Radiology
Douraied Ben Salem, MD Jean-Pierre Cercueil, MD Frede´ric Ricolfi, MD Denis Krause´, MD
Case 75: Erythropoietic Hemochromatosis1 HISTORY An 82-year-old woman with a recent medical history of cholecystectomy for biliary peritonitis underwent magnetic resonance (MR) imaging of the abdomen to look for stones in the extrahepatic bile duct. MR imaging was performed 6 days after the patient was admitted to the hospital. Results of laboratory tests indicated moderate macrocytic anemia, which persisted since the patient was admitted to the hospital (red blood cell count, 2.79 ⫻ 106/mm3 [2.79 ⫻ 1012/L]; hemoglobin level, 9.5 g/dL [95 g/L]; mean corpuscular volume, 113.9 m3 [113.9 fL]; hematocrit level, 28.7% [0.287]). Pancreatic and liver function test results and platelet and white blood cell counts were normal. A digital abdominal radiograph was obtained prior to cholecystectomy. No intraductal calculus was depicted with MR cholangiopancreatography (images not shown), which was performed with a 1.5-T MR imager in association with T1- and T2-weighted breath-hold examinations.
IMAGING FINDINGS The anteroposterior digital abdominal radiograph (Fig 1) showed no abnormal increase in bone opacity at the lumbar spine or pelvis.
Part 1 of this case appeared 4 months previously and may contain larger images.
Index terms: Bone marrow, abnormalities, 30.594, 40.594 Diagnosis Please Hemochromatosis, 30.594, 40.594 Liver, abnormalities Liver, iron contrast Red blood cells Published online 10.1148/radiol.2331021249 Radiology 2004; 233:116 –119 1
From the Departments of Emergency Radiology & Neuroradiology (D.B.S., F.R.) and Radiology (J.P.C., D.K.), Dijon University Hospital, 3 rue du Faubourg Raines, BP 1519, F-21033 Dijon Cedex, France. Received October 1, 2002; revision requested December 12; final revision received May 3, 2003; accepted June 12. Address correspondence to D.B.S. (e-mail:
[email protected]).
Authors stated no financial relationship to disclose. ©
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MR imaging of the abdomen demonstrated low signal intensity (SI) on T1- and T2-weighted images of the liver and bone marrow (Figs 2– 4), with normal SI of the spleen (Figs 2– 4) and pancreas (Fig 3a) and no hepatosplenomegaly.
DISCUSSION The reduced SI of the liver on images obtained with the T1weighted gradient-echo sequence (Figs 2, 4) and the T2weighted fast spin-echo sequence (Fig 3) is caused by the paramagnetic effect of intracellular iron deposits (ferritin and hemosiderin), as occurs in primary (1) or secondary (2,3) hemochromatosis. The inherent dependence of gradient-echo sequences on the effective transverse relaxation time, compared with spin-echo sequences, induces a reduction in SI with iron tissue storage (1), because magnetic field inhomogeneities are not erased with a 180° pulse. The low SI of bone marrow (Figs 2– 4) indicates a siderotic marrow (4,5), which has not been reported in patients with hereditary hemochromatosis (6,7) but has been reported in patients with secondary hemochromatosis and transfusional siderosis (2,7,8). There was no evidence of blood transfusion in the medical history; moreover, a transfusional iron overload of the spleen should produce a strong SI decrease from the spleen (9). Myelofibrosis is another condition in which MR imaging shows low SI from the vertebrae and pelvis (10), which is related to an increase in bone marrow reticulin (11). In this patient, myelofibrosis was unlikely because the abdominal radiograph (Fig 1) showed no substantial increase in bone opacity, and even more important, neither splenomegaly (Figs 2, 4) nor immature blood cells were present (12). Reticuloendothelial agents such as ultrasmall superparamagnetic iron oxide or superparamagnetic iron oxide particles, when administered intravenously, can produce MR SI loss in the liver, spleen, and bone marrow (13,14). However, this patient had no history of ultrasmall superparamagnetic iron oxide or superparamagnetic iron oxide particle injections. The bone marrow biopsy specimen had an erythroid hyperplasia with an abnormally large number of ring sideroblasts (58% of erythroblasts) and major iron overload (grade 5⫹ in the histologic grading system for iron storage in marrow particles [15]). These findings, combined with the moderate macrocytic anemia, indicated a diagnosis of sideroblastic anemia (16). The serum iron level was 44.2 mol/L (normal level, ⬍27 mol/L), the transferrin saturation was 92% (normal saturation, ⬍50%), and the serum ferritin level was 2324 mg/L (nor-
Radiology Figure 1. Anteroposterior digital abdominal radiograph obtained prior to cholecystectomy. No increase in bone opacity is visible at the spine or pelvis.
Figure 2. Coronal scout view of the abdomen obtained with a magnetization-prepared gradient-echo fast low-angle-shot MR sequence (repetition time msec/echo time msec, 15/6; flip angle, 30°; section thickness, 10 mm) shows markedly decreased SI of the liver (arrowheads) and bone marrow (straight arrow), compared with that of the normal-sized spleen (curved arrow).
Figure 3. (a, b) Transverse T2-weighted half-Fourier acquisition single-shot fast spin-echo MR images of the abdomen (⬁/64 [effective]; matrix, 112 ⫻ 256; one signal acquired; section thickness, 7 mm). SI of the liver (arrowheads) and marrow of the lumbar spine (single white arrow) and pelvis (double arrows) is low in comparison to that of the pancreas (black arrow).
mal level for female subjects, ⬍186 mg/L). The serum iron parameters and MR imaging features were consistent with those of hemochromatosis, even if the results of liver function tests were normal. Thus, the most likely diagnosis is erythropoietic hemochromatosis related to sideroblastic anemia. Disorders of ineffective erythropoiesis—including congenital dyserythropoietic anemias, thalassemia, and sideroblastic Volume 233
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anemia— eventually lead to hemochromatosis. In sideroblastic anemia, hemosiderin accumulation occurs in the perinuclear mitochondria of erythroblasts (ring sideroblasts), and heme synthesis is reduced as a result of impaired protoporphyrin production. Destruction of ring sideroblasts occurs in sideroblastic anemia within the marrow (16) but not within the reticuloendothelial cells of the spleen. Erythropoietic Hemochromatosis
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Radiology Figure 4. Transverse two-dimensional T1-weighted half-Fourier acquisition single-shot turbo spin-echo gradient-echo MR images obtained with fat saturation (144.0/4.1; flip angle, 70°; matrix, 107 ⫻ 256; one signal acquired; section thickness, 5 mm) obtained (a) before and (b) after intravenous bolus administration of 15 mL of gadopentetate dimeglumine. Note the markedly decreased SI of the liver (arrowheads) and bone marrow (straight arrow), compared with the normal SI of the spleen (curved arrow).
Increased duodenal absorption of dietary iron occurs in patients with hereditary hemochromatosis (17) and patients with disorders of ineffective erythropoiesis (8). In the absence of a reduction in dietary iron, the iron is stored in the liver and exceeds the binding capacity of transferrin (16). In patients with hereditary hemochromatosis or secondary hemochromatosis related to ineffective erythropoiesis, the iron deposits occur mainly in the hepatocytes (8), which leads to tissue damage and fibrosis (3). Cellular toxicity occurs because iron catalyzes the conversion of hydrogen peroxide to free-radical ions (17). The most common causes of death in patients with sideroblastic anemia are progression to acute nonlymphocytic leukemia and complications of secondary hemochromatosis (18). Many patients with ineffective erythropoiesis require blood transfusions on a regular basis. In this patient subset, iron deposits are found in parenchymal cells and in the reticuloendothelial cells of the bone marrow, spleen, and liver. Iron deposition within the reticuloendothelial cells is harmless, as long as the iron storage capacity of the reticuloendothelial system is not reached (8). The MR signal from the pancreas (Fig 3b) does not help to distinguish between primary and secondary hemochromatosis (3,7–9), because in advanced states of hemochromatosis (3,8) or transfusional siderosis (7,8), the pancreas is involved. SI from the pancreas is low in patients who have received more than 40 units of blood, which corresponds to the maximum amount of iron that can be stored by the reticuloendothelial system (7). In conclusion, this case illustrates the importance of analyzing MR signal from both the spleen and the bone marrow in patients with a marked decrease in SI from the liver.
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Acknowledgment: The authors are grateful for the help provided by Paul M. Walker, PhD, during preparation of this manuscript. 16. References 1. Bonkovsky HL, Rubin RB, Cable EE, et al. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology 1999; 212:227–234. 2. Brasch RC, Wesbey GE, Gooding CA, Koerper MA. Magnetic resonance imaging of transfusional hemosiderosis complicating thalassemia major. Radiology 1984; 150:767–771. 118
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Siegelman ES, Mitchel DG, Rubin R, et al. Parenchymal versus reticuloendothelial iron overload in the liver: distinction with MR imaging. Radiology 1991; 179:361–366. Isokawa M, Kimura F, Matsuki T, et al. Evaluation of bone marrow iron by magnetic resonance imaging. Ann Hematol 1997; 74:269–274. Steiner RM, Mitchell DG, Rao VM, Schweitzer ME. Magnetic resonance imaging of diffuse bone marrow disease. Radiol Clin North Am 1993; 31:383– 409. Valberg LS, Simon JB, Manley PN, Corbett WE, Ludwig J. Distribution of storage iron as body stores expand in patients with hemochromatosis. J Lab Clin Med 1975; 86:479 – 89. Yoon DY, Choi BI, Han JK, Han MC, Park MO, Suh SJ. MR findings of secondary hemochromatosis: transfusional vs erythropoietic. J Comput Assist Tomogr 1994; 18:416 – 419. Siegelman ES, Mitchel DG, Semelka RC. Abdominal iron deposition: metabolism, MR findings, and clinical importance. Radiology 1996; 199:13–22. 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. Rozman C, Cervantes F, Rozman M, Mercader JM, Montserrat E. Magnetic resonance imaging in myelofibrosis and essential thrombocythaemia: contribution to differential diagnosis. Br J Haematol 1999; 104:574 –580. Kaplan KR, Mitchell DG, Steiner RM, et al. Polycythemia vera and myelofibrosis: correlation of MR imaging, clinical, and laboratory findings. Radiology 1992; 183:329 –334. Murray RO, Jacobson HG, Stoker DJ. Myeloid metaplasia. In: The radiology of skeletal disorders. 3rd ed. London, England: Churchill & Livingstone, 1990; 676 – 677. Seneterre E, Weissleder R, Jaramillo D, et al. Bone marrow: ultrasmall superparamagnetic iron oxide for MR imaging. Radiology 1991; 179:529 –533. Hundt W, Petsch R, Helmberger T, Reiser M. Effect of superparamagnetic iron oxide on bone marrow. Eur Radiol 2000; 10:1495–1500. Lee GR. Microcytosis and the anemias associated with impaired hemoglobin synthesis. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe’s clinical hematology. 9th ed. Philadelphia, Pa: Lea & Febiger, 1993; 791– 807. Bottomley SS. Sideroblastic anemias. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe’s clinical hematology. 9th ed. Philadelphia, Pa: Lea & Febiger, 1993; 852– 871. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341:1986 –1995. Cazzola M, Barosi G, Gobbi PG, Invernizzi R, Riccardi A, Ascari E. Natural history of idiopathic refractory sideroblastic anemia. Blood 1988; 71:305–312. Ben Salem et al
Radiology
Congratulations to the 53 individuals who submitted the most likely diagnosis (erythropoietic hemochromatosis) for Diagnosis Please, Case 75. Credit was not given for “hemochromatosis,” unless modified by the word “secondary.” The names and locations of the individuals, as submitted, are as follows: Hisashi Abe, Osaka, Japan Dr Jorge Ahualli, Tucuman, Argentina Canan Altay, MD, Izmir, Turkey Albert Jerviss Alter, Madison, Wis A. Rhett Austin, MD, Kingsport, Tenn Ella Benoza, Mountain View, Calif Debra M. Berger, MD, New York, NY Mahmut Beser, Istanbul, Turkey Brian Bigoni, Del Mar, Calif Eric L. Bressler, MD, Minnetonka, Minn Michael P. Buetow, MD, Okemos, Mich Michael H. Childress, MD, Silver Spring, Md Haris Chrysikopoulos, MD, Corfu, Greece John J. Combs, Heidelberg, Germany Y-S Cordoliani, MD, Paris, France Steve Cremer, MD, Moline, Ill Marc G. de Baets, Lugano, Switzerland Peter C. De Baets, MD, Sijsele, Belgium Wagner Diniz de Paula, MD, Brasilia, Brazil Matthew A. Frick, MD, Rochester, Minn Akira Fujikawa, Tokyo, Japan John D. Grizzard, MD, Midlothian, Va Ferris M. Hall, MD, Boston, Mass Takuji Kiryu, MD, Gifu, Japan Stefanos Lachanis, Athens, Greece Mario Laguna, West Allis, Wis N. B. S. Mani, MD, Nassau, Bahamas
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Bernardo Martins, Brasilia, Brasil Sankar Ranjan Mondal, MD, Nassau, Bahamas Annamalai Muthiah, Jr, MD, Charlottesville, Va Chris Ng, Nashville, Tenn Marcos Nogueira Chagas, Brasilia, Brasil Sanford M. Ornstein, MD, Phoenix, Ariz Anoop Kumar Pandey, Chandigarh, India Carlo L. E. Petralli, Bruderholz, Switzerland Sudhakar Pipavath, MD, Seattle, Wash Hilton Pittman, Pensacola, Fla Kris Saadeh, Mount Pleasant, SC Guis Saint-Martin, Rio de Janeiro, Brazil Satyajit Sarangi, MD, Lewes, Del Pierre J. Sauvage, MD, Maˆcon, France Janet Scheraga, Syracuse, NY Mahomed Seedat, Toowoomba, Australia Matt Shapiro, MD, Charlottesville, Va Taro Shimono, MD, Osaka, Japan Grady Shue, Mosul, Iraq Darrin S. Smith, MD, Fresno, Calif Piet Vanhoenacker, MD, Aalst, Belgium Dr S. R. Vydianath, Birmingham, United Kingdom Joe Yut, Olathe, Kan Jeffrey H. Zapolsky, Oshkosh, Wis Yu Zhang, Nagoya, Japan Stan Zipser, MD, JD, Mountain View, Calif
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