Iron Overload and Iron Chelator
Iron Overload and Translate This Page

SUPERCONDUCTING QUANTUM INTERFERENCE DEVICE (SQUID)

SQUID is an imaging modality that uses a very low-power magnetic field with sensitive detectors that measure the interference of iron within the field. A measurement is performed by lowering the patient into a known, constant magnetic field and then detecting the change in magnetic flux versus the change in a water reference medium. The sensor requires a cryogenic environment, since it must be superconducting to operate [47]. Although SQUID is still considered investigational, linear correlations have been demonstrated between SQUID measurements and iron levels from liver biopsy [48–50].

Technique for taking an iron measurement with SQUID

 

Fischer [47]. © 1998 Wiley-VCH Verlag GmbH & Co KGaA, reprinted with permission.

Linear relationship between SQUID and liver biopsy

 

Fischer [51]. © 1992 Elsevier Inc, reprinted with permission.

Although SQUID directly measures the magnetic susceptibility of ferritin and hemosiderin, at present it does not have sufficient spatial or temporal resolution to evaluate myocardial iron. The use of SQUID is currently limited as there are only four facilities worldwide that have a SQUID machine available for the measurement of iron levels. In addition, during the clinical development of deferasirox, LIC data obtained by SQUID were shown to underestimate LIC values obtained from biopsy by a factor of 0.46 [52].

One of four current SQUID facilities worldwide

ECHOCARDIOGRAPHY, RADIONUCLIDE VENTRICULOGRAPHY

Accurate assessments of LVEF can be provided non-invasively by resting or stress echocardiography [53, 54] or radionuclide ventriculography [55, 56]. These techniques may be useful in the diagnosis of early iron-induced cardiac disease, since diastolic dysfunction has been shown to be of prognostic value in the development of symptomatic iron-induced cardiac disease [10, 57].

Echocardiography is the most widely used technique for the diagnosis and prognosis of left ventricular systolic function [58]. However, an important limitation of this approach is that echocardiographic abnormalities tend to develop relatively late in the course of cardiomyopathy. In addition, the technique is reliant on operator skill and requires assumptions on ventricular geometry to be made, thereby increasing the potential for inter-observer variability. As a result, measurements of resting ejection fraction by radionuclide angiography and MRI are more robust than echocardiography, and are better at recognizing preclinical systolic dysfunction [59]

Summary of primary methods available for assessment of body iron concentration.

Method

Advantages

Disadvantages

Serum ferritin

•  Non-invasive

•  Can be performed frequently, allowing regular monitoring

•  Inexpensive (commercial kits available)

•  Positive correlation with morbidity and mortality

•  Allows longitudinal follow-up of patients

•  Indirect measurement of iron burden

•  Levels are influenced by many factors, including nutrition, infection, and inflammation

•  Serial measurement and/or combination with other indicators is required

Liver biopsy

•  Validated reference standard

•  Direct measurement that provides accurate information

•  Allows non-heme storage iron to be measured

•  Allows accurate assessment of disease progression

•  Positive correlation with morbidity and mortality

•  Invasive, painful, potentially serious complications

•  Requires skilled professional personnel and standardized laboratory procedures

•  Biopsy is small and may not be representative of general iron distribution

•  Spurious measurements may occur as a result of certain hepatic diseases

•  Difficult to follow up

MRI

•  Non-invasive

•  Able to analyze whole organ

•  Pathologic status of the liver can be assessed in parallel

•  Wide availability

•  Allows longitudinal follow-up of patients

•  Requires magnetic resonance imager with a dedicated imaging method

•  Indirect measurement of LIC

•  Children under the age of 7 years require a general anesthetic

SQUID

•  Non-invasive

•  Measurement may be repeated frequently

•  Linear correlation with LIC assessed by biopsy

•  Limited availability

•  High cost

•  Indirect measurement of LIC

•  Complex procedure requiring trained personnel

•  Underestimates LIC versus biopsy

 

Novartis Iron Overload Information

References

    (1) Borgna-Pignatti C, Castriota-Scanderbeg A. Methods for evaluating iron stores and efficacy of chelation in transfusional hemosiderosis. Haematologica. 1991;76(5):409–13. (2) Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331(9):567–73. (3) Jensen PD, Jensen FT, Christensen T, et al. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood. 2003;101(1):91–6. (4) Bassett Ml, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986;6(1):24–9. (5) Otobe Y, Hashimoto T, Shimizu Y, et al. Formation of a fatal arterioportal fistula following needle liver biopsy in a child with a living-related liver transplant: report of a case. Surg Today. 1995;25(10):916–9. (6) Drinkovic I, Brkljacic B. Two cases of lethal complications following ultrasound-guided percutaneous fine-needle biopsy of the liver. Cardiovasc Intervent Radiol. 1996;19(5):360–3. (7) Angelucci E, Baronciani D, Lucarelli G, et al. Needle liver biopsy in thalassaemia: analyses of diagnostic accuracy and safety in 1184 consecutive biopsies. Br J Haematol. 1995;89(4):757–61. (8) Porter JB. Practical management of iron overload. Br J Haematol. 2001;115(2):239–52. (9) Olson LJ, Edwards WD, Mccall JT, et al. Cardiac iron deposition in idiopathic hemochromatosis: histologic and analytic assessment of 14 hearts from autopsy. J Am Coll Cardiol. 1987;10(6):1239–43. (10) Liu P, Olivieri N. Iron overload cardiomyopathies: new insights into an old disease. Cardiovasc Drugs Ther. 1994;8:101–10. (11) Olivieri NF, Nathan DG, Macmillan JH, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331(9):574–8. (12) Worwood M, Cragg SJ, Jacobs A, et al. Binding of serum ferritin to concanavalin A: patients with homozygous beta thalassaemia and transfusional iron overload. Br J Haematol. 1980;46(3):409–16. (13) Brittenham GM, Badman DG. Noninvasive measurement of iron: report of an NIDDK workshop. Blood. 2003;101(1):15–9. (14) Roeser HP, Halliday JW, Sizemore DJ, et al. Serum ferritin in ascorbic acid deficiency. Br J Haematol. 1980;45(3):459–66. (15) Herbert V, Jayatilleke E, Shaw S, et al. Serum ferritin iron, a new test, measures human body iron stores unconfounded by inflammation. Stem Cells. 1997;15(4):291–6. (16) Worwood M. The laboratory assessment of iron status – an update. Clin Chim Acta. 1997;259(1-2):3–23.

    (17) Jensen PD, Jensen FT, Christensen T, et al. Evaluation of transfusional iron overload before and during iron chelation by magnetic resonance imaging of the liver and determination of serum ferritin in adult non-thalassaemic patients. Br J Haematol. 1995;89(4):880–9. (18) Khumalo H, Gomo ZA, Moyo VM, et al. Serum transferrin receptors are decreased in the presence of iron overload. Clin Chem. 1998;44(1):40–4. (19) Esposito BP, Breuer W, Sirankapracha P, et al. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood. 2003;102(7):2670–7. (20) Bothwell T, Charlton RW, Cook JD, et al. In: Iron Metabolism in Man. 1979, Blackwell Scientific Publications: Oxford . p. 105–15. (21) Wheeler CJ, Kowdley KV. Hereditary hemochromatosis: a review of the genetics, mechanism, diagnosis, and treatment of iron overload. Compr Ther. 2006; 32:10–6. (22) Voskaridou E, Douskou M, Terpos E, et al. Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease. Br J Haematol. 2004;126(5):736–42. (23) Perifanis V, Economou M, Christoforides A, et al. Evaluation of iron overload in beta-thalassemia patients using magnetic resonance imaging. Hemoglobin. 2004;28(1):45–9. (24) Papakonstantinou O, Kostaridou S, Maris T, et al. Quantification of liver iron overload by T2 quantitative magnetic resonance imaging in thalassemia: impact of chronic hepatitis C on measurements. J Pediatr Hematol Oncol. 1999;21(2):142–8. (25) Canavese C, Bergamo D, Ciccone G, et al. Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney Int. 2004;65(3):1091–8. (26) Sheth S. SQUID biosusceptometry in the measurement of hepatic iron. Pediatr Radiol. 2003;33(6):373–7. (27) Nielsen P, Engelhardt R, Dullmann J, et al. Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary hemochromatosis. Blood Cells Mol Dis. 2002;29(3):451–8. (28) Brittenham GM, Sheth S, Allen CJ, et al. Noninvasive methods for quantitative assessment of transfusional iron overload in sickle cell disease. Semin Hematol. 2001;38(1 Suppl 1):37–56. (29) Harada M, Hirai K, Sakisaka S, et al. Comparative study of magnetic resonance imaging, computed tomography and histology in the assessment of liver iron overload. Intern Med. 1992;31(2):180–4. (30) De Marchi S, Cecchin E. Hepatic computed tomography for monitoring the iron status of haemodialysis patients with haemosiderosis treated with recombinant human erythropoietin. Clin Sci (Lond). 1991;81(1):113–21. (31) Cecchin E, De Marchi S, Querin F, et al. Efficacy of hepatic computed tomography to detect iron overload in chronic hemodialysis. Kidney Int. 1990;37(3):943–50. (32) Guyader D, Gandon Y, Deugnier Y, et al. Evaluation of computed tomography in the assessment of liver iron overload. A study of 46 cases of idiopathic hemochromatosis. Gastroenterology. 1989;97(3):737–43.

    (33) Wielopolski L, Zaino EC. Noninvasive in-vivo measurement of hepatic and cardiac iron. J Nucl Med. 1992;33(7):1278–82. (34) Wielopolski L, Ancona RC, Mossey RT, et al. Nuclear resonance scattering measurement of human iron stores. Med Phys. 1985;12(4):401–4. (35) Jensen PD. Evaluation of iron overload. Br J Haematol. 2004;124(6):697–711. (36) Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22(23):2171–9. (37) Ernst O, Sergent G, Bonvarlet P, et al. Hepatic iron overload: diagnosis and quantification with MR imaging. AJR Am J Roentgenol. 1997;168(5):1205–8. (38) Gandon Y, Guyader D, Heautot JF, et al. Hemochromatosis: diagnosis and quantification of liver iron with gradient-echo MR imaging. Radiology. 1994;193(2):533–8. (39) St Pierre TG, Clark PR, Chua-Anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005;105(2):855–61. (40) Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood. 2006;107(9):3738–44. (41) Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007; 10;115(14):1876–84. (42) Porter JB. Improved myocardial T2* in transfusion dependent anemias receiving ICL670 (Deferasirox). Blood. 2005;106(11):3600. (43) Fujisawa I, Asato R, Nishimura K, et al. Anterior and posterior lobes of the pituitary gland: assessment by 1.5 T MR imaging. J Comput Assist Tomogr. 1987;11(2):214–20. (44) Fujisawa I, Morikawa M, Nakano Y, et al. Hemochromatosis of the pituitary gland: MR imaging. Radiology. 1988;168(1):213–4. (45) Sparacia G, Midiri M, D'angelo P, et al. Magnetic resonance imaging of the pituitary gland in patients with secondary hypogonadism due to transfusional hemochromatosis. Magma. 1999;8(2):87–90. (46) Lau KY, Chan Yl, Lam WW, et al. Magnetic resonance imaging evaluation of the pituitary gland and hypothalamus in thalassaemic children with elevated serum ferritin levels. J Paediatr Child Health. 1998;34(5):463–6. (47) Fischer R. In: Andra W, Nowak H, editors. Magnetism in medicine: a handbook. Berlin:Wiley-VCH;1998:286–301. (48) Nielsen P, Fischer R, Engelhardt R, et al. Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone. Br J Haematol. 1995;91(4):827–33.

    (49) Pootrakul P, Kitcharoen K, Yansukon P, et al. The effect of erythroid hyperplasia on iron balance. Blood. 1988;71(4):1124–9. (50) Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med. 1982;307(27):1671–5. (51) Fischer R, et al. In: Hoke M et al. editors. Biomagnetism: Clinical Aspects: proceedings of the 8th International Conference on Biomagnetism, Munster, 19–24 August, 1991. Elsevier Science Publishers BV;1992:585–8. (52) Piga A, Fischer R, St Pierre T, et al. Comparison of LIC obtained from biopsy, BLS and R2-MRI in iron overloaded patients with ß-thalassemia, treated with deferasirox (Exjade®, ICL670). Blood. 2005;106(11):abst 2689. (53) Ward RP, Mor-Avi V, Lang RM, Assessment of left ventricular function with contrast echocardiography. Cardiol Clin. 2004;22(2):211–9. (54) Gillespie ND, Struthers AD, Pringle SD, The assessment of left ventricular function by echocardiography. Scott Med J. 1995;40(5):132–3. (55) Brenta G, Mutti LA, Schnitman M, et al. Assessment of left ventricular diastolic function by radionuclide ventriculography at rest and exercise in subclinical hypothyroidism, and its response to L-thyroxine therapy. Am J Cardiol. 2003;91(11):1327–30. (56) Topuzovic N. Worsening of left ventricular diastolic function during long-term correction of anemia with erythropoietin in chronic hemodialysis patients – an assessment by radionuclide ventriculography at rest and exercise. Int J Card Imaging. 1999;15(3):233–9. (57) Hou JW, Wu MH, Lin KH, et al. Prognostic significance of left ventricular diastolic indexes in beta-thalassemia major. Arch Pediatr Adolesc Med. 1994;148(8):862–6. (58) McGowan JH, Cleland JG. Reliability of reporting left ventricular systolic function by echocardiography: a systematic review of 3 methods. Am Heart J. 2003; 146:388–97. (59) Wood JC, Enriquez C, Ghugre N, et al. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci. 2005; 1054:1–10.

About Iron Overload and Iron Chelator
k

Learn about the benefits of chelation therapy in treating transfusional iron overload.