Update on iron overload assessment with...
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© 2019 Medis Medical Imaging Systems
Update on iron overload assessment with MRIEissa Agour, PhD Netherlands
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Value of MRI for iron overload
MR analysis
Trace treatment response with MRI
CONTENTSOverview on iron overload
Iron overload monitoring
Summary
Clinical cases
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© 2019 Medis Medical Imaging Systems
IRON OVERLOAD OVERVIEW
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Common causes of iron overload and possible complications
Primary: • Hereditary haemochromatosis (HHC): HFE gene are associated with up to 90 percent of cases
Secondary: • Transfusional: Iron overload is common in patients on intermittent or regular blood transfusions
• Non-Transfusional: Chronic liver disease
Pituitary gland
Heart
Liver
Pancreas
Gonadal
Increased iron uptake can cause organs damage
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Possible complications in iron overload
Cirrhosis/Liver Failure
Increased Iron uptake Non-transferrin-bound into plasmaProduction of Free hydoroxyl radicals Fibrosis
Heart FailureHealthy heart
Healthy Liver
It is important to monitor iron progress to prevent further complications
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The importance of monitoring affected organs
For early detection of iron overload before advanced complications
Decide on dose for chelation and delivery modes.
Adjust transfusion plans
Monitor the response of the treatment.
Based on the result, you can update the treatment plans
Diagnosis
Treatment plan
Monitor response
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© 2019 Medis Medical Imaging Systems
METHODS TO ASSESS IRON OVERLOAD
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Methods to assess iron depositionBL
OO
D TE
ST- S
ERU
M F
ERRI
TIN
Easy Affordable cost Allows longitudinal follow-up
LIVE
R BI
OPS
YDirect measurement of iron Provides info in histology/pathology T2
* M
RI: L
IVER
& C
ARDI
AC
Direct measurement of iron Iron status Aassessment of liver and heart Allows longitudinal follow-up
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Blood Test
Serum Ferritin
Brittenham et al. Am J Hematol. 1993;42:81, Origa R, et al. Haematologica. 2007;92:583-8., Taher A, et al. Haematologica. 2008;93:1584-5.
.
SERUM FERRITIN
Sickle cell anemiaThalassemia major
• Indirect measurement • Fluctuates in response to inflammation and abnormal liver function • Underestimates iron overload in thalassemia intermedia
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Liver Biopsy
Liver Biopsy
Angelucci E, et al. N Engl J Med. 2000;343:327-331
LIVER BIOPSY
Liver iron concentrations correlate to the total body iron stores
Invasive and painful Sampling error Inadequate standardization between laboratories. Difficult to follow up
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Liver
MRI and analysis
Angelucci E, et al. N Engl J Med. 2000;343:327-331
MRI
Liver
• Requires dedicated MRI sequence and analysis
T2*= 5.1ms
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Today's challenges to assess iron overload with MRI
Blood test result is influenced by other factors Enhance patient outcome through disease progression Difficult to accurately assess and follow up liver iron status without invasive biopsies. Complicated image interpretation
Referring PhysicianRadiologist
Concerns about images quality to support decisions making
Concerns for Diagnosis accuracy
Lack of Standardization and reproducibility
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13
Value of MRI:
✓ Evaluate the iron progression in liver and heart
✓ CMR can quantitatively assess myocardial iron load
✓ CMR can evaluate the heart function through the treatment period
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T2 and T2* MRI for tissue iron assessment
• Signal intensity decreases by the paramagnetic effect of iron
• The time constant of decay for the relaxation time T2 is inversely proportional to the myocardial iron content.
• The more the iron content, the shorter are the T2 and T2*, the time constant of decay for spin echo and gradient echo-induced relaxation time, respectively
Decreasing Echo Time (TE)
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Normal Mild Moderate Heavy
V Berdoukas
E Angelucci (mg/g)
3 – 6.6
3 – 6.9
6.6 – 16
7 – 14
>16.1
>14
T2* (ms) > 6.3 2.8 - 6.3 1.4 - 2.7 < 1.4
T2*= 5.1ms
V Berdoukas et al JCMR 2009 2. E Angelucci et al NEJM 2000
Liver
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Normal Mild Heavy
T2* (ms) > 20.0 10.0 – 20.0 <10.0
R2* (s-1) <50 50-100 >100
T2*= 5.7ms
Carpenter et al. JCMR 2009, v 11, P224 Carpenter et al. Circulation 2011
Heart
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MRI to assess cardiac function after iron overload
cardiac functionIn addition to iron overload quantification, CMR imaging can assess:
• LVEF, LV-End-systolic & LV-E-diastolic volumes
• Left ventricular mass
• Myocardial ischemia
• Myocardial viability
Myocardial viability
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Kirk P, et al. Circulation. 2009;120
Left ventricular ejection fraction (LVEF)
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T2* value versus arrhythmia and heart failure
Kirk et al. Circulation. 2009 Nov 17;120(20):1961-8 Marsella et al. Haematologica April 2011 96: 515-52
Lower T2* values are associated with increased risk of heart failure
Lower T2* values are associated with increased risk of arrhythmia
Prop
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Prop
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s with
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rt fa
ilure
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Lower cardiac T2* value is associated with heart dysfunction and arrhythmias
Maria Marsella et al. Haematologica 2011;96:515-520
Heart dysfunction Arrhythmias
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■ Cardiac T2* can predict cardiac complications and heart failure (e.g. in Thalassemia Major)
■ 98% of patients who developed heart failure had T2* <10 ms.
Kirk P, et al. Circulation. 2009;120
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THERAPY - IRON CHELATION TREATMENT
Therapy of iron overload states is important to prevent or reverse cardiac dysfunction
Deferoxamine, deferiprone, and deferasirox are the 3 iron-chelating drugs approved by the United States for management of chronic secondary iron overload.
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Comparison of combined Deferiprone and Deferoxamine therapy vs. Deferiprone or Deferoxamine monotherapy
Pepe A. et al. J Cardiovasc Magn Reson. 2013 Jan 16;15:1
Combined DFP +DFO is more efficient for liver iron clearance
Liver Heart
But NOT for the heart-without effect on heart function, after 18 months.
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Combined chelation therapy with subcutaneous Deferoxamine and oral Deferiprone reduces myocardial iron and improves cardiac function.
ESVI: LV end-systolic volume index
Myocardial and Liver T2* improved over 12 months
Improvement in LVEF and ESVI over 12 months.
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Reduced iron after 3 years of therapy
Reduction in Cardiac Iron
Enhanced T2* value after 3 years of EXJADE therapy
EXJADE JADENU® (deferasirox)
Reduction in Liver iron concentration
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CLINICAL CASES
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22 YEAR OLD MALE, THALASSEMIA MAJOR
2015 Received 1 packed cell every 15 days • Oral Deferoxamine. • EF: 60% • T2*: 9.4 ms
1.5 years later • Chelation changed to IV Deferoxamine • EF increased to 63% • T2*: 10.5 ms.
Courtesy of Dr. Zahra Hoodbhoy and Dr. Babar Hasan, Department of Paediatrics and Child Health, Aga Khan University
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15 YEAR OLD MALE, THALASSEMIA MAJOR, NYHA CLASS 1
28
2016 Received 1 packed cell every 15 days • On daily oral defesirox • EF: 63% • T2*: 6.2 ms
2 years later • EF increased to 65% • T2*: 10.1 ms.
Courtesy of Dr. Zahra Hoodbhoy and Dr. Babar Hasan, Department of Paediatrics and Child Health, Aga Khan University
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Summary
• Therapy of iron overload states is important to prevent or reverse cardiac dysfunction
• The aim of the treatment is to prevent possible organs damage
• MRI is a useful tool to monitor treatment and response
• MRI can measure iron overload using T2* MRI and assess cardiac function using cine MRI
• Dedicated post-processing tool is needed to analyse T2* MR images and cine MR images
• A reduction in LVEF correlates with the myocardial iron content measured by T2* relaxation time
• Patients with a T2* relaxation time of less than 10 ms are at high risk for developing congestive heart failure and
need chelation therapy
• Iron management future is to be able to provide personalized chelation plan for different damaged organ