維生素 B12 與葉酸缺乏（巨紅血球性貧血）

Buzzwords → Dx

Diagnostic Criteria

• B12 deficiency: serum B12 <200 pg/mL (definite; gray zone 200–300); confirm with MMA >0.4 µmol/L (B12-specific) and homocysteine elevated.
• Folate deficiency: serum folate <4 ng/mL OR RBC folate <280 ng/mL (latter more reliable for chronic). Homocysteine elevated, MMA normal.
• Pernicious anemia: anti-intrinsic factor antibodies (specific ~95 %) + anti-parietal cell antibodies (sensitive but less specific).
• Marrow (rarely needed): megaloblastic erythroid precursors, giant metamyelocytes.

Workup

• CBC + smear (macrocytes, hypersegmented neutrophils, occasional ovalocytes; pancytopenia in severe).
• Reticulocyte count (low; ineffective erythropoiesis).
• B12, folate, RBC folate levels.
• MMA + homocysteine if borderline B12 (200–300).
• Anti-IF + anti-parietal cell antibodies if pernicious anemia suspected.
• Iron studies + TSH + LFTs to evaluate concurrent / alternative causes.
• EGD with biopsy for atrophic gastritis (esp. with PA, gastric ECL hyperplasia / type 1 gastric carcinoid risk).

Treatment Algorithm

flowchart TD
  A[Macrocytic anemia + ↑MCV] --> B[Check B12, folate, RBC folate, MMA, Hcy]
  B --> C{B12 <200 or borderline + ↑MMA}
  C -- yes --> D[Replete B12 BEFORE folate<br>cyanocobalamin 1000 mcg IM daily × 1 wk<br>then weekly × 4 wk<br>then monthly lifelong if PA]
  C -- folate deficient B12 normal --> E[Folate 1-5 mg PO daily<br>4 mo until reticulocyte response + repletion]
  D --> F[Recheck CBC + retic at 1-2 wk<br>response = retic spike + Hb rise]
  E --> F
  F --> G{Underlying cause}
  G -- pernicious anemia --> H[Lifelong B12 IM monthly<br>or high-dose oral 1000-2000 mcg/d]
  G -- malabsorption (gastrectomy, bypass) --> I[Lifelong B12 IM<br>or high-dose oral]
  G -- dietary --> J[Diet correction + supplementation]
  G -- alcohol / poor diet folate --> K[Diet + folate supplementation<br>address EtOH]
  G -- hemolysis high turnover --> L[Folate supplementation + treat hemolysis]

Pearls / Pitfalls

• Replete B12 BEFORE folate if both deficient — folate alone in B12 deficiency can precipitate / worsen subacute combined degeneration.
• Hypersegmented neutrophils (≥5 lobes) is a sensitive smear sign, even before macrocytosis develops.
• Subacute combined degeneration (SCD): symmetric paresthesias, ataxia, dementia, optic atrophy. Treat early — irreversible if delayed >6 mo.
• Normal MCV does not rule out B12 deficiency — co-existing iron deficiency can normalize MCV; rely on B12 + MMA.
• Pernicious anemia + anti-parietal cell antibodies + gastric atrophy → 3× gastric cancer + type 1 gastric carcinoid risk. Surveillance EGD recommended.
• Metformin + long-term PPI are common iatrogenic B12 deficiency causes — check B12 yearly in chronic users.
• Acute methotrexate toxicity → leucovorin (folinic acid) rescue; doesn't replace folate but bypasses MTX block.
• Pregnancy folate prophylaxis 0.4 mg/d preconception (4 mg/d if prior NTD baby) — prevents neural tube defects.
• Alcohol + folate deficiency can also trigger megaloblastic anemia and contribute to thrombocytopenia (myeloid suppression).
• Hemolytic crisis with cobalamin replacement can occur (rapid erythropoiesis). Monitor K (drops with rapid hemoglobin synthesis).
• Schilling test is historical — replaced by anti-IF antibody testing.
• High RBC folate but anemia could indicate B12 deficiency masking folate trapping (methyl folate trap hypothesis).

Cross-references

• Lab Values — B12, folate, MMA, homocysteine
• IDA — coexisting microcytic mask
• Anemia Workup — macrocytic branch
• MDS — DDx for macrocytic anemia

相關題目

• Q-109 — B12 deficiency — confirmation with MMA when borderline
• Q-110 — B12 + folate — order of replacement
• Q-111 — B12 deficiency — pernicious anemia and gastric cancer surveillance

Sources