HEMATOLOGY LECTURE MIDTERM - FOLIC ACID DEFICIENCY MLS 3G | J.Benedicto-M.

Draper

FOLIC ACID DEFICIENCY -This also means that the red blood cells appear bloated and large and
FOLIC ACID have a reduced capacity to carry oxygen

-Also known as Folate or Vitamin B9 ROLE OF FOLATE IN DNA SYNTHESIS

-A form of water-soluble B vitamin plays an important role in the
metabolism of amino acids and nucleotides, and in DNA synthesis
Folate occurs naturally in food
Folic acid synthetic or man-made form found in fortified food and
vitamin supplements

Folic acid is better absorbed by the body than folate

Once absorbed by your body, folic acid is converted into folate
While folate is a naturally occurring and essential vitamin, folic acid
is a synthetic B vitamin found in supplements and fortified foods.
Folate is easily and naturally absorbed and utilized by the body
when its metabolized in the small intestines. On the other hand, folic
acid requires the presence of a specific enzyme named dihydrofolate
reductase, which is relatively rare in the body.

SOURCE

- Green leafy vegetables

- Folate-fortified breads and cereals 5-methyl THF 5- methyltetrahydrofolate
- Legumes THF tetrahydrofolate
- Seeds dUMP Deoxyuridine monophosphate
dTMP Deoxythymidine monophosphate
FUNCTION: (along with Vitamin B12)
1. Within the cytoplasm of the cell, a methyl group is transferred from
Aids in the production of RBCs 5-methyl THF to homocysteine, which converts it to methionine
Aids in the synthesis of DNA and generates tetrahydrofolate (THF).
Works with B12 and vitamin C to help the body digest and utilize This reaction is catalysed by the enzyme methionine
proteins synthase and requires vitamin B12 in the form of
- Deficiency of the vitamin leads to impaired cell replication and other methylcobalamin as a cofactor. (Methylcobalamin is
metabolic alterations synthesized through reduction and methylation of vitamin
B12. This reaction represents the link between folate and
Megaloblastic anemia vitamin B12 coenzymes).
root cause is impaired DNA synthesis (leading to defective cell 2. THF is then converted to 5,10-methylenetetrahydrofolate (5,10-
maturation and cell division methylene THF).
-It is named for the very large cells of the bone marrow that develop The methyl group for this reaction comes from serine as it
due to a reduction in the number of cell divisions is converted to glycine.

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HEMATOLOGY LECTURE MIDTERM - FOLIC ACID DEFICIENCY MLS 3G | J.Benedicto-M.Draper

Impaired PCFT (Proton-Coupled Folate Transporter)

3. The methyl group of 5,10-methylene THF is then transferred to absorption -Food folates must be hydrolzed in the gut before absorption
deoxyuridine monophosphate (dUMP), which converts it to in the small intestine; however only 50% of what is ingested
deoxythymidine monophosphate (dTMP). is available for absorption.
This reaction is catalysed by thymidylate synthase and -Autosomal recessive deficiency that decreases intestinal
results in the conversion of 5,10-methyleneTHF to absorption of folate
dihydrofolate (DHF). Intestinal diseases
Deoxythymidine monophosphate is a precursor to Sprue
deoxthymidine triphosphate (dTTP), which like the Weakness
other nucleotide triphosphates, is a building block of the Weight loss
DNA molecule. Steatorrhea fat in the feces; evidence that the
4. THF is regenerated by the conversion of DHF to THF by the enzyme intestine is not absorbing food properly
dihydrofolate reductase. Tropical sprue cause is considered to be
Because some of the folate is catabolized during the cycle, overgrowth of enteric pathogens
the regeneration of THF also requires additional 5-methyl Celiac disease (Nontropical sprue)
THF from the plasma. Intolerance of gluten in some grains (gluten-
5. Once in the cell, folate is rapidly polyglutamated by the addition of induced enteropathy); can be controlled by
one to six glutamic acid residues. eliminating wheat, barley and rye products from the
This conjugation is required for retention of THF in the cell and diet
also promotes attachment of folate to enzyme Surgical resection of the small intestine
Inflammatory bowel disease
ETIOLOGY Impaired -Numerous drugs impair folate metabolism
use of Anti-epileptic drugs
Inadequate intake Poor diet folate Anticancer drugs (methotrexate)
Good sources of folate
Leafy, green vegetables Excessive -Physiologic loss of folate occurs through the kidney
Dried beans loss of o Patients undergoing renal dialysis lose folate in the
Liver folate dialysate
Beef However supplemental folic acid is routinely provided to
Fortified breakfast cereals prevent megaloblastic anemia
Fruits, especially oranges
Overcooking SYSTEMIC MANIFESTATIONS (both folate and vitamin B12 deficiency)
Increased need Pregnancy and lactation
-Mother must supply her own needs and the - When DNA synthesis and subsequent cell division are impaired by lack of
fetus folate or vitamin b12, megaloblastic anemia an d its systemic
Growth of children manifestations develop.
General symptoms related to the anemia include
o Fatigue
o Weakness
o Shortness of breath

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HEMATOLOGY LECTURE MIDTERM - FOLIC ACID DEFICIENCY MLS 3G | J.Benedicto-M.Draper

Symptoms related to the Alimentary Tract Empty space in replicated DNA sequence which results in single-strand
o Glossitis loss of epithelium on the tongue that results in a breaks
smooth surface and soreness Although the DNA can unwind and replication can begin, at
o Loss of epithelium along the gastrointestinal tract any point where a thymidine nucleotide is needed, there is
- Can result in gastritis, nausea or constipation an empty space in the replicated DNA sequence, which
Compared to vitamin b12 deficiency, folate deficiency was believed results in many single-strand breaks.
to be more benign or less harmful. Repeated DNA strand breaks lead to fragmentation
Cardiovascular disease Of the DNA strand
- Low levels of folate and the resulting high The resulting DNA is non-functional and the DNA
homocysteine levels were risk factors for replication is incomplete
Evidence of depression, peripheral neuropathy and psychosis Cell division is halted, resulting in cell lysis or apoptosis
Folate deficiency during pregnancy can result in impaired formation Cells that survive continue the abnormal maturation with a
of the fetal nervous system, resulting in fewer number of RBCs
o Neural Tube Defects such as spina bifida Remaining erythroid cells are larger
Than normally seen and their
Pregnancy requires an increase in folate to fulfill the requirements related to Nuclei are immature-appearing
rapid fetal growth, uterine expansion, placental maturation and expanded Compared with the cytoplasm
blood volume. The nuclei of megaloblastic erythroid precursors have an
open, finely stippled, reticular pattern
PATHOPHYSIOLOGY Cell cycle delay, prolonged resting phase and arrest in nuclear
maturation
Impaired thymidine nucleotide production The nuclear changes seen in the megaloblastic cells are
When either folate or vitamin b12 is missing, thymidine related to
nucleotide production for DNA synthesis is impaired.
Compared to vitamin B12, folate has the more direct effect LABORATORY TESTS
since it prevents the methylation of dUMP. While vitamin
b12 has an indirect effect preventing the production of THF SCREENING TESTS FOLATE DEFICIENCY
from 5-methyl THF. Complete blood count Decreased HGB, HCT, RBCs, WBCs, PLTs
Folate trap happens when vitamin b12 is deficient thus Increased MCV, MCH
more of the folate becomes metabolically trapped as 5- Manual differential count Hyper-segmented neutrophils, oval
methly THF and is unable to supply the folate cycle with macrocytes, anisocytosis, poikilocytosis, RBC
THF. inclusions
Incorporation of uridine into DNA Absolute reticulocyte count Decreased
So in this state of diminished thymidine availability, uridine Serum total and indirect Increased
is incorporated into DNA. bilirubin
The DNA repair process can remove the uridine, but Serum lactate dehydrogenase Increased
without available thymidine, the repair process is
unsuccessful.

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HEMATOLOGY LECTURE MIDTERM - FOLIC ACID DEFICIENCY MLS 3G | J.Benedicto-M.Draper

CASE STUDY

During a holiday visit, the children of a 76-year-old man noticed that he

Confirmatory Tests
Bone Marrow Exam
Serum Vit. B
12
Serum folate
RBC Folate
Serum Methylmalonic Acid
Serum Homocysteine
Holotranscobalamin Assay
Stool Analysis for parasites
seemed more forgetful than usual and that he had difficulty walking.
Concerned about the possibility of a mild stroke, the children insisted that he
see his physician. The physician diagnosed a peripheral neuropathy affecting
the fathers ability to walk. In addition, the physician noted that he was quite
pale and slightly jaundiced and ordered routine hematologic studies. The
results were as follows:
Folate Deficiency
Megaloblasts present
Normal
Low
Low
Normal
High
Normal
Negative

TREATMENT
Increasing dietary intake of folate
- By eating food like beans, oatmeal, mushrooms,
broccoli, asparagus, beef and liver
Folic acid supplement
Use of a food steamer or a microwave oven when cooking since
they can help keep more folate content in the cooked food, helping
to prevent folate deficiency

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