Letters to the Editor
`
`Disorders of Iron Metabolism
`
`Lack of correlation between iron overload
`cardiac dysfunction and needle liver biopsy iron
`concentration
`
`In 58 patients with transfusion dependent ane-
`mia, we compared cardiac function, as assessed by
`gated pooled cardiac scan at rest and during exer-
`cise stress, with liver iron concentrations (LIC) as
`determined by adequate biopsy samples. There
`was no relationship between LIC and cardiac func-
`tion and deaths occurred in patients with LIC lev-
`els below those that are usually associated with
`cardiac death. LIC should not be used as a surro-
`gate to determine risk of cardiac complications but
`purely for management of the hepatic iron load.
`Other methods, particularly magnetic resonance
`imaging, should be used to assess cardiac iron
`overload.
`
`haematologica 2005; 90:685-686
`
`(http://www.haematologica.org/journal/2005/5/685.html)
`
`In transfused thalassemia patients, liver iron concentra-
`tion (LIC) is said to reflect total iron body load.1
`Assessments by liver biopsy were regarded as the gold
`standard, despite problems with heterogeneity of iron dis-
`tribution and the small size of samples. LIC levels between
`7-15 mg/g dry weight are reported to indicate an increased
`risk of iron related toxicity and levels >15 mg/g dry weight
`a significant risk of fatal cardiomyopathy.2 A table has
`been proposed to indicate these risks.3
`Radionuclide ventriculography (MUGA scan) is a repro-
`ducible and accurate technique that measures resting left
`ventricular ejection fraction (LVEFrest), and left ventricular
`function during exercise (LVEFex). It is a valuable tool in
`the assessment of cardiac dysfunction, particularly sub-
`clinical forms.4 In 58 transfusion-dependent patients, we
`assessed whether LIC, measured on needle biopsy sam-
`ples, can predict subclinical cardiac dysfunction assessed
`by MUGA scan. The patients were aged between 10-45
`years (mean 22.6±6.5 years). There were 53 patients with
`thalassemia major, 3 with sickle cell disease and 2 with
`Diamond-Blackfan anemia. All were on similar transfusion
`regimes and received iron chelation therapy with desfer-
`rioxamine 40-50 mg/kg/infusion 5 days per week.
`Compliance was variable. Each patient had radionuclide
`gated pooled cardiac studies performed at rest and 55 were
`able to perform a semi-supine bicycle test to maximum
`exercise stress as described previously by our unit.5,6
`Liver iron concentration was measured on core needle
`biopsies performed within 6 months before or after the
`cardiac test. The dry weight of all biopsies exceeded 1g
`and all were at least 2 cm in total length. The hepatologist
`used a Menghini 1.6 mm needle and did not stop taking
`samples until satisfied that they were adequate. We have
`recently described our method of sample collection and
`assessments of LIC and degree of fibrosis.7
`Table 1 shows the LVEFrest, LVEFex and change in ejec-
`tion fraction (DLVEF) grouped according to LIC and in all
`patients; the same table also presents the number of
`
`Table 1. Ejection fraction results grouped according to liver iron
`concentration.
`
`N Minimum Maximum Mean
`
`S.D.
`
`Group 1 LIC <7 mg/g dry weight
`resting LVEF
`19
`exercise LVEF
`17
`DLVEF
`17
`*biopsy LIC (mg/g)
`19
`abnormal at rest
`1
`abnormal with exercise
`3
`percentage abnormal
`30
`
`48
`53
`-8
`1.200
`
`72
`82
`23
`6.800
`
`61
`68
`7
`4.238
`
`6.7
`9.0
`7.9
`1.606
`
`Group 2 LIC ≥≥7 mg/g and <15 mg/g dry weight
`resting LVEF
`25
`40
`25
`35
`exercise LVEF
`DLVEF
`25
`-7
`*biopsy LIC (mg/g)
`25
`7.030
`abnormal at rest
`5*
`abnormal with Exercise
`2
`percentage abnormal
`25
`
`70
`82
`24
`14.400
`
`57.3
`64.5
`7.2
`10.422
`
`7.8
`11.2
`7.9
`2.234
`
`Group 3 LIC ≥≥15 mg/g dry weight of liver
`resting LVEF
`14
`30
`exercise LVEF
`13
`57
`DLVEF
`13
`-5
`*biopsy LIC (mg/g)
`14
`17.000
`abnormal at rest
`1*
`abnormal with exercise
`2
`percentage abnormal
`21
`
`72
`81
`22
`62.000
`
`58.9
`69.7
`8.8
`32.417
`
`9.9
`7.9
`7.9
`15.076
`
`All patients
`resting LVEF
`exercise LVEF
`DLVEF
`*biopsy LIC (mg/g)
`abnormal at rest
`abnormal with exercise
`percentage abnormal
`
`72
`81
`24
`62.000
`
`30
`35
`-8
`1.200
`
`58
`55
`55
`58
`7
`16 (7 significantly)
`28
`
`58.6
`66.5
`7.5
`13.705
`
`8.2
`10.1
`7.9
`13.242
`
`*Two from group 2 and one patient from group 1 died.
`(descriptive statistics and regression analysis using Microsoft® Excel 2000.).
`Normal LVEFrest ≥ 52%. DLVEF > 10% of LVEFrest – i.e. if LVEFrest is 60%
`the DLVEF should be £6%. A significant reduction in DLVEF is £ 0. If the
`LVEFrest ≥70% a rise not expected as it considered that the patient was stressed
`even at rest in those circumstances; a fall in LVEFex was regarded as abnormal
`but only significant if ≥ 5%.
`
`patients with abnormal cardiac studies. There were no sig-
`nificant relationships between the patients’ ages and
`LVEFrest (p=0.75), LVEFex (p=0.2) or DLVEF (p=0.09), as
`evaluated by the t-test for independent samples using
`SPSS for Windows (version 8.0.0)
`Figure 1 shows LIC in relation to LVEFrest, LVEFex and
`DLVEF, illustrating that there are no significant relation-
`ships between the LIC and any of the LVEF results. No
`patient with only an abnormal DLVEF died, but three sub-
`sequently developed abnormal LVEFrest and were treated
`with intensified chelation therapy with improvement in
`
`haematologica/the hematology journal | 2005; 90(5) | 685 |
`
`
`Apotex Tech.
`Ex. 2022
`
`

`

`load, only one had an abnormal resting LVEF and only two
`had a significant reduction in their DLVEF. Magnetic reso-
`nance imaging (MRI) techniques can now provide an
`assessment of the myocardial iron load and accurate and
`reproducible evaluation of cardiac function.8-10 Studies have
`shown that liver iron concentration in chelated patients is
`a poor predictor of the amount of iron accumulated in the
`heart or of the risk of developing cardiomyopathy and that
`severe cardiac iron loading affects cardiac function nega-
`tively. In conclusion, there is no relationship between LIC
`by biopsy and cardiac function by MUGA. This analysis
`suggests that: (i) it is not useful to perform liver biopsies
`regularly to determine the risk of developing cardiomyopa-
`thy; (ii) cardiac risk should be assessed by echocardiogra-
`phy, MRI T2* and/or MUGA at rest and during exercise
`stress testing, if available; (iii) liver biopsies should be per-
`formed only to determine LIC and fibrosis for making
`appropriate clinical decisions related to the liver itself. The
`reasons why some patients who have complied very well
`with therapy and who maintain what is regarded as an
`acceptable LIC nevertheless have significant cardiac dys-
`function, and why other patients who are poorly compli-
`ant and have a high LIC manifest little evidence of car-
`diomyopathy, remain to be clarified.
`Vasili Berdoukas,* Carolyn Dakin,* Anthony Freeman,°
`Ian Fraser,# Athanassios Aessopos,@ Timothy Bohane*
`*Sydney Children's Hospital and the °Prince of Wales Hospital;
`#South Eastern Sydney Area Health Service of the Prince of Wales
`and the Sydney Children’s Hospital Randwick, Australia;
`@First Department of Medicine University of Athens, Laiko
`Hospital, Athens, Greece
`Key words: liver iron concentration, iron overload, thalassemia,
`cardiac dysfunction.
`Correspondence: Vasili Berdoukas, Thalassaemia Unit “Aghia
`Sophia” Children’s Hospital, Thivon and Levadias, Goudi,
`Athens, 11527, Greece. E-mail: plomari@hol.gr
`
`References
`
`1. Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani
`D, Giardini C, et al. Hepatic iron concentration and total body
`iron stores in thalassaemia major. N Engl J Med 2000;343:327-31.
`2. Brittenham GM, Griffith PM, Nienhuis AW, McLAren CE, Young
`NS, Tucker EE, et al. Efficacy of deferoxamine in preventing com-
`plications of iron overload in patients with thalassemia major. N
`Engl J Med 1994;331:567-73.
`3. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treat-
`ment of thalassemia Blood 1997;89:739-61.
`4. Leon MB, Borer JS, Bacharach SL, Green MV, Benz EJ Jr, Griffith P,
`et al. Detection of early cardiac dysfunction in patients with
`severe b-thalassemia and chronic iron overload. N Engl J Med
`1979;301:1143-8.
`5. Freeman AP, Giles RW, Berdoukas VA, Walsh WF, Choy D,
`Murray PC. Early left ventricular dysfunction and chelation thera-
`py in thalassaemia major. Ann Int Med 1983;99:450-4.
`6. Freeman AP, Giles RW, Berdoukas VA, Talley P and Murray PC.
`Sustained normalization of cardiac function by chelation therapy
`in thalassaemia major. Clin Lab Haematol 1989;11:299-307.
`7. Berdoukas V, Bohane T, Tobias V, De Silva K, Fraser I, Aessopos
`A, et al. Liver iron concentration and fibrosis in a cohort of trans-
`fusion-dependent patients on long-term desferrioxamine therapy.
`Eur Hem J 2005;5:572-8.
`8. Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell
`DJ. Comparison and effects of oral deferiprone and subcutaneous
`desferrioxamine on myocardial iron concentrations and ventricu-
`lar function in b-thalassaemia. Lancet 2002;360:516
`9. Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce
`NH, et al. Cardiovascular T2* magnetic resonance for the early
`diagnosis of myocardial iron overload. Eur Heart J 2001;22:2171-
`9.
`10. Wood JC, Tyszka M, Carson S, Nelson M, Coates T. Myocardial
`iron loading in transfusion-dependent thalassemia and sickle-cell
`disease. Blood 2003;20:103-5.
`
`Letters to the Editor
`
`A. LIC in relation to resting left ventricular
`ejection fraction
`
`쏆
`쏆
`
`쏆쏆쏆
`
`쏆
`
`쏆
`
`쏆
`
`쏆쏆
`쏆
`쏆쏆
`
`쏆쏆쏆
`
`쏆쏆쏆쏆
`쏆쏆
`쏆쏆
`쏆 쏆
`쏆쏆쏆쏆
`쏆쏆
`쏆쏆쏆쏆
`쏆
`
`쏆쏆
`
`0
`
`20
`
`40
`LVEFrest
`
`60
`
`80
`
`B. LIC in relation to exercise left
`ventricular ejection fraction
`
`쏆
`
`쏆
`
`쏆 쏆
`
`쏆
`
`쏆
`쏆쏆 쏆쏆쏆
`쏆
`쏆
`쏆
`쏆쏆쏆 쏆쏆쏆쏆
`쏆 쏆 쏆
`쏆 쏆쏆
`쏆쏆
`쏆 쏆 쏆쏆
`80
`60
`LVEFex
`
`0
`
`20
`
`40
`
`C. LIC in relation to change in LVEF
`with exercise
`
`70000
`60000
`50000
`40000
`30000
`20000
`10000
`0
`
`LIC in mmg/mg dry weight
`
`p=0.78
`
`70000
`60000
`50000
`40000
`30000
`20000
`10000
`0
`
`p=0.7
`
`LIC in mmg/mg dry weight
`
`100
`
`70000
`60000
`50000
`40000
`30000
`20000
`10000
`0
`
`쏆
`
`쏆
`
`쏆
`
`쏆쏆
`쏆
`쏆
`쏆쏆 쏆
`쏆쏆 쏆
`쏆쏆
`쏆쏆
`쏆
`쏆
`쏆 쏆
`
`쏆
`
`쏆쏆쏆
`쏆쏆
`쏆쏆
`쏆쏆쏆
`쏆쏆
`
`0
`
`10
`DDLVEF
`
`쏆
`쏆쏆 쏆
`
`쏆쏆
`쏆쏆
`
`20
`
`30
`
`LIC in mmg/mg dry weight
`
`쏆
`쏆
`
`-10
`p=0.996
`
`Figure 1. A. LIC in relation to the LVEFrest and the regression
`analysis. The grey line is the line of best fit; r=0.04 and r2=0.001.
`B. LIC and LVEFax and regression analysis. The grey line is the line
`of best fit; r= 0.1 and r2=0.01. C. LIC in relation to the DDLVEF and
`regression analysis. The grey line is the line of best fit. The r and
`r2 are almost zero indicating that the line of best fit is almost hor-
`izontal.
`
`their cardiac function. The LVEF results in patients from
`group 3 (LIC ≥15 mg/g dry weight) were compared with
`those in group 1 (LIC <7 mg/g dry weight) and group 2 (LIC
`≥7 mg/g to <15 mg/g dry weight) combined and the results
`in groups 2 and 3 were compared with those in group 1: no
`statistically significant difference was found (assessed by
`the t-test for equality of means-SPSS). A Pearson 2- tailed
`correlation (SPSS) analyzing the LVEF results and LIC
`showed no significant correlation between any cardiac
`measure and liver iron.
`There were two deaths in group 2 and one in group 1.
`The percentage of patients with abnormal cardiac function
`in each group as well as the number of deaths do not sup-
`port the threshold values proposed by Olivieri and
`Brittenham.2,3 In 15 patients with a LIC in the range in
`which one might expect serious problems from iron over-
`
`| 686 | haematologica/the hematology journal | 2005; 90(5)
`
`
`Apotex Tech.
`Ex. 2022
`
`