Room-temperature Susceptometer Research Articles

Susceptibility based multiparametric quantification of liver disease: Non-invasive evaluation of steatosis and iron overload

PurposeTo evaluate if single-voxel MR spectroscopy (MRS) of iron and fat correlates with biopsy results of hepatic steatosis and iron overload, and to compare MR-measurements with room-temperature susceptometer (RTS), ultrasound, controlled attenuation parameter (CAP) and serum ferritin. Material and methodsIn this prospective study, a set of 42 patients out of 47 screened patients with several chronic liver diseases underwent MRI-examination at 1.5 T including R2-measurements by single-voxel high-speed T2-corrected multiecho spectroscopy, additional liver biopsy, abdominal ultrasound, CAP, and RTS. Routine blood and serum parameters were determined, including ferritin. Atomic absorption spectroscopy (AAS) and histologically confirmed extent of hepatic steatosis from liver biopsy were used as reference standard. For correlation of R2, RTS, CAP, ferritin, and ultrasound with results of AAS and histologically determined fat fraction of liver biopsy specimen, Spearman's and Pearson's correlation as well as receiver operating characteristics curve (ROC) analysis with cut-off values determined by maximizing Youden index was used. ResultsMRS iron assessment correlated best with AAS, with a Pearson correlation coefficient of 0.715 (p < 0.001), followed by RTS 0.520 (p < 0.001), and serum ferritin 0.213 (p = 0.088, not significant). MRS fat quantification correlated best with the histological confirmed extent of steatosis hepatis with a Spearman correlation coefficient of 0.836 (p < 0.001), followed by CAP 0.604 (p < 0.001) and sonographically diagnosed steatosis 0.358 (p = 0.013). ConclusionMRS by T2-corrected multiecho single-voxel spectroscopy correlated best with histological results of hepatic fat and iron content compared to RTS, CAP, abdominal ultrasound, and ferritin. Non-invasive methods to assess hepatic fat and iron are of clinical interest for follow-up examinations of patients with chronic liver diseases, where repeated biopsy is not indicated.

Liver Iron Measurements with Less Expensive Technology: Comparison of a Room-Temperature Susceptometer with SQUID in 84 Subjects

Introduction. Tissue iron measurements with magnetic resonance imaging (MRI) have given doctors a reliable way to monitor iron overload in thalassemias, sickle-cell disease and other disorders. However, MRI remains too expensive for widespread use in the countries where the largest numbers of patients with these disorders live. This abstract describes a test in human subjects of a potentially less expensive method of quantifying excess iron: measurement of liver iron concentrations (LIC) by magnetic susceptometry, using magnetic sensors that work at room temperature.Methods. The room-temperature susceptometer (RTS) in this study was a close copy of the one described by Maliken et al. [Room-temperature susceptometry predicts biopsy-determined hepatic iron in patients with elevated serum ferritin. Ann. Hepatol. 2012;11:77-84]. LIC measurements with the RTS were compared to those of an existing SQUID (superconducting quantum interference device) biosusceptometer [Starr, TN et. al. A new generation SQUID biosusceptometer. Proceedings, 12th International Conference on Biomagnetism. 2000].84 patients, mostly with transfusion-dependent thalassemia major, participated in this comparison. Their LICs based on SQUID ranged from zero to 5250 μg/g wet weight, with median 920 μg/g and standard deviation 960 μg/g. Body-mass indices ranged from 16.6 to 31.7 kg/m2 (median 21.8 kg/m2, standard deviation 3.1 kg/m2). Liver-skin distances measured by ultrasound imaging ranged from 13.0 to 30.0 mm (median 17.5 mm, standard deviation 3.1 mm). For each patient, SQUID and RTS measurements were done in a single session.The agreement of the two susceptometers was assessed in terms of their Pearson product moment correlation coefficient r and the standard deviation σ of the differences between the SQUID results and the least-squares Deming regression line. This standard deviation was slightly dependent on the value of λ, the ratio of the variances of errors for the two susceptometers, that was assumed in the Deming regression. This dependence was estimated by calculating σ for a range of λ values.Results. LICs from RTS and SQUID had a Pearson product moment correlation coefficient r = 0.93. The differences between the two systems had a standard deviation σ = 363 μg/g assuming that the RTS's variance was four times the SQUID's and 353 μg/g assuming equal variances. As a point of reference, applying a similar analysis to published data yielded r = 0.975 and σ = 320 μg/g for a comparison of the Torino-based SQUID used in this study with another SQUID susceptometer at Hamburg [Engelhardt R et al. Agreement of liver iron quantification measurements with low Tc-SQUID biosusceptometers in Oakland, Torino and Hamburg. Elsevier International Congress Series 2007;1300: 279-282].Conclusions. These results indicate that a less expensive susceptometer using room-temperature magnetic sensors can make liver iron measurements that are well correlated with those of the biopsy-validated SQUID technology. Based on the standard deviation of the differences between the two systems, the RTS used in this study was approaching accuracy levels that would be useful clinically, especially in screening patients for dangerously high iron. Since the RTS's errors in measurements on phantoms are significantly lower than those found in this study on human subjects, the room-temperature susceptometer's accuracy appears to be limited not by the noise of the room-temperature magnetic sensors, but by the relationship of the susceptometer to the patient's body. With improvement in areas such as patient positioning, measurement of the sensor-skin distance, and correction for the magnetic response of tissue between the liver and the susceptometer, low-cost susceptometers may ultimately achieve accuracies comparable to those of existing SQUIDs. Such technologies can potentially improve the management of iron overload, especially in regions where MRI is too expensive for routine use. [Display omitted] DisclosuresPiga:Acceleron: Research Funding; La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Apopharma: Honoraria, Research Funding; Bluebird Bio: Honoraria; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Avrin:Insight Magnetics: Employment, Other: Proprietor of company developing the study device, Patents & Royalties: Own rights to patents on the study device.

Advances in Biomagnetic Liver Susceptometry Allow the Measurement of Liver Iron Concentration with a Room Temperature Sensor

Introduction: Iron overload is frequently observed in diverse states ranging from thalassemia, sickle cell disease, hereditary hemochromatosis, transfusion-dependent anemias, cancer chemotherapy and chronic liver disease. Management of iron overload depends on the ability to quantify and monitor the patient's iron stores with precision. Organ iron measurement by relaxometry-based MRI techniques has become the current standard. MRI is expensive and has the added limitations of multiple existing methods and reduced dynamic range with 3 Tesla scanners. Liver iron measurements by magnetic susceptometers using superconductive quantum interference device (SQUID) technology are expensive and have limited availability. In this study an improved low-cost device, the room-temperature susceptometer (RTS, Insight Magnetics, San Diego, CA), was tested against the Model 5700 Ferritometer ® 3-Channel SQUID BioSusceptometer System (Tristan Technologies, Inc. San Diego, CA). Both systems quantify liver iron concentration (LIC) using bulk magnetic susceptibility.Where the SQUID uses an ultra-stable sensing system immersed in liquid helium, the RTS cancels the temperature and magnetic-field fluctuations inherent in an apparatus that works at room temperature. The RTS uses three main techniques to sense the very weak magnetic field produced by liver iron: (a) oscillatory magnetic fields that can be detected with high sensitivity using coils of ordinary copper wire, (b) field-producing and field-sensing coils to cancel the signal due to the applied magnetic field, and (c) movement of the sensing unit periodically toward and away from the patient so as to distinguish the patient's magnetic field response from the interfering signal caused by temperature fluctuations in the sensing system.Methods: This study compared measurements of LIC from RTS to those by the SQUID. The RTS in this study was modified from an earlier model to make the baseline reading more stable, and to increase the accuracy of the water reference measurement to which the patient's magnetic response is compared. The magnetic-field source and sensing coils were enlarged to increase the signal of the liver compared with that of the overlying tissue.LIC was measured once on the SQUID and once on the RTS at a single visit. Using ultrasound imaging, optimum liver measurement position was determined and marked with an x-y-positioning and z-distance sensing Locator Loop (Positronic Systemtechnik GmbH, Germany). The locator loop remained attached to the patient for measurements with both devices to preserve measurement location. LIC calculation was corrected for the susceptibility and geometry of the overlying tissue. Measurement results from SQUID and RTS were analyzed independently by two investigators.Results: Thirteen adults (10 with transfusion-dependent thalassemia and 3 controls) with body mass index (BMI) <25 were enrolled. All measurements were completed at a single visit with no failures. LIC values (µg/g wet-liver weight), ranged from -33 to 6493 with SQUID, and -305 to 7237 with RTS. In the three controls, the LIC was -33, 144 and 427 µg/g with SQUID, and -305, 451 and 230 µg/g with RTS. The overall correlation between the two methods was excellent, yielding an r2 = 0.976 and slope = 1.037 ± 0.068 (p<0.001, Fig 1). Bland-Altman analysis of percent-difference versus the average of the two methods showed bias -2.72 (95% limits of agreement -149.1 to 143.6) for all subjects, which improved to 1.94 (95% limits of agreement -41.1 to 45.3) when the average values below 350 µg/g (n=4) were excluded (Fig 2). The percent difference between the two methods was influenced by the subject's BMI (p=0.050 for all subjects; p=0.031 after excluding average LIC <350 µg/g), with the least difference observed in the BMI range of 20-23 Kg/m2.Conclusion: This study shows that, with the recent improvements in the RTS technology, LIC measurements now closely align with those using SQUID. The remaining difference between the two methods likely results from the models used to compensate for the overlying tissue. Further comparison of RTS to SQUID and MRI-based methods in diverse iron overload states is warranted in a larger study. This work may ultimately make low-cost noninvasive measurement of iron overload accessible to the large number of patients in the US, and to resource-limited countries around the world. DisclosuresLal:Bluebird Bio: Research Funding; Insight Magnetics: Research Funding; Terumo Corporation: Research Funding; Novartis: Research Funding; Celgene Corporation: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding. Avrin:Insight Magnetics: Employment, Other: Proprietor of company developing the study device, Patents & Royalties: Own rights to patents on the study device. Weyhmiller:Insight Magnetics: Research Funding.

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

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). 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). In vitro studies demonstrated a highly linear (r2=0.998) association between RTS-signal and iron concentration, with a detection limit of 0.3mM. 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 1.4mg/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 5.0mg/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. 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.

Non-invasive assessment of hepatic iron in chronic liver disease: First experience with a novel room-temperature susceptometer

Non-invasive assessment of hepatic iron in chronic liver disease: First experience with a novel room-temperature susceptometer

Total Iron-Overload Measurement in the Human Liver Region by the Magnetic Iron Detector

An accurate assessment of body iron accumulation is essential for the diagnosis and therapy of iron overload in diseases, such as hemochromatosis, thalassemia and other forms of severe anemias. The magnetic iron detector (MID) is a room-temperature susceptometer, which measures the total iron overload in the liver. Since February 2005, about 600 patients have been assessed using this device. The iron overload is obtained by calculating the difference between the measured magnetization signal of the patient and the patient's background signal. The latter is the magnetization signal that the patient would generate with normal iron content. This study presents the method for calculating the background signal of healthy volunteers and the application of the same method to patients with iron burden in order to evaluate their overload. The present MID sensitivity is 0.8 g and the reproducibility of the iron overload measurement of the same patients is lower than 0.5 g. The MID does not require calibration with liver biopsies. We correlated the MID measurements with the results of 26 biopsies (R = 0.62), 64 superconducting quantum interference device susceptometer measurements (R = 0.79), 666 serum ferritin concentration measurements (R = 0.72), and 41 MRI- R2* measurements (R = 0.71).

Iron overload detection in rats by means of a susceptometer operating at room temperature

Biosusceptometry is a non-invasive procedure for determination of iron overload in a human body; it is essentially an assessment of the diamagnetic (water) and paramagnetic (iron) properties of tissues. We measured in vivo iron overload in the liver region of 12 rats by a room temperature susceptometer. The rats had been injected with sub-toxic doses of iron dextran. A quantitative relationship has been observed between the measurements and the number of treatments. The assessment of iron overload requires evaluating the magnetic signal corresponding to the same rat ideally without the overload. This background value was extrapolated on the basis of the signal measured in control rats versus body weight (R2 = 0.73). The mean iron overload values for the treated rats, obtained after each iron injection, were significantly different from the means of the corresponding control rats (p < 0.01). The in vivo measurements have been complemented by chemical analysis on excised livers and other organs (R2 = 0.89). The magnetic moment of iron atoms in liver tissues was measured to be 3.6 Bohr magneton. Evaluation of the background signal is the limit to the measure; the error corresponds to about 30 mg (1 SD) of iron while the instrument sensitivity is more than a factor of 10 better.

Noninvasive liver-iron measurements with a room-temperature susceptometer

Magnetic susceptibility measurements on the liver can quantify iron overload accurately and noninvasively. However, established susceptometer designs, using superconducting quantum interference devices (SQUIDs) that work in liquid helium, have been too expensive for widespread use. This paper presents a less expensive liver susceptometer that works at room temperature. This system uses oscillating magnetic fields, which are produced and detected by copper coils. The coil design cancels the signal from the applied field, eliminating noise from fluctuations of the source-coil current and sensor gain. The coil unit moves toward and away from the patient at 1 Hz, canceling drifts due to thermal expansion of the coils. Measurements on a water phantom indicated instrumental errors less than 30 µg of iron per gram of wet liver tissue, which is small compared with other errors due to the response of the patient's body. Liver-iron measurements on eight thalassemia patients yielded a correlation coefficient r = 0.98 between the room-temperature susceptometer and an existing SQUID. These results indicate that the fundamental accuracy limits of the room-temperature susceptometer are similar to those of the SQUID.

Preliminary Results of Full Body Iron Overload Measurement by a Magnetic Susceptometer.

Accurate assessment of body-iron accumulation is essential for managing therapy of iron-chelating diseases characterized by iron overload such as thalassemia, hereditary hemochromatosis, myelodysplasia and other forms of severe anemia. At present, the gold standard to determine liver-iron concentration (LIC) is liver needle biopsy. In this work, we present an alternative non-invasive technique to measure LIC based on a room-temperature susceptometer. SQUID biosusceptometers and MRI are currently the only validated non-invasive methods for LIC measurements. However, SQUIDs are liquid helium-cooled superconducting devices, therefore costly and resource intensive. Furthermore, SQUIDs are only sensitive to a fraction of the liver volume because of their magnetic configuration. MRI requires large magnets with dedicated software and hardware, trained operators, and is accurate only at low iron concentration. The susceptometer presented herein measures iron overload in the whole liver, as the entire human torso fits within its region of sensitivity. Since all of its components operate at room temperature, this susceptometer is more affordable then competing techniques and can reach a wider hospital base. The study was approved by the local Ethics Committee and all subjects gave informed consent. Since February 2005, 40 patients (30 thalassemia major or intermedia, 5 hereditary hemochromatosis, 5 other severe anemia) and 68 healthy volunteers have been measured. The signal picked up by the susceptometer has two sources: an overall magnetic background of the torso and an eventual contribution from liver iron excess. After measuring the magnetic signature of a patient, statistical analysis methods and neural-network simulations (trained using the control data) are employed to estimate the background signal, given the patient anthropometric data. Liver-iron overload is then determined by subtraction of the estimated background from the total measured signal. The refinement of the methodology is in progress and, at present, the error in liver iron is about 1g (SD), corresponding to typical concentrations of 0.5 mg/cm^3. A correlation study between iron overload and blood serum-ferritin concentration in the patient population attained a correlation coefficient R~0.73. Comparison with measurements of LIC via SQUID susceptometry on a subset of 30 patients participating in the present study (carried out by Dr. A. Piga at Ospedale S. Anna, Torino, Italy) yields a correlation coefficient R~0.77. Four patients (3 thalassemia major, 1 hereditary hemochromatosis) under intensive iron depletive therapy have been measured at least twice; our estimate of liver iron reduction is compatible with the clinical data (R~0.76). Comparison with LIC measured via biopsy is in progress. All comparison were blinded. These preliminary results indicate that possible applications of this non-invasive, full-body susceptometer include monitoring the efficacy of the therapy as well as improving the diagnosis and care management of patients with iron overload. [Display omitted]