今日の臨床サポート

巨赤芽球性貧血

著者: 杉本由香 三重大学医学部 地域血液内科講座

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2021/04/21
参考ガイドライン:
  1. British Committee for Standards in Haematology:Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol, 2014
患者向け説明資料

概要・推奨   

  1. ビタミンB12が欠乏すると活性型葉酸が欠乏するため、葉酸欠乏と同様の血液学的異常を示す(推奨度1)
  1. 小球性貧血を示す疾患と合併した巨赤芽球性貧血では、MCVが正常値あるいは低値を示すことがある。すなわち、全自動血球計数器でMCV値が高値である大球性貧血でなくともビタミンB12欠乏あるいは葉酸欠乏による貧血が潜在することも念頭に置く必要がある(推奨度1)
  1. ビタミンB12が欠乏すると、血清または尿中メチルマロン酸が増加する(推奨度1)
  1. 巨赤芽球性貧血ではビタミンB12欠乏による神経症状を高頻度に併発する。
  1. ビタミンB12欠乏に葉酸を投与すると神経症状が悪化することがあるので、葉酸単独投与は行わない(推奨度1)。
  1. 食物を介して十分に摂取しているにもかかわらず、吸収不良によりビタミンB12欠乏を来すfood-cobalamin malabsorption症候群が提唱されている(推奨度2)。
  1. H2受容体拮抗薬とプロトンポンプ阻害薬の長期使用がビタミンB12吸収障害の原因となり得る(推奨度2)。
  1. わが国におけるビタミンB12欠乏による巨赤芽球性貧血に対する治療では、ビタミンB12の投与は筋注あるいは静注で行われているが、欧米ではビタミンB12は経口摂取量の約1%が内因子を必要としない受動的拡散により吸収されるという考え方に基づき、経口投与を行い、その有効性が報告されている(推奨度2)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 抗内因子抗体陽性の悪性貧血症例では血清中のビタミンB12の濃度が偽高値として測定されることがある(推奨度1)。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
杉本由香 : 特に申告事項無し[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報  
  1. 巨赤芽球性貧血とは、骨髄に核と細胞質の成熟度の解離した巨赤芽球がみられる貧血で、ビタミンB12あるいは葉酸の欠乏などによるDNA合成障害が原因で発症する。
  1. DNA合成障害のため、巨赤芽球を含む巨赤芽球系細胞の多くは骨髄内でアポトーシスにより死滅し、無効造血を来す。DNA合成障害による無効造血は白血球系細胞と巨核球系細胞にも及び、汎血球減少を呈する。
  1. 生体のDNA合成障害は細胞増殖の最も活発な血液細胞に強く影響を与えるため、貧血 (血球減少)が他の症状に先行して出現する。
  1. ビタミンB12が欠乏すると活性型葉酸が欠乏する。ビタミンB12欠乏と葉酸欠乏が血液学的に同様の所見を呈するのはこのためである。
  1. ビタミンB12欠乏の原因は悪性貧血、胃切除後などによる吸収不良、菜食主義などによる摂取不足が主なものである。
  1. 悪性貧血とは、胃酸分泌粘膜の萎縮によりビタミンB12の吸収に必要な内因子の分泌不全が生じ、その結果としてビタミンB12の吸収不全が原因となるビタミンB12欠乏による貧血のことをいう。
 
  1. ビタミンB12が欠乏すると活性型葉酸が欠乏するため、葉酸欠乏と同様の血液学的異常を示す(推奨度1)
  1. ビタミンB12はホモシステインからメチオニンを生成させる反応の補酵素として機能する。この反応により貯蔵型葉酸は活性型葉酸に変換される。ビタミンB12が欠乏すると活性型葉酸が欠乏し、葉酸が補酵素である細胞内反応に障害が生じる。ビタミンB12欠乏と葉酸欠乏が血液学的に同様の所見を呈するのはこのためである。葉酸の機能で重要なものは、DNA合成系とりわけチミジン合成とプリン合成への関与である。葉酸が欠乏すると、チミジンの代わりにウリジン塩基がDNAに組み込まれ、DNAの切断が修復されず、DNAが断片化され細胞外へ漏出する[1]。また、プリン塩基の合成障害も起こり、DNAの合成障害を招く。
 
ビタミンB12が欠乏すると活性型葉酸が欠乏するため、葉酸欠乏と同様の血液学的異常を示す。

出典

img1:  片山直之先生ご提供
 
 
問診・診察のポイント  
  1. 貧血症状があれば進行具合を尋ねる(ビタミンB12欠乏では貧血症状が徐々に進行)。
  1. 年齢を確認する(悪性貧血は高齢者に多い。悪性貧血では年齢の割に白髪が目立つことがある)。

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文献 

著者: S J Duthie, P McMillan
雑誌名: Carcinogenesis. 1997 Sep;18(9):1709-14.
Abstract/Text Poor folate status may be important in the aetiology of several epithelial cell malignancies including cancer of the uterine cervix. Folic acid is essential in the synthesis of purine nucleotides and the pyrimidine nucleoside thymidine and it is probable that imbalances in these DNA precursors negatively effect DNA stability and may ultimately lead to malignant transformation. The development of a modified 'comet assay' using the bacterial DNA repair enzyme uracil DNA glycosylase, to detect misincorporated uracil in human DNA is reported here. The effect of perturbing folic acid and deoxyuridine levels on uracil misincorporation in normal human lymphocytes and cultured human tumour cells was investigated using this assay. HeLa cells and peripheral human lymphocytes incubated as agarose-embedded nucleoids, with 1 unit of uracil DNA glycosylase per microg of DNA, contained low levels of uracil in their DNA. Both HeLa cells and stimulated human lymphocytes cultured in folate-deficient medium were growth arrested. Incubating human lymphocytes in folate-deficient medium significantly increased the level of uracil detected compared with control cells. HeLa cells showed an increase in non-specific DNA damage (strand breaks). Deoxyuridine (100 microM) significantly increased the level of uracil detected in the DNA of both folate-deficient and control HeLa cells. It appears that this modified comet assay specifically detects misincorporated uracil in single human cells. It should, therefore, prove valuable in determining the role of folic acid status in DNA instability and cancer.

PMID 9328165  Carcinogenesis. 1997 Sep;18(9):1709-14.
著者: F A Karlsson, P Burman, L Lööf, S Mårdh
雑誌名: J Clin Invest. 1988 Feb;81(2):475-9. doi: 10.1172/JCI113344.
Abstract/Text In autoimmune gastritis antibodies against a membrane-bound parietal cell antigen of previously unknown function are present in the sera of patients. In this study, a vesicular membrane preparation of porcine gastric mucosa cells was found to be a potent antigenic source. This preparation blocked greater than 90% of antibody binding to a lysate of gastric mucosa cells. The membrane fraction contained H+,K+-ATPase (EC 3.6.1.36) as the major protein, which in sodium dodecyl sulfate-polyacrylamide gel electrophoresis migrated with a weight of 92 kD. After reduction and alkylation, this component was resolved into two bands of similar staining intensity (92 and 88 kD). Immunoblotting analysis showed that sera of patients recognized antigen with pattern identical to the major protein of the vesicular membranes. Protein A-Sepharose beads preincubated with immunoglobulins of five individual patient (but not control) sera were all found to reduce both the H+,K+-ATPase activity and the amount of parietal cell antigen of a preparation of vesicular membranes solubilized in n-octylglucoside. Taken together, the results of this study indicate that the major parietal cell antigen is identical to the acid-producing enzyme, H+,K+-ATPase, of the parietal cell.

PMID 2828428  J Clin Invest. 1988 Feb;81(2):475-9. doi: 10.1172/JCI11・・・
著者: David T Yang, Rachel J Cook
雑誌名: N Engl J Med. 2012 May 3;366(18):1742-3. doi: 10.1056/NEJMc1201655.
Abstract/Text
PMID 22551146  N Engl J Med. 2012 May 3;366(18):1742-3. doi: 10.1056/N・・・
著者: Ralph Carmel, Yash Pal Agrawal
雑誌名: N Engl J Med. 2012 Jul 26;367(4):385-6. doi: 10.1056/NEJMc1204070.
Abstract/Text
PMID 22830482  N Engl J Med. 2012 Jul 26;367(4):385-6. doi: 10.1056/NE・・・
著者: J L Spivak
雑誌名: Arch Intern Med. 1982 Nov;142(12):2111-4.
Abstract/Text In six patients, eight episodes of anemia associated with folic acid or vitamin B12 deficiency were unaccompanied by macrocytosis. Six of the eight episodes of anemia were complicated by illnesses of an inflammatory or infectious nature, two patients had iron deficiency, two appeared to have a thalassemia trait, and one had severe renal failure. In five of the eight episodes, erythropoiesis was not megaloblastic and there was insufficient anisocytosis or poikilocytosis to suggest an underlying vitamin deficiency state. Hypersegmented neutrophils were observed in all episodes, but a neutrophil lobe average of greater than 3.5 lobes per cell was observed only once, and in one patient, less than 5% of the circulating neutrophils were hypersegmented. Giant metamyelocytes, however, were present in the marrow in all of the episodes and provided an important clue to the presence of the vitamin deficiency state.

PMID 7138159  Arch Intern Med. 1982 Nov;142(12):2111-4.
著者: R Carmel, C A Spencer
雑誌名: Arch Intern Med. 1982 Aug;142(8):1465-9.
Abstract/Text of 162 patients with pernicious anemia whom we studies, 24.1% had clinical thyroid disease; 11.7% were hypothyroid and 8.6% were hyperthyroid. When abnormal serum thyroid-stimulating hormone (TSH) levels were also considered, thyroid disorders existed in 48.3% of 143 patients. Increased or decreased TSH levels as the sole dysfunction occurred in 14.7% and 6.3% of cases, respectively, and were often associated with thyroid antibodies. The high TSH group fits the picture of subclinical hypothyroidism. The nature of the low TSH group remains to be defined. We conclude that TSH screening in patients with pernicious anemia uncovers frequent abnormalities, which are superimposed on a higher coincidence of overt thyroid disease than previously described. Interestingly, also, eight of nine hyperthyroid patients and all seven patients with low TSH levels had blood type O, contrasting significantly with hypothyroid subjects, who more often had blood type A, and with patients without thyroid disorders.

PMID 7103627  Arch Intern Med. 1982 Aug;142(8):1465-9.
著者: R Carmel
雑誌名: Baillieres Clin Haematol. 1995 Sep;8(3):639-55.
Abstract/Text Food-cobalamin malabsorption is marked by the inability to release cobalamin from food, which therefore cannot be taken up by intrinsic factor for absorption. The defect is not detectable by classical clinical tests like the Schilling test which are all based on the absorption of free, crystalline cobalamin. Tests of food-cobalamin absorption have been devised, the most popular ones using cobalamin bound to eggs or to chicken serum. The disparity between the abnormal results of these tests and the normal results with the Schilling test defines the disorder of food-cobalamin malabsorption. Release of cobalamin from food requires acid and pepsin, and most food-cobalamin malabsorptive states can be traced to gastric defects. However, other mechanisms may also play a role. The malabsorption is limited to food cobalamin and any free cobalamin, presumably including recycled biliary cobalamin, will be absorbed normally, which may explain its frequently insidious nature. The effect on cobalamin status covers a broad spectrum. At one extreme, some individuals, perhaps in the earliest stages, have normal cobalamin status, while at the other extreme may be found deficiency every bit as severe as in the most florid case of pernicious anaemia. Most often, however, the deficiency is mild, frequently marked by only a low serum cobalamin level, mild evidence of metabolic insufficiency and, sometimes, minimal clinical sequelae. Moreover, in some cases the gastric defect progresses and intrinsic factor secretion is affected, thus transforming into classical pernicious anaemia; this is not inevitable, however, and probably occurs in only a minority of patients. The course of food-cobalamin malabsorption is therefore a varied one. Nevertheless, it may be the most common cause of subtle or mild cobalamin deficiency and it is also sometimes associated with severe deficiency. Its identification and treatment need to be considered more widely in the clinical setting.

PMID 8534965  Baillieres Clin Haematol. 1995 Sep;8(3):639-55.
著者: W A Bauman, S Shaw, E Jayatilleke, A M Spungen, V Herbert
雑誌名: Diabetes Care. 2000 Sep;23(9):1227-31.
Abstract/Text OBJECTIVE: Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability Metformin affects calcium-dependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B12 after metformin administration.
RESEARCH DESIGN AND METHODS: A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B12 measurements and holotranscobalamin (holoTCII) (B12-TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered.
RESULTS: Serial serum vitamin B12 determinations revealed a similar decline in vitamin B12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression.
CONCLUSIONS: Patients receiving metformin have diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.

PMID 10977010  Diabetes Care. 2000 Sep;23(9):1227-31.
著者: R W Force, M C Nahata
雑誌名: Ann Pharmacother. 1992 Oct;26(10):1283-6.
Abstract/Text OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin).
DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources.
STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed.
DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs.
CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.

PMID 1358279  Ann Pharmacother. 1992 Oct;26(10):1283-6.
著者: J R Saltzman, J A Kemp, B B Golner, M C Pedrosa, G E Dallal, R M Russell
雑誌名: J Am Coll Nutr. 1994 Dec;13(6):584-91.
Abstract/Text OBJECTIVE: To investigate the effects of hypochlorhydria and acidic drink ingestion on protein-bound vitamin B12 absorption in elderly subjects.
METHODS: Absorption of protein-bound vitamin B12 was examined in elderly normal subjects (n = 8), and in hypochlorhydric subjects due to omeprazole treatment (n = 8) or with atrophic gastritis (n = 3). Subjects underwent absorption tests of protein-bound vitamin B12 ingested with water, cranberry juice and 0.1 N hydrochloric acid.
RESULTS: Protein-bound vitamin B12 absorption was lower in the omeprazole-treated group (0.50%) compared to the normal group (1.21%; p < 0.001). With cranberry juice ingestion, the omeprazole-treated group showed an increase in absorbed protein-bound vitamin B12 (p = 0.025). With dilute hydrochloric acid ingestion, there was a further increase in vitamin B12 absorption (p < 0.001).
CONCLUSION: Omeprazole causes protein-bound vitamin B12 malabsorption, and ingestion of an acidic drink improves protein-bound vitamin B12 absorption.

PMID 7706591  J Am Coll Nutr. 1994 Dec;13(6):584-91.
著者: B E Schenk, H P Festen, E J Kuipers, E C Klinkenberg-Knol, S G Meuwissen
雑誌名: Aliment Pharmacol Ther. 1996 Aug;10(4):541-5.
Abstract/Text AIMS: To evaluate absorption of protein-bound and unbound cyanocobalamin before and during treatment with omeprazole, and cobalamin levels in patients on long-term treatment with omeprazole.
METHODS: In eight former duodenal ulcer patients absorption of unbound and protein-bound cobalamin was determined by measuring 24-h urinary excretion of unbound 58Co-cyancobalamin or protein-bound 57Co-cyanocobalamin during a modified Schilling test. Tests were performed before and during treatment with 20 mg and 40 mg omeprazole daily for 9 days. Serum cobalamin levels were assessed in 25 patients with gastro-oesophageal reflux disease (GERD) before and during long-term maintenance therapy with omeprazole. Mean treatment duration was 56 months (range 36-81 months).
RESULTS: Urinary excretion of unbound cobalamin was unchanged with both dosages of omeprazole. Excretion of 57Co-cyanocobalamin, however, decreased significantly during treatment with both 20 mg omeprazole (mean +/- S.E.M.: 1.31 +/- 0.20 vs. 0.54 +/- 0.17%; P < 0.02) and 40 mg omeprazole (1.25 +/- 0.26 vs. 0.29 +/- 0.06%; P < 0.02). Mean serum cobalamin levels (+/- S.E.M.) before and during therapy with omeprazole in GERD patients were 298 +/- 27 and 261 +/- 16 pg/mL (normal range 180-900 pg/mL), respectively (P = N.S.).
CONCLUSIONS: Absorption of protein-bound, but not unbound, cyanocobalamin is decreased when measured by a modified Schilling test during treatment with omeprazole. However, no change in serum cobalamin levels was observed in patients with GERD after treatment with omeprazole for up to 7 years.

PMID 8853757  Aliment Pharmacol Ther. 1996 Aug;10(4):541-5.
著者: L E Chapman, A L Darling, J E Brown
雑誌名: Diabetes Metab. 2016 Nov;42(5):316-327. doi: 10.1016/j.diabet.2016.03.008. Epub 2016 Apr 26.
Abstract/Text AIM: Metformin is the most widely used oral hypoglycaemic drug, but it may lower B12 status, which could have important clinical implications. We undertook a systematic review and meta-analysis of the relationship between metformin use and vitamin B12 deficiency in persons with type 2 diabetes.
METHODS: Electronic database searches were undertaken (1st January 1957-1st July 2013) using the Cochrane library, Scopus, CINAHL, Grey literature databases, Pub Med Central, NICE Clinical Guidelines UK, and ongoing clinical trials. Included studies were of any study design, with data from patients with type 2 diabetes of any age or gender, taking any dose or duration of metformin. Planned primary outcomes were serum vitamin B12 levels, % prevalence or incidence of vitamin B12 deficiency and risk of vitamin B12 deficiency.
RESULTS: Twenty-six papers were included in the review. Ten out of 17 observational studies showed statistically significantly lower levels of vitamin B12 in patients on metformin than not on metformin. Meta-analysis performed on four trials demonstrated a statistically significant overall mean B12 reducing effect of metformin of 57pmol/L [WMD (fixed)=-0.57 (95% CI: -35 to -79pmol/L)] after 6weeks to 3months of use.
CONCLUSION: The evidence from this review demonstrates an association between metformin usage and lower levels of vitamin B12 by 57pmol/L, which leads to frank deficiency or borderline status in some patients with type 2 diabetes. This suggests that it is prudent to monitor B12 levels in these patients who are at increased risk of deficiency.

Copyright © 2016 Elsevier Masson SAS. All rights reserved.
PMID 27130885  Diabetes Metab. 2016 Nov;42(5):316-327. doi: 10.1016/j.・・・
著者: Mary Ann Gilligan
雑誌名: Arch Intern Med. 2002 Feb 25;162(4):484-5. doi: 10.1001/archinte.162.4.484.
Abstract/Text
PMID 11863489  Arch Intern Med. 2002 Feb 25;162(4):484-5. doi: 10.1001・・・
著者: Emmanuel Andrès, Ester Noel, Bernard Goichot
雑誌名: Arch Intern Med. 2002 Oct 28;162(19):2251-2. doi: 10.1001/archinte.162.19.2251-a.
Abstract/Text
PMID 12390080  Arch Intern Med. 2002 Oct 28;162(19):2251-2. doi: 10.10・・・
著者: S O SCHWARTZ, S R KAPLAN, B E ARMSTRONG
雑誌名: J Lab Clin Med. 1950 Jun;35(6):894-8.
Abstract/Text
PMID 15422230  J Lab Clin Med. 1950 Jun;35(6):894-8.
著者: D G Savage, J Lindenbaum
雑誌名: Baillieres Clin Haematol. 1995 Sep;8(3):657-78.
Abstract/Text Neuropsychiatric syndromes occur in about 40% of Cbl-deficient patients and are characterized by progressive and variable damage to the spinal cord, peripheral nerves and cerebrum. The first abnormality is usually sensory impairment, most often presenting as distal and symmetrical paraesthesiae of the lower limbs and frequently associated with ataxia. Almost all patients demonstrate loss of vibratory sensation, often in association with diminished proprioception and cutaneous sensation and a Romberg sign. Corticospinal tract involvement is common in more advanced cases, with abnormal reflexes, motor impairment and, ultimately, spastic paraparesis. A minority of patients exhibit mental or psychiatric disturbances or autonomic signs, but these rarely if ever occur in the absence of other neurological changes. Because N2O inactivates Cbl, abuse of the gas may lead to typical Cbl neuropathy. Haematological changes are minimal and serum Cbl levels and Schilling tests normal in most patients. The severity of neurological abnormalities prior to treatment correlates with the duration of symptoms and the haemoglobin level. Initial severity, symptom duration and initial haemoglobin also correlate with residual neurological damage after Cbl therapy. The inverse correlation between severity of anaemia and neurological damage is not understood. Diagnosis of Cbl neuropathy can usually be made in the presence of the typical neuropsychiatric abnormalities, a low serum Cbl level and evidence of megaloblastic haemopoiesis. In some patients serum MMA and HCYS determinations or a therapeutic trial may be required. A neurological response usually occurs within the first 3 months, although further improvement may occur with time. Patients with advanced disease may be left with major residual disability. Therefore early diagnosis is critical. Pharmacological doses of folic acid reverse the haematological abnormalities of Cbl deficiency. This may allow neuropathy to develop or progress and make recognition of deficiency more difficult. There is no clear evidence that folic acid therapy precipitates or exacerbates Cbl neuropathy. Haematological improvement may occur in a fraction of patients receiving small doses of folate, but the data are inadequate to predict the danger of low levels of folate supplementation in the general population.

PMID 8534966  Baillieres Clin Haematol. 1995 Sep;8(3):657-78.
著者: Simone J P M Eussen, Lisette C P G M de Groot, Robert Clarke, Jörn Schneede, Per M Ueland, Willibrord H L Hoefnagels, Wija A van Staveren
雑誌名: Arch Intern Med. 2005 May 23;165(10):1167-72. doi: 10.1001/archinte.165.10.1167.
Abstract/Text BACKGROUND: Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B(12) deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain.
METHODS: We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B(12) deficiency in older people with mild vitamin B(12) deficiency, defined as a serum vitamin B(12) level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 mumol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 mug of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B(12) deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration.
RESULTS: Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 mug was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 mug of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration.
CONCLUSION: The lowest dose of oral cyanocobalamin required to normalize mild vitamin B(12) deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 mug daily.

PMID 15911731  Arch Intern Med. 2005 May 23;165(10):1167-72. doi: 10.1・・・
著者: A M Kuzminski, E J Del Giacco, R H Allen, S P Stabler, J Lindenbaum
雑誌名: Blood. 1998 Aug 15;92(4):1191-8.
Abstract/Text Because cobalamin deficiency is routinely treated with parenteral cobalamin, we investigated the efficacy of oral therapy. We randomly assigned 38 newly diagnosed cobalamin deficient patients to receive cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days. Therapeutic effectiveness was evaluated by measuring hematologic and neurologic improvement and changes in serum levels of cobalamin (normal, 200 to 900 pg/mL) methylmalonic acid (normal, 73 to 271 nmol/L), and homocysteine (normal, 5.1 to 13.9 micromol/L). Five patients were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group. Correction of hematologic and neurologic abnormalities was prompt and indistinguishable between the 2 groups. The mean pretreatment values for serum cobalamin, methylmalonic acid, and homocysteine were, respectively, 93 pg/mL, 3,850 nmol/L, and 37. 2 micromol/L in the oral group and 95 pg/mL, 3,630 nmol/L, and 40.0 micromol/L in the parenteral therapy group. After 4 months of therapy, the respective mean values were 1,005 pg/mL, 169 nmol/L, and 10.6 micromol/L in the oral group and 325 pg/mL, 265 nmol/L, and 12.2 micromol/L in the parenteral group. The higher serum cobalamin and lower serum methylmalonic acid levels at 4 months posttreatment in the oral group versus the parenteral group were significant, with P < .0005 and P < .05, respectively. In cobalamin deficiency, 2 mg of cyanocobalamin administered orally on a daily basis was as effective as 1 mg administered intramuscularly on a monthly basis and may be superior.

Copyright 1998 by The American Society of Hematology.
PMID 9694707  Blood. 1998 Aug 15;92(4):1191-8.
著者: Zahit Bolaman, Gurhan Kadikoylu, Vahit Yukselen, Irfan Yavasoglu, Sabri Barutca, Taskin Senturk
雑誌名: Clin Ther. 2003 Dec;25(12):3124-34.
Abstract/Text BACKGROUND: Cobalamin (vitamin B12) deficiency, the most common cause of megaloblastic anemia, is treated with intramuscular (IM) cobalamin. It has been suggested by some investigators that oral (p.o.) cobalamin treatment may be as effective in the treatment of this condition, with the advantages of ease of administration and lower cost.
OBJECTIVE: This study assessed the effects and cost of p.o. versus i.m. cobalamin treatment in patients with megaloblastic anemia due to cobalamin deficiency.
METHODS: This was a 90-day, prospective, randomized, open-label study conducted at the Division of Hematology, Department of Internal Medicine, Adnan Menderes University Research and Practice Hospital (Aydin, Turkey). Patients aged > or =16 years with megaloblastic anemia due to cobalamin deficiency were randomized to receive 1000-microg cobalamin p.o. once daily for 10 days (p.o. group) or 1000-microg cobalamin i.m. once daily for 10 days (i.m. group). After 10 days, both treatments were administered once a week for 4 weeks, and after that, once a month for life. Patients were assessed for the presence of reticulocytosis between treatment days 5 and 10 until it was detected. Therapeutic effectiveness was assessed by measuring hematologic parameters on days 0, 10, 30, and 90 and serum vitamin B12 concentration on days 0 and 90. The Mini-Mental State Examination was used before and after the B12 therapy for cognitive function assessment and 125-Hz diapozone was used for vibration threshold testing. Neurologic sensory assessment, including soft-touch and pinprick examinations, was used to identify neuropathy at baseline and study end. Tolerability was assessed using laboratory tests and patient interview. Cost was assessed using the cost of the study drug and of the injection.
RESULTS: Sixty patients completed the study 26 in the p.o. group (16 men, 10 women; mean [SD] age, 60 [15] years) and 34 in the i.m. group (17 men, 17 women; mean [SD] age, 64 [10] years). Reticulocytosis was observed in all patients. In the p.o. group, at days 30 and 90, all hematologic parameters changed significantly versus day 0 (mean hemoglobin levels increased [both P<0.001]; mean corpuscular volume decreased [both P<0.001]; mean white blood cell count increased [day 30, P<0.01; day 90, P<0.001]; and mean platelet count increased [both P<0.001]). The mean serum vitamin B12 concentration increased significantly from day 0 to 90 (P<0.001). These hematologic parameters and the recovery patterns were similar between the 2 groups. Neurologic findings included sensitive peripheral neuropathy in 9 patients (15.0%), alteration of cognitive function (loss of memory, impaired concentration) in 7 patients (11.7%), and loss of sense of vibration in 5 patients (8.3%). Neurologic improvement was detected in 7 of 9 patients (77.8%) in the p.o. group and 9 of 12 patients (75.0%) in the i.m. group at day 30.
CONCLUSIONS: In this study of patients with megaloblastic anemia due to cobalamin deficiency, p.o. cobalamin treatment was as effective as i.m. cobalamin treatment. P.o. treatment also was better tolerated and less expensive compared with IM treatment. However, because of the small sample size and the short term of this study, further long-term studies are needed to determine the efficacy of p.o. cobalamin treatment.

PMID 14749150  Clin Ther. 2003 Dec;25(12):3124-34.
著者: A Kokkola, S M Sjöblom, R Haapiainen, P Sipponen, P Puolakkainen, H Järvinen
雑誌名: Scand J Gastroenterol. 1998 Jan;33(1):88-92.
Abstract/Text BACKGROUND: This endoscopic follow-up study was undertaken to evaluate the risk of gastric cancer (GC) and carcinoids in patients with pernicious anaemia (PA) and to analyse whether early detection of GC could be provided by regular endoscopic follow-up.
METHODS: Screening gastroscopy was performed in 71 patients with pernicious anaemia, and thereafter they were followed up with gastroscopies at 3-year intervals for a mean time of 5.8 years. Standardized incidence ratios (SIR) were calculated, the expected number being based on incidence rates in the whole Finnish population.
RESULTS: Two GCs were found during the follow-up period; one of these patients was asymptomatic and the other had abdominal symptoms. The SIR was 5.0 (95% confidence interval, 0.6-18). Eight carcinoids were detected, and all but one were removed endoscopically, and no metastases were found. The patients who had carcinoid tumours were younger at the diagnosis of PA than those who did not develop carcinoids (mean, 40 versus 55 years). Additionally, the patients with carcinoids had longer duration of PA (mean, 11 versus 5 years).
CONCLUSIONS: During the follow-up period the risk of GC was increased. The risk of gastric carcinoids seems to be very high in patients with pernicious anaemia when compared with a normal population, but they are mostly relatively benign tumours. Regular routine gastroscopic follow-up is not indicated in patients with pernicious anaemia.

PMID 9489914  Scand J Gastroenterol. 1998 Jan;33(1):88-92.

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