• Clinical science

Vitamin B12 deficiency (Cobalamin deficiency)

Abstract

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 an 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.

Etiology

References:[1]

Pathophysiology

General features of vitamin B12

Dysfunctional biochemical reactions

  • Physiological function: Vitamin B12 is a water-soluble cofactor for enzymatic reactions of DNA synthesis (via methionine synthase) and odd-chain fatty acid metabolism (via methylmalonyl CoA mutase). A deficiency of vitamin B12 leads to enzyme dysfunction.
  • Dysfunctional methionine synthase (normally converts homocysteine to methionine, thereby demethylating N5-methyl-THF to THF)
    • Tetrahydrofolate (THF) DNA synthesislarge, nucleated hematopoietic cells, including megaloblasts → megaloblastic precursors undergo apoptosis or are phagocytosed by macrophagespancytopenia (including megaloblastic anemia)
    • Methionineneuropathy
    • Homocysteineendothelial damage → predisposes to cardiovascular disease
  • Dysfunctional methylmalonyl CoA mutase
    • Methylmalonyl CoA cannot be converted to succinyl CoA → accumulation of methylmalonyl CoA and its precursor propionyl CoA, as well as their associated odd-chain fatty acids, which cannot be completely metabolized
    • Propionyl CoA replaces acetyl CoA in neuronal membranes → demyelination → neurological manifestations

Folate deficiency also leads to low levels of THF and resulting megaloblastic anemia!

Pernicious anemia

References:[2][3][4][5]

Clinical features

Always consider vitamin B12 deficiency when evaluating patients with dementia!References:[2][4]

Diagnostics

Hematological findings

Approach

References:[2][4][6]

Differential diagnoses

Other causes of macrocytic anemia

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

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

Other causes of neuropathy

References:[7][4]

The differential diagnoses listed here are not exhaustive.

Treatment

  • IM supplementation of vitamin B12 (e.g., cyanocobalamin, hydroxocobalamin) initially until symptoms decline and blood counts normalize; afterwards, 1,000 μg every three to sixth months if long-term supplementation is required
  • Prevent future vitamin B12 deficiency by treating the underlying disease if possible (causative therapy): e.g., for fish tapeworm infestation, intestinal bacterial overgrowth, or chronic pancreatitis
  • If causative therapy is not possible, lifelong IM supplementation may be necessary.

References:[8][2]