Vitamin K

forms Synthetic form: menadione

Naturally occurring: phylloquinone
Bacterial form: menaquinone-7
source Major dietary source: phylloquinone
- High amount: leafy plants
- Lesser amount: cereals
- Oils: canola, olive
Heat and light sensitive
DRI Infants AI based on human milk concentration. Assue newborns
receive Vk prophylaxis at birth
Adult AI set at median Vk intake from NHANES III
Microbiome generated menaquiones insufficiently
Controversy: determine setpoint for coagulation or to maximize
protein carboxylation for bone health
Absorption(phylloquinone Does not require digestion:
and menaquinone from - Micelle form with active transport in SI
diet) Enhanced by:
- Dietary fat, pancreatic lipase, bile salts
Absorption of Synthesized by facultative&oligate anaerobic bacteria(E.coli,
menaquinones eubacterium) in lower GI tract
- Absorption varies among individuals by passive diffusion
- Large depot in colon, less bioavailable
- Antibiotics impact Vk production
storage Body pool size: 50-100 mg(quite low)
Minimal storage in liver(metabolize in liver)
Storage primarily in cell membrane
Rapid turnover time: every 2.5hours(colon microbiome is
essential is turnover is fast)
Function: anticoagulation 1. Blood coagulation: activation of factor X,II,XIII to convert
(X)→fibrinogen→(II)→ fibrin(insoluble) →(XIII)→fibrin(soluble)
2.post-translational carboxylation activate factor X, II, XIII
- Produce GLA that bind Ca ion to affect blood clot and
bone mineralization
Anticoagulants(Warfarin, Coumarin) antagonize Vk
- Keep consistent Vk intake
Function: bone health bone protein: osteocalcin, matrix Gla protein to form bone matrix
Interaction with other Antagonist: Va and E inhibit Vk absorption
nutrients - Ve inhibit Vk metabolism at high dose
Inter-relationships: Vk,D,A involved with bone
- 1,25(OH)2D produced osteocalcin, and act on bone,
kidney
- Vk activates osteocalcin
- Va stimulate osteocalcin synthesis
Excretion Phylloquinone almost completely metabolized before excretion,
excreted as glucuronides(via bile) in urine or feces, and
menaquinones
Menadiones as forms of phosphate, sulfate, glucuronide
Assessment plasma /serum phylloquinone: recent dietary intake
Prothrombin time:
- normal 11-13 seconds
- >25 seconds is major bleeding
- Insensitive marker, only works when very deficient
Under-carboxylation of Vk dependent proteins:
- Example prothrombin, osteocalcin
- Very sensitive
- Different protein will have various degree of
undercarboxylated with low Vk
 Vulnerable groups 1.Newborns:
- low placental transfer and milk concentration
- Low bacteria in colon, hard to generate
- Require routine supplementation of all newborns
2. Individuals on prolonged use of antibiotics
3. Fat Malabsorption

Iodine
RDA Adult: 150μg(thyroid iodine accumulation+turnover)
Pregnancy: 220μg
Lactation: 290μg(EAR+ iodine secreted in milk)

Sources Varied based on soil,fertilizer type. Marine food contains

higher iodine

Digestion, absorption,
transport
Function, mechanisms
Physiological effect of thyroid
hormone
Interaction with other nutrients Impaired selenium status affect thyroid hormone metabolism
Iron, Va deficiency may magnify effects
Goitrogen interfere with iodine metabolism
Dairy product contains iodine via animal feed
Iodized salt(1920)
Digestion free organic bound iodine
Absorbed rapidly, completely from stomach(>90%)
Travel as free iodide in blood
Concentrate in thyroid gland by Na/I transporter
Synthesis of thyroid hormones(T3,T4)
Thyroid function primarily regulated by TSH
Transport by
- Bound: thyroxine-binding globulin, albumin,
transthyretin
- <0.1% is unbound
Role of thyroid hormones in gene expression
- T4 convert to T3 by selenium-converting enzyme
- T3 enter nucleus, bind to protein receptor
- Complex bind to DNA regulatory region to increase
transcription
Adipose tissue: enhance lipolysis
Muscle: enhance contraction
Bone: promotes anabolism
Cardiovascular system: increase heart rate
GI tract: stimulate nutrient digestion, absorption
Metabolism: increase metabolic rate, cellular consumption
- Heme iron impact thyroid hormone synthesis and
avoid T3 bind to nuclear receptor
- Va deficiency reduce I uptake at thyroid gland
- Found in staple foods like Cassava(not an issue in
 Canada)
Excretion Urine(kidney unable to conserve), feces(low), sweat(issue in
tropical where intake is inadequate)
Deficiency Reduce thyroid hormone product
- Low metabolic rate
Severe: goiter, cretinism, stunted physical or mental
development
- iodized salt, no longer seen in Canada
Mild: concern in pregnancy to impact neurodevelopment
- Folate supplement and prenatal supplement contains
iodine
Toxicity UL=1100μg based on thyroid dysfunction(elevated serum TSH)

Assessment Urinary iodine excretion: recent intake

Canada iodine status
according to urine iodine level
Question: if iodine is a
problem???
- People not using table
salt
Thyroid size
Serum TSH concentration
Total: high mild iodine deficiency
3-5/6-11yr: high excessive iodine intake
12-19 yr: high more than adequate intake and excessive
intake
20-39/40-59/60-79 yr: high mild iodine deficiency
Fluoride
Sources Fluoridated water, beverages
- added in municipal water
- Well water reflect natural fluoride level
Grain, marine fish
Decaffeinated tea
Toothpaste and rinse
Highly available(80-90% absorbed)
Digestion, absorption, Protein-bound F hydrolyzed
transport, storage, Form insoluble complex with Ca and Mg
excretion Absorbed by passive diffusion(stomach)
Transported as ionic F or hydrofluoric acid, or bound to plasma
protein
Most found in bones teeth
Most excretion in urine
Function, deficiency Stimulate osteoblast proliferation, mineral deposition in bone
Increase resistance to acid demineralization, increase tooth
mineralization
- Able to reverse tooth decay
- Topical F decrease oral bacteria’s acid production
- Fluorohydroxyapatite resistant to cavities
- Deficiency lead to dental cavities
Intake Adequate intake: >7 yrs based on amount to maximally reduce dental
cavities
- Men: 4 mg/day
- Women: 3 mg/day
Acute toxicity due to supplement or too much toothpaste
Chronic toxicity(fluorosis): mottling teeth
Monitor exposure with urine and plasma, but not body’s status
Toxicity Dental fluorosis: critical for 1-4 years
(controversy???) - 16% of Canadian children undergo this
Severe toxicity: skeletal fluorosis
- Exposure from coal burning, industrial exposure,
underground water contains excess fluoride
- 10 millions affected worldwide, China and India with crippling
symptoms
- Crippling result from calcification of ligament, muscle wasting,
neurological defects
controversy Calgary stops water fluoridation(federal government Health Canada
give advice, but municipal government decide to perform)
- It is the responsibility of municipalities or provincial/territorial
authorities to decide to fluoridate

Canada government pregnancy/lactation: fluoride through breastfeeding is not harmful to

recommendation fetus
Formula-fed infants: read label about fluoride status, and decide to
 mix with fluoride drink water
Proper use of Young children may not develop ability to spit, tend to swallow
fluoridated toothpaste 0-36 months: if at risk of tooth decay, brush with minimal amount(5
mm)
3-6 yrs: 5 mm maximum amount
6 yrs: child able to spit, start tooth brushing using fluoridated
toothpaste

Zinc
RDA

Sources (food) In food usually in a complex with nucleic acids and amino acids part of
protein
Red meats, seafood, poultry, pork, diary(provide 40-70% Zinc in
Americans)
Whole grains(bran,germ), legumes
Animal sources Zn better absorbed than plant source
Availability negatively affected by processing(heat, maillard reaction
products)
20-50% Zn absorbed from NA diet
Sources Recycled from pancreatic & biliary secretion
 Zinc supplement(oral tablet/lozenges/topical use depend on skin
integrity/denture cream/throat,nasal spray(may associate with smell
loss)
Digestion, Digestion: hydrolyzed from amino/nucleic acids in stomach(acidic
absorption environment) and SI(proteases and nucleases)
Absorption: primarily in proximal SI by carrier mediated process(ZIP 4-
regulated based on intake) or passive diffusion(high intake)
1. Bound Zn is released from food by HCl, protease, nuclease
2. Most Zn absorbed by ZIP4
3. DMT, amino acid plays minor role in Zn absorption
4. Some Zn not absorbed if bound to inhibitors
5. At high Zn intake, there is paracellular absorption
6. In cells, Zn may be used functionally or stored in vesicles in
trans-golgi network and metallothionein storage
7. Zn may be transported across the basolateral membrane by
ZNT1
8. Zn binds to several proteins for transport in blood

Uptake and Intestinal cell zinc use: used functionally and stored in enterocyte,
transport transport through cytosol and cross basolateral membrane into plasma
for transport
Transport: via blood(bound loosely to albumin mostly, transferrin, IgG,
histidine, cysteine)
Tissue uptake Uptake and release by tissue: 14 ZIP and 10 ZnT facilitate uptake and
release
- ZnT6 in enterocyte brush border mediate exocytosis of Zn into
lumen for excretion
- ZIP4 mutation(SLC39A4) lead to acrodermatitis enteropathica.
- Treatment: high Zn with paracellular transport
Distribution and storage: found in all organs
 - In bones as apatite
- Stored as zinc-containing-metalloproteins and liver
metallothionein
Functions, Involved >300 enzymes in major metabolic pathways
mechanisms Serve as a component of metalloenzymes
- Provide structure integrity to enzyme
- Participate in reaction at catalytic sites
Final question: what Carbonic Anhydrase: acid/base balance and respiration
are the 10 functions Alkaline Phosphatase
of Zn Alcohol Dehydrogenase: convert alcohols to aldehydes
Carboxypeptidase: protein digestion
Aminopeptidase: protein digestion
Delta-aminolevulinic acid dehydratase: heme synthesis
Superoxide Dismutase(SOD): antioxidant
Phospholipase C: hydrolysis of glycerophosphate bond in phospholipids
Polyglutamate Hydrolase
Matrix Metalloproteinases for Wound Repair
Polymerase, Kinase, nuclease, transferase, phosphorylase,
transcriptase: nucleic acid synthesis, cell replication, growth
Other roles Growth: transcription regulation(Zinc finger, bind to aa sequence
involved in transcription regulation)
Cell replication, bone formation, skin integrity, cell-mediated immunity,
carbohydrate metabolism
Interaction with Vitamin A: Zn convert retinol to retinal
other nutrients - Zn necessary for hepatic synthesis of retinol-binding protein
Copper: Zn stimulate synthesis of metallothionein which has high
affinity for Cu than Zn
Calcium: Ca absorption diminished with ingestion of Zn supplements
when low Ca intake
Zn metabolism disrupted in high concentration cadmium via binding to
 sites Zn would normally bind
Excretion GI tract(80%) via ZIP5 and ZnT6, kidney, skin
RDA Low body reserve for Zn, so an adequate supply of dietary Zn is
required
Deficiency: in breastfed infants lead to delayed introduction of
complementary food
- Lead to acrodermatitis enteropathica
- Low protein/high phytate diet(in developing countries)
- Needs increased by trauma, sickle cell anemia, alcoholism,
AIDS, malabsorption
Toxicity UL=40mg(based on interaction with copper)
Use cautions with supplements
Intranasal sprays of zinc associated with permanent loss of smell
Inappropriate overuse of denture cream that contains Zn

Assessment Notoriously difficult to measure(look for environmental contamination)

Recommended: dietary, serum/plasma, stunting
Potential: urinary or hair zinc, neurobehavioural functions

Prevalence of 1-13 yrs: low inadequacy no matter w/wo supplements

inadequacy(CCHS) >14 yrs: low inadequacy for VM intake.
- By diet alone(XXXXXXXXXX)
>14 yrs: people take Zn supplement, easy to go above UL level
Human milk Zn concentration declines(0→ 12 months), want to have children
lean on food contains iron and zinc
Review: Zinc for To assess whether Zn is efficacious in reducing incidence, severity,
Common Cold duration of common cold symptoms
- Issue: only high dose(>75 mg/day) is effective, may lead to UL
- Conclusion: intake of Zn within 24 hours of onset of cold was
associated with a 1 day reduction in the duration of symptoms
- Zinc shows effectiveness lower incidence of common cold
Other finding:
- Severity of cold was not affected by zinc
- Not only zinc supplement, school use of antibiotics help lower
- Huge heterogeneity in the studies(cautious with data use)
- Adverse effects include bad taste and nausea

Zinc and Common Too much Zn impair immune system, lower HDL, impair copper
Cold absorption
Zn lozenges contain 11-14 mg of Zn, so consum 4 of these each day
can exceed UL
Vitamin D and bone health
osteoporosis Osteoporosis is a skeletal disorder characterized by compromised
bone strength predisposing a person to an increased risk of
fracture(affect bone density and quality)
- Risk factors: genetics(Peak Bone Mass)
- Early menopause, loss of estrogen, excessive caffeine
Bone health DXA measure Bone Mineral Density
assessment - Changes in BMD measured after many months or years, and
compare BMD with young healthy reference population
- T-scores are calculated based on BMD

Biochemical Markers Markers used as surrogate measures of changes in BMD, it can alter in
of Bone Turnover weeks
Markers of bone formation:
- serum/plasma
- production of bone matrix protein by osteoblast: bone-specific
alkaline phosphatase, procollagen type 1 N-terminal peptide,
procollagen type-1 C-terminal peptide
Markers of bone resorption:
- Urine
- Breakdown of bone matrix proteins by osteoclast:
deoxypyridinoline, Pyridinoline, N-telopeptide
 Changes in biochemical markers of bone turnover provides a crude
prediction of changes in BMD
Assessment of Bone Ultimate gold of osteoporosis treatments is to reduce risk of fragility
Quality fracture
- Quantitative computed tomography(QCT)
- In humans, we can only truly assess fracture risk by history of
fragility fracture(>2 years of study)
- Changes in BMD are used as surrogate measures of an
individual’s risk of fragility fracture

Vitamin D
DRI DRI based on bone outcomes only, assume sun exposure is minimal
Amount of Vd required to facilitate bone health was 50 nmol/L
AI=400IU/d, RDA=600IU/d, UL=1500IU/d

Food sources Milk, fortified soy, rice and almond beverage(mandatory for cow’s milk;
voluntary for others)
Fortified margarine(mandatory), Infant formula(mandatory)
Voluntary: orange juice
- 1ug Vd= 40 IU/ 1 IU=0.025 ug
- Most supplements provide Vd3
- Vd is fairly stable
Absorption (requires Diffuse BBM via diffusion as micelles
no digestion) Diet Vd: chylomicrons in lymph
Cutaneous Vd: plasma bound to Vd binding protein
Transport, 40% Vd in blood transported by chylomicrons
metabolism, storage Cholecalciferol diffuses from skin into blood, picked up by Vd binding
protein for transport
- Both metabolized to 25-OH D3 in liver
- 25-OH D3 secreted into blood, transported by Vd binding protein
- Kidney convert to 1,25-(OH)2 D3(calcitriol)
- Calcitriol transported in blood via Vd binding protein
Regulation 1,25-(OH)2 D3 influence enzyme activity by binding to VDRE(vitamin D
response element) on promoter of 1-hydroxylase gene
(???)Low level + 1-hydroxylase synthesis
(???)High level + production of other mixed function oxidases

Mechanism of Genomic: calcitriol binds to VDR → changes in gene transcription → changes in

Calcitriol Action protein synthesis
Involves single transduction pathways linked to cell membrane for
intracellular signalling(responsible for rapid Vd effect)
Non-genomic: active in intestine, parathyroid, liver, pancreatic-b-cells
- Actions include increased Ca and Phosphorus uptake

Interaction with other Ca, P, Vk

nutrients
Excretion Bile
<30% in urine
Vitamin D metabolites(calcitroic acid, oxidized, hydroxylated) -- major
excrete as non-biologically metabolite
Prevalence of Children: supplement lower the inadequacy prevalence
Inadequacy Adult: >10% inadequacy even with supplement
Canadian distribution after standardization have lower plasma 25(OH)D
level(XXXXXXX)

Factors affecting Vd Dependent upon: skin pigment, latitude, altitude

 status Risk factors for deficiency: age, dark skin pigment, obesity, malabsorption,
breast-fed infants
- Vd in breastmilk is very low even in healthy women(recommend
give Vd to breastfed babies)
Alterations with age Sunlight exposure, synthesis in skin(decreased 7-dehydrocholesterol)
Dietary intake, intestine, liver(hydroxylation),
kidney(hydroxylation,reabsorption)

Deficiency Deficiency is widespread worldwide

- Ricket in children: bones don’t mineralize lead to growth retardation
- Osteomalacia-adult: prolonged elevation in TSH and bone
demineralization
Supplement breast-fed babies, adults over 50(Health Canada)
Supplement others with impaired Vd absorption
toxicity UL=100 ug(4000IU)
Controversy: conversion from sun exposure can be high as 10,000ug/day
Most likely of all vitamins to cause toxicity

Vitamin C

synthesis
Sources Citrus fruit(orange). Strawberries, cantaloupe, Vegetables in cabbage fam
Vc is unstable, is destroyed by oxygen, light and heat(lost during cooking)
- In food found as Ascorbic acid(major), dehydroascorbic acid(minor

Interconversion of
Ascorbic Acid and
Dehydroascorbic Acid

RDA 0-6 months: RDA set from human milk content

7-12 months: RDA set from HM content + solids
>9 yrs: UL near maximal neutrophil concentration( provide antioxidant
protection and minimal urine loss)
- Special RDA for smoker(+ 35 mg/d)
- 2 recent RCTs suggest 200mg may be the optimal amount of Vc fo
most adults
Absorption With normal intake, absorption efficiency is 70-90%
Absorption decreases with increased intakes
- 16% absorbed at high intake vs. 98% absorbed at low intake
Absorption of Ascorbate(not dehydroascorbic acid):
Occurs throughout the small intestine
Uptake by at least 2 Na-dependent Vc transporter(SVCT1>SVCT2)
Absorption of Dehydroascorbate
Dehydroascorbate is absorbed by GLUT1, GLUT3, facilitated diffusion
Dehydroascorbate is better absorbed than ascorbate
Once absorbed into enterocytes, it rapidly reduced back into ascorbate via
glutathione

Transport Ascorbic acid exported from enterocyte via anion channels

Enter systemic circulation via capillaries
 Ascorbic acid primarily circulate with free form
Plasma concentration: 0.4-1.7 mg/dl
Tissue concentration typically exceed plasma concentration
Cellular uptake SVCT1/2 involved in uptake of ascorbic acid
GLUT uptake dehydroascorbate
Function 1.Maintenance of metalloenzyme redox state:
(i) collagen synthesis: ascorbate regenerate Fe3+ to Fe2+, to enable ly
hydroxylase and proline hydroxylase to catalyze hydroxylation of lysine an
proline residue in collagen.
- Critical for formation/maintenance of skin, bone, tendon, cartilage,
dentine, scar tissue, wound healing
(ii) Phenylalanine hydroxylase which is Fe-dependent, catalyze first step
phenylalanine breakdown(phenylalanine is precursor of tyrosine synthesis
removal is important to prevent phenylketonuria & brain damage), and
generate tetrahydrobiopterin as a co-substrate for the reaction
(iii) Dopamine monooxygenase generate norepinephrine from dopamine
with help of 8 Cu atoms
- Ascorbate reduce Cu2+ to Cu1+
(iv) tryptophan hydroxylase which is Fe dependent, catalyze rate-limiting
step in serotonin synthesis
- Ascorbate regenerate tetrahydrobiopterin as a cosubstrate of the rx
(v) glycine alpha-amidating monooxygenase requires Cu atom, ascorba
maintain it in reduced state
- Convert peptide with C-terminal glycine to X-terminal amidated
peptide(which is already active hormone, neurotransmitter)
- Important for synthesis of calcitonin, oxytocin, vasopressin
2.microsomal Xenobiotic metabolism
Liver microsomes metabolize Xenobiotics to make compound more water
soluble for excretion, this process involves hydroxylation catalyzed by iron
dependent monooxygenase/cytochrome P450 mixed-function oxidase.
- These require reducing agents like Vc to maintain reduced state
Fe-atom
3. Antioxidant Activity as it reserves oxidation with Vc’s 2 hydroxyl group
and carbonyl group to facilitate its ability to act as a hydrogen/electron don
- It react with variety of reactive oxygen species and nitrogen specie
donate an electron in the form of a hydrogen ion
- Act in aqueous environment in blood and cells
- Can generate other antioxidants such as Vitamin E and glutathione
 Excretion Vc primarily excreted by the kidneys
Kidney SVCT1 reabsorb Vc with a threshold, and additional Vc is excreted
- Level at 1.3-1.8mg/dl
- At intake ~500 mg, all vitamin C is usually excreted

Interaction with other Vc enhance non-heme absorption by reducing iron to Fe2+ as it is more
nutrients soluble than Fe3+
- Vc benefit is maximized at 75 mg/d
Assessment Plasma Vc
Vc content in white blood cell(better reflection of tissue store)
Deficiency Scurvy: when body Vc falls below 300mg, plasma concentration drops to
<0.2mg/dl(normal: 0.6-0.8mg/dl)
- Result in death of 2 million sailors between 1500-1800
- Take 8-9 months to manifest in replete Vc patients, but only 1 mon
people with marginal Vc status
- Symptoms resolve with only 10 mg/d
Symptoms: bleeding gum, loose/decaying teeth, impaired wound/fracture
healing
Shakur et al.Journal of 1-13 yrs: low prevalence of inadequacy even w/o supplement
Nutrition 2012 >14 yrs: higher inadequacy for ones not taking supplement
UL: higher prevalence in supplement taking group(not for diet group)

Vc status of Canadian: Fewer than 3% of Canadian had Vc deficiency

CHMS 2012-2013 Highest prevalence among those who rarely or never ate citrus fruit(13%)
who were smoker(10%)

Vitamin A
Definition, structure Retinoids are beta-ionone ring + a polyunsaturated sidechain
Vitamin A = preformed Va=retinoids
- Alcohol = retinol
- Aldehyde = retinal
- Carboxylic group = retinoic acid
- Ester = retinyl ester
Sidechain contains with 4 double bonds of cis/trans configuration
Carotenoid =provitamin A(precursor)
10% of 600 carotenoids have Va activity(have B-ionone ring)
Exist with expanded carbon chain form

Sources Va: animal organ, fortified food,main form as retinyl ester

Carotenoid: brightly colored yellow, orange, vegetables
- Most abundant source: B-carotene
- Other sources include lycopene, lutein
RDA Men:900 ug RAE
women : 700 ug RAE(based on liver stores)
Pregnancy: 770 ug RAE
Lactation: 1300 ug RAE
UL: 3000 ug RAE
- RAE: retinal activity equivalent
- 1 RAE = 1ug retinol = 12 ug B-carotene = 24 ug a-caroten
cryptoxanthin
Conversion Factor 1 IU Va = 0.3 ug retinol(animal product) = 3.6ug B-carotene = 7.2
other proVa carotenoids
Digestion, absorption Requires digestion before absorption
Heating will weaken some, but still require enzymatic digestion
70-90% Va absorbed from meal assume contains fat
Carotenoid absorption <5% for uncooked vegetables, 60% for pu
carotene is 20~50%
1. B-carotene is converted to 2 retinal molecules(occurs via
central cleavage via B-carotene 9’10’ dioxygenase or 15,1
monooxygenase)
2. CRBPii bind to both retinol,retinal intracellularly
3. CRBPii bound retinal is reduced to retinol by retinaldehyde
reductase
4. LRAT esterifies CRBPii-bound retinol with a fatty acid to fo
CRBPii-retinyl palmitate
5. Retinyl esters incorporated with phospholipid, apoproteins
chylomicrons
6. Chylomicrons leave intestinal cell and enter the lymph sys
and ultimately the blood
7. Retinoic acid can directly enter blood, where it attaches to
albumin for transport to the liver

Transport 1.Chylomicrons deliver retinyl esters, some unesterified retinol an

carotenoids to extrahepatic tissues(70-75%) then to liver
2.carotenoid transported as part of lipoproteins, taken up by cells
of lipoproteins and scavenger receptor class B type 1
3.carotenoids stored in liver&adipose
4.Retinol that is esterified may be stored in liver(stellate cells &
parenchymal cells)
5.transported in blood via 2 proteins(RBP, TTR) and uptake as a
complex

Metabolism In hepatic parenchymal cell:

1.retinoic acid binds to CRABP to alter gene expression
 2.Conjugated with glucuronic acid and excrete in bile
3.Convert to 4-OH retinoic acid then to 4-oxoretinoic acid
Function Vision: rhodopsin
Gene expression: homodimers, heterodimers
Cellular differentiation: keratinocytes to mature epidermal cells
Growth and Reproduction: mechanisms are unclear
Bone metabolism: osteoblasts/clasts

Vision 1.Light hit the retina on the back of the eye, rhodopsin in rods is
transformed and signals are sent to the brain
2.Rhodopsin’ transformation involves its cleavage into opsin and
conversion of cis-retinal to trans-retinal
3.Trans-retinal is converted back to cis-retinal
4.Cis-retinal reattaches to opsin to reform rhodopsin
Gene Expression Two forms of Va regulate gene expression: all-trans retinoic acid
retinoic acid
1.they move into nucleus bound to binding protein
2.all-trans retinoic acid bind to RAR, 9-cis retinoic acid bind to RX
enhance transcription of selected genes
Function of Carotenoid Antioxidant: able to react, quench free radical reaction
-contains >9 conjugated double bond which makes them soluble
-quenching: electronically excited molecules are inactivated
Cell proliferation, growth, differentiation
-carotenoids inhibit cell proliferation, inhibit neoplastic transforma
-carotenoids promote eye health(age-related macular degeneratio
cataracts)
Interaction with Other Nutrients
Metabolism, Excretion
Excess Va interfere with Vk absorption
High B-carotene intake decrease plasma Ve
Protein & Zn influence Va status/transport
Iron metabolism interrelated with both carotenoid & Va
- Required for conversion of B-carotene to Va
- Va deficiency associated with iron-deficiency anemia
Excreted in urine(60%) and feces, depend on intake
Small amount via lungs
Carotenoid metabolized into various compound, excreted into bile
Polar Va metabolites return to liver via enterohepatic circulation a
recycled partially conserving Va stores

Assessment Plasma retinol concentration(only observe when low liver store)

Eye examination
Conjunctival impression cytology
Gold standard: measurement of liver stores via isotope dilution

Deficiency Associated with increased mortality, eventually blindness

Night blindness, Bitot’s spots
Xerophthalmia, keratinization
Measles depress Va status(increase urinary Va excretion), supple
recommended by WHO
Toxicity UL= 3000ug RAE( 10000 IU)
Hypervitaminosis A: teratogenic, damage liver, bone fracture, hai
B-carotene causes hypercarotenemia but does not damage liver(
discoloration of skin)
Supplements not advised, consume in diet

CCHS 1-13 yr: lower inadequacy with supplement

>14 yr: higher prevalence of inadequacy
1-13 yr: more percent above UL than non-supplement group(espe
 1-3yr)
>14 yr: no UL for non-supplement group. <5% above UL for supp
group
Prevalence of Low Blood ~1% low serum Va
Levels of Va and C in American ~2% at risk of excess Va
Children 6-11 yrs ~2% of low Ve prevalence

Whole Food vs. Supplement:
Comparing the Clinical
Evidence for Tomato Intake
and Lycopene Supplement
Intake on Cardiovascular Risk
Factors
-Tomato is rich in lycopene, Va, Vc, etc
-lycopene is a potent lipid soluble antioxidant(2* effective as B-ca
which protects cell membrane
-both tomato, lycopene trials show reduction in LDL oxidation
-stronger data support tomato in reducing lipid, protein, DNA oxid
damage, and improve lipid metabolism
-both tomato intake and lycopene supplement have inconsistent e
on inflammation, endothelial function
-both tomato intake and lycopene supplement improve blood pres

Osteoporosis and Aging: Calcium, Phosphorus

RDA

Source Rich source: milk, fortified soy milk, cheese

Poor source: meats, grains, nuts(low in vegetables)
Supplement Calcium carbonate: inexpensive, but needs to be consume with food(sto
acid dependent)
Calcium citrate: not dependent on stomach acid
- Good for older individuals(limited gastric juice)
Look for amount of elemental calcium in each dose
Be sure supplement has one of the following: DIN, NPN, GP, USP
Calcium sources like bone meal, oyster shell may high in lead, aluminum

Absorption Ca enters via TRPV6, bind to calbindin D, exit via Ca-ATPase pump
At high concentration, there is paracellular diffusion

Factors Influencing Amount(more absorbed at low dose)

Absorption Age - efficiency of absorption declines with age
Vd status
Food lactose, cellulose, increase transit time, non/slow fermentable fiber
increase Ca absorption
Oxalate- chelates Ca
Fiber, phytate bind Ca (inhibit absorption)
Competition with other divalent cations(Mg2+, Zn2+)
Formation of insoluble “fatty soap”(Ca+fatty acid)
Individuals on proton pump inhibitors due to insufficient production of HC
Transport 40%: bound to albumin/prealbumin
 10%: complex with sulfate, phosphate, citrate
50%: free in blood, deposit in bone(reservoir)
Regulation Extracellular [Ca]: PTH, Calcitriol, Calcitonin
Intracellular: Ca2+/3Na+ exchanger or Ca2+/2H+-ATPase

Function of Calcium Bone mineralization/Blood coagulation/Nerve conduction/Muscle

contraction/Enzyme regulation/Membrane permeability
- 4 Ca + Calmodulin = Calmodulin-Ca complex(interact with enzym
- Enzymes like: Adenylate Cyclase, Ca-dependent protein kinase,
Ca/Mg-ATPase, Kinase, Glycogen synthase, Myosin kinase, NAD
kinase

Excretion Average 60 mg but up to 182 mg

feces:80%, urine: 20%(high protein intake, caffeine, sodium will increase
Fecal excretion: fiber, phytate, oxalate, fatty acid
Skin

Assessment Serum calcium(control by hormone)

Serum ionized calcium
Protein bound calcium
DXA:Dual-energy X-ray absorption
Deficiency Rickets, increase risk for osteoporosis, Codeficiency of Va, hypocalcemi
may lead to tetany, hypertension, pre-eclampsia

Prevalence of 1-13yr: good until turn into teenager

inadequacy >14 yr: after menopause needs taking Va and Ca supplement
 - Female has high level of inadequacy
Toxicity UL=2500 mg/day, >50yr: 2000 mg/day
Some will experience GI upset below UL(?????)
Milk alkali syndrome
Hypercalciuria increase risk for kidney stones

Phosphorus

RDA

Sources Widely distributed in food: meat, poultry, cola type soft drink
- In both forms: organic(phospholipid) , inorganic( PO4^2-),
or phytic acid(less bioavailable)

Absorption 1.absorbed by diffusion(proximal duodenum)

2.low intake: absorbed by active Na+/PO4-
cotransporter(enhanced by calcitriol)
Factors impact absorption Enhancing: Vitamin D
Inhibitors: phytate, excessive intake of Mg, Ca, Al
Transport Exit BLM via facilitated diffusion
Plasma P: 70% phospholipid, 26.5% inorganic phosphate, 3%
protein, 1.5% Ca,Mg
Uptake into cell via passive(gradient-derived)
Found in all cells in the body
Function Bone P: 85% total body P
- Amorphous calcium phosphate form Ca3(PO4)2, Ca3(PO4)2 •
3H2O
- More crystalline form: hydroxyapatite Ca10(PO4)6(OH)2
- Calcitonin: promote use of P in bone mineralization
- PTH/Calcitriol: promote bone resorption of P from bone
- PTH stimulate P excretion in urine
- Calcitriol stimulate P absorption
Other function Intermediary metabolism:
- High energy phosphate bond(ATP, UDP)
- Phosphorylation of substrate(second messenger, cAMP)
- Phosphoprotein: enzyme inactivation/activation
Backbone of RNA, DNA:
- Alternates with pentose sugar
Acid-Base Buffer:
- Phosphate is the main intracellular buffer
Na2HPO4- + H+ → NaH2PO4 + Na+
Oxygen delivery:
- 2,3 diphosphoglycerate, regulate release of O2 from Hb

Interaction with other Mg, Al, Ca: decrease P absorption by forming complex
nutrients Mg3(PO4)2
3g aluminum hydroxide with meal: decrease P absorption from
70% to 35%
Phytate P is only about 50% available: lack phytase
1,25(OH)2 D: increase P absorption when P intake low(not PTH
mediated)
- Increase resorption of P from bone
Excretion 67-90% in urine, inorganic P
- High dietary P leads to high serum P which lead to
increase urinary excretion
 - If P intake and serum concentration is low, most filtered P
reabsorbed across kidney
10-33% feces
P balance largely regulated at kidney: high P intake=high P
excretion
DRI RDA: 19 to >71 yrs, 700 mg/d(men & women)
- No gender difference, no change in requirement form 19
and up, deficiency is rare
UL: 19-71 yrs, 4g/d >71yrs, 3g/d
- Toxicity is rare, characterized by hypocalcemia & tetany
High intakes above RDA but below UL has been associated with
all-cause mortality, CVD, CKD, mediated through PTH and
fibroblast growth factor(FGF23), a hormone that stimulate urinary
phosphorus excretion
Assessment Serum P or urinary P excretion
In adults, deficiency confined to those consuming large amounts
of antacids containing Ca, Mg, Al
Refeeding syndrome
Premature infants(requirement high, hard to deliver)

Magnesium

DRI

essentially based on balance studies

sources Found in a wide variety of food(salmon)
Mg is found in leafy greens due to chlorophyll(spinach)
Nuts, seeds and bananas, germ, bran of whole grains
Processed food are generally poor source
In area with hard water supply provide significant source of Mg

Absorption Does not require digestion before absorption

Absorption at small/large intestine(primarily in jejunum/ileum, 30-
60% dietary Mg absorbed)
Colon may play a role in absorption
Absorption have 2 system:
- Saturable, carrier-mediated active transport(TRPM6) at
low Mg intake
- Simple diffusion(paracellular) depend on concentration at
high intake
Efflux across BLM Na+/Mg2+ antiporter system depend on
Na+/K+ ATPase to sustain sodium gradient
Enhancing absorption Vitamin D, protein, carbohydrate, fructose, oligosaccharides

Inhibit absorption Phytic acid, fiber, excessive unabsorbed fatty acid

Nutrient interaction Calcium, Phosphorus, Potassium
Transport 50-55% free Mg2+
33% bound to protein(albumin, globulin)
13% complexed with negatively charged ions
Maintenance of constant serum/intracellular level(unknown
mechanism)
PTH increase Mg intestinal absorption, enhances bone
resorption and decrease renal excretion
Whole body distribution Cation cellular abundance 2nd to potassium
50-60% located in bone, 39-49% soft tissue, 1% extracellular
tissue
Several plasma membrane Mg transporter like TRPM7, MagT1
MMgT1/2 control Mg metabolism within Golgi complex, post-
Golgi vesicle
Function Adult body contain 25g of Mg
50-60% of total Mg found in bone
- 30% surface of bone, the exchangeable pool for maintain
serum concentration
- 70% crystal lattice(Ca,P), deposited during formation as
Mg(OH2)/Mg(OH)3
Most non-bone Mg resides in soft tissue
- Mg associated with other 300 enzymatic reactions as
structural cofactor, or allosteric activator of enzyme
activity
- Up to 90% of intracellular Mg associated with ATP, ADP
- Aids in transfer to ATP phosphate group
Glycolysis, TCA cycle, pentose phosphate pathway, B-oxidation,
Nucleic acid synthesis, protein synthesis
Interaction with other Hydroxylation of Vd requires Mg
nutrients Calcium via mechanism:
- Reabsorption at the kidney
- Mg may mimic Ca from Ca-binding sites, decrease flux of
Ca across cell membrane, compete for non-specific
binding sites on troponin C and myosin to alter muscle
contraction
Phosphorus absorption inhibited by Mg(form insoluble complex)
extra/intracellular potassium balance influence by Mg
Excretion Mainly urine: only 3-5% of Mg in filtered urine is excreted
- Plasma Concentration monitored by renal sensors which
 can inhibit reabsorption. Activation of sensor reduce
response to PTH
Feces, sweat
Nutritional assessment Serum concentration(tissue concentration may be depleted
despite normal serum concentration)
RBC concentration(long term status)
Renal excretion before&after administration of Mg load
Prevalence of inadequacy 1-13 yr:okay, but high in 9-13 yrs with bad diet?????)
low Mg level due to most people don’t eat enough unprocessed
food
>14 yrs: high prevalence of inadequacy
Deficiency Inadequate intake is common
Low plasma Mg common is hospitalized patients
Malabsorptive disorder, excessive alcohol/diuretic use,
parathyroid disease, burns increase risk
Hypomagnesemia occur with deficiency:
- Low blood calcitriol, potassium, calcium
Some highly suggestive data that low intakes associated with
CVD, DM, HTN
- Clinical use: prescribe Mg(PO4) to lower pregnancy high
BP
Toxicity Diarrhea is the primary endpoint(osmotic effect of unabsorbed
salt)
Possible with impaired renal function
UL= 350 mg/day(non-food source)
Excessive intake of Mg salt may lead to diarrhea and dehydration

Hypertension & Macrominerals: Sodium, Potassium, Chloride

Sodium
Property Constitute ~93% cations in the body
Total amount in body=105g(70 kg human)
- 30%: surface of bone crystal
- 60-70%: extracellular fluid
- 10%: intracellular in nerves and muscle tissue
DRI 9-50 yrs: UL=2300 mg AI=1500 mg
>50 yrs: ideally keep sodium intake below AI
- 51-70: 1300mg
- >71 yrs: 1200mg
90.2% of men, 65.7% of women have intake > UL in Canada

Sources 75%: consumed added during processing/manufacturing of

food(flavouring/preservatives)
12%: from table salt(All types of salt are high in sodium,they are not
healthier choices)
<1%: from tape water(higher in softened water/mineral water)
Prehistoric diet wasn’t high in salt
1 tsp salt has 2.3g of Na
Daily Value 1-4 yrs: 1500 mg(?????)
New daily value???: 1-4 yrs & >4 yrs: 2300 mg
Absorption 95-100% absorbed
0-5% excreted in feces
3 pathway involved:
- BBM:Na+/glucose cotransporter(SI)
- Electroneutral Na+/Cl- exchange(SI, proximal colon)
- Electrogenic Na+ channel(colon)
Common driving force inwards is gradient created by BLM Na/K
antiporter(20-40% energy), maintains low intracellular Na+
Sodium transported freely in the blood
 Function Maintain osmotic pressure for fluid balance among compartment
Nerve transmission, muscle contraction
- Na-K-ATPase
- Stimulus changes membrane permeability to Na, lead Na rush
into cell and depolarize to generate electric current
Regulation of BP(ANG-converting-pathway)

Excretion Kidney(regulated by aldosterone), sweat

Interaction with other Dietary Na intake increase urinary Ca excretion
nutrients
Assessment 24 Hour Urinary Sodium Excretion Level( best assess day to day
variability)

Potassium

Property Major intracellular cation

Source from unprocessed food: banana, etc
Sometime add to food(salt substitute)
>85% absorption
- BBM:passive diffusion/ K+/H- ATPase
- BLM: diffusion via K+ channel
Metabolism After K-rich diet there is rise in circulation due to insulin
promotes hepatic/muscle uptake
90% excreted via kidney
Function Maintenance cell resting potential
Nerve conduction, muscle contraction, water balance
With Mg, required for pyruvate kinase during glycolysis
 DRI >14 yrs: AI=4700 mg
Based on dietary intake that should lower BP, reduce adverse
effects of NaCl on BP
Pregnancy: age-specific value
Lactation: age-specific value + amount secreted in milk
Not-established UL
Assessment Plasma potassium concentration
Rare deficiency/toxicity. Below AI intake lead to elevated BP in
salt sensitive individuals(hypokalemia/hyperkalemia)

Interaction with other Dietary K+ intake decreases urinary Ca excretion

nutrients

Chloride

Property Most abundant anion in ECF

Primary source in diet is NaCl
Almost absorbed in SI
Absorption follows Na+/glucose cotransporter with passive diffusion
Cystic fibrosis lead to dysfunction of Cl transport

Function Fluid balance, formation of gastric HCl, released from WBC during
phagocytosis
Transport bicarbonate
Excreted via GI tract, skin, kidney
Intestine secretory BLM: Na/K/Cl cotransporter into mucosal cell
mechanism Cl exits cell into lumen via Cl’ channel
- Na/K recycled on BLM membrane
DRI 9-50 yrs: AI=2300 mg
 pregnancy/lactation: age-specified value
UL= 3600 mg
Assessment Serum concentration(depend on body water status)
Deficiency is rare
status(XXXXX) Sodium: males with higher intake
- High population with intake above UL
Potassium:
- High population with AI
Effect of low sodium intake Evidence that reduced Na intake reduce BP with no adverse effects
on health: systematic review on blood lipids, catecholamine level, or renal function
and meta-analyses Na intake associated with increase risk for stroke, stroke mortality,
coronary heart disease mortality
Resting systolic BP favours lower sodium intake
Sodium intake <1.2 mg/day with most reduction on systolic BP
Salt-reduction scenarios with significant reduction is myocardial
infarction, congestive heart failure, cerebrovascular accident
Both systolic/diastolic BP favours treatments with potassium
supplement

DASH diet Similar to Canada’s Food

Tips for reducing sodium: limit condiment, avoid processed meats,
Rinse canned food

Folate
Structure Pteridine + PABA + Glutamic Acid
Forms:
- THF
- N5methyl THF
- N5formyl THF
- N10formyl THF
- N5N10methylene THF
Source Don’t use folacin
Folate is a generic descriptor
Folic acid is the synthetic form of the vitamer(stable, inexpensive)
5-methyl-tetrahydrofolate is a new synthetic form on the market

Folic Acid Fortification Added to white flour at 140-150 ug/100g and select grain products
- to increase folic acid intake by about 100 ug/day
- Makes white bread, enriched pasta as excellent source

Bioavailability supplement/fortification is greater than natural form:

- More stable, not trapped in cellular matrices
1 DFE=1 ug food folate= 0.6 ug folic acid from supplement= 0.5
ug synthetic folate
Absorption Primarily from proximal ⅓ of SI
- Facilitated by GCPII/folate conjugase at BB
- Proton coupled folate transporter(PCFT)
- Reduced folate carrier(RFC)
Folate produced by microorganisms in large intestine also
available with low rate but long transit time, thus large impact
Folate can be absorbed across colon
Metabolism Folate circulate in aqueous fraction of blood as CH3-folate
Fortified-food countries people with unmetabolized folic
Folate circulate as monoglutamyl form
⅓ is free, ⅔ bound to albumin/a-2-macroglobulin
Pregnancy: high affinity
Cellular transport:
- Various transporter both influx/efflux
- In cell, folate is polyglutamylated to trap. Polyglutamation
is necessary for vitamin to act as coenzyme

Function Purine synthesis, pyrimidine synthesis, amino acid metabolism,

remethylation of homocysteine to produce methionine, additional
methylation reaction via SAM
Metabolism

Genetic variation Many SNP identified to affect different enzyme in folate

metabolism
- Best known enzyme 5,10-methylenetetrahydrofolate
- There is a MTHFRC667T polymorphism alters alanine to
valine, lower enzyme activity
- High folate intake stabilizes this enzyme
Excretion Urinary excretion: folate is freely filtered in the glomerulus, mostly
reabsorbed in proximal renal tubule
- Products are para-acetamidobenzoate and para-
acetamidobenzoylglutamate
Enterohepatic circulation: involves release of hepatic 5-CH3-THF
into bile with absorption in SI
 Assessment Dietary: weigh food record, FFQ
Biochemical: plasma folate concentration, RBC folate
concentration, plasma homocysteine, megaloblastic anemia

3 ways of measuring dietary folate intake

Tool What is measured Pros Cons

Weighed Food Dietary folate intake Good standards for 1.quality of nutrients
Records measure intake database(QND)
2.not realistic for large
studies
Food Frequency Dietary folate intake 1.Easy to use 1.tend to overestimate
Questionnaire 2.validated on a 2.QND
number of population

24-hour call Dietary folate intake 1.easy to use 1.single call is not
2.fine to estimate indicative of a typical diet
intake of a group 2.QND

Biochemical Assessment of Folate Status

Tool What is measured Pros Cons

Serum folate Recent intake/balance Easy to measure 1.static measure-higher no

always better
2.not reflective of tissue
stores
 RBC folate Tissue folate stores at 1.measure tissue 1.static measure-higher no
the time RBC formed folate store always better
2.better indicators of 2.more difficult to measure
long-time status

serum/plasma Activity of key enzyme 1.functional measure 1.not specific

homocysteine involved in one- 2.easy to measure 2.expensive
carbon metabolism

Folate (II)
anemia Genesis of RBC:
early stage-Folate deficiency: proerythroblast→basophilic erythroblast→
polychromatophilic erythroblast→ orthochromatic erythrocyte
Later stage-iron deficiency: → reticulocyte→ erythrocytes
- Folate deficiency megaloblastic anemia: observe DNA with
nucleus, fold incorrectly, big cells
- Iron deficiency microcytic hypochromic anemia: small, pale
cell

RDA 0-6 months: 65 ug/d

7-12 month: 80 ug/d
1-18 yrs: 150-400 ug/d
Adult: 400ug/d(maintain normal RBC folate)
Pregnant: 600 ug/d(age requirement + fetal disposition)
Lactating women: 500 ug/d(human milk secretion + maternal folate
status
UL= 1000 ug synthetic folic acid
Preoccupation with Folic acid group with high RBC folate than placebo
folate<1990
 Outcomes post-folic Reduce risk of: neural tube defect, other congenital anomalies,
acid fortification vascular disease, low infant weight, cervical dysplasia

Current strategies 1.consumption of folic acid supplement(400ug) if capable of

increase women intake pregnant(prenatal supplement)
2.fortification of white wheat flour
3.nutrition education
Neural tube defect Improper development and closure of neural tube during 3rd-4th
week of gestation
2 common types
- spina bifida: meningomyelocele(paralyzed),
meningocele(fixable)
- anencephaly

Folate status of Canadians

In 1970-1972 Nutrition Canada Survey, high prevalence of moderate risk(national & provincial)
of serum folate values
There is more folic acid in fortified food than indicated on label(1.5*)
Very low prevalence of Inadequacy among children: little benefit from supplement
Prevalence of inadequacy low among females: little impact of supplement
Cumulative Percentile Distribution of RBC folate concentration by age among female: majority
females are protected with high cut-off level
Many people above UL, thus fortification is not a problem, but supplement is not always
good( U-shape relationship btw intake & risk)
Recommendation for Neural Tube Defect Prevention:
- Follow Canada’s Food Guide to Health Eating
- Consume 0.4 mg/d folic acid + MV starting 2-3 months prior to pregnancy, and through
breastfeed
- If personal health issues(previous pregnancy affected by NTD), consume high level of
folic acid during periconceptional period
Potential Adverse Health Outcomes Associated with Supra-physiological intake: VERY
CONTROVERSY
- Masking of Vitamin B12 deficiency
- Progression of preneoplastic cells to cancers
- In offspring, increased obesity, retinoblastoma, asthma
In chile, there is a increased colorectal cancer rates after fortification

Vitamin B12
Structure Corrin nucleus + nucleotide lysine linked by D-1-amino-2-propanol
2nd bond between cobalt to one of the nitrogen of nucleotide
- Aquacobalamin/hydro- -H2O
Synthetic form(stable):
- Cyanocobalamin -CN
- Hydroxocobalamin - OH
Coenzyme form(unstable):
- 5’-deoxyadenosylcobalamin
- Methylcobalamin -CH3

Source Animal products(derive cobalamin from micro-organism):

- Best source: meat, poultry, fish, egg
- less amounts: Also found in milk, milk products(binder increas
bioavailability)
- ~50% absorption(11-65%), amount decreases with increased
Vegan:
- Fortified beverage
- Fortified meat alternatives
- Red Star nutritional yeast, Vb12 supplement
Absorption Vb12 released from blood→ binds to R proteins found in saliva & gastric ju
within SI, R protein is digested to release B12→ Vb12 binds to intrinsic fac
→ complex absorbed into enterocytes
Issue:
- Younger: intake issue
- Older: absorption issue( less gastric juice production)
- Gastric bypass surgery: lack of IF

Metabolism Within enterocyte, B12 released from IF, binds to transcobalamin(TC

circulation via portal system
B12 circulates in blood primarily as methylcobalamin(80%), and
adenosylcobalamin(20%)
Mostly B12 in blood is bound:
- TCII-newly absorbed Vb12(20%)
- TCI(80%)
- ~20% population have homozygous TCii genetic mutation(TC
affect Vb12 binding
TC-Vb12 complex bind to TC receptor on cell and absorbed by endo
Function Involved in 2 known enzyme:methionine synthetase
- Remethylation homocysteine to methionine by pick up methy
from 5-methyl THF and form THF and methylcobalamin
Oxidation of methionine/threonine/isoleucine
- 5’deoxyadenosylcobalamin convert L-methylmalonyl-CoA to
Succinyl-CoA
Storage, Excretion 2-3 mg with 50% in liver, 30% in muscle primarily as adenosylcobala
Sufficient reserves to last for years
Low body turnover(0.1-0.2%/d)
well conserved: 0.606 ug/d of Vb12 participate in enterohepatic circu
If enterohepatic circulation is damaged, progression of B12 deficienc
rapid
Undergo little degradation before excretion

Assessment Serum Vb12(severe: <148 pmol/L)

Plasma holotranscobalamin TCii( recent absorption)
Plasma homocysteine(non-specific Vb12 vs. folate)
Good Standard: Methylmalonic acid in urine/blood
Megaloblastic anemia(don’t see in chronic marginal Vb12 deficiency)
Breath test of CO2 following administration of labelled propionate

RDA 0-6 months: 0.4 ug/d (human milk content)

7.12 months: 0.5 ug/d
1-18 yrs: 0.9-2.4 ug/d
Adult: 2.4 ug/d( >51 yrs: recommend foods fortified or B12 suppleme
Pregnancy: 2.6 ug/d
Lactating: 2.8 ug/d
Relevance to Humans Inadequacy are underestimated due to belief that deficiency only in
vegetarians/pernicious anemia
Prevalence among
- adult(5% severe, 14-16% marginal)
- >70 yrs(6% severe, >20% marginal)
Most of Vb12 deficiency symptoms affect hematological/neural syste
In Canada Majority have adequate intake( not just an issue with older people, is
throughout life)
Elderly
Vb12 and Cognitive
Function: An Evidence-
Based Analysis
Risk of Being the Mother of
an NTD-Affected Child
According to Pregnancy
Vb12 Status an AP/NAP
Others time at risk
Suggest >51 yrs consume foods fortified with Vb12 or consume
supplement
10-30% of olders don’t absorb Vb12 due to :
- Pernicious anemia
- Decrease gastric acidity
- Atrophic gastritis
- Bacterial overgrowth(use up Vb12)
Objective: determine clinical utility of B12 testing in patients with susp
dementia/cognitive decline
3 question:
1. Association btw Vb12 deficiency and onset of dementia/cogn
decline
2. B12 supplement improve cognitive function
3. Oral vs. parenteral(肠胃外的) Vb12 supplement
Conclusion:
- Association btw elevated homocysteine with dementia(low qu
evidence)
- B12 treatment does not change cognitive function(moderate q
evidence but loss follow-up)
- B12 treatment + folate to mild patients lead to slow
progression( low-moderate quality evidence)
- Oral B12 is as effective as parenteral B12
Women should have plasma Vb12> 300 ng/L(221 pmol/L) before
pregnancy
- However in early pregnancy, 35% marginal + 17% deficient(n
protected)
- At parturition: 38% deficient + 43% marginal
Breast milk Vb12 reflect maternal status
- Vegan mothers should take B12 supplement
Impaired intestinal function
Resection of portion of stomach/SI
 Use of metaformin
N2O Operating room use 50-70% concentration for
- Megaloblastic anemia
- Neuropathy
- Elevated homocysteine
Longer N2O exposure time, higher serum homocysteine change in c

Masking of Vitamin B12 Deficiency

High Folic Acid Produce high THF, even B12 deficient
By high homocysteine, may lead to demyelination

Iron

Overview Human body contains 2-4g of iron

- >65% hemoglobin, 10% myoglobin, 1-5% enzyme, rest in
blood/storage
2 stable forms: Ferric iron or Ferrous iron
RDA Breastfed baby have AI(iron in breast milk is low)
Women have higher iron requirement
DRI 0-6 months: AI=0.27 mg(reflect iron in breastmilk)
7-12 months: 11 mg
- Stores from birth become depleted, thus introduce iron fortified
cereals
1-3 yrs: 7 mg, 4-8 yrs: 10mg
- Iron required to support rapid growth
Pregnancy: 27 mg
- Placenta contains 150 mg iron
- Iron intake support increase maternal blood volume, fetus
growth
Lactation: 9-10 mg
- Low iron in breastmilk
- Lactational amenorrhea reduce iron requirement
Source Animal source: Heme + Non-Heme
- Heme more efficiently absorbed than non-heme
Plant source: non-heme
- Grains may enriched with iron
- Cereal, cooked lentil, tofu, spinach
Supplement: non-heme iron(ferrous more soluble)
- Maintain iron tatus( 8-18 mg)
- Treat deficiency(>30mg)
Absorption Enhancer of non-heme: sugar, acids(ascorbic, citric)
- Iron absorption efficacy ranges from 2-60%
Enhancer of Iron absorption from gut: meat, mucin
- Stimulate gastric/intestinal secretion
- Chelate ferric iron at low pH maintain solubility
Amount of iron available for absorption can be estimated from
the amount of Vc, meat, fish, poultry ingested with non-heme
iron
- 75 units Vc, 1g cooked meat
- Without enhancer, non-heme absorption is 2-3%

Inhibitor:
1. polyphenols(tea/coffee)
2. oxalate(bond mineral complex and insoluble)- spinach, berries
tea
3. phytate( bind to metal, found in maize, reduced by
fermentation)
4. High levels of Dietary Calcium & Phosphorus
- Decrease Fe absorption by 70%, with critical amount of 300-
600 mg
- Long term: chelate non-heme iron and form insoluble
5. High level of Zn, Manganese(compete for transporter DMT1)
6. Rapid Transit Time/Malabsorption/Alkalinization of GI tract
Digestion Heme:
hemoglobin/myoglobin hydrolyzed by HCl/protease to release 4 heme + 4
globins( → amino acid), then absorbed into enterocytes, heme hydrolyzed
release ferrous iron
Non-heme:
Ferric, ferrous released by HCl/protease, convert to ferrous at low pH.
But in more alkaline SI, ferric complex is insoluble,
aggregates/precipitate in Fe(OH)3
Absorption:
Ferric iron absorption
- At BB, reduce ferric to ferrous by reductase like cytochrome B
reductase 1
- Minor absorption of ferric by membrane protein(integrin)
Ferrous Iron Absorption
- Soluble at alkaline pH, with main transporter of DMT1,
synthesis of DMT1 stimulated by hypoxia(upregulated by low
iron status)

Iron in enterocyte: Storage Little iron unbound due to oxidative damage

Inside enterocyte:
- Used for functional purpose
- Transport across to BLM, enter circulation( ferroportin
transport Fe across membrane, coupled by copper-containing
protein--hephaestin to convert ferrous to ferric, attach to
transferrin for blood transportation)
- Store as ferritin(Fe2+ bound to poly rC binding protein, store
as ferritin)
- Excreted with sloughing of enterocyte
 Heme enter enterocyte via hcp1, catabolized by heme oxygenase to
produce protoporphyrin & Fe2+
Circulation Transferrin(33% saturation, 100% saturation lead to toxicity)
Major iron transport protein in blood
Binds & transport up to 2 iron atoms in the blood
Transport only ferric iron(new & recycled)

Regulation of Dietary Hepcidin Signaling initiated by high blood iron, degrade ferroportin
Uptake on enterocyte to decrease absorption/increase loss

Cellular Iron Uptake 1.Ferric iron + transferrin absorbed into cell by transferrin receptor
2.low pH in endosome convert ferric to ferrous iron, pump out vi a
DMT1
3.ferrous oxidized, stored as ferritin, used for heme synthesis
4.ferrous can be oxidized by ceruloplasmin + Cu and exported via
ferroportin

Storage liver(60%), bone marrow, spleen

Ferritin as primary storage form in cells
Hemosiderin is another storage protein(high ferritin convert to
hemosiderin)
Function Hemoglobin & myoglobin
- Fe in center of heme transport O2
Cytochromes & other enzymes
- Effect electron transport via respiratory chain(electron transfer
to next cytochrome via convert ferrous to ferric iron)
Monooxygenases & dioxygenases
- Insert 2 oxygen for AA metabolism and carnitine/procollagen
synthesis
Peroxidase
- Antioxidant, thyroid hormone synthesis(thyroid peroxidase)
Other iron-containing enzyme
- CHO metabolism, DNA synthesis
Pro-oxidant

Excretion GI tract, skin, urine, hemorrhage/menses

Assessment Deficiency 1st stage: iron store diminished
- Serum ferritin
2nd stage: iron store low & transport decreases
- Decrease serum ferritin, transferrin saturation
- Rise protoporphyrin rise
- Increase soluble transferrin receptor
Final stage: anemia occurs
- hemoglobin/hematocrit altered
- MCV, MCH of Hgb
- Hypochromic, microcytic
Deficiency Iron deficiency with vs. without anemia
Vulnerable: infants, adolescent, menstruating, pregnant
Iron Deficiency of Internationally iron deficiency affect 20-25% of world population
Canadians: CHMS Canada: 4% female >12 yrs are anemic, 10% women 65-79
Anemia inversely associated with household income
Males <65 yrs with adequate hemoglobin approach 100%

Expert Recommendation: Cow’s milk not recommended due to low iron

infants Recommend iron-fortified formula, meant, iron-fortified cereal

Hospital for Sick Children Invention of pre-cooked baby cereal enriched with iron
Invention of Pablum: 1930

Expert Recommendation: Eating meat associated with a decreased odds of iron deficiency
young children Factors associated with iron deficiency include: >2 cups milk/day,
longer breastfeeding

Expert Recommendation: Eat according to Canada’s Food Guide, take supplement of 16-20 mg
Pregnancy of iron

Expert Recommendation: Bioavailability only 10%, vegan with 5%

vegetarian

Toxicity UL= 45 mg, overload lead to acute iron toxicity

- Unbound Fe act as free radicals
Hemochromatosis( chronic iron overload)
- Genetic disorder
- Lead to cirrhosis
Interaction with Other Vitamin C: enhance iron absorption
Nutrients Copper: copper deficiency lead to iron deficiency anemia(Hephaestin
is Cu2+ dependent)
Zinc: inhibit iron absorption
Vitamin A: iron accumulation in organs mediated via erythropoietin
- Va interact with transferrin receptor gene
 Lead: lead poisoning associate with iron-deficiency anemia secondary
to decreased hemoglobin production

Choline
property Water soluble
As part of phosphatidylcholine
Sources Liver produce endogenous: insufficient
Main source: animal-based product(beef liver, egg) as
phosphatidylcholine
Supplement, but not in prenatal supplement due to overload
concern
Absorption Gut bacteria impact bioavailability by breaking down choline to
betaine absorption with pancreatic/intestinal mucosal cell
contains enzyme, break phosphatidylcholine
Uptake into enterocyte by choline transporter
Free choline enter portal circulation
PC may enter lymph system
Choline Metabolic Pathway Derived endogenously by methylation of PE to PC
Dietary choline convert to PC mostly
Once enter the cell, choline phosphorylated/convert to
betaine(essential in donation of methyl group to
homocysteine)
Metabolic Methyl-Exchange Between choline and methionine, folate, Vb12
Relationship
Function Neurotransmitter synthesis(acetylcholine)
Cell membrane signalling
Hepatic lipid export(VLDL, HDL)
Component of cell membrane
Role in brain, memory development and reduction in NTD

Choline Metabolism in Low PEMT in fetal tissue, thus require adequate supply of
Maternal Liver and Delivery to maternal choline
the Fetus Placenta contains 50X more choline than maternal blood

Storage Membrane lipids are a large storage pool for choline

Assessment Plasma choline
Plasma choline in combination with metabolites: betaines
Marker for liver dysfunction

AI non-pregnant/non-lactating women requires < choline due to

estrogen increase choline synthesis

Serum Alanine High choline with high serum ALT level

Aminotransferase activity in
Men ingesting control/choline
deficient diet
UL
1-8 yrs: 1000 mg/d
9-13 yrs: 2000 mg/d
14-18 yrs: 3000 yrs/d
Adult: 3500 mg/d
- Based on prevention of hypotension, fishy odor
Active areas of research Infant development
Memory loss with aging
Nonalcoholic fatty liver disease
CVD
Maternal choline status Observational evidence that choline during pregnancy may be
influence cord plasma choline beneficial for the neurological health of child. In adults, choline
metabolite concentration may have beneficial effects on cognition, but high-quality
studies are lacking. Results on the effects of choline on body
composition, blood lipids, and CV health were inconsistent