Update on Imaging: Detection of Iron in Liver and Heart

Tim St. Pierre, BSc, PhDProfessor

School of PhysicsThe University of Western Australia

Crawley, Australia

Iron Loading Is Different in Different Organs

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

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 Eng J Med. 2000;343:327-331.

LIC Thresholds and Associated Risks

LIC Threshold

(mg Fe/g dry weight)

Clinical Relevance

1.8 Upper 95% of normal

3.2 Suggested lower limit of optimal range for LICs for chelation therapy in transfusional iron overload1

7.0 Suggested upper limit of optimal range for LICs for transfusional iron overload and threshold for increased risk of iron-induced complications1

15.0 Threshold for greatly increased risk for cardiac disease and early death in patients with transfusional iron overload1

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

LIC and Long-Term Prognosis

Initial LIC(mg Fe/g dw)

13-Year Cardiac Disease–Free

Survival

Patients (n) Group

<7 93.3% (SE 6.4) 15 (i)

7–15 71.4% (SE 17.1) 7 (ii)

>15 50.0% (SE 15.8) 10 (iii)

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

32 thalassaemia major patients followed for median period of 13.6 years after single biopsy LIC measurement32 thalassaemia major patients followed for median period of 13.6 years after single biopsy LIC measurement

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

Relationship Between Liver and Heart Iron

Heart Iron Changes Generally Lag Behind Liver Iron Changes

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

Strengths and Weaknesses of Various Imaging Methods

Methods of Monitoring Iron Loading

• Serum ferritin

• Liver biopsy

• Biomagnetic susceptometry

• MRI

Methods of Monitoring Body Iron Stores

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

Serum Ferritin in Thalassaemia Major and Intermedia

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

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

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

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

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

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

• 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

Heterogeneity of Iron Concentration Throughout the Liver

Sample Size and Type CV of LIC Pathology Source

Needle biopsy

(<4 mg dw)19% Normal Emond, et al. 1999

Kreeftenberg, et al. 1984

Needle biopsy

(<4 mg dw)>40% End-stage

liver diseaseEmond, et al. 1999

Kreeftenberg, et al. 1984

Needle biopsy

(9 mg dw)9% Normal Barry, Sherlock. 1971

“Cubes”

(200–300 mg wet weight)17%

24%

-thalassaemia

Noncirrhotic

Ambu, et al. 1995

“Cubes”

(1000–3000 mg wet weight)19% -thalassaemia

Part-cirrhotic

Clark, et al. 2003

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

Biomagnetic Liver Susceptometry(SQUID)

Biomagnetic Liver Susceptometry

Liver

Liver

Bellows

Cryogenic package

Liquid helium

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

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 Measurement

Magnetic Resonance Imaging(MRI)

Principles of MRI

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

• 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

• 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

Calculating Tissue Iron from MRI Measurements

Typical non–iron-loaded tissue

Effect of increasing

iron loading

Intensity ratio methods

Relaxometry methods, eg R2 or R2*

The rate at which signal decays is known

as R2 or R2*

The characteristic time of decay is

known as T2 or T2*

Echo Time (ms)

Sig

nal

Str

eng

th

100

80

60

40

20

015 200 5 10

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

• 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

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

R2 (s-1)Transverse Relaxation Rate R2 (s-1)

LIC = 7.7 mg.g-1

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.

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

Dissected Liver Samples

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

Iron Concentration (mg/g dw)

Mea

n T

rans

vers

e R

elax

atio

n R

ate

<R

2>

(s-1

)

Relationship Between R2 and Needle Biopsy LIC (dw)

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

Biopsy Iron Concentration (mg/g dry tissue)

Me

an

Tra

ns

ve

rse

Re

lax

ati

on

Ra

te <

R2>

(s

-1)

R2-MRI Is a Reliable Measure of LIC

• High sensitivity and specificity over entire range of LIC encountered

• Unaffected by presence of fibrosis/cirrhosis

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

Fibrosis stages:0–1 = 2–4 = 5–6 =

Example—R2-MRI Measurements to Monitor Iron Chelation Therapy

High iron

Low 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.Graphic courtesy of Dr. Tim St. Pierre.

Methods of Monitoring Heart Iron

Methods for Heart Iron Assessment

T2* methods are used to assess heart iron loading

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

Echo time increasing

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

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

0

20

40

60

80

100

0 50 100 150 200 250

R2* (s-1

)

Transform using R2* = 1/T2*

Graphic courtesy of Dr. Tim St. PierreGraphic courtesy of Dr. Tim St. PierreAbbreviation: LVEF, left ventricular ejection fraction.Abbreviation: LVEF, left ventricular ejection fraction.

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

Implementing These Methods at Your Institution

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 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

• 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

• 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