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IRON IN HEALTH AND DISEASE. Dilys Rapson. PERCEPTIONS OF IRON. UK Iron man Triathlon, Llanberis 8th September 2002 One of the toughest Iron man 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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perceptions of iron
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 anironcurtain has descended across the Continent.”

Pumping Iron

1 iron metabolism introductory background
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
clinical relevance
Clinical Relevance
  • Iron deficiency affects the whole body
  • Excess free iron can lead to serious organ damage
2 body iron distribution
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
approximate distribution of body iron in a man
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

2 body iron distribution9
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
clinical relevance body iron status can be measured
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
3 dietary sources of iron
3. DIETARY SOURCES OF IRON

Organic iron eg beef

Inorganic Iron eg lentils

DAILY IRON REQUIREMENT 10-15mg/day (5-10% absorbed)

4 iron absorption
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
absorption of iron
ABSORPTION OF IRON

Enterocyte

Gut

Fe+++

Ferritin

Fe++

Tf-Fe+++

Fe++

Fe++

Haem

Tf

4 iron absorption cont
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.

5 proteins involved in iron metabolism
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

clinical relevance18
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
slide19

CHRONIC TRANSFUSION OVERWHELMS IRON BALANCE

PRBC is the red cells in a single donation or “unit” of blood

what you need to know
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
iron deficiency
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
1 evolution of iron deficiency anaemia
1.EVOLUTION OF IRON DEFICIENCY ANAEMIA
  • Earliest stage : depletion of body iron stores only
  • “Biochemical” iron deficiency without anaemia
  • Iron deficiency anaemia
2 clinical features iron deficiency
2. CLINICAL FEATURES IRON DEFICIENCY
  • Symptoms eg. fatigue, dizziness, headache
  • Signs eg. pallor, glossitis, angular cheilosis, koilonychia, Plummer Vinson syndrome

Koilonychia

Glossitis

slide24

CLINICAL FEATURES OF IRON DEFICIENCY

Plummer Vinson Syndrome : Oesophageal Web

Angular Cheilosis or Stomatitis

3 laboratory diagnosis iron deficiency
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 )
things you need to know about laboratory testing for iron status
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
5 principles of treatment
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
6 causes of iron deficiency
6. CAUSES OF IRON DEFICIENCY
  • Increased physiologic demand eg. pregnancy, lactation, rapid growth
  • Blood loss from GI tract, uterus, haemoglobinuria
  • Malabsorption
  • Diet

colon cancer

what you need to know34
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
effects of iron overload

Iron overload

Capacity of serum transferrin to bind iron is exceeded

Non-transferrin-bound iron (NTBI) circulates in the plasma

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

HSC senescence

Diabetes mellitus

Cardiac failure

Growth failure

Infertility

when does iron become a problem
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
laboratory diagnosis
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
treatment and prevention
TREATMENT AND PREVENTION
  • Phlebotomy until ferritin <50µg/ml
  • Maintenance venesection
  • Screen family members
  • Prevention

Cirrhosis of liver

causes of iron overload
CAUSES OF IRON OVERLOAD
  • Hereditary haemochromatosis
  • Multiple transfusions
  • Liver disease
  • Prolonged use medicinal iron
  • Ineffective erythropoiesis
  • African Iron Overload
hereditary haemochromatosis
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
clinical diagnosis
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
what you need to know43
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