Transcript Iron Deficiency & Clinical Sequelae, Diagnosis

1
Desferrioxamine for
Treatment and Monitoring:
Iron overload in Thalassaemia
BY:
Dr. Mahdi Shahriari
2
Thalassaemia major:
transfusion without
chelation
250
50
Hereditary
haemochromatosis
(homozygous)
Hereditary
haemochromatosis
(heterozygous)
200
40
30
150
Threshold for cardiac
disease and early death
100
20
Increased risk of complications
50
10
Optimal level in chelated patients
0
0
Normal
10
20
30
40
0
Hepatic Iron (mg/g of Liver, Dry Weight)
Hepatic Iron (µmol/g Wet Weight)
Iron Loading Rates in Thalassaemia Major and
Hereditary Haemochromatosis
50
Age (years)
Olivieri N, et al. Blood. 1997;89:739.
3
4
Transfusion Therapy Results
in Iron Overload


1 blood unit contains 200 mg iron1
A 60-kg thalassaemia patient receiving 45 units of blood
annually has transfusional iron intake of 9 g iron/year
– 0.4 mg iron/kg body weight/day

In addition, up to 4 mg/day may be absorbed from the
gut1
– up to 1.5 g iron/year

Overload can occur after 10–20 transfusions1
Transfusional iron intake = volume of packed RBCs (mL) x 1.082
Volume of packed RBCs (mL) = volume of blood (mL) x haematocrit (%)2
Example:
285 mL blood transfused x 65% haematocrit =
185 mL RBCs x 1.08 mg iron/mL RBCs = 200 mg iron
1. Porter JB. Br J Haematol. 2001;115:239. 2. Cappellini MD, et al. Blood. 2006;107:3455.
5
Threshold Levels of Liver Iron


Liver iron concentration (LIC) predicts total body storage
iron in thalassaemia major1
Liver pathology
– Abnormal alanine aminotransferase (ALT) level if LIC >7 mg/g dry
weight2
– Liver fibrosis progression if LIC >16 mg/g dry weight3

Cardiac pathology at high levels
– LIC >15 mg/g dry weight associated with cardiac death
 All of 9/53 thalassaemia major patients who died4
 Improvement of subclinical cardiac dysfunction with venesection
post–bone-marrow transplant5
1. Angelucci E, et al. N Engl J Med. 2000;343:327. 2. Jensen PD, et al. Blood. 2003;101:91.
3. Angelucci E, et al. Blood. 2002;100:17. 4. Brittenham GM, et al. N Engl J Med. 1994;331:567.
5. Mariotti E, et al. Br J Haematol. 1998;103:916.
6


Change in serum ferritin
over time reflects change in LIC
Proportion of ferritin
measurements >2500 ng/mL
affects cardiac disease-free
survival1 (see graph)
Maintenance of serum ferritin
<2500 ng/mL
– Significantly correlates with
cardiac disease-free survival2–
5
<33% ferritin measures
>2500 ng/mL
1.00
1.00
0.75
0.50
Survival probability

Proportion Without Cardiac Disease
Benefits of Ferritin Control
33%–67% ferritin
measures
Ferritin
>2500 ng/mL
>2500
ng/mL
on >1/3 of occasions
0.75
0.50
0.25
>67% ferritin
measures
Maintenance of Lower Ferritin Levels
>2500 ng/mL
0.25
a Positive Indicator for Survival
0
. UCLH (unpublished data)
at
0.00
0
0
2
5
10
15
4
6 Years
8 of
10Follow-Up
12 14 16
Chelation Therapy (years)
1. Olivieri NF, et al. N Engl J Med. 1994;331:574. 2. Gabutti V, Piga A. Acta Haematol. 1996;95:26.
3. Telfer PT, et al. Br J Haematol. 2000;110:971. 4. Davis BA, et al. Blood. 2004;104:263.
5. Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.
7
Measuring and Interpreting
Serum Ferritin1-3
Advantages
Disadvantages
• Easy to evaluate
• Indirectly measures iron burden
• Inexpensive
• Fluctuates in response to
inflammation, abnormal liver
function, ascorbate deficiencies
• Serial measures to monitor chelation
therapy
• Positively correlates with morbidity
and mortality
• Individual measures may not
accurately reflect iron levels and
response to chelation therapy
• Allows longitudinal follow-up of
patients
Serial measurement of serum ferritin is a simple, reliable, indirect measure
of total body iron
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008. 3. Brittenham GM, et al. Blood. 2003;101:15-19.
8
Serum Ferritin Level (ng/mL)
Serum Ferritin Underestimates Iron
Burden in Thalassaemia Intermedia
Thalassaemia Patients
intermedia (TI)
Linear (TI)
10,000
9000
Thalassaemia major (TM)
Linear (TM)
8000
7000
6000
5000
4000
3000
2000
1000
0
0
5
10
15
20
25
30
35
40
45
50
Liver Iron Concentration (LIC) (mg Fe/g dry weight)
Serum ferritin correlates with LIC in patients with TM and TI. However, for the same LIC, patients
with TI had lower ferritin levels than corresponding patients with TM.
With permission from Taher A, et al. Haematologica. 2008;93:1584-1586.
9
Measuring LIC by Liver Biopsy1,2
Advantages
Disadvantages
• Directly measures LIC (quantitative, • Invasive, painful, and
specific, sensitive)
potentially serious
complications (eg, bleeding)
• Validated reference standard
• Sampling error risk, especially
• Measures nonheme storage iron
in patients with cirrhosis
• Evaluates liver histology/pathology
• Inadequate standardization
• Positively correlates with morbidity
between laboratories
and mortality
• Difficult to follow up
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
10
Mean Transverse Relaxation Rate <R2> (s-1)
Correlation Between R2 MRI and
Liver Biopsy
300
250
Hereditary
haemochromatosis
200
β-thalassaemia
150
β-thalassaemia/
haemoglobin E
50
100
40
Hepatitis
30
50
20
0.5
1.0
1.5
2.0
0
0
10
20
30
40
50
Biopsy Iron Concentration (mg/g-1 dry weight)
R2 MRI is a validated and standardized technique approved by the Australia Therapeutic
Goods Administration, FDA, and European Medicines Agency
With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.
11
Measuring LIC with MRI1,2
Advantages
Disadvantages
• Estimates iron content throughout
the liver
• Indirectly measures LIC
• Increasingly available worldwide
• Status of liver and heart can be
assessed in parallel
• Validated relationship with LIC
• Requires MRI imager with
dedicated imaging method
• Children younger than age 7
years require a general
anaesthetic
• Allows longitudinal patient followup
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
12
Left Ventricular Ejection Fraction (LVEF) (%)
T2* MRI—Emerging New Standard for Cardiac
Iron Assessment in TM Patients
90
80
70
60
50
Cardiac T2* value of
37 in a normal heart
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Heart T2* (ms)
Myocardial T2* values <20 ms are associated with
progressive and significant decline in LVEF
With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.
Photos courtesy of Maria D. Cappellini, MD.
Cardiac T2* value of 4
in a significantly iron
overloaded heart
13
Measuring Cardiac Iron with MRI1,2
Advantages
Disadvantages
• Rapidly assesses iron content in
the septum of heart
• Indirectly measures cardiac iron
• Relative iron burden can be
estimated reproducibly
• Requires MRI imager with
dedicated imaging method
• Functional parameters can be
examined concurrently
• Iron status of liver and heart can be
assessed in parallel
• Allows longitudinal follow-up
MRI is a nonvalidated method to rapidly and effectively assess
cardiac iron
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
14
Measuring Cardiac Iron with MRI1,2
Advantages
Disadvantages
• Rapidly assesses iron content in
the septum of heart
• Indirectly measures cardiac iron
• Relative iron burden can be
estimated reproducibly
• Requires MRI imager with
dedicated imaging method
• Functional parameters can be
examined concurrently
• Iron status of liver and heart can be
assessed in parallel
• Allows longitudinal follow-up
MRI is a nonvalidated method to rapidly and effectively assess
cardiac iron
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
15
Thresholds for Parameters Used to
Evaluate Iron Overload
Iron Overload State
Parameter
LIC (mg Fe/g dw)1
Serum ferritin
(ng/mL)2,3
Cardiac T2* (ms)4
Normal
Range
Mild
Moderate
Severe
<1.2
3–7
>7
>15
<300, male
<200, female
>20
>1000 to <2500
14–20
8–14
>2500
<8
1. Wood JC, et al. Blood. 2005;106:1460-1465. 2. Taher A, et al. Semin Hematol. 2007;44
(suppl 3):S2-S6. 3. Brissot P, et al. Blood Rev. 2008;22:195-210. 4. Anderson LJ, et al. Eur
Heart J. 2001;22:2171-2179.
16
Iron Overload in Thalassaemia

Thalassaemia major
– Iron overload primarily a
function of chronic
transfusion1
– Iron loading in a
regularly transfused
patient with
thalassaemia major is
approximately 7–9
g/year

Thalassaemia intermedia
– Iron overload primarily a
function of increased GI iron
absorption1
 Sporadic transfusion
– Although rate of iron
accumulation is slow,
complications do occur late
in life
– Iron loading may be on the
order of 2–5 g/year
1. Thalassaemia International Federation. Guidelines for the Clinical Management
of Thalassaemia, 2nd ed. 2007.
17
Goals of Chelation Therapy
in Thalassaemia

Prevent accumulation of harmful levels of body iron
– Start treatment before iron accumulation is excessive
– Maintain iron balance
 Match iron excretion with transfusional loading

Prevent tissue damage from labile iron pools
– Provide 24-hour chelation to
 Minimize non–transferrin-bound iron uptake into tissues
 Minimize exposure to labile iron in tissues and plasma


Minimize toxicity from excessive chelation
Rescue
– Necessary if iron has already accumulated in tissues
18
The Challenge of Iron Chelation
A Question of Balance

Uncoordinated iron

Uncoordinated chelator

Free-radical generation

Inhibition of metalloenzymes

Organ damage

Neurotoxicity

Growth failure

Growth failure

Organ failure

Bone marrow toxicity

Cardiac death
Too much iron
Graphic courtesy of Dr. J. Porter.
Too much chelator
19
Treatment Options for
Iron Chelation
Agent
Indication
TM
TI

Desferrioxamine1
Treatment of acute iron poisoning and
chronic iron overload due to transfusional
anaemias

Deferasirox2
Treatment of chronic iron overload due to
frequent transfusion in patients with
thalassaemia major, or due to infrequent
transfusion when desferrioxamine therapy is
inadequate or contraindicated

Treatment of iron overload in patients with
thalassaemia major when desferrioxamine
therapy is inadequate or contraindicated

Deferiprone3
TM = Thalassaemia major; TI = Thalassaemia intermedia
1.
2.
3.
Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998.
Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006.
Ferriprox (deferiprone). Summary of Product Characteristics. EMEA, 2007.
20
Administration of Chelating Agents
Agent
Administration
Desferrioxamine1,2
8–12 hours subcutaneous infusion 5–7 days per week;
dose, infusion duration, and number of administrations
to be decided according to patient age and severity of
iron overload
Deferasirox3
Once-daily oral dosing; initial daily dose of 20 mg/kg
(10–30 mg/kg)
Deferiprone4
Thrice-daily oral dosing; total daily dose of 75 mg/kg
1. Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998.
2. Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia,
2nd ed; 2007. 3. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006. 4. Ferriprox
(deferiprone). Summary of Product Characteristics. EMEA, 2007.
21
Increasing Efficacy of Chelation Therapy Has
Significantly Improved Patient Survival
1.00
Survival Probability
0.75
Birth cohort
1985–1997
1980–1984
1975–1979
1970–1974
1965–1969
0.50
1960–1964
0.25
(P < .00005)
0
0
5
10
15
Age (years)
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.
20
25
30
22
Monitoring Iron Load in Patients on Iron
Chelation Therapy

Thalassaemia major1
– Periodic monitoring of serum
ferritin level
 Assess LIC if increasing or
decreasing (<1000 ng/mL)
serum ferritin trend to avoid
under- or overtreatment
– In patients with LIC prior to
start, LIC (liver biopsy,
SQUID, or MRI) should be
repeated every year

Thalassaemia intermedia*
– Periodic monitoring of serum
ferritin, transferrin saturation
and LIC (or UIE, if LIC not
available)
– Decrease iron load to safe limit,
ie, LIC <4 mg/g dry weight (or
UIE <3 mg/24 h, if LIC not
available)
LIC = liver iron concentration; SQUID = superconducting quantum interference;
MRI = magnetic resonance imaging; UIE = urinary iron excretion.
* M. Domenica Cappellini, MD (oral communications, 2008)
1. Angelucci E, et al. Haematologica. 2008; In press.
23
Candidates for Aggressive
Iron Chelation



Serum ferritin values persistently >2500 ng/mL
Liver iron >15 mg/g dry weight
Significant cardiac disease
– Cardiac dysrhythmias
– Evidence of failing ventricular function
– Evidence of severe cardiac iron loading

Other indications
– Female patient considering pregnancy
– Patients planning bone marrow transplant
– Patient with active hepatitis C
Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia,
2nd ed. 2007.
24
Switching Chelating Agents

Patients receiving desferrioxamine standard-dose therapy who
develop severe iron overload (LIC >15 mg/g dry weight or serum
ferritin >3000 ng/mL)
– First, advise to strictly adhere to the chelation protocol
– In absence of a reversal of iron overload, shift to an intensive or
combined chelation therapy (grade B)


Available evidence favours use of deferiprone as chelator to be
associated with desferrioxamine (grade B)
Switch to alternative iron chelator is mandatory in cases of
nonadherence to desferrioxamine, or the occurrence of severe
adverse effects that preclude its continuation (grade D)
Angelucci E, et al. Haematologica. 2008, In press.
25
Conclusions






Many tools are available for assessing iron overload
Combining these tools allows more accurate
assessment of iron load
Serial ferritin evaluation (every 3–4 months) is the
most practical tool for following iron load and iron
chelation efficacy
Measure LIC (biopsy/MRI/SQUID) at least once
Assess cardiac iron load by MRI at least once
Closer monitoring is indicated in certain cases
–
–
–
Changes in transfusional iron load
Changes in chelation therapy
New signs of iron load toxicity
26
Combination of desferrioxamine,
defrasirox






• Both deferasirox and DFO improved cardiac T2* over 2
years in this patient population with severe iron overload.
• Improvement in cardiac T2* was comparable between
patients treated with deferasirox and DFO.
in the DFO treatment arm for the extension were low and the
study was not powered to detect differences
between groups over a 2-year treatment duration.
• The magnitude of cardiac T2* improvement with deferasirox
was consistent with that observed in previous long-term
studies of up to 3-year duration.
• Improvement with defrasirox or DFO treatment was
observed in patients with both low and high baseline LIC (<
and ≥15 mg Fe/g dw) and with moderate and severe baseline
cardiac iron (T2* 10–20 and <6–10 ms).
27
Combination of defroxamine, defrasirox











• Increased cardiac iron removal over the longer study duration may relate to the continued
decrease in LIC
from very high baseline levels.
– In patients with very high LIC, liver iron burden may have an impact on the rate of cardiac
iron removal
during defrasirox treatment. Thus, greater improvements in cardiac T2* over the long term
may occur
because LIC continues to decrease over time, or due to later initiation of cardiac iron
removal among
patients with high baseline LIC.
• Mean LVEF was stable and remained within normal limits in defrasirox and DFO patients.
• The long-term safety profiles of defrasirox and DFO were consistent with those observed
in previous
reports.
• We conclude that both defrasirox and DFO at the treatment doses used in this study are
effective for
improvement of cardiac iron over 2 years in patients with a wide range of baseline LIC and
cardiac T2* values.
28
Defroxamine, Desferrioxamine
Names
IUPAC name
N'-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide
Other names
N'-[5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)
propanoylamino]pentyl]-N-hydroxy-butane diamide
29
Preperations

Defroxamine is a bacterial siderophore
produced by the Actinobacteria
Streptomyces pilosus. It has medical
applications as a chelating agent used to
remove excess iron from the body.

The mesylate salt of DFO is commercially
available as 500 mg vial & 2 gm for IV and
SQ administration.
30
31
32
Mechanism

Deferoxamine acts by binding free iron in
the bloodstream and enhancing its
elimination in the urine. By removing
excess iron, the agent reduces the
damage done to various organs and
tissues, such as the liver, heart and
endocrine glands.
33
‫‪IV or SQ‬‬
‫‪‬‬
‫‪34‬‬
‫با توجه به نیمه عمر ده دقیقه ای دفروکسامین هر چه مدت‬
‫زمان تزریق بیشتر باشد تاثیر بیشتر است بنابراین در‬
‫شروع تزریق ‪ 9-6‬ساعته زیرجلدی توصیه میشود ولی در‬
‫کسانی که هنوز سن کمتر از دوو نیم سال دارند و فریتین‬
‫بیشتر از ‪1000‬؛ تزریق وریدی آهسته طی ‪ 4‬ساعت‬
‫یعنی از زمان نمونه گیری تا شروع تزریق خون توصیه‬
‫میشود تا ‪ 200‬میلی گرم آهن وارد شده توسص این کیسه‬
‫خون دفع شود‪.‬‬
!‫توجه ! توجه‬

Deferoxamine Mesylate for Injection,
should not be administered concurrently
with the blood transfusion as this can lead
to errors in interpreting side effects such
as rash, anaphylaxis and hypotension.
35
‫‪IV or SQ‬‬
‫‪‬‬
‫‪36‬‬
‫همچنین در کسانی که تزریق زیرجلدی شبانه قادر به کاهش‬
‫بار آهن نشده و بیمار نمیتواند از دفریپرون (به دلیل‬
‫عوارض گوارشی یا مفصلی یا هماتولوژیک آن) استفاده‬
‫کند یا تزریق مداوم زیرجلدی (با یک بار تعویض اسکالپ‬
‫در شبانه روز) را تحمل نمیکند؛ و فریتین بیشتر از ‪2500‬‬
‫باشد تزریق وریدی ‪ 24‬ساعته (‪ 5-3‬روز در ماه) مفید‬
‫است‪.‬در این صورت دوز دفروکسامین ‪ 50-60‬میلی گرم‬
‫در شبانه روز محاسبه میشود‪.‬‬
IV INJECTION

The reconstituted solution is added to
physiologic saline, (e.g., 0.9% sodium
chloride, 0.45% sodium chloride), glucose
in water, or Ringer’s lactate solution.

The intravenous infusion rate should not
exceed 15 mg/kg/hr
37
Stability after Reconstitution

The product should be used immediately
after reconstitution (commencement of
treatment within 3 hours) for
microbiological safety. When reconstitution
is carried out under validated aseptic
conditions (in a sterile laminar flow hood
using aseptic technique), the product may
be stored at room temperature for a
maximum period of 24 hours before use.
38
Stability after Reconstitution

Do not refrigerate reconstituted solution.
Reconstituting Deferoxamine Mesylate for
Injection, in solvents or under conditions
other than indicated may result in
precipitation.

Turbid solutions should not be used.
39
Drug Interactions

Vitamin C: Patients with iron overload
usually become vitamin C deficient,
probably because iron oxidizes the
vitamin. As an adjuvant to iron chelation
therapy, vitamin C in doses up to 200 mg
for adults may be given in divided doses,
starting after an initial month of regular
treatment with Desferal .
40

Vitamin C increases availability of iron for
chelation. In general, 50 mg daily suffices
for children under 10 years old and 100
mg daily for older children. Larger doses of
vitamin C fail to produce any additional
increase in excretion of iron complex.

Vitamin C supplements should not be
given to patients with cardiac failure.
41
Adverse Reactions

At the Injection Site: localized irritation,
pain, burning, swelling, induration,
infiltration, pruritus, erythema, wheal
formation, eschar, crust, vesicles, local
edema. Injection site reactions may be
associated with systemic allergic reactions
(see Body as a Whole, below).
42
Adverse Reactions

Hypersensitivity Reactions and Systemic
Allergic Reactions: generalized rash,
urticaria, anaphylactic reaction with or
without shock, angioedema.

Body as a Whole: Local injection site
reactions may be accompanied by
systemic reactions like arthralgia, fever,
headache, myalgia, nausea, vomiting,
abdominal pain, or asthma.
43
Adverse Reactions



Infections with Yersinia and Mucormycosis
have been reported in association with
Deferoxamine mesylate use
. Cardiovascular: tachycardia,
hypotension, shock.
Digestive: abdominal discomfort, diarrhea,
nausea, vomiting.
44
Adverse Reactions

Hematologic: blood dyscrasia
(thrombocytopenia, leukopenia).

Hepatic: Increased transaminases, hepatic
dysfunction.
45
Adverse Reactions

Musculoskeletal: Muscle spasms. Growth
retardation and bone changes (e.g.,
metaphyseal dysplasia) are common in
chelated patients given doses above 60
mg/kg, especially those who begin iron
chelation in the first three years of life. If
doses are kept to 40 mg/kg or below, the
risk may be reduced (see WARNINGS,
PRECAUTIONS/Pediatric Use).
46
Adverse Reactions

Nervous System: neurological
disturbances including dizziness,
peripheral sensory, motor, or mixed
neuropathy, paresthesias, seizures;
exacerbation or precipitation of aluminumrelated dialysis encephalopathy
47
Adverse Reactions

Special Senses: High-frequency sensorineural
hearing loss and/or tinnitus are uncommon if
dosage guidelines are not exceeded and if dose
is reduced when ferritin levels decline. Visual
disturbances are rare if dosage guidelines are
not exceeded. These may include decreased
acuity, blurred vision, loss of vision,
dyschromatopsia, night blindness, visual field
defects, scotoma, retinopathy (pigmentary
degeneration), optic neuritis, and cataracts.
48
Adverse Reactions

Respiratory: acute respiratory distress
syndrome (with dyspnea, cyanosis, and/or
interstitial infiltrates) (see WARNINGS).

Skin: very rare generalized rash.

Urogenital: dysuria, acute renal failure,
increased serum creatinine and renal
tubular disorders
49
50
51
Patient Presentation


12-year-old boy of Mediterranean origin
Previously diagnosed with
– β-thalassaemia major at age 6 months
– Hepatitis C virus infection at age 4 years




Splenectomized at the age of 6 years
Received ~45 packed red blood cell transfusions
in his childhood
Never received iron chelation therapy
Presenting for assessment of iron overload
52
Relevant Laboratory Value
Serum ferritin level = 7200 ng/mL
How reliable is serum ferritin for the
assessment of iron overload in this case?
53
Case Continues—Liver Biopsy

A liver biopsy was recommended
– To determine the liver iron concentration
– To evaluate histopathologic changes secondary
to hepatitis C infection

Patient’s mother refused due to concerns about
the associated risks of invasive intervention
54
Measuring LIC by Liver Biopsy1,2
Advantages
Disadvantages
• Directly measures LIC (quantitative, • Invasive, painful, and
specific, sensitive)
potentially serious
complications (eg, bleeding)
• Validated reference standard
• Sampling error risk, especially
• Measures nonheme storage iron
in patients with cirrhosis
• Evaluates liver histology/pathology
• Inadequate standardization
• Positively correlates with morbidity
between laboratories
and mortality
• Difficult to follow up
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
55
Case Continues—Assessing Liver
Iron
Patient underwent R2 MRI of the liver = 16
mg/g dry weight
How well does liver R2 MRI correlate
with liver biopsy?
56
Mean Transverse Relaxation Rate <R2> (s-1)
Correlation Between R2 MRI and
Liver Biopsy
300
250
Hereditary
haemochromatosis
200
β-thalassaemia
150
β-thalassaemia/
haemoglobin E
50
100
40
Hepatitis
30
50
20
0.5
1.0
1.5
2.0
0
0
10
20
30
40
50
Biopsy Iron Concentration (mg/g-1 dry weight)
R2 MRI is a validated and standardized technique approved by the Australia Therapeutic
Goods Administration, FDA, and European Medicines Agency
With permission from St. Pierre TG, et al. Blood. 2005;105:855-861.
57
Measuring LIC with MRI1,2
Advantages
Disadvantages
• Estimates iron content throughout
the liver
• Indirectly measures LIC
• Increasingly available worldwide
• Status of liver and heart can be
assessed in parallel
• Validated relationship with LIC
• Requires MRI imager with
dedicated imaging method
• Children younger than age 7
years require a general
anaesthetic
• Allows longitudinal patient followup
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
58
Case Continues—Assessing Cardiac
Iron
The patient underwent myocardial T2* MRI =
16 ms
Can cardiac dysfunction be predicted on
the basis of this value alone?
59
Left Ventricular Ejection Fraction (LVEF) (%)
T2* MRI—Emerging New Standard for Cardiac
Iron Assessment in TM Patients
90
80
70
60
50
Cardiac T2* value of
37 in a normal heart
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Heart T2* (ms)
Myocardial T2* values <20 ms are associated with
progressive and significant decline in LVEF
With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.
Photos courtesy of Maria D. Cappellini, MD.
Cardiac T2* value of 4
in a significantly iron
overloaded heart
60
T2* and Left Ventricular Ejection
Fraction (LVEF)
A shortening of
myocardial T2* to <20
ms (ie, increased
myocardial iron) is
associated with an
increased chance of
decreased LVEF
T2* Value
(ms)
Chance of
Decreased
LVEF
>20
Low chance
10–20
10%
8–10
18%
6
38%
4
70%
TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
61
Measuring Cardiac Iron with MRI1,2
Advantages
Disadvantages
• Rapidly assesses iron content in
the septum of heart
• Indirectly measures cardiac iron
• Relative iron burden can be
estimated reproducibly
• Requires MRI imager with
dedicated imaging method
• Functional parameters can be
examined concurrently
• Iron status of liver and heart can be
assessed in parallel
• Allows longitudinal follow-up
MRI is a nonvalidated method to rapidly and effectively assess
cardiac iron
1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of
thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.
62
Thresholds for Parameters Used to
Evaluate Iron Overload
Iron Overload State
Parameter
LIC (mg Fe/g dw)1
Serum ferritin
(ng/mL)2,3
Cardiac T2* (ms)4
Normal
Range
Mild
Moderate
Severe
<1.2
3–7
>7
>15
<300, male
<200, female
>20
>1000 to <2500
14–20
8–14
>2500
<8
1. Wood JC, et al. Blood. 2005;106:1460-1465. 2. Taher A, et al. Semin Hematol. 2007;44
(suppl 3):S2-S6. 3. Brissot P, et al. Blood Rev. 2008;22:195-210. 4. Anderson LJ, et al. Eur
Heart J. 2001;22:2171-2179.
63
Conclusions

Assessment of iron overload is essential in the clinical
management of patients with thalassaemia because it
guides chelation therapy

Historically, serum ferritin and liver biopsy have been the
diagnostic methods of choice
– However, limitations to the reliability of the first and invasiveness
of the latter call for novel noninvasive approaches

Liver R2 MRI and cardiac MRI T2* are becoming highly
sought methods for the diagnosis of iron overload and
monitoring of chelation therapy
64