diagnosis of iron deficiency and iron overload nov 06

7/27/2019 Diagnosis of Iron Deficiency and Iron Overload Nov 06

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A REGULAR CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs

The Royal Co llege o f Pa thologists of Australasia The Royal Co llege o f Pa thologists of Australasia

NOVEMBER 200

A J OINT INITIATIVE OF

Normal iron status

Iron deficiency

Case studies

CONTENTS

CSPCommon Sense Pathology


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Dr Alan R McNeil, head, department of chemical

pa thology, Dorevitch P atho log y, Heidelberg, Victo ria .

Emeritus Professor Jack Metz,consultant haematologist,

Dorevitch Pathology, Heidelberg, Victoria; and honorary

cons ultant, depa rtment of ha ematology, Royal Melbourne

Hospital, Victoria.

For an electronic version of t his and previous articles, you can visit www.australiandoctor.com.au Click on

Clinical and Library, then Common Sense Pathology. You c an also visit the Royal College of Patho logists of

Australasias web site atwww.rcpa.edu.auClick on Publications and Forms, then Common Sense Pathology.

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Normal iron statusHealthy adults have 3000-4000mg of iron in their body, most of which is found inside haemoglobin.

Iron is efficiently recycled, so daily requirements are only 1-2mg. These requirements are increased in

children and women of reproductive age, and can be five times higher during pregnancy.

Bleeding is the most common cause of increased iron losses with each 1mL of blood containing

0.5mg of iron. For example, daily iron requirements may be doubled in someone losing 80mL of

menstrual blood per month or 2-3mL of blood each day from a bleeding bow el cancer.

Because most of t he iron in food is not a bsorbed, da ily dieta ry requirements range from 10mg to

20mg. Depending on diet, most iron comes from plant sources even though this is less well

absorbed than the iron in red meat. The fraction absorbed increases in people with iron deficiency.

Absorption is increased by ascorbic acid a nd d ecreased b y drugs such as t etracyclines and a ntacids,

as w ell as by natura lly occurring iron binders in food like phytates in vegetables and ta nnins in tea.

Iron status can be viewed as a continuum between iron-deficiency anaemia at one end and iron

overload at the other. Many people lie between these extremes with milder degrees of iron deficiency

and excess. They typically have normal haematological parameters and diagnosis depends on the

detection of reduced serum ferritin and increased transferrin saturation, respectively (table 1).

Diagnosis of iron deficiencyand iron overload

Co ver: Computer artwo rk of ana emia. David Mac k/Sc ience Pho to Library.


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Common indications for requestingiron studiesThere are five common reasons to request iron

studies because of suspected iro n deficiency.

1. Investigation of fatigue.

2. Investigation of anaemia.

3. Investigat ion of someone with blood loss.

4. N utritional assessment, particularly in earlychildhood and pregnancy.

5. Monitoring iron therapy.

Fatigue is a common reason for attending the

doctor. Full blood examination is an important

investigation in a ny pat ient w ith unexplained

fatigue, as are iron studies in any women of

reproductive age because of the high prevalence of

iron deficiency in this group.

Groups of patients at increased risk

of iron deficiencyInfants, growing children and pregnant women

are at high risk of iron deficiency. Iron deficiency

can develop by 2-3 months of age in premature

infants but is more common in t hose older tha n

six months w ho a re exclusively breast fed, a nd in

infants 9-18 months who are fed with cows milk

or low -iron-content formulas. Pa tients on

haemodialysis are also at high risk due to d ialysis-

related blood loss and the demands on erythro-

poiesis from erythropoietin therapy.

Case study 1A 21-year-old woman presented to her doctor

with fatigue as her major complaint. She was

of Mediterranean ancestry and had an

unremarkable medical history and a normal

diet. The results of a full blood examination,

iron studies and subsequent haemoglobinanalyses were:

H aemoglo bin 120g/L (reference interval

[RI] 115-165g/L)

Packed cell volume (PCV) 37.3%

(RI 37.0-47.0%)

Red cell count (RC C) 5.29 1012

/L (RI

3.80-5.80 1012

/L)

M ean cell volume (M CV) 71fL* (RI

80-96fL)

Mean corpuscular haemoglobin (MCH)

22.7pg* (RI 27.0-32.0pg)

Iron 11mol/L (R I 7-27mo l/L) Tra nsferrin 3.8g/L* (RI 2.0-3.6g/L)

Transferrin sat ura tion 14% (RI 13-47%)

Ferritin 13g/L* (RI 15-165g/L) Haemoglobin A 94.6%* (RI >95.6%)

Haemoglobin A2 4.7%* (RI


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What is your interpretation of theseresults?This patient has iron deficiency (low ferritin and

raised t ransferrin) and beta-thalassaemia minor

(raised haemoglobin A2). Low serum ferritin is

the single most reliable marker of reduced iron

stores in all clinical settings (children, adults and

pregnant women). Serum iron is usually reduced

in people with iron deficiency, although it w as

normal in t his patient. The main problem with

using serum iron measurements to assess iron defi-

ciency is that levels are often decreased in people

with normal iron stores.

Iron deficiency is often also a ssociated w ith

increased serum transferrin concentration.

However, assessment using serum transferrin is

limited because it is increased by high oestrogen

levels in pregnancy and in w omen taking hormone

replacement therapy or the oral contraceptive pill,

and decreased in people w ith infection, inflamma-

tion, renal fa ilure and malignancy.

Why is it important to establish thecause of microcytosis in a young

woman?Distinguishing the microcytosis and hypo chromia of

iron-deficiency ana emia from t hat of thala ssaemia

minor is essential because iron therapy is indicated

in the former but contraindicated in the latter, unless

there is concomitant iron deficiency (as in this case).

The distinction is particularly important in preg-

nancy due to the potential impact on the fetus if

both parents have a haemoglobinopathy. In people

with thalassaemia, serum iron, transferrin saturation

and ferritin a ll tend to be increased, so the low fer-

ritin in this patient is particularly significant. The

main distinguishing features of iron deficiency andthalassaemia are shown in table 1 (page 3).

What other investigations arerequired?No other tests are needed in t his patient although

the cause of t he iron deficiency should alw ays be

established. This is particularly important in

groups where iron deficiency is less common, such

as men and postmenopausal women, and causes

such as bloo d loss from bo w el cancer need to b e

excluded. Young women a re often in a precarious

iron balance, so diet and menstrual history is

important. Coeliac disease should be considered

as one of the less common causes of iron deficien-

cy, particularly if there is a family history.

Case study 2A 42-year-old woman presented with pain in

her hands and wrists. She had been taking

increasing doses of NSAID s to contro l the

pain. Examination showed active synovitis

affecting the wrists and metacarpophalangeal

joints in both hands. Her blood results

showed:

H aemo glob in 87g/L* (RI 115-165g/L)

PCV 31.0%* (RI 37.0-47.0%)

RCC 4.28 1012

/L (RI 3.80-5.80 1012

/L)

M CV 72fL* (RI 80-96fL)

MCH 20.3pg* (RI27.0-32.0pg)

Iron 4mol/L* (RI 7-27mo l/L) Tra nsferrin 3.0g/L (RI 2.0-3.6g/L)

Transferrin saturation 8%* (RI 13-47%)

Ferritin 45g/L (R I 15-165g/L) C-reactive prot ein 112mg/L* (RI


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hypochromic and microcytic. Serum ferritin levels

are typically decreased in iron deficiency and

increased w ith inflamma tion, w hereas serum

transferrin levels are usually high in iron deficien-

cy and low with inflammation (table 1, page 3).

It is important to remember that in people with

iron deficiency and concurrent infla mmation,

serum ferritin levels may be tow ard the low er end

of t he reference interval but not f rankly a bnormal,

because inflammation tends to increase ferritin

levels. People with ferritin levels less than 50g/L

may be iron deficient, although those with

levels greater than 100g/L are usually ironreplete.

If the iron studies are inconclusive, options

include:

Repeating the blood tests in 1-2 weeks.

Investigating fo r gut blood loss, regardless.

Review ing the patient after a 2-3 w eek trial of

oral iron therapy.

If standard blood tests are unhelpful in

haemodialysis patients the response to a dose of

intravenous iron may be the most effective way to

establish a diagnosis of iron deficiency.

What new tests are available forassessing iron status?Soluble transferri n recepto rTransferrin recepto rs

are responsible for the uptake of transferrin-

bound iron by cells in the bone marrow. They

increase when t here is increased red cell turnover

(haemolytic anaemias and thalassaemia) and with

iron deficiency, as the bone marrow seeks more

iron. They decrease with iron overload. The con-centration of soluble transferrin receptors in the

serum reflects the number of these receptors in the

bone marrow and can be used as a w ay of diag-

nosing iron deficiency. This test is not widely

available but its theoretical advantage is that it is

a go od ma rker of iron deficiency that , unlike fer-

ritin, is not affected by inflammation.

Red cell zinc protoporphy rinIf there is insuffi-

cient iron to insert into protoporphyrin to make

haem the body incorporates zinc instead, making

zinc protoporphyrin (ZPP). ZPP has a distinctivefluorescent fingerprint that can be measured a s an

indicator of iron deficiency. Levels also increase

w ith lead poisoning, disorders of haemoglobin

synthesis and chronic inflamma tion.

Reticulocyte haemoglobin concentr ation (RET-

H e) and percent hypochr omi c red cell sThese

measurements are availab le on some new a uto-

mated haematology analysers and may be useful

in diagnosing iron deficiency in the presence of

inflammation. They are not widely available and

5

Figure 1. Normal blood film (top) and

hypochromic, microcytic changes of

moderate iron deficiency (bottom).


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their true value will not be know n until research

has been completed.

Case study 3A 61-year-old woman presented with fatigue.

Abnormal liver function tests had been noted

one year earlier but not investigated. H er

latest blood tests w ere:

Iron 42mol/L* (RI 7-27mo l/L) Tra nsferrin 1.9g/L* (RI 2.0-3.6g/L)

Transferrin saturation 95%* (RI 13-47%)

Ferritin 3241g/L* (RI 15-165g/L) H aemoglo bin 155g/L (RI 115-165g/L)

M CV 103fL* (RI 80-96fL)

Bilirubin 14mol/L (R I


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sis in people with northern European ancestors

but there are many people with haemochromato-

sis who do not have these particular mutations.

They would be missed if gene testing alone was

used to screen for disease.

Some people with the C282Y mutation never

develop haemochromatosis because other genet-

ic and environmental changes are required to

develop disease. Because it is assumed that peo-

ple with high levels of serum ferritin and trans-

ferrin saturation will develop clinical disease

eventually, treatment decisions are based on

measurements of these parameters: it is not

necessary to w ait unt il signs and symptoms

develop.

As with all genetic tests, counselling must be

provided before any testing is undertaken.

If a patient has an increased transferrin satura-

tion the first thing to do is check whether they

are ta king iron supplements and to find out if

they have a family history of haemochromatosis.

The iron studies should be repeated and the gene

test requested if the transferrin saturation is still

increased after cessation of supplements.

Conclusions Low serum ferritin, not low serum iron, is the most reliable marker of uncomplicated iron deficiency.

If serum ferritin exceeds 100g/L iro n deficiency is unlikely (Table 2). Babies, grow ing children and pregnant w omen are at high risk of iron deficiency.

Iron deficiency is a sign, not a diagnosis. You must establish the cause, particularly in men and

postmenopausal w omen in w hom iron d eficiency is usually due to chronic blood loss.

Ra ised t ransferrin satura tion, not ferritin or haemoglobin, is the most useful marker for the early

diagnosis of haemochrom at osis and other iron overload syndromes (Tab le 3, page 8).

Take ca re w ith the H FE gene test for haemochromatosis. Some people w ith the C282Y mutat ion do

not have the disease and some people with disease do not have the C282Y mutation.

References1. Schmitt B, et al. Screening primary care patients for

hereditary haemochromatosis with t ransferrin satura-

tion and serum ferritin level: systematic review for the

American College of Physicians. Annals of Int ernal

M edicine2005; 143:522-36.

Further reading Andrews N C. Disorders of iron metabolism. N ew

England Journal of M edicine1999; 341:1986-95.

Cook JD. Diagnosis and management of iron defi-

ciency anaemia. Best Practice & Research. Cl ini cal

H aematology2005; 18:319-32.

Table 2. Common misconceptions about iron deficiency

Misconception Comment

Lo w s erum iro n e q ua ls iro n d efic ie nc y S e rum iro n c o nc e nt ra t io ns c o mm only d ec re a se

during illness regardless of iron status. Iron levels

may be lower in the a fternoon tha n the morning.

Ferritin is the b es t ma rker of iron d efic ienc y.

Normal serum ferritin rules out iron deficiency So me people with iron deficiency ma y have

serum ferritin concentrations in the lower part of

the reference interval. Ferritin is increas ed during

inflammation and with liver disease.


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Table 3. Common misconceptions about iron overload

Misconception Comment

Se rum ferritin is a go od sc reening Increas ed ferritin is a sign of esta blished iron overloa d and is

te s t fo r h a em oc hro ma t os is no t s e en in e a rly d is ea s e . It is no t s a fe t o us e t his a s a

sc reening test. Increas ed serum iron a nd trans ferrin

saturation are the tests of choice.

Po lycy thaemia is a fea ture of Full b lood count is typica lly normal in haemochromatos is

ha emoc hroma tos is a lthoug h there ma y be mild ma croc ytos is . Ha ema tologic al

examination does not ha ve a s ignifica nt role in diagno sis of

hereditary haemochromatosis.

Inc reas ed se rum ferritin eq ua ls S erum ferritin is co mmonly inc reas ed during infla mma tion

ha emoc hroma tos is a nd liver d is ea se. If the tra ns ferrin s atura tion is norma l a

raised ferritin is likely to be ca used by some thing other than

haemochromatosis.

Homozygo us C282Y mutations Many people with the clas sica l hae mochroma tosis mutations

eq ual hereditary do not develop disea se. Conversely, so me people with

ha emochroma tos is ha emoc hroma tos is do not ha ve the C 282Y muta tion,

presumab ly ha ving s ome othe r mutation instea d. Iron stud ies

are essential for the diagnosis of haemochromatosis.

Actors in the drama of iron metabolism

Actor Role

Iro n Hig hly s o ug ht-a ft er s ta r p erfo rm er. Ma jo r ro le in h a em og lo bin w he re it ha s a n

ambivalent relationship with oxygen. Minor roles in other proteins, such as

myoglobin and cytochromes. Destructive if allowed to wander freely about stage.

Transferrin The chaperone that meets iron on its arrival in the bloodstream and ca rries it to

its d estination in the ma rrow. Keeps iron bo und a nd out o f trouble. Each

transferrin can bind two iron atoms, although it carries 13-47% of its maximum

iron c arrying c a pa city on a verage. This percentag e is increa sed in peop le ta king

iron a nd in those with haemo chromato sis. Transferrin a lso bec omes overloa ded

if the bo ne ma rrow is not w orking.

Haemoglobin An important character with a four-part personality. Dependent upon the support

of iron, folate and vitam in B12

. Normal ca reer spa n is four months, a lthough it mayend early being lost in action, eg, in faeces. Sometimes injured by antibody

a ttac k or by b eing flailed b y a n a rtificial heart valve. Occ a sionally troubled b y

inherited character defects and problems with small size and reduced performance.

Fe rrit in Ve ry la rg e , be hind the sce ne s p la y er w ith a m a jo r ro le in iro n s to ra g e . On-s ta g e

visibility reflec ts the s ize o f the iron s tores, a lthough levels ma y b e increase d by

inflamma tion and liver diseas e.

Transfe rrin The com pa nion of tra ns ferrin. Wa its fa ithfully in the ma rrow for a brief mee ting

re ce ptor w here the y excha ng e iro n. If the ma rro w is s t a rve d o f iro n, s o luble fra g m ents o f

the transferrin receptor are released in the blood in increasing numbers. Yet to

ga in a n es tab lished role as a diagno stic ma rker of iron d eficiency.

diagnosis of iron deficiency and iron overload nov 06

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