Vitamin B12 deficiency

Last updated: July 29, 2023

Summarytoggle arrow icon

Vitamin B12 (cobalamin) plays an essential role in enzymatic reactions responsible for red blood cell (RBC) formation and proper myelination of the nervous system. Thus, a deficiency of vitamin B12 may lead to megaloblastic anemia and a wide range of neurological disturbances. Deficiency may be caused by malabsorption, malnutrition, or increased demand. The most common underlying cause of vitamin B12 deficiency is pernicious anemia, an autoimmune disorder characterized by the absence of intrinsic factor (IF). IF is a protein that is crucial for vitamin B12 absorption. Patients present with signs of anemia (e.g., fatigue) and/or neurological manifestations such as paresthesia, spasticity, ataxia, and neuropsychiatric disorders. After detecting low serum vitamin B12 levels, the diagnostic approach consists of identifying the underlying cause by measuring autoantibodies and possibly conducting a Schilling test. When testing patients with suspected vitamin B12 deficiency, it is important to remember that folate deficiency also causes megaloblastic anemia. However, only vitamin B12 deficiency can be accompanied by neuropathy and exhibits elevated levels of methylmalonic acid (MMA). Treatment consists of parenteral supplementation; depending on the underlying cause, long-term supplementation may be needed.

Etiologytoggle arrow icon

Pathophysiologytoggle arrow icon

Dysfunctional biochemical reactions

Folate deficiency also leads to low levels of THF, resulting in megaloblastic anemia.

Pernicious anemia

Clinical featurestoggle arrow icon

The Spinocerebellar tracts, lateral Corticospinal tracts, and Dorsal columns are affected in Subacute Combined Degeneration.

Always consider vitamin B12 deficiency when evaluating patients with dementia.

Diagnosticstoggle arrow icon

Hematological findings


Stages of Schilling test
Description Radiolabeled vitamin B12 measures in urine
Stage 1
  • Normal excretion: Malnutrition or an increased demand is the most likely cause.
  • ↓ Excretion: perform stage 2
Stage 2
Stage 3
  • Normal excretion: bacterial overgrowth
  • ↓ Excretion: perform stage 4
Stage 4

Differential diagnosestoggle arrow icon

Differential diagnoses of vitamin B12 deficiency

Differential diagnosis of vitamin B12, B9, and B1 deficiencies
Vitamin B12 deficiency Vitamin B9 deficiency Vitamin B1 deficiency
Motor signs
  • No neurological symptoms
  • N/A
  • N/A
Sensory signs
  • Sensory deficit and paresthesias in distal parts of extremities ("socks and gloves" distribution)
  • N/A
  • N/A
  • Sensory deficit and paresthesias in distal parts of extremities ("socks and gloves" distribution)
Other neurological features
  • N/A
  • N/A
Neuropsychiatric signs
  • N/A
  • Confusion
  • Cognitive deficits
  • Potentially reversible (neurological damage may be permanent)
  • Reversible
  • Irreversible
  • Mostly reversible

Starting folate treatment before excluding vitamin B12 deficiency may correct anemia, but it can worsen neuropathy!

In contrast to vitamin B12 deficiency, folic acid deficiency is generally not associated with neurological symptoms.

Other causes of macrocytic anemia

Other causes of neuropathy

The differential diagnoses listed here are not exhaustive.

Treatmenttoggle arrow icon


Referencestoggle arrow icon

  1. Vitamin B 12.,-dependency,-and-toxicity/vitamin-b-12. Updated: September 1, 2016. Accessed: December 21, 2016.
  2. Scalabrino G. Cobalamin (vitamin B(12)) in subacute combined degeneration and beyond: traditional interpretations and novel theories.. Exp Neurol. 2005; 192 (2): p.463-79.doi: 10.1016/j.expneurol.2004.12.020 . | Open in Read by QxMD
  3. Johnson LE. Vitamin B 12. . 2016.
  4. Mazokopakis EE. The old Schilling test as a necessary criterion at present for the diagnosis of food-cobalamin malabsorption (FCM) syndrome. Hell J Nucl Med. 2012; 15 (3): p.262-263.
  5. Ramphul K, Mejias SG. Schilling Test. StatPearls. 2020.
  6. Guidelines for the Investigation & Management of vitamin B12 deficiency. Updated: January 3, 2017. Accessed: January 3, 2017.

Icon of a lock3 free articles remaining

You have 3 free member-only articles left this month. Sign up and get unlimited access.
 Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer