We greatly appreciated the comments of Dr Nielsen and colleagues on the guidelines for the management of iron overload in thalassemia we produced on behalf of the Italian Society of Hematology.1 Dr Nielsen and colleagues are concerned about our interpretation of data regarding the accuracy of biomagnetic liver susceptometry (BLS) as a non-invasive method for assessing liver iron concentration. By analyzing the existing evidence, we relied on the only two references dealing with a correlation between BLS and liver iron concentration by biopsy in patients with thalassemia. Our conclusion on the inaccuracy of BLS was mainly grounded on a paper published as an abstract by Piga et al.2 in which the sentence “on average, the LIC data obtained from BLS and biopsy were related by a factor of 0.46” was interpreted as 0.46 being the correlation coefficient of the two measurements. Thus, from this factor, we derived a R of 0.21. We also relied on the conclusion of the abstract that states “overall, LIC from biopsy was generally larger than that obtained from BLS”.
Regarding the use of SQUID/BLS after the first study published by Gary Brittenham in 1982,3 no other published study has confirmed the capability of SQUID to predict hepatic iron concentration with adequate methods. Any validation study of a new diagnostic quantitative procedure must compare the new methodology with a reference gold standard. Particularly a determination coefficient (R) with a prediction interval (95% CI) should be reported.
Above all in this specific case the 95% prediction interval would be reasonably narrow not extending over the identified threshold for iron concentration tissue damage and death risk.4 In the setting of iron overload, the reference standard is the validated biochemical determination of hepatic iron concentration adequate, non cirrhotic, liver biopsy specimens.5 We are not aware of any such study with results similar to that reported by Dr Brittenham with similar 95% confidence prediction interval. Studies comparing SQUID/BLS with other technologies are of minor relevance. Moreover the cited debate on dry weight-wet weight relationship developed after an industry sponsored trial,2 which, although important for future development, raises concern for the thousands of determinations performed for clinical practice before 2006.
In conclusion, although SQUID/BLS is a highly scientific methodology, because of the limited availability, the limited literature in peer reviewed journals, the reported difficulties, and the availability of other non-invasive methods (MRI-R2) it appears rational to recommend its utilization only inside clinical trials.
References
- Angelucci E, Barosi G, Camaschella C, Cappellini MD, Cazzola M, Galanello R. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008; 93:741-52. Google Scholar
- Piga A, Fisher R, Harmatz P, St Pierre TG, Longo F, Fung E. Comparison of LIC obtained from biopsy, BLS and R2-MRI in iron overloaded patients with β-thalassemia, treated with deferasirox (Exjade, ICL670). Blood. 2005; 106:755a. Google Scholar
- Brittenham GM, Farrell DE, Harris JW, Feldman ES, Danish EH, Muir WA. Magnetic-susceptibility measurement of human iron stores. N Engl J Med. 1982; 307:1671-5. Google Scholar
- Olivieri NF. The {beta}-Thalassemias. N Engl J Med. 1999; 341:99-109. Google Scholar
- Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000; 343:327-31. Google Scholar