Disorders of Vitamin B12 Metabolism

Solomon LR • Blood Rev

Key Finding

Early detection prevents irreversible neurological damage

Original title: “Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment”

Plain English Summary

Comprehensive review of B12 metabolism disorders, diagnostic approaches, and emerging treatment concepts.

In-Depth Analysis

Background

Dr. Lawrence R. Solomon published this review in Blood Reviews (PMID: 16814909), covering disorders of cobalamin (B12) metabolism with emerging concepts in pathophysiology, diagnosis, and treatment.

Study Design

Comprehensive review synthesizing advances in understanding B12 absorption, transport, cellular metabolism, and clinical manifestations of deficiency.

Key Findings

B12 metabolic pathway:

•Dietary B12 binds intrinsic factor (IF) in stomach
•IF-B12 complex absorbed in terminal ileum
•Transcobalamin II transports B12 to tissues
•Intracellular conversion to methylcobalamin and adenosylcobalamin

Causes of deficiency by mechanism:

Mechanism	Examples
Inadequate intake	Vegan diet, malnutrition
Malabsorption	Pernicious anemia, gastric surgery, Crohn's
Transport defects	Transcobalamin deficiency (rare)
Cellular defects	Inborn errors of metabolism
Drug-induced	Metformin, PPIs, H2 blockers

Mechanistic Insights

B12 functions as coenzyme for:

•Methionine synthase: Homocysteine → methionine (methylation)
•Methylmalonyl-CoA mutase: Propionate metabolism (myelin synthesis)

Deficiency causes both methylation defects (neuropsychiatric) and propionate accumulation (neurological).

Clinical Implications

Functional markers (MMA, homocysteine) detect deficiency earlier than serum B12 alone. Neurological damage can occur with "low-normal" B12 levels.

Metabolic Health Perspective

Understanding B12 metabolism explains why supplementation works differently by route. High-dose oral B12 (1000-2000 mcg) can overcome absorption defects through mass action.