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What are exogenous sources of Iron? Endogenous?
- exogenous: diet
- endogenous: recycled RBCs
- senescent RBCs are degraded by macrophages of the reticuloendothelial system (RES), primarily in LIVER, SPLEEN, & BONE MARROW
- ~60% of the iron in a degraded RBC is recycled into a new RBC
How is dietary (exogenous) iron ingested?
- in two forms: heme or non-heme iron
- Heme Iron comes from animal sources like meat, fish, & poultry (animal sources also contain iron not complexed to heme which can represent up to 50% of iron in animal foods)
- Non-heme Iron: found in plant sources + iron supplements (nuts, vegetables, fruits, grains, tofu, & dairy)
- whole grains may contain iron
- refined flour is fortified with iron
- non-galvanized cooking pots may also contribute dietary iron
How is iron is transported in the blood?
- the protein transferrin carries it between the intestine, RES, bone marrow, & sites of storage
- there is very little free iron in the blood; it's primarily bound to transferrin or other binding proteins
In what form & where is iron stored?
- 1. ferritin
- 2. hemosiderin
- it's primarily stored in the liver & RES
Why is free, unbound iron tightly regulated?
to prevent reactive oxygen species from forming
Heme Carrier Protein 1
- protein in the duodenum & jejunum that absorbs the heme part of heme-iron
- this occurs after heme-containing foods undergo protein hydrolysis in the stomach + small intestine
- after uptake into the intestinal mucosal cell, hydrolysis separates the iron from heme
- the free iron is then bound to ferritin in the enterocyte
After eating heme-containing foods (meat, fish, poultry), what form of iron is found in enterocytes after heme-iron has been taken up?
inorganic ferrous Fe
How is non-heme iron digested?
- 1. non-heme iron is hydrolyzed from food components in the stomach & intestine --> mostly ferric (Fe3+) iron is released into the small intestine
- 2. in the alkaline SI, Fe3+ may complex to hydroxide --> Fe(OH)3
- ferric hydroxide is insoluble & can't be absorbed into intestinal epithelial cells
- 3. ferric reductase (ferric/cupric duodenal CYTOCHROME B reductase, Dcytb), a protein located on the brush border surface of enterocytes reduces Fe+3 to Fe+2
- 4. Fe2+ is absorbed via the divalent cation transporter 1 (DCT1, DMT1)
In what form must non-heme iron be in to be absorbed in the intestinal mucosa (i.e. iron supplements, nuts, vegetables, fruits, grains, tofu, dairy)?
- the soluble Fe2+ form
After being absorbed into the enterocyte, what must happen to iron before it can be exported into the portal circulation?
- Fe 2+ is transported out of the enterocyte at the basolateral membrane by FERROPORTIN (Fp)
- hephaestin or ceruloplasmin (basolateral membrane protein) OXIDIZES Fe 2+ --> Fe 3+ (ferric form)
- TRANSFERRIN binds ferric iron & transports it through the portal circulation
What factors may ENHANCE non-heme iron absorption?
- Reducing Agents
- Acids in the small intestine like Vitamin C (help solubilize iron)
- Chelation by organic molecules [ligands] - maintain reduced iron (meat, poultry, fish, mucin, sugars)
- Iron deficiency (results in increased synthesis of DMT1 -> increases absorptive capacity)
By what mechanism do factors that impair non-heme iron absorption act?
- by binding iron in the intestinal lumen, by reducing solubility, or by competition with absorptive mechanisms
- Polyphenols (tannic acid in tea + red wine or chlorogenic acid in coffee)
- Oxalic acid (vegetables, fruits, some grains)
- Phytates (vegetables, fruits, some grains)
- Phosphorylated serine residues (eggs)
- Divalent Minerals (Calcium, calcium phosphate salts, zinc, manganese, nickel)
How is iron transported in the blood?
- it must be bound to transferrin
- saturation of iron binding sites on transferrin is usually ! 30%. Saturation may be decreased in iron deficiency or increased in iron overload syndromes.
What is the saturation of iron binding sites on transferrin usually?
- it may be decrease in iron deficiency or increase in iron overload syndromes
How is iron delivered to tissues from the circulation?
- 1. transferrin binds to the transferrin receptor (TfR)
- 2. the transferrin-receptor complex is endocytosed into the cell
- 3. once internalized, proton pumping occurs to lower the pH in the vesicle containing the transferrin-receptor + iron complex
- 4. the low pH causes the iron to separate from transferrin
- 5. transferrin alone is returned to the blood & TfR returns to the cell surface
- 5. iron is either incorporated into functional proteins or stored in ferritin or hemosiderin
Where does storage of iron primarily occur?
the liver & RES (reticuloendothelial system, which consists mainly of phagocytic cells in reticular connective tissue)
Where is iron primarily lost from the body?
- 1. the gastrointestinal tract as microscopic (occult blood) loss
- 2. mucosal cell loss
- 3. in bile
- 4. desquamated (flaked off) skin cells
- 5. urine
- 6. general blood loss
- men lose ~1 mg/day
- menstruating women lose~1.5 mg/day
What is the physiologic mechanism to excrete excess iron?
there is none
What is the most common nutritional deficiency world-wide?
- Iron Deficiency
- populations susceptible include:
- 1. Infants/young children
- 2. Adolescents
- 3. Menstruating females
- 4. *Pregnant women
- 5. Patients with malabsorption syndromes
- 6. Patients with intestinal parasites
- 7. Vegetarians
- 8. People with chronic gastrointestinal or other losses
What is the progression of iron deficiency?
- negative iron balance --> iron depletion --> iron deficiency anemia
- fatigue, lethargy, cognitive impairment, reduced physical capacity, cold intolerance, immune impairment, poor pregnancy outcomes, & increased risk of lead poisoning can occur during iron depletion even without concomitant anemia b/c lots of reactions in the body require iron
- condition in which the tongue is swollen and changes color, often making the surface of the tongue appear smooth
- caused by IRON deficiency (sometimes vitamin B12 also)
Angular Stomatitis (Cheilitis)
- Iinflammation of the corners (angles) of the lips
- a sign of underlying iron deficiency anemia, or vitamin B deficiencies (eg. B2-riboflavin, B9-folate or B12-cobalamin, which in turn may be evidence of poor diets or malnutrition such as celiac disease)
- spoon nails; a nail disease that can be a sign of iron-deficiency anemia
- abnormally thin nails which have lost their convexity, becoming flat or even concave in shape
How is iron deficiency treated?
- iron supplements (or intravenous iron)
- increasing consumption of iron in food
- decreasing inhibitors of non-heme iron absorption
- addition of enhancers of absorption (vitamin C)
- iron has low bioavailability so treatment may be needed for weeks to months
What are the primary side effects of oral iron supplements?
nausea & constipation
given the generally poor bioavailability of iron in a mixed diet and the ability of the intestine to regulate iron absorption and transport from enterocytes dietary iron overload sufficient to cause disease is rare unless there are genetic or other factors that promote overload
- a peptide hormone produced by the liver that acts as the master regulator of iron homeostasis
- when present it inhibits iron transport out of both enterocytes AND macrophages, preventing excess iron absorption and maintaining normal iron levels within the body
- it also regulates (decreases) expression of ferroportin on the basolateral membrane of enterocytes, without which iron can't leave/be transported out of enterocytes
hereditary hemochromatosis (HH)
- is the most common form of iron overload; due to genetic defects in hepcidin or its pathway of action
- results in iron absorption despite high levels of excess iron
- dietary modification doesn't work as a treatment, patients need to undergo regular phlebotomy (bleeding)
African (Bantu) Iron Overload
- genetic form of iron overload in which iron overload occurs but only with HIGH LEVELS of iron intake (iron pots/containers for cooking may activate it)
- such people can more easily change diet than people with HH to prevent iron overload
Daily Iron RDAs
- adult men, postmenopausal women: 8 mg
- premenopausal women: 18 mg
- pregnant women: 27 mg
- adolescent males: 11 mg
- adolescent females: 15 mg (growth/RBC expansion needs)
What is the UL of iron?
- 45 mg/day based on GI symptoms (nausea/vomiting, constipation)
- very high acute doses can result in death due to CNS, cardiac, & pulmonary toxicity
- in children, iron supplements are a common cause of accidental overdose
- a metal that plays key roles in:
- 1. nerve function
- 2. transport of iron out of enterocytes
Where is copper found in the diet?
liver, shellfish, meats, whole grains, nuts, seeds, & legumes
Where is dietary copper predominantly absorbed?
- in the reduced state in the STOMACH & duodenum by Ctr & DMT1 transporters
- after which it's taken up by the liver & incorporated into ceruloplasmin
- copper is secreted from the liver on ceruloplasmin
How does the body get rid of excess hepatic copper?
- it's secreted by the liver into bile via the copper ATPase
- from there it's excreted in feces
Wilson’s Disease (WD)
mutations in the copper ATPase causes hepatic copper OVERLOAD as copper cannot be transported out of and therefore accumulates in the liver & other tissues
Menkes’ disease (MD)
a mutation of the copper transporter that results in copper DEFICIENCY
What are biochemical measurements of copper status?
- 1. serum copper
- 2. ceruloplasmin (copper carrying protein)
- 3. CBC & iron tests may provide information about hematologic complications of deficiency
ocular signs of copper overload that can be detected by a slit-lamp exam
What are risk factors for copper deficiency?
- upper gastrointestinal surgery (gastrectomy, gastric bypass surgery)
- use of zinc supplements other zinc source (eg. denture cream)
- Celiac disease
- Menkes’ disease
What are symptoms of copper deficiency?
- • Neurologic: sensory and motor manifestations may mimic vitamin B12 deficiency, which can delay diagnosis/treatment in relation to gastric bypass
- Myelopathy (spinal chord)
- Peripheral neuropathy
- • Hematologic
- Anemia (normo, micro, macrocytic)
- • Iron deficiency due to impaired copper-mediated transport
How might zinc supplementation cause copper deficiency?
- more zinc (aka supplementation) feeds-forward more metallothionein production
- while metallothionein binds zinc, it binds copper more avidly
- therefore copper gets trapped in enterocytes & disposed of when they shed
What is a risk of chronic copper toxicity?
- liver disease and cirrhosis
- Wilson’s disease = most common cause of copper overload
- Dietary overload can be caused by supplements or copper cook-ware
What is a complication for patients who require parenteral nutrition of copper because of a deficiency?
- hepatic cholestasis - where bile cannot flow from the liver to the duodenum
- more prevalent in infants than in adults
- an essential trace element found in nearly 100 enzymes
- it's a catalyst for hydrogenation
- provides structure to proteins & cell membranes
- is involved in regulatory functions in gene expression, cell signaling, and apoptosis
- it may improve healing of poorly healing wounds (eg. decubitus ulcers, aka bed sores)
What are the physiologic functions of zinc?
- Growth & development
- Neurological function
- Macronutrient metabolism
- Taste & olfaction
What are the main sources of zinc in the US? Where else is it found in the diet?
- meat & poultry
- it can also be found in shellfish, meat, poultry, nuts, legumes whole grain or fortified cereals, eggs, & dairy
- zinc is absorbed by enterocytes & once inside is carried by metallothionein, the production of which is increased in response to high doses of zinc
- approximately 1/3 of ingested zinc is absorbed in the small intestine
Why does zinc supplementation cause copper deficiency?
- because copper can also bind to metallothionein but isn't exported once bound
- if high zinc levels increase the amount of metallothionein, more copper becomes bound and trapped in enterocytes
- copper is lost when the enterocyte is shed
In zinc better absorbed from animal or plant sources?
- it is better absorbed from ANIMAL sources since phytates in plant foods bind zinc & reduce its bioavailability
- phytates can be destroyed by the fermentation process in leavened bread
How is zinc primarily lost?
- from secretion into the gastrointestinal tract
- a small amount is excreted by the kidneys, which may be increased in certain conditions (alcoholism)
- a small amount is lost on body surface (in skin & sweat)
How are zinc levels measured?
- by assessing dietary intake, potential losses, & supplement use
- biochemical tests do not consistently reflect tissue zinc
- normal blood concentration levels of alkaline phosphatase suggest zinc sufficiency b/c it's a zinc-dependent enzyme
- low plasma zinc concentrations suggest deficiency
- severe: caused by intestinal malabsorption, chronic diarrhea, burns, or acrodermatitis enteropathica
- moderate: caused by inadequate intake, restricted or vegetarian diets, alcoholism, pregnancy, lactation, rapid growth due to increased demands, exclusively breastfeeding after the first 6 months of life, or aging
- a rare metabolic disorder caused by a mutation in a transmembrane protein that serves as a zinc uptake protein --> zinc deficiency
- can be treated with oral zinc but requires high dose lifelong therapy
Symptoms of Zinc Deficiency
- Skin rashes around orifices (mouth, anus, perineum) & extremities
- rashes appear erythematous & scaly but may become pustular, crusted or erosive
- Infection (pneumonia)
- Impaired taste/smell --> anorexia
- Impaired wound healing
- Infants and children may experience irritability, failure to thrive, developmental delay, or delayed sexual development
How is zinc deficiency treated?
oral or parenteral zinc
- acute causes abdominal pain, nausea, vomiting, & dizziness
- chronic (high intakes exceeding 100mg/day) can cause immune dysfunction & a drop in HDL cholesterol
- intakes greater than 60mg/day may result in a copper deficiency & its associated neurological damage
- zinc can be found in some denture adhesives and toxicity has occurred in those who swallow large amounts