Iron deficiency and anaemia of chronic disease

Question 1

What are the haematinics

Answer 1

Components needed to make red blood cells
B12
Folate
Iron

Question 2

State the iron containing proteins

Answer 2

Haemoglobin
Myoglobin
catalase
Cytochrome P450
Cytochrome a, b, and c
succinate dehydrogenase
COX
Ribonucleotide reductase
§ Iron is found in may proteins as seen on the left however most iron in the body is found in Hb. 
o Therefore, low iron à low Hb à anaemia.

Question 3

Describe the roles of iron in Hb

Answer 3

CRUCIAL ROLE - holds onto oxygen
Most obvious consequences of iron deficiency are seen in the blood
Iron- incorporated into haem- which combines with globin to form haemoglobin

Question 4

Describe the association of haem with a globin chain

Answer 4

Each haem group is associated with a single globin chain, and we can see a picture of the association here in this slide.

Haem sits in a pocket formed by the globin chain and in the final haemoglobin molecule, the haem groups are near the surface of the molecule.

Question 5

Describe the structure of haem

Answer 5

Here we can see the structure of haem, which is responsible for the red colour of Hb

Essentially it consists of a ring of carbon, hydrogen and nitrogen atoms and in its centre is an iron atom in the ferrous (Fe2+) state.

Heme combines reversibly with oxygen

Question 6

Summarise iron haemostasis

Answer 6

Red cells live for 120 days

To re-make huge numbers of red cells on a daily basis you need 20mg iron/day

Fortunately - Iron is recycled

Question 7

Describe iron usage/loss

Answer 7

Iron usage/loss: need 1mg/day for males and 2mg/day for females to compensate for losses
Desquamated cells of skin/gut - traces lost from these cells
Bleeding (menstruation or pathological)
Normal use in proteins

Question 8

Describe the iron found in the diet

Answer 8

Human diet provides 12-15mg iron/day
Iron occurs in most natural foods
		- Meat and fish(haem iron) 
		- Vegetables
		- Whole grain cereal
		- chocolate

Question 9

Describe the absorption of iron

Answer 9

o Most iron eaten is NOT absorbed though as you can only absorb ferrous (Fe2+) and not ferric (Fe3+).
§ Tea turns iron into the FERRIC form and can lead to chronic low levels of ferrous!
§ Orange juice AIDS absorption of iron.

Question 10

Describe the factors that can affect iron absorption

Answer 10

DIET:		   increase in haem iron
				ferrous iron
INTESTINE:     acid (duodenum)- acid increases conversion of 3+ to 2+
				ligand (meat)
SYSTEMIC: 	   iron deficiency
				anaemia/hypoxia
				pregnancy

Question 11

Describe the factors that will increase iron absorption

Answer 11

§ Factors that increase iron absorption are:
o Iron deficiency.
o Anaemia/hypoxia.
o Pregnancy.

Question 12

Describe how iron is absorbed in the duodenum

Answer 12

Iron absorption: iron in diet absorbed to enterocytes, where can be stored as ferritin or carried using transferrin in plasma via ferroportin on basolateral membrane
Iron freely transports into the cell but ferroportin facilitates transport of iron into the blood.

Question 13

How does the gut cell alter iron absorption

Answer 13

High iron - high hepcidin - low ferroportin- low absorption

Question 14

How is the level of hepcidin regulated

Answer 14

There are certain proteins (such as hepcidin) that have iron-responsive elements in their genes
So iron is part of the complex that switches on hepcidin transcription

Question 15

How is iron stored within cells

Answer 15

In ferritin micelles

Question 16

Where is ferroportin found

Answer 16

§ Ferroportin is found in; enterocytes of duodenum, macrophages of spleen, hepatocytes.

Question 17

Describe the role of transferrin

Answer 17

§ Iron from the diet is taken into the cell à protein shell forms around it to form ferritin OR can bind to transferrin in the blood plasma.

Question 18

Describe the different ways in which we can measure transferrin

Answer 18

§ Transferrin:
o The transferrin is usually 20-40% saturated with iron.
o Transferrin levels, Total Iron Binding Capacity (TIBC) and Transferrin saturation can therefore usually be measured.
o TF cannot enter cells directly and binds with the TF-R and is internalised as a whole. As the pH drops, iron is released and transferrin receptors are recycled.
o The reason for TF being around is that iron is TOXIC and INSOLUBLE so TF fixes this.

Question 19

Describe the roles of erythropoietin

Answer 19

§ Erythropoietin (EPO):
o Produced in the kidneys.
o Production is increased in response to hypoxia and this triggers more RBC precursors to be released.
o The RBC precursors survive longer and will; survive, grow and differentiat

Question 20

When is EPO released

Answer 20

Anaemia
Tissue hypoxia
Increase in EPO
Increased survival, growth and differentiation of RBC precursors.

Question 21

Essentially, what is anaemia of chronic disease

Answer 21

Anaemia in patients who are unwell

	bleeding?   NO
	marrow infiltrated? NO
	iron/B12 or folate deficient? NO

NO OBVIOUS CAUSE EXCEPT THAT THE PATIENT IS ILL

Question 22

What are the laboratory signs of being ill

Answer 22

C-reactive protein
Erythrocyte Sedimentation Rate
Acute phase response- increases in
			- ferritin
			- FVIII
			- fibrinogen
			- immunoglobulins 

All these factors will be raised

Question 23

Describe some conditions associated with anaemia of chronic disease

Answer 23

Chronic infections e.g. TB/HIV
Chronic inflammation e.g. RhA/SLE
Malignancy
Miscellaneous e.g. cardiac failure

Question 24

Describe the pathogenesis of anaemia of chronic disease

Answer 24

ACD is due to the cytokine release that happens when someone is unwell
The cytokines block utilisation of iron by red blood cells (prevent flow from duodenum to red cells)
They also stop erythropoietin from increasing
Stop iron flowing out of cells
Increase production of ferritin
Increased death of red cells

Therefore
		- make less red cells
		- more red cells die
		- less availability of iron 
				(stuck in cells/ferritin)

Question 25

State some cytokines involved in the pathogenesis of anaemia of chronic disease

Answer 25

Cytokines include

- TNF alpha     - interleukins

Question 26

State the main causes of iron deficiency anaemia

Answer 26

1. Bleeding e.g. menstrual/GI
   2. Increased use e.g. growth/pregnancy
   3. Dietary deficiency e.g. vegetarian
   4. Malabsorption e.g. coeliac

Question 27

When should full GI investigations be performed if a patient has iron deficiency anaemia

Answer 27

Good diet and no coeliac antibodies…..
Male
Women over 40
Post menopausal women
Women with scanty menstrual loss

This is to look for G.I bleeding- early stomach cancers, polyps (pre-cancerous) or piles

Question 28

What are the full G.I investigations

Answer 28

Upper GI endoscopy - oesophagus, stomach, duodenum
Take duodenal biopsy
Colonoscopy

IF FIND NOTHING
- small bowel meal and follow through

Question 29

State some other investigations that could be performed

Answer 29

Menstruating woman <40 ….if heavy periods OR multiple pregnancies and no GI symptoms do nothing
? Urinary blood loss- renal cancers or fibroids or uterine cancers.
Antibodies for coeliac disease

Question 30

State some important laboratory parameters to measure in iron deficiency anaemia

Answer 30

MCV (mean cell volume)
Serum iron
Ferritin
Transferrin 
		(= total iron binding capacity, TIBC)
5.  Transferrin saturation

Question 31

What is important to remember about iron deficiency

Answer 31

Can cause tiredness before it results in an anaemia

Question 32

What are 3 causes of a low MCV

Answer 32

3 causes of a low MCV

1. Iron deficiency
2. Thalassaemia trait
3. Anaemia of chronic disease (low or N)

Question 33

How can you discriminate between the causes of low MCV by measuring serum iron

Answer 33

Iron deficiency LOW

Anaemia of chronic disease LOW

Thalassaemia trait normal

Question 34

How can you confirm the thalassaemia trait

Answer 34

• Haemoglobin electrophoresis

- confirms an additional type of haemoglobin is present

Question 35

Describe the 3 parameters used to distinguish between a low MCV caused by iron deficiency anaemia or anaemia of chronic disease

Answer 35

Ferritin
Transferrin
Transferrin saturation

Question 36

How can ferritin be used to distinguish between iron deficiency anaemia or anaemia of chronic disease

Answer 36

LOW in iron deficiency

HIGH in chronic disease (ferritin is an acute phase protein)

Question 37

Describe the limitations of measuring ferritin

Answer 37

what if Mrs Jones has iron deficiency but she also has a chronic underlying disease??
e.g.RhA plus bleeding ulcer

Ferritin can be normal DESPITE iron def

So check for signs of illness

Raised CRP
Raised ESR

Question 38

How can transferrin be used to distinguish between iron deficiency anaemia and anaemia of chronic disease

Answer 38

Iron deficiency: transferrin goes up

Chronic disease: Normal or even low

Iron deficiency: Low saturation (less iron but more transferrin)

Chronic disease: Normal

Question 39

Summarise the further investigations you should perform in the context of iron deficiency anaemia

Answer 39

Endoscopy and colonoscopy
Duodenal biopsy
Anti-helicobacter antibodies
Anti-coeliac antiodies
		? Abdo ultrasound to look at kidneys
		? Dipstick urine
		? Pelvic ultrasound to exclude fibroids

Question 40

What are the potential pitfalls in reaching a diagnosis

Answer 40

Have to remember lots of ups and downs
If you are looking at 4 things then what if 2 go in the iron deficient direction and 2 go in the anaemia of chronic disease direction

Question 41

What is important to remember if you find a man of any age with a low ferritin

Answer 41

Man of ANY AGE (even your age) with a low ferritin

This suggests iron deficiency and he needs to have upper and lower GI endoscopies to look for a source of bleeding

Question 42

Describe the parameters in classic iron deficiency

Answer 42

Hb					LOW
MCV					LOW
Serum iron 			LOW
Ferritin 				LOW
Transferrin 			HIGH
Transferrin saturation 	LOW

Question 43

Describe the parameters in classic anaemia of chronic disease

Answer 43

Hb					LOW
MCV					LOW or N
Serum iron 			LOW
Ferritin 				HIGH or N
Transferrin 			normal/low
Transferrin saturation 	normal

Question 44

Describe the parameters in thalassaemia trait

Answer 44

Hb LOW
MCV LOW
Serum iron NORMAL
Ferritin NORMAL

Transferrin NORMAL
Transferrin saturation NORMAL

Question 45

What will RhA with a bleeding ulcer look like

Answer 45

Hb					LOW
MCV					LOW
Serum iron 			LOW
Ferritin 				NORMAL
Transferrin saturation 	LOW

Question 46

Describe some additional tests to look at

Answer 46

Additional tests

	- blood film - small, pale, strange shapes including pencil cells			
	- bone marrow? Stain for iron

Question 47

Where can haem be found in the diet

Answer 47

Dietary iron is found in large amounts in red meat, offal and to a lesser extent other animal products. It is also found in relatively large amounts in green vegetables. Because free iron is toxic and because there is no mechanism for excretion of iron the absorption of iron from food is strictly regulated by the intestinal mucosa and this is governed by the amount of iron in the body.

Question 48

Summarise the factors that affect haem absorption

Answer 48

Other factors that affect iron absorption include the form of iron. Haem consists of a protoporphyrin ring with an iron atom at its centre. Haem is better absorbed than free iron (up to 10% absorption) and its absorption is not adversely affected by other food components. In contrast, non-haem iron (i.e. Fe2+ and Fe3+) from vegetable sources are less well absorbed (1-2% absorption) and may be affected by other dietary factors.

Question 49

Describe the factors that improve haem absorption

Answer 49

Factors which improve non-haem iron absorption include acid pH, ascorbic acid (e.g. glass of orange juice) and digestive enzymes, whilst those that inhibit iron absorption include alkaline pH, phytates and phosphates (e.g. cups of tea).

Question 50

Describe the different pools of iron found in the adult

Answer 50

The total amount of iron in an adult is between 3-5 grams. This is divided into three pools:

(i) a metabolic pool in haemoglobin and myoglobin (2-3 grams),
(ii) a storage pool in ferritin and haemosiderin of up to 1 gram, and
(iii) a proportionately small but extremely important transit pool which consists mainly of plasma protein-bound iron of which the most important component is transferrin-bound iron (about 3 milligrams).

Question 51

What is transferrin

Answer 51

Transferrin is a glycoprotein made in the liver with two binding sites for iron. It interacts with a transferrin receptor on the surface of erythroblasts. The complex is internalised; the iron is removed from the transferrin, which is then recirculated.

Question 52

Describe the role of iron in regulation

Answer 52

Iron itself will act as a positive regulator of erythropoiesis and expression of the gene that codes for ferritin. Iron is a negative regulator for expression of the gene that codes for transferrin receptor.

Question 53

Describe hypochromic microcytic anaemias

Answer 53

This is a term used to describe an anaemia where the red cells contain less haemoglobin than normal [low mean cell haemoglobin (MCH)], have a lower concentration of haemoglobin [hypochromia, low mean cell haemoglobin concentration (MCHC)] and are small (microcytic low mean cell volume MCV). The three commonest causes for this type of anaemia are iron deficiency, anaemia of chronic disease and the thalassaemias.
In milder forms of thalassaemia there is often microcytosis without anaemia.

Question 54

Summarise iron deficiency anaemia

Answer 54

The main sources of blood loss are uterine in women of childbearing age group, followed by gastrointestinal blood loss, which may be overt or occult.
Dietary deficiency occurs in vegans and vegetarians with unbalanced diets poor in iron but can also occur in nonvegetarians.
Increased needs occur during childhood and especially during the pubertal growth spurt and during child bearing.
Malabsorption is a less common cause of iron deficiency
Treatment: iron replacement is simply, effectively and cheaply effected with oral iron compounds and the most commonly used is ferrous sulphate. Side effects include constipation and indigestion and may reduce compliance. Compounds containing less iron (ferrous fumarate or ferrous gluconate) may be better tolerated. In case of difficulties, iron can be given parenterally (IM or IV).

Question 55

What else may be useful in assessing iron status

Answer 55

visualisation of haemosiderin in bone marrow aspirates using the Prussian blue reaction.

Question 56

If you are struggling to reach a diagnosis, what else could you look at

Answer 56

Anemia of chronic disease plus iron deficiency. This is not uncommon. Additional tests which may help to establish whether a patient is iron deficient are:-
blood film….you may see changes of iron deficiency, such as elliptocytes
bone marrow aspirate….slides can be stained to see whether or not iron stores are present

Question 57

Summarise anaemia of chronic disease

Answer 57

This is an anemia associated with chronic inflammatory, infectious or neoplastic conditions. ACD can cause a mild to moderate normocytic or microcytic hypochromic anaemia. In ACD the inflammatory markers such as CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) are raised.
The serum ferritin may also be raised and there is accumulation of excess iron in the bone marrow storage pool but with a block in iron incorporation into erythroblasts, which may lead to reduced haemoglobin synthesis and hypochromia.
The pathogenesis of ACD is complex but it usually responds to treatment of the underlying disorder.