Folic Acid Deficiency.doc

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Folic Acid Deficiency

Author: Angela Gentili, MD; Chief Editor: Emmanuel C Besa, MD

Background

The prevalence of folic acid deficiency has decreased since

the nited !tates and Canada introduced a mandatory folic acid

food fortification program in "ovem#er $%%&' (eople )ith e*cessive

alcohol inta+e and malnutrition are still at high ris+ of folic acid

deficiency'

istologically, the megalo#lastosis caused #y

folic acid deficiency cannot #e differentiated from that o#served )ith

vitamin B-$. deficiency'

The significance of folic acid deficiency is compounded further #y

the follo)ing attri#utes:

• An association of folate deficiency )ith elevated homocysteine,

leading to increased arteriosclerosis ris+s/$0

• The reduced incidence of neural tu#e defects )ith folate

supplementation• The role of folate in the occurrence of cancer

ence, folic acid clearly is of conse1uence in pu#lic health in

the nited !tates, especially #ecause heart disease and cancer

constitute the num#er $ and num#er . causes of mortality in the

nited !tates' This article e*plores the mechanisms and

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manifestations #ehind folate deficiency, as )ell as its ramifications

)ith regard to health and disease at large'

Pathophysiology

2olic acid is composed of a pterin ring connected to p-

amino#en3oic acid 4(ABA5 and con6ugated )ith one or more

glutamate residues' 7t is distri#uted )idely in green leafy vegeta#les,

citrus fruits, and animal products' umans do not generate folate

endogenously #ecause they cannot synthesi3e (ABA, nor can they

con6ugate the first glutamate'

2olates are present in natural foods and tissues as

polyglutamates #ecause these forms serve to +eep the folates

)ithin cells' 7n plasma and urine, they are found as

monoglutamates #ecause this is the only form that can #e

transported across mem#ranes' En3ymes in the lumen of the small

intestine convert the polyglutamate form to the monoglutamate form

of the folate, )hich is a#sor#ed in the pro*imal 6e6unum via #oth

active and passive transport'

8ithin the plasma, folate is present, mostly in the 9-

methyltetrahydrofolate 49-methyl T2A5 form, and is loosely

associated )ith plasma al#umin in circulation' The 9-methyl T2A

enters the cell via a diverse range of folate transporters )ithdiffering affinities and mechanisms 4ie, adenosine triphosphate

/AT(0dependent cotransporter or anion e*changer5' <nce inside,

9-methyl T2A may #e demethylated to T2A, the active form

participating in folate-dependent en3ymatic reactions' Co#alamin 4B-

$.5 is re1uired in this conversion, and in its a#sence, folate is

=trapped= as 9-methyl T2A'



2rom then on, folate no longer is a#le to participate in its

meta#olic path)ays, and megalo#lastic anemia results' >arge doses

of supplemental folate can #ypass the folate trap, and megalo#lastic

anemia )ill not occur' o)ever, the neurologic?psychiatric

a#normalities associated )ith B-$. deficiency ensue progressively'

The #iologically active form of folic acid is tetrahydrofolic acid

4T2A5, )hich is derived #y the .-step reduction of folate involving

dihydrofolate reductase' T2A plays a +ey role in the transfer of $-

car#on units 4such as methyl, methylene, and formyl groups5 to the

essential su#strates involved in the synthesis of D"A, @"A, and

proteins' More specifically, T2A is involved )ith the en3ymatic

reactions necessary to synthesis of purine, thymidine, and amino

acid' Manifestations of folate deficiency thereafter, not surprisingly,

)ould involve impairment of cell division, accumulation of possi#ly

to*ic meta#olites such as homocysteine, and impairment of

methylation reactions involved in the regulation of gene e*pression,

thus increasing neoplastic ris+s'

A healthy individual has a#out 9-., mcg of folate in

#ody stores' umans need to a#sor# appro*imately 9-$ mcg of

folate per day in order to replenish the daily degradation and loss

through urine and #ile' <ther)ise, signs and symptoms of deficiencycan manifest after months'

Epidemiology

Frequency

United States

The current standard of practice is that serum folate levels

less than ng?m> and a red #lood cell 4@BC5 folate level less than



$ ng?m> puts an individual at high ris+ of folate deficiency' The

@BC folate level generally indicates folate stored in the #ody,

)hereas the serum folate level tends to reflect acute changes in

folate inta+e'

Data from the "ational ealth and "utrition E*amination

!urvey 4"A"E!5 $%%%-. indicate the prevalence of lo) serum

folate concentrations 4 '& nmol?>5 decreased from $F #efore

folic acid fortification to '9F after folic acid fortification'/.07n elderly

persons, the prevalence of high serum folate concentrations 49'

nmol?>5 increased from HF #efore fortification to &F after

fortification' The latest results from "A"E! are availa#le'/0

International

Countries that do not have a mandatory folic acid food

fortification program have higher rates of folic acid deficiency' 2or

e*ample, a population #ased study in 7ran 4)here there is no

fortification5 sho)ed an age-ad6usted prevalence of

hyperhomocysteinemia 4cy I$9 micromol?>5 of H'$F in men and

$'HF in )omen 4aged .9- y5'

Casey et al e*amined the effects over $ year of a free )ee+ly iron-

folic acid supplementation and de)orming program in 9.,

Jietnamese )omen of child#earing age'

/0

The investigators collecteddemographic data and #lood and stool samples at #aseline and at

and $. months follo)ing the implementation of the program'

2indings included a mean # increase of %' g?> 4( '$5

and a reduction in the presence of anemia from H'9F of the

)omen at #aseline to $%'F at $. months'/07ron deficiency )as

also reduced, from ..'&F at #aseline to %'F #y $. months, as



accumulates' !everal recent clinical studies have indicated that mild-

to-moderate hyperhomocystinemia is highly associated )ith

atherosclerotic vascular disease such as coronary artery disease

4CAD5 and stro+e' 7n this case, mild hyperhomocystinemia is

defined as total plasma concentration of $9-.9 mmol?> and

moderate hyperhomocystinemia is defined as .-9 mmol?>'

Genest et al found that a group of $H men )ith premature

coronary artery disease had a significantly higher average level of

homocysteine 4$'H K '5'/07n another study, Coull et al found that

among %% patients )ith stro+e or transient ischemic attac+s 4T7As5,

a#out one third had elevated homocysteine'/H0

Elevated homocysteine levels might act as an atherogenic

factor #y converting a sta#le pla1ue into an unsta#le, potentially

occlusive, lesion' 8ang et al found that in patients )ith acute

coronary syndromes, levels of homocysteine and monocyte

chemoattractant protein-$ 4MC(-$5 )ere significantly higher'/&0MC(-$

is a chemo+ine characteri3ed #y the a#ility to induce migration and

activation of monocytes and therefore may contri#ute to the

pathogenesis of CAD' omocysteine is #elieved to have atherogenic

and prothrom#otic properties via multiple mechanisms'

Bo+hari et al found that among patients )ith CAD, thehomocysteine level correlates independently )ith left ventricular

systolic function'/%0The mechanism is un+no)n, #ut it may #e due to

a direct to*ic effect of homocysteine on myocardial function

separate from its effect on coronary atherosclerosis'

Although in multiple o#servational studies elevated plasma

homocysteine levels have #een positively associated )ith increased



ris+ of atherosclerosis, randomi3ed trials have not #een a#le to

demonstrate the utility of homocysteine-lo)ering therapy' 7n the

eart <utcomes (revention Evaluation 4<(E5 . trial, supplements

com#ining folic acid and vitamins B and B$. did not reduce the

ris+ of ma6or cardiovascular events in patients )ith vascular

disease'/$0

!imilarly, in the trial of Bonaa et al treatment )ith B

vitamins did not lo)er the ris+ of recurrent cardiovascular disease

after acute myocardial infarction'/$$0

Pregnancy complications

(ossi#le pregnancy complications secondary to maternal folate

status may include spontaneous a#ortion, a#ruption placentae,

congenital malformations 4eg, neural tu#e defect5, and severe

language delay in the offspring' 7n a literature revie), @ay et al

e*amined & studies that demonstrated association #et)een

hyperhomocystinemia and placental a#ruption?infarction'/$.0

2olate

deficiency also )as a ris+ factor for placental a#ruption?infarction,

although less statistically significant'/$0

!everal o#servational and controlled trials have sho)n that

neural tu#e defects can #e reduced #y &F or more )hen folic

acid supplementation is started #efore conception' 7n countries li+e

the nited !tates and Canada, the policy of )idespread fortificationof flour )ith folic acid has proved effective in reducing the num#er

of neural tu#e defects'/$0

Although the e*act mechanism is not understood, a relative

folate shortage may e*acer#ate an underlying genetic predisposition

to neural tu#e defects'



may have chronic hemolytic anemia; or may have underlying

mala#sorption'

!ome patients complain of a sore tongue or pain upon

s)allo)ing' The tongue may appear s)ollen, #eefy, red, or shiny,

usually around the edges and tips initially' Angular stomatitis also

may #e o#served' These oral lesions typically occur at the time

)hen folate depletion is severe enough to cause megalo#lastic

anemia, although, occasionally, lesions may occur #efore the

anemia'

(atients may present )ith G7 symptoms, such as nausea,

vomiting, a#dominal pain, and diarrhea, especially after meals'

Anore*ia also is common and, in com#ination )ith the a#ove

symptoms, may lead to mar+ed )eight loss' o)ever, #e a)are

that an underlying mala#sorption disorder could #e causing these

symptoms, as )ell as folate depletion' The lac+ of folate itself may

not #e the culprit'

Physical

(atients )ith folate deficiency may have dar+ening of the s+in

and mucous mem#ranes, particularly at the dorsal surfaces of the

fingers, toes, and creases of palms and soles' Distri#ution typically

is patchy' 2ortunately, the hyperpigmentation gradually should

resolve after )ee+s or months of folate treatment' A modest

temperature elevation 4 $.N25 is common in patients )ho are

folate deficient, despite the a#sence of any infection' Although the

underlying mechanism is o#scure, the temperature typically falls



)ithin .-& hours of vitamin treatment and returns to normal )ithin

a fe) days'

%auses

2olate deficiency can result from several possi#le causes,

including inade1uate ingestion, impaired a#sorption, impaired

meta#olism leading to ina#ility to utili3e folate that is a#sor#ed,

increased re1uirement, increased e*cretion, and increased

destruction'

• 7nade1uate ingestion of folate-containing foods: (oor nutrition

is prevalent among people )ith alcoholism and patients )ith

psychiatric mor#idities, as )ell as elderly people 4due to

conditions such as ill-fitting dentures, physical disa#ilities, and

social isolation5' Because folates are destroyed #y prolonged

e*posure to heat, people of certain cultures that involve

traditionally coo+ing food in +ettles of #oiling )ater may #e

predisposed to folate deficiency' Moreover, for patients )ith

renal and liver failure, anore*ia and restriction of foods rich in

protein, potassium, and phosphate contri#ute to decreased

folate inta+e'

• 7mpaired a#sorption

o The limiting factor in folate a#sorption is its transport

across the intestinal )all' 2olate transport across the gut

)all mainly is carrier mediated, satura#le, su#strate

specific, p dependent 4optimal at lo) p5, sodium

dependent, and suscepti#le to meta#olic inhi#itors'

(assive, diffusional a#sorption also occurs, to a minor



degree' 8ith this in mind, a decreased a#sorptive area

due to small #o)el resection or mesenteric vascular

insufficiency )ould decrease folate a#sorption'

o Celiac disease and tropical sprue cause villous atrophy'

The process of aging causes shorter and #roader villi in

.9F of the elderly population' Achlorhydria leads to

elevation of gastric p a#ove the optimal level 4ie, p of

95 for folate a#sorption' Anticonvulsant drugs, such as

Dilantin, interfere )ith mucosal con6ugase, hence

impairing folate a#sorption' Oinc deficiency also

decreases folate a#sorption #ecause 3inc is re1uired to

activate mucosal con6ugase' Bacterial overgro)th in #lind

loops, stricture formation, or 6e6unal diverticula li+e)ise

)ould decrease folate a#sorption'

• 7mpaired meta#olism, leading to ina#ility to utili3e a#sor#ed

folate: Antimeta#olites that are structurally analogous to the

folate molecule can competitively antagoni3e folate utili3ation'

Methotre*ate and trimethoprim #oth are folate antagonists that

inhi#it dihydrofolate reductase' ypothyroidism has #een +no)n

to decrease hepatic levels of dihydrofolate reductase as )ell

as methylene T2A reductase' 2urthermore, congenital

deficiency involving the en3ymes of folate meta#olism also can

sho) impaired folate utili3ation' (eople )ith alcoholism can

have very active alcohol dehydrogenase that #inds up folate

and thus interferes )ith folate )ith folate utili3ation'



• 7ncreased re1uirement: 2actors that increase the meta#olic

rate can increase the folic re1uirement' 7nfancy 4a period of

rapid gro)th5, pregnancy 4rapid fetal gro)th5, lactation 4upta+e

of folate into #reast mil+5, malignancy 4increased cell turnover5,

concurrent infection 4immunoproliferative response5, and chronic

hemolytic anemia 4increased hematopoiesis5 all can result in

an increased folate re1uirement'

• 7ncreased e*cretion?loss: 7ncreased e*cretion of folate can

occur su#se1uent to vitamin B-$. deficiency' During the

course of vitamin B-$. deficiency, methylene T2A is +no)n

to accumulate in the serum, )hich is +no)n as the folate trap

phenomenon' 7n turn, large amounts of folate filter through the

glomerulus, and urine e*cretion occurs' Another mechanism of

e*cess e*cretion occurs in people )ith chronic alcoholism )ho

can have increased e*cretion of folate into the #ile' (atientsundergoing hemodialysis also have #een +no)n to have

e*cess folate loss during procedures'

• 7ncreased destruction: !upero*ide, an active meta#olite of

ethanol meta#olism, is +no)n to inactivate folate #y splitting

the folate molecule in half #et)een the C% and "$ position'

The relationship #et)een cigarette smo+ing and lo) folate

levels has #een noted as possi#ly due to folate inactivation in

e*posed tissue'

Differential Diagnoses

• (ernicious Anemia

http://emedicine.medscape.com/article/204930-overview

http://emedicine.medscape.com/article/204930-overview



&a!oratory Studies

• !erum folate 4reference range .'9-. ng?m>5 and serum

co#alamin 4reference range .-% pg?m>5

o As the initial test, ruling out co#alamin deficiency is very

important #ecause folate treatment )ill not improve

neurologic a#normalities due to co#alamin deficiency'

o By statistical definition, .-9F of healthy individuals )ill

have serum folate of less than .'9 ng?m>; hence, the

serum folate level cannot #e used alone to esta#lish the

diagnosis of folate deficiency' Therefore, the serum folate

test is useful only to rule out folate deficiency in patients

)ith serum folate greater than 9' ng?m>' <ther)ise,

additional follo)-up tests include serum homocysteine

4reference range 9-$ mmol?>5, )hich is elevated in B-$.

and folate deficiency, and serum methylmalonic acid4reference range H-.H mmol?>5, )hich is elevated in B-

$. deficiency only'

o @ed #lood cell folate levels 4reference range $

ng?m>5 tend to reflect chronic folate status rather than

acute changes in folate that are reflected in serum folate

levels, although many confounding factors, such as

transfused red cells, can ma+e this unrelia#le as a test

for folate deficiency states'

o <ther than folate or co#alamin deficiency, the only other

confounding causes for elevation of these compounds

include renal failure, intravascular volume depletion, and



some rare in#orn errors of meta#olism involving folate or

co#alamin-dependent en3ymes'

Procedures

Bone marro) #iopsy and aspirate may sho) a hypercellular

#one marro) )ith a megalo#lastic maturation of cells 4see 7mages

- or #elo)5' This cannot #e differentiated from changes o#served

)ith vitamin B-$. deficiency'

istologically, the megalo#lastosis caused #y

folic acid deficiency cannot #e differentiated from that o#served )ith

vitamin B-$. deficiency' (eripheral smear of

#lood in a patient )ith pernicious anemia' Macrocytes are o#served

and some of the red #lood cells sho) ovalocytosis' A -lo#ed

polymorphonuclear leucocyte is present' Bone

marro) aspirate from a patient )ith untreated pernicious anemia'






Megalo#lastic maturation of erythroid precursors is sho)n' T)o

megalo#lasts occupy the center of the slide )ith a megalo#lastic

normo#last a#ove'

Medical %are

2ruits and vegeta#les constitute the primary dietary source of

folic acid' The minimal daily re1uirement is a#out 9 mcg, #ut this

may #e increased several fold during periods of enhanced meta#olic

demand such as pregnancy'

%onsultations

Consult a dietitian'

Diet

Diet should include fruits and vegeta#les'

Medication Summary

The goals of pharmacotherapy are to eliminate the vitamin

deficiency, reduce mor#idity, and prevent complications'

'itamins

%lass Summary

These agents are essential for normal D"A synthesis and for

the formation of a num#er of coen3ymes in many meta#olic

systems'

Folic acid (Fol#ite)

Cofactor for en3ymes involved in production of red #lood cells'

@eplenishes depleted folate stores consumed during chronic

hemolysis'

Adult Dosing * Uses

Dosing Forms * Strengths

http://reference.medscape.com/drug/folvite-folic-acid-344419

http://reference.medscape.com/drug/folvite-folic-acid-344419



cream

• '9F

ointment

• '9F

ta#let

• 'mg

• '&mg

• $mg

in6ecta#le solution

• 9mg?m>

+ecommended Daily Allo,ance

Males: mcg?d (<;

2emales: mcg?d (<;

(regnant: mcg?d (<;

"ursing: 9 mcg?d (<;

pper >imit: $ g?d (<

Pre#ention of -eural .u!e Defects

2emales of child#earing potential: mcg?d (<

2emales )? high ris+ or family h* of neural tu#e defects: mg?d

(<

Deficiency

'-$ mg 7J?7M?(< 1D

Methanol .o$icity

9-H9 mg 7J 1hr * . hr

/ther Indications * Uses

Megalo#lastic anemias due to folic acid deficiency 4i'e' sprue5,

anemias of nutritional origin



"ot effective alone in treatment of pernicious, aplastic, or

normocytic anemias

(regnancy

Elevated serum homocysteine

Pediatric Dosing * Uses

Dosing Forms * Strengths

cream

• '9F

ointment

• '9F

ta#let

• 'mg

• '&mg

• $mg

in6ecta#le solution

• 9mg?m>

+ecommended Daily Allo,ance

- mth: 9 mcg?d (<

H-$. mth: & mcg?d (<

$- years: $9 mcg?d (<

-& years: . mcg?d (<

%-$ years: mcg?d (<

$-$& years: mcg?d (<

pper >imit

• $. mth: "?A

• $- years: mcg?d (<

• -& years: mcg?d (<



Deficiency

7nfants: $9 mcg?+g?d or 9 mcg?d 7J?(<?7M?!C

$-$ years: $ mg?d 7J?(<?7M?!C initially, then '$-' mg?d

Methanol .o$icity

$ mg?+g 7J 1hr * . hr

/ther Indications * Uses

Megalo#lastic anemias due to folic acid deficiency 4i'e' sprue5,

anemias of nutritional origin

"ot effective alone in treatment of pernicious, aplastic, or

normocytic anemias

(revention of spina #ifida P other congenital neural tu#e

disorders in )omen of child #earing potential

(regnancy

Elevated serum homocysteine

%ontraindications

ypersensitivity

%autions

ndiagnosed anemias

(rotect vials from heat P light

Ad#erse Effects

Frequency -ot Defined

7rrita#ility

Difficulty sleeping

Confusion

Mas+s pernicious anemia

Bronchospasm

@ash

http://opencalc%28%27/calculator/dosing/weight-dosing','Methanol%20Toxicity','Pediatric','1%20mg/kg%20IV%20q4hr%20x%2024%20hr');

http://opencalc%28%27/calculator/dosing/weight-dosing','Deficiency','Pediatric','Infants:%2015%20mcg/kg/d%20or%2050%20mcg/d%20IV/PO/IM/SC');

http://opencalc%28%27/calculator/dosing/weight-dosing','Methanol%20Toxicity','Pediatric','1%20mg/kg%20IV%20q4hr%20x%2024%20hr');



Can cause deficiency of phenytoin

-utrition

!ources: #lac+ eye peas, pinto #eans, navy #eans, spinach, +idney,

liver, vegeta#les, meats, cereals, fruits, some dar+ green vegeta#les

Function

Enchances elimination of formic acid in methanol to*icity via

provision of coen3yme to folate dehydrogenase

(articipates in D"A synthesis and erythropoiesis

/ther Information

Deficiency: macrocytic anemia; inflammation of tongue; diarrhea

To*icity: mas+ vitamin B$. deficiency; may incr ris+ of sei3ures in

some people

Further /utpatient %are

Treat the underlying disease or condition causing folic acid

deficiency'

DeterrencePre#ention

• (atients )hose folic acid deficiency is related to dietary

factors should #e counseled to include green vegeta#les and

fruit in their diet'

• (rophylactic treatment of pregnant patients and patients )ith

chronic hemolytic anemias can prevent folic acid deficiency

due to the increased re1uirement for folate in these

conditions'

%omplications

• Megalo#lastic anemia

• >eu+openia

• Throm#ocytopenia



• Angular stomatitis

• Glossitis

• "ausea and vomiting

• Diarrhea

• yperpigmentation

• >o)-grade fever

• Elevated serum homocysteine

Patient Education

• Educate patients regarding proper nutrition, including eating

fruits and vegeta#les'

• Educate patients regarding the need to reduce alcohol

ingestion'

• Discuss the need to ta+e folic acid supplementation'

Medicallegal pitfalls

• 2ailure to provide folic acid supplementation to pregnant

females may lead to spontaneous a#ortion and fetal

a#normalities, including neural tu#e defects and increased ris+

of severe language delay in the child'

• (roviding only folic acid supplementation to a patient )ho has

co#alamin deficiency may lead to development of irreversi#le

neuropathies'• "o randomi3ed clinical trial has proven the efficacy of lo)ering

the homocysteine concentration to improve cognition or to

lo)er the incidence of cardiovascular disease 4CJD5' ntil ne)

evidence is availa#le, clinicians should not promise patients

that folate supplementation )ill improve cognition or decrease

cardiovascular ris+'

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