Case Summary:

At Morning Report we discussed a case of 65 year old man with a history of hypothyroidism, previous obesity with prior gastric bypass surgery, T2DM, GERD, migraines and depression who presented with fatigue and anemia. On exam, he was found to have a smooth tongue and neurologic deficits including hyporeflexia, diminished sensation to soft touch and vibration and mild ataxia. His blood work revealed mild hemolysis with a negative DAT, and blood smear showed hypersegmented neutrophils. Finally, his vitamin B12 levels were found to be very low, in keeping with vitamin B12 deficiency with associated anemia and subacute combined degeneration of the spinal cord. Screening for pernicious anemia was negative, thus his vitamin B12 deficiency was though to be as a result of malabsorption after gastric bypass.

Learning Points:

1. Approach to Anemia
2. Physical Examination for Anemia
3. Investigations for Anemia
4. Review of Vitamin B12 Absorption
5. Clinical Manifestations of B12 Deficiency
6. Causes of B12 Deficiency
7. Treatment of B12 deficiency

1. Approach to Anemia

• Microcytic Anemia DDx (“TAILS”)
  • Thalassemia
  • Anemia of chronic disease
  • Iron deficiency
    • Bleeding
    • Malabsorption (celiac, etc.), poor diet
    • Renal failure
    • Intravascular hemolysis (PNH)
  • Lead poisoning (an acquired sideroblastic anemia)
  • Sideroblastic anemia
    • Hereditary
    • Acquired (idiopathic, lead, EtOH)
• Normocytic Anemia DDx

• Macrocytic Anemia DDx
  • Reticulocytosis
  • Megaloblastic (hypersegmented neutrophils)
    • Vit B12 deficiency
    • Folate def
  • Non-megaloblastic
    • Liver disease
    • Drugs (e.g., MTX, septra, AZT, phenytoin, hydroxurea, chemotherapy)
    • EtOH
    • Hypothyroidism
    • MDS
    • Aplastic anemia
    • Acute leukemia
• Also, you can potentially have two processes occurring at once.

• Important points on our patient’s history that may relate to underlying anemia:
  • GERD- UGIB from PUD + SSRI (may UGIB; consider stopping in acute setting). Iron malabsorption may result from PPI use.
  • Hypothyroidism- may lead to macrocytic anemia or be associated with other autoimmune conditions
  • Roux-en-Y- may be associated with nutritional deficiency (B12, folate)

2. Physical Examination for Anemia

• General: Pallor (Conjunctival, palmar creases), height, weight to calculate BMI
• Vitals: Orthostatic hypotension (volume loss as with bleeding), tachycardia, Hypoxia, tachypnea
• HEENT: blue sclear or alopecia (iron deficiency), jaundice (hemoloysis), gingival changes, tonsillar hypertrophy, lead lines, atrophic glossitis (B12 deficincy), angular cheilitis or stomatitis (Iron deficiency), alcohol on breath
• CVS: Flow murmur
• RESP: Nothing specific
• GI: Signs of chronic liver disease, splenomegaly, hypopigmentation, peripheral bruising/purpura, DRE (If iron deficiency)
• NEURO: ataxia, reduced proprioception/vibration
• Nails: Spoon nails (iron)

3. Investigations for Anemia

• Microcytic Anemia:
  • CBC + diff, peripheral smear, reticulocyte count. Ferritin +/- other iron studies (iron, transferrin sat, TIBC). Consider hemolytic work up if concern for intravascular hemolysis eg, PNH
  • If there is evidence of iron deficiency (ferritin <30, high TIBC, low T-sat), depending on age and history consider GI referral for scope, screen for celiac disease
  • If in keeping with anemia of chronic disease (ferritin N or high, Fe low, TIBC low/N, T-sat low/N), look for and treat underlying cause
  • If suspect thalessemia (ferritin N/high, high RBC number, MCV/RBC <13) proceed to Hb electrophoresis
• Normocytic Anemia:
  • CBC +diff, peripheral smear, reticulocyte count, Cr, lytes, liver enzymes and function tests
  • Hemolytic work up: reticulocyte count, LDH, bilirubin, haptoglobin-> if positive consider DAT and further work up
  • Cancer work up: SPEP, Ca
  • Depending on history could consider autoimmune work up such as ANA, ENA, dsDNA, etc. or work up for causes of bone marrow infiltration

• Macrocytic Anemia:
  • Rule out reticulocytosis
  • Peripheral smear, TSH, B12 levels (Folate deficinecy rare in developed countries), liver function tests
  • Look for underlying causes and treat appropriately

4. Vitamin B12 Absorption and Metabolism

•  Vitamin B₁₂ is mainly derived from animal sources. Following intake, it is released from food by proteolysis in the stomach, where it binds to haptocorrin.
• Haptocorrin is produced by the salivary glands and protects B12 from acid degradation. Degradation of haptocorrin and the pH change in the duodenum favour B12 binding to gastric intrinsic factor, which is produced by gastric parietal cells.
• The intrinsic factor–B12 complex binds to the the enterocytes of the distal ileum. It later binds to transcobalamin, the blood carrier of B12 that is responsible for cellular delivery of B12
• The majority of B12 is stored in the liver; some B12 is excreted in bile and undergoes enterohepatic circulation
• Full details about intarcellular metabolism can be found here https://www.nature.com/articles/nrdp201740.

5. Clinical Manifestations of B12 Deficiency

• Patients with vitamin B₁₂ deficiency may have hematologic or neurologic abnormalities, but the absence of either abnormality does not preclude a clinically significant deficiency.
• Hemolytic anemia, as in our patient, can occur rarely
• See the figure below from NEJM for a review of the features of B12 deficiency

6. Causes of B12 Deficiency

• Decreased Ileal Absorption
  • IBD (Crohn’s)
  • Bacterial overgrowth
  • Fish Tapeworm (Diphyllobothrium latum)
  • Celiac disease
  • Chronic pancreatitis
• Decreased Intrinsic Factor
  • Atrophic gastritis
  • Pernicious anemia
  • Gastrectomy/bariatric surgery
  • Chronic H. Pylori associated gastritis
• Inadequate intake
  • Vegan or strict vegetarian
  • Chronic EtOH use
• Medication
  • >12 months of PPI/H2 blocker
  • >4 months metformin
  • Nitrous oxide–> inactivates methionine synthase
• Genetic
  • Transcobalamin deficiency

7. Treatment of B12 Deficiency

• Vitamin B₁₂ deficiency can be treated with either parenteral or high-dose oral cyanocobalamin, however, oral is preferred as it is as effective as parenteral B12 administration in improving hematologic abnormalities and raising B12 levels and is more cost effective.
• In severe depletion, despite the fact that high-dose oral cyanocobalamin is probably adequate, parenteral therapy is generally preferred for initial repletion to ensure adequate absorption. After that, oral maintenance therapy of 1000 to 2000 μg of cyanocobalamin daily should be adequate.
• Given our patient’s neurologic deficits, initial parenteral therapy was indicated. He received 1000 μg of intramuscular cyanocobalamin daily for 1 week and then once a weekly for 4 weeks. After that he received a prescription of 2000 μg of oral cyanocobalamin daily for life but may require parental therapy if due to malabsorption this is insufficient
• We screened our patient for other deficiencies (Copper, Zinc, ADEK), and reassessed his medications (PPI, metformin)

Further Reading:

• https://www.nejm.org/doi/10.1056/NEJMcp1113996
• https://www.nature.com/articles/nrdp201740
• https://www.cmaj.ca/content/171/3/251.figures-only