Megaloblastic anemia

Japanese: 巨赤芽球性貧血

Definition/Concept Megaloblastic anemia is a hematopoietic disorder characterized by the appearance of megaloblasts, and is caused by impaired DNA synthesis due to a deficiency of vitamin _B12 or folic acid.
ClassificationMegaloblastic anemia is broadly divided into those caused by vitamin _B12 deficiency and those caused by folic acid deficiency. Among megaloblastic anemia caused by vitamin _B12 deficiency, megaloblastic anemia that develops when vitamin _B12 absorption is reduced due to an autoimmune mechanism is called pernicious anemia. This benign anemia is called pernicious anemia because it was a fatal disease before the 1920s, when its cause was unknown.
CausesThe causes of vitamin _B12 deficiency are shown in Table 14-9-3. Dietary vitamin _B12 deficiency rarely occurs except in strict vegans. Vitamin _B12 deficiency due to stomach disorders is caused by pernicious anemia, anemia due to gastrectomy, and atrophic gastritis associated with aging. Pernicious anemia is thought to develop through an autoimmune mechanism. It is known that autoantibodies such as anti-intrinsic factor antibodies and anti-parietal cell antibodies are detected in patients with pernicious anemia. Autoimmune mechanisms mediated by these autoantibodies and activated T lymphocytes result in impaired binding of vitamin _B12 to intrinsic factor, damage to parietal cells, and atrophy of the gastric mucosa (type A gastritis). This series of pathological changes impairs the absorption of vitamin _B12 through insufficient secretion of intrinsic factor and impaired release of food-vitamin _B12 due to low acidity in the stomach.
Table 14-9-4 shows the causes of folic acid deficiency. Causes of folic acid deficiency include inadequate intake due to dieting or alcoholism, and absorption disorders, as well as increased demand due to pregnancy, etc. Deficiency can also occur due to drugs that antagonize folic acid metabolism, such as methotrexate.
Epidemiology Comparing the frequency of vitamin _B12 deficiency and folate deficiency among megaloblastic anemias, the frequency of megaloblastic anemia due to vitamin _B12 deficiency is overwhelmingly higher. In a Japanese survey, the frequency of vitamin _B12 deficiency was higher than that of folate deficiency, with pernicious anemia accounting for 61% of cases, vitamin _B12 deficiency after gastrectomy for 34%, other vitamin _B12 deficiency for 2%, and folate deficiency _for 2%. Among vitamin _B12 deficiency cases, pernicious anemia was the most frequent (Komine, 2006). The incidence of pernicious anemia is high in Northern Europeans and white Americans, and although reports vary, the annual incidence rate is said to be 10-50 per 100,000 people. In contrast, the incidence rate is low, at 1-5 in Asia, including Japan. It is more common among the elderly, with the peak age at onset being 65 years old.
Pathophysiology Vitamin _B12 is ingested from animal foods, and the daily intake in the Western diet is 3-30 μg. Since the required amount is 1-3 μg per day, vitamin _B12 deficiency rarely occurs due to inadequate intake. In addition, since 1-5 mg is stored in the body, deficiency does not develop immediately even if absorption is stopped due to gastrectomy, and it is said that it takes an average of 5-6 years for megaloblastic anemia after gastrectomy to develop. Vitamin _B12 bound to protein in food is released by the presence of hydrochloric acid in gastric juice and binds to haptocorrin. When it reaches the duodenum, haptocorrin is broken down by pancreatic enzymes, and vitamin _B12 binds to intrinsic factor secreted from the parietal cells of the stomach and is absorbed at the terminal ileum. However, it is thought that 1-5% of vitamin _B12 is absorbed by passive diffusion. Absorbed vitamin _B12 binds to transcobalamin II (TCII) and is taken up via the TCII receptor on the cells. Figure 14-9-5 shows the metabolism of vitamin _B12 within cells. Once inside cells, vitamin _B12 functions as a coenzyme. One of its functions is as a coenzyme for methionine synthase. Methionine is synthesized from ^N5 -methyl-tetrahydro-folate ( ^N5 - _CH3 -THF) by donating a methyl group to homocysteine, and the enzyme that catalyzes this reaction is methionine synthase, for which vitamin _B12 acts as a coenzyme. This methionine synthesis reaction converts ^N5 - _CH3 -THF to THF. Another function of vitamin _B12 is the synthesis of succinyl-CoA in mitochondria. Vitamin _B12 acts as a coenzyme for malonyl-CoA mutase, which catalyzes the isomerization of methyl-malonyl-CoA to succinyl-CoA, and the synthesized succinyl-CoA is used in the TCA cycle.
On the other hand, folic acid is found widely in plant and animal foods, and the daily requirement is said to be 50 to 100 μg. The normal diet contains several times this amount of folic acid, and like vitamin _B12 , inadequate intake rarely leads to deficiency; however, compared to vitamin _B12 , the amount stored is smaller relative to the required amount, so the time from deficiency to onset is shorter than with vitamin _B12 . Folic acid is absorbed in the upper jejunum, and like vitamin _B12 , it is absorbed by passive diffusion and active uptake. The absorbed folic acid is transported to and taken up by cells throughout the body in the form of ^N5 - _CH3 -THF. As mentioned above, the taken-up ^N5 - _CH3 -THF is converted to THF by the removal of the methyl group in a reaction that synthesizes methionine from homocysteine. THF is used as a coenzyme in nucleic acid synthesis via the conversion to N ⁵ , N ¹⁰ methylene (CH ₂ )-tetrahydro-folate (N ⁵ , N ¹⁰ -CH ₂ -THF) and formyl-THF (Figure 14-9-5). In other words, both folic acid deficiency and vitamin B ₁₂ deficiency result in impaired nucleic acid synthesis through the same metabolic disorder, namely insufficient synthesis of THF from N ⁵ -CH ₃ -THF.
Clinical symptoms: The symptoms of anemia are similar to those of other anemias, and include fatigue, headache, shortness of breath, and palpitations. Mild jaundice may be present, reflecting intrabone marrow hemolysis. Because vitamin _B12 and folate deficiency is essentially caused by impaired nucleic acid synthesis, megaloblastic anemia is accompanied by other symptoms besides anemia. Neurological abnormalities are particularly important as symptoms other than anemia, and are present in approximately 30% of cases at the time of diagnosis. Typical neuropathy is peripheral neuropathy, with symptoms such as numbness, hypoesthesia, and decreased vibratory sense, but symptoms such as dementia and depression may also be present. Other symptoms include Hunter glossitis, which is characteristic of atrophy of the tongue papillae, and digestive symptoms associated with atrophic gastritis. Younger individuals may also experience an increase in gray hair that is disproportionate to their age.
Pernicious anemia is often accompanied by other autoimmune diseases, particularly thyroid diseases such as chronic thyroiditis. In addition, the risk of developing stomach cancer is said to increase two to three times, making this a complication that requires caution.
Test results
1) Peripheral blood findings:
Macrocytic anemia is observed. It is not uncommon for macrocytic anemia to be observed in hematopoietic deficiencies other than megaloblastic anemia, such as aplastic anemia and myelodysplastic syndrome, but compared to these anemias, megaloblastic anemia has more pronounced macrocytic changes and the MCV value often exceeds 120 fL. In addition to anemia, pancytopenia accompanied by leukopenia and thrombocytopenia is not uncommon.
2) Bone marrow findings:
The bone marrow is normoplastic-hyperplastic, and displays characteristic morphological abnormalities. Erythroblasts are large erythroblasts with immature nuclei with delicate nuclear chromatin structure, and this delicate chromatin structure is maintained even at the stage where hemoglobin synthesis is observed. In other words, a maturation discrepancy between the nucleus and cytoplasm is observed (Figure 14-9-6A). Morphological abnormalities are also observed in the myeloid system, with atypia such as giant metamyelocytes being observed (Figure 14-9-6B). Although segmented neutrophils with six or more segments are not usually observed, in megaloblastic anemia, hypersegmented neutrophils with six or more segments are observed, which is an important diagnostic finding (Figure 14-9-6C).
3) Biochemical findings:
Serum vitamin _B12 or folate levels are low. Also, reflecting ineffective hematopoiesis in the bone marrow, signs of hemolysis such as elevated bilirubin with a predominance of indirect bilirubin, elevated LDH, and decreased haptoglobin are observed. Decreased activity of intracellular methionine synthase causes the accumulation of its substrate, homocysteine, and its blood concentration increases. In the case of vitamin _B12 deficiency, decreased activity of malonyl-CoA mutase causes the accumulation of its substrate, methyl-malonyl-CoA, and urinary methylmalonic acid concentrations increase.
4) Immunological findings:
Specific findings in pernicious anemia include positive autoantibodies such as anti-intrinsic factor antibodies and anti-parietal cell antibodies. Although the sensitivity of anti-intrinsic factor antibodies is 50-70%, it has a high specificity of over 90%. On the other hand, although anti-gastric wall antibodies have a high sensitivity, they can also be positive in other types of atrophic gastritis, so their specificity is not high.
Treatment In the case of vitamin _B12 deficiency, the cause is malabsorption, so the treatment is basically parenteral administration of vitamin _B12 by injection. Initial treatment involves parenteral administration of 1000 μg of _B12 three times a week for one month. Blood findings usually return to normal in about one month. Glossitis and digestive symptoms also improve relatively quickly after starting vitamin _B12 administration, but neurological symptoms take time to improve and may remain as irreversible symptoms. As hematopoiesis recovers, iron deficiency may become apparent, and anemia may not improve sufficiently, in which case iron supplements are administered. After initial treatment, parenteral administration of 1000 μg of vitamin _B12 is continued once every three months as maintenance therapy. Oral administration may be effective to a certain extent because there are absorption routes other than intrinsic factor, such as passive diffusion. In fact, there are reports that oral administration of large amounts of vitamin _B12 , 1000 to 2000 μg per day, can achieve the same effect as parenteral administration. However, these reports were not based on large-scale clinical studies, and the efficiency of vitamin _B12 absorption is expected to vary greatly depending on the condition, so its reliability is unclear. Because there are risks associated with using oral administration in the early stages of treatment, when it is necessary to obtain therapeutic effects as soon as possible, it seems realistic to attempt oral administration after sufficient effects have been obtained with parenteral administration. However, even in this case, it is necessary to observe test results and subjective symptoms and to comply with medication. Folic acid is absorbed very well if there is no absorption disorder, and since the causes of folic acid deficiency are often heavy alcohol drinkers and insufficient intake in the elderly, as mentioned above, and increased demand during pregnancy, oral administration of about 5 mg/day is usually effective.
Prognosis: If appropriate treatment is given, the same life prognosis as normal can be expected. However, if a definitive diagnosis is delayed, neurological symptoms may remain, leading to a decline in quality of life, so caution is required. [Hideo Harigae]
■References <br /> Komine Mitsuhiro: Anemia due to DNA synthesis, Miwa Hematology, 3rd ed., pp972-1000, Bunkodo, Tokyo, 2006.

Table 14-9-3
Causes of Vitamin B12 Deficiency

Table 14-9-3

Table 14-9-4
Causes of folic acid deficiency

Table 14-9-4

Figure 14-9-5
Intracellular folate and vitamin B12 metabolism

Figure 14-9-5

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　巨赤芽球性貧血は巨赤芽球の出現を特徴とする造血障害であり，ビタミンB₁₂もしくは葉酸の欠乏によるDNA合成障害を原因とする．
分類
　巨赤芽球性貧血はビタミンB₁₂不足によるものと葉酸不足によるものに大別される．ビタミンB₁₂不足による巨赤芽球性貧血のうち，自己免疫機序によりビタミンB₁₂の吸収が低下し発症する巨赤芽球性貧血を悪性貧血（pernicious anemia）と称する．良性疾患であるこの貧血が悪性貧血とよばれる理由は，その原因が不明であった1920年代以前は致死的疾患であったことによる．
原因
　ビタミンB₁₂欠乏の原因を表14-9-3に示す．食事性のビタミンB₁₂欠乏はきわめて厳格な菜食主義（ヴィーガニズム，veganism）以外で起こることは少ない．胃の障害によるビタミンB₁₂欠乏は，悪性貧血，胃切除による貧血，加齢に伴う萎縮性胃炎により引き起こされる．悪性貧血は自己免疫性機序により発症すると考えられている．悪性貧血の患者においては，抗内因子抗体，抗壁細胞抗体などの自己抗体が検出されることが知られており，これらの自己抗体や活性化Tリンパ球を介した自己免疫性機序により，ビタミンB₁₂と内因子との結合障害や壁細胞の傷害，胃粘膜の萎縮（typeA gastritis）がもたらされる．この一連の病的変化により，内因子の分泌不全，胃内の低酸状態に起因する食物-ビタミンB₁₂の遊離不全などを介して，ビタミンB₁₂の吸収が障害される．
　表14-9-4に葉酸欠乏の原因を示す．葉酸欠乏の原因として，ダイエット，アルコール依存による栄養不足，吸収障害などの摂取不足のほか，妊娠などによる需要の増大があげられる．また，メトトレキサートなどの葉酸代謝に拮抗する薬剤により，欠乏することがある．
疫学
　巨赤芽球性貧血のなかで，ビタミンB₁₂欠乏と葉酸欠乏の頻度を比較すると，ビタミンB₁₂の欠乏による巨赤芽球性貧血の頻度の方が圧倒的に高い．ビタミンB₁₂欠乏においては，日本の調査研究においても，悪性貧血が61％，胃切除後ビタミンB₁₂欠乏が34％，その他のビタミンB₁₂欠乏2％，葉酸欠乏2％と，葉酸欠乏に比してビタミンB₁₂欠乏の頻度が高く，ビタミンB₁₂欠乏のなかでは，悪性貧血の頻度が最も高かった（小峰，2006）．悪性貧血の発症率は北欧・米国白人で高く，報告によりばらつきがあるものの10万人あたりの年間発症率は10～50人とされている．これに対し，日本を含むアジアでは1～5人と発症率は低い．発症は高齢者に多く，発症のピークは65歳とされている．
病態生理
　ビタミンB₁₂は動物性食品から摂取され，欧米の食事を基準にすると摂取量は1日あたり3～30 μgである．必要量は1日あたり1～3 μgであることから，摂取不足によりビタミンB₁₂欠乏が起こることはまれである．また，体内には1～5 mgの貯蔵があることから，胃切除などにより吸収が停止してもすぐには欠乏症の発症に至らず，胃切除後の巨赤芽球性貧血は発症までに平均して5〜6年を要するとされている．食物中の蛋白質と結合しているビタミンB₁₂は，胃液中の塩酸の存在により遊離し，ハプトコリンと結合する．十二指腸に移行すると膵酵素によりハプトコリンが分解され，ビタミンB₁₂は胃の壁細胞から分泌される内因子と結合し，回腸末端にて吸収される．ただし，1～5％のビタミンB₁₂は受動的拡散により吸収されると考えられている．吸収されたビタミンB₁₂はトランスコバラミンⅡ（TCⅡ）と結合し，細胞上にあるTCⅡ受容体を介して取り込まれる．図14-9-5に細胞内におけるビタミンB₁₂の代謝を示す．細胞内に取り込まれたビタミンB₁₂は補酵素として機能する．その1つは，メチオニン合成酵素の補酵素としての作用である．メチオニンは，N⁵-methyl-tetrahydro-folate（N⁵-CH₃-THF）からホモシステインにメチル基が供与されることで合成されるが，この反応を触媒する酵素がメチオニン合成酵素であり，ビタミンB₁₂はこの補酵素として作用する．このメチオニン合成反応によりN⁵-CH₃-THFがTHFへと変換される．もう1つのビタミンB₁₂の機能はミトコンドリアでのスクシニルCoA合成反応である．ビタミンB₁₂は，methyl-malonyl-CoAからスクシニル-CoAへの異性化を触媒するmalonyl-CoA mutaseの補酵素として作用し，合成されたスクシニルCoAはTCA回路で用いられる．
　一方，葉酸は植物性・動物性食物に幅広く含まれており，1日所要量は50～100 μgとされている．通常の食にはこの数倍の葉酸が含まれており，ビタミンB₁₂同様摂取不足により欠乏状態になることはまれであるが，ビタミンB₁₂と比較すると所要量に対する貯蔵量が少ないため，欠乏から発症までの時間はビタミンB₁₂よりも短い．葉酸は空腸上部で吸収され，ビタミンB₁₂同様，受動的拡散と能動的取り込みにより吸収される．吸収された葉酸はN⁵-CH₃-THFの形で全身の細胞へと運ばれ，取り込まれる．取り込まれたN⁵-CH₃-THFは，前述のようにホモシステインからメチオニンを合成する反応で，メチル基がはずれることによりTHFとなる．THFはN⁵, N¹⁰ methylene（CH₂）-tetrahydro-folate（N⁵, N¹⁰-CH₂-THF）やformyl-THFを経て，核酸合成における補酵素として用いられる（図14-9-5）．すなわち，葉酸の不足もビタミンB₁₂の不足もN⁵-CH₃-THFからのTHFの合成不全という同じ代謝障害を介して核酸の合成障害をもたらすことになる．
臨床症状
　貧血の症状は他の貧血と同様であり，易疲労感，頭痛，息切れ，動悸などを訴える．骨髄内溶血を反映し，軽度の黄疸を認めることがある．ビタミンB₁₂・葉酸欠乏の本態が核酸合成の障害にあることから，巨赤芽球性貧血においては，貧血以外の症状を伴う．特に，貧血以外の症状として神経学的な異常は重要であり，診断時約30％の症例でその症状が認められる．典型的な神経障害は，しびれ感，感覚鈍麻，振動覚の低下などの末梢性神経障害であるが，認知症，抑うつなどの症状を呈することもある．このほか，舌乳頭の委縮による特徴的なHunter舌炎，萎縮性胃炎に伴う消化器症状などの症状を合併する．また，若年者では，年齢不相応の白髪の増加が認められることもある．
　悪性貧血については，ほかの自己免疫疾患，特に慢性甲状腺炎などの甲状腺疾患の合併がしばしば認められる．また，胃癌発症の危険率が2〜3倍に上昇するとされており，胃癌は注意すべき合併症である．
検査成績
1）末梢血所見：
大球性貧血を認める．巨赤芽球性貧血以外の再生不良性貧血や骨髄異形成症候群などの造血不全症においても大球性貧血を認めることはまれではないが，巨赤芽球性貧血ではこれらの貧血に比べ，大球性変化が著明でありMCV値が120 fLをこえることが多い．また，貧血だけでなく白血球，血小板減少を伴った汎血球減少症を呈することが少なくない．
2）骨髄所見：
骨髄は正形成-過形成骨髄であり，特徴的な形態異常を呈する．赤芽球は核クロマチン構造が繊細な幼若な核を有する大型の赤芽球であり，この繊細なクロマチン構造はヘモグロビン合成が認められる段階においても保持されている．すなわち，核と細胞質の成熟乖離が認められる（図14-9-6A）．また，骨髄球系においても形態異常が認められ，巨大後骨髄球などの異型が観察される（図14-9-6B）．分節核球も通常は6分節以上の分節核球は認められないが，巨赤芽球性貧血においては6分節以上の過分節好中球が認められ，診断上重要な所見である（図14-9-6C）．
3）生化学所見：
血清ビタミンB₁₂もしくは葉酸が低値を呈する．また，骨髄での無効造血を反映して，間接ビリルビン優位のビリルビン上昇，LDHの上昇，ハプトグロビンの低下などの溶血所見が認められる．細胞内メチオニン合成酵素の活性低下により，基質であるホモシステインが蓄積され，その血中濃度が上昇する．ビタミンB₁₂欠乏の場合は，malonyl-CoA mutaseの活性低下によりその基質であるmethyl-malonyl-CoAが蓄積し，尿中メチルマロン酸濃度が上昇する．
4）免疫学的所見：
悪性貧血における特異的所見として，抗内因子抗体，抗壁細胞抗体などの自己抗体が陽性となる．抗内因子抗体の感度は50～70％であるものの，特異度は90％以上と特異性が高い．一方，抗胃壁抗体の感度は高いが，ほかの萎縮性胃炎でも陽性となることがあり，その特異性は高くない．
治療
　治療としてはビタミンB₁₂欠乏の場合，吸収不全を原因とするため，注射によるビタミンB₁₂の非経口投与を原則とする．初期治療として，B₁₂ 1000 μgの非経口投与を週3回，1カ月継続する．通常，血液所見は1カ月ほどで正常化する．舌炎，消化器症状もビタミンB₁₂投与開始から比較的早期に改善するが，神経症状の改善は時間がかかり，不可逆的な症状として残存する場合がある．造血の回復とともに鉄欠乏状態が顕在化し，貧血が十分に改善しない場合があるが，その際は鉄剤の投与を行う．初期治療後，維持療法として3カ月に1度，ビタミンB₁₂ 1000 μgの非経口投与を継続する．経口投与については，受動的拡散など内因子以外の吸収経路があることから，ある程度の効果が期待できる可能性がある．実際に，1日あたり1000～2000 μgの大量のビタミンB₁₂の経口投与でも非経口投与と同等の効果が得られるとする報告もある．ただし，それらの報告は大規模な臨床研究によるものではなく，また，ビタミンB₁₂の吸収効率も病態により大きく異なることが予想されることから，その確実性については不明である．早急に治療効果を得る必要がある初期治療の段階で経口投与法を用いることはリスクを伴うため，経口投与法については，非経口投与により十分な効果が得られてから試みることが現実的であると思われる．ただし，その場合も検査値や自覚症状の観察と服薬の順守が必要である．葉酸の吸収は，吸収障害がなければ非常に良好であり，葉酸欠乏の原因は，前述のようにアルコール多飲者，高齢者にみられる摂取不足，妊娠に伴う需要増大などが多いため，通常5 mg/日程度の経口投与にて効果が認められる．
予後
　適切な治療がなされれば，通常と同じ生命予後が期待できる．ただし，確定診断が遅れると，神経症状が残存しQOLの低下につながる場合があるため，注意が必要である．［張替秀郎］
■文献
小峰光博：DNA合成による貧血，三輪血液病学，第3版，pp972-1000，文光堂，東京，2006.

表14-9-3
ビタミンB12 欠乏の原因">

表14-9-3

表14-9-4
葉酸欠乏の原因">

表14-9-4

図14-9-5
細胞内葉酸・ビタミンB12 代謝">

図14-9-5

出典　内科学第10版内科学第10版について　情報

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