G 1 貧血3 巨赤芽球性

1. 巨赤芽球性貧血
2. 巨赤芽球性貧血• MCV >=130flならばほぼ100%が巨赤芽球性貧血 ▫ MCV 115-129fl 50% MCV 80-100fl <25% MCV <80fl 0% (混合性でない限り) (Am J Med 1994;96:239-46)• PLT減少(<150000)は12%, WBC減少(<4000)は9%で合併• LDHの異常高値も, (CK, ALT正常より血液由来と確認されれば) 溶血性貧血, 巨赤芽球性貧血などの無効造血と言える ▫ LDH >=3000U/Lならば溶血性よりは巨赤芽球性貧血 (Indian J Pathol Microbiol 2000;43:325-9)
3. 巨赤芽球性貧血の原因, 頻度• 原因別の頻度 (AFP 2009;79:203-8) 原因入院患者外来患者 >75yr 患者 @NY* @Finland† @Finland‡ @US, Finland¶ アルコール 26% 65% 15% 36% Vit B12, 葉酸欠乏 6% 9% 28% 21% 薬剤性 37% 3% 2% 11% 甲状腺機能低下 - 1% 12% 5% 骨髄異形成 6% 1% 5% 5% 肝疾患 6% - 2% 6% Reticulocytosis 8% - - 7% その他 3% 21% 13% 7% 不明 7% - 22% 12% * Am J Med Sci 2000;319:343-52 † J Stud Alcohol 1996;57:97-100 ‡ Age Ageing 1996;25:310-2 ¶ Med Clin North Am 1992;76:581-97
4. 巨赤芽球性貧血を来す薬剤 (AFP 2009;79:203-8)• HIV治療薬; 逆転写酵素阻害薬 ▫ Stavudine, Lamivudine(ゼフィックス®), Zidovudine(レトロビル®)• 抗てんかん薬 ▫ Valproic acid(デパケンR®), Phenytoin(アレビアチン®)• Folate Antagonist; MTX• 化学療法; Alkylating agents, Pyrimidine, Purine inhibitors• ST合剤• Biguanide; Metformin(メルビン®, グリコラン®, メデット®)
5. 好中球過分葉• 好中球過分葉: 5分葉が3つ以上, 6分葉以上が1つ以上で判断 ▫ アルコール症患者での巨赤芽球性貧血の予測 Sn(%) Sp(%) LR(+) LR(-) MCV >100fl 66[49-79] 68[56-77] 2.0[1.4-3.0] 0.5[0.3-0.8] MCV >110fl 27[15-43] 98[90-100] 11[2.5-46] 0.8[0.6-0.9] 大型卵形RBC 90[76-97] 68[56-77] 2.8[2.0-3.9] 0.1[0.1-0.4] 大型卵形RBC>3% 56[40-71] 96[89-99] 15[4.8-47] 0.5[0.3-0.7] 好中球過分葉 78[57-85] 95[87-98] 16[5.9-41] 0.2[0.1-0.4] LDH >225IU/L 73[57-85] 45[34-57] 1.3[1.0-1.8] 0.6[0.4-1.0] 葉酸値<2.1 ng/mL 42[27-58] 76[65-85] 1.8[1.0-3.0] 0.8[0.6-1.0] ▫ 過分葉を伴う大球性貧血の原因(West J Med 1974;121:179-84) 葉酸欠乏 44% VitB12欠乏 2% 葉酸+鉄欠乏 13% VitB12+鉄欠乏 2% 葉酸+VitB12欠乏 6% 腎不全 11% 葉酸+VitB12+鉄欠乏 2% 未測定 11% 不明 9%
6. Vit B12欠乏, 葉酸欠乏 Vit B12欠乏の原因葉酸欠乏の原因胃からの内因子欠乏 76% アルコール症 87% 熱帯スプルー 9% 栄養不良 9% 腸管切除 7% それ以外 4% 空腸憩室 2% 吸収不良 1%• Vit B12欠乏では, ベジタリアン 1% Am J Med 回盲部病変にも注意すべき不明 5% 1994;96:239-4• アルコールは葉酸吸収を低下させる ▫ アルコール依存患者では摂取不足も大きな要素 ▫ 葉酸は加熱にて半分に低下 ▫ フェニトイン, フェノバルビタール, 経口避妊薬でも吸収低下 ▫ MTX, ST合剤, サルファでは体内での利用障害が生じる ▫ 空腸病変(クローン, リンパ腫, スプルー, 強皮症, DM, アミロイド) でも吸収障害あり
7. Vit B12, 葉酸欠乏• 血液検査 ▫ Vit B12は200-400pg/mlがCut-off ▫ 葉酸は2-4ng/mLがCut-off だが, 病院食を1回でも摂取すると正常化また, 絶飲食患者では低下する ▫ 鉄欠乏性貧血の治療に伴い, 葉酸値も有意に上昇を示す. (Blood 1970;35:821-8) Vit B12 Level Sn(%) Sp(%) < 100pg/mL ― 90% < 200pg/mL 90-95% 60% 200-300pg/mL 5-10% ― > 300pg/mL <1% ― Arch Intern Med 1999;159:1289-98
8. Am J Clin Nutr 1987;46:387-402 葉酸, Vit B12欠乏モデル • 葉酸欠乏 Normal Negative Balance Folate Depletion Folate欠乏Liver FolatePlasma FolateErythron Folate血清葉酸値 >5ng/mL <3ng/mL <3ng/mL <3ng/mL <3ng/mLRBC内葉酸値 >200ng/mL >200ng/mL <160ng/mL <120ng/mL <100ng/mL分葉 <3.5 <3.5 <3.5 >3.5 >3.5肝内葉酸値 >3mcg/g >3mcg/g <1.6mcg/g <1.2mcg/g <1mcg/gRBC 正常正常正常正常巨赤芽球性貧血
9. Am J Clin Nutr 1987;46:387-402 • Vit B12欠乏 Normal Negative Balance B12低下 B12欠乏Liver B12HoloTC IIRBC+WBC B12HoloTC II >30pg/mL <20pg/mL <20pg/mL <12pg/mL <12pg/mLTC II % >5% <5% <2% <1% <1%Holohap >150pg/mL >150pg/mL <150pg/mL <100pg/mL <100pg/mL過分葉 No No No Yes YesTBBC % >15% >15% >15% <15% <10%Hap % >20% >20% >20% <20% <10%RBC中葉酸 >160ng/mL >160 >160 <140 <140RBC 正常正常正常正常巨赤芽球性貧血TC II 正常正常正常上昇上昇Methylmalonate (-) (-) (-) ? (+) • HoloTC II; Holotranscobalamin II TC II %; Transcobalamin IIとCobalamin比 Holohap; Holohaptocorrin TBBC %; Total B12 binding capacity of plasma with B12 Hap %; Total haptocorrinとB12比
10. 1057歳男性, 18ヶ月前からの両側下肢の痺れと痛 N Engl J Med 2013;368:149-60.• 身体所見では, 下肢の振動覚, 関節位置覚の低下あり.• 整形学的には問題無し.• アルコール摂取は無し. 糖尿病も無し.• 血液検査では, Hb 14.2g/dL, MCV 96fl, Vit B12 205pg/mL• この患者の痺れの原因としてビタミンB12欠乏の可能性はあるか？ ▫ Methylmalonic acid 3600nmol/L (正常<400) Hemocysteine 49.1 µmol/L (正常<14)
11. Methylmalonic Acid, Arch Intern Med 1999;159:1289-98 Homocysteine • 両者の代謝にVit B12, 葉酸のどちらか, 双方が必要 ▫ 欠乏により血中濃度が上昇する ⇒ Markerとなり得る ▫ が, 国内ではMethylmalonic Acidの測定は不可能… 代謝産物 Vit B12欠乏葉酸欠乏Methylmalonic Acid MMA上昇 98% 12% Hydrolase Homocysteine上昇 96% 91%Methylmalonyl-CoA MMA ↑, Hcy → 4% 2% MMA→, Hcy ↑ 1% 80% Ado-Cbl MMA→, Hcy→ 0.2% 7%Succinyl-CoAFolate DNA Synthesisに使用 CNSのメチル化に使用Methyltetrahydrofolate Methionine + Methyl-Cbl, TetrahydrofolateHomocysteine Methionine Synthetase
12. with daily oral treatment (169 nmol per liter, vs. 265 nmol per liter with parenteral treatment) 12 300,000 and vitamin B12 levels were significantly higher (1005 pg per milliliter vs. 325 pg per milliliter [741.5 vs. 239.8 pmol per liter]). A more recent Serum Methylmalonic Acid (nmol/liter) 100,000 50,000 491名のVit B12欠乏患者の trial with a similar design involving a proprie- tary oral vitamin B12 preparation also revealed significantly lower levelsMethylmalonic acid Homocysteine, of methylmalonic acid 10,000 in the oral-treatment group at the 3-month follow- up.30 In a randomized trial comparing oral with Ht<35%, Ht≥38%. 5,000 intramuscular vitamin B12 (1000-µg doses, daily Methylmalonic acid; for 10 days, then weekly for 4 weeks, and month- ly thereafter), the two groups had similar im- 1,000 >500nmol/Lは感度98%, provements in hematologic abnormalities and 500 vitamin B12 levels at 90 days.44 Case series of >1000nmol/Lは感度86% patients treated with oral vitamin B12 have yielded variable results; elevated levels of meth- 100 ylmalonic acid, homocysteine, or both were re- 0 10 50 100 150 200 250 300 350 400 450 ported in about half of patients with malabsorp- N Engl J Med 2013;368:149-60. Serum Total Homocysteine (µmol/liter) tion who were treated with twice-weekly oralFigure 4. Serum Methylmalonic Acid and Total Homocysteine Concentrations doses of 1000 µg,45 whereas normal homocyste-in 491 Episodes of Vitamin B12 Deficiency. ine levels were reported in patients treated withThe data shown have been combined from studies performed over a period 1500 µg daily after gastrectomy.46 Data are lack-of 25 years.4,6,22,24,26,35,37,38 Most of the patients with clinically confirmed ing from long-term studies to assess whethervitamin B12 deficiency had documented pernicious anemia and a proven re- oral treatment is effective when doses are ad-sponse to vitamin B12 therapy. Open circles indicate episodes in patients ministered less frequently than daily. Studieswith a hematocrit lower than 38%, and solid circles indicate episodes inthose with a hematocrit of 38% or higher. Patients without anemia had involving older adults, many of whom hadneurologic manifestations of vitamin B12 deficiency and similar values of chronic atrophic gastritis, showed that 60% re-methylmalonic acid and total homocysteine. The axis for serum methylmalo- quired large oral doses (>500 µg daily) to correctnic acid is plotted on a log scale. The dashed lines indicate values that are elevated levels of methylmalonic acid.47,483 SD above the mean for healthy blood donors: 376 nmol per liter for meth- Proponents of parenteral therapy state thatylmalonic acid and 21.3 µmol per liter for total homocysteine. The level ofmethylmalonic acid was greater than 500 nmol per liter in 98% of the pa- compliance and monitoring are better in patientstients and greater than 1000 nmol per liter in 86%. Adapted from Stabler.7 who receive this form of therapy because they
13. 13• >65yrのランダム抽出された高齢患者1562名にて Vit B12, 葉酸欠乏を評価 ▫ Vit B12欠乏; Vit B12 <150pmol/Lもしくは, Vit B12 150-200pmol/L + MMA>0.35mcmol/L, tHcy >15.0mcmol/L ▫ 葉酸欠乏; Folate <5nmol/Lもしくは, Folate 5-7nmol/L + tHcy >15mcmol/L Am J Clin Nutr 2003;77:1241-7 ▫ Vit B12欠乏に当てはまるのは, 65-74yrの男性で11%, 女性で9% >=75yrの男性で24%, 女性で17% ▫ 葉酸欠乏に当てはまるのは, 65-74yrの男性で10%, 女性で8% >=75yrの男性で20%, 女性で16%• 高齢者では10-20%はVit B12, 葉酸欠乏である.
14. 14Vit B12, 葉酸欠乏と神経障害 Lancet Neurol 2006;5:949-60• Vit B12欠乏患者の40%で神経障害を合併する ▫ Vit B12欠乏性神経障害の20％, 葉酸欠乏の25%が貧血(-) ▫ 逆に巨赤芽球貧血患者の1/3で神経障害(-) ▫ 末梢神経障害, 認知障害など様々な神経障害を呈する神経障害 Vit B12欠乏葉酸欠乏正常 32% 35% 認知障害 26% 27% 情動障害 20% 56% 亜急性連合変性症 16% 0% 末梢神経障害 40% 18% 視神経萎縮 2% 0% ▫ 末梢神経障害∼中枢神経障害, 認知症, 精神疾患様々な症状をとり得る.
15. 15• 末梢神経障害は双方で認めるが機序は異なる ▫ Vit B12欠乏による振動覚低下, 下肢より上行性に出現する. Vit B12は中枢, 末梢神経のミエリン合成に重要であり, 欠乏にて脱髄性の変化を来す. ▫ 葉酸欠乏患者での末梢神経障害はアルコールによるもの ▫ 舌の痛はVit B12欠乏で65%, 葉酸欠乏患者の33%で認める (Br Med J 1969;3:436-9)• Peak年齢は60-70yrであり, 大半が40-90yrで生じる
16. Brain 16 Altered mental status Cognitive defects “Megaloblastic madness”: depression,Vit B12欠乏の症状, 症候 Optic atrophy, anosmia, loss of taste, mania, irritability, paranoia, delusions, lability glossitis Spinal cord Myelopathy Spongy degeneration Abnormalities in infants and children Developmental delay or regression, permanent disability Does not smile Feeding difficulties Hypotonia, lethargy, coma Hyperirritability, convulsions, tremors, Paresthesias myoclonus Loss of proprioception: vibration, Microcephaly position, ataxic gait, limb weakness; spasticity (hyperreflexia); positive Choreoathetoid movements Romberg sign; Lhermitte’s sign; segmental cutaneous sensory level Autonomic nervous system Postural hypotension Infertility Incontinence Impotence Peripheral nervous system Peripheral blood Cutaneous sensory loss Macrocytic red cells, macroovalocytes Hyporeflexia Anisocytosis, fragmented forms Symmetric weakness Hypersegmented neutrophils, 1% with Paresthesias six lobes or 5% with 5 lobes Leukopenia, possible immature white cells Bone marrow Thrombocytopenia Hypercellular, increased erythroid Pancytopenia precursors Elevated lactate dehydrogenase level Open, immature nuclear chromatin (extremes possible) Dyssynchrony between maturation of Elevated indirect bilirubin and cytoplasm and nuclei aspartate aminotransferase levels Giant bands, metamyelocytes Decreased haptoglobin level Karyorrhexis, dysplasia Elevated levels of methylmalonic acid, Abnormal results on flow cytometry homocysteine, or both and cytogenetic analysis N Engl J Med 2013;368:149-60.
17. Vit B12欠乏の治療 Family Practice 2006;23:279-85• 悪性貧血, 胃切患者でもVit B12の吸収はある ▫ 内因子を必要としない吸収経路, 回腸からも吸収（摂取量の約1%程度）（内因子を通しての吸収率は60%に達する）• Cobalamin 2mg/day POと1mg IV*を比較 (RCT, N=38, 内28名が吸収不良あり)(Blood 1998;92:1191-1198) ▫ 2mo, 4moでの血中Vit B12濃度は経口投与群で有意に高値• Cobalamin 1mg/day POと1mg IV‡を比較 (RCT, N=70, 内35名が吸収不良あり)(Clin Ther 2003;25:3124-34) ▫ 両群で有意なVit B12上昇を認めたが, 両群間では比較していない * 1mg IV 1,3,7,10,14,21,30,60,90D• 日本の保険適応は1.5mg/dayまで ‡ 1mg IV 10日間 ⇒ 週1回 4wk ⇒ 月1回
18. 治療への反応• 6hr後; 骨髄反応の開始• 48hr後; 骨髄中巨赤芽球性変化消失, LDH低下, K低下• 1wk; 網状赤血球増加のピーク• 1-2wk; 末梢のWBC過分葉の消失• 8wk; Hbの正常化• 6mo; 神経学的異常の改善治療が思ったように上手くゆかない場合 ⇒ 鉄欠乏の合併を考慮治療開始時に鉄欠乏(-)でも起こり得る治療失敗の最も多い原因とされる (自己免疫性胃炎や胃全摘では鉄の吸収も低下している！)
19. 19Vit B12欠乏の原因• 重度の吸収障害; • 摂取不良 ▫ 悪性貧血(自己免疫性胃炎) ▫ (成人)ベジタリアン ▫ 胃全摘後 ▫ (乳児)母乳中のVit B12欠乏 ▫ Gastric bypass, bariatric surgery ▫ (小児)成人と同様 ▫ 空腸切除 ▫ 炎症性腸疾患, Tropical aprue • Nitrous oxide中毒 ▫ Imerslund-Grasbeck syndrome • Nitrous oxide麻酔• 中等症の吸収障害; ▫ Protein-bound vit B12 malabsorption ▫ 軽度の萎縮性胃炎 ▫ メトフォルミン使用 ▫ 制酸剤使用 N Engl J Med 2013;368:149-60.
20. 20Vit B12欠乏の検査のまとめ N Engl J Med 2013;368:149-60.Table 2. Laboratory Testing in Vitamin B12 Deficiency.*Test Sensitivity Specificity CommentsMeasurement to detect deficiency Serum vitamin B12 <200 pg/ml or labo- 65–95% for proven clinical deficiency†; 50% 50–60% for clinical response†; 80% for de- Current vitamin B12 assays are especially ratory cutoff level for detecting elevated level of methylma- tecting elevated level of methylmalonic problematic in patients with anti–intrinsic lonic acid acid factor antibodies Serum vitamin B12 <350 pg/ml 90% 25% for detecting elevated level of methyl- malonic acid Holotranscobalamin <20 to 45 pmol/ Insufficient data on sensitivity for clinical de- Insufficient data on specificity for clinical de- Levels of holotranscobalamin increase in re- liter‡ ficiency; 46–89% for detecting elevated ficiency; 28–96% for detecting elevated nal failure; superior to measurement of level of methylmalonic acid level of methylmalonic acid total vitamin B12 in pregnancy, when the total level decreases Serum methylmalonic acid >400 nmol/ 98% for clinical deficiency Poor specificity for clinical response in patients Renal failure and volume depletion may in- liter§ with modest elevation of level of methyl- crease level of serum methylmalonic malonic acid (300–1000 nmol/liter)¶ acid, but rarely to >1000 nmol/liter Serum or plasma total homocysteine 96% for clinical deficiency Homocysteine level also increased in clinical >21 µmol/liter folate deficiency and renal insufficiencyTest to determine cause of deficiency Pernicious anemia Anti–intrinsic factor antibodies 50% 100% Must be tested >7 days after vitamin B12 in- jection to prevent false positive result Anti–parietal-cell antibodies 80% 50–100% Atrophic body gastritis (antral sparing)** Fasting high serum gastrin level 85% (>100 pmol/liter) Low level of serum pepsinogen I 90% (<30 µg/liter) Endoscopy with pentagastrin-fast 100% Rarely performed hypochlorhydria Malabsorption of vitamin B12†† Vitamin B12 absorption test Schilling test no longer available Increase in serum holotranscobalamin Unknown Unknown Promising preclinical data, but still experi- level after oral loading mental
21. 21Vit B12欠乏と皮膚色素沈着• Vit B12欠乏患者では, 皮膚のHyperpigmentationを認めることがある ▫ 貧血に先立って(1yr程度)色素沈着を生じることもあり, Vit B12欠乏の初発症状としてもあり得る. ▫ 手足の皺, 関節の伸側で多いが, 顔面, 体幹に生じることもある. 他には爪の縦方向に走る縞や, 歯肉の色素沈着, 白髪も認める. ▫ それらはVit B12補充にて6mo後には完全に消失 hair follicle might lead to cavities whereas in the skin a ▫ hyperpigmentation would be the result. Department of Dermatology, Shiro NIIYAMA Yokohama Rosai Hospital, 3211 Kozukue, Hideki MUKAI Kohoku-ku, Yokohama, Kanagawa, Vit B12補充 6mo後 222-0036 Japan sniiyama@aol.com 1. Gilliam JN, Cox AJ. Epidermal changes in vitamin B12 deficiency. Arch Dermatol 1973; 107: 231-6. 2. Marks VJ, Briggaman RA, Wheeler CE Jr.. Hyperpigmentation in megaloblastic anemia. J Am Acad Dermatol 1985; 12: 914-7. 3. Mori K, Ando I, Kukita A. Generalized hyperpigmentation of the skin due to vitamin B12 deficiency. J Dermatol 2001; 28: 282-5. 4. Commo S, Gaillard O, Bernard BA. Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. Br J Dermatol 2004; 150: 435-43. 5. Noppakun N, Swasdikul D. Reversible hyperpigmentation of skin and nails with white hair due to vitamin B12 deficiency. Arch Dermatol 1986; 122: 896-9. EJD 2007;17:551-2
22. 22Vit B12欠乏と皮膚色素沈着• 色素沈着の機序 ▫ Vit B12欠乏はGlutathioneの低下を来す. Glutathioneの低下はtyrosinase上昇を来たし, tyrosinaseがHypermelanosisを引き起こす. ▫ また, Melaninの輸送が障害されるとの機序も報告されている.
23. to have megaloblastic anaemia, a low serum vitamin B12 TABLE II.-Urinary Ketogenic Steroid Excretion Before and (15 ,tqg./ml.), and a defect in vitamin-B12 absorption After A.C.T.H. Administration 17-Ketogenic Steroids (mg./24 hours) (Table III). On treatment with vitamin 12 he had a haematological remission and the pigment disappeared. 23 Case No. Sex In 1957 he still had a defect of vitamin-B12 absorption, Before A.C.T.H. After A.C.T.H. 2 F 2-6 8-6 a haemoglobin of 11 g., a serunim vitamin B12 in the 3 M 4-4 14-5 • Vit B12欠乏 + 色素沈着の成人患者(15), 小児患者(6名) III.-Case 15. 5 6 8 10 TABLE M F M F 15-0 4-0 7-7 4-6 28-5 14-9 12-0 13-7 Clinical and Haematological Data Serum pg. Vit. B12 12 M 8-1 11-2 Pigmen- Hb (g./ Bone- Vit. B12 Absorbed 15 M 5-6 18-2 Date tation 100 ml.) marrow (ppg./ Alone Pl.u ▫ 成人の年齢は16-50yr, 小児では1-10 mo. September, 1956 ++++ 6-2 Megalo- ml.) 15 0-05 IF. 0-06 In every case the pigmentation disappeared with the blastic administration of vitamin B12 As might be expected, November, 1957 - 110 Normo- 170 0-08 - ▫ Hgは2.9-14.3g/dL. 成人でHg>10g/dLであったのは4/15. this occurred more rapidly in the infants than in the August, 1958 adults. In the infants the pigmentation frequently June, 1960 .. .. + ++ ++ 7-2 10 0 blastic Megalo- blastic Megalo- 35 62 0*11 0-07 0-10 0 11 disappeared within three weeks. In the adults obvious blastic ▫ 平均Vit B12値は49pg/mL, ACTH負荷試験では副腎機能は正常. hyperpigmentation. change was usually present within two weeks of starting vitamin B12 therapy, but in many cases it took from normal range, and no In 1958 he 6 to 12 weeks to restore the colour to normal. returned complaining of a recurrence of pigmentation. In the two cases where there was pigmentation of the At this time he again had a megaloblastic bone-marrow, ▫ 色素沈着は手足の末端、IP関節から手指末端までが多い. nails and nail beds a definite band between the distal pigmented areas which had formed while the patient was with a serum vitamin B12 of 35 tttzg./ml. and a defective absorption. He was again treated with vitamin B12 by vitamin-Bl2 deficient and the new proximal unpigmented injection, when his haematological condition improved 爪は白色のままであることが多い. areas could be seen growing up with the nail (Fig. 3). and the pigmentation disappeared. He was not seen subsequently until 1960, when he noticed the return of In Case 13 0.2 mg. of folic acid was given daily by injection, but this produced no haematological or clinical pigmentation. At this time he also had a megaloblastic • Vit B12投与により全例が色素沈着改善 response and the serum-vitamin-B12 level remained low. On giving 15 mg. of folic acid daily by injection the marrow, a low serum vitamin B12, and a defect of vitamin-B12 absorption. Again he responded to paren- marrow reverted to normoblastic and a decrease in teral vitamin-B12 therapy. He has not been seen since. ▫ 乳児例では改善が早く, 3wk以内に全例改善. pigmentation was noted. This larger dose of folic acid produced a temporary rise in serum-vitamin-B12 levels. Discussion The decrease in pigmentation, however, was not sustained, and it finally cleared only with the administra- In each of the 21 cases included in this report the 成人例では2wk以内に目に見える変化があり, 6-12wkで改善する. tion of vitamin B12-1 ttg./day by injection. characteristic pigmentation of the hands and feet wasBMJ 1963;June 29:1713-5