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transferrin saturation = (serum Fe/TIBC) x 100. (normal is 20-50%)

BLOOD NUTRITENTS
Iron, Folic Acid, Vitamin B12

WHY WE NEED THEM
iron essential to hemoglobin, oxygen binding, electron transport and energy metabolism
in cytochromes, antioxidant (catalase, peroxidase) and pro-oxidant (WBC's kill bact) functions
folate coenzymes work in synthesis and modification of DNA and RNA
B12 needed to maintain adequate active folate coenzyme in cell
either folate or B12 def results in immature RBC's and fewer circulating cells

IRON
most common deficiency in US and world
essential in many proteins and enzymes: hemo/myo globin, cytochromes (ATP production)
carried in blood bound to transferrin
in myoglobin, resp enzymes, hemoglobin, marrow
storage in reticuloendothelial system: liver, spleen, marrow
also in ferritin, hemosiderin
ferritin is most useful measure clinically
two oxidation states: ferrous +2 or ferric +3
useful in redox rxns as cofactor
in catalase and peroxidase (anti-oxidant enzymes)

IRON ABSORPTION
varies from 3-35% depending on many factors
heme iron is 10-15% of iron in mixed diets but 1/3 of total absorbed iron
non-heme iron in animal and plant foods, fortified foods and supplements
absorbed in +2 ferrous state in intestine, best for passage through membrane
+3 ferric state binds to transferrin, ferritin
vitamin C helps absorption of iron by keeping it in +2 state
seen on supplements: ferrous gluconate (gentle), ferrous sulfate, "reduced" iron
increased by: def, growth, preg,
food factors: heme, vit c, animal flesh proteins beneficial because they contain heme group which we absorb very well (3-4x better than non-heme iron)
decreased by: hypochlorhydria and other GI pathologies, oxalate (spinach), phytate (in bran), tannate (in black tea), other divalent cations (Ca++)
ABSORPTION BLOCKED BY
phytate in legums and whole grains
oxalate in spinach
polyphenols in fruit, veggies, tea, coffee, wine

IRON DEFICIENCY
--depleted stores: check ferritin or transferrin saturation
--early functional deficiency: check plasma iron
--anemia: visible on CBC, microcytic hypochromic anemia, RBCs are small and pale
Sx: fatigue, impaired athletic performance and work capacity
cardiopulmonary compensation: rapid heart rate and breathing
tissue degeneration: spoon nails (flattened or concave)
pallor esp in mucus membranes
oral tissues: angular cheilitis aka stomatitis
early deficiency may impair infant/child/adolescent intellectual development

RISK GROUPS FOR IRON DEF
rapid growth: age 6 mo to 4 years, adolescence
pregnancy: 50% higher requirement
chronic blood loss: menstruation, Gi bleeds, intense exercise
reduced absorption: vegetarians, GI dz

RDA
based on maintaining stores on non-vegetarian diet
males & postmenopausal women: 8mg
7-11mg chdilren
15mg adolescent females
18mg adult remales
27mg pregnant females

VEGETARIAN RDA
14mg males & postmenopausal females
26mg adolescent females
33mg adult females

SUPPLEMENTS
UL set based on preventing acute GI upset: 45 mg/day for ages 14 and older
65mg in a dose not good for a person who is not deficient
well absorbed but may cause GI upset
enteric coating helps with upset and reduces absorption
ferrous sulfate most common: absorbs well but causes the most GI side effects
better: ferrous fumarate, gluconate, citrate, aspartate, other chelates

DELICATE BALANCE
iron overload possible even in pregnancy: too much iron can increase some complications of pregnancy: preterm delivery, pre-eclampsia, fetal DM, growth restriction, etc
immune system needs iron but so do pathogens
normal body response to infx includes removing iron from cirulation
some infx are worsened by irons
malaria is not helped by iron supplementation
TB also likes iron

IRON OVERLOAD
Gerber does not seem well informed on this topic
he's kind of cranky about it
he says we aren't likely to have any pts with hemochromatosis
hemochromatosis only with genetic disorder, N Eur and African descent???
(I know the gene is 1/300 or so in Northern Europeans)
((student remark: Africans least likely to have hemochromatosis, bubonic plague survivors had iron sequestered. I know that the thalassemias are more common in the Med region))
hereditary anemia: thalassemias (he says body increases absorption to boost RBC prod)
heme iron most absorbable so high iron stores may relate to high meat diet
**high iron stores in elderly more common than deficiency**
heart disease relates to overload
CRC related? or dt meat consumption?

FOLATE AND VITAMIN B12
must have for nucleic acid synthesis, amino acid synthesis
used to move carbons around in many synthesis rxns
"one carbon metabolism" is transfer of methyl, methlene, formyl, formimino, methenyl, etc
catabolism of homocysteine (is toxic when builds up)

REMEMBER THE CIRCLE OF RXNS????
methionine synthase (homocysteine to methionine-->methylation rxns)(make TH4)
TH4 folate
folate
5,10-methylene TH4
methylene TH4 reductase
riboflavin (FAD)
turns NADPH+H+ to NADP+
5-methyl TH4
folate

FOLIC ACID = stable molecule used in food fortification and supplements
folate in food harder to absorb, more complex, requires better digestion
several forms used in cellular processes: TH4, 5-methyl TH4, etc
"folate and cancer: timing is everything", editorial on interaction

FOLATE DEFICIENCY
once called the most common vit deficiency
but no more because it's added to foods
now mostly dt malabsorption and some meds (epilepsy meds)
DEFICIENCY
causes macrocytic anemia
hypersegmented neutrophils
symptoms similar to iron of B12 deficiency (fatigue)

RDA
based on maintainin adequate tissue levels
(not on preventing birth defects or keeping homocysteine low)
more than RDA may be needed
200 mcg for youth
400 mcg for age 14 and up
requirement increases 50% during pregnancy
individuals with folate-related gene polymorphism may have higher requirement

DFE = dietary folate equivalents
needed to account for greater bioavailability of folic acid compared to food folate

SOURCES
naturally occuring in green leafies, citrus juices, legumses
fortification mandated in refined grain products since 1998
since then population homcysteine levels and nerual tube birth defects have declined

SUPPLEMENTATION
synthesized folic acid easy to absorb
amount restricted to under 1000 mcg/dose dt concerns about detecting B12 deficiency
800 usual max but prescription goes up to 5000
if high folic acid levels then masking effect:
B12 no longer necessary because you don't have to recycle folate
can use folate once and throw it away
no amount of B12 deficiency will result in anemia
but there is other pathology from B12 deficiency: n
nervous system
folic acid doesn't help with this

PRE-CONCEPTION PREVENTION OF SPINA BIFIDA BIRTH DEFECT
to prevent neural tube defects mother must have adequate levels before conception
RDA as supplement seems to be sufficient: 400 mcg/day, may be low end of requirement
up to 4000 mcg/day may help more, esp for moms with previous birth defect babies
may impact other defects and pregnancy complications

HOMOCYSTEINE
high levels-->heart dz and stroke, osteoporosis
give folate to prevent vascular events in pts with genetic homocystinuria
trying to prevent second event: studies don't show it helps
helps healthy person to stay healthy
MAY HELP PREVENT FIRST STROKES
B12 used in tx of homocysteinuria

CANCER
JAMA article on "timing is everything"
most promising for breast and colorectal CA prevention, at moderate intakes
esp in alcohol drinkers and those with specific genetic polymorphisms
folate-->methylation of DNA helps prevent mutation
don't take too much: it may support growth of existing precancerous lesions

RECOMMENDATIONS
LPI thinks we should take a daily supplement
Willet (Harvard School of Public Health): no more than 400mcg, avoid heavily fortified foods
Ctr for Sci in the Public Interest (nutritiona action) men and postmenopausal women should use low folic acid multis or take them every other day

UL = 1000mcg based on concerns about "masking" B12 deficiency
anemia easiest way to screen for B12 eficiency


VITAMIN B12
contains cobalt
only biological fx of this mineral
many forms of cobalamin in nature and in suplements
cyanocobalamin is most common supplement because it is very stable
injectable might be hydroxy or methyl cobalamin
synthesized by bact but not in human gut

STEPS IN B12 ABSORPTION
proteins digested in stomach and duodenum releases B12
intrinsic factor must be present and binds to B12
(if IF absent, absorption declines to as low a 1%, this can be overcome with megadoses)
B12-IF complex must be absorbed in distal ileum

FUNCTIONS OF B12
lowers homoysteine
production of SAMe, a major methyl donor in hundreds of rxns
cofactor for one other enzyme rxn
CNS effects, mechanism unclear

RISK FACTORS FOR B12 DEFICIENCY
elderly: 10-15% are deficient, on lots of drugs that affect digestion and absorption
elders have more pernicious anemia, more hypochlorhydria
no HCl needed to absorb supplement because B12 not bound to protein
also: malabsorption, acid suppressing drugs, vegan diet

B12 DEFICIENCY
looks like folate deficiency early: anemia, macrocytic-->megaloblastic
angular cheilitis aka stomatitis
elevated homocysteine
neurologic symptoms: mbdt myelin damage, can affect sensory, motor, cognition or mood
can occur without anemia

TESTING
serum B12 standard
more sensitive: methylmalonic acid or homocysteine in serum

SUPPLEMENET DOSAGES
assumes normal absorption
2.4 mcg/day for ages 14 and up
elderly are advised to get B12 from unbound sources
if homocysteine is high, use 500 mcg/day
for pernicious anemia use 1000 mcg/day or more

CANCER
methylation of DNA important to maintain genomic stability
7mcg/day B12 and 700 mcg/day folic reduced indications of chormosome damage in one study
no UL has been set, no toxicity
on study guide don't worry about cancer assoc with low b12

SOURCES
Gerber lecture
et al

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