II. Epidemiology

  1. Prevalence
    1. U.S.: 6% in patients under age 60 years (20% in those over age 60 years)
    2. Latin America: 40%
    3. Kenya: 70%
    4. East India: 70-80%

III. Pathophysiology

  1. See Vitamin B12
  2. Symptoms may lag Vitamin B12 Deficiency for as many as 10 years until vast hepatic stores are exhausted

IV. 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 as part of a chronic autoimmune Gastritis
      2. Results in insufficient Intrinsic Factor production
      3. B12 Deficiency is preceded by Iron Deficiency by 20 years, and asymptomatic Gastritis by 30 years
  3. Elderly with atrophic Gastritis (10-30% over age 60 years)
    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 Disease
    4. Short-Bowel Syndrome
    5. Celiac Disease
    6. Intestinal infection (e.g. Parasite or Tapeworm)
    7. Postgastrectomy Syndrome or Blind Loop Syndrome
      1. Gastrectomy and ileal resection
      2. Roux-en-Y gastric bypass
    8. Diphyllobothrium latum (fish Tapeworm) infection
  5. Inadequate Vitamin B12 intake
    1. Vegan patients
    2. Elderly (over age 75 years old)
    3. Alcoholism
    4. Psychiatric patients
    5. Exclusively Breastfed infants of vegan mothers
  6. Prolonged medication use
    1. See Medications Affecting Cobalamin
    2. Metformin (Glucophage) for >4 months
      1. de Jager (2010) BMJ 340:C2181 [PubMed]
    3. Prolonged acid suppression (>12 months)
      1. Proton Pump Inhibitors
      2. H2 Blockers (e.g. Ranitidine, Cimetidine)
      3. Lam (2013) JAMA 310(22): 2435-42 [PubMed]
  7. Miscellaneous Causes (uncommon)
    1. Transcobalamin II Deficiency
    2. Nitrous Oxide Abuse
      1. Nitrous Induced Subacute Combined Degeneration of the Spinal Cord
    3. Inherited disorders of Cobalamin metabolism (Imerslund Syndrome)

V. Symptoms

  1. Initial
    1. Generalized weakness
    2. Exertional Fatigue
    3. Somnolence
    4. Palpitations
    5. Skin pallor
    6. Paresthesias or numbness in hands (precedes lower extremity neurologic symptoms)
  2. Next
    1. Leg stiffness
    2. Ataxia
  3. Late
    1. Memory Impairment or Dementia
    2. Personality change (apathy, irritability)
    3. Depressed mood
    4. Psychosis

VI. Signs

  1. Mnemonic: "The 5 P's"
    1. Pancytopenia
    2. Peripheral Neuropathy
    3. Papillary atrophy of Tongue (Atrophic Glossitis)
    4. Posterior spinal column Neuropathy (Symmetrical dorsal column degeneration)
      1. Decreased proprioception bilaterally
      2. Decreased vibration sense bilaterally
      3. Ataxia
      4. Hyporeflexia (e.g. decreased Ankle Jerk)
    5. Pyramidal tract signs (Corticospinal tract, corticobulbar tract)
      1. Spasticity
      2. Paraplegia
      3. Incontinence
  2. Neurologic
    1. Cognitive Impairment to Dementia
    2. Progressive demyelination
      1. Gait disturbance with Ataxia
      2. Peripheral Neuropathy (see dorsal column effects as above)
      3. Generalized weakness
      4. Optic Neuritis or optic atrophy
      5. Olfactory Impairment
      6. Areflexia (may be permanent)
  3. Psychiatric
    1. Major Depression
    2. Psychosis
  4. Gastrointestinal
    1. Anorexia
    2. Jaundice
    3. Atrophic Glossitis or linear Glossitis
    4. Angular Cheilitis
  5. Skin
    1. Hair depigmentation
    2. Vitiligo
    3. Skin pallor
    4. Skin Hyperpigmentation
      1. Addison Disease-like distribution (palmar creases, flexor creases, pressure points)

VII. 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 (risk of Pancytopenia, with all cell lines affected)
      1. Leukopenia
      2. Thrombocytopenia
    4. Secondary effects of abnormal erythropoesis
      1. Decreased Haptoglobin
      2. Increased Lactate Dehydrogenase (LDH)
      3. Inctreased Reticulocyte Count
  2. Peripheral Blood Smear
    1. Megaloblastosis: Oval Macrocytes
    2. Hypersegmented Neutrophils
    3. Giant Platelets
  3. Serum Vitamin B12 <200 pg/ml (148 pmol/L)
    1. Serum Vitamin B12 <150 pg/ml (111 pmol/L) is diagnostic for Vitamin B12 Deficiency
    2. Neurologic changes occur in normal B12 level (50%)
    3. Low serum Vitamin B12 is poorly specific for deficiency
    4. Vitamin B12 levels are falsely elevated in Alcoholism, liver disease, cancer
    5. Confirm low value with additional testing (substrates for B12 synthesis that accumulate when it is deficient)
      1. Serum Methylmalonic acid increased (preferred due to higher Specificity and Test Sensitivity)
      2. Serum Homocysteine increased
  4. Holotranscobalamin (active form of Vitamin B12)
    1. Limited availability, but appears to be a better marker of Vitamin B12 Deficiency than Serum Vitamin B12
  5. Other concurrent altered components
    1. Serum RBC Folate decreased
    2. Homocysteine increased
      1. More common than Folate Deficiency in developed countries
  6. Pernicious Anemia specific labs (when indicated, in the absence of other B12 Deficiency risk factors)
    1. Anti-Intrinsic Factor antibodies (increased)
      1. First-line test
    2. Serum Gastrin (increased)
      1. Second line test, indicated if anti-Intrinsic Factor antibodies negative
    3. Pepsinogen (increased)
      1. Other testing, not typically obtained
    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

VIII. Evaluation

  1. Indications for screening
    1. Universal screening is NOT recommended
    2. Screen those with risk factors (see above), Megaloblastic Anemia, Peripheral Neuropathy or other suspicious findings
  2. Step 1: Obtain Vitamin B12 Level
    1. Also consider obtaining Folic Acid Level (although Folic Acid Deficiency is uncommon in U.S.)
      1. Consider empirically treating patients with Folic Acid supplementation with B12 Replacement
      2. However only replace Folic Acid after B12 levels have been assessed
  3. Step 2: Interpret Vitamin B12 level
    1. Vitamin B12 > 400 pg/ml: Normal, no further testing
    2. Vitamin B12 150 to 400 pg/ml
      1. Option 1: Go to Step 3
      2. Option 2: Treat empirically with Vitamin B12 1000-2000 mcg orally and recheck Vitamin B12 in 3 months
    3. Vitamin B12 < 150 pg/ml
      1. Treat Vitamin B12 Deficiency
      2. Consider Pernicious Anemia testing (see labs above)
        1. Antiintrinsic factor antibodies
        2. Serum Gastrin level
  4. Step 3: 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. Schrier in Mentzer (2015) Diagnosis and Treatment of Vitamin B12 and Folate Deficiency, UpToDate, accessed 2/9/2016
    2. Oh (2003) Am Fam Physician 67(5):979-86 [PubMed]
    3. Snow (1999) Arch Intern Med 159:1297 [PubMed]

IX. Management

  1. See Vitamin B12 Supplementation
  2. Vitamin B12 1000 to 2000 mcg orally daily for >1 month
    1. As effective as IM crystalline injections for replacement and supplementation
    2. Neurologic symptoms warrants daily injections for up to 3 weeks, or until no further improvement
    3. Replace Vitamin B12 before replacing Folate (otherwise risk of spinal cord degeneration)
    4. Repeat testing after treatment and maintenance is not typically indicated
    5. Expect improvement in symptoms and lab markers within 3 months of starting B12 supplementation
      1. Lab markers (Homocysteine, methylmalonic acid, Reticulocyte Count) improve in the first week
      2. Neurologic symptoms improve within 6 weeks to 3 months
      3. Anemia, Leukopenia, MCV and Thrombocytopenia improve within 2 months
  3. Monitor Serum Potassium levels while replacing Vitamin B12
    1. Hypokalemia occurs as hematopoiesis increases

X. Prognosis

  1. More than 50% of patients with B12 Deficiency related symptoms will have incomplete resolution despite treatment

XI. Complications: Maternal Vitamin B12 Deficiency

XII. Prevention

  1. Routine supplementation in age over 50 years, post-Gastric Bypass
  2. Consider B12 supplementation in longterm Metformin or Antacid use

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