Comprehensive Review of Vitamin B12 Deficiency

Stabler SP • N Engl J Med

Key Finding

MMA testing identifies tissue-level deficiency missed by serum B12

Original title: “Vitamin B12 deficiency”

Plain English Summary

Authoritative NEJM review covering B12 deficiency pathophysiology, diagnosis using serum B12, MMA and homocysteine, and treatment strategies.

In-Depth Analysis

Background

Dr. Sally P. Stabler from the University of Colorado published this authoritative review in the New England Journal of Medicine (PMID: 23301732), providing a comprehensive clinical overview of vitamin B12 deficiency.

Study Design

Clinical review synthesizing diagnosis, pathophysiology, and management of B12 deficiency for practicing clinicians.

Key Findings

Diagnostic approach:

Test	Sensitivity	Specificity
Serum B12 (<200 pg/mL)	95%	80%
Methylmalonic acid (MMA)	98%	95%
Homocysteine	95%	50%

Interpretation:

•Low B12 + elevated MMA = definite deficiency
•Normal B12 + elevated MMA = tissue deficiency (treat)
•Low B12 + normal MMA = consider other causes

Clinical manifestations:

System	Findings
Hematologic	Macrocytic anemia, pancytopenia
Neurologic	Paresthesias, ataxia, cognitive impairment
Psychiatric	Depression, psychosis, dementia
Other	Glossitis, infertility

Mechanistic Insights

MMA accumulation reflects intracellular B12 deficiency affecting methylmalonyl-CoA mutase. It's more specific than homocysteine because folate deficiency also raises homocysteine but not MMA.

Clinical Implications

MMA is the key test when serum B12 is borderline. Treatment should not wait for anemia—neurological damage may be irreversible. High-dose oral B12 is effective for most causes except pernicious anemia with severe malabsorption.

Metabolic Health Perspective

This NEJM review established the modern diagnostic paradigm. For metabolic optimization, serum B12 >500 pg/mL with normal MMA provides assurance of adequate status.