Megaloblastic anemia is a macrocytic anemia characterized by ineffective erythropoiesis and the presence of large, structurally abnormal, immature red blood cell precursors (megaloblasts) in the bone marrow.

It is most commonly caused by:

• Vitamin B12 (cobalamin) deficiency

• Folate (vitamin B9) deficiency

Both vitamins are essential for DNA synthesis, and their deficiency results in defective nuclear maturation with preserved cytoplasmic development (nuclear–cytoplasmic asynchrony).

Pathophysiology

• Impaired thymidine synthesis → defective DNA replication

• Delayed nuclear maturation

• Ineffective hematopoiesis

• Intramedullary hemolysis

• Pancytopenia (in severe cases)

Vitamin B12 deficiency uniquely affects the nervous system, leading to demyelination (subacute combined degeneration).

Risk Factors

Vitamin B12 Deficiency

• Pernicious anemia (autoimmune intrinsic factor deficiency)

• Gastrectomy or bariatric surgery

• Chronic gastritis

• Malabsorption (Crohn’s disease, celiac disease)

• Long-term metformin use

• Strict vegan diet

• Elderly age

• Fish tapeworm (Diphyllobothrium latum)

Folate Deficiency

• Poor dietary intake

• Chronic alcoholism

• Pregnancy

• Hemolytic anemia (increased demand)

• Malabsorption

• Methotrexate or anticonvulsant therapy

Signs and Symptoms

General Anemia Features

• Pallor

• Fatigue

• Dyspnea

• Tachycardia

Characteristic Features

• Mild jaundice (lemon-yellow tint)

• Glossitis (beefy red tongue)

• Hyperpigmentation of palms

• Hair loss

• Depression

• Weight loss

Neurological Features (Vitamin B12 Deficiency)

• Paresthesia (pins and needles)

• Numbness (hands and feet)

• Ataxic gait

• Loss of vibration and position sense

• Tremors

• Peripheral neuropathy

• Cognitive changes

• Psychosis (rare)

Neurological symptoms may occur even without severe anemia.

Diagnostic Criteria

Diagnosis is based on:

1. Macrocytic anemia

2. Laboratory evidence of B12 or folate deficiency

3. Characteristic peripheral smear findings

4. Clinical features

Investigations

Perform the following investigations as appropriate:

• Full blood count (FBC):

  • Low haemoglobin

  • Raised mean corpuscular volume (MCV)

  • Pancytopenia may be present

  • MCV may be normal or low if iron deficiency coexists (combined deficiency anaemia)

• Peripheral blood smear

• Serum vitamin B12 level

• Serum folate level

• Thyroid-stimulating hormone (TSH)

• Reticulocyte count

• Bone marrow aspiration, when indicated

Differential Diagnosis

• Liver disease

• Hypothyroidism

• Alcoholism

• Myelodysplastic syndrome

• Aplastic anemia

• Drug-induced macrocytosis

Treatment

Treatment depends on the underlying deficiency.

Non-Pharmacological Management

• Dietary counseling

• Alcohol cessation

• Management of malabsorption

• Treat underlying gastrointestinal pathology

Pharmacological management

Management depends on the underlying cause and the presence or absence of neurological involvement.

Vitamin B12 deficiency without neurological involvement

Hydroxocobalamin (IM)

• 1 mg three times weekly for 2 weeks.

• Then 1 mg every 3 months.

Monitoring

• Review blood counts and perform clinical assessment every 3 months.

Pernicious anaemia (vitamin B12 deficiency with neurological involvement)

Hydroxocobalamin (IM)

• 1 mg on alternate days until there is no further neurological improvement (maximum reversal of neurological or neuropsychiatric signs and symptoms).

• Then 1 mg every 2–3 months.

AND

Folic acid (PO)

• 5 mg once daily for at least 3 months.

Important: Folic acid must be started simultaneously with vitamin B12 therapy.

AND

Ferrous sulphate (PO)

• 200 mg every 8 hours for at least 3 months.

Monitoring Response

• Reticulocyte rise within 5–7 days

• Hemoglobin improves within 2–3 weeks

• Full correction in ~2 months

• Neurological recovery may take months

Complications

• Irreversible neuropathy (untreated B12 deficiency)

• Cognitive impairment

• Subacute combined degeneration

• Heart failure (severe anemia)

• Infertility

• Increased thrombotic risk (elevated homocysteine)

Prevention

• Balanced diet rich in:

  • Meat, fish, dairy (B12)

  • Leafy greens (folate)

• Supplementation in:

  • Pregnancy

  • Chronic hemolytic anemia

  • Malabsorption syndromes

• Lifelong B12 in pernicious anemia

• Screening high-risk elderly patients

Prognosis

• Excellent with early treatment

• Neurological complications reversible if treated promptly

• Pernicious anemia requires lifelong therapy