Iron deficiency and anaemia of chronic disease Flashcards
What are the haematinics
Components needed to make red blood cells
B12
Folate
Iron
State the iron containing proteins
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.
Describe the roles of iron in Hb
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
Describe the association of haem with a globin chain
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.
Describe the structure of haem
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
Summarise iron haemostasis
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
Describe iron usage/loss
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
Describe the iron found in the diet
Human diet provides 12-15mg iron/day Iron occurs in most natural foods - Meat and fish(haem iron) - Vegetables - Whole grain cereal - chocolate
Describe the absorption of iron
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.
Describe the factors that can affect iron absorption
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
Describe the factors that will increase iron absorption
§ Factors that increase iron absorption are:
o Iron deficiency.
o Anaemia/hypoxia.
o Pregnancy.
Describe how iron is absorbed in the duodenum
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.
How does the gut cell alter iron absorption
High iron - high hepcidin - low ferroportin- low absorption
How is the level of hepcidin regulated
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
How is iron stored within cells
In ferritin micelles
Where is ferroportin found
§ Ferroportin is found in; enterocytes of duodenum, macrophages of spleen, hepatocytes.
Describe the role of transferrin
§ 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.
Describe the different ways in which we can measure transferrin
§ 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.
Describe the roles of erythropoietin
§ 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
When is EPO released
Anaemia
Tissue hypoxia
Increase in EPO
Increased survival, growth and differentiation of RBC precursors.
Essentially, what is anaemia of chronic disease
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
What are the laboratory signs of being ill
C-reactive protein Erythrocyte Sedimentation Rate Acute phase response- increases in - ferritin - FVIII - fibrinogen - immunoglobulins
All these factors will be raised
Describe some conditions associated with anaemia of chronic disease
Chronic infections e.g. TB/HIV
Chronic inflammation e.g. RhA/SLE
Malignancy
Miscellaneous e.g. cardiac failure
Describe the pathogenesis of anaemia of chronic disease
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)
State some cytokines involved in the pathogenesis of anaemia of chronic disease
Cytokines include
- TNF alpha - interleukins
State the main causes of iron deficiency anaemia
- Bleeding e.g. menstrual/GI
- Increased use e.g. growth/pregnancy
- Dietary deficiency e.g. vegetarian
- Malabsorption e.g. coeliac
When should full GI investigations be performed if a patient has iron deficiency anaemia
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
What are the full G.I investigations
Upper GI endoscopy - oesophagus, stomach, duodenum
Take duodenal biopsy
Colonoscopy
IF FIND NOTHING
- small bowel meal and follow through
State some other investigations that could be performed
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
State some important laboratory parameters to measure in iron deficiency anaemia
MCV (mean cell volume) Serum iron Ferritin Transferrin (= total iron binding capacity, TIBC) 5. Transferrin saturation
What is important to remember about iron deficiency
Can cause tiredness before it results in an anaemia
What are 3 causes of a low MCV
3 causes of a low MCV
- Iron deficiency
- Thalassaemia trait
- Anaemia of chronic disease (low or N)
How can you discriminate between the causes of low MCV by measuring serum iron
Iron deficiency LOW
Anaemia of chronic disease LOW
Thalassaemia trait normal
How can you confirm the thalassaemia trait
- Haemoglobin electrophoresis
- confirms an additional type of haemoglobin is present
Describe the 3 parameters used to distinguish between a low MCV caused by iron deficiency anaemia or anaemia of chronic disease
Ferritin
Transferrin
Transferrin saturation
How can ferritin be used to distinguish between iron deficiency anaemia or anaemia of chronic disease
LOW in iron deficiency
HIGH in chronic disease (ferritin is an acute phase protein)
Describe the limitations of measuring ferritin
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
How can transferrin be used to distinguish between iron deficiency anaemia and anaemia of chronic disease
Iron deficiency: transferrin goes up
Chronic disease: Normal or even low
Iron deficiency: Low saturation (less iron but more transferrin)
Chronic disease: Normal
Summarise the further investigations you should perform in the context of iron deficiency anaemia
Endoscopy and colonoscopy Duodenal biopsy Anti-helicobacter antibodies Anti-coeliac antiodies ? Abdo ultrasound to look at kidneys ? Dipstick urine ? Pelvic ultrasound to exclude fibroids
What are the potential pitfalls in reaching a diagnosis
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
What is important to remember if you find a man of any age with a low ferritin
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
Describe the parameters in classic iron deficiency
Hb LOW MCV LOW Serum iron LOW Ferritin LOW Transferrin HIGH Transferrin saturation LOW
Describe the parameters in classic anaemia of chronic disease
Hb LOW MCV LOW or N Serum iron LOW Ferritin HIGH or N Transferrin normal/low Transferrin saturation normal
Describe the parameters in thalassaemia trait
Hb LOW
MCV LOW
Serum iron NORMAL
Ferritin NORMAL
Transferrin NORMAL
Transferrin saturation NORMAL
What will RhA with a bleeding ulcer look like
Hb LOW MCV LOW Serum iron LOW Ferritin NORMAL Transferrin saturation LOW
Describe some additional tests to look at
Additional tests
- blood film - small, pale, strange shapes including pencil cells - bone marrow? Stain for iron
Where can haem be found in the diet
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.
Summarise the factors that affect haem absorption
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.
Describe the factors that improve haem absorption
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).
Describe the different pools of iron found in the adult
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).
What is transferrin
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.
Describe the role of iron in regulation
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.
Describe hypochromic microcytic anaemias
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.
Summarise iron deficiency anaemia
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).
What else may be useful in assessing iron status
visualisation of haemosiderin in bone marrow aspirates using the Prussian blue reaction.
If you are struggling to reach a diagnosis, what else could you look at
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
Summarise anaemia of chronic disease
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.
