Updated: 2/7/2019

Folic Acid Deficiency

Topic
Review Topic
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Questions
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Evidence
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Snapshot
  • A 50-year-old alcoholic man presents to the hospital in a florid alcohol withdrawal. He confabulates and trembles uncontrollably. He is started on supportive therapy for now. An alcohowal withdrawal score is done regularly to assess for the need for medical therapy. In the meantime, bloodwork comes back with megaloblastic anemia and increased homocysteine and normal methylmalonic acid. He is immediately started on folic acid supplementation.
Introduction

  • Folic acid (or vitamin B9) is found in leafy green vegetables
  • Pathogenesis
    • folic acid is absorbed in jejunum and ileum
      • used in tetrahydrofolate (THF) as coenzyme
      • important for DNA and RNA synthesis
      • small reserve pool in liver
    • causes megaloblastic anemia due to impaired DNA synthesis
  • Epidemiology
    • most common vitamin deficiency in the US
    • most common cause of megaloblastic anemia
    • can manifest after 4 months (depleted storage from liver) 
  • Associated conditions
    • chronic hemolytic anemias
    • malnutrition
      • alcoholism
      • elderly
      • psychiatric comorbidity
    • pregnancy
      • increased folate requirement
    • malabsorption
      • celiac disease
      • tropical sprue
    • pregnancy
      • risk of neural tube defects in infant
    • certain drugs (anti-folates)
      • phenytoin
      • methotrexate
      • trimethoprim
Presentation
  • Symptoms
    • no neurological symptoms (unlike in B12 deficiency)
    • anemia 
      • fatigue
      • weakness
      • shortness of breath
  • Physical exam
    • glossitis
    • pallor
Evaluation
  • Peripheral blood smear
    • hypersegmented lobes seen in neutrophils
    • macrocytosis
  • Serum 
    • ↓ folic acid
    • ↑ homocysteine
    • NORMAL methylmalonic acid (MMA) 
      • unlike in vitamin B12 deficiency, which has ↑MMA
    • ↓ reticulocyte count
    • may see pancytopenia due to destruction of abnormal cells
  • Also test for B12 deficiency and TSH (to rule out hypothyroidism)
Differential
  • Vitamin B12 deficiency
  • Pernicious anemia
  • Other causes of macrocytic anemia
    • alcoholism
    • hypothyroidism
    • liver dysfunction
    • drugs 
Treatment
  • Folic acid supplementation
  • Eat a more balanced diet
    • fruits and vegetables
Prognosis, Prevention, and Complications
  • Prognosis
    • good with supplementation
  • Prevention
    • folic or folinic acid supplementation, especially if chronically on drugs such as methotrexate
  • Complications
    • neural tube defects in infant if deficient during pregnancy
    • in the setting of a B12 deficiency, the anemia can correct with aggressive folate supplementation but the patient will still be at risk for neurological complications of B12 deficiency including peripheral neuropathy and posterior column defects due to deficiencies in myelin production
 

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Questions (4)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
Calculator

(M2.HE.96) A 34-year-old female with a past medical history of a gastric sleeve operation for morbid obesity presents for pre-surgical clearance prior to a knee arthroplasty. Work-up reveals a hemoglobin of 8.7 g/dL, hematocrit of 26.1%, and MCV of 106 fL. With concern for folate deficiency, she is started on high dose folate supplementation, and her follow-up labs are as follows: hemoglobin of 10.1 g/dL, hematocrit of 28.5%, and MCV of 96 fL. She is at risk for which long-term complication? Review Topic

QID: 104736
1

Neural tube defects

8%

(2/24)

2

Macular degeneration

0%

(0/24)

3

Peripheral neuropathy

75%

(18/24)

4

Hypothyroidism

8%

(2/24)

5

Microcytic anemia

4%

(1/24)

M2

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

(M2.HE.4692) A 29-year-old woman, who is 16 weeks into her pregnancy, comes to your office with symptoms of fatigue and dizziness. She has been taking iron, but no other vitamins or minerals. She denies any medical history and states all her physician visits before pregnancy were normal. She also denies taking any supplements or medications. On exam, she has no neurological deficits, but her complete blood count (CBC) is significant for hemoglobin of 10.2 g/dL. The mean corpuscular volume (MCV) of her red blood cells (RBCs) is 105 fl, and Figure A illustrates the peripheral blood smear of the patient. Her methylmalonic acid level is normal. What is the most likely cause of her condition? Review Topic

QID: 107667
FIGURES:
1

Iron deficiency

0%

(0/0)

2

Thalassemia

0%

(0/0)

3

Vitamin B12 deficiency

0%

(0/0)

4

Folate deficiency

0%

(0/0)

5

Anemia of chronic disease

0%

(0/0)

M2

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

(M3.HE.112) A 52-year-old female presents to her rheumatologist with complaints of fatigue, a sore mouth, and occasional nausea and abdominal pain over the past several months. Her medical history is significant for 'pre-diabetes' treated with diet and exercise, hypertension managed with lisinopril, and rheumatoid arthritis well-controlled with methotrexate. Her vital signs are within normal limits. Physical examination is significant for an overweight female with the findings as shown in Figures A and B. The physician orders laboratory work-up including complete blood count with peripheral blood smear as well as basic metabolic panel and serum methylmalonic acid and homocysteine levels. These tests are significant for a hematocrit of 29.5, a decreased reticulocyte count, normal serum methylmalonic acid level, increased homocysteine level, as well as the peripheral smear shown in Figure C. Which of the following could have reduced this patient's risk of developing their presenting condition? Review Topic

QID: 103475
FIGURES:
1

Discontinuation of lisinopril and initiation of triamterene for blood pressure control

0%

(0/0)

2

Administration of daily, high-dose PO vitamin B12

0%

(0/0)

3

Monthly injection of vitamin B12 supplementation

0%

(0/0)

4

Initiation of folinic acid

0%

(0/0)

5

Addition of metformin

0%

(0/0)

M2

Select Answer to see Preferred Response

PREFERRED RESPONSE 4
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