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Update on Imaging: Detection of Iron in Liver and Heart. Tim St. Pierre, BSc, PhD Professor School of Physics The University of Western Australia Crawley, Australia. Iron Loading Is Different in Different Organs. Why Is Measurement of Liver Iron Concentration Important?.

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update on imaging detection of iron in liver and heart

Update on Imaging: Detection of Iron in Liver and Heart

Tim St. Pierre, BSc, PhD

Professor

School of Physics

The University of Western Australia

Crawley, Australia

why is measurement of liver iron concentration important
Why Is Measurement of Liver Iron Concentration Important?
  • A patient’s liver iron concentration (LIC) value is the best measure of total body iron stores
  • A patient’s LIC value enables better informed decisions on when to
    • Initiate chelation therapy
    • Increase chelation dose
    • Decrease chelation dose
    • Change mode of chelator delivery (eg, IV mode)
lic is a reliable measure of total body iron stores in patients with thalassaemia major
LIC Is a Reliable Measure of Total Body Iron Stores in Patients with Thalassaemia Major

There is a very strong correlation between LIC and total body iron stores in thalassaemia major patients

Abbreviation: LIC, liver iron concentration.

With permission from Angelucci E, et al. N Engl J Med. 2000;343:327-331.

lic thresholds and associated risks
LIC Thresholds and Associated Risks

1. Olivieri NF, Brittenham GM. Blood. 1997;89:739-761.

lic and long term prognosis
LIC and Long-Term Prognosis

32 thalassaemia major patients followed for median period of 13.6 years after single biopsy LIC measurement

Telfer PT, et al. Br J Haematol. 2000;110:971-977.

why is measurement of heart iron important
Why Is Measurement of Heart Iron Important?
  • Heart iron measurements (by cardiac MRI) have been shown to have a high sensitivity and specificity for predicting cardiac failure within 12 months for thalassaemia major patients
  • In a study of 652 thalassaemia major patients
    • 83% of patients who developed arrhythmia had a cardiac T2* of <20 ms
    • 98% of patients who developed heart failure had a cardiac T2* of <10 ms

Kirk P, et al. Circulation. 2009;120: in press.

heart iron changes generally lag behind liver iron changes
Heart Iron Changes Generally Lag Behind Liver Iron Changes

With permission from Noetzli LJ, et al. Blood. 2008;112:2973-2978.

methods of monitoring iron loading

Methods of Monitoring Iron Loading

Serum ferritin

Liver biopsy

Biomagnetic susceptometry

MRI

is serum ferritin a reliable indicator of lic
Is Serum Ferritin a Reliable Indicator of LIC?
  • Cross-sectional study of 37 patients with sickle cell anaemia and 74 patients with thalassaemia major
  • Only 57% of the variability in plasma ferritin concentration could be explained by the variation in hepatic iron stores
  • The 95% prediction intervals for hepatic iron concentration, given the plasma ferritin, were so broad as to make a single determination of plasma ferritin an unreliable predictor of body iron stores
  • Eg, given a plasma ferritin of 1000 ng/mL, the 95% prediction interval for hepatic storage iron was 0–6.948 mg Fe/g liver, wet weight

Brittenham GM, et al. Am J Hematol. 1993;42:81-85.

serum ferritin in thalassaemia major and intermedia
Serum Ferritin in Thalassaemia Major and Intermedia

Abbreviations: TI, Thalassaemia intermedia; TM, Thalassaemia major.

With permission from:

Origa R, et al. Haematologica. 2007;92:583-588.

With permission from:

Taher A, et al. Haematologica. 2008;93:1584-1585.

Serum ferritin has almost no sensitivity or specificity for iron stores in thalassaemia intermedia

serum ferritin
Serum Ferritin

Serum ferritin can be used for monitoring trends in patient transfusional iron loading

Serum ferritin does not give reliable information on degree of patient iron loading

measuring liver iron concentration by biopsy
Measuring Liver Iron Concentration by Biopsy
  • Methods
    • Percutaneous
    • Laparoscopic
    • Transjugular
  • Risk of Complications
    • Death 1:10,000–1:12,000
    • Bile leak 1:1,000
    • Bleeding 1:100
    • Any pain 1:4
    • Significant pain 1:10–1:20

Siegel CA, et al. Cleve Clin J Med. 2005;72:199-224.

heterogeneity of iron concentration throughout the liver
Heterogeneity of Iron Concentration Throughout the Liver

Abbreviations: CV, coefficient of variation; dw, dry weight; LIC, liver iron concentration.

Ambu R, et al. J Hepatol. 1995;23:544-549. Barry M, Sherlock S. Lancet.1971;1:100-103. Clark PR, et al. Magn Reson Med. 2003;49:572-575. Emond MJ, et al. Clin Chem.1999;45:340-346. Kreeftenberg HG, et al. Clin Chim Acta. 1984;144:255-262.

noninvasive methods of tissue iron measurement
Noninvasive Methods of Tissue Iron Measurement

Biomagnetic Liver Susceptometry

(SQUID)

biomagnetic liver susceptometry
Biomagnetic Liver Susceptometry

Liquid helium

Cryogenic package

Bellows

Liver

Liver

Fischer R. In: Magnetism In Medicine: A Handbook. Wiley-VCH;1998:286-301.

needle biopsy lic vs biomagnetic liver susceptometry
Needle Biopsy LIC vs Biomagnetic Liver Susceptometry
  • There is a good correlation between LIC by biopsy and LIC by SQUID up to 3.5 mg Fe/g wet tissue
  • Above 3.5 mg Fe/g wet tissue, correlation decreases, most likely because of increased sampling error on biopsy

Fischer R. In: Magnetism In Medicine: A Handbook. Wiley-VCH;1998:286-301.

noninvasive methods of tissue iron measurement1
Noninvasive Methods of Tissue Iron Measurement

Magnetic Resonance Imaging

(MRI)

principles of mri
Principles of MRI
  • Magnetic field and radio signal pulses
  • Initial pulse excites protons in tissue
  • Signal received from tissue decays with time after initial pulse
  • Rate of decay different for different tissues
  • Rate of decay highly influenced by presence of iron
  • Rate known as either R2 or R2* depending on data acquisition technique
  • Characteristic time of decay known as T2 or T2* depending on data acquisition technique

Clark PR, St. Pierre TG. Mag Res Imaging. 2000;18:431-438.

calculating tissue iron from mri measurements
Calculating Tissue Iron from MRI Measurements

Typical non–iron-loaded tissue

Relaxometry methods, eg R2 or R2*

Intensity ratio methods

The rate at which signal decays is known as R2 or R2*

100

The characteristic time of decay is known as T2 or T2*

80

60

Signal Strength

Effect of increasing iron loading

40

20

0

0

5

10

15

20

Echo Time (ms)

St. Pierre TG. Ann N Y Acad Sci. 2005;1054:379-385. Graphic courtesy of Dr. Tim St. Pierre.

methods of measurement of tissue iron concentrations with mri
Methods of Measurement of Tissue Iron Concentrations with MRI

Relaxometry measurement of R2 is the most widespread method for measurement of liver iron concentration

Relaxometry measurement of T2* is the most widespread method for assessing iron in the heart

proton transverse relaxation rate r2 image and distribution
Proton Transverse Relaxation Rate (R2) Image and Distribution

LIC = 7.7 mg.g-1

Transverse Relaxation Rate R2 (s-1)

R2 (s-1)

With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.

liver r2 images and distributions
Liver R2 Images and Distributions

Non–iron-loaded subject

3 iron-loaded subjects

R2 distribution shifts to higher values as LIC increases

With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.

dissected liver samples
Dissected Liver Samples

Mean R2 vs iron concentration for 32 cubes of liver dissected from a single iron–loaded liver postmortem

Mean Transverse Relaxation Rate <R2> (s-1)

Iron Concentration (mg/g dw)

With permission from Clark PR, et al. Mag Res Med. 2003;49:572–575.

relationship between r2 and needle biopsy lic dw
Relationship Between R2 and Needle Biopsy LIC (dw)

Mean Transverse Relaxation Rate <R2> (s-1)

Biopsy Iron Concentration (mg/g dry tissue)

With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.

r2 mri is a reliable measure of lic
R2-MRI Is a Reliable Measure of LIC

High sensitivity and specificity over entire range of LIC encountered

Unaffected by presence of fibrosis/cirrhosis

Fibrosis stages:

0–1 = 

2–4 = 

5–6 = 

With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.

example r2 mri measurements to monitor iron chelation therapy
Example—R2-MRI Measurements to Monitor Iron Chelation Therapy

Low

iron

High

iron

LIC map

Before chelation therapy intervention

Mean LIC = 16.0

After 12 months of chelation therapy intervention

Mean LIC = 1.6

Graphic courtesy of Dr. Tim St. Pierre.

methods for heart iron assessment
Methods for Heart Iron Assessment

T2* methods are used to assess heart iron loading

Echo time increasing

With permission from Westwood M, et al. J Magn Reson Imaging. 2003;18:33-39.

relationship between t2 and cardiac function
Relationship Between T2* and Cardiac Function

With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.

relationship between r2 and cardiac function
Relationship Between R2* and Cardiac Function

Transform using R2* = 1/T2*

With permission from Anderson, LJ, et al. Eur Heart J. 2001;22:2171-2179.

Abbreviation: LVEF, left ventricular ejection fraction.

Graphic courtesy of Dr. Tim St. Pierre

calibration of cardiac t2 r2 against tissue iron concentration
Calibration of Cardiac T2*/R2* Against Tissue Iron Concentration

Preliminary calibration over small iron concentration range obtained from a single human heart

With permission from Ghugre, et al. Magn Reson Med. 2006;56:681-686.

implementing these methods at your institution1
Implementing These Methods at Your Institution
  • MRI data acquisition
    • Relatively simple for liver
    • More involved for heart
      • Requires extra hardware and software on scanner
  • MRI data analysis
    • Problematic for liver
      • High risk of erroneous analysis due to low signal to noise ratios; need to account for background noise, etc.
    • Relatively simple for heart
implementing these methods at your institution2
Implementing These Methods at Your Institution
  • MRI data acquisition
    • Liver
      • No face-to-face training required
    • Heart
      • May require expert training of technicians
  • MRI data analysis
    • Liver
      • ISO9001 Quality Assurance should be implemented, or data analysis should be outsourced to quality assured core lab
    • Heart
      • Technicians should receive training from experts
when to measure iron in the liver vs the heart
When to Measure Iron in the Liver vs the Heart
  • Patients on regular blood transfusion
    • Measure liver iron annually
    • Measure heart iron annually after 20 units have been transfused
  • Patients with hereditary haemochromatosis
    • Measure liver iron at diagnosis if >40 years of age and serum ferritin >1000 ng/mL
  • Patients with thalassaemia intermedia
    • Measure liver and heart iron annually after age 10 years
    • If the baseline cardiac T2* in normal range, subsequent cardiac T2* no more frequent than 3–5 years unless there is difficulty controlling the liver iron
conclusions
Conclusions
  • It is now possible in most major hospitals to monitor iron in the liver and the heart using magnetic resonance imaging
  • The ability to measure iron in these 2 organs provides the basis for making better informed decisions concerning the need to adjust patients’ chelation regimens