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Diagnosis of Iron Overload

Diagnosis of Iron Overload. M. Domenica Cappellini, MD Professor of Internal Medicine University of Milan Maggiore Hospital Milan, Italy. Iron Overload and Disease States. Causes of Iron Overload. Primary (hereditary)

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Diagnosis of Iron Overload

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  1. Diagnosis of Iron Overload M. Domenica Cappellini, MDProfessor of Internal MedicineUniversity of MilanMaggiore HospitalMilan, Italy

  2. Iron Overload and Disease States

  3. Causes of Iron Overload • Primary (hereditary) • Resulting from a primary defect in the regulation of iron balance, eg, hereditary haemochromatosis • Secondary (acquired) • Caused by another condition or by its treatment • Anaemias requiring repeated blood transfusion (eg, thalassaemia, sickle cell disease, and myelodysplastic syndromes) • Ineffective erythropoiesis • Toxic ingestion Feder JN, et al. Nat Genet. 1996;13:399. Porter JB. Br J Haematol. 2001;115:239.

  4. Conditions at Risk of Iron OverloadSources of Iron AbsorptionTransfusion Redistribution • Haemochromatosis +++ • Thalassaemia major + +++ • Thalassaemia intermedia +++ + • Sideroblastic anaemia ++++ • CDA ++++ • Aplasias +++ • Chronic haemolytic anaemias + • Myelodysplasias ++ • Off-therapy leukaemias + • Bone marrow transplant + + • Liver disease + • Porphyria cutanea tarda + • Neonatal iron overload +++ • Atransferrinaemia +++ • Aceruloplasminaemia ++ • Dietary iron overload ++ • Iatrogenic iron overload ++ • Dialysis patients ++ Courtesy of A. Piga.

  5. Iron overload Capacity of serum transferrin to bind iron is exceeded Non–transferrin-bound iron circulates in the plasma Complications of Iron Overload Excess iron promotes the generation of free hydroxyl radicals, propagators of oxygen-related tissue damage Insoluble iron complexes are deposited in body tissues and end-organ toxicity occurs Liver cirrhosis/ fibrosis/cancer Diabetes mellitus Cardiac failure Growth failure Infertility Courtesy of Dr. M. D. Cappellini.

  6. Consequences of Iron-Mediated Toxicity During Iron Overload Increased LPI or “free” iron Hydroxyl radical generation Lipid peroxidation Organelle damage TGF-β 1 Lysosomal fragility Collagen synthesis Enzyme leakage Fibrosis Cell death LPI = labile plasma iron; TGF = transforming growth factor. Cohen AR & Porter JB. In: Steinberg MH, et al, eds. Cambridge University Press;2001:979–1027.

  7. Organ Systems Susceptible to Iron Overload Clinical sequelae of iron overload Pituitary → impaired growth Heart → cardiomyopathy, cardiac failure Liver → hepatic cirrhosis Pancreas → diabetes mellitus Gonads → hypogonadism, infertility Courtesy of Dr. M. D. Cappellini.

  8. 250 200 150 100 50 Liver Iron and Risk from Iron Overload Thalassaemia major: transfusion without chelation 50 Homozygous haemochromatosis 40 Heterozygote Hepatic Iron (µmol/g wet weight) 30 Hepatic iron, mg/g of liver, dry weight Threshold for cardiacdisease and early death 20 Increased risk of complications 10 Optimal level in chelated patients Normal 0 0 0 10 20 30 50 40 Age (years) Olivieri N, et al. Blood. 1997;89:739.

  9. Assessing Iron Overload

  10. Diagnosis of Iron Overload • Established • % transferrin saturation • Ferritin • Liver iron concentration (biopsy) • Investigational • Biomagnetic liver susceptometry (SQUID) • Magnetic resonance imaging SQUID = superconducting quantum interference device.

  11. Transferrin Saturation • Normal values: 16%–30% • > 40%: iron overload

  12. Monitoring—Plasma Ferritin • Relatively noninvasive • Inexpensive • Routine laboratory assay • Values confounded by • Inflammation • Liver function • Ascorbate status 24,000 Sickle cell anaemia (n = 37) Thalassaemia major (n = 74) 12,000 Plasma Ferritin (µg/L) 8000 4000 0 0 4000 8000 12000 Hepatic Iron (µg Fe/g liver) Brittenham G, et al. Am J Hematol. 1993;42:81.

  13. Serum Ferritin and Risk fromIron Loading • Change in serum ferritin over time reflects change in liver iron concentration • Sequential evaluation of ferritin provides good index of chelation history1 • Maintenance of serum ferritin <2500 µg/L significantly correlates with cardiac disease-free survival2-5 1. Gabutti V, et al. Acta Haematol. 1996;95:26. 2. Olivieri NF, et al. N Engl J Med. 1994;331:574. 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.

  14. Measuring and Interpreting Serum Ferritin

  15. Monitoring—Why LIC? • Liver iron concentration (LIC) predicts total body storage iron1 • Absence of pathology • Heterozygotes of hereditary haemochromatosis where liver levels <7 mg/g dry weight • Liver pathology • Abnormal ALT if LIC >17 mg/g dry weight2 • Liver fibrosis progression if LIC >16 mg/g dry weight3 • Cardiac pathology at high levels • Liver iron >15 mg/g dry weight association with cardiac death • All of 15/53 thalassaemia major patients who died4 • Improvement of left ventricular ejection fraction with venesection post bone marrow transplantation5 1. Angelucci E, et al. N Engl J Med. 2000;343:327. 2. Jensen P, et al. Blood. 2003;101:4632. 3. Angelucci E, et al. Blood. 2002;100:17. 4. Porter JB. Hematol/Oncol Clinics. 2005;S7. 5. Mariotti E, et al. Br J Haematol. 1998;103:916.

  16. 25 patientswith iron overloadand cirrhosis ≥1 mg dry weight liver sample LIC Accurately Reflects Total Body Iron Stores 300 r = 0.98 r = 0.98 r2 = 0.98 250 200 Total Body Iron Stores (mg/kg) 150 100 50 5 10 15 25 0 20 LIC (mg/g, dry weight) LIC = liver iron concentration. Angelucci E, et al. N Engl J Med. 2000;343:327.

  17. LIC and Prognosis Approximate LIC, mg/g dry weight liver Haemochromatosis Age (years) β-thalassaemia Major Normal Heterozygous Homozygous 5 <1.2 <1.2 >3.2 >15 10 <1.2 <1.2 ~7 >15 15 <1.2 <1.2 >7 >15 20 <1.2 ~1.2 ~15 >15 25 <1.2 >1.2 >15 (Not surviving) 30 <1.2 ~3.2 >15 35 <1.2 >3.2 >15 3.2–7 (adequate iron chelation) 7–15 (increased risk of complications) 15 (cardiac disease and early death) LIC changes are presented for patients without phlebotomy or iron chelation therapy.LIC = liver iron concentration. Courtesy of Dr. J. Porter.

  18. Estimation of LIC Liver biopsy • Distribution artifact • Debate about safe levels • Safety • Patient acceptance • Sample size • ≥1 mg dry weight • >4 mg wet weight 2 cm Photos courtesy of Dr. J. Porter. Porter JP. Br J Haematol. 2001;115:239.

  19. Measuring LIC by Liver Biopsy

  20. Noninvasive Measurement of Liver Iron • SQUID • Measures paramagnetic properties of liver iron • 4 operational machines worldwide • MRI techniques • Potentially widely available • Gradient echo (T2*) • Insensitive at levels >15 mg/g1 • Spin echo (T2)(R2) • Linear over larger range, longer acquisition time2 • Gradient with SIR3 • Spin echo with SIR4 SQUID = superconducting quantum interface device; MRI = magnetic resonance imaging; SIR = signal intensity ratio. 1. Anderson LH, et al. Eur Heart J. 2001;22:2171. 2. St. Pierre TG, et al. Blood. 2005;105:855.3. Gandon Y, et al. Lancet. 2004;363:357. 4. Jensen, et al. Blood. 2003;101:4632.

  21. Superconductivity Josephson effect Meissner effect Superconductive Conductive 0.8 0.26 0.2 Resistance (ohm) 0.16 0.1 0.06 0 0 2 4 6 8 temperature (°K) T>Tc T<Tc T<Tc Normal(nonsuperconducting) Flux expulsion(superconducting state) Persistent current(superconducting state) V S S I I -Ic Ic SQUID Biomagnetic Susceptometer Superconductive Quantum Interference Device SQUID Thalassaemia Center. Turin, Italy Courtesy of A. Piga, Turin Thalassaemia Centre.

  22. LIC Assessment by SQUID LIC = liver iron concentration; SQUID = superconducting quantum interference device.

  23. Quantitative IronAssessment by MRI T2 (heart, liver) Spin echo, gradient-echo sequences Signal intensity ratio (SIR) R2 (liver) Gradient-echo sequences s-1 T2*(heart) Gradient-echo sequences ms

  24. Liver R2 images and distributions for a healthy volunteer and 3 iron-loaded subjects with sequentially increasing liver iron concentrations St Pierre TG, et al. Blood. 2005;105:855.

  25. R2 MRI—A New Measure for LIC 300 R2 MRI is a validated and standardized method for measuring LIC. This technique is now approved by TGA and FDA and in the EU 250 Hereditary haemochromatosis 200 β-thalassaemia Mean Transverse Relaxation Rate <R2> (s-1) β-thalassaemia/ haemoglobin E 150 50 Hepatitis 100 40 30 50 20 0.5 1.0 1.5 2.0 0 50 0 10 20 30 40 Biopsy Iron Concentration (mg/g-1 dry tissue) St Pierre TG, et al. Blood. 2005;105:855.

  26. R2* Measurement of LIC R2* (Hz) Estimated HIC (mg/g dry weight) HIC = hepatic iron concentration. Wood JC, et al. Blood. 2005;106:1460.

  27. MRI Assessment of LIC Liver iron levels can be assessed using a technique known as R2 (spin echo) MRI, which is a validated and standardized method for measuring LIC MRI = magnetic resonance imaging; LIC = liver iron concentration.

  28. Assessing Cardiac Function and Iron Load

  29. Monitoring—Heart • Rhythm • Resting or exercise ECG • 24-hr Holter monitoring • Left ventricular function • ECHO • Quantitative sequential (MUGA or MRI)1 • Wall motion abnormalities • Heart “iron” • T2*2 • SIR (T2 weighted)3 ECG = electrocardiogram; ECHO = echocardiogram; MUGA = multiple gated acquisition;MRI = magnetic resonance imaging; SIR = signal intensity ratio. 1. Davis BA, et al. Blood. 2004;104:263. 2. Anderson LH, et al. Eur Heart J. 2001;22:2171. 3. Jensen P, et al. Blood. 2003;101:4632.

  30. T2* MRI: Emerging New Standard for Cardiac Iron 90 80 70 60 50 LVEF (%) 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) Cardiac T2* value of 4 in a significantly iron overloaded heart Relationship between myocardial T2* values and left ventricular ejection fraction (LVEF). Below a myocardial T2* of 20 ms, there was a progressive and significant decline in LVEF (R = 0.61, P < .0001) Photos courtesy of Dr. M. D. Cappellini.Anderson LJ, et al. Eur Heart J. 2001;22:2171.

  31. Cardiac T2* and Risk for Cardiac Dysfunction • In a study of 67 patients with thalassaemia major, 5 had systolic dysfunction LVEF <56% • All 5 patients also had myocardial T2* significantly <20 msec (the lower limit of normality) Westwood MA, et al. J Magn Reson Imaging. 2005;22:229.

  32. No Correlation of Heart Iron Concentration with Liver Iron Concentration? Anderson LJ, et al. Eur Heart J. 2001;22:2171.

  33. MRI Assessment of Cardiac Iron Cardiac iron levels can be rapidly and effectively assessed using a technique known as T2* (gradient echo) MRI, which is becoming the new standard method MRI = magnetic resonance imaging.

  34. Tools for MonitoringIron Overload Prognostic significance demonstrated • Serum ferritin (= body iron)1 • Liver iron (= body iron)2 • Heart function (LVEF)3 1. Olivieri NF, et al. Blood. 1994;84:3245. 2. Brittenham G, et al. N Engl J Med. 1994;331:567. 3. Davis BA, et al. Blood. 2004;104:263.

  35. Tools for MonitoringIron Overload Prognostic significance not yet demonstrated • Cardiac iron (T2*), linked to LVEF1 • NTBI, LPI • LPI measures the redox-active component of plasma iron2 • Can form reactive radicals responsible for many clinical consequences of iron overload2 1. Anderson LJ, et al. Eur Heart J. 2001;22:2171. 2. Esposito BP, et al. Blood. 2003;102:2670.

  36. Iron Overload EvaluationRecommendations • Do not use a single test alone for iron overload management • Exclude haemochromatosis • Serum ferritin is the basic parameter, but • Do not use it alone • Be aware of its poor predictive value • Use the trend of repeated measures (iron load direction) • Measure liver iron concentration (iron load amount and “buffer reserve”) • By biopsy, if indicated • By SQUID, where available • By MRI (method, calibration, error) • Assess the heart iron by MRI T2* (cardiac risk), at least once • If positive, use it as the main result to set treatment • If negative, do not exclude body iron overload • In transfused patients • Accurately record the iron input • Do iron balance, where feasible • Integrate available tests for effective management of iron chelation Angelucci E, et al. Haematologica. 2008, in press.

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