Advertisement
Research Article| Volume 67, ISSUE 3, P535-542, September 2017

Download started.

Ok

Sensitive and non-invasive assessment of hepatocellular iron using a novel room-temperature susceptometer

      Highlights

      • Non-invasive and sensitive detection of hepatocellular iron overload.
      • Performance comparable to AAS and MRI.
      • Promising cost-effective tool for liver iron screening.
      • Follow-up of hepatic iron after phlebotomy.
      • Detection of hepatic iron overload in metabolic liver diseases.

      Background & Aims

      Liver iron accumulates in various chronic liver diseases where it is an independent factor for survival and carcinogenesis. We tested a novel room-temperature susceptometer (RTS) to non-invasively assess liver iron concentration (LIC).

      Methods

      Two hundred and sixty-four patients with or without signs of iron overload or liver disease were prospectively enrolled. Thirty-five patients underwent liver biopsy with semiquantitative iron determination (Prussian Blue staining), atomic absorption spectroscopy (AAS, n = 33), or magnetic resonance imaging (MRI, n = 15).

      Results

      In vitro studies demonstrated a highly linear (r2 = 0.998) association between RTS-signal and iron concentration, with a detection limit of 0.3 mM. Using an optimized algorithm, accounting for the skin-to-liver capsule distance, valid measurements could be obtained in 84% of cases. LIC-RTS showed a significant correlation with LIC-AAS (r = 0.74, p <0.001), LIC-MRI (r = 0.64, p <0.001) and hepatocellular iron (r = 0.58, p <0.01), but not with macrophage iron (r = 0.32, p = 0.30). Normal LIC-RTS was 1.4 mg/g dry weight. Besides hereditary and transfusional iron overload, LIC-RTS was also significantly elevated in patients with alcoholic liver disease. The areas under the receiver operating characteristic curve (AUROC) for grade 1, 2 and 3 hepatocellular iron overload were 0.72, 0.89 and 0.97, respectively, with cut-off values of 2.0, 4.0 and 5.0 mg/g dry weight. Notably, the positive and negative predictive values, sensitivity, specificity and accuracy of severe hepatic iron overload (HIO) (grade ≥2) detection, were equal to AAS and superior to all serum iron markers. Depletion of hepatic iron could be efficiently monitored upon phlebotomy.

      Conclusions

      RTS allows for the rapid and non-invasive measurement of LIC. In comparison to MRI, it could be a cost-effective bedside method for LIC screening.
      Lay summary: Novel room-temperature susceptometer (RTS) allows for the rapid, sensitive, and non-invasive measurement of liver iron concentration. In comparison to MRI, it could be a cost-effective bedside method for liver iron concentration screening.

      Graphical Abstract

      Keywords

      Linked Article

      • Is room temperature susceptometer really an accurate method to assess hepatocellular iron?
        Journal of HepatologyVol. 67Issue 6
        • Preview
          We read with interest the study by Mueller et al. describing the use of room temperature susceptometer (RTS) to assess hepatic iron content (HIC).1 This is an interesting clinical application of the methods described by Avrin et al.2,3 This topic is relevant as there is still a need for a cost-effective and efficient iron quantification method in liver disease.
        • Full-Text
        • PDF
      • Reply to: “Is room temperature susceptometry really an accurate method to assess hepatocellular iron?”
        Journal of HepatologyVol. 67Issue 6
        • Preview
          We acknowledge the letter from Dr. Paisant et al. and thank them for their comments in response to our paper “Sensitive and noninvasive assessment of hepatocellular iron using a novel room temperature susceptometer”.1 However, we do not accept the idea of being more cautious with the interpretation. We not only performed a prospective study on a large and heterogeneous cohort that was carefully characterized for fibrosis stage and steatosis using transient elastography (TE) and controlled attenuation parameter (CAP), it also included a wide array of in vitro experiments.
        • Full-Text
        • PDF
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bacon B.R.
        • Adams P.C.
        • Kowdley K.V.
        • Powell L.W.
        • Tavill A.S.
        • American Association for the Study of Liver D
        Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.
        Hepatology. 2011; 2011: 328-343
      1. Liver EAFTSOT. EASL clinical practice guidelines for HFE hemochromatosis.
        J Hepatol. 2010; 53: 3-22
        • Mueller S.
        • Rausch V.
        The role of iron in alcohol-mediated hepatocarcinogenesis.
        Adv Exp Med Biol. 2015; 815: 89-112
        • Hann H.W.
        • Stahlhut M.W.
        • Blumberg B.S.
        Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice.
        Cancer Res. 1988; 48: 4168-4170
        • Tsukamoto H.
        • Horne W.
        • Kamimura S.
        • Niemela O.
        • Parkkila S.
        • Yla-Herttuala S.
        • et al.
        Experimental liver cirrhosis induced by alcohol and iron.
        J Clin Invest. 1995; 96: 620-630
        • Fenton H.J.
        Oxidation of tartaric acid in presence of iron.
        J Chem Soc Lond. 1894; 65: 899-910
        • Niederau C.
        • Fischer R.
        • Purschel A.
        • Stremmel W.
        • Haussinger D.
        • Strohmeyer G.
        Long-term survival in patients with hereditary hemochromatosis.
        Gastroenterology. 1996; 110: 1107-1119
        • D'Amico G.
        • Garcia-Tsao G.
        • Pagliaro L.
        Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
        J Hepatol. 2006; 44: 217-231
        • Ko C.
        • Siddaiah N.
        • Berger J.
        • Gish R.
        • Brandhagen D.
        • Sterling R.K.
        • et al.
        Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry.
        Liver Int. 2007; 27: 1394-1401
        • Asare G.A.
        • Bronz M.
        • Naidoo V.
        • Kew M.C.
        Synergistic interaction between excess hepatic iron and alcohol ingestion in hepatic mutagenesis.
        Toxicology. 2008; 254: 11-18
        • Zacharski L.R.
        • Chow B.K.
        • Howes P.S.
        • Shamayeva G.
        • Baron J.A.
        • Dalman R.L.
        • et al.
        Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.
        J Natl Cancer Inst. 2008; 100: 996-1002
        • Villeneuve J.P.
        • Bilodeau M.
        • Lepage R.
        • Cote J.
        • Lefebvre M.
        Variability in hepatic iron concentration measurement from needle-biopsy specimens.
        J Hepatol. 1996; 25: 172-177
        • Bonkovsky H.L.
        • Slaker D.P.
        • Bills E.B.
        • Wolf D.C.
        Usefulness and limitations of laboratory and hepatic imaging studies in iron-storage disease.
        Gastroenterology. 1990; 99: 1079-1091
        • Isa L.
        • Jean G.
        • Silvani A.
        • Arosio P.
        • Taccagni G.L.
        Evaluation of iron stores in patients with alcoholic liver disease: role of red cell ferritin.
        Acta Haematol. 1988; 80: 85-88
        • Adams P.
        • Barton J.C.
        • McLaren G.D.
        • Acton R.T.
        • Speechley M.
        • McLaren C.E.
        • et al.
        Screening for iron overload: lessons from the hemochromatosis and iron overload screening (HEIRS) study.
        Can J Gastroenterol. 2009; 23: 769-772
        • Joe E.
        • Kim S.H.
        • Lee K.B.
        • Jang J.J.
        • Lee J.Y.
        • Lee J.M.
        • et al.
        Feasibility and accuracy of dual-source dual-energy CT for noninvasive determination of hepatic iron accumulation.
        Radiology. 2012; 262: 126-135
        • Fischer M.A.
        • Gnannt R.
        • Raptis D.
        • Reiner C.S.
        • Clavien P.A.
        • Schmidt B.
        • et al.
        Quantification of liver fat in the presence of iron and iodine: an ex-vivo dual-energy CT study.
        Invest Radiol. 2011; 46: 351-358
        • Hankins J.S.
        • McCarville M.B.
        • Loeffler R.B.
        • Smeltzer M.P.
        • Onciu M.
        • Hoffer F.A.
        • et al.
        R2∗ magnetic resonance imaging of the liver in patients with iron overload.
        Blood. 2009; 113: 4853-4855
        • Gandon Y.
        • Olivie D.
        • Guyader D.
        • Aube C.
        • Oberti F.
        • Sebille V.
        • et al.
        Non-invasive assessment of hepatic iron stores by MRI.
        Lancet. 2004; 363: 357-362
        • St Pierre T.G.
        • Clark P.R.
        • Chua-Anusorn W.
        Measurement and mapping of liver iron concentrations using magnetic resonance imaging.
        Ann N Y Acad Sci. 2005; 1054: 379-385
        • Wood J.C.
        • Enriquez C.
        • Ghugre N.
        • Tyzka J.M.
        • Carson S.
        • Nelson M.D.
        • et al.
        MRI R2 and R2∗ mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients.
        Blood. 2005; 106: 1460-1465
        • Jensen J.H.
        • Helpern J.A.
        Iron-fortified MRI: effects and applications of iron-induced NMR relaxation in biological tissues.
        NMR Biomed. 2004; 17: 425-426
        • Ghugre N.R.
        • Coates T.D.
        • Nelson M.D.
        • Wood J.C.
        Mechanisms of tissue-iron relaxivity: nuclear magnetic resonance studies of human liver biopsy specimens.
        Magn Reson Med Sci. 2005; 54: 1185-1193
        • Fung E.B.
        • Fischer R.
        • Pakbaz Z.
        • Fagaly R.L.
        • Vichinsky E.
        • Starr T.N.
        • et al.
        The new SQUID biosusceptometer at Oakland: first year of experience.
        Neurol Clin Neurophysiol. 2004; 2004: 5
        • Fischer R.
        • Harmatz P.R.
        Non-invasive assessment of tissue iron overload.
        Hematology. 2009; : 215-221
        • Nielsen P.
        • Engelhardt R.
        • Dullmann J.
        • Fischer R.
        Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary hemochromatosis.
        Blood Cells Mol Dis. 2002; 29: 451-458
        • Marinelli M.
        • Gianesin B.
        • Balocco M.
        • Beruto P.
        • Bruzzone C.
        • Carrara P.
        • et al.
        Total iron-overload measurement in the human liver region by the magnetic iron detector.
        IEEE Trans Biomed Eng. 2010; 57: 2295-2303
        • Gianesin B.
        • Zefiro D.
        • Musso M.
        • Rosa A.
        • Bruzzone C.
        • Balocco M.
        • et al.
        Measurement of liver iron overload: noninvasive calibration of MRI-R2∗ by magnetic iron detector susceptometer.
        Magn Reson Med. 2012; 67: 1782-1786
        • Casanas R.
        • Scharfetter H.
        • Altes A.
        • Remacha A.
        • Sarda P.
        • Sierra J.
        • et al.
        Measurement of liver iron overload by magnetic induction using a planar gradiometer: preliminary human results.
        Physiol Meas. 2004; 25: 315-323
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • Behling C.
        • Contos M.J.
        • Cummings O.W.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Mueller S.
        • Englert S.
        • Seitz H.K.
        • Badea R.I.
        • Erhardt A.
        • Bozaari B.
        • et al.
        Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease.
        Liver Int. 2015; 35: 2514-2521
        • Mueller S.
        • Millonig G.
        • Sarovska L.
        • Friedrich S.
        • Reimann F.M.
        • Pritsch M.
        • et al.
        Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.
        World J Gastroenterol. 2010; 16: 966-972
        • Mueller S.
        • Seitz H.K.
        • Rausch V.
        Non-invasive diagnosis of alcoholic liver disease.
        World J Gastroenterol. 2014; 20: 14626-14641
        • Avrin W.F.
        • Kumar S.
        Noninvasive liver-iron measurements with a room-temperature susceptometer.
        Physiol Meas. 2007; 28: 349-361
        • Fischer R.
        • Farrell D.
        Live iron susceptometry. Magnetism in medicine.
        A Handbook, 1998
        • Pineda N.
        • Sharma P.
        • Xu Q.
        • Hu X.
        • Vos M.
        • Martin D.R.
        Measurement of hepatic lipid: high-speed T2-corrected multiecho acquisition at 1H MR spectroscopy–a rapid and accurate technique.
        Radiology. 2009; 252: 568-576
        • Bland J.M.
        • Altman D.G.
        Statistical methods for assessing agreement between two methods of clinical measurement.
        Lancet. 1986; 1: 307-310
        • Kohlhaas A.
        • Durango E.
        • Millonig G.
        • Bastard C.
        • Sandrin L.
        • Golriz M.
        • et al.
        Transient elastography with the XL probe rapidly identifies patients with non-hepatic ascites.
        Hepat Med. 2012; 4: 11-18
        • Allen P.D.
        • St Pierre T.G.
        • Chua-anusorn W.
        • Strom V.
        • Rao K.V.
        Low-frequency low-field magnetic susceptibility of ferritin and hemosiderin.
        Biochim Biophys Acta. 2000; 1500: 186-196
        • Shoden A.
        • Gabrio B.W.
        • Finch C.A.
        The relationship between ferritin and hemosiderin in rabbits and man.
        J Biol Chem. 1953; 204: 823-830
        • Hackett S.
        • Chua-anusorn W.
        • Pootrakul P.
        • St Pierre T.G.
        The magnetic susceptibilities of iron deposits in thalassaemic spleen tissue.
        Biochim Biophys Acta. 2007; 1772: 330-337
        • Kmiec Z.
        Cooperation of liver cells in health and disease.
        Adv Anat Embryol Cell Biol. 2001; 161 (1–151): Iii-xiii