Administrative Office
St. Joseph's Hospital Site, L301-10
50 Charlton Avenue East
HAMILTON, Ontario, CANADA L8N 4A6
PHONE: (905) 521-6141
FAX: (905) 521-6142
http://www.fhs.mcmaster.ca/hrlmp/
Issue No. 89
QUARTERLY NEWSLETTER
August 2006
Folate: A Test No Longer Routinely Warranted
Background
Folate, a water-soluble B vitamin, is found naturally in raw leafy vegetables, citrus fruits, dried beans and peas.
Natural folate is 50% bioavailable compared to 85% in fortified foods and almost 100% when taken as a
supplement.
In blood 95% of folate is within erythrocytes. Folate is taken up only by the developing erythrocyte. Folate
concentration in erythrocytes therefore reflects overall tissue folate concentration better than serum folate.
Serum folate reflects transitory changes in folate concentration and low levels do not differentiate between
reduced intake and chronic deficiency signifying depleted folate stores and functional changes. Since
erythrocyte folate represents the average folate availability over the past 2-3 months it gives a better indication
of tissue stores than serum folate.
Fortification of foods with folate
Fortification of foods with folate was fully implemented in Canada
beginning January 1998. The purpose of fortification was to reduce the
risk of neural tube defects (NTD). The incidence of NTDs was reduced
by 47% from 1995 to 1999 in Ontario (16.2 to 8.5 per 10,000
pregnancies).1
Folate fortification in Canada
150 μg/100 g
200 μg/100 g
white flour in foods
uncooked pasta
μg/10
g cornflour
Widespread consumption of foods fortified with folate has increased the level 150-200
of folate
in the
population. In
addition folate is consumed through nutritional supplements and from other fortified foods and drinks.
(voluntary)
Causes of low folate levels
 Low consumption of foods containing folate
 Undernutrition in the elderly and in persons with alcoholism
 Malabsorption due to inhibition of folic absorption (e.g., alcoholism,
medications) and gastrointestinal diseases
 Decreased metabolism (e.g., elderly, medications)
 Increased loss (renal failure, dialysis)
 Increased demand including pregnancy and cancer
Megaloblastic anemia
Folate and vitamin B12 deficiency are both associated with a reduction in
hemoglobin and production of megaloblastic cells. Although folate
supplementation can reverse vitamin B12 deficiency megaloblastic
anaemia, it does not treat and may even worsen the neurological
disease associated with vitamin B12 deficiency
Medications that may lower folate
Antacids and anti-ulcer medications
Folic acid antagonist drugs
Anticonvulsants
Phenytoin
Primidone,
Phenobarbital
Anticancer drugs
Aminopterin
Methotrexate
Antibiotics/antibacterials
Sulfasalazine
Pyrimethamine
Trimethoprim
Trimetrexate
Sodium channel-blocking
potassium sparing diuretics
Oral contraceptives
Nonsteroidal anti-inflammatory drugs
Oral hypoglycemic agents
Metformin
Reference interval
There is no accepted standard for folate deficiency or inadequacy based
on folate concentrations. In addition, there is currently no standard for
folate measurement and values can vary significantly from one
laboratory to another because of method differences.2 For this reason it
is important to interpret folate results from different laboratories and published studies with caution.
The Institute of Medicine (IOM) publication on Dietary Reference Intakes (DRI) 1998 reviewed the literature and
based on several studies suggested a value of < 317 nmol/L (140 ug/L) to be a reasonable indicator of
deficiency.3 The Hamilton Regional Laboratory Medicine Program (HRLMP) uses a method, which gives higher
values than methods used in the studies described in the IOM document (Quantaphase II, Bio-Rad
Laboratories). Based on published comparisons, the IOM value was converted to the corresponding value for
the method used by the HRLMP (E170, Roche Diagnostics).4 The converted HRLMP value for RBC folate
deficiency is < 520 nmol/L.
2 -
Population studies
Results from our laboratory and other studies suggest that American and Canadian populations have reached
unprecedented levels of folate and that folate deficiency has been essentially eliminated. The prevalence of
folate deficiency has decreased by 61% in the National Health and Nutrition Examination Surveys (NHANES,
1988-1996 to 2001-2002) and 84% in the Framingham Study (1995 to 1998) after folate fortification was
initiated. A survey conducted in Ontario between 1997 and 2000 showed a decrease in RBC folate deficiency of
77%.5
The 95% confidence interval for RBC
folate performed by the HRLMP is 813
to 3453 nmol/L. The percentage of tests
with a low level (< 520 nmol/L) is 0.3%.
Frequency distribution of RBC folate tests performed within the
HRLMP ( 2004 to 2006, n = 19,885)
9
Age distribution of RBC
folate tests ordered:
7
< 18 y
19 – 40 y
41 – 65 y
> 65 y
6
5
Deficiency
< 520 nmol/L
4
3
6%
18%
33%
44%
2
1
5700
5500
5300
4100
4900
4700
4500
4300
4100
3900
3700
3500
3300
3100
2900
2700
2500
2300
2100
1900
1700
1500
1300
900
1100
700
500
300
0
100
Based on these statistics, and
because 60% of the folate tests also
have a vitamin B12 test ordered at the
same time, routine ordering of folate
(serum or RBC) is no longer
warranted. The low incidence of
folate deficiency indicates that
vitamin B12 should be the
preferential test for investigating
megaloblastic anemia.
Frequency (%)
8
RBC folate (nmol/L)
Nonetheless, higher folate levels may be required for risk reduction of neural tube defects but the optimum level
is unknown.
Further research is required to decide what the implications of folate may be for cardiovascular disease, cancer,
cognitive function and if there are adverse effects to high levels of folate. 6
References
1.
2.
Dietary Reference Intakes
Gucciardi E, Pietrusiak M-A, Reynolds DL, Rouleau J.
Incidence of neural tube defects in Ontario, 1986-1999. CMAJ
2002; 167: 237-40.
Gunter EW, Bowman BA, Cuadill SP, Twite DB, Adams MJ,
Sampson EJ. Results of an international round robin for serum
and whole-blood folate. Clin Chem 1996; 42: 1689-94.
Food and Nutrition Board, Institute of Medicine, Dietary
Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6,
folate, vitamin B12, pantothenic acid, biotin, and choline.
National Academy Press, Washington, DC (1998)
Owen WE, Roberts WL. Comparison of five automated serum
and whole blood folate assays. Am J Clin Pathol 2003; 120:
121-6.
Ray JG, Vermeulen MJ, Boss SC, Cole DEC. Declining rate of
folate insufficiency among adults following increased folic acid
food fortification in Canada. Can J Public Health 2002; 93: 24953.
Ulrich CM, Potter JD. Folate supplementation: too much of a
good thing? Cancer Epidemiol Biomarkers Prev 2006; 15: 18993.
Reference Values for Folate
Adapted from Health Canada’s Food and Nutrition
website.
Males and Females
3.
μg/day (DFE)
Age
EAR
RDA/AI
UL
0 – 6 mo *
ND
65
ND
7 – 12 mo *
ND
80
ND
4.
1–3y
120
150
300
4–8y
160
200
400
9 – 13 y
250
300
600
5.
14 – 18 y
330
400
800
19+ y
320
400
1000
Pregnancy
520
600
1000†
Lactation
450
500
1000†
6.
*AI
Adequate Intake
DFE
Dietary Folate Equivalents
1 DFE = 1 μg food folate = 0.6 μg folic
acid supplements and fortified foods
Websites:
EAR
Estimated Average Requirement
Dietary Supplement Fact Sheet: Folate
RDA
Recommended Dietary Allowances
http://dietary-supplements.info.nih.gov/factsheets/folate.asp
UL
Tolerable Upper Intake Level
Investigation & Management of Vitamin B12 and Folate Deficiency http://www.healthservices.gov.bc.ca/msp/protoguides
†
800 μg/day for < 18 y
Cynthia Balion MSc, PhD, FCACB, Clinical Chemist
Karina Rodriguez-Capote MD, PhD, Postdoctoral Fellow, Clinical Biochemistry
Richard Cleve, MSc, MD, Resident, Medical Biochemistry
Discipline of Chemistry
Hamilton Regional Laboratory Medicine Program