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FOLIC ACID DEFICIENCY
More Wine, Anyone?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level I
Jonathan M. Kline, PharmD, CACP, BCPS, CDE
CASE SUMMARY
A 43-year-old woman presents to the ED with a one-day history of
vomiting and abdominal pain. Physical examination reveals right
flank and bilateral lower quadrant tenderness, signs of dehydration, and bilateral lower extremity weakness. Laboratory evaluation
indicates acute pancreatitis and macrocytic anemia. The macrocytic
findings along with a low folate level are consistent with folic acid
deficiency anemia. Factors contributing to this patient’s folic acid
deficiency are alcohol consumption and celiac disease. Correction
of folic acid deficiency is usually accomplished by oral administration of exogenous folic acid for approximately 4 months provided
that the underlying cause of the deficiency can be identified and
corrected. This time frame allows all folate-deficient red blood cells
(RBCs) to be cleared from the circulation. The patient should also
be informed of the types of foods that are high in folate content.
Patient symptoms should begin to improve early in the course of
therapy, but it may take several months to normalize the hematocrit. The importance of adherence to the regimen for the full course
of therapy and limiting alcohol consumption or abstaining from
alcohol should be emphasized to the patient.
QUESTIONS
Problem Identification
1.a. Create a drug therapy problem list for this patient.
• Untreated folic acid deficiency.
• Disease states without treatment: Osteopenia is not being
treated with calcium and vitamin D supplementation. The
patient’s celiac disease leads to decreased absorption of calcium
and an increased risk of osteoporosis.
• Potential for drug–drug interaction: Estradiol can decrease free
T4 concentrations by increasing thyroxine-binding globulin.
The patient’s levothyroxine dose may need to be adjusted with
initiation or titration of estrogen products.1
• The patient is at an increased risk for the formation of venous
thromboembolism, including pulmonary embolism, due to
concomitant use of estrogen products while smoking tobacco.
• Potential for alcohol–disease state interactions: Alcohol is a
major cause of acute pancreatitis, and chronic alcohol ingestion predisposes to folic acid deficiency by preventing release
of folate from the liver.
1.c. Could the patient’s folate deficiency have been caused by
drug therapy or comorbidity?
• Drug therapy can be a direct cause of folate deficiency. The
most common medications implicated include phenytoin, phenobarbital, sulfasalazine, cholestyramine, oral contraceptives,
nitrofurantoin, methotrexate, tetracycline, trimethoprim, and
triamterene.4 These drugs often do not have a well-identified
mechanism for interaction but could include impaired folate
absorption, inactivation of folate, or inhibition of dihydrofolate
reductase.4 The patient is not taking any of these medications.
• It is likely that the deficiency can be attributed to chronic alcohol consumption or celiac disease. Alcohol is a known antagonist of folate metabolism, and alcoholism is often associated
with poor dietary intake. Alcohol impairs the release of folate
from the liver into bile, which impairs enterohepatic recycling
of folate.3 Celiac disease is associated with folic acid deficiency
due to poor absorption of folate in the jejunum.5
• The presence of other disease states can cause folate deficiency.
These include states that lead to folic acid hyperutilization
(malignancy, hemolysis, infancy, and pregnancy), malabsorption (Crohn disease, short-bowel syndrome, and post-bariatric
surgery), or bacterial overgrowth competing for dietary folate.3
1.d.What additional information can be used to assess this
patient’s folate deficiency?
• A peripheral blood smear may show signs of macrocytic anemia. Two signs suggesting macrocytosis are the presence of
oval macrocytes and hypersegmented neutrophils.3 The presence of stomatocytes is common among those with alcohol use
as the cause of the macrocytosis.6
• Because serum folate levels decrease rapidly with alcohol
consumption or short periods of dietary restriction, the
erythrocyte folate level can be tested to better determine folate
stores in these cases. The level of folate in erythrocytes does
not change over the life of the cell.3 There is little reason to test
erythrocyte folate levels in the setting of normal serum values.
• A reticulocyte count will give evidence of erythrocyte production in the last 2 days before the reticulocytes mature into RBCs.
• Signs: Generalized muscle weakness.
• Methylmalonic acid (MMA) can be checked to differentiate
folic acid deficiency from vitamin B12 deficiency. Cobalamin
is a required cofactor for the metabolism of MMA, and an
elevated MMA level is consistent with B12 deficiency.
• Symptoms: Malaise and fatigue. These symptoms occur from
the inability to increase cardiac output to compensate for the
decreased oxygen-carrying capacity in anemia. While folate
• Homocysteine depends on both folate and cobalamin for conversion to its remethylated form methionine, and it can be a
marker of B12 or folate deficiency. Besides vitamin B12 and folic
1.b. What signs, symptoms, and laboratory values indicate that
this patient has anemia secondary to folate deficiency?
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Folic Acid Deficiency
Amber Nicole Chiplinski, PharmD, BCPS
• Laboratory values: The mean corpuscular volume (MCV) is
elevated indicating a macrocytic anemia. The MCV is most
often elevated in either vitamin B12 or folate deficiency, and the
rise in MCV occurs before the decline in hemoglobin (Hgb)
levels. In this patient, the folate is low and the vitamin B12 level
is normal while the Hgb is at the low end of the normal range
due to hemoconcentration secondary to dehydration. The Hgb
and Hct would be expected to decline with rehydration. The
RBC count is decreased as well. The MCV may remain normal
in patients with concurrent iron deficiency, but in this patient
the mean corpuscular hemoglobin concentration (MCHC) is
also normal. The MCHC is typically low with iron deficiency.3
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and vitamin B12 deficiencies have been associated with depression and dementia, a Cochrane Review concluded that folic
acid supplementation did not improve the cognitive function
of elderly patients with dementia. However, a small trial demonstrated an improved response to cholinesterase inhibitors
with folate supplementation.2
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SECTION 15
acid deficiency, homocysteine may be increased in the elderly,
with renal insufficiency, hypothyroidism, hypovolemia, psoriasis, inherited metabolic defects, or pyridoxine deficiency.3
1.e. Why is it important to differentiate folate deficiency from
vitamin B12 deficiency, and how is this accomplished?
Hematologic Disorders
• Both vitamin B12 and folic acid deficiencies are macrocytic
anemias. It is important to distinguish between the two disease
states due to the severity of neurologic complications with
vitamin B12 deficiency (ie, demyelinating neuropathy). Supplementation with folate may improve the hematological effects
of vitamin B12 deficiency but will not correct any neurological
symptoms. Vitamin B12 levels should be checked whenever
investigating folate deficiency. If the vitamin B12 levels are only
slightly low (100–400 pg/mL), then an MMA level should be
obtained and would be elevated with vitamin B12 deficiency.3
Desired Outcome
2.What are the goals of pharmacotherapy for this patient’s
anemia?
• Relieve symptoms of anemia (weakness and fatigue) and
improve laboratory abnormalities.
✓Reticulocyte counts will increase in 2–3 days3
✓Hematocrit and hemoglobin begin to rise in 2 weeks7
✓RBC count will increase in 1 week and normalize in
4–8 weeks3
✓MCV will return to reference range within 4–11 weeks3
• Replenish folic acid stores with a diet high in folic acid and folic
acid supplementation.
• Rule out concurrent vitamin B12 deficiency.
• Educate the patient about the relationship between alcohol
use and folic acid deficiency and encourage abstaining from
consumption in the future.
• Educate the patient about the relationship between celiac disease and folic acid deficiency to encourage a diet high in folic
acid yet compatible with celiac disease (fruits, vegetables, dairy,
and low-gluten cereals).5
Therapeutic Alternatives
3.a. What nondrug therapies may be used to correct this patient’s
folic acid deficiency?
• The patient’s diet should include foods that are naturally rich
or fortified with folate. Extended cooking can remove up to
90% of the folic acid content of food.8 Foods naturally rich in
folate include beef liver, black-eyed peas, spinach, asparagus,
vegetarian baked beans, green peas, broccoli, avocado, peanuts, romaine lettuce, wheat germ, tomato juice, orange juice,
cantaloupe, papaya, and bananas. In addition, the US government’s Folate Fortification Program has increased the number
of folate-enhanced foods, which include breakfast cereals, rice,
egg noodles, and breads. The Folate Fortification Program has
likely reduced the incidence of folic acid deficiency, and most
folate levels are normal or high.9
• The patient’s concurrent celiac disease should be considered
when counseling her about dietary choices because the restriction of a gluten-free diet for celiac disease may limit the types
of folate-rich foods she can consume. Additionally, most
gluten-free foods are lower in folate than other comparable
pastas, breads, and cereals.
• The patient should be advised to minimize her alcohol intake.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
3.b.What pharmacotherapeutic alternatives are available for
treating this patient’s anemia?
• Oral folic acid tablets are the most commonly used form of
supplementation in patients who are not acutely ill. While folic
acid can also be found in varying amounts in multivitamins
and prenatal vitamins, the doses are appropriate for use as daily
supplementation, not for treatment of folic acid deficiency.
Intravenous folic acid is available but is limited to inclusion in
total parenteral nutrition for patients with diminished folate
stores.
• Folinic acid (leucovorin calcium), the 5-formyl derivative of
tetrahydrofolic acid, is needed for patients with congenital
dihydrofolate reductase deficiency, rescue after high-dose
methotrexate therapy, or those experiencing toxicity from
folate antagonists such as pyrimethamine or trimethoprim.
Leucovorin can be used to treat any folate deficiency, but it
does not provide benefit over folic acid in most cases.8
Optimal Plan
4.What are the most appropriate drug, dosage form, dose,
schedule, and duration of therapy for resolving this patient’s
anemia?
• Oral folic acid is the most appropriate selection for this patient.
The recommended dose of folic acid is 1 mg daily for at least
4 months. After this initial treatment, 0.4–1 mg of folic acid
by mouth daily should be considered to prevent future anemia
and continued indefinitely. A consideration for continuing
chronic therapy in this patient would be likely malabsorption
secondary to celiac disease. Repeat testing for B12 deficiency is
recommended with extended folic acid therapy, particularly
with persisting hematologic and/or neurologic symptoms.10
Outcome Evaluation
5.What parameters should be used to evaluate the efficacy
and adverse effects of folic acid replacement therapy in this
patient?
Efficacy:
• Symptomatic improvements in appetite, fatigue, weakness,
irritability, and restlessness should be monitored.
• A compete blood count should be done 10–14 days after initiation of therapy and repeated at 8 weeks to verify a response. No
other routine monitoring is required. Reticulocytosis should
occur within 2–3 days and peak within 5–8 days. Hemoglobin and hematocrit should return to the normal range within
2 months. The MCV will initially increase and then return to
normal in 4–11 weeks. A delay in response usually suggests an
additional abnormality or incorrect diagnosis (iron deficiency,
infection, hypothyroidism, or malignancy).3
• Serum electrolytes should also be monitored at week 2 due
to the possibility of severe hypokalemia. Potassium may
decrease due to a marked increase in utilization during new
hematopoietic cell production in patients who were severely
anemic.
Adverse effects:
• Side effects are rare with replacement doses of folic acid but
may include allergic reaction, bronchospasm, hypokalemia,
erythema, flushing, malaise, pruritus, and rash. Very high
doses (eg, 15 mg/day) have been associated with GI side effects
and mental status changes.
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6.What information would you provide to this patient about her
folic acid replacement therapy?
• Folic acid is part of the vitamin B family and is required for
your body to make red blood cells and prevent anemia.
• This medication can be taken with or without food but should
be taken with food if it causes upset stomach.
• Take the medication once daily as directed by your doctor.
• Be sure to follow-up with your doctor and appointments for
laboratory work so that your progress with the medication can
be monitored.
• Follow the suggested diet carefully to include folic acid rich
foods. Good sources of folic acid include liver, kidneys, foods
prepared from dried yeasts, fruit, and fresh leafy green vegetables. Cooking these foods excessively can eliminate a substantial amount of folic acid.
• If you forget to take a dose, take it as soon as you remember;
if it is close to your next scheduled dose, skip the missed dose
and continue your regular schedule.
• Rare side effects include skin rash, itching, redness, upset stomach, and difficulty breathing.
• Tell your doctor and pharmacist what prescription and nonprescription drugs you are taking.
• Do not allow anyone else to take your medication.
• Keep this medication out of reach of children.
1. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001;344:1743–1749.
2. Malouf R, Grimley Evans J. Folic acid with or without vitamin B12
for the prevention and treatment of healthy elderly and demented
people. Cochrane Database Syst Rev 2008;(4):CD004514.
doi:10.1002/14651858.CD004514.pub2.
3.Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med
1999;159:1289–1298.
4.Hesdorffer CS, Longo DL. Drug-induced megaloblastic anemia.
N Engl J Med 2015;373:1649–1658.
5. Presutti RJ, Cangemi JR, Cassidy HD, Hill DA. Celiac disease. Am Fam
Physician 2007;76:1795–1802.
6.Seppa K, Sillanaukee P, Saarni M. Blood count and hematologic
morphology in nonanemic macrocytosis: differences between alcohol
abuse and pernicious anemia. Alcohol 1993;10:343–347.
7. Kaushansky K, Kipps TJ. Hematopoietic agents: growth factors, minerals, and vitamins. In: Brunton LL, Chabner B, Knollman B, eds. Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 12th ed.
New York, NY, McGraw-Hill, 2011. p. 1067–1100.
8. Rampersaud GC, Kauwell GP, Bailey LB. Folate: a key to optimizing health and reducing disease risk in the elderly. J Am Coll Nutr
2003;22:1–8.
9.Theisen-Toupal J, Horowitz G, Breu A. Low yield of outpatient
serum testing: eleven years of experience. JAMA Intern Med
2014;174(10):1696–1697.
10. Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher
serum folate is associated with increased total homocysteine and
methylmalonic acid concentrations. Proc Natl Acad Sci USA
2007;104:19995–20000.
• Store the medication at room temperature and away from
direct sunlight.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Folic Acid Deficiency
• You may start to feel better within a few weeks but do not stop
taking the medication unless directed by your doctor.
REFERENCES
CHAPTER 115
Patient Education