USE OF MRI IN EVALUATING LIVER IRON LOADING (AND MONITORING THERAPY) G-EXJ-1030713 May 2012 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 Outline ● Introduction to iron and liver iron overload ● Key methods for assessing liver iron – liver biopsy – SF – SQUID – liver MRI • SIR method • relaxometry methods (R2 and R2*) ● Clinical recommendations for measuring LIC ● Summary 2 G-EXJ-1030713 May 2012 LIC = liver iron concentration; MRI = magnetic resonance imaging; SF = serum ferritin; SIR = signal intensity ratio; SQUID = superconducting quantum interface device. Introduction to iron and iron overload G-EXJ-1030713 May 2012 Iron overload ● Iron overload is common in patients who require intermittent or regular blood transfusions to treat anaemia and associated conditions – it may be exacerbated in some conditions by excess gastrointestinal absorption of iron ● Iron overload can lead to considerable morbidity and mortality1 ● Excess iron is deposited in major organs, resulting in organ damage – the organs that are at risk of damage due to iron overload include the liver, heart, pancreas, thyroid, pituitary gland, and other endocrine organs2,3 4 G-EXJ-1030713 May 2012 1Ladis V, et al. Ann NY Acad Sci. 2005;1054:445-50. 2Gabutti V, Piga A. Acta Haematol. 1996;95:26-36. 3Olivieri NF. N Engl J Med. 1999;341:99-100. Importance of analysing liver iron ● A patient’s LIC is the best measure of total body iron stores ● Knowing the liver iron concentration helps to predict the risk of hepatic and extra-hepatic complications1–4 5 G-EXJ-1030713 May 2012 1Batts KP. Mod Pathol. 2007;20:S31-9. 2Jensen PD, et al. Blood. 2003;101:91-6. 3Angelucci E, et al. Blood. 2002;100:17-21. 4Telfer PT, et al. Br J Haematol. 2000;110:971-7. Mean LIC + SD over previous year prior to enrolment in EPIC trial (mg Fe/g dry wt) Importance of analysing liver iron (cont.) 25 20 15 10 LIC threshold of 7 mg Fe/g dry wt 5 0 All (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 loading 6 G-EXJ-1030713 May 2012 Cappellini MD, et al. Blood. 2008;112:[abstract 3880]. Overview of LIC correlations with other measurements Body iron stores1 LIC Cardiac iron5 7 G-EXJ-1030713 May 2012 Hepatocellular injury2 and fibrosis3 Cardiac DFS4 DFS = disease-free survival. 1Angelucci E, et al. N Engl J Med. 2000;343:327-31. 2Jensen PD, et al. Blood. 2003;101:91-6. 3Angelucci E, et al. Blood. 2002;100:17-21. 4Telfer PT, et al. Br J Haematol. 2000;110:971-7. 5Noetzli LJ, et al. Blood. 2008;112:2973-8. LIC prediction of total body iron stores β-TM2 Hereditary haemochromatosis1 Sample > 1 mg dry wt (n = 25) Body iron stores (mg/kg) 50,000 LIC (µg/g) 40,000 30,000 20,000 10,000 0 0 5 10 15 Iron removed (g) 20 25 300 250 200 r = 0.98 150 100 50 0 0 5 10 20 LIC (mg Fe/g dry wt) LIC is a reliable measure of total body iron stores in hereditary haemochromatosis and β-TM 8 G-EXJ-1030713 May 2012 15 BMT = bone marrow transplantation. 1Olynyk JK, et al. Am J Gastroenterol. 1998;93:346-50. 2Angelucci E, et al. N Engl J Med. 2000;343:327-31. 25 Serum ferritin measurement alone underestimates the body iron load 10,000 14,000 -TI -TM 12,000 9,000 8,000 7,000 SF (g/L) SF (g/L) 10,000 8,000 6,000 6,000 5,000 4,000 3,000 4,000 2,000 2,000 0 -TI -TM 1,000 0 5 10 15 20 25 30 35 LIC (mg Fe/g dry wt) 0 0 5 10 15 20 25 30 35 40 45 50 LIC (mg Fe/g dry wt) SF has almost no sensitivity or specificity for iron stores in thalassaemia intermedia 9 G-EXJ-1030713 May 2012 Origa R, et al. Haematologica. 2007;92:583-8. Taher A, et al. Haematologica. 2008;93:1584-6. Assessing liver iron overload G-EXJ-1030713 May 2012 Key methods for assessing liver iron ● Liver biopsy LIC – advantages and disadvantages Direct method – correlation of LIC with other measurements ● SF concentration over time – advantages and disadvantages – correlation of SF levels with other measurements ● SQUID – advantages and disadvantages ● Liver MRI – advantages and disadvantages – relaxometry methods (T2 and T2*) – SIR method 11 G-EXJ-1030713 May 2012 Olivieri NF, Brittenham GM. Blood. 1997;89:739-61. Indirect methods Liver biopsy G-EXJ-1030713 May 2012 Technique for taking a percutaneous liver biopsy Liver biopsy A 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 anaesthesia 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 site Step 1. The patient lies on his back, or his left side Area where a tissue sample is taken from Step 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 side Step 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 tissue adam.com 13 G-EXJ-1030713 May 2012 Overall: 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 after Processing the liver biopsy sample ● Gross histopathological examination – reveals presence of abnormal cells or liver tissue – used to determine presence and degree of cirrhosis and fibrosis ● LIC measurement – by iron staining – by atomic absorption spectroscopy: the current gold standard! ● Who does the test? – preparation of the samples might be by a trained technician – the analysis requires a qualified pathologist 14 G-EXJ-1030713 May 2012 Angelucci E, et al. Haematologica. 2008;93:741-52. Image from: www.pathguy.com/lectures/cirrhosis_trichrome.jpg Liver biopsy Liver biopsy with iron measurement by atomic absorption spectroscopy is the gold standard for measuring LIC1 LIC threshold (mg Fe/g dry wt)2 LIC threshold (mol Fe/g dry wt) Clinical relevance 1.8 32 Upper 95% of normal 15.0 269 Greatly increased risk of cardiac disease and early death 15 G-EXJ-1030713 May 2012 1Angelucci E, et al. Haematologica. 2008;93:741-52. 2St Pierre TG, et al. Blood. 2005;105:855-61. Liver biopsy: pros and cons Pros1 Cons ● ● ● ● Direct measurement of LIC Validated reference standard Quantitative, specific, and sensitive Allows for measurement of non-haem storage iron ● Invasive and painful procedure with risk of potentially serious complications1 ● May involve sampling errors, especially in patients with cirrhosis1 ● Requires skilled physicians1 ● Laboratory techniques not standardized1 ● Provides information on liver histology/pathology ● Correlates with morbidity and mortality – iron measurement by atomic absorption spectroscopy2 or chemical determination3 ● wet or dry weight quoted ● iron concentration varies throughout the liver,4 sample size often insufficient (requires ≥ 1 mg dry weight, or > 4 mg wet weight) 16 G-EXJ-1030713 May 2012 1TIF. Guidelines for the Clinical Management of Thalassemia. 2nd rev. ed. Cyprus: TIF; 2008. Available from: www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition_EN.pdf. Accessed December 2010. 2Angelucci E, et al. Haematologica. 2008;93:741-52. 3Wood JC. Blood Rev. 2008;22 Suppl 2:S14-21. 4Ambu R, et al. J Hepatol. 1995;23:544-9. Heterogeneity 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 LIC 17 G-EXJ-1030713 May 2012 From autopsy of a patient with beta-zero-thalassaemia. Ambu R, et al. J Hepatol. 1995;23:544-9. SF Concentration G-EXJ-1030713 May 2012 Ferritin and SF ● ● Ferritin is primarily an intracellular protein that – stores iron in a form readily accessible to cells – releases iron in a controlled fashion The molecule is shaped like a hollow sphere and it stores ferric (Fe3+) iron in its central cavity – SF > 1,000 µg/L is a marker of excess body iron 19 G-EXJ-1030713 May 2012 the storage capacity of ferritin is approximately 4,500 Fe3+ ions per molecule ● Ferritin is found in all tissues, though primarily in the liver, spleen, and bone marrow ● A small amount is also found in the blood as serum ferritin Harrison PM, Arosio P. Biochim Biophys Acta. 1996;1275:161-203. SF: pros and cons ● SF levels from a blood sample are measured Pros Cons ● Easy to assess ● Inexpensive ● Positive correlation with morbidity and mortality ● Allows longitudinal follow-up of patients ● Indirect measurement of iron burden ● Fluctuates in response to inflammation, abnormal liver function, ascorbate deficiencies 20 G-EXJ-1030713 May 2012 TIF. Guidelines for the Clinical Management of Thalassaemia. 2nd rev. ed. Cyprus: TIF; 2008. Available from: www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition_EN.pdf. Accessed December 2010. SQUID G-EXJ-1030713 May 2012 SQUID: 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 LIC Magnetizing coil Dewar Patient 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 tissues Step 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 field Step 2. LIC corresponds to the variation of magnetization detected and is calculated using custom-made Matlab 6.5 software Overall: 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 examination 22 G-EXJ-1030713 May 2012 Carneiro AA, et al. Reson Med. 2005;43:122-8. Liquid helium H2O SQUID Pick to coil Water bag Patient Mattress Bed Piston SQUID: pros and cons Pros Cons ● Non-invasive1 ● Wide linear range1 ● Good correlation with LIC by biopsy2 ● Requires expensive, specialized equipment and expertise1 ● Not widely available1 ● Each machine should be individually calibrated1 ● SQUID can underestimate LIC3 Hepatic iron (biopsy) (mol Fe/g wet wt) 250 R = 0.99 p < 0.001 200 150 100 50 0 0 50 100 150 200 250 Hepatic iron (magnetic) (mol Fe/g wet wt) SQUID is a non-invasive method that has been calibrated, validated, and used in clinical studies, but the complexity, cost and technical demands limit its use 23 G-EXJ-1030713 May 2012 1TIF. Guidelines for the Clinical Management of Thalassaemia. 2nd rev. ed. Cyprus: TIF; 2008. Available from: www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition_EN.pdf. Accessed December 2010. 2Sheth S. Pediatr Radiol. 2003;33:373-7. 3Piga A, et al. Blood. 2005;106:[abstract 2689]. Liver MRI G-EXJ-1030713 May 2012 MRI Principle 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 tissue Patient preparation: All infusion and medication pumps should be removed. The scan does not require contrast agent, and so no peripheral vein access is needed Main magnet coils x,y,z gradient coils Step 1. Image acquisition: Images are taken at various TEs Step 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 method Overall: 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 afterwards 25 G-EXJ-1030713 May 2012 ROI = 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. Patient table Integral radiofrequency transmitter (body) coil Main magnet coils MRI is increasingly being used as a non-invasive method to measure LIC Pros Cons ● ● ● ● ● Indirect measurement of LIC2 ● Requires MRI with dedicated imaging method2 ● Sensitivity depends on type of scanner, degree of iron overload, presence of fibrosis, and inflammation7 Non-invasive1,2 Assesses iron content throughout the liver2 Increasingly and widely available worldwide2 Pathological status of liver and heart can be assessed in parallel2 ● Validated relationship with biopsy LIC3‒6 1Chavhan 26 G-EXJ-1030713 May 2012 GB, et al. Radiographics. 2009;29:1433-49. 2TIF. Guidelines for the Clinical Management of Thalassaemia. 2nd rev. ed. Cyprus: TIF; 2008. Available from: www.thalassaemia.org.cy/pdf/Guidelines_2nd_ revised_edition_EN.pdf. Accessed December 2010. 3Christoforidis A, et al. Eur J Haematol. 2009;82:388-92. 4St Pierre TG, et al. Blood. 2005;105:855-61. 5Wood JC, et al. Blood. 2005;106:1460-5. 6Hankins JS, et al. Blood. 2009;113:4853-5. 7Sirlin CB, Reeder SB. Magn Reson Imaging Clin N Am. 2010;18:359-81. MRI scanners ● Manufacturers – Siemens Healthcare (Erlangen, Germany; www.siemensmedical.com) – GE Healthcare (Milwaukee, WI, USA; www.gemedicalsystems.com) – Philips Healthcare (Best, the Netherlands; www.medical.philips.com) ● Magnetic field strength ● – most imaging is done on 1.5 T machines – 3 T machines give • better signal:noise ratio1 • worse susceptibility artefacts1 • The upper detection limit is halved, therefore it is too low for many patients1 • lower T2 and T2* values than 1.5 T machines2 Liver package (including standard sequences and analysis of the data) is included in the software provided together with the MRI machine – specialized LIC analysis software can be bought separately 27 G-EXJ-1030713 May 2012 1Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96. 2Storey P, et al. J Magn Reson Imaging. 2007;25:540-7. Overview of MRI techniques used to measure LIC DATA ACQUISITION Signal Intensity Ratio (SIR) method (Gandon/Ernst) DATA ANALYSIS A combination of gradient and spin echos Free website Gradient 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) Liver MRI Technique R2*(T2*) Relaxometry method R2(T2) (Ferriscan®) 28 G-EXJ-1030713 May 2012 Spin echo (15min) Done centrally by Resonance Health (300 USD per scan) MAJOR PROS AND CONS + Fast acquisition Simple data analysis − Limited sensitivity Reproducibility + Fast acquisition Correlates well with LIC − Susceptible to artefacts Training needs + Gold Standard Little training need − Longer data acquisition time Cost of analysis MRI measurement of LIC: techniques ● There are 2 broad groups of techniques – SIR methods (Gandon et al. methods) – relaxometry methods (FerriScan® and T2* (R2*) methods) SIR method Relaxometry method 29 G-EXJ-1030713 May 2012 Pros Cons ● Fast data acquisition ● Relatively simple algorithms and data analysis ● Limited range of sensitivity (upper limit is 21 mg Fe/g dry wt [380 mol/L]) ● Assumptions on reference tissue ● Can be used in scanners with different magnetic strengths (0.5, 1.0, 1.5 T) ● Greater range of sensitivity ● Does not rely on reference tissue assumptions ● T2* (or R2*) is very quick (requires a single breath-hold) ● Not reliable in cirrhosis ● Smaller reproducibility ● Has only been calibrated at 1.5 T ● Takes longer to acquire data, when done as T2 (or R2) Argyropoulou MI, Astrakas L. Pediatr Radiol. 2007;37:1191-200. Gandon Y, et al. Lancet. 2004;363:357-62. St Pierre TG, et al. Ann N Y Acad Sci. 2005;1054:379-85. Wood JC. Curr Opin Hematol. 2007;14:183-90. Wood JC, et al. Blood. 2005;106:1460-5. SIR methods 1. Patient preparation 2. Image acquisition (5 min) ● 3. Data analysis (depends on experience) (approx. 5-20 min) Most common protocol includes – 4-gradient echo sequences with different TEs – 1 spin-echo sequence 400 MRI LIC (µmol Fe/g dry wt) Study group Validation group 300 200 100 0 0 30 G-EXJ-1030713 May 2012 100 200 Biopsy LIC (µmol Fe/g dry wt) Gandon Y, et al. Lancet. 2004;363:357-62. 300 400 SIR methods (cont.) 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (relatively fast) ● The ROI is selected in the liver and the reference tissue (muscle or fat), in each image ● The SI of the liver region is divided by that of the reference tissue ● A calculation algorithm to assist has been developed for 0.5, 1.0, and 1.5 T MRI machines1 31 G-EXJ-1030713 May 2012 1Gandon Y. Available from: http://www.radio.univ-rennes1.fr/Sources/EN/HemoResult.html. Accessed December 2010. Relaxometry methods: T2, T2*, T2′, R2, and R2* ● If a spin-echo sequence is used, the relaxation time is T2 ● If a gradient-echo sequence is used, it is T2* ● These are related by the equation1 1/T2* = 1/T2 + 1/T2′ ● T2′ is the magnetic field inhomogeneity of the tissue ● To attain a positive linear relationship with HIC – T2* 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] 32 G-EXJ-1030713 May 2012 1Anderson LJ, et al. Eur Heart J. 2001;22:2171-9. 2Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96. Relaxometry methods: R2 and R2* ● Several pulse sequences are included in the MRI software package R2 (for FerriScan®) spin echo sequence T2* (and R2*) gradient echo sequence FOV (mm) 300 x 225 350 x 300 Matrix (lines) 256 x 176 128 x 80 1.17 x 1.28 x 5.0 2.73 x 3.75 x 10.0 TR (ms) 2500 200 TE (ms) 6, 9, 12, 15, 18 Minimum possible (ideally < 2.0 ms) NEX (n) 1 1 Flip angle (°) 90 20 BW (Hz/px) 300 1,950 – 8 On On Parameters Resolution (mm) Segments (n) FatSat 33 G-EXJ-1030713 May 2012 Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96. Correlation between R2-estimated LIC and LIC by biopsy R2-LIC calibration curve by Wood et al. 20051 R2-LIC calibration curve by St Pierre et al. 20052 300 300 250 250 200 Mean R2 (Hz) R2 (Hz) 350 200 150 100 LIC by biopsy, R = 0.98 Linear fit using biopsy data Controls, LIC by norms alone 50 150 -thalassaemia/Hb E -thalassaemia Hepatitis Hereditary haemochromatosis 100 50 0 0 0 10 20 30 40 Biopsy LIC (mg Fe/g dry wt) 34 G-EXJ-1030713 May 2012 1Wood 50 60 0 10 20 30 Biopsy LIC (mg Fe/g dry wt) JC, et al. Blood. 2005;106:1460-5. 2St Pierre TG, et al. Blood. 2005;105:855-61. 40 Correlation between R2*-estimated LIC and LIC by biopsy R2*-LIC calibration curve by Wood et al.1 R2*-LIC calibration curve by Hankins et al.2 Patients Controls Fit 2,000 1,800 1,600 30 25 LIC (mg Fe/g dry wt) R2* (Hz) 1,400 1,200 1,000 800 600 400 20 15 10 5 R = 0.97 200 0 Correlation coefficient = 0.98 p < 0.001 0 0 10 20 30 40 50 60 0 200 Biopsy LIC (mg Fe/g dry wt) 35 G-EXJ-1030713 May 2012 1Wood JC, et al. Blood. 2005;106:1460-5. 2Hankins JS, et al. Blood. 2009;113:4853-5. 400 600 R2*MRI (Hz) 800 1000 LIC estimated with R2 and R2* MRI correlate well with each other Estimated HIC (mg/dry) by R2-SP 50 40 30 20 Patient data Linear fit, R=0.94 10 0 0 10 20 30 Estimated HIC (mg/dry) by R2* 36 G-EXJ-1030713 May 2012 Wood JC, et al. Blood. 2005;106:1460-5. 40 50 Gradient relaxometry (T2*, R2*) can conveniently measure cardiac and liver iron Liver MRI HIC (mg Fe/g of dry weight liver) Cardiac MRI [Fe] (mg/g dry wt) 14 12 10 8 6 4 R2 = 0.82540 2 0 0 100 200 300 400 30 Hankins, et al. 25 20 Wood, et al. 15 10 Anderson, et al. 5 0 0 Cardiac R2* (Hz) 200 400 Liver R2* (Hz) Cardiac and liver iron can be assessed together conveniently by gradient echo during a single MRI measurement. 37 G-EXJ-1030713 May 2012 HIC = hepatic iron concentration Carpenter JP, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:P224. Hankins et al Blood. 2009;113:4853-4855. 600 800 1000 Relaxometry methods: pros and cons Pros Cons R2* ● Correlate well to biopsy LIC1–4 ● Greater sensitivity to iron deposits5 ● Faster (images can be obtained in a single breath-hold) and easier6 ● Can perform cardiac and liver iron assessment at the same time ● More susceptible to artefacts ● Requires expert training of a technician/ radiologist for data acquisition and data analysis ● Multiple breath-holds required which increases MRI time R2 (Ferriscan®) ● Correlate well to biopsy LIC1–4 ● Less affected by susceptibility artefacts6 ● Highly sensitive and specific over a large range of LIC, including patients with severe haemosiderosis7 ● The gold standard method in clinical trials ● Requires no training for data analysis (done centralized by Resonance Health) 38 G-EXJ-1030713 May 2012 1Christoforidis ● Cost of analysis (300 USD per scan) A, et al. Eur J Haematol. 2009;82:388-92. 2St Pierre TG, et al. Blood. 2005;105:855-61. 3Wood JC, et al. Blood. 2005;106:1460-5. 4Hankins JS, et al. Blood. 2009;113:4853-5. 5Anderson LJ, et al. Eur Heart J. 2001;22:2171-9. 6Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96. 7Papakonstantinou, O, et al. J Magn Reson Imaging. 2009;29:853-9. Relaxometry methods: R2 and R2* (cont.) 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (depends on experience) ● Correct position is important so that the LIC across the whole liver can be measured ● Images are taken at various TEs Red line indicates correct position of the slice 39 G-EXJ-1030713 May 2012 Liver R2* MRI Liver with normal iron levels TE=1.3ms TE=3.6ms TE=7.1ms T2* = 15.7 ms or R2* = 63.7 Hz or LIC = 1.3mg/g Liver with severe iron overload TE=1.3ms TE=3.6ms TE=7.1ms T2* = 1.1 ms or R2* = 909 Hz or LIC = 25.0 mg/g 40 G-EXJ-1030713 May 2012 Images courtesy of Dr J. de Lara Fernandes. FAQ: 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 repeated How 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) 41 G-EXJ-1030713 May 2012 Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil. Relaxometry methods: R2 and R2* (cont.) 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (depends on experience) ● Determine ROI – entire liver boundary, excluding obvious hilar vessels1 ● Slice thickness – varies, generally 5–15 mm1–4 ● Number of slices Red outline shows position of ROI – anything from about 1 to 20 slices can be studied1–4 42 G-EXJ-1030713 May 2012 1Wood JC, et al. Blood. 2005;106:1460-5. 2St Pierre TG, et al. Blood. 2005;105:855-61. O, et al. J Magn Reson Imaging. 2009;29:853-9. 4Hankins JS, et al. Blood. 2009;113:4853-5. 3Papakonstantinou Relaxometry methods: R2 and R2* (cont.) 1. Patient preparation As TE increases, SI should decrease ● When plotted on a graph – as iron load increases, the curve gets steeper – T2 or T2* can be calculated from the curve – R2 and R2* can also be calculated Calculations are done – manually, or – by specific licensed software (e.g. CMRtools®), or – images could be directly sent to a validated centre performing FerriScan® for analysis 43 G-EXJ-1030713 May 2012 (depends on experience) (approx. 5-20 min) ● ● 3. Data analysis 100 Typical non-iron-loaded tissue 80 SI (5 min) 2. Image acquisition 60 40 20 0 0 5 10 TE (ms) 15 20 Analysis of the data ● The data can be analysed manually or using post-processing software 44 G-EXJ-1030713 May 2012 Manually Post-processing software •Excel spreadsheet •ThalassaemiaTools (CMRtools) •cmr42 •FerriScan •MRmap •MATLAB Analysis of the data (cont.) Method Pros Cons Excel spreadsheet Low cost Time-consuming Tedious ThalassaemiaTools (CMRtools)1 Fast (1 min)2 Easy to use FDA approved GBP 3,000 per year cmr42(3) Easy to use FDA approved3 Can generate T2*/R2* and T2/R2 maps with same software Allows different forms of analysis Generates pixel-wise fitting with colour maps 40,000 USD first year costs 12,000 USD per year after 45 G-EXJ-1030713 May 2012 FDA = Food and Drug Administration. 1www.cmrtools.com/cmrweb/ThalassaemiaToolsIntroduction.htm. Accessed Dec 2010. 2Pennell DJ. JACC Cardiovasc Imaging. 2008;1:579-81. 3www.circlecvi.com. Accessed Dec 2010. Analysis of the data (cont.) Method Pros Cons FerriScan1 Centralized analysis of locally acquired data (206 active sites across 25 countries) Easy set-up on most MRI machines EU approved Validated on GE, Philips, and Siemens scanners USD 300 per scan Patients data are sent to reference centre MRmap2 Uses IDL runtime, which is a commercial software (less expensive than cmr42/CMRtools) Can quantify T1 and T2 map with the same software Purely a research tool Not intended for diagnostic or clinical use MATLAB3 Low cost Available only locally Physicists or engineers need to write a MATLAB program for display and T2* measurement 46 G-EXJ-1030713 May 2012 1www.resonancehealth.com/resonance/ferriscan. Accessed Dec 2010. Accessed Dec 2010. 3Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202:173-9. 2www.cmr-berlin.org/forschung/mrmapengl/index.html. FAQ: 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 > 0.995. 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? 47 G-EXJ-1030713 May 2012 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 correctly Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil. FAQ: mistakes in manual analysis of liver MRI data (cont.) Analysis without truncation of the data Non-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 ms 48 G-EXJ-1030713 May 2012 Analysis with truncation of the data The same patient, but analysing the data with only the 3 first data points results in a better (although not perfect) R 2. The LIC results in severe iron overload, reflecting the real concentrations of iron FAQ: 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 followed 1. Check MRI machine requirements • 0.5–1.5 T (1.5 T is highly recommended for T2* and T2 calculations; 0.5 T only for SIR) • calibrated • includes a liver package 2. Optional: buy software for analysing the data (otherwise, Excel spreadsheet can be used) 3. Optional: training of personnel for acquiring MRI images 4. Optional: training of personnel on how to analyse the data 49 G-EXJ-1030713 May 2012 Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil. LIC: interpretation of results ● LIC threshold values for classification of iron overload Iron levels LIC (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 > 11.4 Mild overload ≥ 2−7 ≥ 35.6 − 125.0 ≥ 50 – 100 ≥ 88 – 263 > 3.8 – 11.4 Moderate overload ≥ 7−15 ≥ 125 − 269 ≥ 100 – 155 ≥ 263 – 555 > 1.8 – 3.8 Severe overload ≥ 15 ≥ 269 ≥ 155 ≥ 555 ≤ 1.8 50 G-EXJ-1030713 May 2012 †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. Implementation of liver and cardiac MRI 1.5T MRI Scanner US$1.000.000 Yes ½ day training Liver Analysis Experienced radiologist No 1 day training Post-processing analysis Cardiac acquisition package US$50.000 Yes US$40.000 or US$4.000/y or in-house or outsource 1-2 day training Routine cardiac MR exams No 51 G-EXJ-1030713 May 2012 4 day training Slide presented at Global Iron Summit 2011 - With the permission of Juliano de Lara Fernandes Heart Analysis Summary G-EXJ-1030713 May 2012 Summary ● Iron overload is a serious problem among patients who require blood transfusions to treat anaemia and associated conditions ● Analysing liver iron overload is important – to predict risk of hepatic and extra-hepatic complications ● The extent of iron accumulation in the liver is a key prognostic indicator for morbidity and mortality ● MRI 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 53 G-EXJ-1030713 May 2012 GLOSSARY OF TERMS G-EXJ-1030713 May 2012 GLOSSARY ● AML = acute myeloid leukemia ● APFR = Atrialp peak filling rate ● BA = basilar artery ● ß-TM = Beta Thalassemia Major ● ß-TI = Beta Thalassemia Intermedia ● BM = bone marrow ● BTM = bone marrow transplantation ● BW = bandwidth ● CFU = colony-forming unit ● CMML = chronic myelomonocytic leukemia ● CT2 = cardiac T2*. ● DAPI = 4',6-diamidino-2-phenylindole 55 G-EXJ-1030713 May 2012 GLOSSARY ● DFS = = disease-free survival. ● DysE = dyserythropoiesis ● ECG = electrocardiography ● EDV = end-diastolic velocity ● EF = ejection fraction ● EPFR = early peak filling rate ● FatSat = fat saturation ● FAQ = frequently asked questions ● FDA = Food and Drug Administration ● FISH = fluorescence in situ hybridization. ● FOV = field of view ● GBP = Currency, pound sterling (£) 56 G-EXJ-1030713 May 2012 GLOSSARY ● Hb = hemoglobin ● HbE = hemoglobin E ● HbF = fetal hemoglobin ● HbS = sickle cell hemoglobin. ● HbSS = sickle cell anemia. ● HIC = hepatic iron concentration ● HU = hydroxyurea ● ICA = internal carotid artery. ● ICT = iron chelation therapy ● IDL = interface description language ● IPSS = International Prognostic Scoring System ● iso = isochromosome 57 G-EXJ-1030713 May 2012 GLOSSARY ● LIC = liver iron concentration ● LVEF = left-ventricular ejection fraction ● MCA = middle cerebral artery ● MDS = Myelodysplastic syndromes ● MDS-U = myelodysplastic syndrome, unclassified ● MRA = magnetic resonance angiography ● MRI = magnetic resonance imaging ● MV = mean velocity. ● N = neutropenia ● NEX = number of excitations ● NIH = National Institute of Health ● OS = overall survival 58 G-EXJ-1030713 May 2012 GLOSSARY ● pB = peripheral blood ● PI = pulsatility index ● PSV = peak systolic Velocity ● RA =refractory anemia ● RAEB = refractory anemia with excess blasts ● RAEB -T = refractory anemia with excess blasts in transformation ● RARS = refractory anemia with ringed sideroblasts ● RBC = red blood cells ● RF = radio-frequency ● RCMD = refractory cytopenia with multilineage dysplasia ● RCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblasts ● RCUD = refractory cytopenia with unilineage dysplasia 59 G-EXJ-1030713 May 2012 GLOSSARY ● RN = refractory neutropenia ● ROI = region of interest ● RT = refractory thrombocytopenia ● SCD = sickle cell disease ● SD = standard deviation ● SI = signal intensity ● SIR = signal intensity ratio ● SF = serum ferritin ● SNP-a = single-nucleotide polymorphism ● SQUID = superconducting quantum interface device. ● STOP = = Stroke Prevention Trial in Sickle Cell Anemia ● STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia 60 G-EXJ-1030713 May 2012 GLOSSARY ● T = thrombocytopenia ● TAMMV = time-averaged mean of the maximum velocity. ● TCCS = transcranial colour-coded sonography ● TCD = transcranial doppler ultrasonography ● TCDI = duplex (imaging TCD) ● TE = echo time ● TR = repetition time ● WHO = World Health Organization ● WPSS = WHO classification-based Prognostic Scoring System 61 G-EXJ-1030713 May 2012
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