IRON
• 7 mg/1000 cal in diet; 10% absorbed
• Heme iron absorbed best, Fe2+ much better
than Fe3+
– Some foods, drugs enhance and some inhibit
absorption of ionic iron
– Ability to regulate absorption limited
• Absorption in proximal small intestine
• Absorption greater if there is erythroid
hyperplasia or hypoxia
N Engl J Med 2004;350:2383
Regulation of iron uptake and
storage. Hepcidin, a peptide
produced in the liver, is a key
regulator of iron release from
villus enterocytes and
macrophages. Hepcidin,
whose production is
upregulated by high plasma
iron levels or inflammation,
inhibits iron release from
these cells and lowers GI
absorption. Low iron levels
decrease hepcidin production,
which in turn stimulates iron
absorption and release into
the blood. The HFE gene
modulates hepcidin
production. Mutations in HFE
can cause diminished
hepcidin release, and can
eventually cause iron overload
(hereditary hemochromatosis).
1 cc of red cells contains about 1 mg iron
1 cc of whole blood contains 0.5 mg iron
IRON BALANCE
• 1-2 mg/day lost via desquamation, GI blood loss in
adult
• Negative iron balance possible in early childhood
• Menstruation, pregnancy, lactation promote
negative balance
• Positive balance (and eventual iron overload) can
occur in inherited disorders (hemochromatosis),
or as a result of repeated blood transfusions
♀
♂
Plasma levels of iron are closely
regulated to ensure a daily supply of
about 20 mg to the bone marrow for
incorporation into hemoglobin. Most
of the iron in the plasma derives from
the continuous breakdown of
hemoglobin in senescent red cells by
macrophages. 1 to 2 mg per day of
iron is also taken up by duodenal
enterocytes and transferred to the
plasma compartment or, depending
on body needs, stored in the
enterocytes as ferritin. These stores
are eliminated when enterocytes are
sloughed at the end of their life
cycles; apart from menstrual blood
loss, this is the only significant means
by which excess body iron is
excreted. Iron recycled by
macrophages and that absorbed from
the gut is loaded onto serum
transferrin and delivered primarily to
the bone marrow for reincorporation
into new red-cell precursors. The
remaining body iron (about 1000 mg)
is stored, primarily in hepatocytes.
N Engl J Med 2004;350:2383
IRON TRANSPORT AND STORAGE
• Absorbed iron oxidized to Fe3+ form
• Bound tightly to transferrin in blood
– Transferrin = total iron binding capacity (TIBC)
– Normally serum iron about 100 μg/dl, TIBC
about 300 μg/dl
• Iron transferred to cells and reduced to Fe2+
form, then inserted into heme or stored
• Storage iron (Fe3+) bound to ferritin
– Hemosiderin is denatured ferritin
– Small amount of ferritin in blood (nanograms)
ASSESSMENT OF BODY IRON
• Serum iron low in iron deficiency,
inflammation
• TIBC high in iron deficiency, normal or low
in inflammation
• Ferritin low in iron deficiency, increases in
inflammation
• Marrow iron stores absent in iron deficiency
• Combination of iron deficiency and
inflammation makes assessing iron stores
difficult
TESTS OF IRON STATUS
Practical aspects
• Low serum ferritin almost always indicates iron deficiency
• Low serum iron and high TIBC almost always indicate iron
deficiency
• Ferritin > 100 rarely found in iron deficiency
– Exception - liver inflammation/necrosis
• Normal serum iron rarely found in iron deficiency
– Exception - iron deficiency recently treated with oral
iron
• When TIBC is low or normal, low serum iron not a reliable
indicator of iron deficiency
• Iron deficiency may be hard to diagnose via blood tests in
setting of inflammation (eg, low iron, low TIBC,
intermediate ferritin level)
– Therapeutic trial of iron +/- EPO a reasonable alternative
to marrow biopsy
HYPOPROLIFERATIVE ANEMIA
Lower than expected red cell production
(erythroid cells in marrow and
reticulocytes) for degree of anemia
HYPOPROLIFERATIVE ANEMIA
Causes and examples
• Insufficient iron for hemoglobin synthesis
– Iron deficiency
• Diminished iron release from storage sites
– Inflammation
• Blunted or impaired erythropoietin production
– Inflammation, renal failure
• Inhibition of red cell progenitor proliferation by
cytokines
– Inflammation
• Marrow damage
– Aplastic anemia, myelophthisic disease
IRON DEFICIENCY
• Most common cause of anemia
• Usually due to chronic blood loss
– Exceptions: rapidly growing child,
malabsorption
• In young women this is usually due to
menstrual blood loss  pregnancy
• In anyone else must rule out GI blood loss
– Esophageal disease, hiatal hernia, ulcer,
inflammatory bowel disease, angiodysplasia,
hemorrhoids, cancer
Iron deficiency
Atrophic glossitis
“Spoon nails”
Absent iron stores
Normal iron stores
IRON DEFICIENCY ANEMIA
Treatment
• Oral ferrous salts
– Some patients have GI side effects
• Oral iron-polysaccharide complex
• IV iron dextran
– If oral iron not absorbed or not tolerated
– Slight risk of anaphylaxis
• Should see increased hemoglobin within 2-3
weeks
IRON OVERLOAD
• Hereditary hemochromatosis
– Autosomal recessive, HFE gene; genotype common but
low penetrance
• Other inherited disorders
– Mutations in other genes that regulate iron metabolism
– Africans, African-Americans
• Chronic ineffective erythropoiesis
– Thalassemia
• Repeated transfusion
– Toxicity after about 100 Units
IRON OVERLOAD
• Increased serum iron and high transferrin
saturation (90%+ in hemochromatosis)
• Very high serum ferritin
• Increased liver and marrow iron
– Quantitation of liver iron best indicator of
severity
• DNA test available for hereditary HC
IRON OVERLOAD
Clinical consequences
•
•
•
•
Cirrhosis, hepatocellular carcinoma
Cardiomyopathy, heart failure
Endocrine failure (esp diabetes)
Arthropathy
• Treatment of hereditary HC by phlebotomy
prevents these problems and can reverse
early tissue damage