Correspondence

Hepatic Iron Concentration and Total Body Iron Stores in Thalassemia Major

N Engl J Med 2000; 343:1656-1657November 30, 2000

Article

To the Editor:

The study by Angelucci et al. (Aug. 3 issue)1 provides useful evidence that the estimated hepatic iron concentration is an indirect measure of total mobilizable body iron stores, but the authors misinterpreted the results of our study.2 The main point of our study was that magnetic resonance imaging (MRI) techniques that use a gradient–echo sequence with a flip angle of 10 degrees and short repetition and echo times do make possible the accurate, noninvasive estimation of hepatic iron concentrations. Our results extend the results of other studies demonstrating the value of such special MRI algorithms for the noninvasive estimation of hepatic iron concentration.3 Another recent study 4 also used MRI techniques for the estimation of hepatic iron concentrations; the authors commented that it is a “validated method of iron quantification.”

MRI methods have potential for estimating hepatic iron concentration noninvasively, even in the presence of clinically significant hepatic fibrosis or cirrhosis, and they permit the operator to choose regions of interest in which to perform measurements. This is not the case for estimates obtained by needle biopsy, which have considerable variability,5 and superconducting quantum-interference-device (SQUID) susceptometers. These susceptometers are not generally available, and because of the limited applicability of the information they provide, it is unlikely that they will become so. In contrast, MRI scanners are now available in virtually all major medical centers.

Herbert L. Bonkovsky, M.D.
Ashley Davidoff, M.D.
University of Massachusetts Medical School, Worcester, MA 01655

David D. Stark, M.D.
State University of New York Downstate Medical Center, Brooklyn, NY 11203-2098

5 References

1. 1

   Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000;343:327-331
   Full Text | Web of Science | Medline

2. 2

   Bonkovsky HL, Rubin RB, Cable EE, Davidoff A, Rijcken TH, Stark DD. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology 1999;212:227-234
   Web of Science | Medline

3. 3

   Gandon Y, Guyader D, Heautot JF, et al. Hemochromatosis: diagnosis and quantification of liver iron with gradient-echo MR imaging. Radiology 1994;193:533-538
   Web of Science | Medline

4. 4

   Chen FE, Ooi C, Ha SY, et al. Genetic and clinical features of hemoglobin H disease in Chinese patients. N Engl J Med 2000;343:544-550
   Full Text | Web of Science | Medline

5. 5

   Villeneuve JP, Bilodeau M, Lepage R, Cote J, Lefebvre M. Variability in hepatic iron concentration measurement from needle-biopsy specimens. J Hepatol 1996;25:172-177
   CrossRef | Web of Science | Medline

To the Editor:

We agree with Angelucci et al. that all recipients of hematopoietic stem-cell transplants should be assessed for iron overload and that phlebotomy or chelation therapy may improve the prognosis when iron overload is present. However, it remains unknown whether the long-term outcome of hematopoietic stem-cell transplantation is improved by phlebotomy.

We have several questions for Angelucci et al. Was the tissue damage caused by excess iron stores in their patients reversed? When should phlebotomy be started to prevent tissue damage? In their study, phlebotomy was initiated an average of 4.3±2.7 years after transplantation. Is this soon enough to prevent complications of iron overload?

Masahiro Kami, M.D.
Tamae Hamaki, M.D.
Yukiko Kishi, M.D.
Toranomon Hospital, Tokyo 105-8470, Japan

Author/Editor Response

The authors reply:

To the Editor: In answer to the questions of Kami and colleagues: the timing and benefits of our phlebotomy program for the treatment of iron overload in patients who are cured of thalassemia by bone marrow transplantation have been described in detail elsewhere.1 In brief, we begin phlebotomy as early as two years after transplantation and have documented improvements in cardiac function, hepatic function, and histologic findings.

Although we realize that Bonkovsky and colleagues have a more favorable opinion than ours of their method for using MRI to assess hepatic iron concentrations,2 we cited their paper because their results provide an excellent illustration of our point that MRI yields “estimates of hepatic iron that are too variable to be clinically useful.” For example, patients with transfusion-related iron overload who have body iron burdens that correspond to hepatic iron concentrations of more than about 15 mg of iron per gram of liver, dry weight, have a greatly increased risk of cardiac disease and early death.3 Such patients are candidates for continuous intravenous infusions of deferoxamine and other special treatment programs, whereas patients with lower hepatic iron concentrations can usually be treated with a subcutaneously administered chelating agent.

As shown in Figure 2 in the study by Bonkovsky et al.,2 patients with identical MRI measures (a natural logarithm [ln] of the signal-intensity ratio, calculated by dividing the mean signal intensity of the liver by the mean signal intensity of the overlying air [noise], of 1.0) may have hepatic iron concentrations that range from approximately 10 mg to more than 20 mg of iron per gram of liver, dry weight. Consequently, this MRI measure cannot be used to distinguish patients who urgently require intensive chelation from those who could be treated with conventional therapy. Conversely, patients with the same hepatic iron concentrations (about 10 mg of iron per gram of liver, dry weight) may have values for the ln of signal-intensity ratios that range from 1 to 3 on a scale of 0 to 4. Moreover, Bonkovsky and coworkers examined only patients with hepatic iron concentrations that were less than 25 mg of iron per gram of liver, dry weight; in patients with transfusion-related iron overload, hepatic iron concentrations may rise as high as 50 mg of iron per gram of liver, dry weight.

As described in detail elsewhere,4,5 the available data show that SQUID susceptometry can provide accurate, direct, reliable, and repeated noninvasive measurements of hepatic iron stores — results that are not possible with MRI or any other method. Finally, recent technological advances, including the development of high-transition-temperature superconductors that can operate at liquid nitrogen temperatures, promise to make SQUID susceptometers widely available at low cost.5

Emanuele Angelucci, M.D.
Azienda Ospedale di Pesaro, 61100 Pesaro, Italy

Gary M. Brittenham, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032-3795

Guido Lucarelli, M.D.
Azienda Ospedale di Pesaro, 61100 Pesaro, Italy

5 References

1. 1

   Angelucci E, Muretto P, Lucarelli G, et al. Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Blood 1997;90:994-998
   Web of Science | Medline

2. 2

   Bonkovsky HL, Rubin RB, Cable EE, Davidoff A, Rijcken TH, Stark DD. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology 1999;212:227-234
   Web of Science | Medline

3. 3

   Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997;89:739-761[Erratum, Blood 1997;89:2621.]
   Web of Science | Medline

4. 4

   Angelucci E, Giovagnoni A, Valeri GL, et al. Limitations of magnetic resonance imaging in measurement of hepatic iron. Blood 1997;90:4736-4742
   Web of Science | Medline

5. 5

   Brittenham GM, Sheth S, Allen CJ, Farrell DE. Non-invasive methods for quantitative assessment of transfusional iron overload. Semin Hematol 2000;37:Suppl 8:37-56