Hematology and Oncology Book

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Vitamin B12 Deficiency

Aka: Vitamin B12 Deficiency, Pernicious Anemia, B12 Deficiency, Cobalamin Deficiency
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  1. See Also
    1. Macrocytic Anemia
    2. Vitamin B12
  2. Causes: Vitamin B12 Deficiency
    1. See Medications Affecting Cobalamin
    2. Decreased intrinsic factor
      1. Atrophic Gastritis
      2. Rouz-en-Y Gastric Bypass and other post-gastrectomy syndromes (see malabsorption below)
      3. Pernicious Anemia
        1. Autoimmune parietal cell destruction
        2. Results in insufficient intrinsic factor production
    3. Elderly with atrophic Gastritis (10-30% over age 60)
      1. Can not absorb Vitamin B12 bound to protein
      2. However can absorb crystalline Vitamin B12 normally
    4. Malabsorption
      1. Crohn's Disease
      2. Zollinger-Ellison Syndrome (Gastrinoma)
      3. Whipple's Disease
      4. Intestinal infection (e.g. parasite or Tapeworm)
      5. Blind Loop Syndrome (Gastrectomy and ileal resection)
      6. Diphyllobothrium latum (fish Tapeworm) infection
    5. Inadequate Vitamin B12 intake
      1. Vegan
      2. Elderly
      3. Alcoholism
      4. Exclusively Breastfed infants of vegetarian mothers
    6. Prolonged medication use
      1. See Medications Affecting Cobalamin
      2. Proton Pump Inhibitors
      3. H2 Blockers (e.g. Ranitidine, Cimetidine)
      4. Metformin (Glucophage)
    7. Miscellaneous Causes (uncommon)
      1. Transcobalamin II Deficiency
      2. Nitrous oxide abuse
      3. Inherited disorders of Cobalamin metabolism (Imerslund Syndrome)
  3. Symptoms
    1. Initial
      1. Generalized weakness
      2. Paresthesias
    2. Next
      1. Leg stiffness
      2. Ataxia
    3. Late
      1. Memory Impairment
      2. Personality change
      3. Depressed mood
  4. Signs
    1. Mnemonic: "The 5 P's"
      1. Pancytopenia
      2. Peripheral Neuropathy
      3. Posterior spinal column Neuropathy
        1. Dorsal Column Degeneration
        2. Decreased proprioception
        3. Decreased vibration sense
        4. Ataxia
        5. Hyporeflexia (e.g. decreased Ankle Jerk)
      4. Pyramidal tract signs
      5. Papillary atrophy of Tongue (Atrophic Glossitis)
    2. Other changes
    3. Neurologic
      1. Cognitive Impairment to Dementia
      2. Gait disturbance
      3. Peripheral Neuropathy
      4. Generalized weakness
    4. Psychiatric
      1. Major Depression
      2. Psychosis
      3. Optic Neuritis
    5. Gastrointestinal
      1. Anorexia
      2. Glossitis
      3. Jaundice
    6. Skin
      1. Hyperpigmentation
      2. Vitiligo
  5. Labs
    1. Complete Blood Count (CBC)
      1. Anemia (Test Sensitivity: 72%)
        1. See Hemoglobin Cutoffs for Anemia
        2. See Hematocrit Cutoffs for Anemia
      2. Megaloblastic Macrocytic Anemia (Test Sensitivity: 83%)
        1. Mean Corpuscular Volume >100 um^3
        2. MCV cutoff varies by age and per reference
      3. Changes in other cell lines
        1. Leukopenia
        2. Thrombocytopenia
    2. Peripheral Blood Smear
      1. Megaloblastosis: Oval Macrocytes
      2. Hypersegmented Neutrophils
      3. Giant platelets
    3. Serum Vitamin B12 <200 pg/ml (<150 pmol/L)
      1. Neurologic changes occur in normal B12 level (50%)
      2. Low serum Vitamin B12 is poorly specific for deficiency
      3. Confirm low value with additional testing
        1. Serum Methylmalonic acid increased (preferred due to higher Specificity and Test Sensitivity)
        2. Serum Homocysteine increased
    4. Serum RBC Folate decreased
    5. Pernicious Anemia specific labs (when indicated)
      1. Anti-intrinsic factor antibodies (increased)
      2. Serum Gastrin (increased)
      3. Pepsinogen (increased)
      4. Upper endoscopy
        1. Recommended if Pernicious Anemia diagnosis (due to associated Gastric Cancer and Carcinoid)
      5. Schilling Test: Radiolabeled Vitamin B12 excretion
        1. No longer available in the United States
  6. Evaluation
    1. Step 1: Obtain Vitamin B12 and Folic Acid Levels
    2. Step 2: Interpret Folic Acid Level
      1. Folic Acid Normal: Go to Step 3
      2. Folic Acid deficiency
        1. Provide Folic Acid Supplementation
        2. Return to Step 1 to recheck levels
    3. Step 3: Interpret Vitamin B12 level
      1. Vitamin B12 > 400 pg/ml: Normal, no further testing
      2. Vitamin B12 100 to 400 pg/ml: Go to Step 4
      3. Vitamin B12 < 100 pg/ml: Treat Vitamin B12 Deficiency
    4. Step 4: Obtain secondary B12 Deficiency markers
      1. Lab markers (B12 dependent reaction substrates)
        1. Serum methylmalonic acid (preferred)
          1. Falsely elevated in renal insufficiency, dehydration
        2. Serum Homocysteine
          1. Falsely elevated in Folate Deficiency, renal insufficiency, Levodopa use, and Hyperhomocysteinemia
      2. Interpretation
        1. Either level high: Treat Vitamin B12 Deficiency
        2. Levels normal: Normal, no further testing
    5. References
      1. Oh (2003) Am Fam Physician 67(5):979-86
      2. Snow (1999) Arch Intern Med 159:1297
  7. Management
    1. See Vitamin B12 Supplementation
    2. Vitamin B12 1000 to 2000 mg orally daily is as effective as IM crystalline injections for replacement and supplementation
  8. Prevention
    1. Routine supplementation in age over 50 years, post-Gastric Bypass
    2. Consider B12 supplementation in longterm Metformin or antacid use
  9. References
    1. Babior in Wilson (1991) Harrisons, McGraw, p. 1523-9
    2. Brigden (1995) Postgrad Med 97(5):171-86
    3. Dharmarajan (2003) Geriatrics 58(3):30-8
    4. Lagan (2011) Am Fam Physician 83(12): 1425-30
    5. Oh (2003) Am Fam Physician 67(5):979-86

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