This document summarizes folic acid deficiency, including its physiologic roles, clinical presentation, investigations, treatment, and prevention. It notes that folic acid is important for DNA and RNA synthesis and hematopoiesis. Deficiency can cause macrocytic anemia and megaloblastic changes in the bone marrow. It is investigated through CBC, serum and red blood cell folate levels, and metabolites. Treatment involves oral folic acid supplementation.

1. FOLIC ACID DEFICIENCY
Dr G VENKATA RAMANA
MBBS DNB FAMILY MEDICINE

2. FOLIC ACID
• Folic (pteroylglutamic) acid is a yellow, crystalline,
water-soluble substance.
• Most dietary folate is present as polyglutamates
• These are converted to monoglutamate in the upper
small bowel and actively transported into plasma.
• Reduction to DHFA and methylation also occurs at
this site.
• Alcohol interferes with release of methyl-THFA from
hepatocytes.
• RDI of Folic acid
• Adults : 400mcg
• Pregnancy: 600mcg
• Lactation: 500mcg
• Total body stores of folate are small and deficiency
can occur in a matter of weeks

4. Folic acid Absorption

5. Physiologic roles of folic acid
• DNA synthesis, RNA synthesis, DNA methylation
• Folic acid play a critical role in DNA and RNA
synthesis.
• Folic acid deficiency can therefore impair DNA
synthesis, which in turn can cause a cell to arrest in
the DNA synthesis (S) phase of the cell cycle, make
DNA replication errors, and/or undergo apoptotic death
• Hematopoiesis
• Hematopoietic precursor cells are among the most
rapidly dividing cells in the body and hence are one of
the cell types most sensitive to abnormal DNA
synthesis.

6. • Two major effects of the deficiency on hematopoiesis
• Megaloblastic changes
• caused by slowing of the nuclear division cycle relative to the
cytoplasmic maturation cycle (ie, nuclear-cytoplasmic
dyssynchrony).
• Ineffective erythropoiesis
• occurs when there is premature death (eg, phagocytosis or
apoptosis) of the developing erythropoietic precursor cells in the
bone marrow .
• There may be hypercellularity of the bone marrow
• laboratory findings of hemolysis, including elevated serum iron,
indirect bilirubin, and lactate dehydrogenase (LDH), and low
haptoglobin.
• The reticulocyte count is typically low.

11. Clinical presentation
• Macrocytic anemia
• Symptoms of anemia-fatigue, irritability,
cognitive decline,chest pain, shortness of
breath,palpitations,light-headedness
• Yellowed skin
• Gastrointestinal symptoms
• Oral ulcers
• Glossitis
• Neuropsychiatric changes
• Depression, irritability, or forgetfulness
• Neural tube defects
• Spina bifida

12. lnvestigations
• CBC and blood smear
• Anemia
• Macrocytic red blood cells (MCV >100 fL) or macro-ovalocytosis
• An MCV value >115 fL is more specific to vitamin B12 or folate
deficiency
• Mild leukopenia and/or thrombocytopenia
• Low reticulocyte count
• Hypersegmented neutrophils on the peripheral blood smear (ie, >5
percent of neutrophils with ≥5 lobes or ≥1 percent of neutrophils with
≥6 lobes)
• Increased lactate dehydrogenase
• Increased bilirubin

13. Peripheral smear and Bone marrow
Peripheral blood smear showing a
hypersegmented neutrophil (seven
lobes) and macroovalocytes, a pattern
that can be seen with vitamin B12
(cobalamin) or folate deficiency
Erythroid precursors in the bone marrow
(Left panel) Normal erythropoiesis.
(Right panel) Megaloblastic
erythropoiesis
.

14. Serum folic acid levels
• Serum folate measurement is very sensitive to dietary intake; a
single folate-rich meal can normalise it in a patient with true folate
deficiency, whereas anorexia, alcohol and anticonvulsant therapy
can reduce it in the absence of megaloblastosis.
• For this reason, red cell folate levels are a more accurate indicator
of folate stores and tissue folate deficiency
• Above 4 ng/mL (above 9.1 nmol/L) – Normal.
• Suggests folate is not deficient, unless the individual has recently
consumed a folate-containing meal or supplement.
• In such cases, RBC folate can be obtained or prefer metabolite
testing .
• RBC folate more costly to obtain.
• From 2 to 4 ng/mL (from 4.5 to 9.1 nmol/L) – Borderline
Additional testing may be indicated depending on the clinical
circumstances and the degree of suspicion for folate deficiency.
• Below 2 ng/mL (below 4.5 nmol/L) – Low
• Consistent with folate deficiency.
• Values may be slightly higher in the first six months of life.

15. • MMA and homocysteine normal – No deficiency of
folate,vitamin B12.
• MMA and homocysteine elevated – Deficiency of
vitamin B12 (does not eliminate the possibility of folate
deficiency).
• MMA normal, homocysteine elevated – No deficiency
of vitamin B12. Consistent with deficiency of folate.
• RBC folate Surrogate for tissue folate levels.
• RBC folate provides information about folate status
over the lifetime of RBCs, similar to hemoglobin A1C for
blood glucose levels.
• An RBC folate level below 150 ng/mL (<150 mcg/L;
<340 nmol/L) is consistent with folate deficiency as long
as there is not concomitant vitamin B12 deficiency (RBC
folate is lower in individuals with vitamin B12
deficiency).
• False-normal results -Recent blood transfusion or if a
patient has a raised reticulocyte count

16. Treatment of folate deficiency
• Oral folic acid 1 to 5 mg daily
• Folinic Acid (5-Formyl-THF) stable form of fully reduced folate.
• It is given orally or parenterally to overcome the toxic effects of
methotrexate or other DHF reductase inhibitors, for example,
trimethoprim or cotrimoxazole.
• Duration
• Reversible cause of deficiency- one to four months or until there is
laboratory evidence of hematologic recovery.
• For those with a chronic cause of folate deficiency, such as chronic
hemolytic anemia - indefinitely.
• Intravenous folic acid indications
• Unable to take an oral medication (eg, due to vomiting or obtundation)
• Severe or symptomatic anemia
• Can partially reverse some of the hematologic abnormalities associated
with vitamin B12 deficiency .however, the neurologic manifestations of
vitamin B12 deficiency are not treated by folic acid.
• Thus, administration of folic acid to an individual with vitamin B12 deficiency
can potentially mask untreated vitamin B12 deficiency or even worsen the
neurologic complications.
• Because of this, testing for (and treatment of) vitamin B12 deficiency may
be appropriate in certain patients being treated with folic acid

17. • Adverse effects
• Oral folic acid is entirely nontoxic.
• Injections rarely cause sensitivity reactions.
• Prevention of folate deficiency
• Enrich cereals and grain products with folic acid to
reduce the risk of neural tube defects.
• Folic acid prophylaxis
• All women,from the moment they begin trying to
conceive until 12 weeks of gestation to prevent neural
tube defects
• Hemolytic anemias/hyperproliferative hematologic states
• Patients with rheumatoid arthritis or psoriasis on
methotrexate
• Patients on antiepileptic drugs
• Patients with ulcerative colitis