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IRON IN HEALTH AND DISEASE
Dilys Rapson
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PERCEPTIONS OF IRON

• UK Ironman Triathlon,
• Llanberis 8th September 2002
• One of the toughest Ironman courses ever devised

From Stettin in the Baltic to Trieste in the
Adriatic an iron curtain has descended across the
Continent.
Pumping Iron
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1. IRON METABOLISM INTRODUCTORY BACKGROUND

• Essential element in all living cells
• Transports and stores oxygen
• Integral part of many enzymes
• Usually bound to other molecules
• Quantity of body iron carefully controlled

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Clinical Relevance

• Iron deficiency affects the whole body
• Excess free iron can lead to serious organ damage
  

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2. BODY IRON DISTRIBUTION

• Metabolically Active Iron
• Haemoglobin
• Serum iron bound to a protein transferrin
  in blood
• Tissue Iron in cytochromes and enzymes
• Myoglobin oxygen reserve in muscles

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APPROXIMATE DISTRIBUTION OF BODY IRON IN A MAN

• Hemoglobin 2000mg
• Storage Iron 1000mg
• Myoglobin iron 130mg
• Labile Pool 80mg
• Other tissue Iron 8mg
• Transport Iron 3mg

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HAEM MOIETY HAEMOGLOBIN
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2. BODY IRON DISTRIBUTION

• B. Storage Iron
• Ferritin found in blood, tissue fluids, and
  cells
• Haemosiderin found in macrophages and assessed
  by staining bone marrow with Prussian Blue stain

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BONE MARROW FILM STAINED FOR HAEMOSIDERIN
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Clinical Relevance Body Iron status can be
measured

• Serum Iron level ( Transferrin bound iron)
• Total iron binding capacity (TIBC) measurement
  of transferrin
• transferrin saturation (Serum iron/TIBC x
  100)
• Serum ferritin Level correlates with body
  stores
• Haemosiderin assessment in bone marrow

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3. DIETARY SOURCES OF IRON
Inorganic Iron eg lentils
Organic iron eg beef
DAILY IRON REQUIREMENT 10-15mg/day (5-10
absorbed)
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4. IRON ABSORPTION

• Iron kept soluble and in ferrous state by gastric
  acid
• Absorbed mainly in duodenum
• Quantity absorbed regulated by enterocyte
• Multiple proteins involved in control of iron
  transport
• Haem iron enters the enterocyte through
  different process than inorganic iron

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ABSORPTION OF IRON
Enterocyte
Gut
Fe
Ferritin

Fe
Tf-Fe
Fe
Fe

Haem
Tf
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4. IRON ABSORPTION (cont)

• Transferrin bound iron in plasma delivered to
  body cells according to cellular iron
  requirements
• Note
• Only 20 of plasma bound iron derived from
  gut. Most plasma iron is derived from breakdown
  of senescent red cells.

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BODY IRON CYCLING
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5. PROTEINS INVOLVED IN IRON METABOLISM
Upstream regulators eg. HFE
HEPCIDIN
Synthesized in liver. Present in blood
Infections and inflammatory stimuli
degrades
X
Transferrin receptors
FERROPORTIN
Apoferritin
No cellular egress of iron
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Clinical Relevance

• Iron balance physiologically regulated by control
  of iron absorption at enterocyte.
• Mutations in the gene HFE associated with most
  common form of hereditary iron overload (HFE-
  haemochromatosis)
• Humans unable to excrete excess iron.
  Interventions which circumnavigate the enterocyte
  can result in iron loading
• Conditions such as infection and inflammation
  have an effect on iron metabolism

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CHRONIC TRANSFUSION OVERWHELMS IRON BALANCE
PRBC is the red cells in a single donation or
unit of blood
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WHAT YOU NEED TO KNOW

• Daily requirements and dietary sources of iron
• Where iron is absorbed in the gut
• Control of iron balance at level of enterocyte
• How body stores of iron are assessed
• Proteins involved in regulation of iron

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IRON DEFICIENCY

• Commonest cause of anaemia worldwide
• Cause of chronic ill health
• May indicate the presence of important underlying
  disease eg. blood loss from tumour

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1.EVOLUTION OF IRON DEFICIENCY ANAEMIA

• Earliest stage depletion of body iron stores
  only
• Biochemical iron deficiency without anaemia
• Iron deficiency anaemia

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2. CLINICAL FEATURES IRON DEFICIENCY

• Symptoms eg. fatigue, dizziness, headache
• Signs eg. pallor, glossitis, angular cheilosis,
  koilonychia, Plummer Vinson syndrome

Koilonychia
Glossitis
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CLINICAL FEATURES OF IRON DEFICIENCY
Plummer Vinson Syndrome Oesophageal Web
Angular Cheilosis or Stomatitis
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3. LABORATORY DIAGNOSIS IRON DEFICIENCY

• Microcytic hypochromic anaemia
• Often pencil cells and target cells on blood film
• Decreased serum ferritin
• Decreased serum iron, increased TIBC, decreased
  transferrin saturation
• Absent bone marrow haemosiderin (rarely
  required for diagnosis )

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Hypochromic microcytic red cells
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Pencil Cell
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ABSENT IRON STORES IN BONE MARROW IN IRON
DEFICIENCY
Iron deficiency
Normal control
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Things you need to know about Laboratory Testing
for Iron Status

• Serum ferritin most useful test
• Low serum ferritin certain proof patient iron
  deficient
• Normal serum ferritin does not always rule out
  iron deficiency
• Certain conditions raise ferritin for reasons
  unrelated to iron status

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4.DIFFERENTIAL DIAGNOSIS IRON DEFICIENCY ANAEMIA
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5. PRINCIPLES OF TREATMENT

• Use oral iron ( not enteric coated tablets )
• Replace iron deficit in total
• Restore haemoglobin and MCV to normal
• Replenish iron stores
• Establish and treat the cause

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LOOK FOR THE CAUSE OF IRON DEFICIENCY
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6. CAUSES OF IRON DEFICIENCY

• Increased physiologic demand eg. pregnancy,
  lactation, rapid growth
• Blood loss from GI tract, uterus, haemoglobinuria
• Malabsorption
• Diet

colon cancer
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WHAT YOU NEED TO KNOW

• Symptoms and signs of iron deficiency
• Laboratory diagnosis of iron deficiency
• Differential diagnosis of a microcytic
  hypochromic anaemia
• Importance of finding a cause for iron deficiency
• Principles of treatment

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IRON OVERLOAD
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EFFECTS OF IRON OVERLOAD
O2- H2O2 O2 OH- HO
Excess iron promotes the generation of free
hydroxyl radicals, propagators of oxygen-related
tissue damage
Insoluble iron complexes are deposited in body
tissues and end-organ toxicity occurs
(Fenton Reaction)
Liver cirrhosis/ fibrosis/cancer
Diabetes mellitus
Cardiac failure
HSC senescence
Growth failure
Infertility
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WHEN DOES IRON BECOME A PROBLEM?

• Normally 2.5 3.5g of iron in the body.
• Tissue damage when total body iron is 7 15 g

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LABORATORY DIAGNOSIS

• Elevated transferrin saturation
• Increased serum ferritin
• Genetic testing for mutations of HFE gene
• Evidence parenchymal iron overload on liver
  biopsy
• Amount of iron removed by venesection

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TREATMENT AND PREVENTION

• Phlebotomy until ferritin lt50µg/ml
• Maintenance venesection
• Screen family members
• Prevention

Cirrhosis of liver
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CAUSES OF IRON OVERLOAD

• Hereditary haemochromatosis
• Multiple transfusions
• Liver disease
• Prolonged use medicinal iron
• Ineffective erythropoiesis
• African Iron Overload

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HEREDITARY HAEMOCHROMATOSIS

• Most common cause of iron overload in North
  America
• Most cases due to mutations of the HFE gene
• Results in increased inappropriate iron
  absorption from gut

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CLINICAL DIAGNOSIS

• Commonly made on basis of biochemical changes
  increased serum ferritin or transferrin
  saturation
• May have non-specific symptoms/signs such as
  fatigue or arthropathy
• Discovered as part of family screening
• Rarely fullblown picture cirrhosis, diabetes,
  cardiomyopathy, skin pigmentation, gonadal
  dysfunction

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WHAT YOU NEED TO KNOW

• Association of mutations of the HFE gene with the
  most common inherited iron overload disorder
  HFE- hemochromatosis
• Hereditary haemochromatosis common in North
  America
• Early symptoms/signs non-specific. Have to
  think of it
• Severe morbidities avoidable if early diagnosis
• Genetic testing available for patient and family