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 oral
Figure 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 with
The 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 whether
vitamin 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. Studies
with a hematocrit lower than 38%, and solid circles indicate episodes in
those with a hematocrit of 38% or higher. Patients without anemia had
involving older adults, many of whom had
neurologic 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 correct
nic acid is plotted on a log scale. The dashed lines indicate values that are elevated levels of methylmalonic acid.47,48
3 SD above the mean for healthy blood donors: 376 nmol per liter for meth- Proponents of parenteral therapy state that
ylmalonic acid and 21.3 µmol per liter for total homocysteine. The level of
methylmalonic acid was greater than 500 nmol per liter in 98% of the pa-
compliance and monitoring are better in patients
tients 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.
20. 20
Vit 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 Comments
Measurement 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 insufficiency
Test 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. 21
Vit 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. 22
Vit 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 was
BMJ 1963;June 29:1713-5