Vitamin B12 Deficiency

Introduction and Pathophysiology

• Vitamin B12 (cobalamin) is a water-soluble vitamin essential for two critical metabolic reactions: the methylation of homocysteine to methionine (via methionine synthase, requiring methylcobalamin) and the conversion of methylmalonyl-coenzyme A (CoA) to succinyl CoA (via methylmalonyl-CoA mutase, requiring adenosylcobalamin).
• The products of these enzymatic reactions are crucial for DNA, RNA, and protein synthesis.
• Impaired DNA synthesis resulting from vitamin B12 deficiency leads to megaloblastic anemia, a disorder characterized by delayed nuclear development and a maturational asynchrony between the nucleus and cytoplasm in hematopoietic cells.
• Cobalamin is synthesized exclusively by microorganisms, making humans entirely dependent on dietary sources such as meat, eggs, fish, and milk.
• During digestion, cobalamin is released from food protein in the stomach through peptic digestion and binds to haptocorrin, a salivary glycoprotein.
• In the duodenum, pancreatic proteases digest haptocorrin, liberating cobalamin, which then binds to intrinsic factor (IF) produced by gastric parietal cells.
• The cobalamin-IF complex is absorbed in the distal ileum via receptor-mediated endocytosis (using the cubam receptor) and is transported in the bloodstream bound to transcobalamin II (TC II).

Etiology

Inadequate Dietary Intake

• Older children and adults generally possess sufficient hepatic vitamin B12 stores to last 3 to 5 years, but infants born to mothers with low vitamin B12 stores can present with clinical deficiency within the first 6 to 18 months of life.
• In pediatrics, the most common cause is nutritional deficiency in exclusively breastfed infants of mothers who are B12-deficient (e.g., vegans, strict vegetarians, or those with unrecognized pernicious anemia or previous gastric bypass).
• Due to active placental transport, infants are generally born with normal prenatal development but depleted stores, leading to a gradual onset of postnatal symptoms.

Defective Absorption

• Gastric Abnormalities: Impaired gastric function (atrophic gastritis, partial gastrectomy, Helicobacter pylori infection, or prolonged use of proton pump inhibitors) impairs the release of cobalamin from food.
• Intrinsic Factor (IF) Deficiency: Hereditary intrinsic factor deficiency is a rare autosomal recessive disorder where gastric acid is secreted normally, but IF is absent or dysfunctional, presenting typically between 6 to 24 months of age. Juvenile pernicious anemia (autoimmune gastritis) is rare in children but can present in adolescence with antibodies against IF and gastric parietal cells.
• Intestinal Malabsorption: Imerslund-Gräsbeck syndrome is an autosomal recessive disorder characterized by a selective defect in the ileal cubam receptor (genes CUBN or AMN), leading to vitamin B12 malabsorption, often accompanied by benign proteinuria.
• Other Intestinal Causes: Inflammatory bowel disease (Crohn's disease), celiac disease, extensive ileal resection, neonatal necrotizing enterocolitis, and small-bowel bacterial overgrowth (e.g., blind loops) can severely impair absorption.
• Parasitic Infection: Infestation with the fish tapeworm Diphyllobothrium latum can cause deficiency through direct consumption of the vitamin within the gastrointestinal tract.

Defective Transport and Metabolism

• Transcobalamin II Deficiency: A rare autosomal recessive condition presenting in the first weeks of life with severe megaloblastic anemia, failure to thrive, diarrhea, and neurologic abnormalities, despite seemingly normal total serum vitamin B12 levels.
• Intracellular Metabolism Disorders: Pathogenic variants in various complementation groups (e.g., cblC, cblD, cblF) disrupt intracellular processing, causing combined methylmalonic acidemia and homocystinuria.
• Inactivation: Chronic recreational exposure to nitrous oxide ("Whippets") or medical nitrous oxide anesthesia can permanently inactivate vitamin B12, precipitating acute deficiency symptoms.

Clinical Manifestations

Hematologic and Systemic Features

• The onset is usually insidious, presenting with nonspecific manifestations such as weakness, extreme lethargy, failure to thrive, feeding difficulties, and irritability.
• Physical examination frequently reveals marked pallor, icterus, and a smooth, red, painful tongue (atrophic glossitis).
• Hyperpigmentation of the skin, characteristically noted on the knuckles and terminal phalanges, is a prominent finding that may mistakenly mimic Addison disease.
• Gastrointestinal disturbances including vomiting and chronic diarrhea are common.
• Hyperhomocysteinemia secondary to the deficiency places these children at an increased risk for vascular thrombosis.

Neurologic Features

• Neurologic problems are a hallmark of vitamin B12 deficiency and can uniquely occur in the complete absence of any hematologic abnormalities.
• Infants: Typically present with severe developmental delay, loss of acquired motor milestones (e.g., head control, sitting), extreme hypotonia, athetoid movements, seizures, and apathy.
• Older Children: May develop subacute combined degeneration of the spinal cord (affecting the posterior and lateral columns), which manifests as a loss of vibration and position sense, an ataxic gait, positive Romberg sign, paresthesias, diminished reflexes, and spasticity.
• Prolonged deficiency can lead to irreversible cognitive impairment, memory loss, confusion, and neuropsychiatric changes.
• Magnetic Resonance Imaging (MRI) may demonstrate increased T2-weighted signals in the spinal cord, delayed myelination, or brain atrophy.

Laboratory Findings

Hematologic Profile

• Complete blood count reveals a macrocytic anemia with a mean corpuscular volume (MCV) significantly elevated for age (often 110–140 fL) and an increased red cell distribution width (RDW).
• The absolute reticulocyte count is inappropriately low for the degree of anemia.
• The peripheral blood smear is characterized by macro-ovalocytes, striking anisocytosis and poikilocytosis, teardrop cells, Howell-Jolly bodies, and hypersegmented neutrophils (neutrophils with >5 nuclear lobes).
• In severe or advanced cases, progressive pancytopenia (neutropenia and thrombocytopenia) occurs, which can mimic bone marrow failure syndromes or acute leukemia.

Bone Marrow Examination

• Bone marrow aspiration is generally not required if biochemical tests are conclusive but, if performed, shows a markedly hypercellular marrow due to erythroid hyperplasia.
• Megaloblastic changes are prominent, demonstrating nuclear-cytoplasmic dissociation (immature, lacy nuclei paired with mature cytoplasm).
• Giant metamyelocytes with large horseshoe-shaped nuclei and hypersegmented megakaryocytes are also observed.

Biochemical Markers

• Total serum vitamin B12 levels are typically low (<80 pg/mL is highly indicative), though false-normal values can occur, necessitating metabolic assays.
• Methylmalonic Acid (MMA): Both serum and urinary MMA levels are markedly elevated; this is a highly sensitive and specific functional indicator of cobalamin deficiency.
• Homocysteine: Serum levels are elevated (though this finding is shared with folate deficiency).
• Functional ineffective erythropoiesis results in intramedullary apoptosis, clinically presenting with massively elevated serum lactate dehydrogenase (LDH), increased indirect bilirubin, elevated serum iron and ferritin, and decreased haptoglobin.
• Folic acid levels are usually normal or elevated.

Diagnosis

• A comprehensive medical, dietary (e.g., maternal vegan diet), and surgical history is paramount.
• Diagnosis is initially suspected based on clinical features alongside macrocytic anemia with hypersegmented neutrophils and confirmed by low serum B12 levels coupled with elevated serum and urinary MMA.
• If dietary lack is ruled out, malabsorption evaluation is required; tests for anti-intrinsic factor and anti-parietal cell antibodies are indicated to rule out juvenile pernicious anemia.

Management

• Administration: Because oral absorption is frequently impaired in congenital and acquired GI defects, lifelong parenteral (intramuscular or intravenous) or high-dose intranasal cobalamin is the mainstay of therapy.
• Dosing: For children older than 10 years, a parenteral dose of 1 mg (1000 µg) of vitamin B12 is recommended daily for 2 weeks, followed by weekly injections until the hematocrit normalizes, and then continued as a monthly maintenance dose for life.
• Neurologic Complications: Patients presenting with neurologic deficits require intensive therapy: 1000 µg daily for 2 weeks, then every 2 weeks for 6 months, followed by monthly injections.
• Infants: Lower parenteral doses (e.g., 250 µg) are utilized in infants and young children.
• Crucial Precaution: The administration of folic acid alone in a patient with unrecognized vitamin B12 deficiency is strictly contraindicated; while it may correct the megaloblastic anemia, it fails to halt and may aggressively accelerate irreversible neurologic degeneration.
• Treatment Response: Reticulocytosis begins promptly by the third or fourth day, peaking between the sixth and eighth days.
• Bone marrow morphology rapidly reverts from megaloblastic to normoblastic within 48 to 72 hours of initial treatment.
• Clinical alertness and responsiveness often improve drastically within 48 hours, and hemoglobin normalizes in approximately 1 to 2 weeks, though established neurologic deficits may be permanent if therapy is delayed.