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G-EXJ-1030713 May 2012 USE OF MRI IN EVALUATING LIVER IRON LOADING (AND MONITORING THERAPY) NOTE: These slides are for use in educational oral presentations.

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Presentation on theme: "G-EXJ-1030713 May 2012 USE OF MRI IN EVALUATING LIVER IRON LOADING (AND MONITORING THERAPY) NOTE: These slides are for use in educational oral presentations."— Presentation transcript:

1 G-EXJ-1030713 May 2012 USE 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

2 2 G-EXJ-1030713 May 2012 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 LIC = liver iron concentration; MRI = magnetic resonance imaging; SF = serum ferritin; SIR = signal intensity ratio; SQUID = superconducting quantum interface device.

3 G-EXJ-1030713 May 2012 Introduction to iron and iron overload

4 4 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 mortality 1 ● 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 organs 2,3 1 Ladis V, et al. Ann NY Acad Sci. 2005;1054:445-50. 2 Gabutti V, Piga A. Acta Haematol. 1996;95:26-36. 3 Olivieri NF. N Engl J Med. 1999;341:99-100.

5 5 G-EXJ-1030713 May 2012 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 complications 1–4 1 Batts KP. Mod Pathol. 2007;20:S31-9. 2 Jensen PD, et al. Blood. 2003;101:91-6. 3 Angelucci E, et al. Blood. 2002;100:17-21. 4 Telfer PT, et al. Br J Haematol. 2000;110:971-7.

6 6 G-EXJ-1030713 May 2012 LIC threshold of 7 mg Fe/g dry wt 0 5 10 15 20 25 All (n = 1,744) TM (n = 937) TI (n = 84) SCD (n = 80) Mean LIC + SD over previous year prior to enrolment in EPIC trial (mg Fe/g dry wt) Cappellini MD, et al. Blood. 2008;112:[abstract 3880]. Importance of analysing liver iron (cont.) All transfusion-dependent patients prior to study enrolment had moderate-to-severe hepatic iron loading

7 7 G-EXJ-1030713 May 2012 Overview of LIC correlations with other measurements DFS = disease-free survival. 1 Angelucci E, et al. N Engl J Med. 2000;343:327-31. 2 Jensen PD, et al. Blood. 2003;101:91-6. 3 Angelucci E, et al. Blood. 2002;100:17-21. 4 Telfer PT, et al. Br J Haematol. 2000;110:971-7. 5 Noetzli LJ, et al. Blood. 2008;112:2973-8. LIC Hepatocellular injury 2 and fibrosis 3 Body iron stores 1 Cardiac iron 5 Cardiac DFS 4

8 8 G-EXJ-1030713 May 2012 LIC prediction of total body iron stores BMT = bone marrow transplantation. 1 Olynyk JK, et al. Am J Gastroenterol. 1998;93:346-50. 2 Angelucci E, et al. N Engl J Med. 2000;343:327-31. Sample > 1 mg dry wt (n = 25) r = 0.98 0510152025 300 250 200 150 100 50 0 Body iron stores (mg/kg) LIC (mg Fe/g dry wt) Hereditary haemochromatosis 1 Iron removed (g) LIC (µg/g) 0510152025 50,000 40,000 30,000 20,000 10,000 0 β-TM 2 LIC is a reliable measure of total body iron stores in hereditary haemochromatosis and β-TM

9 9 G-EXJ-1030713 May 2012 Serum ferritin measurement alone underestimates the body iron load Origa R, et al. Haematologica. 2007;92:583-8. Taher A, et al. Haematologica. 2008;93:1584-6.  -TI  -TM 05101520253035 LIC (mg Fe/g dry wt) SF (  g/L) 2,000 4,000 6,000 8,000 10,000 12,000 14,000 0 SF (  g/L) 05101520253035404550 LIC (mg Fe/g dry wt) 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 10,000 0  -TI  -TM SF has almost no sensitivity or specificity for iron stores in thalassaemia intermedia

10 G-EXJ-1030713 May 2012 Assessing liver iron overload

11 11 G-EXJ-1030713 May 2012 Key methods for assessing liver iron ● Liver biopsy  LIC –advantages and disadvantages –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 Olivieri NF, Brittenham GM. Blood. 1997;89:739-61. Direct method Indirect methods

12 G-EXJ-1030713 May 2012 Liver biopsy

13 13 G-EXJ-1030713 May 2012 Technique for taking a percutaneous liver biopsy Step 1. The patient lies on his back, or his left 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 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 3. A special hollow needle is inserted into the liver, usually between the 2 lower ribs on the right hand side Step 2. The place for the biopsy is cleaned with antiseptic and local anaesthesia is provided (s.c. on the right hand side) 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 Area where a tissue sample is taken from 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 adam.com

14 14 G-EXJ-1030713 May 2012 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 Angelucci E, et al. Haematologica. 2008;93:741-52. Image from: www.pathguy.com/lectures/cirrhosis_trichrome.jpg

15 15 G-EXJ-1030713 May 2012 Liver biopsy Liver biopsy with iron measurement by atomic absorption spectroscopy is the gold standard for measuring LIC 1 LIC threshold (mg Fe/g dry wt) 2 LIC threshold (  mol Fe/g dry wt) Clinical relevance 1.832Upper 95% of normal  15.0 269 Greatly increased risk of cardiac disease and early death 1 Angelucci E, et al. Haematologica. 2008;93:741-52. 2 St Pierre TG, et al. Blood. 2005;105:855-61.

16 16 G-EXJ-1030713 May 2012 Liver biopsy: pros and cons Pros 1 Cons ● Direct measurement of LIC ● Validated reference standard ● Quantitative, specific, and sensitive ● Allows for measurement of non-haem storage iron ● Provides information on liver histology/pathology ● Correlates with morbidity and mortality ● Invasive and painful procedure with risk of potentially serious complications 1 ● May involve sampling errors, especially in patients with cirrhosis 1 ● Requires skilled physicians 1 ● Laboratory techniques not standardized 1 –iron measurement by atomic absorption spectroscopy 2 or chemical determination 3 ● 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) 1 TIF. 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. 2 Angelucci E, et al. Haematologica. 2008;93:741-52. 3 Wood JC. Blood Rev. 2008;22 Suppl 2:S14-21. 4 Ambu R, et al. J Hepatol. 1995;23:544-9.

17 17 G-EXJ-1030713 May 2012 Heterogeneity of iron concentration throughout the liver From autopsy of a patient with beta-zero-thalassaemia. Ambu R, et al. J Hepatol. 1995;23:544-9. 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

18 G-EXJ-1030713 May 2012 SF Concentration

19 19 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 (Fe 3+ ) iron in its central cavity –the storage capacity of ferritin is approximately 4,500 Fe 3+ 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 > 1,000 µg/L is a marker of excess body iron

20 20 G-EXJ-1030713 May 2012 SF: pros and cons ● SF levels from a blood sample are measured ProsCons ● 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 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.

21 G-EXJ-1030713 May 2012 SQUID

22 22 G-EXJ-1030713 May 2012 SQUID: superconducting quantum interference device Carneiro AA, et al. Reson Med. 2005;43:122-8. Magnetizing coil Dewar Liquid helium SQUID Pick to coil Water bag Patient Mattress Bed Piston H2OH2O 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 2. LIC corresponds to the variation of magnetization detected and is calculated using custom-made Matlab 6.5 software 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 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 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

23 23 G-EXJ-1030713 May 2012 SQUID: pros and cons ProsCons ● Non-invasive 1 ● Wide linear range 1 ● Good correlation with LIC by biopsy 2 ● Requires expensive, specialized equipment and expertise 1 ● Not widely available 1 ● Each machine should be individually calibrated 1 ● SQUID can underestimate LIC 3 1 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. 2 Sheth S. Pediatr Radiol. 2003;33:373-7. 3 Piga A, et al. Blood. 2005;106:[abstract 2689]. 250 200 150 100 50 0 0 100150200250 Hepatic iron (magnetic) (  mol Fe/g wet wt) Hepatic iron (biopsy) (  mol Fe/g wet wt) R = 0.99 p < 0.001 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

24 G-EXJ-1030713 May 2012 Liver MRI

25 25 G-EXJ-1030713 May 2012 MRI 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. Integral radiofrequency transmitter (body) coil Main magnet coils x,y,z gradient coils Patient table 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 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 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 Step 1. Image acquisition: Images are taken at various TEs 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

26 26 G-EXJ-1030713 May 2012 MRI is increasingly being used as a non-invasive method to measure LIC ProsCons ● Non-invasive 1,2 ● Assesses iron content throughout the liver 2 ● Increasingly and widely available worldwide 2 ● Pathological status of liver and heart can be assessed in parallel 2 ● Validated relationship with biopsy LIC 3 ‒ 6 ● Indirect measurement of LIC 2 ● Requires MRI with dedicated imaging method 2 ● Sensitivity depends on type of scanner, degree of iron overload, presence of fibrosis, and inflammation 7 1 Chavhan GB, et al. Radiographics. 2009;29:1433-49. 2 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. 3 Christoforidis A, et al. Eur J Haematol. 2009;82:388-92. 4 St Pierre TG, et al. Blood. 2005;105:855-61. 5 Wood JC, et al. Blood. 2005;106:1460-5. 6 Hankins JS, et al. Blood. 2009;113:4853-5. 7 Sirlin CB, Reeder SB. Magn Reson Imaging Clin N Am. 2010;18:359-81.

27 27 G-EXJ-1030713 May 2012 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 ratio 1 worse susceptibility artefacts 1 The upper detection limit is halved, therefore it is too low for many patients 1 lower T2 and T2* values than 1.5 T machines 2 ● 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 1 Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96. 2 Storey P, et al. J Magn Reson Imaging. 2007;25:540-7.

28 28 G-EXJ-1030713 May 2012 Overview of MRI techniques used to measure LIC DATA ACQUISITION DATA ANALYSIS MAJOR PROS AND CONS A combination of gradient and spin echos Free website + Fast acquisition Simple data analysis − Limited sensitivity Reproducibility 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) + Fast acquisition Correlates well with LIC − Susceptible to artefacts Training needs Spin echo (15min) Done centrally by Resonance Health (300 USD per scan) + Gold Standard Little training need − Longer data acquisition time Cost of analysis Signal Intensity Ratio (SIR) method (Gandon/Ernst) Relaxometry method R2*(T2*) R2(T2) (Ferriscan ® ) Liver MRI Technique

29 29 G-EXJ-1030713 May 2012 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) ProsCons SIR method ● Fast data acquisition ● Relatively simple algorithms and data analysis ● Can 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 tissue ● Not reliable in cirrhosis ● Smaller reproducibility Relaxometry method ● Greater range of sensitivity ● Does not rely on reference tissue assumptions ● T2* (or R2*) is very quick (requires a single breath-hold) ● 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.

30 30 G-EXJ-1030713 May 2012 SIR methods ● Most common protocol includes –4-gradient echo sequences with different TEs –1 spin-echo sequence 0 100 300 400 200 0100200400300 Study group Validation group Biopsy LIC ( µ mol Fe/g dry wt) MRI LIC ( µ mol Fe/g dry wt) Gandon Y, et al. Lancet. 2004;363:357-62. 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (depends on experience)

31 31 G-EXJ-1030713 May 2012 SIR methods (cont.) ● 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 machines 1 1 Gandon Y. Available from: http://www.radio.univ-rennes1.fr/Sources/EN/HemoResult.html. Accessed December 2010. 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (relatively fast)

32 32 G-EXJ-1030713 May 2012 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 equation 1 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] 1 Anderson LJ, et al. Eur Heart J. 2001;22:2171-9. 2 Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.

33 33 G-EXJ-1030713 May 2012 Relaxometry methods: R2 and R2* ● Several pulse sequences are included in the MRI software package Parameters R2 (for FerriScan ® ) spin echo sequence T2* (and R2*) gradient echo sequence FOV (mm)300 x 225350 x 300 Matrix (lines)256 x 176128 x 80 Resolution (mm)1.17 x 1.28 x 5.02.73 x 3.75 x 10.0 TR (ms)2500200 TE (ms)6, 9, 12, 15, 18Minimum possible (ideally < 2.0 ms) NEX (n)11 Flip angle (°)9020 BW (Hz/px)3001,950 Segments (n)–8 FatSatOn Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.

34 34 G-EXJ-1030713 May 2012 1 Wood JC, et al. Blood. 2005;106:1460-5. 2 St Pierre TG, et al. Blood. 2005;105:855-61. Biopsy LIC (mg Fe/g dry wt) Mean R2 (Hz) 300 250 200 150 100 50 0 Hepatitis Hereditary haemochromatosis  -thalassaemia/Hb E  -thalassaemia 010203040 Biopsy LIC (mg Fe/g dry wt) 350 300 250 200 150 100 50 0 0102030405060 R2 (Hz) LIC by biopsy, R = 0.98 Linear fit using biopsy data Controls, LIC by norms alone Correlation between R2-estimated LIC and LIC by biopsy R2-LIC calibration curve by St Pierre et al. 2005 2 R2-LIC calibration curve by Wood et al. 2005 1

35 35 G-EXJ-1030713 May 2012 Correlation between R2*-estimated LIC and LIC by biopsy 1 Wood JC, et al. Blood. 2005;106:1460-5. 2 Hankins JS, et al. Blood. 2009;113:4853-5. R2* (Hz) Biopsy LIC (mg Fe/g dry wt) R = 0.97 Patients Controls Fit 0 200 400 600 800 1,000 1,200 1,400 1,600 1,800 2,000 0102030405060 30 25 20 15 10 5 0 02004006008001000 R2*MRI (Hz) LIC (mg Fe/g dry wt) Correlation coefficient = 0.98 p < 0.001 R2*-LIC calibration curve by Hankins et al. 2 R2*-LIC calibration curve by Wood et al. 1

36 36 G-EXJ-1030713 May 2012 LIC estimated with R2 and R2* MRI correlate well with each other Wood JC, et al. Blood. 2005;106:1460-5. 0 10 20 30 40 50 01020304050 Estimated HIC (mg/dry) by R2-SP Estimated HIC (mg/dry) by R2* Patient data Linear fit, R=0.94

37 37 G-EXJ-1030713 May 2012 30 25 20 15 10 5 0 02004006008001000 Liver R2* (Hz) HIC (mg Fe/g of dry weight liver) Hankins, et al. Wood, et al. Anderson, et al. [Fe] (mg/g dry wt) Cardiac R2* (Hz) 0 2 4 6 8 10 12 14 0100200300400 R 2 = 0.82540 Liver MRICardiac MRI Gradient relaxometry (T2*, R2*) can conveniently measure cardiac and liver iron 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. Cardiac and liver iron can be assessed together conveniently by gradient echo during a single MRI measurement.

38 38 G-EXJ-1030713 May 2012 Relaxometry methods: pros and cons ProsCons R2* ● Correlate well to biopsy LIC 1–4 ● Greater sensitivity to iron deposits 5 ● Faster (images can be obtained in a single breath-hold) and easier 6 ● 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 R2 (Ferriscan ® ) ● Correlate well to biopsy LIC 1–4 ● Less affected by susceptibility artefacts 6 ● Highly sensitive and specific over a large range of LIC, including patients with severe haemosiderosis 7 ● The gold standard method in clinical trials ● Requires no training for data analysis (done centralized by Resonance Health) ● Multiple breath-holds required which increases MRI time ● Cost of analysis (300 USD per scan) 1 Christoforidis A, et al. Eur J Haematol. 2009;82:388-92. 2 St Pierre TG, et al. Blood. 2005;105:855-61. 3 Wood JC, et al. Blood. 2005;106:1460-5. 4 Hankins JS, et al. Blood. 2009;113:4853-5. 5 Anderson LJ, et al. Eur Heart J. 2001;22:2171-9. 6 Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96. 7 Papakonstantinou, O, et al. J Magn Reson Imaging. 2009;29:853-9.

39 39 G-EXJ-1030713 May 2012 Relaxometry methods: R2 and R2* (cont.) ● 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 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (depends on experience)

40 40 G-EXJ-1030713 May 2012 Liver R2* MRI Liver with normal iron levels Liver with severe iron overload Images courtesy of Dr J. de Lara Fernandes. T2* = 15.7 ms or R2* = 63.7 Hz or LIC = 1.3mg/g T2* = 1.1 ms or R2* = 909 Hz or LIC = 25.0 mg/g TE=1.3msTE=3.6ms TE=7.1ms TE=1.3msTE=3.6ms TE=7.1ms

41 41 G-EXJ-1030713 May 2012 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) 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 FAQ: artefacts Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.

42 42 G-EXJ-1030713 May 2012 Relaxometry methods: R2 and R2* (cont.) ● Determine ROI –entire liver boundary, excluding obvious hilar vessels 1 ● Slice thickness –varies, generally 5–15 mm 1–4 ● Number of slices –anything from about 1 to 20 slices can be studied 1–4 Red outline shows position of ROI 1 Wood JC, et al. Blood. 2005;106:1460-5. 2 St Pierre TG, et al. Blood. 2005;105:855-61. 3 Papakonstantinou O, et al. J Magn Reson Imaging. 2009;29:853-9. 4 Hankins JS, et al. Blood. 2009;113:4853-5. 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (depends on experience)

43 43 G-EXJ-1030713 May 2012 Relaxometry methods: R2 and R2* (cont.) ● 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 100 80 60 40 20 0 1520 0 5 10 SI TE (ms) Typical non-iron-loaded tissue Increasing iron loading 1. Patient preparation (5 min) 2. Image acquisition (approx. 5-20 min) 3. Data analysis (depends on experience)

44 44 G-EXJ-1030713 May 2012 Analysis of the data ● The data can be analysed manually or using post-processing software ManuallyPost-processing software Excel spreadsheet ThalassaemiaTools (CMRtools) cmr 42 FerriScan MRmap MATLAB

45 45 G-EXJ-1030713 May 2012 Analysis of the data (cont.) MethodProsCons Excel spreadsheetLow cost Time-consuming Tedious ThalassaemiaTools (CMRtools) 1 Fast (1 min) 2 Easy to use FDA approved GBP 3,000 per year cmr 42(3) Easy to use FDA approved 3 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 FDA = Food and Drug Administration. 1 www.cmrtools.com/cmrweb/ThalassaemiaToolsIntroduction.htm. Accessed Dec 2010. 2 Pennell DJ. JACC Cardiovasc Imaging. 2008;1:579-81. 3 www.circlecvi.com. Accessed Dec 2010.

46 46 G-EXJ-1030713 May 2012 MethodProsCons FerriScan 1 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 MRmap 2 Uses IDL runtime, which is a commercial software (less expensive than cmr 42 /CMRtools) Can quantify T1 and T2 map with the same software Purely a research tool Not intended for diagnostic or clinical use MATLAB 3 Low costAvailable only locally Physicists or engineers need to write a MATLAB program for display and T2* measurement 1 www.resonancehealth.com/resonance/ferriscan. Accessed Dec 2010. 2 www.cmr-berlin.org/forschung/mrmapengl/index.html. Accessed Dec 2010. 3 Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202:173-9. Analysis of the data (cont.)

47 47 G-EXJ-1030713 May 2012 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 R 2 > 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? 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 FAQ: mistakes in manual analysis of liver MRI data Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.

48 48 G-EXJ-1030713 May 2012 Non-truncated analysis with results with a poor R 2 (< 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 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 Analysis without truncation of the data Analysis with truncation of the data FAQ: mistakes in manual analysis of liver MRI data (cont.)

49 49 G-EXJ-1030713 May 2012 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 FAQ: how to start measuring liver iron loading? Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.

50 50 G-EXJ-1030713 May 2012 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 † 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.

51 51 G-EXJ-1030713 May 2012 Implementation of liver and cardiac MRI Slide presented at Global Iron Summit 2011 - With the permission of Juliano de Lara Fernandes 1.5T MRI Scanner Experienced radiologist Cardiac acquisition package Routine cardiac MR exams Post-processing analysis US$1.000.000 US$50.000 US$40.000 or US$4.000/y or in-house or outsource Yes No ½ day training 1 day training Yes No 1-2 day training 4 day training Liver Analysis Liver Analysis Heart Analysis Heart Analysis

52 G-EXJ-1030713 May 2012 Summary

53 53 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

54 G-EXJ-1030713 May 2012 GLOSSARY OF TERMS

55 55 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

56 56 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 (£)

57 57 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

58 58 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

59 59 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

60 60 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

61 61 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


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