Severe B12 Deficiency

During morning report this past week, we were introduced to a patient with severe alcoholism who presented with a hemoglobin of 24 g/L due to B12 deficiency, whose only presenting symptom was 'fatigue.' That's pretty low. Low enough to hear orbital bruits. It is important to note that it takes months to years to deplete one's Vitamin B12 stores as it did in this patient's case.

On physical examination, the patient appeared "pale and yellow," ( a lemony yellow) due to the combination of anemia and hemolysis, a classic appearance of patients with severe B12 Deficiency. Let's go over the important pieces of diagnosing and treating B12 deficiency:

Causes
To develop a differential diagnosis of B12 deficiency, think of the anatomic components necessary for B12 absorption, from mouth to terminal ileum:
Mouth (Diet) - Vegans, alcoholics, patients with eating disorders
Stomach - Pernicious anemia results from autoantibiodies to parietal cells due to Autoimmune Atrophic Gastritis. This is the most common cause of B12 deficiency in adults.
Proximal Small Bowel - Post Roux-en-Y, Celiac Disease, Chronic Pancreatitis,
Terminal Ileum - IBD is a disease with classic TI manifestations.

Physical Examination
Aside from the above mentioned finding of "pale and yellow," another important aspect of physical examination is looking for risk factors for B12 deficiency, such as manifestations of alcoholism, general malnutrition, IBD, and other autoimmune disease.

The neurological examination is unique in patients with B12 deficiency. It is one of the very few diseases that can manifest with both upper and lower neuron lesions. Manifestations classically include subacute combined degeneration of the dorsal (posterior) and lateral spinal columns. SCD manifests as symmetrical primarily lower limb neuropathy with loss of vibration and position sense, which can result in ataxia. Other neurologic findings in B12 deficiency include axonal degeneration of peripheral nerves and central nervous system symptoms including memory loss, irritability, and dementia. Notably, not all patients with neurologic abnormalities secondary to B12 deficiency have hematologic manifestations. 

Investigations
Aside from macrocytic anemia, the other findings on investigation that are suggestive of B12 deficiency include a low or undetectable serum B12 level, and megaloblastic anemia.

Blood films from patients with severe B12 deficiency will also show hemolysis, due to improper RBC production in the bone marrow. Low platelets may also be seen because B12 is necessary for the production of megakaryocytes. The finding of anemia, hemolysis, and thrombocytopenia on a blood film may be confused with a MAHA. The distinction is that the patients with B12 deficiency will also megaloblastic anemia:
- Megaloblasts (immature RBCs) in the bone marrow
- Hypersegmented neutrophils (>5  nuclear lobes) on their peripheral blood film,  

Important tests to help diagnose the etiology of B12 deficiency include antibodies to IF, the Schilling Test, and endoscopy.

Important Tips for treatment outlined during our discussion with Dr. Wayne Gold:

1) Use B12 Injections to Supplement B12 - Once a diagnosis of Vitamin B12 deficiency is made, use injection rather than oral supplements to replete patients. This will allow you to bypass the entire GI tract and will reliably provide patients with your supplement.

2) Watch out for Hypokalemia - When treating patients with severe B12 deficiency, new RBCs are being produced and numerous building blocks are consumed. This includes potassium, which is a major intracellular electrolyte. Remember to carefully replace patient's potassium during treatment.

3) Watch out for folate deficiency - As new RBCs are being produced, folate is rapidly consumed and so when patients are receiving B12 supplementation they will also require folate supplementation as well.

4) Don't transfuse too much - Patients with severe, chronic anemia compensate slowly over time with a hyperdynamic cardiac state, and will have no symptoms of hemodynamic instability. Over-treatment by physicians to rapidly transfuse these patients to a normal hemoglobin values can lead to cardiac failure due to volume overload in an already stressed cardiovascular system.

Here are some good review articles:
Click here for a good article on the treatment of B12 deficiency from Blood.
And a good review from NEJM is found here from 2013.