IRON IN HEALTH AND DISEASE

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Dec 13, 2013 (3 years and 8 months ago)

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IRON IN HEALTH AND DISEASE



WHAT YOU NEED TO KNOW


1.

Daily requirements and dietary sources of iron

2.

Absorption of iron from the gut

3.

How body stores of iron are assessed

4.

Consequences of iron deficiency and iron overload

5.

The association of mutations of the
H
FE

gene with the most common inherited iron overload
disorder: HFE
-
haemochromatosis

6.

A diagnostic approach to microcytic anaemia

7.

Common causes of iron deficiency anaemia

8.

Management of iron deficiency anaemia

9.

Management of iron overload



A. IRON METABOLIS
M



A. 1.

INTRODUCTORY BACKGROUND


Iron is an essential element in living cells, and takes part in numerous metabolic
pathways. It is used to transport and store oxygen, and is an integral part of many
enzymes. Iron is almost always present as either the

ferrous or ferric ion, and can easily
cycle between these states. Because ferrous and ferric ions are so reactive, iron exists
only transiently as a free cation. It is usually found either bound to a specialized protein
called transferrin when it is tra
nsported in the blood, in an iron
-
protein complex for
storage, or as part of functional compounds such as enzymes. Under physiologic
circumstances, the quantity of iron in the body is carefully controlled to prevent
accumulation exceeding the storage capa
city of the body, which leads to progressive
injury to vital organs.












Clinical Relevance




Iron deficiency affects the whole body, but is commonly recognized
clinically when haemoglobin decreases and the patient becomes anaemic



Because free iron is so reactive, excess iron, which overwhe
lms binding
capacities, can lead to serious organ damage, e.g. iron loading disorders
such as haemochromatosis

Iron in Health and Disease


Haematological Aspects


Page
2



A.
2
.

IRON DISTRIBUTION

IN THE BODY


A.

Metabolically Active Iron




Haemoglobin


Most iron in the body is found in haemoglobin.

Iron binds with protoporphyrin
to form haem, wh
ich then binds with globin chains to form haemoglobin. 1
ml of packed red blood cells contains approximately 1 mg of iron. This means
that in a healthy 70 kg man, with a blood volume of about 5 litres, and red cell
volume of about 2 litres, there will be

2 grams of iron in haemoglobin alone.






















Iron Transported

in Blood


Iron is transported in the blood bound to the pr
otein transferrin.
The amount of
iron attached to transferrin is measured as the
serum iron
. The total capacity
of transf
errin to bind iron is called the
total iron binding capacity (TIBC)
, and
the
%

transferrin saturation

is the proportion of available iron binding sites
on transferrin, already occupied by iron atoms. These three parameters, serum
iron, TIBC, and % saturat
ion can be used in assessing patients for either iron
deficiency or iron overload.




Tissue Iron


Includes cytochromes and a wide variety of enzymes.




Myoglobin


This

muscle protein
, which acts a
s an oxygen reserve,
contains a haem group.



B.

Storage Iron


Storage iron exists in two forms:


A
P
PROXIMATE
DISTRIBUTION OF BODY IRON IN A MAN


Haemoglobin



2000

mg


Storage Iron



1000

mg


Myoglobin Iron



130
mg

Labile Pool




80
m
g

O
ther Tissue Iron



8
m
g

Transport Iron



3
m
g



Iron in Health and Disease


Haematological Aspects


Page
3



(a)

Ferritin


Ferritin is a
complex of ferric hydroxide and a protein (apoferritin), found
in virtually all cells and

tissue fluids. Ferritin

can be measured in the
b
lood, and
is the test commonly used to assess iron store
s
under most
circumstances.



Serum ferritin

(adult male) 10
-
300 µg/L


(adult female) 10
-
200 µg/L


(b)

Haemosiderin


Haemosiderin is found predominantly in cells of the monocyte
-
macrophage system in the marrow, and is derived from degraded ferritin.
Haemos
iderin is routinely assessed in marrow smears by a

special stain
(Perl’s reaction), which causes the haemo
siderin to appear blue. The
quantity of
marrow
haemosiderin is

another useful indicator of body iron
stores.

















A.

3.

DIETARY SOURCES O
F IRON


Haem iron derived from meat is a better source than dairy products, eggs, and vegetables.
The average western diet contains 10
-
15 mg/day of which only 5
-
10% is absorbed.
Absorption is increased at times of increased demand such as pregnancy or ir
on
deficiency.



Clinical Relevance:

Body Iron Statu
s Can be Measured




Serum iron level (transferrin bound iron)



Total iron binding capacity (TIBC): Measurement of
transferrin



Percentage transferrin saturation (Serum iron/TIBC x 100)



Serum ferritin: Level correlates with body stores



Haemosiderin assessment

in bone marrow

Iron in Health and Disease


Haematological Aspects


Page
4



A.
4.

IRON ABSORPTION


Elemental iron or dietary haem iron is absorbed principally in the duodenum and, to a
lesser extent, the jejunum. Gastric acid plays an important role in keeping iron soluble
and in the ferrous state. The control
of iron absorption at the level of the mucosal cell is
complex, and there are multiple proteins involved in iron transport int
o and from the
enterocyte.

Haem

iron enters the enterocyte by a different process from elemental ferrous
iron and is better absor
bed. Regulation of iron absorption is critical, because excess iron,
once it has entered the body, is not readily excreted. However, small amounts of iron are
lost daily mainly in the stool
, and, in women

additional losses occur during menstruation,
preg
nancy, and lactation. Absorbed iron, which passes through the mucosal cell, binds to
transferrin, and joins the iron transport pool. Most iron in this pool is derived from
senescent red cells. Iron in the transport pool is utilized predominantly by the
marrow for
red cell production.




A. 5.

PROTEINS INVOLVED IN
CELLULAR
IRON METABOLISM






Hepcidin



This peptide
, synthes
ized

in the liver,

is found in the blood. It
is the

most important regulator of

iron absorption and

metabolism
.

It functions by degra
ding
a transmembrane protein,

F
erroportin
, which is
found on all iron exporting cells
including enterocytes, macrocytes, and placenta. Ferroportin is
the sole
known cellular
iron exporter.

Hepcidin synthesis is partially
reg
ulated
by the

protein product of

the
HFE

gene
.
Hepcidin levels increase with infection and inflammati
on.




Transferrin receptors

are found on the surface membrane of all nucleated cells
in numbers that are a function of cellular iron requirements.
Transferrin carrying iron
binds to trans
ferrin receptors.





Apoferritin

binds to free iron to form ferritin, which functions both as a safe
storage site for iron, and a readily accessible reserve of iron.
















Clinical Relevance




Iron balance physiologically regulated by c
ontrol of iron absorption at
enterocyte. Surgical removal of stomach and duodenum associated with
development of iron deficiency



Mutations in the gene HFE associated with the most common form of
hereditary iron overload (HFE
-
haemochromatosis)



Humans unabl
e to excrete excess iron. Interventions which circumnavigate
the enterocyte, e.g. blood (red cell) transfusion can result in iron loading



Conditions such as infection and inflammation have an effect on iron
metabolism

Iron in Health and Disease


Haematological Aspects


Page
5




B. IRON DEFICIENCY


Iron deficiency is the commonest cause of anaemia
worldwide, and is of great socioeconomic
importance.



B. 1.

EVOLUTION OF IRON DEFICIENCY ANAEMIA




The earliest stage is the depletion of body iron stores, which is asymptomatic and
does not produce anaemia. Women, especially in the childbearing years, ha
ve lower
iron stores than men, and are more at risk of developing iron deficiency. As
deficiency progresses, iron deficient red cell production (erythropoiesis) develops,
followed by iron deficiency anaemia. During evolution to anaemia, the patient’s
hae
moglobin may still be in the reference range but well below “normal” for that
individual. Serum ferritin, however, will be low, indicating iron stores are
exhausted.



B. 2.

CLINICAL FEATURES: IRON DEFICIENCY


Clinical Symptoms:


Fatigue, headache, alter
ation in mentation, irritability, sore tongue, rarely pica or
dysphagia


Clinical Signs:


Pallor, smooth red tongue, angular cheilosis, spooning of nails (koilonychia), Plummer
Vinson Syndrome



B. 3.

LABORATORY DIAGNOSIS


Blood Count
:

Haemoglobin, MCV, an
d Red Cell Count decline together
with increasing iron deficiency. Causes a microcytic
hypochromic anaemia. Platelet count may be increased.

Blood Film:

H
ypochromic, microcytic
red cells, and may include
pencil
cells and target cells.

Serum Ferritin
:



De
creased.

Serum Iron
:



Reduced.

TIBC
:




Increased.

% Transferrin Saturation
:

Decreased (less than 16%).

Bone Marrow
:

Only performed in more complicated cases where results of
serum tests may be misleading. Haemosiderin will be
absent.


Iron in Health and Disease


Haematological Aspects


Page
6















B.

4.

DIFFERENTIAL DIAGNOSIS OF IRON DEFICIENCY ANAEMIA


Laboratory tests will help differentiate iron deficiency anaemia from two other common
causes of a microcytic anaemia: the anaemia of chronic disease and thalassemia (see
algorithm of microcytic anaemi
a). Usually only serum ferritin needs to be performed for
diagnosis of iron deficiency. If this is decreased, iron deficiency is confirmed.






MCV


SERUM
IRON



TIBC


%
SATURATION


SERUM

FERRITIN

BONE


MARROW
HAEMOSIDERIN

Iron Deficiency

Decreased

Low

High

Low

Decreased

Absent

Anaemia of
Chronic Disease

Normal to
Decreased

Low

Low

Low

Normal to
Increased

Increased

Thalassemia

Decreased

Normal to
High

Normal

Normal or High

Normal to
Increased

Normal or Increased



B. 5.

PRINCIPLES OF TREATMENT




Use O
ral Iron

-

Not enteric coated tablets



Replace Iron Deficit in Total:

Restore haemoglobin and MCV to normal








Replenish iron stores



Establish and Treat the Cause


ALWAYS REMEMBER THAT THE MANAGEMENT OF A PATIENT WITH
IRON DEFICIENCY IS NOT COMPLETE UNT
IL THE CAUSE HAS BEEN
ESTABLISHED AND TREATED AND/OR REMOVED.


Causes of Iron Deficiency


A.

Increased Physiologic Demand
, e.g. pregnancy, lactation, and rapid growth


B.

Blood Loss


Things you need to know about Laboratory Testing for Iron Status




Serum ferritin most useful single test. Sensitive for iron deficiency and excess



Low serum ferritin certain proof a patient is iron de
ficient



Normal serum ferritin does not entirely rule out iron deficiency



Certain conditions, e.g. infection, neoplasm, inflammation, raise serum
ferritin for reasons unrelated to iron status


Iron in Health and Disease


Haematological Aspects


Page
7



1.

From GI Tract
, e.g. hiatal hernia, gastritis, cancer of the colon, hae
morrhoids,
colitis, oesophageal varices, NSAIDS (non
-
steroidal anti
-
inflammatory drugs),
and aspirin

2.

From Uterus
, e.g. menorrhagia

3.

From Intravascular Haemolysis
with Haemoglobinuria


C.

Malabsorption
, e.g. partial or total gastrectomy, coeliac disease


D.

Dietary Iron Deficiency
, e.g. prolonged breast or bottle feeding of infants, poor nutrition
due to poverty, advanced age, adolescent dietary habits




C. IRON OVERLOAD



Iron overload is an important condition to be aware of because it is often both prev
entable and
treatable. Untreated it may cause serious organ dysfunction.


Causes of Iron Overload


1.

Hereditary haemochromatosis

2.

Multiple transfusions

3.

Liver disease

4.

Prolonged use of medicinal iron

5.

Ineffective erythropoiesis

6.

African Iron Ov
erload



Hereditary (homozygous HFE) Haemochromatosis


This is the most common cause of iron overload in North America. Missense mutations in the
HFE

gene are responsible for the majority of cases of hereditary haemochromatosis.
Haemochromatosis is trans
mitted as an autosomal recessive trait. In Caucasian populations of
northern European origin, approximately 15 percent are heterozygous for the most common
HFE

mutation, the C282Y mutation.


In this condition, iron overload results from a genetically det
ermined abnormality in the
regulation of iron absorption and delivery, which leads to increased iron absorption inappropriate
to need. Characteristically, iron accumulates preferentially in parenchymal cells rather than the
reticulo
-
endothelial system. T
he increased iron is deposited predominantly in the liver, but
subsequently in the pancreas, heart, and other organs. The pathogenesis appears to be related to
abnormal regulation of hepcidin synthesis by the HFE gene.


Iron in Health and Disease


Haematological Aspects


Page
8



Homozygosity for the C282Y
HFE

m
utation is the most prevalent mutation found in diagnosed
patients (± 80 percent). The second most common
HFE

mutation is H63D. Some patients are
compound heterozygotes for the C282Y/H63D
HFE

mutation. However, even on a biochemical
level, the homozygou
s state for C282Yis not always expressed, and the clinical penetrance of the
homozygous state is low.


Clinical Manifestations


Clinical expression of disease is modified by several factors including dietary iron intake, blood
loss, menstruation, pregnancy
, and blood donation. It is more common in men then women and,
in nearly 70 percent of cases, first symptoms develop between ages 40
-
60. Women generally
present later than men.


Most patients are diagnosed on the basis of biochemical changes such as a tr
ansferrin saturation
> 45
-
50 percent, increased serum ferritin, abnormal liver function tests, or non
-
specific
symptoms such as fatigue and arthropathy. Others may be diagnosed after referral for testing
because of the diagnosis in a family member.


Patie
nts with full
-
blown haemochromatosis may manifest with diabetes, cirrhosis,
cardiomyopathy, darkening of the skin, gonadal dysfunction, and impotence. Patients also
manifest increased susceptibility to infection. Where cirrhosis is present, there is an i
ncreased
risk for hepatocellular carcinoma.


Laboratory Diagnosis


1.

Elevated transferrin saturation (> 45
-
50 percent)

2.

Increased serum ferritin

3.

Genetic testing for mutations, i.e. C282Y and H63D at the
HFE

locus

4.

Evidence of parenchymal iron overload on live
r biopsy (Liver biopsy only performed in
selected cases)

5.

Amount of iron removed by venesection


Hereditary Haemochromatosis must be differentiated from other causes of iron overload. It may
be missed where there is already a clinical explanation for liver

disease such as excessive alcohol
intake. Some secondary causes of iron overload such as multiple transfusions are obvious.


Treatment


Phlebotomy by weekly removal of 450 cc of blood until serum ferritin is below 50 µg/L .

Then begin maintenance venesec
tion with frequency dictated by ferritin level.


Prevention


Screen family members




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