CSIM2.

25 IRON METABOLISM & STORAGE

BACKGROUND
It is important for 1) O2 transportation (Hb) and storage (Mb) molecules, 2) energy production
molecules Krebs cycle enzyme & oxidative phosphorylation, 3) liver detoxification molecule (CY P450),
4) host defence molecule (NADPH oxidase).

IRON DISTRIBUTION
1. Hematologists have been especially interested in the system of iron metabolism because iron is
essential for red blood cells, where most of the human body's iron is contained; in rbc as Hb
50%, Stored as ferritin, In muscles as myoglobin. In other haem proteins, eg. Cytochromes. Free
in serum 0.1%.
2. Understanding this system is also important for understanding disease of iron overload, like
HAEMOCHROMATOSIS and iron deficiency like IRON DEFICIEINCY ANAEMIA.
WHAT ARE HAEMS?

A haem is a prosthetic group consisting of an iron atom contained in the centre of a large
organic (porphyrin) ring.
Haems are most commonly recognized as components of haemoglobin,
the red pigment in blood.
Haem = >half of iron in western diet but much less in other diets.
Split from globin in intestine & absorbed by enterocytes.
o process not well understood

IRON STORAGE
Ferritin is a protein with a capacity of about 4500 iron (III) ions per protein molecule. This is the
major form of iron storage. Outer shell: apoferritin.
2. If the capacity for storage of iron in ferritin is exceeded, a complex of iron with phosphate and
hydroxide forms. This is called hemosiderin; it is physiologically available. (Bila ferritin penuh,
pakai hemosiderin)
3. As the body burden of iron increases beyond normal levels, excess hemosiderin is deposited in
the liver and heart. This can reach the point that the function of these organs is impaired, and
death ensues.
4. Ferritin always indicates Fe deficiency, but normal Ferritin cannot always exclude it, due to
acute phase effect, etc
1.

IRON REGULATION HEPCIDIN THE MASTER REGULATOR

Antimicrobial activity; Hepatic bacteriocidal protein

Hepcidin is a key regulator of the entry of iron into the circulation in mammals.
It has been found to have anti-inflammatory properties. This is a negative feedback: it reduces
the inflammation which caused the elevated hepcidin level
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. This
typically leads to anemia due to an inadequate amount of serum iron being available for
developing red cells.
When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs
due to excessive ferroportin mediated iron influx.
Blocks Fe release from enterocytes and RES macrophages by degrading the Fe exporter
Ferroportin.

REGUL ATORY MECHANISM

Erythropoiesis hepcidin
Makes intuitive sense, but exact mechanisms are unclear.

pO2 hepcidin
By transcription of FURIN and TMPRSS6 (matriptase-2) - genes that are responsive to
hypoxia-inducible factor (HIF).

Increased body Fe status hepcidin via

a circulating-iron signal (ferri-transferrin)
A cellular-iron-stores signal (BMP-6).

Infections and other forms of inflammation hepcidin

via IL6 cytokine & LPS
Direct antimicrobial action of hepcidin & inhibition of replication by limiting bacterial
access to circulating iron.

IRON BAL ANCE

Intestinal iron absorption

Increases with
decreased iron stores
increased erythropoietic activity
anaemia
hypoxia
Decreases with..inflammation
Hepcidin is the signal that transduces these inputs - It keeps Fe locked in
enterocytes until they eventually die & drop off into gut lumen (desquamation)
Excess iron absorption relative to body iron stores is the hallmark of hereditary
haemochromatosis (HFE, mainly).

IRON TRANSPORT
1. Red cells
- As haemoglobin
- Cannot be exchanged
2. Plasma
- Bound to transferrin
- Carries iron between body locations. Eg: between gut, liver, bone marrow, macrophages.
- Fe taken up into cells by transferrin receptors.
- Production in iron overload. Production in iron deficiency
SERUM IRON TEST

The serum contain about 0.1% of iron. Whereas, >95% serum iron is bound to transferrin.

It measure all serum iron (not in red cells)

Of limited use on its own in the interpretation of iron status.
Commonly combined with serum transferrin to express transferrin saturation (%).

TRANSFERRIN SATURATION TEST

% of transferrin iron-binding sites that are filled with iron

Combines two lab tests (Fe & transferrin) to sensitivity
Iron overload:
o iron + transferrin saturation (50100%)
= Best serum marker of increased body iron.
Used as biochemical screen for iron overload.

DISRUPTED IRON HOMEOSTASIS

1. Hepcidin Deficiency:
a. Hereditary Haemochromatosis:
i. Absorb excessive iron relative to body stores implying the set-point for the stores
regulator is altered.
b. Ineffective erythropoiesis:
i. Destruction of erythroid precursors (eg. thalassemia), but this is coupled to increased
iron absorption.
2. Hepcidin Excess:
a. Anaemia of Chronic disease:
i. Infection/inflammation induces iron sequestration in macrophages and decreases
intestinal absorption.
GENETIC HAEMOCHROMATOSIS

>95% defect in HFE gene

- typically homozygous C282Y mutation
- nearly 10% of Northern Europeans carry 1 allele
- Founder effect ~4-5,000 y.a. (spread by Vikings?)
HFE hepcidin overactivity of ferroportin
- duodenal iron absorption
Also hepcidin-independent mechanisms
- DMT1 and DcytB activity (= iron transporters)
Limited penetrance:
- Other genetic & environmental factors likely to be involved.
- Biochemical penetrance = 36-76%.
- clinical disease penetrance = 2-38% (men); 1-10% (women)
- Lower penetrance in younger women due to menstrual loss.

CELLS AND TISSUES THAT MIGHT BE AFFECTED BY IRON OVERLOAD FROM GHAEMO
1.
2.
3.
4.
5.

Beta cells in endocrine pancreas Diabetes mellitus.

Hepatocytes liver disease fibrosis cirrhosis -USS/biopsy.
Articular surfaces arthritis.
Heart muscle restrictive cardiomyopathy -Echo.
Pituitary gonadotrophs hypogonadotropic hypogonadism
a. LH+FSH deficiency causing 20 low testosterone -MRI

MANAGEMENT FOR IRON EXCESS

1. VENESECTION
2. Global (specific & general) & tissue-specific measures:
a. Depletion of iron stores by regular venesection. (takes years to achieve maximum
benefit)
b. Avoid EtOH & lose weight (hepatotoxic & insulin-resistance).
c. Diet, drugs and/or Insulin for Diabetes (interim or lifelong).
d. Testosterone replacement (may be interim or lifelong).

i. Testosterone for hypogonadism will energy levels, muscle function, bone

health/density, erythropoiesis & sexual function.
ii. Fertility (& testis volume) can be restored with a prolonged course of LH (hCG) &
FSH injections.