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Haematology > Iron Metabolism > Flashcards

Iron Metabolism Flashcards

1
Q

Iron Facts

A

All body cells need iron
• Human body contains an average of 3.5 g iron
– Men 4 g, women 3 g
• Typical Western diet contains 10-12 mg iron/day
– Only 10% of iron in food is absorbed (1-2 mg)

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2
Q

key Functions of Iron

A
  1. Cellular proliferation
  2. Cellular growth
  3. Energy production
  4. Oxygen storage (myoglobin)
  5. Oxygen transport (haemoglobin)
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3
Q

Iron Homeostasis

A

Maintenance of iron homeostasis (balance) depends primarily
on the control of ABSORPTION from the GIT
BECAUSE
the mechanisms for iron EXCRETION are very limited.
Iron deficiency or iron overload may lead to disease.

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4
Q

Iron Metabolism

A

The steps involved in Iron Metabolism are:

Intake

Absorption

Transport

Storage

Los

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5
Q

Iron Metabolism:

Intake

A

Western diet: 10-20 mg iron/day

Form of iron NB!
– Haem iron (red meat, poultry, fish) – 30% absorbed
– Inorganic iron (meat, vegetables) – poor absorption
(<10%)

Clinical Importance:

Assessing the diet requires looking at the form, not just the amount of iron!

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6
Q

Iron Metabolism:

Absorption

A

First step – remove Fe from food source:

-HCl in gastric fluid dissolves Fe from food and inorganic salts

Iron in food in Fe3+ form:
-Poor solubility at pH >3 → poorly absorbed

Fe2+:

  • More soluble, even at pH 7-8 in the duodenum → absorbed easier
  • Reducing factors present in the gut which reduces Fe3+ →Fe2+

Mucin taxi
-Fe3+ released from food sources bind in the stomach to mucin

-Travels to the duodenum and jejenum where it is absorbed

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7
Q

Factors affecting Iron Absorption

A

There are factors which affect Iron Absorption by either increasing or decreasing the absorption

Clinical Importance:

If your patient has to increase his/her Fe-intake, maximise absorption by prescribing the following:
– a source of haem iron (red meat, to a lesser degree
chicken and fish), and
– a source of vit C (orange juice or oranges)

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8
Q

Factors which increase Iron Absorption

A

Vit C:

  • ↑absorption of non-haem iron by 50%
  • Facilitates reduction of Fe3+ to Fe2+

Meat or fish:
-Haem iron

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9
Q

Factors which inhibit Iron Absorption

A

Phytates:
-Rye, oats, bran

Polyphenoles:
-Tea, some vegetables and
cereals

Dietary calcium

Soya protein

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10
Q

The key regulator of Iron Absorption

A

Hepcidin:

Hepcidin is produced in the liver – plays an important role in the prevention of iron overload

Hepcidin production ↑: ferroportin is “locked” and iron
absorption is low/decreased

Hepcidin production↓: ferroportin stays “open” for iron
uptake and iron absorption increases

– Physiological consequence of iron deficiency
– Pathological response in diseases that lead to iron overload (e.g. haemochromatosis)

Clinical Importance:
-In patients with iron deficiency, absorption can take place up to the distal ileum.

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11
Q

Iron Metabolism:

Transport

A

Transferrin:
Transports iron in plasma

Tightly binds 1 or 2 ferric (Fe3+) ions

Circulating Tf is saturated ⅓ with iron in normal individuals

Measured in lab as the Total Iron Binding Capacity; TIBC

Why is transferrin necessary:
-Free iron is toxic to the body

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12
Q

Iron Metabolism:

Storage

A

Two important Iron stores are:

  1. Ferritin
  2. Haemosiderin
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13
Q

Ferritin

A

Most iron is stored as ferritin

Ferritin iron is soluble

Iron ions are stored in a protein capsule

Cellular storage protein for iron

Huge protein (440 kDa), 24 subunits symmetrically
arranged to form a spherical capsule

is found in all human tissue, but primarily in the liver, spleen and bone marrow

Acute phase reactant

Iron enters the ferritin molecule as Fe2+

On the inner surface of ferritin, Fe2+ is oxidised to Fe3+

Iron continues to enter the ferritin molecule until the
hollow core is completely filled with iron

Core can take in approximately 4000 iron atoms

Iron is released from ferritin by reducing substances

Ferritin can be measured in the serum and gives a good indication of iron stores:
– 1 ng/ml s-ferritin ~ 10 mg iron in tissue stores
– Normal adult male: 50-100 ng/ml ~ 500-1000 mg iron
stores

Remember!
– Serum ferritin is also an acute phase reactant
– In diseases with severe tissue damage (e.g. hepatitis) or chronic inflammation (e.g. rheumatoid arthritis) serum ferritin will INCREASE disproportionately to actual iron stores

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14
Q

Heamosiderin

A

Degradation product of ferritin

With increasing iron overload, progressively more iron is stored as haemosiderin

Accumulation of ferritin → aggregation → proteolysis by
lysosomal enzymes → converted into iron-rich

Haemosiderin releases iron slowly

Detected in cells using the Prussian blue stain

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15
Q

Iron Metabolism:

Loss

A

Daily iron loss is mainly due to desquamation of cells of the GIT and skin (1 mg/day)

Menstruating women: 16 mg loss with normal menstruation:

  • Only 10% of daily 10-20 mg intake is absorbed
  • Iron balance in women is critical
  • Iron deficiency develops easily during pregnancy or menorrhagia
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16
Q

Iron Deficiency Anaemia:

Causes

A

Blood Loss

Increased Demand

Insufficient Intake

Malabsorption

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17
Q

Iron Deficiency Anaemia:

Blood Loss

A

Haematemesis

Haemoptysis

Haematochezia

Epistaxis

Menorrhagia

Vaginal bleeding

Haematuria

Melena

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18
Q

Iron Deficiency Anaemia:

Increased Demand

A

Prematurity

Growing children

Pregnancy (additional 1.5 mg iron/day)

19
Q

Iron Deficiency Anaemia:

Malabsorption

A

Gastrectomy

Diseases of the small bowel

20
Q

Iron Deficiency Anaemia:

Insufficient Intake

A

Vegetarians

21
Q

Iron Deficiency Anaemia:

Clinical Manifestations

A 
1.Symptoms of anaemia:
– Tiredness
– Weakness
– Decreased exercise tolerance
– Headache
– Irritability
(Most patients are asymptomatic and are diagnosed incidentally
during routine examination)
  1. Pica
    – Appetite for non-food substances (e.g. soil, paper,
    cigarette butts)
  2. Pagophagia
    – Pica for ice (relatively specific for iron deficiency)
  3. Atrophic glossitis:
    – Painful tongue
    – Tongue dry due to decreased saliva flow
    – Atrophy of tongue papillae-Smooth appearance
  4. Angular stomatitis
    - Fissures at corners of the mouth
  5. Beeturia:
    – Intake of beetroot discolours urine red in patients with iron deficiency
    – Due to uptake and excretion of betanin
  6. Koilonychia
    – “Spoon-shaped” nails
  7. Rare:Plummer-Vinson or Patterson-Kelly syndrome

Combination of:

  • Iron deficiency anaemia
  • Oesophageal webs (dysphagia)
  • Koilonychia
  • Atrophic glossitis
  • Blue sclerae
22
Q

Iron Deficiency Anaemia:

Laboratory Diagnosis

A

Full blood count:
↓ MCV (microcytic)
↓ MCH (hypochromic)
- Also seen on blood smear (small, pale RBCs)

Bone marrow: iron stores ↓

↓ RPI (indicates ↓ RBC production)

↓ S-ferritin:
< 15 ng/ml:
-Almost always iron deficiency
-Specificity 99%, but sensitivity 59%

< 40 ng/ml:
-Specificity 98%, sensitivity 98%

23
Q

Serum Ferritin

A

Acute phase reactant

Increases in liver disease, infection, inflammation and
malignancy

Pt with iron deficiency AND inflammation often have “false normal” ferritin levels
-Inflammation increases the serum ferritin about 3x

“Rule of thumb”:

  • Divide pt’s s-ferritin by 3 (in pt with inflammation)
  • Value of 20 ng/ml or less (i.e. original value ≤ 60 ng/ml) indicates probable iron deficiency
24
Q

Treatment of Iron Deficiency

A

Treat underlying cause

Dietary advice

Replenish iron stores (oral, IM, IV)

25
Q

Tx: Iron Deficiency:

Treat underlying cause

A

Blood loss

If no obvious cause of blood loss, examine the GIT:

  • Particularly in males and post-menopausal women over 40
  • Gastroscopy / barium meal
  • Colonoscopy / barium enema
  • Small bowel
26
Q

Tx-Iron Deficiency:

Dietary Advice

A

Increase intake of
• Iron-rich food:
– Haem iron (red meat, poultry, fish)

• Vit C-rich food with meals:
– Tomatoes, broccoli, citrus, papaya, etc.•

Avoid:
•Excessive phytates:
– In brown bread, unrefined cereals and soya
– Bind iron & renders it inabsorbable

•Excessive tea (especially with meals):
– Can ↓ iron absorption with up to 50%

•EDTA (preservative in food) :
– ↓ Absorption of non-haem iron with up to 50%

•Other factors affecting absorption:
–Milk proteins and albumin
–Vegetable fibre inhibits uptake of non-haem iron
–Iron in egg yolk is poorly absorbed due to the presence of phosvitin

27
Q

Treatment

A

First choice – oral FeSO4
– Cheap, effective
– 67 mg elemental iron / 200 mg tablet

Side effects:
– Nausea
– Abdominal pain
– Constipation
– Diarrhoea
– Common cause for poor patient compliance if treatment is started at the full dose!

If the side effects are unacceptable:
-Take FeSO4 with food which decrease the dose

Start treatment slowly:
– FeSO4 200 mg 1x/d, then 2x/d, then 3x/d
– Best if taken on an empty stomach
– Space doses at least 6-hourly

For how long?
• Iron should be taken long enough to
– Correct the ANAEMIA and
– Replenish the iron STORES
• Treat for at least 6 months
• Hb should rise at a rate of 2 g/dl every 3 weeks

AIM:
Ferritin > 100 ng/ml
Transferrin saturation >20%

What if the patient does not respond to oral iron therapy?

Before giving parenteral iron(IM/IV), exclude all possible causes of a suboptimal response
to oral iron

28
Q

What causes a poor response to Iron

A
  1. Disease that influences the bone marrow response
  2. Wrong Dx
  3. Does the patient take the medication
  4. Medication is taken,but not absorbed
  5. Continuing iron(Blood) loss or demand greater than the iron administered
29
Q

Diseases that influence the bone marrow response?

A 
Infection
Inflammation
Malignancy
Other nutritional deficiency (vit B12 or folate)
Another cause for BM suppression
30
Q

Wrong Diagnosis

A

Thalassaemia ( ↑ RBC count)

Anaemia of chronic disease

Lead poisoning

Copper deficiency

31
Q

Does the patient take the medication?

A

Side effects

Insufficient explanation to patient

Not enough tablets issued

32
Q

Medication is taken, but not absorbed?

A

Enteric coated (slow release) formulation-Coating does not dissolve

Malabsorption of iron

Medication/food taken that inhibits absorption
-Antacids, tetracyclins, tea, phytates

33
Q

Continuing iron (blood) loss or demand greater than the iron administered?

A

Cause of blood loss treatable
-E.g. peptic ulcer

Cause of blood loss untreatable
-E.g. Osler-Weber-Rendu syndrome

Demand too great for oral iron
-E.g. pt with renal failure that responds to Epo

34
Q

Indications for IV Iron

A

When body stores have to be replenished quickly:
– Late in pregnancy
– Haemodialysis
– Epo therapy

If oral iron is ineffective
– Only after other causes for a suboptimal response have been excluded!

Venofer®
– Ferrihydroxide-sucrose
– Give by slow IV infusion
– Allergic reactions may occur, thus give a test dose first

REMEMBER:
Haematological response to parenteral iron is not
quicker than a sufficient dose of oral iron,
BUT the stores are replenished much quicker!

35
Q

Iron Overload:

A

Haemochromatosis:

Total body iron increased and there is excessive iron
deposition in tissues which results in a damage ton various organs

Types of Haemochromatosis:
Primary:
-Hereditary Haemochromatosis

Secondary:

  • Multiple transfusions
  • Diet-Use of iron pots(Home brewing)/Alcohol
36
Q

Hereditary Haemochromatosis

A

Total body iron as high as 20-60 g (normal: 4 g)

Widespread deposition of iron in various organs, especially:
– Liver
– Heart
– Pancreas and other endocrine glands

37
Q

Hereditary Haemochromatosis:

Etiology

A

Increased absorption of dietary iron due to inability to limit iron absorption from the gut

Autosomal recessive gene on chromosome 6 (C282Y-mutation in 90% of pt’s)

Iron loss during menstruation and pregnancy protects women (90% of pt’s seen are male)

38
Q

Haemochromatosis:

Clinical Picture

A

Usually presents in males aged 40+ and women 50+ with:

  • Tiredness
  • Liver cirrhosis (mostly hepatomegaly)
  • Diabetes mellitus
  • Heart failure
  • Slate-grey skin pigmentation due to excessive melanin-Especially in axillae, groin and genitals (also called “bronze diabetes”)

Impotence, loss of libido, testicular atrophy

Arthritis (especially 2th and 3th MCP joints)

39
Q

Haemochromatosis:

Laboratory Diagnosis

A

Blood tests:
– Serum ferritin and transferrin saturation very high
– Genetics: C282Y mutation

Liver biopsy confirms the diagnosis
– Severe iron deposition
– Fibrosis ± cirrhosis
– Iron in liver can be quantified

40
Q

Haemochromatosis:

Treatment

A

Venesection:

  • 500 ml blood (250 mg iron) weekly until the ferritin and transferrin saturation are normal
  • Can take up to 2 years to normalise
  • Thereafter, venesect as needed to keep transferrin saturation normal

Treat complications:
-Liver cirrhosis, diabetes, etc.

Avoid alcohol, iron supplements

Limit iron-rich food

41
Q

Haemochromatosis:

Further Management

A

Test first degree relatives
– Genetics, ferritin, transferrin saturation
– Liver biopsy in asymptomatic relatives if LFT abnormal and/or ferritin > 1000 µg/l

Asymptomatic disease is treated with venesection as soon as s-ferritin rises above normal

Prognosis:

  • Good prognosis compared to other forms of cirrhosis
  • If treated early→ all complications are preventable
  • If left untreated→ potentially fatal
  • ⅓ of patients with cirrhosis develop hepatocellular carcinoma
42
Q

Acquired/Secondary Iron Overload

A

Clinical characteristics similar

Treat the underlying disease/cause

In some patients iron chelation therapy is needed
– E.g. transfusion-related iron overload

43
Q

Iron Transfer Block:

A

Iron for erythropoiesis is released from macrophage stores in the bone marrow to developing erythroid precursors, via ferroportin

Hepcidin thus also influences the amount of iron which is released from stores for erythropoiesis

Hepcidin levels increase in response to inflammation and infection:
-Driven mostly by IL-6

Leads to reduced release of iron from bone marrow macrophages for erythropoiesis:
-Anaemia

44
Q

Anaemia of Chronic Disease

A

One of the most common anaemias in clinical practice
• Full blood count:
– Normochromic, normocytic or mildly hypochromic, microcytic
(MCV rarely < 75 fl)
– Usually moderate and non-progressive (Hb rarely < 9.0 g/dl)
• Serum iron and TIBC are reduced
• Serum ferritin is normal or increased
• Bone marrow storage iron is normal or increased, but
erythroblast iron is reduced
DOES NOT RESPOND TO ORAL IRON THERAPY
• Anaemia is corrected by successful treatment of the
underlying cause

Haematology (10 decks)

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