Wk 1 TBL 2 Nutrition: Iron, Mineral Metabolism Flashcards
List essential micronutrients
Macrominerals:
1. calcium
2. chlorine
3. magnesium
4. phosphorus
5. potassium
6. sodium
7. sulfur
Trace minerals:
1. copper
2. iodine
3. iron
4. manganese
5. molybdenum
6. selenium
7. zinc
8. fluoride
List essential macronutrients for humans
Fat
PRO
CHO
Describe the life-cycle of iron homeostasis
managed more at the level of protein synthesis (translation of mRNA to PRO) than at the level of transcription (mRNA synthesis).
Regulation of the synthesis of the transferrin receptor-1 (TfR-1) and divalent metal transporter-1 (DMT-1), responsible for the uptake of iron by cells
regulation of the iron uptake proteins and the iron storage protein occurs through posttranscriptional modification of TfR-1 and ferritin messenger RNAs (mRNAs)
What is the role of transferrin?
Carry iron around in the body
-carries 2 ferric (Fe3+)
What is the role of ferritin?
Store iron (primarily in the liver)
What is the role of ferroportin and DMT1?
-Transport iron across enterocyte membranes
-DMT1 is also responsible for the transport of zinc, copper and cobalt
What is the role of hepcidin?
Decreases plasma [iron] by:
1. blocking ferroportin in enterocytes
2. blocking ferroportin in the liver
What is the role of HFE?
Regulate the production of hepcidin
What is the role of transferrin receptor?
Bind Fe2+ to the apical surface of enterocytes to allow iron absorption
How does altered iron homeostasis (anemia & iron overload) affect different organs and tissues?
Anemia:
1. mitochondria fxn inhibited b/c iron is a cofactor
2. arrhythmias -> enlargement
3. confusion, depression
4. low O2 -> can affect all organ systems
Overload:
1. Liver disease, cirrhosis
2. Heart dysfunction, failure
3. hypothyroid
4. pancreatic islet cell damage -> diabetes
5. hypogonadism
6. immune system dysfunction
7. renal dysfunction
Compare iron deficiency anemia with anemia of chronic disease and hemochromatosis
What are signs of iron deficiency?
Fatigue
pale conjunctiva and skin
weakness
cold extremities
arrhythmias, palpitations
SOB
Kids - behavioral, frequent infections
What are signs of copper deficiency?
anemia
leukopenia
chronic: neurologic and growth defects in children
What are signs of zinc deficiency?
Growth retardation
hair loss
skin lesions (acrodermatitis)
diarrhea
delayed wound healing
How is dietary iron absorbed?
Iron:
1. heme (fe2+) picked up by heme transporter on enterocytes
2. non-heme iron (fe3+) is first reduced to Fe2+ then taken in by DMT1 (divalent metal transporter)
3. some binds ferritin while other transported over via ferroportin 1
4. Fe2+ oxidized to Fe3+ and picked up by transferrin
5. Goes to either erythroid marrow or to liver
6. Hepcidin produced by liver -> downregulation of ferroportin 1 protein
What are the primary uses for iron?
Hb production
Transport O2 in Hb and myoglobin
DNA synthesis
Respiration and energy metabolism
Synthesis of collagen and some NTs
Immune fxn
What are the primary uses for copper?
Needs for many enzymes:
1. ceruloplasmin, a blood protein req’d for oxidizing Fe2+ to Fe3+, which allows it to bind to transferrin
2. monoamine oxidase
3. cytochrome C oxidase (complex IV of the respiratory chain)
4. superoxide dismutase
5. hephaestin (HEPH), a copper-dependent ferroxidase needed for iron transport from enterocytes to blood
What are the primary uses for zinc?
- Req’d cofactor of many enzymes like alkaline phosphatase, superoxide dismutase
- Req’d in structural proteins like Zn-finger transcription factor
What is the role of hepatocytes in iron homeostasis?
Produce hepcidin, which downregulates ferroportin 1, the protein that takes iron from the enterocytes into blood
What is the role of enterocytes in iron homeostasis?
Absorb Fe2+ from the lumen of sm intestine
What is the role of macrophages in iron homeostasis?
Digest RBCs and recycle iron
Can one be iron deficient with a normal Hb and Hct?
Yes, anemia is a later symptom of iron deficiency
Dietary sources of iron
red meats, fish, poultry, fortified cereals, spinach, beans, tomatoes, etc
How can iron absorption be increased?
- iron in diet as heme (Fe2+) (high bioavailability)
- vit C consumed w/ non-heme iron
What decreases iron absorption?
- chelators - binds to iron in Fe3+ state in GI, prevents it from being reduced to Fe2+ so it cannot be absorbed
- calcium - prevents binding of chelators so Fe3+ can be reduced and taken up by cells
What are some natural chelators?
oxalates - found in spinach
polyphenols - veggies
What can cause iron deficiency in infants?
- iron deficiency during pregnancy -> infant iron deficiency b/c they are very dependent on their fetal stores
- breast milk has low [iron] but it’s very bioavailable
- feeding an infant (<12 mos) cow’s milk -> iron deficiency b/c it causes increased sloughing of enterocytes
What are downsides to iron fortified foods?
Iron overload:
1. 1/100-200 Americans have hemochromatosis -> beta-cell destruction
2. high serum ferritin and dietary (heme) iron associated w/ diabetes
Iron poisoning:
1. corrosive to GI mucosa-> unregulated absorption
2. systemic affects on heart, lungs, and liver incl acidosis
What is used to tx iron poisoning?
deferoxamine, an iron chelator
How are zinc and copper absorbed?
What foods are abundant in zinc?
seafood
meats
beans
dairy
nuts
When are copper deficiencies seen?
Rare but can be seen when
1. zinc supplements are taken in excess
2. Menkes disease - X-linked mutation in a copper transporter
What is the daily iron requirement?
10-20 mg
heme (ferrous) iron = Fe2+
ferric iron = Fe2+
What form of iron is absorbed by enterocytes?
Fe2+
so, Fe3+ must be converted
What enzyme converts Fe3+ to Fe2+?
Vitamin C ferrireductase on the apical size of enterocytes
What is the iron cotransporter across the enterocyte apical membrane?
Divalent metal transporter 1 (DMT1) - through which Fe2+ crosses the membrane, H+ is also taken in
What happens to iron after it’s absorbed into the enterocyte?
- Can be oxidized back to Fe3+ and stored as ferritin
- Fe2+ can be transported around the body - mostly carried to liver and BM
How does iron leave enterocytes?
Through a transporter on the basal surface called ferroportin (Ireg-1) as Fe2+
What happens to iron after it’s in circulation?
Hephaestin converts Fe2+ (ferrous) to Fe3+ (ferric) form
What is apotransferrin?
Unbound transferrin the blood
What are the 2 primary fates for iron?
- ~75% to the BM for erythropoiesis. Iron used for Hb to carry O2
- ~10-20% transferrin carries iron to liver where it is stored in ferric form (Fe3+) as ferritin
How does iron enter the liver?
There is a transferrin receptor on the hepatocyte membrane that endocytoses the transferrin w/ iron attached.
What happens after transferrin enters the hepatocyte?
- A vesicle forms around the transferrin
- H+ enters the vesicle -> decreased pH, which causes expression of DMT on the vesicle membrane and detachment of the transferrin/Fe3+
- Fe3+ (ferric) reduced to Fe2+ (ferrous), released into cytosol w/ H+
- Fe2+ oxidized to Fe3+ (ferric) so it can be stored as ferritin w/in hepatocyte
- vesicle releases transferrin back into circulation
What factors regulate plasma [iron]?
- hepcidin - produced and secreted by liver
-inhibits fxn of ferroportin (transporter on basal surface of enterocytes), so prevents release of iron into circulation, decreasing plasma [iron]
-blocks ferroportin in spleen to block splenic macrophages that breakdown RBCs from releasing iron into circulation
What stimulates hepcidin release?
- cytokines like IL-6
- increased [iron] (attached to transferrin)
- LPS (pathogenic components)
- HFE protein made by HFE gene (AKA hemochromatosis gene) is the primary regulator as it regulates the production of hepcidin
What happens if there is a mutation of the HFE gene?
Hereditary hemochromatosis
What happens with hemochromatosis?
Iron overload b/c hepcidin is not acting to block absorption in the intestines, from the liver, or from splenic macrophages
What is hemosiderosis?
Iron deposition in tissue
What is hemochromatosis?
Excess iron that -> organ damage due to free radical formation which damage the cell through lipid peroxidation, fibrosis & collagen deposition, and DNA damage
What is primary hemochromatosis?
Hereditary - autosomal recessive
-most common mutation in HFE gene (C282Y) but could also be due to mutations in the transferrin receptor (TFR2), or the hepcidin gene - HAMP
-> excess absorption of Fe2+
What is secondary hemochromatosis?
Due to transfusions (as w/ beta-thalassemia), excessive iron intake, chronic liver disease, porphyria cuteana tarda
What 3 genes control hepcidin production?
- TFR-2
- HJV: hemojuvelin
- HFE- encodes hepcidin
How does hemochromatosis present?
males 40 yo/ females 50yo
Common triad:
1. cirrhosis -> hepatocellular carcinoma
2. DM2
3. bronze skin
Other symptoms:
-dilated cardiomyopathy
-hypogonadism
-arthropathy (CPPD (arthritis) calcium pyrophosphate - Ca2+ in joints)
What is tx for hemochromatosis?
- phlebotomy
- deferiprone (chelation therapy) feri = ferric
What do labs look like w/ hemochromatosis?
increased ferritin, iron, % saturation ferrition
decreased TIBC
definitive w/ transferrin > 45 and serum ferritin >200 m, >150 females
Compare Wilson’s w/ hemochromatosis
Wilson’s: excess copper
age: teens-20’s (<40 yo)
mechanism: decreased excretion of copper
Hemochromatosis: excess iron
age: 40+, 50+
mechanism: increased absorption of iron
