DISORDERS OF IRON METABOLISM.pdfTOXICOLOGY 2024.pdf

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1. DISORDERS OF IRON
METABOLISM
DR MRS SANDRA A N A CRABBE

4. Iron Distribution and functions
Compartment Iron content, mgFunction Total Body Iron, %
Haemoglobin Iron 2000 Oxygen transport 67
Storage iron (ferritin,
haemosiderin)
1000 Intracellular iron storage27
Myoglobin 130 Muscle oxygen storage 3.5
TransportIron (apotransferrin and
transferrin) -plasma
3 Plasma iron transport 0.08
Other tissue iron 8 0.2
Labile pool 80 No clear anatomic location2.2

5. Compartments
•Haemoglobin:-Most of the body’s iron is incorporated into
haemoglobin
•Ferritin:-Consists of a protein shell surrounding an iron core. Only
ferrous iron is taken up by ferritin and then oxidized to ferric iron.
Ferritin is present in nearly all cells of the body and provides a reserve
for the formation of Hb and other haem proteins. This stored iron is
shielded from body fluids and so is unable to cause oxidative damage.
(Free ionic forms are toxic). In serum minute quantities of ferritin are
present in concentrations proportional to total body stored iron. Liver
injury and many other pathologic processes not associated with iron
overload may cause release of relatively large amounts of ferritin into
plasma, leading to hyperferritinaemia

6. Compartments (cont’d)
•Haemosiderin:-it is aggregated partially deproteinised ferritin. It is
insoluble in aqueous solution and iron is only slowly released from it.
Also found predominantly in cells of the liver, spleen and bone
marrow.
•Tissue iron:-integral part of numerous cellular enzymes and
coenzymes eg peroxidases and cytochromes. Nearly half of the
enzymes of the Kreb’s cycle contain iron. These enzymes and
coenzymes which occur in all nucleated cells of the body are referred
to as tissue iron compartment and some iron enzyme activities
diminish early in the course of iron deficiency

7. Compartments (cont’d)
•Myoglobin:-similar to a single haemoglobin subunit
•Labile pool:-Has no clear anatomic location. It a concept derived
from kinetic measurements with radiolabeled iron

8. Haem (Iron protoporphyrin) Proteins
Involved in numerous biological functions such as
•oxygen binding and transport (haemoglobins),
•oxygen metabolism (catalases, peroxidases),
•cellular respiration, and electron transport (cytochromes).

9. Nonhaemiron proteins
Are important for fundamental cellular processes such as
•DNA synthesis,
•cell proliferation and differentiation,
•gene regulation,
•drug metabolism,
•steroid synthesis.

10. •Iron can also cause damage, because Fe(II) catalyzes the generation of
highly reactive hydroxyl radicals from hydrogen peroxide
•These hydroxyl radicals damage cellular membranes, proteins, and DNA.
•A large number of scavenger molecules protect cells against iron-mediated
tissue damage.
•Proteins sequester iron to reduce this threat. Iron circulates bound to
plasma transferrin, which is needed to offer the highly insoluble Fe(III) to
cells via the transferrin receptor
•Iron can safely be stored within cells in the form of ferritin and hemosiderin

11. Iron Regulation
•Takes place at 2 levels
•Systemic: requires tightly regulated communication between cells
responsible for absorption of iron from diet (duodenal enterocytes),
consumption of iron (mainly erythroid precursors) and storage of iron
(hepatocytes and tissue macrophages)
•Cellular: Cells involved in iron homeostasis are duodenal enterocytes,
hepatocytes, macrophages, and erythroid precursors

12. Iron Absorption

14. Iron Metabolism (Absorption)
•Iron from the diet is absorbed by an active process in the duodenum
and proximal jejunum.
•To be absorbed, inorganic iron must be in the ferrous state (Fe2+).
Haem is absorbed directly through a specific receptor
•Free ferrous iron via the divalent metal transporter 1 (DMT-1) and
•Haem-bound iron via the haem carrier protein 1
•In the enterocyte, some of the iron combines with apoferritin to form
ferritin
•Free iron in the enterocyte is exported via ferroportininto circulation

15. Iron metabolism
•In circulation, iron binds with apotransferrin (and becomes transferrin)
and gets into target cells by binding to transferrin receptors expressed on
the surface of such cells
•The receptor-transferrin complex is internalized into vacuole, that becomes
acidified, releasing the iron from transferrin, while the apotransferrin is
transported back to the cell surface and released ready to transport
additional iron. (transferrin cycle)
•The transferrin receptor forms a complexwith the human
haemochromatosis protein, producing changes in hepatic production of
hepcidin, a hormone produced by the liver that regulates iron homeostasis
in humans. Hepcidin deficiency underlies most known forms of hereditary
haemochromatosis

16. Iron metabolism (role of hepcidin)
•Hepcidin inhibits intestinal iron uptake
•It also inhibits release of iron from macrophages
•Hepcidin is homeostatically regulated by iron and erythropoietic activity
•Increased iron stimulates hepcidin production which in turn blocks
absorption of dietary iron and thus prevents further iron loading.
Decreased iron levels suppress its production leading to an increased
absorption of dietary protein and thus replenishing of iron stores
•Increase in erythropoietic activity suppresses hepcidin production thus
leading to both increased absorption of iron and rapid release of stored
iron from macrophages and hepatocytes all promoting the erythropoietic
activity
•Inflammation and infection also lead to increased hepcidin levels

17. Iron metabolism
•Many proteins influence iron homeostasis.
•Mutations in genes that encode these proteins may cause iron
overload or iron deficiency
•Proteins include:

18. Some proteins that affect iron homeostasis
Protein Function Effect of deficiency
Human hemochromatosis proteinMay transmit signal that upregulates
hepcidin
Increase Fe
Hemojuvelin Helps regulate hepcidin Increase iron absorption
Transferrin receptor 1 Binds and internalizes trans errinat the
membrane
Transferrin receptor 2 May transmit signal that upregulates
hepcidin
Hephaestin
Caeruloplasmin
Steap3
B2-macroglobulin
Transferrin
Hepcidin
Ferroportin

19. •Iron deficiency and iron overload are the major disorders of iron
metabolism.
•Abnormal distribution of iron or abnormal production of iron-related
proteins may play a primary or secondary role in other heritable or
acquired disorders

20. •hereditary hyper ferritinaemia–cataract syndrome,
•aceruloplasminaemia,
•GRACILE (growth retardation, aminoaciduria, cholestasis, iron
overload, lactic acidosis, and early death) syndrome,
•neuroferritinopathy,
•pantothenate kinase–associated neurodegeneration (formerly
Hallervorden-Spatzdisease),
•atransferrinemia, and possibly
•neurodegenerative disorders such as Parkinsonism, Alzheimer
disease, and amyotrophic lateral sclerosis (Lou Gehrig’s disease)

21. Indications for iron studies
Are useful in investigations for iron overload and iron deficiency
•Iron overload:-
i.at early stages may be asymptomatic or present with vague
symptoms
ii.Later stage manifestations might include deranged liver enzymes,
cirrhosis, erectile dysfunction, arthritis, cardiomyopathy
iii.Suspected iron overdose or toxicity

22. Indications cont’d
•Iron deficiency
i.Investigating aetiology of low Hb
ii.Symptoms of anaemia
iii.Menorrhagia
iv.Anaemia in pregnancy
v.Investigating poor growth in infants
vi.Distinguishing low iron store from functional iron deficiency

23. Parameters of iron studies
•Serum Iron:-refers to ferric iron bound to serum transferrin and not
iron contained in free Hb. It is decreased in many but not all patients
with iron deficiency anaemia. Conditions that are known to affect
serum iron concentration include the following
i.Diurnal variation
ii.Menstrual cycle
iii.Pregnancy:-may elevate due to progesterone and lower due to iron
deficiency
iv.Ingestion of iron
v.Oral contraceptives (progesterone-like)

24. Parameters
vi. Iron contamination
vii. Iron dextran injection
viii. Hepatitis:-owing to hypferritinaemia from hepatocyte injury
ix. Acute inflammation:-eg respiratory infection, abscess, immunization,
myocardial infarction:-low or normal
x. Chronic inflammation or malignancy:-low or normal
xi. Iron deficiency:-low or normal
xii. Iron overload:-high
These also tend to affect transferrin saturation(TSAT%) and total iron binding
capacity (TIBC)

25. Parameters
•Total iron binding capacity:-since only a third of iron-binding sites of
transferrin are occupied by ferric iron in normal subjects, serum
transferrin has considerable reserve iron-binding capacity
(unsaturated iron-binding capacity, UIBC). The TIBC is a measurement
of the maximum concentration of iron that transferrin can bind. It
varies in disorders of iron metabolism. It is increased in many persons
with chronic inflammatory disorders or malignancies. In many with
untreated haemochromatosis, the TIBC is slightly decreased.
•Transferrin saturation(%):-is calculated as follows 100 X Serum Iron
TIBC

26. Parameters
•Serum transferrin concentration g/L:-may be estimated
0.007xTIBC(ug/dl). Transferrin concentration may be measured
immunologically too but has little clinical utility. TIBC is used instead
•Serum ferritin:-Normally present in blood in very low concentrations.
Its serum concentration roughly reflects body iron content. It is an
acute phase protein. Levels decline very early in the development of
iron deficiency long before changes in Hb concentration, erythrocyte
size etc in blood is noticed. It is therefore a sensitive indicator of iron
deficiency uncomplicated by other concurrent disease.Alternatively,
other disorders result in increased serum ferritin levels

27. Parameters
•Such disorders include chronic infections, chronic inflammatory
disorders (rheumatoid arthritis, renal disease), common liver
conditions, heart disease, numerous malignancies
•In patients with these disorders who also have iron deficiency the
serum ferritin level is often normal
•Also increased in iron overload of any cause. For early detection
TSAT% is more sensitive

28. Parameters
•Serum transferrin receptor:-the cell membranes of developing
erythroid cells in bone marrow are rich in transferrin receptors
(remember transferrin cycle). The number of these receptors increase
in the presence of iron deficiency and decrease in iron excess. The
variations in quantity of the receptors is reflected in changes in
soluble serum transferrin receptors and these can be measured by
standard immunoassay technique. To a large extent, serum transferrin
receptor concentrations reflect rate of erythropoietic activity,
regardless of iron status of patient.

29. A Guide to interpreting iron studies
SerumIronSerum transferrin or
TIBC/TSAT%
Serum ferritin Soluble transferrin
receptors
Considerable
variation
occurs within
a day in
individuals
and
assessment of
serum iron
alone provides
little helpful
clinical
information.
Iron is bound to
transferrin in the plasma.
Total iron binding capacity
(TIBC) is a direct measure
of level of transferrin.
Transferrin levels are
reduced in inflammation.
Level of transferrin
saturation is particularly
helpful if assessment of
early stages of iron
overload with levels >
55% for males and > 50%
for females indicative of
iron overload (should be
fasting level for more
accurate assessment)
Small amount of circulating
serum ferritin reflects body iron
stores.
Is now well established in
assessment of iron stores
Normal range 15 –300 ug/l
(reference ranges vary
depending on the method used)
Levels < 15 ug/l reflect absent /
reduced iron stores
Elevated levels may reflect iron
overload but will be increased in
liver disease, inflammation or
malignant disease. In the
presence of
inflammation, a level of > 100
ug/l generally excludes iron
Transferrin receptors are
present on cell surfaces and
are responsible
for the internalization of
transferrin resulting in
intracellular release or
iron. In the absence of
adequate iron stores,
expression of transferrin
receptors increases.
The amount of soluble
transferrin receptor closely
reflects iron stores
and is not affected by the
inflammatory process.
Increased levels of
soluble transferrin receptor

30. Ferritin Iron TIBC TSAT%
Function Total body ironAmount of
circulationg iron
bound to transferrin
Blood capacity to
bind iron with
transferrin
Ratio of serum iron
to TIBC
Interpretation Increased:-Acute
phase protein,, iron
overload, liver
disease etc
Decreased:-iron
deficiency
Increased:-iron
overload, iron
therapy
Decreased:-iron
deficiency, chronic
illness
Increased:-iron
deficiency
Decreased:-chronic
disease
Increased:-iron
overload, iron
therapy
Decreased:-iron
deficiency, chronic
disease
Important notesFalse normal or
elevated result due
to inflammation,
hepatocellular
damage, malignancy
Low result due to
inflammation,
malignancy,
hypoproteinaemia
Increased result in
pregnant women,
patients taking
oestrogen
supplements, oral
contraceptive pills
Falsely elevated
result due to recent
iron ingestion.
Fasting sample
should be taken

31. iron TSAT Ferritin STfR Trial of iron
therapy
Iron deficiencydecreased decreased decreased increased Hbnormalizes
Iron deficiency +
acutephase
reaction
decreased decreased Normal
<100ug/dl
increased Partial response
Acute phase
reaction
decreased decreased increased normal No response
Iron overloadincreased increased increased decreased Not appropriate