II. 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
      1. Nitrous Induced Subacute Combined Degeneration of the Spinal Cord
    3. Inherited disorders of Cobalamin metabolism (Imerslund Syndrome)

III. 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

IV. 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

V. 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

VI. Evaluation

  1. 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
  2. Step 2: Interpret Vitamin B12 level
    1. Vitamin B12 > 400 pg/ml: Normal, no further testing
    2. Vitamin B12 100 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 < 100 pg/ml: Treat Vitamin B12 Deficiency
  3. 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
  4. 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]

VII. Management

  1. See Vitamin B12 Supplementation
  2. Vitamin B12 1000 to 2000 mcg orally daily is as effective as IM crystalline injections for replacement and supplementation

VIII. 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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Ontology: Vitamin B 12 Deficiency (C0042847)

Definition (CSP) condition due to a deficiency of vitamin B12.
Definition (MSH) A nutritional condition produced by a deficiency of VITAMIN B 12 in the diet, characterized by megaloblastic anemia. Since vitamin B 12 is not present in plants, humans have obtained their supply from animal products, from multivitamin supplements in the form of pills, and as additives to food preparations. A wide variety of neuropsychiatric abnormalities is also seen in vitamin B 12 deficiency and appears to be due to an undefined defect involving myelin synthesis. (From Cecil Textbook of Medicine, 19th ed, p848)
Concepts Disease or Syndrome (T047)
MSH D014806
ICD10 E53.8
SnomedCT 190634004, 124904006
English Deficiencies, Vitamin B12, Deficiency, Vitamin B 12, Deficiency, Vitamin B12, Vitamin B 12 Deficiency, Vitamin B12 Deficiencies, Vitamin B12 Deficiency, VITAMIN B 12 DEFICIENCY, VITAMIN B12 DEFICIENCY, Deficiency of vitamin B12, Deficiency of vitamin B<sub>12</sub>, DEFIC VITAMIN B 12, VITAMIN B A 12 DEFICIENCY, VITAMIN B12 DEFIC, VITAMIN B 12 DEFIC, DEFIC VITAMIN B12, vitamin B12 deficiency, vitamin B12 deficiency (diagnosis), Cyanocobalamin deficiency, Vitamin B 12 Deficiency [Disease/Finding], b12 vitamin deficiency, deficiency of vitamin b 12, of vitamin b 12 deficiency, vitamin b12 deficiency, Deficiency;vitamin B12, cobalamin deficiency, b12 deficiency vitamins, b12 deficiency vitamin, deficiency of vitamin b12, of vitamin b12 deficiency, b12 deficiency disease vitamin, deficiency vitamin b12, vitamin b12 deficiencies, cyanocobalamin deficiency, vitamin b 12 deficiency, vitamin b12 deficiency disease, deficiency cobalamin, Deficiency of vitamin B12 (disorder), Deficiency of vitamin B<sub>12</sub> (disorder), Deficiency of vitamin B>12< (disorder), Cobalamin deficiency, Vitamin B12 deficiency, Cobalamin deficiency (disorder), Deficiency of vitamin B>12<, cyanocobalamin; deficiency, deficiency; cyanocobalamin, deficiency; vitamin, B12, vitamin; deficiency, B12
German VITAMIN-B12-MANGEL, Cobalaminmangel, VITAMIN B A 12 MANGEL, Vitamin B12-Mangel, Vitamin-B12-Mangel
Dutch cobalaminedeficiëntie, cyanocobalamine; deficiëntie, deficiëntie; cyanocobalamine, deficiëntie; vitamine, B12, vitamine; deficiëntie, B12, vitamine-B12-deficiëntie, Vitamine-B12-gebrek, Cyanocobalaminedeficiëntie, Deficiëntie, vitamine-B12-, Vitamine-B12-deficiëntie
French Carence en cobalamine, CARENCE EN VITAMINE B12, Carence en vitamine B12, Carence en cyanocobalamine, Carence en vit B12, Déficit en cyanocobalamine, Déficit en vitamine B12
Italian Carenza di cobalamina, Carenza di vitamina B12
Portuguese Carência de cobalamina, DEFICIENCIA DE VITAMINA B12, Deficiência de Vitamina B12, Carência de vitamina B12, Deficiência de Vitamina B 12
Spanish Deficiencia de cobalamina, déficit de vitamina B>12< (trastorno), déficit de vitamina B<sub>12</sub> (trastorno), déficit de vitamina B12 (trastorno), Deficiencia de Vitamina B12, deficiencia de cobalamina (trastorno), deficiencia de cobalamina, deficiencia de vitamina B12, Déficit de vitamina B12, Deficiencia de Vitamina B 12
Japanese ビタミンB12欠乏, コバラミン欠乏, コバラミンケツボウ, ビタミンB12ケツボウ, ビタミンB12欠乏, ビタミンB12欠乏症
Swedish Vitamin B12-brist
Finnish B12-vitamiinin puutos
Czech Deficit kobalaminu, Deficit vitaminu B12, vitamin B 12 - nedostatek, nedostatek vitaminu B 12, nedostatek vitaminu B12, deficit vitaminu B12
Croatian Not Translated[Vitamin B 12 Deficiency]
Polish Niedobór witaminy B12, Hipowitaminoza B12
Hungarian B12-vitamin hiány, Cobalamin hiány
Norwegian Vitamin B12-mangel, B12-vitaminmangel