要 旨 MRI Gandon MRI GRE M / L/C LIC-MRI LIC-MRI LIC-MRI 10 LIC-MRI MRI はじめに MRI Magnetic Resonance Imaging ) MRI 3),6) Ga

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1 原 著 血 液 疾 患 患 者 の 鉄 過 剰 症 に 対 する 評 価 方 法 の 検 討 : MRI による 非 侵 襲 的 肝 鉄 量 定 量 測 定 井 本 しおん 1) 2) 大 野 良 治 2) 青 山 信 和 2) 藤 井 正 彦 1) 後 藤 正 德 杉 本 3) 健 4) 西 郷 勝 康 Assessment of iron overload in patients with hematological diseases: Non-invasive measurement of liver iron concentration using MRI Shion IMOTO 1), Yoshiharu OHNO 2), Nobukazu AOYAMA 2), Masahiko FUJII 2), Masanori GOTO 1), Takeshi SUGIMOTO 3), and Katsuyasu SAIGO 4) SUMMARY Background: Iron overload is a major problem for patients with hematological diseases. Liver iron concentration (LIC) is an important marker of iron overload. LIC has been measured by MRI (Magnetic Resonance Imaging) instead of invasive hepatic biopsy in European countries, but not yet in Japan. Methods: LIC was measured by MRI according to Gandon s method (Lancet 2004;363: ) using gradient echo sequence (GRE). Signal intensity ratio of the liver and muscle (L/M) was measured. LIC was estimated from the linear correlation curve of L/M and LIC shown in Gandon s paper. LIC estimated from MRI (LIC-MRI) was compared with serological markers such as serum ferritin level. Patients: Three patients with hematological diseases (post-transfusion iron overload, chronic hemolytic anemia, secondary myelofibrosis) and three healthy persons as normal controls. Results: LIC-MRI and serological markers were normal among the three normal controls. Two patients showed ten times higher LIC-MRI and ferritin levels than normal ranges. Conclusion: LIC-MRI showed an excellent correlation with serum ferritin level. Because of low examination numbers for the present cases, further study is necessary. Keywords: Iron overload, hematological diseases, liver iron concentration, MRI, oxidative stress 1) 2) 3) 4) 1

2 要 旨 MRI Gandon MRI GRE M / L/C LIC-MRI LIC-MRI LIC-MRI 10 LIC-MRI MRI はじめに MRI Magnetic Resonance Imaging ) MRI 3),6) Gandon 9) MRI 1),10) d-roms Reactive Oxygen Metabolites 11) 対 象 及 び 方 法 対 象

3 表 1. 症 例 および 正 常 対 照 の 背 景 U/ / U/1 Ct 1 55 Ct 2 58 Ct 3 55 調 査 項 目 RBC Ht Hb WBC plt ALT, AST, CRP MRI Case 1, 2 IV d-roms Reactive Oxygen Metabolites FRAS4 Free Radical Analytical System; ROOH 11) ph4.8 ROOH A-NH2; Carratelli CARR U MRI による 肝 鉄 量 測 定 Gandon Lancet 2004; 363: MRI MRI PHILIPS Achieva 1.5T 1.5T MRI 1.5T MRI Gradient echo sequences GRE 5 T1, PD, T2, T2+,T2++ T1 T1PD proton density T2 T2 T2, T2+ T2++ T2 L M / 3

4 表 2.MRI による 肝 鉄 量 定 量 のためのシークエンス TR (ms) TE (ms) PA ( ) T PD T T T Gandon* T PD T T T TR: repetition time TE: echo time PA: pulse angle PD: proton density *Gandon Y et al. Lancet 2004; 363: 358 Table 1 L L L M M L/M = 1.29 M M 1-1. T2++ での 肝 臓 (L)と 筋 肉 ( 背 筋 M) の 信 号 強 度 測 定 および L/M 算 出 1-2. T2++ での L/M - B-HIC( 肝 生 検 によ る 肝 鉄 量 ) 近 似 直 線 :Gandon らの 論 文 Figure1 の 模 式 図 B-HIC<100 μ mol/g dry weight で 定 量 可 能 1-3. T1 での L/M - B-HIC( 肝 生 検 による 肝 鉄 量 ) 近 似 直 線 :Gandon らの 論 文 Figure2 の 模 式 図 B-HIC100~340 μ mol/g dry weight で 定 量 可 能 図 1.MRI による 肝 鉄 量 測 定 方 法 MRI LIC-MRI 1-1 T1 L/M L/M T11 L/M T figure1 LIC-MR T1 L/M L/M T1 L/M T1 1-3 figure 2 LIC-MR Gandon 9) LIC-MRI MRI LIC-MRI L/M T1, PD, T2, T2+, T2++ T mol/g dry weight 4

5 T mol/g dry weight 1-3 結 果 血 液 検 査 データの 比 較 Hb<10 g/dl Hb7.3g/dl MCV97 fl 1,440ng/ ml / x CRP Hb9.3g/dl MCV109 fl 940ng/ml 40 ALT AST CRP Hb9.0g/dl MCV98 fl 124 ng/ml 10 85ng/ml 29 CRP CRP 肝 線 維 化 マーカーの 測 定 結 果 IV IV IV ng/ ml 酸 化 ストレス(d-ROM テスト) 測 定 結 果 364 CARR U309 CARR U Ct CARR U 10) / CARR U LIC-MRI の 測 定 結 果 とフェリチンとの 関 連 LIC-MRI の 測 定 MRI L/M T1>1.02-1L/M T2++ 表 3. 症 例 および 正 常 対 照 の 血 液 検 査 所 見 TIBC * ** (ng/ml) RBC Plt total bilirubin Ht Hb MCV WBC id-bil AST ALT Cr CRP % % % Ct % Ct % Ct % */

6 LIC-MRI 1-1 Ct 1 3 LIC-MRI 1520mol/g dry weight 3020mol/g dry weight 520mol/g dry weight 36 mol/ g dry weight L/M T1<1.0, L/M T1 LIC-MRI 34050mol/g dry weight mol/g dry weight MRI L/M L/M T2++ LIC-MRI 520mol/g dry weight フェリチン 値 との 比 較 LIC-MRI 2-4 r = 0.98 鉄 キレート 剤 による 治 療 経 過 1000 ng/ml LIC- MRI RCC ,000 ng/ ml 2009 Deferasirox 1,440ng/ml 77LIC-MRI mol/g dry weight mg/day 1,000mg/day 2-1. 正 常 対 照 の MRI 2-2. 症 例 1の MRI( 治 療 開 始 時 ) 2-3 症 例 2 の MRI( 治 療 開 始 時 ) 2-4. フェリチンと 肝 鉄 量 (LIC-MRI)の 相 関 図 相 関 係 数 r = 0.98 図 2.MRI による 肝 鉄 量 測 定 例 6

7 RCC tranfusion deferasirox TIBC 図 3. 症 例 1の 臨 床 経 過 ng/ml, 10~220TIBC g/dl g/dl WBC x100/ l Hb g/dlplt; x10000/ l 500mg/day 1,120ng/ml Hb 10g/dl MCV 109 fl 3 mg/dl ,000ng/ml ALT, AST ng/ml 40LIC-MRI mol/g dry weight ALT 68 IU/l AST 44IU/l 12) Deferoxamine 500mg ng/ml LIC-MRI mol/g dry weight Hb 10g/dl 3mg/dl 7

8 desferrioxamine 4-2. 症 例 2の 治 療 6カ 月 後 の MRI 図 4. 症 例 2の 臨 床 経 過 4-1. 血 液 データの 推 移 ;ALT (IU/l) AST (IU/l) 総 ビリ ルビン(mg/dl) 間 ビリルビン( 間 接 ビリルビン; mg/dl) 他 は 図 3と 同 様 図 5. 鉄 制 限 食 指 導 パンフレット 8

9 考 察 MRI Gandon St Pierre SSE R2 (=1/T2) 13) LIC mg Fe/g 5.4~763 mol/g) Anderson LJ GRE T2-star (T2*) 14) LIC 3.2mg Fe/g (57 mol/g) MRI LIC-MRI Gandon LIC 36 mol/g dry weight 10 LIC-MRI 36 mol/g dry weight LIC-MRI 1000ng/ml LIC-MRI 10 LIC-MRI 0.98 Deferasirox 15) LIC-MRI 11 LIC-MRI 270 mol/g non-transferrin-bound iron; NTBI labile plasma iron; LPI 1),6),14) d-roms d-roms 結 語 MRI 9

10 謝 辞 21 文 献 Iron Overload Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology Am Soc Hematol Educ Program. 2003: Iron Overload 2007, Vermylen C. What is new in iron overload? Eur J Pediatr. 2008; 167(4): Fischer R, Harmatz PR. Non-invasive assessment of tissue iron overload. Hematology Am Soc Hematol Educ Program. 2009: III Cohen AR. New advances in iron chelation therapy. Hematology Am Soc Hematol Educ Program. 2006: Gandon Y, Olivié D, Guyader D, Aubé C, Oberti F, Sebille V, Deugnier Y. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004; 363(9406): EN/HemoCalc15.html 10III Komatsu F, Kagawa Y, Sakuma M, Kawabata T, Kaneko Y, Otgontuya D, Chimedregzen U, Narantuya L, Purvee B. Investigation of oxidative stress and dietary habits in Mongolian people, compared to Japanese people. Nutr Metab (Lond). 2006; 3: intro/intro.html 13 St Pierre TG, Clark PR, Chua-anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK, Pootrakul P, Robins E, Lindeman R. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005; 105(2): Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM, Pennell DJ. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001; 22(23): Vol.8 No /02/

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