Folate Deficiency

Clinical Features

Folate (Vitamin B9) plays a pivotal role in DNA and RNA synthesis and one-carbon metabolism. Deficiency primarily affects tissues with rapid cell turnover, such as the hematopoietic system and the gastrointestinal mucosa.

Hematological Manifestations

The hallmark of folate deficiency is megaloblastic anemia, which is morphologically indistinguishable from that caused by Vitamin B12 deficiency.

• Anemia: Children present with nonspecific symptoms of anemia, including progressive pallor, fatigue, lethargy, and irritability.
• Pancytopenia: Severe deficiency affects all myeloid cell lines, leading to leukopenia and thrombocytopenia in addition to anemia.
• Hemorrhagic Tendencies: Thrombocytopenia may manifest as petechiae, bruising, or bleeding, although this is more common in severe cases associated with malnutrition.

Gastrointestinal Manifestations

Since the intestinal mucosa has a high turnover rate, it is frequently affected by folate deficiency.

• Glossitis: The tongue becomes sore, smooth, and beefy red due to papillary atrophy.
• Stomatitis: Inflammation of the oral mucosa and angular stomatitis (fissuring at the corners of the mouth) may occur.
• Diarrhea: Malabsorption and chronic diarrhea can result from the blunting of intestinal villi, creating a vicious cycle of deficiency and malabsorption.
• Growth Failure: In infants and young children, chronic deficiency leads to anorexia, weight loss, and failure to thrive (growth stunting).

Dermatological Manifestations

• Hyperpigmentation: Similar to Vitamin B12 deficiency, folate deficiency can cause hyperpigmentation of the skin, particularly over the knuckles (dorsal aspect of fingers) and nail beds.
• Hair Changes: Hair may become sparse or brittle in the context of general malnutrition associated with the deficiency.

Neurological Manifestations

Unlike Vitamin B12 deficiency, nutritional folate deficiency typically does not cause subacute combined degeneration of the cord. However, specific forms and severe states have profound neurological implications.

• Irritability and Behavioral Changes: Listlessness and apathy are common constitutional symptoms.
• Cerebral Folate Deficiency: This is a specific neurological syndrome where serum folate is normal, but cerebrospinal fluid (CSF) folate is low due to transport defects. It manifests in infancy (4–6 months) with:
  • Severe irritability and sleep disturbances.
  • Microcephaly and developmental delay.
  • Cerebellar ataxia and hypotonia.
  • Pyramidal tract signs (spasticity).
  • Choreoathetosis, ballismus, and intractable seizures.
  • Blindness due to optic atrophy.

Developmental and Congenital Effects

• Neural Tube Defects (NTDs): Maternal folate deficiency during the critical period of embryogenesis (first 28 days of conception) is a major risk factor for fetal NTDs such as spina bifida and anencephaly.
• Other Anomalies: Periconceptional deficiency is also linked to an increased risk of orofacial clefts, congenital heart defects, and low birth weight.

Diagnosis

A stepwise approach is recommended to confirm the diagnosis and distinguish it from Vitamin B12 deficiency.

Hematological Screening

• Complete Blood Count (CBC):
  • Macrocytosis: Elevated Mean Corpuscular Volume (MCV) is the screening hallmark.
    • Children 2–10 years: MCV > 84 + (0.6 × age in years) fL.
    • Children >10 years: MCV > 90–100 fL.
  • Cytopenias: Low hemoglobin, leukopenia, and thrombocytopenia may be present.
• Peripheral Blood Smear:
  • Macro-ovalocytes: Large, oval-shaped red blood cells are characteristic.
  • Hypersegmented Neutrophils: The presence of neutrophils with ≥5 lobes (in >5% of neutrophils) or any neutrophil with ≥6 lobes is pathognomonic of megaloblastic anemia.
• Reticulocyte Count: Typically low, indicating ineffective erythropoiesis.

Biochemical Confirmation

• Serum Folate: Levels <4 ng/mL (<10 nmol/L) indicate deficiency. Serum levels fluctuate with recent dietary intake and are sensitive to short-term changes.
• Red Blood Cell (RBC) Folate: This is a more reliable indicator of tissue stores as it reflects folate status over the 120-day lifespan of the RBC. Levels <100 ng/mL (<226 nmol/L) confirm chronic deficiency.
• Metabolite Testing: Used when folate levels are borderline.
  • Plasma Homocysteine: Elevated in both folate and B12 deficiency (>15 µmol/L).
  • Methylmalonic Acid (MMA): Normal in folate deficiency but elevated in B12 deficiency. This distinguishes the two causes.

Bone Marrow Examination

• Bone marrow aspiration is not routinely required if serological tests are diagnostic. If performed, it shows hypercellularity with megaloblastic erythropoiesis (nuclear-cytoplasmic asynchrony) and giant metamyelocytes.

Management

The goals of management are to replenish folate stores, correct anemia, and treat the underlying cause.

Principles of Therapy

• Rule out Vitamin B12 Deficiency: Before starting folic acid monotherapy, it is imperative to exclude Vitamin B12 deficiency. Treating a B12-deficient patient with folic acid alone can correct the hematological parameters ("masking" the anemia) while allowing severe neurological damage (subacute combined degeneration) to progress irreversibly.
• Combined Therapy: In cases where B12 deficiency cannot be ruled out or in dimorphic anemia, both vitamins should be supplemented. B12 should preferably be started 10–14 days before folic acid.

Therapeutic Regimens

• Oral Folic Acid Therapy:
  • Dosage: The standard therapeutic dose for children is 1–5 mg/day orally.
  • Duration: Therapy should continue for 3–4 months to replenish body stores and ensure complete hematological recovery.
  • Maintenance: A lower maintenance dose (e.g., 0.2 mg/day) may be used subsequently if the cause persists.
• Parenteral Therapy: Rarely required but may be used in severe malabsorption. Folinic acid (Leucovorin) is used if there is a metabolic block (e.g., methotrexate toxicity).

Management in Severe Acute Malnutrition (SAM)

Children with SAM often have subclinical folate deficiency and require a specific protocol during rehabilitation.

• Day 1: Give 5 mg folic acid orally.
• Subsequent Days: Give 1 mg folic acid daily.
• Note: Iron is withheld during the stabilization phase (first week) but folate is started immediately.

Management of Specific Conditions

• Cerebral Folate Deficiency: Requires high doses of folinic acid (0.5–1 mg/kg/day) orally or parenterally. Folic acid is ineffective because it cannot cross the blood-brain barrier in this condition.
• Hereditary Folate Malabsorption: Treated with parenteral or high-dose oral folinic acid.
• Drug-Induced Deficiency: Patients on anticonvulsants (phenytoin, phenobarbital) or methotrexate require prophylactic supplementation to prevent deficiency.

Dietary Management

• Dietary counseling should emphasize the consumption of folate-rich foods:
  • Vegetables: Dark green leafy vegetables (spinach, mustard greens), beans, peas, broccoli, cauliflower.
  • Fruits: Citrus fruits (oranges, lemons), melons, bananas, papaya.
  • Animal Sources: Liver, kidney, eggs.
  • Preparation: Avoid overcooking or repeated washing of vegetables in large amounts of water, as folate is heat-labile and water-soluble.

Prophylaxis and Prevention

• Periconceptional Supplementation: All women of childbearing age should consume 400–800 µg/day of folic acid starting at least 1 month before conception and continuing through the first trimester to prevent NTDs.
  • Women with a previous history of NTD-affected pregnancy require a high dose of 4 mg/day.
• Anemia Mukt Bharat Program:
  • Prophylactic Iron and Folic Acid (IFA) supplementation is recommended for all children >6 months.
  • Infants (6–59 months): 20 mg elemental iron + 100 µg folic acid biweekly (1 mL syrup).
  • School-age children (5–9 years): 45 mg elemental iron + 400 µg folic acid weekly.
  • Adolescents (10–19 years): 60 mg elemental iron + 500 µg folic acid weekly.
• Preterm Infants: Supplementation with ~65 µg/day (up to 400 µg/day in some protocols) is recommended due to low stores and rapid growth.

Response to Therapy

• Subjective Improvement: Improved appetite and well-being occur within 24–48 hours.
• Reticulocytosis: Begins in 2–4 days and peaks by 7 days.
• Hematological Correction:
  • Hypersegmentation of neutrophils disappears within 10–14 days.
  • MCV begins to fall by day 14 and normalizes by 6–8 weeks.
  • Hemoglobin normalizes within 4–8 weeks.
• Follow-up: CBC and reticulocyte count should be checked after 14 days to document response. If there is no response, re-evaluate for compliance, malabsorption, or alternative diagnoses.