Iron in Health Disease

Question 1

Functions of iron?

Answer 1

Structural component of haemoglobin (oxygen transport)

Electron transport, e.g: mitochondrial production of ATP

Question 2

Iron is a component of which structures?

Answer 2

Haemoglobin, myoglobin and enzymes, e.g: cytochromes

Question 3

Why is iron dangerous?

Answer 3

Generates ROS and oxidative stress

Question 4

How are the dangers of iron subdued?

Answer 4

1. Safe transport
2. Safe storage
3. Iron absorption is regulated

Question 5

How is iron excreted?

Answer 5

There is no mechanism for excretion

Question 6

Structure of Hb?

Answer 6

4 globin chains, each containing a haem group

In haem, an Fe2+ ion sits in the porphyrin ring

Question 7

Where is the majority of bodily iron found?

Answer 7

In haem

Question 8

Synthesis of haem?

Answer 8

Porphyrin ring + Fe3+ used to make haem

The Fe2+ comes from iron and the protoporphyrin from porphobilinogen

Question 9

Describe the iron exchange system

Answer 9

A closed system; only 1mg is absorbed and lost per day

4mg in the plasma

150mg in the erythroid marrow and 2500mg in red cell Hb

500mg in macrophage stores

Parenchymal tissues (liver stores and others) contain 500mg

Question 10

Where is iron absorbed from?

Answer 10

Duodenum

Question 11

Steps in iron absorption?

Answer 11

1. DMT-1 (divalent metal transporter 1) - transports iron into the duodenal enterocyte
2. Ferroportin then facilitates iron export from the enterocyte; it is passed onto transferrin and then transported elsewhere
3. Hepcidin then down-regulates ferroportin

Question 12

Factors regulating iron absorption?

Answer 12

1. Intraluminal factors:
   • Solubility of inorganic iron
   • Haem iron is easier to absorb
   • Reduction of ferrin (Fe3+) to ferrous (Fe2+) ions
2. Mucosal factors - expression of iron transporters:
   • DMT-1 at the mucosal surface
   • Ferroportin at the serosal surface
3. Systemic factors:
   • Hepcidin - produced in the liver in response to iron load and inflammation

Question 13

Function of hepcidin?

Answer 13

Major -ve regulation of iron uptake; it down-regulates ferroportin and so iron becomes ‘trapped’ in duodenal cells and macrophages

Question 14

How to assess iron status?

Answer 14

There are 3 compartments:
• Functional iron - check Hb conc.
• Transport of iron / iron supply to tissues - check % transferrin saturation
• Storage iron - check serum ferritin; a tissue biopsy is rarely required

Question 15

What is transferrin?

Answer 15

Protein with 2 binding sites for iron atoms

It transports iron FROM donor tissues (macrophages, enterocytes and hepatocytes) TO tissues expressing transferring receptors

Question 16

Major tissue expressing transferrin receptors?

Answer 16

ERYTHROID MARROW is esp. rich in transferrin receptors

Question 17

What does transferrin saturation measure?

Answer 17

Measures iron supply

(Serum iron / total iron binding capacity to transferrin) X 100

Question 18

Forms of transferrin?

Answer 18

Holotransferrin - iron is bound to transferrin

Apotransferrin - unbound transferring

Question 19

Normal transferring saturation?

Answer 19

20-50%

Question 20

What happens to transferrin saturation in different situations?

Answer 20

In iron overload, transferrin saturation is elevated

In iron deficiency, transferrin saturation is decreased

Question 21

What is ferritin?

Answer 21

A spherical IC protein that stores up to 4000 ferric (Fe3+) ions

It also acts as an acute phase protein, thus increasing with infection, malignancy, etc

Question 22

Use of ferritin?

Answer 22

Indirect measure of storage iron

Question 23

What happens to serum ferritin in different situations?

Answer 23

In iron deficiency, low serum ferritin

In iron overload, high serum ferritin

With inflammation, e.g: sepsis, malignancy, liver injury, raised serum ferritin

Question 24

Broad categories of iron metabolism disorders?

Answer 24

Iron deficiency

Iron malutilisation, i.e: anaemia of chronic disease

Iron overload

Question 25

Consequences of negative iron balance?

Answer 25

1. Exhaustion of iron stores 2. Iron deficiency erythropoiesis, leading to a decreased MCV 3. Microcytic, hypochromic anaemia 4. Epithelial changes, e.g: • Skin • Koilonychia • Angular stomatitis/cheilitis

Question 26

Causes of hypochromic, microcytic anaemia?

Answer 26

Haem deficiency: • Lack of iron for erythropoiesis - iron deficiency anaemia (low body iron) OR anaemia of chronic disease (normal body iron) • Congenital sideroblastic anaemia (very rare) Globin deficiency: • Thalassaemias

Question 27

How can iron deficiency be confirmed?

Answer 27

Combination of anaemia (decreased Hb iron) AND low serum ferritin (reduced storage iron)

Question 28

Causes of iron deficiency?

Answer 28

Insufficient intake - more common in women and children, due to higher requirements; there may be other dietary factors Haemorrhage Malabsorption (relatively uncommon)

Question 29

Causes of chronic blood loss?

Answer 29

Menorrhagia ``` GI: • Tumours • Ulcers • NSAIDs • Parasitic infection ``` Haematuria

Question 30

What is occult blood loss and explain how it can cause iron deficiency?

Answer 30

GI blood loss of 8-10 ml per day (4-5 mg iron) can occur without any symptoms/signs of bleeding Max dietary iron absorption of iron is around 4-5 mg/day, so negative iron balance can occur

Question 31

Treatment of iron deficiency anaemia?

Answer 31

IDENTIFY A CAUSE Iron replacement therapy is treating a symptom

Question 32

Explain normal Hb recycling

Answer 32

Macrophage deals with old RBC and it is broken down into: • Globin - broken down into amino acids • Haem - broken down into porphyrin (and then bilirubin) and iron (and then ferritin) Transferrin is used to carry iron to marrow erythroblasts

Question 33

How does anaemia of chronic disease occur?

Answer 33

Inflammatory macrophage iron block 1. Increased transcription of ferritin mRNA stimulated by inflammatory cytokines so ferritin synthesis increased 2. Increased plasma hepcidin blocks ferroportin-mediated release of iron 3. Results in impaired iron supply to marrow erythroblasts and eventually hypochromic red cells

Question 34

Causes of iron overload?

Answer 34

Primary - long-term excess iron absorption with parenchymal, rather than macrophage, iron loading: • Hereditary haemochromatosis Secondary: • Transfusional • Iron loading anaemias

Question 35

Occurrence of hereditary haemochromatosis?

Answer 35

Most common form is due to mutations in HFE gene Usually present in middle age or later, with iron overload >5g

Question 36

Cause of hereditary haemochromatosis?

Answer 36

Decreased hepcidic synthesis leads to increased iron absorption Result is gradual iron accumulation with a risk of end-organ damage

Question 37

Clinical features of hereditary haemochromatosis?

Answer 37

May be asymptomatic until irreversible organ damage has occurred Weakness / fatigue Joint pains Impotence Arthritis Liver cirrhosis Diabetes Cardiomyopathy

Question 38

Genetics of hereditary haemochromatosis?

Answer 38

Mutations in HFE gene account for 95% of cases Patients are usually C282Y homozygotes; occasionally, C282Y / H63D compound heterozygotes It has incomplete penetrance

Question 39

Mutations, other than in HFE gene, that can cause hereditary haemochromatosis?

Answer 39

Mutations of other iron regulatory proteins (very rare), e.g. transferrin receptor, hepcidin, ferroportin

Question 40

Diagnosis of hereditary haemochromatosis?

Answer 40

Risk of iron loading: • Transferrin saturation >50% Increased iron stores: • Serum ferritin >300 micrograms/litre in men OR >200 micrograms/litre in pre-menopausal women Liver biopsy - only done if uncertain about iron loading OR to assess tissue damage; can stain for iron

Question 41

Treatment of hereditary haemochromatosis?

Answer 41

Weekly venesection - initial aim is to exhaust iron stores (ferritin <20 micrograms/l) but thereafter keep ferritin <50 micrograms/l

Question 42

Causes of death in hereditary haemochromatosis?

Answer 42

Hepatoma Hepatic failure/bleeding varices Diabetes Infections

Question 43

Family screening for hereditary haemochromatosis?

Answer 43

1st degree relatives of patients, esp. siblings (1/4 risk) Children - wait until adulthood for informed consent HFE genotype and iron status - ferritin and transferring saturation

Question 44

Sources of iron-loading anaemias?

Answer 44

Repeated red cell transfusions Excessive iron absorption related to over-active erythropoiesis

Question 45

Disorders responsible for over-active erythropoiesis?

Answer 45

Massive ineffective erythropoiesis: • Thalassaemias • Sideroblastic anaemias Refractory hypoplastic anaemias: • Red cell aplasia • Myelodysplasia (MDS)

Question 46

Use of transfusions for iron-loading anaemias?

Answer 46

Patients with thalassaemia may require lifelong transfusions every 2-3 weeks In MDS, need for transfusion is highly variable

Question 47

Source and result of iron loading?

Answer 47

If red cell transfusion (200mg/unit), leads to iron overload of >5g total If increased iron absorption (up to 5mg/day), leads to liver >15mg/g dry weight; the risk of excess intestinal iron absorption may be hidden until tissue damage becomes asymptomatic Both lead to liver, heart and endocrine gland damage

Question 48

Inevitable outcome of regular red cell transfusions?

Answer 48

Iron overload

Question 49

Treatment of secondary iron overload?

Answer 49

Venesection is not an option in patients who are already anaemic Iron chelating agents: • Desferrioxamine (s/c OR IV infusion) • Newer oral agents, like Deferiprone and Deferasirox