) infection. Resistin could play a role in the pathogenesis of hepatitis, although results on HCV infection are ambiguous. Here we retrospectively analyzed anti-CRP and resistin levels in the sera of 38 untreated and well-characterized HCV patients at the time of their first liver biopsy. HCV activity and general health were assessed by a physician at least yearly until follow-up ended. Anti-CRP and resistin were also measured in patients with autoimmune hepatitis (AIH) and nonalcoholic fatty liver disease (NAFLD). Anti-CRP antibodies were registered in all HCV patients, whereas only a few AIH (11%) and NAFLD (12%) sera were positive. Anti-CRP levels were related to histopathological severity and were highest in patients with cirrhosis at baseline. Resistin levels were similar in HCV, AIH, and NAFLD patients, but high levels of resistin were associated with early mortality in HCV patients. Neither anti-CRP nor resistin predicted a response to interferon-based therapy or cirrhosis development or was associated with liver-related mortality. We conclude that anti-CRP antibodies are frequently observed in chronic HCV infection and could be a useful marker of advanced fibrosis and portal inflammation.

  • 45.
    Sjöwall, Christopher
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Cardell, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease2015In: Translational research : the journal of laboratory and clinical medicine, ISSN 1878-1810, Vol. 165, no 6, p. 658-666Article in journal (Refereed)
    Abstract [en]

    The identification of individuals with severe liver fibrosis among patients with chronic liver disease is of major importance when evaluating prognosis, potential risk for complications, and when deciding treatment strategies. Although percutaneous liver biopsy is still considered a "gold standard" for staging of liver fibrosis, attempts to find reliable noninvasive markers of liver fibrosis are frequent. Inflammation is essential for the progression of fibrosis. The urokinase plasminogen activator and its receptor have been associated with hepatic inflammation and fibrosis in mice. High serum concentrations of soluble urokinase plasminogen activator receptor (suPAR) are suggested to be involved in inflammation, tissue remodeling, and cancer metastasis. Here, we evaluated serum suPAR as a noninvasive test to detect liver fibrosis in 82 well-characterized patients with nonalcoholic fatty liver disease (NAFLD), and in 38 untreated patients with chronic hepatitis C virus (HCV) infection at the time of their first liver biopsy. suPAR levels were increased in chronic liver disease compared with blood donors (P < 0.001). Patients with HCV had higher suPAR concentrations than patients with NAFLD (P < 0.002). suPAR levels were associated with the severity of fibrosis, particularly in NAFLD, but did not correlate with inflammation. Regarding the performance in predicting severity of fibrosis, suPAR was essentially as good as other commonly used noninvasive fibrosis scoring systems. The results in HCV confirm previous observations. However, this is the first study to investigate suPAR as a biomarker in NAFLD, and the results indicate that suPAR may constitute a severity marker related to fibrosis and prognosis rather than reflecting inflammation.

  • 46.
    Wiggins, Sally
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    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.
    Hammar Chiriac, Eva
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Larsson Torstensdotter, Gunvor
    Törnqvist, Tove
    Being a professional, or just being a student? A discursive analysis of video-recorded interprofessional learning tutorials in a medical faculty2018Conference paper (Other academic)
  • 47.
    Wiggins, Sally
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    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.
    Hammar Chiriac, Eva
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Larsson Torstensdotter, Gunvor
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Törnqvist, Tove
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    On doing ‘being a student amongst other kinds of students’: Managing academic identities in an interprofessional tutorial group2018Conference paper (Other academic)
1 - 47 of 47
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