Micronutrients: Trace Elements

Question 1

Iron Function and Food Sources

Answer 1

a. Function:
i. Oxygen transport in blood (hemoglobin) and muscle (myoglobin)
ii. Electron transfer enzymes (cytochromes)
iii. Enzymes for activation of oxygen (oxidases and oxygenases)

b. Food Sources:
i. Heme iron: Cellular animal protein: meats, poultry, liver; (milk is poor source)
ii. Non-heme: legumes, nuts, whole grains (esp when enriched/fortified, green leafy vegetables;

Note: absorption of non-heme iron, much lower (<10%) compared to animal sources (≥ 20%)

Question 2

Factors Affecting Iron Absorption

Answer 2

Factors affecting absorption:

a. Dietary factors that form insoluble complexes (phytate, tannins, phosphate, oxalate)
b. Factors affecting oxidation state (ascorbic acid: Fe3+–> Fe2+; absorption enhanced for reduced state)
c. Chemical form (non-heme/inorganic vs heme (heme iron enhances absorption of non-heme))
d. Mineral-mineral interactions: excessive Zn or Cu —> decreased Fe absorption

e. Host factors: physiologic states (Pregnancy, growth, erythropoiesis); Fe deficiency —> increased absorption;
i. inflammation: ↑ hepcidin from liver ↓ absorption at enterocyte

f. Quantity present in the meal/gut lumen (inverse relationship)

Question 3

Homeostasis of Body Iron

Answer 3

Homeostasis:

a. Main site of regulation is intestinal absorption; once absorbed, very efficiently/ effectively retained (e.g. recycling from rbc/Hb breakdown); bleeding = major route of iron loss; stores: liver, bone marrow, spleen

b. Transport: Transferrin
Storage form: ferritin or hemosiderin (aggregated ferritin molecules)

c. Iron distribution:
i. Males: 2500 mg in circulating hemoglobin; 500-1000mg in stores
ii. Females: 1500 mg in circulation; stores 500 mg

Question 4

Transport vs storage form of Fe

Answer 4

a. Transport: Transferrin

b. Storage form: ferritin or hemosiderin (aggregated ferritin molecules)

Question 5

Deficiency of Iron

Answer 5

a. Most common nutritional deficiency in the world;
b. Populations “at risk”: infants > 6 mo old (low stores, high requirement); premature infants (very low stores, high requirement); adolescents (relatively high requirement + poor intake); pregnant women (increased requirement); populations with chronic infestations (e.g. helminths, causing intestinal blood loss), bariatric surgery patients, hospitalized elderly or elderly in long term care facilities.
c. Deficiency in men or in post-menopausal women merits investigation for source of bleeding.

d. Manifestations: Anemia (microcytic, hypochromic), exercise/work tolerance, fatigue, listlessness;
deficiency w/o anemia impaired cognitive function (permanent if onset in infancy?), impaired growth

e. Diagnosis: nutritional deficiency suggested by low Hb/Hct & microcytic/ hypochromic rbc (= severe deficiency); low ferritin (= mild, moderate or severe deficiency
i. Caveat: ferritin is an acute phase protein, and is elevated with inflammatory conditions; need to check inflammatory marker (ESR or CRP) coincidentally w/ ferritin for accurate interpretation); low serum Fe w/ high total Fe binding capacity (TIBC) low % saturation

f. Treatment: Oral iron supplements (ferrous sulfate) 30-60 mg/d x 2-6 mo for replenishment of iron stores (infants/children: 2-6 mg/kg/day)

Question 6

Toxicity of high Fe

Answer 6

a. Iron is a potent pro-oxidant unnecessary iron supplementation to be avoided; normal individuals generally able to regulate absorption well enough to avoid iron overload syndrome; conditions requiring frequent blood transfusions can lead to iron overload (regular blood donation avoids excessive iron accumulation!)
b. Excess iron deposited mainly as hemosiderin in reticuloendothelial cells
c. Large doses of supplemental iron interfere with absorption of zinc, copper & possibly other minerals
d. Hereditary Hemochromatosis –relatively common inherited condition in which Fe absorption is excessive due to defect in hepcidin; individuals accumulate increased Fe stores that are damaging, esp to liver (Increased risk of hepatocellular carcinoma)

e. Medicinal Fe overdose is esp toxic; effects:
i. hemorrhagic gastroenteritis, shock & acidosis, coagulation defects, hepatic failure; in children, 1-2 grams of iron may be fatal.

Question 7

Function of Zinc

Answer 7

Functions:

a. Regulation of gene expression (zinc finger transcription proteins, both RNA & DNA metabolism)
b. Structural roles in membrane stability
c. Metalloenzymes (> 200 !)
d. Especially critical during periods of growth and cellular/tissue proliferation (immune system, wound healing, skin & gi tract integrity); physiologic functions for which zinc is essential include normal growth, sexual maturation, sense of taste, immune function, night vision (possibly mediated through Vit A & retinol binding protein)

Question 8

Food Sources and Absorption of Zinc

Answer 8

Food Sources & Absorption:

a. Widely distributed in foods, but richest sources = animal products; (oysters extremely high); beef > poultry > fish, milk, eggs; relatively high in whole grains, legumes, seeds, etc but lower absorption from plant foods;
b. Absorption impaired by phytate (found only in plants; esp high in corn, legumes, nuts)
c. Absorption not increased w/ deficiency (unlike iron)

Question 9

Homeostasis of Zinc

Answer 9

Homeostasis:
a. Absorption of dietary zinc and excretion of zinc from gi tract are important in regulating body zinc “pool”;

b. Zinc secreted into gi tract w/ digestion, as part of pancreatic-biliary secretions; some reabsorbed, some excreted, so route to excrete excess Zn exists (vs iron)

Question 10

Populations at risk for zinc deficiency

Answer 10

Deficiency: Populations at risk:

a. Infants (esp premature) & young children (high growth rate +/- marginal intake); breastfed infants > 6 mo; human milk low [Zn] after 6 mo – need source from foods
b. Pregnant women (high demand; critical for normal embryogenesis)
c. Monotonous, plant based diets (esp if high in phytate);
d. Bariatric surgery patients (up to 40% may be deficient due to decreased protein intake and malabsorption)

e. Elderly: poor zinc status common and may be associated with higher incidence of pneumonia;
i. Copper to zinc ratio (CuZ) – increased ratio in elderly associated with higher mortality; may be biomarker of aging.

f. GI illness/injury: diarrhea associated w/ losses (World Health Organization: 20 mg/d x 10 days for acute diarrhea in young children)
g. Wounds, burns: increased requirement for synthesis of new tissue

Question 11

Manifestations of Zinc deficiency:

Answer 11

a. Mild: growth delays/stunting, anorexia, impaired immune function; impaired neurocognitive development
b. Moderate – severe: severe, characteristic dermatitis (acro-orificial); diarrhea, immune dysfunction, delayed wound healing, taste impairment, anorexia, personality changes
c. Acrodermatitis Enteropathica: mutation in enterocyte Zn transporter (ZIP4); fatal condition if not treated; responds to high doses of Zn supplements (lifetime); presents w/ severe dermatitis, growth failure, diarrhea.

Question 12

Toxicity and other uses for Zinc

Answer 12

a. Toxicity: relatively low; > 50 mg/d can HDL-cholesterol, impair absorption of Fe & Cu, cause nausea, diarrhea
b. Other uses for zinc: Lozenges within 24 hr of first symptoms of a cold, may decrease the duration of illness by one to four days & significantly reduce the severity of cold symptoms; more research needed re dose and formulation; postulate Zn may prevent viral replication or attachment to nasal membranes.

Question 13

Iodine Function

Answer 13

a. Function: Integral part of thyroid hormones: thyroxine (tetraiodothyronine) (T4) and triiodothyronine (T3); thyroid gland able to concentrate iodine; amount in the gland intake

Question 14

Iodine food sources

Answer 14

a. Food Sources: Seafoods & seaweed (most iodine resides in the ocean); I content of crops grown and animal products (esp dairy & eggs) variable, dependent on composition of feeds and/or content of soil (“geochemical distribution”); iodized salt provides substantial source.
b. Iodine content of soil varies (geochemical), depending on glaciation, rainfall, runoff into rivers.

Question 15

Iodine absorption and metabolism

Answer 15

Absorption, metabolism, and excretion:

a. Readily absorbed from food, reaches circulation as Iodide. In circulation, 95% as organic Iodine, 5% as Iodide; most T4 and T3 trannsported via carrier proteins (eg thyroxine binding globulin). Iodide uptake—> binding to T4 & T3—> circulation

Question 16

Deficiency of Iodine

Answer 16

Deficiency: common worldwide endemic goiter & cretinism in children (5.7 million cretins exist; estimate 1 billion persons at risk for I deficiency disorders)

a. Cretin child: (“deaf mutism”) dwarfed, mentally retarded, typical “dull” facies, large tongue; results from I deficiency during pregnancy; fetus: abortions, stillbirths, congenital anomalies;
b. Goiter: enlarged thyroid gland as compensation for I for thyroid hormone synthesis
c. In populations w/ endemic iodine deficiency, estimated to be responsible for a mean IQ loss of 13.5 points in the population.

Question 17

Copper Quick Stats

Answer 17

a. Functions: oxidative enzymes (cytochrome oxidase, ferroxidase, amine oxidase)
b. Food sources: shellfish, meats, nuts; low in milk
c. Absorption & Metabolism: 30-40% absorption from mixed diet; stored in liver; excreted in bile

d. Deficiency:
i. Mild- Anemia
Neutropenia, osteoporosis, seborrheic skin lesions
ii. Severe- Mental retardation, seizures, connective tissue defects, fractures

Question 18

Selenium Quick Stats

Answer 18

a. Functions: Glutathione peroxidase (GSHx); deiodinase; important anti-oxidant

b. Food sources: Present in foods associated w/ amino acids (e.g. selenomethionine); intake varies widely w/ soil content (“geochemical” distribution). E.g., in areas of China, New Zealand, Finland, Venezuela, soil levels low, populations w/ much lower blood levels - ? functional consequences.
i. Keshan disease, a cardiomyopathy in China which can be prevented w/ Se supplementation may represent interaction w/ other nutritional deficits (e.g. I) and/or viral infection (viral mutation to virulence in Se deficient host).

c. Absorption & Metabolism: 60-80% absorbed from diet; kidneys main site homeostasis & urine excretion

d. Deficiency:
i. Mild- Macrocytosis, loss of hair pigment, hypothyroidism
ii. Severe- Cardiomyopathy
Skeletal myopathy

Question 19

Definition of Trace elements

Answer 19

Major elements: 11 elements that accounts for 99.7% of the human body’s weight

*The remaining 0.3% consists of 25 trace elements.

Question 20

Concepts of Bioavailability

Answer 20

Bioavailability: the extent to which other dietary constituents affect the absorption & retention of a nutrient;

Trace minerals especially susceptible to interference w/ absorption

Question 21

IRON – What does it do?

Answer 21

a. Total body iron ~ 5 g
i. ~ 50% as hemoglobin iron, 10 % myoglobin and 5%in enzymes
ii. Storage Fe: adults 300-1500 mg; (Fe overload disorders: 40-50,000 mg)

b. Functions:
Tissue oxygenation
1. O2 transport in blood & muscle (Hb & myoglobin)
2. Electron transport (cytochromes)/respiratory chain
3. Enzymes for activation of O2 ( oxidases, oxygenases)
CNS myelination: Dopamine synthesis, (< 1% of total body iron)

Question 22

Where do we get Fe?

Answer 22

Food Sources:

1. Heme:
   Meats/flesh, liver
2. Non-heme:
   i. Plant sources: legumes, whole grains, nuts;
   ii. Fe-fortified foods (infant formula, cereals/grains)

Question 23

Fe Homeostasis – Factors Affecting Absorption/Bioavailability

Answer 23

a. Form: Heme Fe&raquo_space; non-heme ( 30% vs < 10%)
b. Calcium: the only dietary factor that can decrease heme iron absorption

c. Positive Factors:
i. Ascorbic acid
ii. Meat or fish ( factors in meat other than heme iron enhance the absorption of non-heme iron)

d. Negative factors (decrease Fe absorb)
i. Phyate ( bran, oat, beans, rye..)
ii. Calcium
iii. Polyphenols ( tea, some vegetables)
iv. Dietary fiber
v. Soy protein

Question 24

Phyate ( bran, oat, beans, rye..)
Calcium
Polyphenols ( tea, some vegetables)
Dietary fiber
Soy protein

Answer 24

a. Binds cations – Zn, Fe, Ca – in gut lumen; humans w/o phytases
(Most common feed enzyme: added to ~90% poultry & ~70% pig diets; P pollution)

b. High in grains, legumes:
Maize/wheat > legumes > rice
Globally, likely = major cause of dietary deficiencies

Question 25

Food Sources & Fe Absorption

Answer 25

a. Meat (3 oz)
3. 2 mg x .30 = 0.96 mg

b. Kidney beans (1/2 c, )
2. 6 mg x 0.05 = 0.13 mg

c. Fe-enriched bread (1 sl)
0. 8 mg x 0.05 = 0.04 mg

d. Human milk vs formula:
0.5 mg/l x 0.2 = 0.1 mg
12 mg/l x 0.05= 0.6 mg

Question 26

Iron Homeostasis

Answer 26

a. Occurs in the proximal duodenum
b. The first step is reduction: Fe3+ Fe2+ better absorbed

c. Absorption = main point of regulation.
i. Once absorbed beyond GI tract, very efficiently retained/recycled

d. Loss (excretion): bleeding, cell sloughing
e. Key factors: form of Fe/meal composition & host status.

f. Host factors:
i. Deficiency–> increased absorption
ii. Inflammation—> absorption

Question 27

Overview of Iron Homeostasis

Answer 27

a. In the duodenal enterocyte, dietary iron is reduced to the ferrous state by the duodenal ferric reductase, then the divalent metal transporter (DMT1) shuttles Fe++ inside the enterocytes where it can be stored as ferritin or released by way of ferroportin into the circulation.
b. In the circulation iron is transferrin-bound and its uptake by the hepatocytes is facilitated by Transferrin receptor 1 and 2 .
c. This uptake by the hepatocytes influences the exression of the iron regulatory hormone hepcidin.

d. Another source of iron is the senescent erythrocytes that are taken up by macrophages.
i. Macrophages export the recovered iron via ferroportin.

Hepcidin: blocks transport of Fe:
↓ iron deficiency
Increased inflammation

Question 28

Hepcidin levels

Answer 28

a. When hepcidin levels are low, iron-exporting cells, including duodenal enterocytes, macrophages, and hepatocytes display abundant ferroportin and release iron intro plasma.
b. When hepcidin concentrations increase, hepcidin binds to ferroportin, ferroportin is degraded, and iron is retained within cells in cytoplasmic ferritin.

Question 29

Iron Homeostasis/Correlation to Lab Values

Answer 29

a. Stores: ferritin - liver, bone marrow, spleen

b. Inflammation ↑Hepcidin ↓ uptake
i. However the ferritin level may be normal or high.

c. Always obtain inflammatory makers with Ferritin level.
d. Transferrin: transports Fe in body; ~ no “free Fe”

Question 30

Systemic iron homeostasis.

Answer 30

Systemic iron homeostasis.

a. By regulating ferroportin, hepcidin controls the entry of iron into plasma. The major iron flows that are regulated by hepcidin–ferroportin interactions include the release of iron from macrophages that recycle iron in the spleen and other organs, dietary iron absorption in the duodenum, and the release of iron from storage in hepatocytes.
b. The feedback stimulation of hepcidin by plasma iron saturation and iron stores ensures that extracellular iron concentration and iron stores stay within normal limits.
c. Hepcidin synthesis is suppressed by erythropoietic activity, ensuring a sufficient supply of iron to the bone marrow when demand for erythrocytes is high.
d. During inflammation, hepcidin production is stimulated and iron entry into plasma is inhibited, causing the hypoferremia and anemia of inflammation.

Question 31

Iron Deficiency - Etiology

Answer 31

a. Poor bioavailability dietary Fe – plant/cereal staples
b. Dietary inadequacy – e.g. excessive milk intake

c. High demand
i. Hemolysis: Increased losses / rbc production (e.g. helminths)
ii. Pregnancy & infancy: Increased rbc production & growth, low stores at birth (“early” cord clamping)

d. Chronic immuno-stimulation ( hepcidin)

Question 32

Prevalence of Iron deficiency

Answer 32

Most common micronutrient deficiency in the world, including the U.S.

Iron Deficiency: very common in older infants & toddlers (~ 75% in many settings)

Question 33

At risk” populations: Iron Deficiency

Answer 33

BF Infants (> 6 mo ) - low stores / increasedrequirement

Premature/SGA infants

Young children - poor intake / ~ increased requirement

Adolescent girls/young women – menstrual loss

Pregnant women - very increased requirement

Blood loss (e.g. chronic infestations)

Obese (inflammation) & s/p bariatric surgery

Question 34

Iron Deficiency: Effects

Answer 34

a. Iron is prioritized to the erythrocytes because of its vital role in oxygen transport.
b. Decreasing—>Hepatic stores skeletal muscles and intestine cardiac iron brain iron finally erythrocyte iron.
c. Fatigue, listlessness, irritability, attention deficit, sleep disturbance (e.g. RLS)
d. Impaired growth

e. Anemia (microcytic, hypochromic)
i. Reduced O2 carrying capacity

f. Impaired cognitive function in developing brain
i. Irreversible, even w/ correction of deficiency/anemia

Question 35

Iron Deficiency: understanding the lab values

Answer 35

a. Small erythrocytes: low MCV
b. Hypochromia: low MCH and MCHC
c. Loss of uniformity in shape and size: high RDW

However:
All of the above may be normal in earlier stages when brain stores are depleted and you will only have low ferritin

Question 36

Effects of Iron Deficiency in Early Infancy

on Cognitive Function

Answer 36

a. Even in absence of anemia, ID produces biochemical changes that impair behavioral and cognitive development in infants 9-12 months old
b. Participants with chronic, severe ID in infancy performed less well on frontostriatal-mediated executive functions, including inhibitory control, set-shifting, and planning

Question 37

Long-term Effects of Iron Deficiency

Answer 37

a. Children treated for ID in infancy had deficiencies in cognitive function persisting for 10 years after iron treatment
b. Functional significance of early-life iron deficiency, possibly leading to a loss of human potential at 25 years of age

Question 38

Iron Toxicity

Answer 38

a. Potent pro-oxidant avoid unnecessary supplementation
(if replete, ↓ growth, ↑ oxidant stress, ↑ inflammatory markers, ↑ mortality; (-) effects on microbiome)

b. Normal individuals able to regulate absorption
c. Hereditary hemochromatosis (=defect in hepcidin): absorption excessive—> accumulate Fe–> liver damage

d. Fe overdose = toxic
i. hemorrhagic gastroenteritis, shock, liver failure;± fatal

Question 39

Clinical Implications:

Fe deficiency

Answer 39

a. Iron deficiency (w/o anemia) very common
i. Behavioral & learning/ developmental effects
ii. Critical window of brain development

b. In setting of acute inflammation/illness…
i. Absorption will be poor due to hepcidin stimulation
ii. In developing countries, chronic immuno-stimulation likely contributes to iron deficiency
iii. Administering Fe ineffective, pro-inflammatory

Question 40

Zinc: What does it do?

Answer 40

Total body Zn: ~ 2 gram

Multiple, diverse functions
1. Regulation of gene expression (Zn fingers)

2. Stabilize molecular structures - subcellular constituents and membranes
3. Co-factor for hundreds of enzymes
4. Modulates activity of hormones & neurotransmitters

Question 41

Nutritional/Physiologic Roles of Zn

Answer 41

a. Growth & cellular/tissue proliferation
i. Somatic/linear growth
ii. Immune system
iii. Wound healing
iv. GI tract integrity
v. Skin

b. Antioxidant
c. Sexual maturation

Question 42

Zinc - Food Sources

Answer 42

a. Foods:
Widely distributed, but animal sources = richest (beef > poultry > fish)
Plants: whole grains, legumes

b. Breast milk
Adequate for the first 6 months of life

Question 43

Zn Homeostasis: Absorption

Answer 43

a. Determined by 2 factors:
1) The amount of zinc ingested
2) The dietary phytate

b. Zn status of the host is not a major determinant of absorption efficiency
* The current understanding of zinc homeostasis indicates that the primary determinants of zinc absorption are the amount of zinc ingested and dietary phytate, phytate plays a major effect on zinc bioavailabiltiy

Question 44

Zn Homeostasis: Role of GI tract

Answer 44

Role of GI Tract:
i. Absorption: ~ crude control

ii. Endogenous Zn (controlled)
-Secretion
-Reabsorption/excretion
(vs Fe – can excrete Zn;
~ no stores)

The GI tract is the major site of zinc losses resulting from secretion of endogenous zinc into the lumen and subsequent excretion in the feces. The amount excreted depends on host status but also can increase in certain conditions like diarrhea and steatorrhea.

Question 45

Zinc Deficiency – Who’s at Risk?

Answer 45

BF Infants (> ~ 6 mo) & young children – high growth rate, low intakes

Pregnant & lactating women

Elderly – low intake

Monotonous. plant based diets: increased phytate

GI illness/injury: increased endogenous losses

Wounds/burns healing: tissue repair

Question 46

Zinc Deficiency

Answer 46

a. Moderate-severe:
1. Dermatitis (periacral-periorifical)
2. Personality changes
3. Immune dysfunction
4. Delayed sexual maturation
5. Anorexia
6. Diarrhea

b. Inherited defect in Zn absorption:
i. Acrodermatitis Enteropathica (AE)
ii. Transient neonatal zinc deficiency

Question 47

Dietary Reference Intake for Iron (mg/day)

Answer 47

a. IOM-determined level of adequate intake (AI) of iron for first 6 months of life based on human milk content

b. After 6 months of age,
RDAs are based on factorial modeling using requirement for growth and expansion of blood volume, and iron losses

Question 48

Identification of Human Zn Deficiency:

Answer 48

Identification of Human Zn Deficiency:

Stunting & Hypogonadism in Mid-Eastern Males:
whole grain, unleavened wheat flatbread, low animal source foods

Question 49

Severe Zn Deficiency (Acquired AE)

Answer 49

5 mo presented with h/o diarrhea, growth failure, rash
(Cystic Fibrosis)

Severe Zn Deficiency- Rapid Response
-giving Zn supplement will cause quick treatment

Question 50

Zinc Deficiency

Answer 50

a. Mild:
i. Growth delays
ii. Anorexia
iii. Impaired immune function

b. Mild Zn deficiency much more common than moderate-severe deficiency;
c. Globally, Zn deficiency 2nd only to Fe deficiency

Question 51

Stunting and Zinc

Answer 51

Of the world’s chronically malnourished children…

a. Stunting is strongly associated w/ Zn deficiency
b. Meta analysis: (+) effect of Zn supp in stunted pop’s
c. No pharmacologic effect of Zn on growth;
d. Response to Zn supplement c/w deficiency

Question 52

Impact of Zn Supplementation

in Young Children in Developing Countries

Answer 52

20-25 % ↓ incidence & prevalence of diarrhea
WHO: 20 mg/d Zn x 14 d for acute diarrhea (+ORS)

~ 20-40 % ↓ incidence of pneumonia

Zn supplementation cited as 4th most effective way to prevent child deaths

Question 53

Zn Deficiency in US

Answer 53

a. Older infants & toddlers, esp breastfed
i. Breast milk low in Zn after 6 mo
ii. Diets low in meat
iii. Presentation:
- Growth faltering (weight & linear)
- Poor appetite
iv. Prompt response to supplementation; transition to dietary sources

b. Specific subgroups: premature infants, celiac disease, cystic fibrosis, and liver disease.
c. Elderly – associated w/ ↑ incidence pneumonia

Question 54

Zinc Toxicity w/ Supplements

Answer 54

a. LOW – much less so compared to iron

b. High doses (> 50 mg/d)—> decreasedCu absorption
(& neuropathy)

c. High doses associated w/ decreased HDL-cholesterol

d. High dose Zn lozenges x few days for acute pharyngitis?
i. (mechanism: suppresses viral replication?)

Question 55

Assessment of Zinc Status: A Clinical Challenge

Answer 55

a. Currently we lack a sensitive biomarker
b. Signs and symptoms of Zn deficiency can be non specific
c. Assessment of the risk of Zn deficiency in the clinical setting relies on good history ( especially diet history) and a good ROS ( GI pathology?)

Question 56

Great Hepcidin Summary

Answer 56

a. In states in which the hepcidin level is abnormally high such as inflammation, serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption.
i. This typically leads to anemia due to an inadequate amount of serum iron being available for developing red cells.

b. When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to decreased ferroportin mediated iron efflux.