CASE REPORT
The Long-Lasting Effect of Ferumoxytol on Abdominal Magnetic Resonance Imaging Aaron Harman, MD,* Kevin J. Chang, MD,* Damian Dupuy, MD,* and Peter Rintels, MD† Abstract: Ferumoxytol is a parenteral iron therapy that the Food and Drug Administration recently approved for the treatment of irondeficiency anemia. The form of the iron, ultrasmall superparamagnetic iron oxide nanoparticles, causes T1, T2, and T2* shortening on magnetic resonance imaging, which can mimic hemosiderosis. We report such a case, with laboratory findings that demonstrate normal iron stores, and discuss the potential implications. Key Words: ferumoxytol, ultrasmall superparamagnetic iron oxide nanoparticles, mimic hemosiderosis, magnetic resonance imaging (MRI) (J Comput Assist Tomogr 2014;38: 571–573)
F
erumoxytol (Feraheme, AMAG Pharmaceuticals, Lexington, Mass) is a compound containing iron that was approved in 2009 by the Food and Drug Administration for the treatment of iron-deficiency anemia. It consists of an ultrasmall superparamagnetic iron oxide (SPIO) core coated with a carbohydrate shell, which isolates the bioactive iron until it is taken up by macrophages in the reticuloendothelial system of the liver, the spleen, and bone marrow.1 We report a case in which a patient undergoing treatment with ferumoxytol, most recently treated 50 days prior, was found to have decreased T1- and T2-weighted signal intensity throughout the liver, spleen, adrenals, and bone marrow, with associated susceptibility effects best demonstrated on dual-echo gradient echo images related to iron deposition, with low to normal serum iron studies, normal liver function test results, and random cortisol levels. We discuss the clinical significance of the findings and the experimental use of ferumoxytol as a contrast agent.
CASE REPORT A 59-year-old woman with a history of iron-deficiency anemia on parenteral iron therapy was referred for magnetic resonance imaging (MRI) of the abdomen for epigastric pain for which a recent computed tomographic scan was performed, which found no cause of pain (Fig. 1.) She had been treated with iron replacement therapy in the form of ferumoxytol for years, most recently 50 days before the MRI. Serum iron studies had reflected low to normal iron stores, ferritin ranging 4 to 158 ng/mL. Liver function tests had also been followed, which had been normal most recently: aspartate aminotransferase, 18 U/L; alanine aminotransferase, 16 U/L; alkaline phosphatase, 52 U/L; total bilirubin, 0.5 mg/dL; direct bilirubin, less than 0.1 mg/dL. Magnetic resonance imaging was performed using our institution’s standard liver mass protocol on a 1.5-T MRI scanner
From the *Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI; and †Hematology & Oncology Associates of RI, Inc, Cranston, RI. Received for publication February 1, 2014; accepted February 4, 2014. Reprints: Aaron Harman, MD, Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 (e‐mail: [email protected]). The authors declare no conflicts of interest. Copyright © 2014 by Lippincott Williams & Wilkins
J Comput Assist Tomogr • Volume 38, Number 4, July/August 2014
(Achieva, Philips Medical Systems, Best, Netherlands). Sequences included the following: axial in- and out-of-phase dual-echo gradient echo, T2-weighted single-shot fast spin echo, and fatsuppressed T1-weighted 3-dimensional spoiled gradient echo sequences in the precontrast, arterial, portal venous, and delayed postcontrast phases. Five milliliters of gadobutrol (Gadavist, Bayer HealthCare Pharmaceuticals, Montville, NJ) intravenous contrast was injected. There was diffuse signal decrease in the liver, spleen, adrenal glands, and bone marrow on in-phase when compared to out-ofphase gradient-echo images (Figs. 2, 3) as well as diffusely decreased signal intensity on all T2-weighted images (Fig. 4). Given MRI findings of significant iron deposition in the adrenal glands, a random cortisol level was checked, which was found to be normal at 7.7 μg/dL.
DISCUSSION Ferumoxytol is a parenteral iron replacement therapy that has been approved in the United States and Europe as a treatment of iron-deficiency anemia in patients with chronic kidney disease. The paramagnetic properties of SPIOs like ferumoxytol have been known for several years, and have even been used experimentally as contrast agents since 1990.2 Superparamagnetic iron oxides have been found to be useful in characterization of hepatocellular lesions, with a drop in signal of normal hepatic parenchyma due to uptake by Kupffer cells without a drop in signal of lesions not containing Kupffer cells.3 Harisinghani et al4 found that ferumoxytol could be used to detect lymph node metastases in prostate cancer before the lymph nodes demonstrated an increase in size. Superparamagnetic iron oxides have also been suggested as an alternative contrast agent to gadolinium in patients with renal failure to avoid the risk of nephrogenic systemic fibrosis.5,6
FIGURE 1. Axial contrast-enhanced computed tomography of the abdomen and pelvis: there is normal appearance of the liver (L), spleen (S), and left adrenal gland (arrow). www.jcat.org
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
571
J Comput Assist Tomogr • Volume 38, Number 4, July/August 2014
FIGURE 2. Unenhanced T1-weighted dual-echo gradient echo images obtained at 1.5 T with 150-milliseconds (ms) repetition time (TR)/2.18-ms echo time (TE) and 150-ms TR/4.35-ms TE, 75-degree flip angle, and 8-mm section thickness. Axial in-phase image (A) shows signal dropout in the liver (L), spleen (S), and bone marrow (M) compared with axial out-of-phase image (B), consistent with susceptibility effects related to iron accumulation.
FIGURE 3. Unenhanced T1-weighted dual-echo gradient echo images obtained at 1.5 T with 150-ms TR/2.18-ms TE and 150-ms TR/4.35-ms TE, 75-degree flip angle, and 8-mm section thickness at the level of the adrenal glands. Axial in-phase image (A) shows signal dropout in the adrenal glands compared with axial out-of-phase image (B), consistent with susceptibility effects related to iron accumulation.
Despite these benefits, the only SPIO approved by the FDA as a contrast agent, Feridex, has been discontinued. The findings in our case of loss of signal of the liver, spleen, and adrenal parenchyma as well as bone marrow on the in-phase sequence are consistent with iron accumulation seen in hemosiderosis. However, this patient’s serum iron studies had been carefully monitored throughout the course of her treatment,
and serum ferritin was always found to be low or normal. Additionally, normal liver function test results and random cortisol level suggest no injury to the liver or adrenals. A handful of cases have recently been published describing clinically benign changes associated with recent ferumoxytol administration. McCullough et al7 described a case in which ferumoxytol, given only 2 and 16 days before MRI caused T1
FIGURE 4. Axial (A) and coronal (B) unenhanced T2-weighted single-shot fast spin echo images obtained at 1.5 T (851-ms TR/90-ms TE, 90-degree flip angle, and 8-mm section thickness) demonstrated diffusely decreased signal intensity throughout the liver (L), spleen (S), and left adrenal gland (arrow).
572
www.jcat.org
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Comput Assist Tomogr • Volume 38, Number 4, July/August 2014
shortening in the spleen, but not in the liver. Schieda8 described another case in which a patient had received ferumoxytol 3 days before MRI, which caused T1 shortening in both the liver and spleen. Gunn et al9 also described 9 cases with iron deposition in the liver, spleen, and adrenal glands 48 hours after ferumoxytol administration. In our case, ferumoxytol had been administered 50 days before the MRI. To our knowledge, this is the first case describing a longer-lasting effect of ferumoxytol appearing on abdominal MRI. There is some debate about the significance of these findings. The intended mechanisms of action of ferumoxytol and other forms of iron replacement therapy is to be taken up by macrophages within the reticuloendothelial system in the liver, spleen, and bone marrow, where it is available for use in erythropoeisis. However, findings by Rostoker et al found that estimated tissue iron levels in patients receiving parenteral iron therapy may be higher than previously thought. They used an MRI technique for the estimation of liver iron concentration in patients receiving parenteral iron replacement for end-stage renal disease on hemodialysis. Although most of the patients in their study had normal or low serum ferritin levels, 84% of the patients were estimated to have hepatic iron concentrations in the range of overload (>50 μmol/g), 36% of which were in the severe range (>201 μmol/g.) Despite the classical teaching that serum ferritin levels reflect ferritin stores within macrophages, the conclusion of Rostoker10 was that his subjects with low serum ferritin but high estimated hepatic iron concentrations had hemosiderosis. In addition, as the adrenal glands are not part of the reticuloendothelial system, the mechanism of iron deposition in the adrenal glands remains unknown.9 Regardless of the clinical significance of MRI findings after ferumoxytol administration, it is important for radiologists to be aware of them. The package insert warns of potential MRI effects lasting for up to 3 months,7 and therefore we advocate querying patients regarding prior ferumoxytol use on MRI screening forms.
© 2014 Lippincott Williams & Wilkins
Long-Lasting Effect of Ferumoxytol on Abdominal MRI
REFERENCES 1. Lu M, Cohen MH, Fieves D, et al. FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol. 2010;85:315–319. 2. Weissleder R, Elizondo G, Wittenberg J, et al. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agent for MR imaging. Radiology. 1990;175:489–493. 3. Tanabe M, Ito K, Shimizu A, et al. Hepatocellular lesions with increased iron uptake on superparamagnetic iron oxide–enhanced magnetic resonance imaging in cirrhosis or chronic hepatitis: comparison of four magnetic resonance sequences for lesion conspicuity. Magn Reson Imaging. 2009;27:801–806. 4. Harisinghani M, Ross RW, Guimaraes AR, et al. Utility of a new bolus-injectable nanoparticle for clinical cancer staging. Neoplasia. 2007;9:1160–1165. 5. Neuwelt EA, Hamilton BE, Varallyay CG, et al. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int. 2009;75:465–474. 6. Hamilton BE, Nesbit GM, Dosa E, et al. Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging. AJR Am J Roentgenol. 2011;197:981–988. 7. McCullough BJ, Kolokythas O, Maki JH, et al. Ferumoxytol in clinical practice: implications for MRI. J Magn Reson Imaging. 2013;37:1476–1479. 8. Schieda N. Parenteral ferumoxytol interaction with magnetic resonance imaging: a case report, review of the literature and advisory warning. Insights Imaging. 2013;4:509–512. 9. Gunn AJ, Seethamraju RT, Hedgire S, et al. Imaging behavior of the normal adrenal on ferumoxytol-enhanced MRI: preliminary findings. AJR Am J Roentgenol. 2013;201:117–121. 10. Rostoker G, Griuncelli M, Loridon C, et al. Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: an MRI study. Am J Med. 2012;125:991–999.
www.jcat.org
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
573
The Long-Lasting Effect of Ferumoxytol on Abdominal Magnetic Resonance Imaging Aaron Harman, MD,* Kevin J. Chang, MD,* Damian Dupuy, MD,* and Peter Rintels, MD† Abstract: Ferumoxytol is a parenteral iron therapy that the Food and Drug Administration recently approved for the treatment of irondeficiency anemia. The form of the iron, ultrasmall superparamagnetic iron oxide nanoparticles, causes T1, T2, and T2* shortening on magnetic resonance imaging, which can mimic hemosiderosis. We report such a case, with laboratory findings that demonstrate normal iron stores, and discuss the potential implications. Key Words: ferumoxytol, ultrasmall superparamagnetic iron oxide nanoparticles, mimic hemosiderosis, magnetic resonance imaging (MRI) (J Comput Assist Tomogr 2014;38: 571–573)
F
erumoxytol (Feraheme, AMAG Pharmaceuticals, Lexington, Mass) is a compound containing iron that was approved in 2009 by the Food and Drug Administration for the treatment of iron-deficiency anemia. It consists of an ultrasmall superparamagnetic iron oxide (SPIO) core coated with a carbohydrate shell, which isolates the bioactive iron until it is taken up by macrophages in the reticuloendothelial system of the liver, the spleen, and bone marrow.1 We report a case in which a patient undergoing treatment with ferumoxytol, most recently treated 50 days prior, was found to have decreased T1- and T2-weighted signal intensity throughout the liver, spleen, adrenals, and bone marrow, with associated susceptibility effects best demonstrated on dual-echo gradient echo images related to iron deposition, with low to normal serum iron studies, normal liver function test results, and random cortisol levels. We discuss the clinical significance of the findings and the experimental use of ferumoxytol as a contrast agent.
CASE REPORT A 59-year-old woman with a history of iron-deficiency anemia on parenteral iron therapy was referred for magnetic resonance imaging (MRI) of the abdomen for epigastric pain for which a recent computed tomographic scan was performed, which found no cause of pain (Fig. 1.) She had been treated with iron replacement therapy in the form of ferumoxytol for years, most recently 50 days before the MRI. Serum iron studies had reflected low to normal iron stores, ferritin ranging 4 to 158 ng/mL. Liver function tests had also been followed, which had been normal most recently: aspartate aminotransferase, 18 U/L; alanine aminotransferase, 16 U/L; alkaline phosphatase, 52 U/L; total bilirubin, 0.5 mg/dL; direct bilirubin, less than 0.1 mg/dL. Magnetic resonance imaging was performed using our institution’s standard liver mass protocol on a 1.5-T MRI scanner
From the *Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI; and †Hematology & Oncology Associates of RI, Inc, Cranston, RI. Received for publication February 1, 2014; accepted February 4, 2014. Reprints: Aaron Harman, MD, Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 (e‐mail: [email protected]). The authors declare no conflicts of interest. Copyright © 2014 by Lippincott Williams & Wilkins
J Comput Assist Tomogr • Volume 38, Number 4, July/August 2014
(Achieva, Philips Medical Systems, Best, Netherlands). Sequences included the following: axial in- and out-of-phase dual-echo gradient echo, T2-weighted single-shot fast spin echo, and fatsuppressed T1-weighted 3-dimensional spoiled gradient echo sequences in the precontrast, arterial, portal venous, and delayed postcontrast phases. Five milliliters of gadobutrol (Gadavist, Bayer HealthCare Pharmaceuticals, Montville, NJ) intravenous contrast was injected. There was diffuse signal decrease in the liver, spleen, adrenal glands, and bone marrow on in-phase when compared to out-ofphase gradient-echo images (Figs. 2, 3) as well as diffusely decreased signal intensity on all T2-weighted images (Fig. 4). Given MRI findings of significant iron deposition in the adrenal glands, a random cortisol level was checked, which was found to be normal at 7.7 μg/dL.
DISCUSSION Ferumoxytol is a parenteral iron replacement therapy that has been approved in the United States and Europe as a treatment of iron-deficiency anemia in patients with chronic kidney disease. The paramagnetic properties of SPIOs like ferumoxytol have been known for several years, and have even been used experimentally as contrast agents since 1990.2 Superparamagnetic iron oxides have been found to be useful in characterization of hepatocellular lesions, with a drop in signal of normal hepatic parenchyma due to uptake by Kupffer cells without a drop in signal of lesions not containing Kupffer cells.3 Harisinghani et al4 found that ferumoxytol could be used to detect lymph node metastases in prostate cancer before the lymph nodes demonstrated an increase in size. Superparamagnetic iron oxides have also been suggested as an alternative contrast agent to gadolinium in patients with renal failure to avoid the risk of nephrogenic systemic fibrosis.5,6
FIGURE 1. Axial contrast-enhanced computed tomography of the abdomen and pelvis: there is normal appearance of the liver (L), spleen (S), and left adrenal gland (arrow). www.jcat.org
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
571
J Comput Assist Tomogr • Volume 38, Number 4, July/August 2014
FIGURE 2. Unenhanced T1-weighted dual-echo gradient echo images obtained at 1.5 T with 150-milliseconds (ms) repetition time (TR)/2.18-ms echo time (TE) and 150-ms TR/4.35-ms TE, 75-degree flip angle, and 8-mm section thickness. Axial in-phase image (A) shows signal dropout in the liver (L), spleen (S), and bone marrow (M) compared with axial out-of-phase image (B), consistent with susceptibility effects related to iron accumulation.
FIGURE 3. Unenhanced T1-weighted dual-echo gradient echo images obtained at 1.5 T with 150-ms TR/2.18-ms TE and 150-ms TR/4.35-ms TE, 75-degree flip angle, and 8-mm section thickness at the level of the adrenal glands. Axial in-phase image (A) shows signal dropout in the adrenal glands compared with axial out-of-phase image (B), consistent with susceptibility effects related to iron accumulation.
Despite these benefits, the only SPIO approved by the FDA as a contrast agent, Feridex, has been discontinued. The findings in our case of loss of signal of the liver, spleen, and adrenal parenchyma as well as bone marrow on the in-phase sequence are consistent with iron accumulation seen in hemosiderosis. However, this patient’s serum iron studies had been carefully monitored throughout the course of her treatment,
and serum ferritin was always found to be low or normal. Additionally, normal liver function test results and random cortisol level suggest no injury to the liver or adrenals. A handful of cases have recently been published describing clinically benign changes associated with recent ferumoxytol administration. McCullough et al7 described a case in which ferumoxytol, given only 2 and 16 days before MRI caused T1
FIGURE 4. Axial (A) and coronal (B) unenhanced T2-weighted single-shot fast spin echo images obtained at 1.5 T (851-ms TR/90-ms TE, 90-degree flip angle, and 8-mm section thickness) demonstrated diffusely decreased signal intensity throughout the liver (L), spleen (S), and left adrenal gland (arrow).
572
www.jcat.org
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Comput Assist Tomogr • Volume 38, Number 4, July/August 2014
shortening in the spleen, but not in the liver. Schieda8 described another case in which a patient had received ferumoxytol 3 days before MRI, which caused T1 shortening in both the liver and spleen. Gunn et al9 also described 9 cases with iron deposition in the liver, spleen, and adrenal glands 48 hours after ferumoxytol administration. In our case, ferumoxytol had been administered 50 days before the MRI. To our knowledge, this is the first case describing a longer-lasting effect of ferumoxytol appearing on abdominal MRI. There is some debate about the significance of these findings. The intended mechanisms of action of ferumoxytol and other forms of iron replacement therapy is to be taken up by macrophages within the reticuloendothelial system in the liver, spleen, and bone marrow, where it is available for use in erythropoeisis. However, findings by Rostoker et al found that estimated tissue iron levels in patients receiving parenteral iron therapy may be higher than previously thought. They used an MRI technique for the estimation of liver iron concentration in patients receiving parenteral iron replacement for end-stage renal disease on hemodialysis. Although most of the patients in their study had normal or low serum ferritin levels, 84% of the patients were estimated to have hepatic iron concentrations in the range of overload (>50 μmol/g), 36% of which were in the severe range (>201 μmol/g.) Despite the classical teaching that serum ferritin levels reflect ferritin stores within macrophages, the conclusion of Rostoker10 was that his subjects with low serum ferritin but high estimated hepatic iron concentrations had hemosiderosis. In addition, as the adrenal glands are not part of the reticuloendothelial system, the mechanism of iron deposition in the adrenal glands remains unknown.9 Regardless of the clinical significance of MRI findings after ferumoxytol administration, it is important for radiologists to be aware of them. The package insert warns of potential MRI effects lasting for up to 3 months,7 and therefore we advocate querying patients regarding prior ferumoxytol use on MRI screening forms.
© 2014 Lippincott Williams & Wilkins
Long-Lasting Effect of Ferumoxytol on Abdominal MRI
REFERENCES 1. Lu M, Cohen MH, Fieves D, et al. FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol. 2010;85:315–319. 2. Weissleder R, Elizondo G, Wittenberg J, et al. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agent for MR imaging. Radiology. 1990;175:489–493. 3. Tanabe M, Ito K, Shimizu A, et al. Hepatocellular lesions with increased iron uptake on superparamagnetic iron oxide–enhanced magnetic resonance imaging in cirrhosis or chronic hepatitis: comparison of four magnetic resonance sequences for lesion conspicuity. Magn Reson Imaging. 2009;27:801–806. 4. Harisinghani M, Ross RW, Guimaraes AR, et al. Utility of a new bolus-injectable nanoparticle for clinical cancer staging. Neoplasia. 2007;9:1160–1165. 5. Neuwelt EA, Hamilton BE, Varallyay CG, et al. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int. 2009;75:465–474. 6. Hamilton BE, Nesbit GM, Dosa E, et al. Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging. AJR Am J Roentgenol. 2011;197:981–988. 7. McCullough BJ, Kolokythas O, Maki JH, et al. Ferumoxytol in clinical practice: implications for MRI. J Magn Reson Imaging. 2013;37:1476–1479. 8. Schieda N. Parenteral ferumoxytol interaction with magnetic resonance imaging: a case report, review of the literature and advisory warning. Insights Imaging. 2013;4:509–512. 9. Gunn AJ, Seethamraju RT, Hedgire S, et al. Imaging behavior of the normal adrenal on ferumoxytol-enhanced MRI: preliminary findings. AJR Am J Roentgenol. 2013;201:117–121. 10. Rostoker G, Griuncelli M, Loridon C, et al. Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: an MRI study. Am J Med. 2012;125:991–999.
www.jcat.org
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
573
