Anaemia Flashcards
What is anaemia?
Reduced total red cell mass
What are haemoglobin concentration and haematocrit in terms of anaemia markers?
Surrogate markers
What are the normal levels of Hb and Hct for males?
<130g/l, 0.38-0.52
What are the normal levels of Hb and Hct for females?
<120g/l, 0.37-0.47
What type of method is used to measure Hb concentration?
Spectrophotomeric
How is Hg measured?
Lyse the RBCs to create Hb solution
Stabilise the Hb molecules
Measure optical density at 540nm
OD proportional to concentration (Beer’s Law)
Hb concentration calculated against known reference standard cyan-metHb solution
What is the response to anaemia?
Reticulocytosis
What are Reticulocytes?
RBCs that have just left the bone marrow Large than average red cells Still have RNA remnants Stain purple/deep red as a result Blood film appears polychromatic
How long does up regulation of reticulocyte production by the bone marrow in response to anaemia take?
A few days
What red cell indices are measured?
Hb concentration
No. of red cells
Size of red cells (MCV)
What red cell indices are calculated?
Hct
Mean cell Hg
Mean cell Hg concentration
How is anaemia classified?
Pathophysiology or Morphology (practical and useful)
What may cause anaemia due to decreased production of red cells (low reticulocyte count)?
Hypoproliferative- reduced amount of erythropoiesis
Maturation abnormality- erythropoiesis present but ineffective: cytoplasmic defects (impaired haemoglobinisation), nuclear defects (impaired cell division
What may cause anaemia due to an increased loss or destruction of red cells (high reticulocyte count)?
Bleeding
Haemolysis
What is a useful tool in distinguishing cytoplasmic and nuclear defects?
MCV
If low consider problems with haemoglobinisation
If high consider problems with maturation
Where does Hg synthesis occur?
Cytoplasm
What do you need to make Hb?
Globins
Haem- porphyrin ring, Iron (Fe2+)
What does shortage of the products required to make Hb result in?
Small red cells with low Hb content
Cells are microcytic and hypochromic
What will be the cause of hypochromic microcytic anaemias?
Deficient Hb synthesis due to cytoplasmic defect
What can cause a haem deficiency?
Lack of iron for erythropoiesis- iron deficiency (low body iron), some causes of anaemia of chronic disease (normal body iron but lack of available iron, most normocytic)
Problems with porphyrin synthesis (rare)- lead poisoning, pyridoxine responsive anaemias
Congenital siderobastic anaemia (rare)
What can cause a globin deficiency?
Thalassaemia (trait, intermedia, major)
What is iron essential for?
Oxygen transport- Hb, myoglobin
Electron transport- mitochondrial production of ATP
In what forms can Iron exist?
Fe 2+ or 3+
What does iron generate making it potentially toxic?
Free radicals
Describe the structure of an adult haemoglobin
4 globin sub units, each containing a single haem molecule
Haem groups contains a single Fe2+ ion
Each haem group can bind one O2 molecule
When fully saturated, how much O2 will 1g Hb bind?
1.34ml
How much iron do we absorb and lose each day?
1mg
How much iron is stores in parenchymal tissues?
500mg (liver, other)- as ferritin
How much iron is in plasma?
4mg
How much iron is in erythyroid marrow?
150mg
How much iron is in red cell Hb?
2500mg
How much iron is in macrophage (reticuloendothelial) stores?
500mg- as ferritin
What is circulating iron bound to?
Transferrin
What tests are available to test functional iron?
Hg
What tests are available to test transported iron?
Serum ion
Transferrin
Transferrin saturation
What tests are available to test storage iron?
Serum ferritin
What is transferrin?
Protein with two binding sites for iron atoms
What does transferrin do?
Transports iron from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors (esp. erythroid marrow)
What does % saturation of transferrin with iron measure?
Iron supply
When would transferrin saturation be reduced?
Iron deficiency
Anaemia of chronic disease
When would transferrin saturation be increased?
Genetic haemochromatosis
What is ferritin?
Large spherical intracellular protein that stores up to 4000 ferric ions
How much ferritin is present in the serum?
Tiny amount- reflects intracellular ferritin synthesis in response to iron status of the host
What is serum ferritin a measure of?
Indirect measure of storage iron
What does low ferritin mean?
Iron deficiency
What can iron deficiency be confirmed by?
A combination of anaemia (decreased functional iron) and reduced storage iron (low serum ferritin)
What are the causes of iron deficiency?
- Not eating enough:
Relative deficiency- esp women of child bearing age and children
Absolute- vegetarian diets
Unlikely in men - Losing too much- blood loss (usually GI)
- Not absorbing enough- malabsorption (coeliac, achlorhydria)
What are some causes of chronic blood loss?
Menorrhagia
GI- tumours, ulcers, NSAIDs
Haematuria
How much iron is lost in menstruation?
30-40ml blood/month, so 15-20mg iron/month
What are the sequential consequences of -ve iron balance?
Exhaustion of iron stores
Iron deficient erythropoiesis- falling red cell MCV
Microcytic anaemia
Epithelial changes- skin, koilonychia
How does occult blood loss outstrip the maximum dietary iron absorption of iron?
Small volume GI blood loss can occur without any symptoms or signs
Results in anaemia
Iron absorption can be increased by supplements
Is iron deficiency anaemia a diagnosis or symptom?
Symptom
What are the true causes of macrocytosis?
Megaloblastic
Non-megaloblastic
What is an erythroblast?
A normal red cell precursor with a nucleus
What is the difference between precursors of red cells and reticulocytes?
Have a nucleus
Marrow-based
Name each cell in erythropoiesis from pronormoblast to erythrocyte
Pronormoblast Basophilic/early normoblast Polychromatophilic/ intermediate normoblast Orthochromatic/late normblast Reticulocyte Erythrocyte
Between what stages does enucleation occur in erythrocyte?
Late normoblast and reticulocyte
What is a megaloblast?
An abnormally large nucleated red cell precursor with an immature nucleus
What are megaloblastic anaemias characterised by?
Predominant defects in DNA synthesis and nuclear maturation with relative preservation of RNA and Hb synthesis
What do defects in DNA synthesis and nuclear maturation cause for the cell?
Cytoplasm has developed and becomes mature enough to divide, but nucleus is still immature
Leads to bigger than normal red cell precursor
Cell can sense it has enough Hb and doesn’t need to divide anymore
What are the causes of megaloblastic anaemia?
B12 deficiency
Folate deficiency
Others- drugs, rare inherited abnormalities
Why does lack of B12 or folate cause megaloblastic anaemia?
They’re essential co-factors for nuclear maturation, enable chemical reactions that provide enough nucleosides for DNA synthesis
What does the B12 methionine cycle produce?
S-adenosyl methionine, a methyl donor to DNA, RNA, proteins, lipids, folate intermediates
What is the folate cycle important for?
Nucleoside synthesis
What are the causes of B12 deficiency?
Veganism Atrophic gastritis PPIs/H2 receptor antagonist Gastrectomy/bypass Chronic pancreatitis Bacterial overgrowth Coeliac Duodenum resection Crohn's Inherited cubulin deficiency
What are dietary folates converted to?
Monoglutamate
Where is folate absorbed?
Jejunum (diffusion and actively)
Duodenum
What is the source of B12?
Animals
What is the source of folate?
Leafy veg, yeast
Destroyed by cooking
How long is B12 stored for?
2-4y
How long is folate stored for?
4 months
Where is B12 absorbed?
Ileum
What is the daily requirement for B12 and folate?
1-3μgday and 100μgs/day respectively
What are the causes of folate deficiency?
Inadequate intake (more likely than B12)
Malabsorption- Coeliac, Crohn’s
Excess utilisation- haemolysis, exfoliating dermatitis, pregnancy, malignancy
Drugs- anticonvulsants
What are the clinical features of B12/folate deficiency?
Symptoms/signs of anaemia Weight loss, diarrhoea, infertility Sore tongue, jaundice Developmental problems Neuro problems (B12 deficiency)- posterior/dorsal column abnormalities, neuropathy, dementia, psychiatric manifestations
What is pernicious anaemia?
AI condition with resulting destruction of gastric parietal cells
What is pernicious anaemia associated with?
Atrophic gastritis and personal or FHx of other AI disorders (e.g. hypot, vitiligo, Addison’s)
What is seen on lab diagnosis in pernicious anaemia?
Macrocytic anaemia (red cells low)
Pancytopenia in some patients
Blood film shows macrovalocytes and hypersegmented neutrophils (normally 3-5 nuclear segments)
Assess B12 and folate levels
Check for auto-antibodies (anti GPC and anti IF)
What is the treatment of megaloblastic anaemia?
Treat cause where possible
Vitamin B12 injections for life in pernicious anaemia
Folic acid tablets (5mg per day orally
Only if life-threatening, transfuse red cells
What are the causes of non-megaloblastic macrocytosis?
Alcohol
Liver disease
Hypothyroidism (All 3 may not be assoc. with anaemia, due to red cell membrane changes)
Marrow failure- myelodysplasia, myeloma, aplastic anaemia
What will be seen in spurious macrocytosis?
Size of mature red cell is normal, but MCV measured as being high
What are the causes of spurious macrocytosis?
When there is an increase in reticulocyte numbers as a marrow response to acute blood loss or red cell breakdown (haemolysis)
Reticulocytes are bigger than mature red cells and are analysed along with these for MCV measurement
Cold-agglutinins
