Iron - Anaemia and Overload Flashcards
What is anaemia?
Insufficient amount of red blood cells or Hb
In which circumstances is Hb not a good measure of RBC mass, and why?
Acute haemorrhage - there is no change in Hb as even though there is a lot of RBC loss the loss is proportional to other components
Large volume fluid restriction - plasma expands showing a reduction in Hb when there is no RBC loss
What is the general presentation of anaemia?
Exertional SOB Dizziness Palpitations Fatigue Headache Fainting Anorexia Conjunctival or general pallor
What are the 2 main classifications of anaemia?
Microcytic
Macrocytic
What is the pathophysiology of microcytic hypochromic anaemia?
Reduction in Hb production which means Hb level in cells takes longer to build up and switch off cell division
Cells divide more so RBCs are smaller and paler
What aspects of Hb can go wrong leading to reduction in Hb production?
Haem group
Porphyrin ring
Globin chain
What are the causes of microcytic anaemia, and which components of Hb are defective in each?
Thalassaemia - globin chain Anaemia of chronic disease - haem group Iron deficiency - haem group Lead poisoning - porphyrin ring Sideroblastic anaemia - porphyrin ring
What is iron deficiency?
Anaemia caused by there being insufficient iron to produce haemoglobin
Not a diagnosis - look for a cause
What are causes of iron deficiency anaemia?
Chronic blood loss (menorrhagia, GI bleeds)
Malabsorption (coeliac, post-gastrectomy)
Poor dietary intake
Infection (hookworm)
Contributing factors (lots of tea, PPIs, age)
What is the presentation of iron deficiency anaemia?
General features of anaemia (fatigue, exertion SOB, dizziness, headache, fainting etc)
Koilonychia
Angular stomatitis, atrophic gastritis
Post-cricoid webs
What do iron studies show in iron deficiency anaemia?
Low serum ferritin
Low % transferrin saturation
What is the management of iron deficiency anaemia?
Look for a cause, treat that
Oral iron replacement (ferrous sulphate or fumarate)
What are the side effects of oral iron replacement?
Nausea
Black stool
Diarrhoea
Constipation
How much should Hb increase on iron replacement?
10 per week
Who should be referred for GI screening in iron deficiency anaemia?
Iron deficiency anaemia with dyspepsia
Iron deficiency anaemia with rectal bleeding or symptoms of colorectal cancer
Iron deficiency anaemia not responding to treatment
What is sideroblastic anaemia?
Disorder of production of the porphyrin ring
This leads to ineffective erythropoiesis, driving iron absorption and deposition in organs other than the liver
What are the causes of sideroblastic anaemia?
X linked hereditary
Chemotherapy
Anti-TB drugs
Lead poisoning
What will a marrow biopsy show in sideroblastic anaemia?
Ring sideroblasts
What is seen on blood film in sideroblastic anaemia?
Atypical blood cells of varying sizes and shapes
What is seen in iron studies in sideroblastic anaemia?
High iron
High ferritin
High transferrin saturation
What is the management of sideroblastic anaemia?
Treat underlying cause if any
Regular blood transfusions
What is thalassaemia?
A group of conditions of defective production of globing chains in Hb
Abnormal cells are small and more susceptible to premature haemolysis
What is the cause of thalassaemia?
Hereditary - autosomal recessive
What are the types of thalassaemia?
Alpha thalassaemia - trait, HbH disease, Hb Barts hydros fettles
Beta thalassaemia: trait, intermedia, major
What is alpha thalassaemia?
Alpha globin chain is affected
One or more alpha genes are deleted
How many alpha genes are there, and which chromosome are they on?
4 - chromosome 16
Which types of Hb are affected in alpha thalassaemia?
HbA
HbA2
HbF
Which genes are missing in alpha thalassaemia trait?
1 or 2 alpha genes
What are the clinical features of alpha thalassaemia trait?
Asymptomatic carrier state
What do investigations show in alpha thalassaemia trait?
May have microcytic hypochromia
Ferritin will be normal
What is the treatment of alpha thalassaemia trait?
None needed
Which genes are missing in HbH disease?
3 - only one alpha gene left
What is the pathophysiology in HbH disease?
Reduction in alpha chains so excess beta chains form tetramers called HbH
Why is HbH bad?
It’s unstable and has an extremely high oxygen affinity, making it ineffective as an oxygen delivery device
What do investigations show in HbH disease?
Moderate anaemia
Very low MCV and MCH (disproportionate the the anaemia)
What are the clinical features of HbH disease?
Jaundice
Splenomegaly
Leg ulcers
Gallstones
What is the management of HbH disease?
May need transfusion in circumstances such as intercurrent infection
If severe - regular transfusions, splenectomy
Which genes are missing in Hb Barts hydros fetalis?
All - no functional alpha genes
What are the clinical features of Hb Barts hydros fetalis?
Incompatable with life Profound anaemia Cardiac failure Growth retardation Severe hepatosplenomegaly
What is the pathophysiology of Hb Barts hydros fetalis?
Minimal or no alpha chain production so HbF and HbA can’t be made
Tetramers of Hb Barts and HbH are produced
What is beta thalassaemia?
Beta globin chain is affected
Reduced or absent beta chain production
What is the usual mutation in beta thalassaemia?
Point mutation
Which types of Hb are affected in beta thalassaemia?
Only HbA
How many beta genes are there?
2
What genes are affected in beta thalassaemia trait?
1 reduced or absent beta gene
What are the clinical features of beta thalassaemia trait?
Asymptomatic
What does FBC and Hb analysis show in beta thalassaemia trait?
No/mild anaemia
Low MCV, MCH
Raised HbA2
What is the management of beta thalassaemia trait?
None needed
What genes are affected in beta thalassaemia intermedia?
2 reduced beta genes or 1 reduced and one absent gene
What are the clinical features of beta thalassaemia intermedia?
Similar to HbH disease (Jaundice Splenomegaly Leg ulcers Gallstones)
What is the management of beta thalassaemia intermedia?
Occasional transfusion
What genes are affected in beta thalassaemia major?
All - no functional beta genes
What are the clinical features of beta thalassaemia major?
Presents at 6-24 months (as HbF fails) Pallor Failure to thrive Hepatosplenomegaly Skeletal changes Organ damage Caused by extra medullary haematopoiesis
What does Hb analysis show in beta thalassaemia major?
Mainly HbF
High HbA2
No HbA
What is the management of beta thalassaemia major?
Lifelong transfusion dependency
Bone marrow transplant may be an option if carried out before complications
What is the risk of treatment of beta thalassaemia major?
Iron overload
What is anaemia of chronic disease?
Diseases which cause chronic inflammation can cause anaemia
Inflammatory cytokines cause problems with iron utilisation
Iron is being absorbed so stores are high but Hb is low
How do inflammatory cytokines cause problems with iron utilisation?
Increase production of hepcidin (which inhibits release of iron from cells)
Reduces erythropoietin (which stimulates erythropoiesis)
Inhibit bone marrow production of erythrocytes
Macrophage red cell destruction is increased
What are some causes of anaemia of chronic disease?
Malignancy Hypothyroidism Chronic infection Connective tissue disease CKD
What do investigations show in anaemia of chronic disease?
FBC: low Hb, can be microcytic or normocytic
High ferritin
What is macrocytic anaemia?
Low Hb with large, hyperchromic red cells
What is the pathophysiology of macrocytic anaemia?
Cells become large due to defective nuclear maturation and DNA synthesis
This leads to growth without division
Due to their size the cells are more prone to early breakdown
What is the main classification of macrocytic anaemia?
Megaloblastic
Non-megaloblastic
What are megaloblasts?
Abnormally large, nucleated red cell precursors
How do B12 and folate contribute to erythropoiesis?
Required for DNA synthesis
What are the sources of B12 and folate?
B12 - animal foods
Folate - plant foods
Where are B12 and folate absorbed?
B12 - terminal ilium
Folate - duodenum
How is B12 absorbed?
By binding to intrinsic factor
How long are B12 and folate stored in the body?
B12 - 2-4 years
Folate - 4 months
What are causes of B12 deficiency?
Diet: vegan, alcoholism
Stomach: pernicious anaemia, gastrectomy, PPI, anti-histamines
Small intestine: bacterial overgrowth, coeliac disease, Crohn’s disease, bowel resection
Chronic pancreatitis
What is pernicious anaemia?
Autoimmune atrophic gastritis causing reduction in intrinsic factor
What are the autoantibodies in pernicious anaemia?
Anti gastric parietal cell
Anti intrinsic factor
What are causes of folate deficiency?
Low intake: poverty, old age, alcoholism
Malabsorption: coeliac, tropical sprue
Increased demand: pregnancy, malignancy, myelofibrosis, exfoliating dermatitis, haemolytic anaemia
Drugs: methotrexate, trimethoprim, anticonvulsants
What is the presentation of B12 and folate deficiency?
Symptoms of anaemia
Mouth - glossitis, angular stomatitis
Jaundice
Psychiatric - irritability, depression
What clinical features are seen in B12 deficiency (not folate)?
Neurological - numbness, tingling, subacute combined degeneration of the cord (paraesthesia, ataxia, weakness)
What do investigations show in B12 and folate deficiency?
Low serum B12/folate
FBC - low Hb, high MCV, reticulocytes
Bone marrow biopsy: megaloblasts
Blood film: howel jolly bodies, hyper-segmented neutrophils
What is the management of B12 and folate deficiency?
Folate - folate tablets
B12 - IM B12 (for life)
What are causes of non-megaloblastic macrocytosis?
Alcohol Pregnancy Hypothyroidism Liver disease Marrow failure: myelodysplasia, aplastic anaemia, myeloma
What is seen on blood film in macrocytosis caused by liver disease?
Target cells
What is spurious macrocytosis?
False macrocytosis where the volume of the mature red cell is normal but the MCV is measured as high
What are the causes of spurious macrocytosis?
Reticulocytosis
Cold-agglutinins
What is reticulocytosis?
Increase in reticulocyte numbers as a marrow response to acute blood loss or haemolysis
MCV measured as higher as reticulocytes are bigger than mature RBCs
What are cold agglutinins?
Abnormal proteins produced in certain cancers or infections
Cause clumping of red cells at lower temperatures
The clumps are registered as one giant cell
Causes extraordinarily high MCV
What is the pathophysiology of sickling disorders?
Mutation of beta globin chain which alters the structure, chainging it from Hb to HbS
This distorts the cell, damaging the membrane and leading to formation of rod/needle-like structures in the cell
Makes it more prone to binding to vascular epithelium - more sticky
What are the types of sickling disorders?
Sickle cell trait
Sickle cell anaemia
Sickle cell disease
Sickle crisis
What genes are affected in sickle cell trait?
One normal, one abnormal beta gene
What are the clinical features of sickle cell trait?
Asymptomatic
May sickle in severe hypoxia, e.g. high altitude, under anaesthesia
What do investigations show in sickle cell trait?
Blood film normal
Hb analysis: mainly HbA, HbS <50%
What genes are affected in sickle cell anaemia?
2 abnormal beta genes
What do investigations show in sickle cell anaemia?
Blood film: sickle cells
Hb analysis: HbS >80%, no HbA
What are the clinical features of sickle cell anaemia?
Episodes of sickle crisis (severe pain and variable other symptoms)
Chronic haemolysis
Splenic infarcts - leading to hyposplenism
What causes splenic infarcts in sickle cell anaemia?
Sequestration of sickled RBCs in liver and spleen
What genes are affected in sickle cell disease?
One beta gene causing HbS, plus another beta chain mutation
What are the clinical features of sickle cell disease?
Same as sickle cell anaemia
What is sickle crisis also known as?
Sickle vaso-occlusion
What is the pathophysiology of sickle crisis?
Sickle cells can get wedged, stick to vessel wall and block microvascular flow
Inflammatory response and recruitment of neutrophils and platelets
Leads to tissue ischaemia and pain
What factors precipitate sickle crisis?
Hypoxia Dehydration Infection Cold exposure Stress/fatigue
What is the treatment of sickle crisis?
Opiate analgesia Hydration Rest Oxygen Red cell exchange in severe crisis (lung, brain)
What measures are taken as long-term management of sickling disorders?
Prophylactic penicillin and vaccination to reduce the risk of infection
Folic acid supplementation
Hydroxycarbamide (reduces severity by increasing HbF production)
Regular transfusion to prevent stroke in selected cases (e.g. children who have had strokes)
What are causes of iron overload?
Hereditary haemochromatosis
Long term transfusions
What disorders require long-term transfusions?
Thalassaemia
Sideroblastic anaemia
What is hereditary haemochromatosis?
Genetic condition with increased iron absorption due to mutations that reduce the production of hepcidin
What is the pathophysiology of hereditary haemochromatosis?
Reduced production of hepcidin results in increased iron absorption (as heparin inhibits absorption of iron)
This results in iron deposition in tissues other than the liver, which causes inflammation and end organ damage
What are the clinical features of hereditary haemochromatosis?
Usually presents in middle age or later
Early: fatigue, arthralgia, weakness
Late: slate grey skin, liver failure, diabetes (to then bronzed diabetes), cardiomyopathy
What do investigations show in hereditary haemochromatosis?
Abnormal LFTs
Iron studies: high iron, high ferritin
What is the management of hereditary haemochromatosis?
Regular venesection
What causes secondary iron overload?
Anaemias can cause overactive erythropoiesis, leading to excessive iron absorption
These patients also require regular blood transfusions which makes this worse
What disorders cause secondary iron overload?
Thalassaemia
Sideroblasdtic anaemia
Red cell aplasia
Myelodysplasia
What is the treatment of secondary iron overload?
NOT venesection - as the patients are already anaemic
Iron chelating agents - desferrioxamine, deferiprone, deferasirox
What is haemolysis?
The premature breakdown of red blood cells
What is the body’s response to haemolysis?
Erythroid hyperplasia
Reticulocytosis
What do reticulocytes look like?
Larger and more blue/purple on film
What are the different types of haemolysis?
Extravascular
Intravascular
What is extravascular haemolysis?
Breakdown of RBCs outside of the circulation - in the liver and spleen
Is extravascular haemolysis pathological or physiological?
Both
Which breakdown products are detected in extravascular haemolysis?
Normal products in excess
Unconjugated bilirubin
What are causes of extravascular haemolysis?
Autoimmune haemolytic anaemia
Thalassaemia
Sickle cell disease
Hereditary spherocytosis
What is intravascular haemolysis?
Pathological breakdown of red cells within the circulation
Which breakdown products are detected in intravascular haemolysis?
Abnormal products
Haemoglobinaemia
Met-haem-albuminaemia
Haemoglobinuria
What feature of urine demonstrates haemoglobinuria?
Pink urine, turns black when left to stand
What are causes of intravascular haemolysis?
Drug-induced ABO mismatch blod transfusion G6PD deficiency Severe malaria Microangiopathic haemolytic anaemia
Does haemolysis always cause anaemia, why?
No
In compensated haemolysis Hb is maintained by reticulocytosis
In decompensated haemolysis Hb is not maintained and anaemia results
What are the general clinical features of haemolysis?
Jaundice
Change in colour of urine
Abdominal pain/swelling
What aspects of haemolysis cause which abnormalities on blood film?
Membrane damage - spherocytes
Mechanical damage - red cell fragments
Oxidative damage - Heinz bodies
HbS - sickle cells
What does the Coomb’s test test for?
Direct Coomb’s test - positive in autoimmune disease
Indirect Coomb’s test - positive in immune response to foreign antibodies
What ways can causes of haemolysis be classified?
Haemolysis of normal red cells
Haemolysis of red cells with abnormal membrane
Haemolysis of red cells with abnormal metabolism
Haemolysis of red cells with abnormal haemoglobin
What are the causes of haemolysis of normal red cells?
Autoimmune haemolysis
Alloimmune haemolysis
What type of haemolysis is autoimmune haemolysis?
Extravascular
How is autoimmune haemolysis classified?
Warm or cold autoantibody - the temperature in which the antibodies bind
Which immunoglobulin is responsible in warm autoantibody autoimmune haemolysis?
IgG
Which immunoglobulin is responsible in cold autoantibody autoimmune haemolysis?
IgM
What are the causes of warm and cold autoantibody autoimmune haemolysis?
Warm - idiopathic
Cold - idiopathic or secondary to leukaemia, lymphoma
Is direct or indirect Coomb’s test positive in warm and cold autoantibody autoimmune haemolysis?
Warm - direct
Cold - indirect
What are the causes of alloimmune haemolysis?
Disseminated intravascular coagulation Haemolytic uraemia syndrome Thrombotic thrombocytopenia purpura Leaking heart valve Infections (e.g. malaria) Severe burns
Why do leaking heart valves cause alloimmune haemolysis?
Red cell fragmentation occurs due to mechanical damage on the damaged valve
What cells are seen on blood film in alloimmune haemolysis, and what do they look like?
Schistocytes - red cell fragments
Irregularly shaped, jagged, 2 pointed ends
What is the main cause of haemolysis of cells with abnormal cell membrane?
Hereditary spherocytosis
What is the inheritance pattern of hereditary spherocytosis?
Autosomal dominant
What is the pathophysiology of hereditary spherocytosis?
Reduced membrane deformability means increased transit time though the spleen
Oxidant environment in the spleen causes extravascular red cell destruction
Leads to chronic extravascular haemolysis
What are the clinical features of hereditary spherocytosis?
Young children with family history of splenectomy Jaundice Splenomegaly Mild anaemia Increased risk of gallstones
What cells are seen on blood film in hereditary spherocytosis?
Spherocytes
What is the long-term management of hereditary spherocytosis?
Folate replacement
Splenectomy is curative
What is the management of hereditary spherocytosis in a haemolytic crisis?
Supportive
Transfusion if necessasry
What is the main cause of haemolysis of cells with abnormal red cell metabolism?
G6PD deficiency
What is the inheritance pattern of G6PD deficiency?
X linked
What is the pathophysiology of G6PD deficiency?
Deficiency of an enzyme in red cell metabolism - a pathway that prevents against oxidative stress, and generates energy
When exposed to increased oxidative stress the red cells undergo intravascular haemolysis
What is the presentation of G6PD deficiency?
Rapid onset jaundice and anaemia after exposure to:
- henna
- acute illness
- broad beans
- drugs: aspirin
What are the features of G6PD deficiency on a blood film?
Heinz bodies, bit cells
What is diagnostic for G6PD deficiency?
Enzyme assay - showing reduced G6PD
What is the management of G6PD deficiency?
Avoid triggers
Transfuse if acutely anaemic
