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      Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study

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          Abstract

          Background

          Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis.

          Methods

          Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy.

          Findings

          PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5–14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27–11%)) or mild iron overload (PDFF: 5% (0.30–11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 μmol/g, final 160 μmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 μmol/g, final: 45 μmol/g; P = 0.002).

          Interpretation

          Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients.

          Trial registration number (ISRCTN)

          80100088.

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          Most cited references35

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          Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease.

          Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥ 18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P 1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P 1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P = 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P = 0.033). A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis. Copyright © 2011 American Association for the Study of Liver Diseases.
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            Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement.

            Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group has produced comprehensive clinical practice guidelines for the management of anaemia in CKD patients. These guidelines addressed all of the important points related to anaemia management in CKD patients, including therapy with erythropoieis stimulating agents (ESA), iron therapy, ESA resistance and blood transfusion use. Because most guidelines were 'soft' rather than 'strong', and because global guidelines need to be adapted and implemented into the regional context where they are used, on behalf of the European Renal Best Practice Advisory Board some of its members, and other external experts in this field, who were not participants in the KDIGO guidelines group, were invited to participate in this anaemia working group to examine and comment on the KDIGO documents in this position paper. In this article, the group concentrated only on those guidelines which we considered worth amending or adapting. All guidelines not specifically mentioned are fully endorsed.
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              Hepatic steatosis: quantification by proton density fat fraction with MR imaging versus liver biopsy.

              To determine utility of proton density fat fraction (PDFF) measurements for quantifying the liver fat content in patients with nonalcoholic fatty liver disease (NAFLD), and compare these results with liver biopsy findings. This retrospective study was approved by the institutional review board with waivers of informed consent. Between June 2010 and April 2011, 86 patients received a diagnosis of NAFLD. Ten patients did not accept liver biopsy and six patients had contraindications for magnetic resonance (MR) imaging. Seventy patients were included in this study. Seventy patients with NAFLD (40 men, 30 women; mean age, 44.7 years; range, 16-69 years) underwent T1-independent volumetric multiecho gradient-echo imaging with T2* correction and spectral fat modeling. Median time interval between MR imaging and liver biopsy was 14.5 days (range, 0-259 days). MR examinations were performed with a 1.5-T MR imaging system. Complex-based PDFF measurements were performed by placing regions of interest in Couinaud system segments V-VI and all liver segments from I to VIII. All liver biopsy specimens were retrieved from archives and evaluated by one pathologist for hepatic steatosis according to criteria from a previous study. Pearson correlation coefficient, receiver operating characteristics, and linear regression analyses were used for statistical analyses. Mean PDFF calculated with MR imaging was 18.1% ± 9.5 (standard deviation). Close correlation for quantification of hepatic steatosis was observed between PDFF and liver biopsy (r = 0.82). PDFF was effective in discriminating moderate or severe hepatic steatosis from mild or no hepatic steatosis, with area under the curve of 0.95. The correlation between biopsy and PDFF-determined steatosis was less pronounced when fibrosis was present (r = 0.60) than when fibrosis was absent (r = 0.86; P = .02). PDFF measurement by MR imaging provided a noninvasive, accurate estimation of the presence and grading of hepatic steatosis in patients with NAFLD. Hepatic fibrosis reduced the correlation between biopsy results and PDFF.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                28 November 2018
                January 2019
                28 November 2018
                : 39
                : 461-471
                Affiliations
                [a ]Division of Nephrology and Dialysis, Ramsay Générale de Santé, Hôpital Privé Claude Galien, Quincy-Sous-Sénart, France
                [b ]Division of Dialysis, Ramsay Générale de Santé, Clinique du Landy, Saint-Ouen, France
                [c ]Division of Nephrology and Dialysis, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
                [d ]Division of Nephrology and Dialysis, Centre Hospitalier Marc Jacquet, Melun, France
                [e ]Division of Radiology, Ramsay Générale de Santé, Hôpital Privé Claude Galien, Quincy-Sous-Sénart, France
                Author notes
                [* ]Corresponding author: HP Claude Galien, Ramsay Générale de Santé, 20 route de Boussy-Saint-Antoine, 91480, Quincy-Sous-Sénart, France. rostotom@ 123456orange.fr
                Article
                S2352-3964(18)30513-9
                10.1016/j.ebiom.2018.11.020
                6354439
                30502056
                183c07ff-9022-4c24-ad50-5d7dfa4361a2
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 October 2018
                : 8 November 2018
                : 12 November 2018
                Categories
                Research paper

                dialysis,iron overload,mri,liver iron concentration (lic),liver proton density fat fraction (liver-pdff),nafld

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