Presentation on theme: "USE OF MRI IN EVALUATING LIVER IRON LOADING (AND MONITORING THERAPY)"— Presentation transcript:
1USE OF MRI IN EVALUATING LIVER IRON LOADING (AND MONITORING THERAPY) NOTE: These slides are for use in educational oral presentations only. If any published figures/tables from these slides are to be used for another purpose (e.g. in printed materials), it is the individual’s responsibility to apply for the relevant permission.Specific local use requires local approval
2Outline Introduction to iron and liver iron overload Key methods for assessing liver ironliver biopsySFSQUIDliver MRISIR methodrelaxometry methods (R2 and R2*)Clinical recommendations for measuring LICSummaryLIC = liver iron concentration; MRI = magnetic resonance imaging;SF = serum ferritin; SIR = signal intensity ratio;SQUID = superconducting quantum interface device.
4Iron overloadIron overload is common in patients who require intermittent or regular blood transfusions to treat anaemia and associated conditionsit may be exacerbated in some conditions by excess gastrointestinal absorption of ironIron overload can lead to considerable morbidity and mortality1Excess iron is deposited in major organs, resulting in organ damagethe organs that are at risk of damage due to iron overload include the liver, heart, pancreas, thyroid, pituitary gland, and other endocrine organs2,31Ladis V, et al. Ann NY Acad Sci. 2005;1054: Gabutti V, Piga A. Acta Haematol. 1996;95: Olivieri NF. N Engl J Med. 1999;341:
5Importance of analysing liver iron A patient’s LIC is the best measure of total body iron storesKnowing the liver iron concentration helps to predict the risk of hepatic and extra-hepatic complications1–41Batts KP. Mod Pathol. 2007;20:S Jensen PD, et al. Blood. 2003;101: Angelucci E, et al. Blood. 2002;100: Telfer PT, et al. Br J Haematol. 2000;110:971-7.
6Importance of analysing liver iron (cont.) 510152025Mean LIC + SD over previous year prior to enrolment in EPIC trial (mg Fe/g dry wt)LIC threshold of 7 mg Fe/g dry wtAll (n = 1,744)TM (n = 937)TI (n = 84)SCD (n = 80)All transfusion-dependent patients prior to study enrolment had moderate-to-severe hepatic iron loadingCappellini MD, et al. Blood. 2008;112:[abstract 3880].
7Overview of LIC correlations with other measurements Hepatocellularinjury2 andfibrosis3Body ironstores1Cardiaciron5DFS4DFS = disease-free survival.1Angelucci E, et al. N Engl J Med. 2000;343: Jensen PD, et al. Blood. 2003;101: Angelucci E, et al. Blood. 2002;100: Telfer PT, et al. Br J Haematol. 2000;110: Noetzli LJ, et al. Blood. 2008;112:
8LIC prediction of total body iron stores Hereditary haemochromatosis1β-TM2Sample > 1 mg dry wt (n = 25)50,00040,00030,00020,00010,00051015202530025020015010050r = 0.98LIC (µg/g)Body iron stores (mg/kg)510152025Iron removed (g)LIC (mg Fe/g dry wt)LIC is a reliable measure of total body iron stores in hereditary haemochromatosis and β-TMBMT = bone marrow transplantation.1Olynyk JK, et al. Am J Gastroenterol. 1998;93: Angelucci E, et al. N Engl J Med. 2000;343:1. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343:
9Serum ferritin measurement alone underestimates the body iron load -TM2,0004,0006,0008,00010,00012,00014,0001,0002,0003,0004,0005,0006,0007,0008,0009,00010,000-TI-TMSF (g/L)SF (g/L)51015202530355101520253035404550LIC (mg Fe/g dry wt)LIC (mg Fe/g dry wt)SF has almost no sensitivity or specificity for iron stores in thalassaemia intermediaOriga R, et al. Haematologica. 2007;92:583-8.Taher A, et al. Haematologica. 2008;93:
11Key methods for assessing liver iron Liver biopsy LICadvantages and disadvantagescorrelation of LIC with other measurementsSF concentration over timecorrelation of SF levels with other measurementsSQUIDLiver MRIrelaxometry methods (T2 and T2*)SIR methodDirect methodIndirect methodsOlivieri NF, Brittenham GM. Blood. 1997;89:
13Technique for taking a percutaneous liver biopsy Patient preparation: Blood tests are done shortly before the biopsy to check blood clotting time, to exclude risk of bleeding following the biopsy. The biopsy is commonly preceded by an ultrasound examination of the liver to determine the best and safest biopsy siteLiver biopsyA tiny incision is made between the ribs, and a needle is inserted to reach the area of the liver where a tissue sample is taken. The procedure requires local anaesthesiaStep 1. The patient lies on his back, or his left sideArea where a tissue sample is taken fromStep 2. The place for the biopsy is cleaned with antiseptic and local anaesthesia is provided (s.c. on the right hand side)Step 3. A special hollow needle is inserted into the liver, usually between the 2 lower ribs on the right hand sideStep 4. The patient must hold breath for 5-10 seconds when the needle is quickly pushed in and out. As the needle comes out it brings with it a small sample of liver tissueOverall: The procedure is carried out by a qualified physician or surgeon in an outpatient care centre or hospital. It is fast (not longer than 5 min) and the patient is discharged shortly afteradam.com
14Processing the liver biopsy sample Gross histopathological examinationreveals presence of abnormal cells or liver tissueused to determine presence and degree of cirrhosis and fibrosisLIC measurementby iron stainingby atomic absorption spectroscopy: the current gold standard!Who does the test?preparation of the samples might be by a trained technicianthe analysis requires a qualified pathologistAngelucci E, et al. Haematologica. 2008;93:Image from:
15LIC threshold (mol Fe/g dry wt) Liver biopsyLiver biopsy with iron measurement by atomic absorption spectroscopy is the gold standard for measuring LIC1LIC threshold (mg Fe/g dry wt)2LIC threshold (mol Fe/g dry wt)Clinical relevance1.832Upper 95% of normal 15.0269Greatly increased risk of cardiac disease and early death1Angelucci E, et al. Haematologica. 2008;93: St Pierre TG, et al. Blood. 2005;105:
16Liver biopsy: pros and cons Direct measurement of LICValidated reference standardQuantitative, specific, and sensitiveAllows for measurement of non-haem storage ironProvides information on liver histology/pathologyCorrelates with morbidity and mortalityInvasive and painful procedure with risk of potentially serious complications1May involve sampling errors, especially in patients with cirrhosis1Requires skilled physicians1Laboratory techniques not standardized1iron measurement by atomic absorption spectroscopy2 or chemical determination3wet or dry weight quotediron concentration varies throughout the liver,4 sample size often insufficient (requires ≥ 1 mg dry weight, or > 4 mg wet weight)1TIF. Guidelines for the Clinical Management of Thalassemia. 2nd rev. ed. Cyprus: TIF; Available from:Accessed December Angelucci E, et al. Haematologica. 2008;93: Wood JC. Blood Rev. 2008;22 Suppl 2:S Ambu R, et al. J Hepatol. 1995;23:544-9.
17Heterogeneity of iron concentration throughout the liver 0–20%20–40%40–60%60–80%80–100%Iron is unevenly distributed in the liver; therefore, a small sample may not give an absolutely representative mean LICFrom autopsy of a patient with beta-zero-thalassaemia.Ambu R, et al. J Hepatol. 1995;23:544-9.
19SF > 1,000 µg/L is a marker of excess body iron Ferritin and SFFerritin is primarily an intracellular protein thatstores iron in a form readily accessible to cellsreleases iron in a controlled fashionThe molecule is shaped like a hollow sphere and it stores ferric (Fe3+) iron in its central cavitythe storage capacity of ferritin is approximately 4,500 Fe3+ ions per moleculeFerritin is found in all tissues, though primarily in the liver, spleen, and bone marrowA small amount is also found in the blood as serum ferritinSF > 1,000 µg/L is a marker of excess body ironHarrison PM, Arosio P. Biochim Biophys Acta. 1996;1275:
20SF: pros and cons SF levels from a blood sample are measured Pros Cons Easy to assessInexpensivePositive correlation with morbidity and mortalityAllows longitudinal follow-up of patientsIndirect measurement of iron burdenFluctuates in response to inflammation, abnormal liver function, ascorbate deficienciesTIF. Guidelines for the Clinical Management of Thalassaemia. 2nd rev. ed. Cyprus: TIF; Available from:Accessed December 2010.
22SQUID: superconducting quantum interference device Principle of the technique: Normal tissue is diamagnetic and has a magnetic susceptibility similar to that of water. In the presence of iron, tissue susceptibility is changed proportional to the amount of iron present. This alteration is detected, allowing non-invasive measurement of LICMagnetizing coilDewarLiquid heliumSQUIDPick to coilWater bagPatientMattressBedPistonH2OPatient preparation: No special patient preparation is required. Ultrasound is used to evaluate the depth and size of the liver. The patient lies on their back with their torso surrounded by a 5-L water bag to minimize contributions from other tissuesStep 1. The susceptometer applies a low-power (114 T and 7.7 Hz) homogeneous magnetizing field in the hepatic region. Sensitive detectors measure the interference of tissue iron vs the water reference medium within the fieldStep 2. LIC corresponds to the variation of magnetization detected and is calculated using custom-made Matlab 6.5 softwareOverall: The procedure is carried out by a qualified radiologist in a hospital. It is fast (not longer than 5 min) and the patient is discharged immediately after. Processing could be done on the spot and is faster then LIC histopathological examinationCarneiro AA, et al. Reson Med. 2005;43:122-8.
23Hepatic iron (magnetic) (mol Fe/g wet wt) SQUID: pros and consProsConsNon-invasive1Wide linear range1Good correlation with LIC by biopsy2Requires expensive, specialized equipment and expertise1Not widely available1Each machine should be individually calibrated1SQUID can underestimate LIC325020015010050Hepatic iron (magnetic) (mol Fe/g wet wt)Hepatic iron (biopsy)(mol Fe/g wet wt)R = 0.99p < 0.001SQUID is a non-invasive method that has been calibrated, validated, and used in clinical studies, but the complexity, cost and technical demands limit its use1TIF. Guidelines for the Clinical Management of Thalassaemia. 2nd rev. ed. Cyprus: TIF; Available from:Accessed December Sheth S. Pediatr Radiol. 2003;33: Piga A, et al. Blood. 2005;106:[abstract 2689].
25MRIPrinciple of the technique: A strong magnetic field is used to organize the protons in the tissue in 1 direction. Then radiofrequency is used to “knock” them off. The time for them to re-align with the magnetic field and the energy they release during the process depend on the interactions of the proton with other ions, notably iron ions. These events could be measured at various TEs and then analysed to reveal the iron content in the tissueMain magnet coilsx,y,z gradient coilsPatient preparation: All infusion and medication pumps should be removed. The scan does not require contrast agent, and so no peripheral vein access is neededIntegral radiofrequency transmitter (body) coilStep 1. Image acquisition: Images are taken at various TEsPatient tableStep 2. Post-processing: As TE increases, the image’s SI decreases. The relationship between TE and SI in a selected part of the image (i.e. ROI) is analysed with specialized software or manually. Data are reported as relaxation times (T2 or T2*), depending on the acquisition methodT1 - LONGITUDINAL RELAXATION TIME - determines the rate at which excited protons return to equilibrium within the lattice. A measure of the time taken for spinning protons to re-align with the external magnetic field. The magnetization will grow after excitation from zero to a value of about 63% of its final value in a time of T1.T2 - spin-spin or transverse relaxation time. The time constant for loss of phase coherence among spins oriented at an angle to the static magnetic field due to interactions between the spins. Results in a loss of transverse magnetization and the MRI signal.T2* ("T-two-star") - the time constant for loss of phase coherence among spins oriented at an angle to the static magnetic field due to a combination of magnetic field inhomogeneities and the spin-spin relaxation. Results in a rapid loss of transverse magnetization and the MRI signal.T2* < T2.TE (Echo Time) - represents the time in milliseconds between the application of the 90° pulse and the peak of the echo signal in Spin Echo and Inversion Recovery pulse sequences.Main magnet coilsOverall: The procedure is carried out by a qualified radiologist in a hospital. Acquisition is fast (approx. 5 min), and the patient is discharged immediately after. Processing may require specialized software and is done afterwardsROI = region of interest; SI = signal intensity; TE = echo time.Brittenham GM, Badman DG. Blood. 2003;101:15-9. Ridgway JP. J Cardiovasc Magn Reson. 2010;12:71.
26MRI is increasingly being used as a non-invasive method to measure LIC ProsConsNon-invasive1,2Assesses iron content throughout the liver2Increasingly and widely available worldwide2Pathological status of liver and heart can be assessed in parallel2Validated relationship with biopsy LIC3‒6Indirect measurement of LIC2Requires MRI with dedicated imaging method2Sensitivity depends on type of scanner, degree of iron overload, presence of fibrosis, and inflammation71Chavhan GB, et al. Radiographics. 2009;29: TIF. Guidelines for the Clinical Management of Thalassaemia. 2nd rev. ed. Cyprus: TIF; Available from: revised_edition_EN.pdf. Accessed December Christoforidis A, et al. Eur J Haematol. 2009;82: St Pierre TG, et al. Blood. 2005;105: Wood JC, et al. Blood. 2005;106: Hankins JS, et al. Blood. 2009;113: Sirlin CB, Reeder SB. Magn Reson Imaging Clin N Am. 2010;18:
27MRI scanners Manufacturers Siemens Healthcare (Erlangen, Germany;GE Healthcare (Milwaukee, WI, USA;Philips Healthcare (Best, the Netherlands;Magnetic field strengthmost imaging is done on 1.5 T machines3 T machines givebetter signal:noise ratio1worse susceptibility artefacts1The upper detection limit is halved, therefore it is too low for many patients1lower T2 and T2* values than 1.5 T machines2Liver package (including standard sequences and analysis of the data) is included in the software provided together with the MRI machinespecialized LIC analysis software can be bought separately1Wood JC, Ghugre N. Hemoglobin. 2008;32: Storey P, et al. J Magn Reson Imaging. 2007;25:540-7.
28Overview of MRI techniques used to measure LIC DATA ACQUISITIONDATA ANALYSISMAJOR PROS AND CONSA combination ofgradient and spinechosFree websiteFast acquisition Simple data analysisLimited sensitivity ReproducibilityGradient echo (same technique as cardiac iron measurement) (1 min)Manually (free xls sheet) or with dedicated software (e.g CMR tool 3,000 GBP per year)Fast acquisition Correlates well with LICSusceptible to artefacts Training needsSpin echo (15min)Done centrally by Resonance Health (300 USD per scan)Gold Standard Little training needLonger data acquisition time Cost of analysisSignal Intensity Ratio (SIR) method (Gandon/Ernst)Liver MRI TechniqueR2*(T2*)Relaxometry methodR2(T2)(Ferriscan®)
29MRI measurement of LIC: techniques There are 2 broad groups of techniquesSIR methods (Gandon et al. methods)relaxometry methods (FerriScan® and T2* (R2*) methods)ProsConsSIRmethodFast data acquisitionRelatively simple algorithms and data analysisCan be used in scanners with different magnetic strengths (0.5, 1.0, 1.5 T)Limited range of sensitivity (upper limit is 21 mg Fe/g dry wt [380 mol/L])Assumptions on reference tissueNot reliable in cirrhosisSmaller reproducibilityRelaxometry methodGreater range of sensitivityDoes not rely on reference tissue assumptionsT2* (or R2*) is very quick (requires a single breath-hold)Has only been calibrated at 1.5 TTakes longer to acquire data, when done as T2 (or R2)Argyropoulou MI, Astrakas L. Pediatr Radiol. 2007;37: Gandon Y, et al. Lancet. 2004;363: St Pierre TG, et al. Ann N Y Acad Sci. 2005;1054: Wood JC. Curr Opin Hematol. 2007;14: Wood JC, et al. Blood. 2005;106:
30(depends on experience) SIR methods1. Patient preparation(5 min)2. Image acquisition(approx min)3. Data analysis(depends on experience)Most common protocol includes4-gradient echo sequences with different TEs1 spin-echo sequence100300400200Study groupValidation groupMRI LIC (µmol Fe/g dry wt)100200400300Biopsy LIC (µmol Fe/g dry wt)Gandon Y, et al. Lancet. 2004;363:
31SIR methods (cont.)1. Patient preparation(5 min)2. Image acquisition(approx min)3. Data analysis(relatively fast)The ROI is selected in the liver and the reference tissue (muscle or fat), in each imageThe SI of the liver region is divided by that of the reference tissueA calculation algorithm to assist has been developed for 0.5, 1.0, and 1.5 T MRI machines11Gandon Y. Available from: Accessed December 2010.
32Relaxometry methods: T2, T2*, T2′, R2, and R2* If a spin-echo sequence is used, the relaxation time is T2If a gradient-echo sequence is used, it is T2*These are related by the equation11/T2* = 1/T2 + 1/T2′T2′ is the magnetic field inhomogeneity of the tissueTo attain a positive linear relationship with HICT2* can be transformed into reciprocal R2*: R2* [Hz] = 1,000/T2* [ms]T2 can be transformed into reciprocal R2: R2 [Hz] = 1,000/T2 [ms]1Anderson LJ, et al. Eur Heart J. 2001;22: Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.
33Relaxometry methods: R2 and R2* Several pulse sequences are included in the MRI software packageParametersR2 (for FerriScan®) spin echo sequenceT2* (and R2*) gradient echo sequenceFOV (mm)300 x 225350 x 300Matrix (lines)256 x 176128 x 80Resolution (mm)1.17 x 1.28 x 5.02.73 x 3.75 x 10.0TR (ms)2500200TE (ms)6, 9, 12, 15, 18Minimum possible (ideally < 2.0 ms)NEX (n)1Flip angle (°)9020BW (Hz/px)3001,950Segments (n)–8FatSatOnWood JC, Ghugre N. Hemoglobin. 2008;32:85-96.
34Correlation between R2-estimated LIC and LIC by biopsy R2-LIC calibration curve by Wood et alR2-LIC calibration curve by St Pierre et al30025020015010050350300250200R2 (Hz)Mean R2 (Hz)150-thalassaemia/Hb E100LIC by biopsy, R = 0.98-thalassaemiaHepatitisLinear fit using biopsy data50Hereditary haemochromatosisControls, LIC by norms alone10203040506010203040Biopsy LIC (mg Fe/g dry wt)Biopsy LIC (mg Fe/g dry wt)1Wood JC, et al. Blood. 2005;106: St Pierre TG, et al. Blood. 2005;105:
35Correlation between R2*-estimated LIC and LIC by biopsy R2*-LIC calibration curve by Wood et al.1R2*-LIC calibration curve by Hankins et al.2PatientsControlsFit2004006008001,0001,2001,4001,6001,8002,00030252015105Correlation coefficient = 0.98p < 0.001R2* (Hz)LIC (mg Fe/g dry wt)R = 0.971020304050602004006008001000Biopsy LIC (mg Fe/g dry wt)R2*MRI (Hz)1Wood JC, et al. Blood. 2005;106: Hankins JS, et al. Blood. 2009;113:
36LIC estimated with R2 and R2* MRI correlate well with each other 1020304050Estimated HIC (mg/dry) by R2-SPPatient dataLinear fit, R=0.94Estimated HIC (mg/dry) by R2*Wood JC, et al. Blood. 2005;106:
37Gradient relaxometry (T2. , R2 Gradient relaxometry (T2*, R2*) can conveniently measure cardiac and liver ironCardiac MRILiver MRI302468101214Hankins, et al.2520Wood, et al.HIC (mg Fe/g of dry weight liver)15[Fe] (mg/g dry wt)10Anderson, et al.R2 =51002003004002004006008001000Cardiac R2* (Hz)Liver R2* (Hz)Cardiac and liver iron can be assessed together conveniently by gradient echo during a single MRI measurement.HIC = hepatic iron concentrationCarpenter JP, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:P224. Hankins et al Blood. 2009;113:
38Relaxometry methods: pros and cons Correlate well to biopsy LIC1–4Greater sensitivity to iron deposits5Faster (images can be obtained in a single breath-hold) and easier6Can perform cardiac and liver iron assessment at the same timeMore susceptible to artefactsRequires expert training of a technician/ radiologist for data acquisition and data analysisR2 (Ferriscan®)Less affected by susceptibility artefacts6Highly sensitive and specific over a large range of LIC, including patients with severe haemosiderosis7The gold standard method in clinical trialsRequires no training for data analysis (done centralized by Resonance Health)Multiple breath-holds required which increases MRI timeCost of analysis (300 USD per scan)1Christoforidis A, et al. Eur J Haematol. 2009;82: St Pierre TG, et al. Blood. 2005;105: Wood JC, et al. Blood. 2005;106: Hankins JS, et al. Blood. 2009;113: Anderson LJ, et al. Eur Heart J. 2001;22: Wood JC, Ghugre N. Hemoglobin. 2008;32: Papakonstantinou, O, et al. J Magn Reson Imaging. 2009;29:853-9.
39Relaxometry methods: R2 and R2* (cont.) 1. Patient preparation(5 min)2. Image acquisition(approx min)3. Data analysis(depends on experience)Correct position is important so that the LIC across the whole liver can be measuredImages are taken at various TEsRed line indicates correct position of the slice
40Liver R2* MRI Liver with normal iron levels TE=1.3msTE=3.6msTE=7.1msT2* = 15.7 ms or R2* = 63.7 Hz or LIC = 1.3mg/gLiver with severe iron overloadTE=1.3msTE=3.6msTE=7.1msT2* = 1.1 ms or R2* = 909 Hz or LIC = 25.0 mg/gImages courtesy of Dr J. de Lara Fernandes.
41FAQ: artefacts How frequent are artefacts in liver MRI? In contrast to cardiac MRI, the risk for motion artefacts (e.g. due to breathing) or susceptibility artefacts is much lower when performing liver MRI. As in cardiac MRI, if artefacts are present and too severe, scans may have to be repeatedHow can I avoid artefacts when assessing LIC by MRI?When assessing LIC, one thing that is really important is to use fat saturation (usually automatically included in all the sequences). This is especially important if a patient has steatosis (e.g. adults with haemochromatosis)Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.
42Relaxometry methods: R2 and R2* (cont.) 1. Patient preparation(5 min)2. Image acquisition(approx min)3. Data analysis(depends on experience)Determine ROIentire liver boundary, excluding obvious hilar vessels1Slice thicknessvaries, generally 5–15 mm1–4Number of slicesanything from about 1 to 20 slices can be studied1–4Red outline shows position of ROI1Wood JC, et al. Blood. 2005;106: St Pierre TG, et al. Blood. 2005;105:3Papakonstantinou O, et al. J Magn Reson Imaging. 2009;29: Hankins JS, et al. Blood. 2009;113:
43Relaxometry methods: R2 and R2* (cont.) 1. Patient preparation(5 min)2. Image acquisition(approx min)3. Data analysis(depends on experience)As TE increases, SI should decreaseWhen plotted on a graphas iron load increases, the curve gets steeperT2 or T2* can be calculated from the curveR2 and R2* can also be calculatedCalculations are donemanually, orby specific licensed software (e.g. CMRtools®), orimages could be directly sent to a validated centre performing FerriScan® for analysis1008060402015510SITE (ms)Typical non-iron-loaded tissueIncreasing iron loading
44Analysis of the dataThe data can be analysed manually or using post-processing softwareManuallyPost-processing softwareExcel spreadsheetThalassaemiaTools (CMRtools)cmr42FerriScanMRmapMATLAB
45Analysis of the data (cont.) MethodProsConsExcel spreadsheetLow costTime-consumingTediousThalassaemiaTools (CMRtools)1Fast (1 min)2Easy to useFDA approvedGBP 3,000 per yearcmr42(3)FDA approved3Can generate T2*/R2* and T2/R2 maps with same softwareAllows different forms of analysisGenerates pixel-wise fitting with colour maps40,000 USD first year costs12,000 USD per year afterFDA = Food and Drug Administration.1www.cmrtools.com/cmrweb/ThalassaemiaToolsIntroduction.htm. Accessed Dec 2010.2Pennell DJ. JACC Cardiovasc Imaging. 2008;1:3www.circlecvi.com. Accessed Dec 2010.
46Analysis of the data (cont.) MethodProsConsFerriScan1Centralized analysis of locally acquired data (206 active sites across 25 countries)Easy set-up on most MRI machinesEU approvedValidated on GE, Philips, and Siemens scannersUSD 300 per scanPatients data are sent to reference centreMRmap2Uses IDL runtime, which is a commercial software (less expensive than cmr42/CMRtools)Can quantify T1 and T2 map with the same softwarePurely a research toolNot intended for diagnostic or clinical useMATLAB3Low costAvailable only locallyPhysicists or engineers need to write a MATLAB program for display and T2* measurement1www.resonancehealth.com/resonance/ferriscan. Accessed Dec 2010.2www.cmr-berlin.org/forschung/mrmapengl/index.html. Accessed Dec 2010.3Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202:173-9.
47FAQ: mistakes in manual analysis of liver MRI data What is truncation?After the selection of the ROI, the signal decay can be fitted using different models. In the truncation model, the late points in the curve (the plateau) are subjectively discarded to obtain a curve with an R2 > A new single exponential curve is made by fitting the remaining signals.What is the most frequent mistake made when interpreting the data from an MRI scan?Interpreting a liver MRI is more challenging than for a cardiac MRI, especially in patients with severe liver iron overload. Correcting the data using truncation analysis is very important (done automatically by some software). The example (see following slide) clearly shows what happens, if the truncation is not done correctlyQuestions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.
48FAQ: mistakes in manual analysis of liver MRI data (cont.) Analysis without truncation of the dataAnalysis with truncation of the dataNon-truncated analysis with results with a poor R2 (< 0.995). The apparent LIC of 4.65 suggests mild LICs. Observe the flat plateau of the data points after a TE of 3.62 msThe same patient, but analysing the data with only the 3 first data points results in a better (although not perfect) R2. The LIC results in severe iron overload, reflecting the real concentrations of iron
49FAQ: how to start measuring liver iron loading? How to start measuring liver iron loading in a hospital? What steps need to be taken?To start assessing liver iron loading by MRI, these steps can be followedCheck MRI machine requirements0.5–1.5 T (1.5 T is highly recommended for T2* and T2 calculations; 0.5 T only for SIR)calibratedincludes a liver packageOptional: buy software for analysing the data (otherwise, Excel spreadsheet can be used)Optional: training of personnel for acquiring MRI imagesOptional: training of personnel on how to analyse the dataQuestions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.
50LIC: interpretation of results LIC threshold values for classification of iron overloadIron levelsLIC (mg Fe per g dry weight)LIC (µmol Fe per g dry wt)R2 (s−1)†R2* (s−1)T2* (ms)Normal< 2< 35.6< 50< 88> 11.4Mild overload≥ 2−7≥ 35.6 − 125.0≥ 50 – 100≥ 88 – 263> 3.8 – 11.4Moderate overload≥ 7−15≥ 125 − 269≥ 100 – 155≥ 263 – 555> 1.8 – 3.8Severe overload≥ 15≥ 269≥ 155≥ 555≤ 1.8†Values estimated based on R2 LIC calibration curve; R2, R2* and T2* values valid for MRI machines with 1.5T only.St Pierre TG, et al. Blood 2005;105:855–861; Wood JC, et al. Blood 2005;106:1460–1465.
51Implementation of liver and cardiac MRI 1.5T MRI ScannerUS$Yes½ day trainingLiverAnalysisExperienced radiologistNo1 day trainingPost-processing analysisUS$ or US$4.000/yor in-house or outsourceCardiac acquisition packageUS$50.000Yes1-2 day trainingHeartAnalysisRoutine cardiac MR examsNo4 day trainingSlide presented at Global Iron Summit With the permission of Juliano de Lara Fernandes
53SummaryIron overload is a serious problem among patients who require blood transfusions to treat anaemia and associated conditionsAnalysing liver iron overload is importantto predict risk of hepatic and extra-hepatic complicationsThe extent of iron accumulation in the liver is a key prognostic indicator for morbidity and mortalityMRI has the added advantage that iron levels throughout the liver can be analysed, rather than just the biopsied section (iron levels throughout the liver can vary)R2 is the most commonly used technique in clinical practice, although R2* is a comparable alternative across most ranges of iron overload and is faster
58GLOSSARY LIC = liver iron concentration LVEF = left-ventricular ejection fractionMCA = middle cerebral arteryMDS = Myelodysplastic syndromesMDS-U = myelodysplastic syndrome, unclassifiedMRA = magnetic resonance angiographyMRI = magnetic resonance imagingMV = mean velocity.N = neutropeniaNEX = number of excitationsNIH = National Institute of HealthOS = overall survival
59GLOSSARY pB = peripheral blood PI = pulsatility index PSV = peak systolic VelocityRA =refractory anemiaRAEB = refractory anemia with excess blastsRAEB -T = refractory anemia with excess blasts in transformationRARS = refractory anemia with ringed sideroblastsRBC = red blood cellsRF = radio-frequencyRCMD = refractory cytopenia with multilineage dysplasiaRCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblastsRCUD = refractory cytopenia with unilineage dysplasia
60GLOSSARY RN = refractory neutropenia ROI = region of interest RT = refractory thrombocytopeniaSCD = sickle cell diseaseSD = standard deviationSI = signal intensitySIR = signal intensity ratioSF = serum ferritinSNP-a = single-nucleotide polymorphismSQUID = superconducting quantum interface device.STOP = = Stroke Prevention Trial in Sickle Cell AnemiaSTOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia
61GLOSSARY T = thrombocytopenia TAMMV = time-averaged mean of the maximum velocity.TCCS = transcranial colour-coded sonographyTCD = transcranial doppler ultrasonographyTCDI = duplex (imaging TCD)TE = echo timeTR = repetition timeWHO = World Health OrganizationWPSS = WHO classification-based Prognostic Scoring System