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
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?
populations susceptible include:
1. Infants/young children
3. Menstruating females
4. *Pregnant women
5. Patients with malabsorption syndromes
6. Patients with intestinal parasites
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
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)
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)
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
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
Impaired taste/smell --> anorexia
Impaired wound healing
Infants and children may experience irritability, failure to thrive, developmental delay, or delayed sexual development