Anaemia Flashcards
Define anaemia
Decrease of haemoglobin in the blood below the reference for the age and sex of the individual
2 general reasons for anaemia
Low red cell mass (RCM)
Increased plasma volume e.g.pregnancy
What is average normal lifespan of a RBC
120 days
Causes of anaemia
Reduced production from bone marrow or increased loss of RBCs i.e. by the spleen, liver, BM and blood loss
How can you determine if BM production of RBCs is the problem in anaemia
Reticulocyte count
count of immature RBCs in the bone marrow
What does reticulocyte count tell you about the anemia and red blood cells
If R count is low, production is the issue
If R count is high, removal is the issue
What would happen to Hb levels in blood in dehydration
Reduction in plasma volume and thus a falsely high haemoglobin (Hb)
3 major types of anaemia
Microcytic - low MCV or small size (<80fL)
Normocytic - normal MCV
Macrocytic - high MCV (>96fL)
What is MCV
Mean Corpuscular Volume (MCV) which is essentially the average volume of RBCs (or their size)
Consequences of anaemia
Reduced oxygen transport
Tissue hypoxia
Compensatory changes (increased tissue perfusion, increased oxygen transfer to tissues, increased RBC production)
Pathological consequences of anaemia
Myocardial fatty change Fatty change in liver Aggravates angina and claudication Skin and nail atrophic changes CNS cell death (cortex and basal ganglia)
Non-specific symptoms of anaemia
- Fatigue, headaches and faintness
- Dyspnoea and breathlessness
- Angina (if there is pre-existing coronary disease)
- Anorexia
- Intermittent claudication
- Palpitations
Signs of anaemia
- May be absent even in severe anaemia
- Pallor
- Tachycardia
- Systolic flow murmur
- Cardiac failure
Main causes of microcytic anaemia
- Iron deficiency anaemia - the MOST COMMON CAUSE WORLDWIDE
- Anaemia of chronic disease
- Thalassaemia
Rare causes of microcytic anaemia
Congenital sideroblastic anaemia
Lead poisoning
What is average daily intake of iron?
15-20mg
What % of dietary iron is absorbed in the duodenum
10%
What is iron used for in body
For formation of haem in haemoglobin
How is iron absorbed from gut
Iron ions are actively transported into the duodenal intestinal epithelial cells by the Intestinal Haem Transporter (HCP1).
What happens to most iron from the gut
Incorporated into haemoglobin
What happens to iron that’s not incorporated into haemoglobin
Stored in reticuloendothelial cells, hepatocytes and skeletal muscle cells as FERRITIN (most, found in plasma and most cells - esp liver spleen BM) or HAEMOSIDERIN (in macrophages of bone marrow, liver and spleen)
Why is more iron stored as ferritin than haemosiderin
Ferritin is more easily mobilised for Hb formation
What % of menstruating women show iron deficiency anaemia
14%
Causes of iron deficiency anaemia
Blood loss:
Menorrhagia, GI bleeding, Hookworm
Poor diet:
Especially in children and babies (but rarely in adults where there is poverty
Increased demands such as during growth and pregnancy
Malabsorption:
Poor intake - rare in developed countries
Coeliac disease
What is leading cause of iron deficiency anaemia worldwide
Hookworm
results in GI blood loss
Risk factors of iron deficiency anemia
- Undeveloped countries
- High vegetable diet
- Premature infants
- Introduction of mixed feeding delayed - since breast milk contains low iron
Iron deficiency anaemia pathophysiology
Less iron available for haem synthesis
Crucial for haemoglobin
production thus reduction in iron will result in a decrease in haemoglobin
and thus smaller RBC’s resulting in microcytic anaemia
Iron deficiency anaemia clinical presentation
- *Brittle nails and hair
- Spoon-shaped nails (koilonychia)
- Atrophy of the papillae of the tongue (*atrophic glossitis)
- *Angular stomatitis/cheilosis - Ulceration of the corners of the mouth
Iron deficiency anaemia differential diagnosis
- Thalassaemia
- Sideroblastic anaemia
- Anaemia of chronic disease
Iron deficiency anaemia diagnosis
Blood count and film:
RBCs are microcytic and hypochromic. RBC also show Poikilocytosis and Anisocytosis
Serum ferritin:
Low - confirms diagnosis (but may be normal in malignancy or infection e.g. due to inflammation)
Low serum iron
Transferrin saturation falls below 19% means iron deficiency present
Serum soluble transferrin receptor number increases
Further investigations into cause of blood loss
What is meant by a RBC being hyppchromic
pale
What is difference between Poikilocytosis and Anisocytosis
Poikilocytosis = variation in RBC shape Anisocytosis = variation in RBC size
What happens to total iron-binding capacity in iron deficincy
TIBC rises
Treatment of Iron deficiency anemia
Find and treat cause
Oral iron: FERROUS SULPHATE
Parenteral iron e.g. IV iron or deep intramuscular iron in extreme cases such as severe malabsorption.
Side effects of ferous sulphate
Nausea, Abdominal discomfort, Diarrhoea/constipation, Black stools
If side effects of ferrous sulphate are bad, what can you give instead?
Ferrous Gluconate
What is second most common cause of anaemia
Chronic disease that leads to secondary anaemia (due to bone marrow also being sick)
What is most common anaemia in hospital patients
anaemia of chronic disease
What chronic infections are likely to result in anaemia
Tuberculosis Crohn's Rheumatoid arthritis SLE Malignant disease
Pathophysiology of anemia from chronic infections
- There is decreased release of iron from the bone marrow to developing
erythroblasts (early RBC, before reticulocyte) - An inadequate erythropoietin response (cytokine which increases RBC production) to anaemia
- Decreased RBC survival
Clinical presentation of anaemia from chronic infections
- Fatigue, headaches and faintness
- Dyspnoea and breathlessness
- Angina if there is pre-existing coronary disease
- Anorexia
- Intermittent claudication
- Palpitations
Diagnosis of anaemia from chronic infections
Low serum iron and TIBC (total iron-binding capacity)
Normal or raised serum ferritin due to inflammatory process
Normal serum transferrin receptor level
Blood count and film - RBCs are normocytic or microcytic and hypochromic as in Rheumatoid arthritis and Crohn’s
Treatment of anaemia from chronic infection
Treat underlying chronic cause
Erythropoietin - effective in raising Hb level and is used in anemia or renal disease and inflammatory disease e.g. rheumatoid arthritis and inflammatory bowel disease
Side effects of Erythropoietin as a treatment for anaemia
flu-like symptoms, hypertension, mild rise in the platelet count and thromboembolism
Clinical presentation of anaemia in general
Fatigue Lethargy Dyspnoea Faintness Palpitations Headache
**Main causes of Normocytic anaemia
Acute blood loss (commonest presenting)
Anaemia of chronic disease
Combined Haematinic deficiency (B12 or folate and iron deficiency)
Less common causes of normocytic anaemia
Renal failure
Pregnancy
Endocrine disorders
Diagnosis of normocytic anaemia
Normal B12 or folate
Riased reticulocytes
Hb down
Blood count and film - RBCs are normocytic
Treatment of normocytic anaemia
Treat underlying cause
Improve diet with plenty of vitamins
Erythropoietin injections
Normal male concentration of Haemoglobin in the blood
131-166g/L
Normal female concentration of Haemoglobin in the blood
110-147g/L
Normal male RBC size
81.8-96.3fL
Normal female RBC size
80-98.1fL
2 types of Macrocytic anaemia
Megaloblastic
Non-megaloblastic (normoblastic)
What is meant by megaloblastic macrocytic anaemia
Presence of erythroblasts with delayed nuclear maturation because of
delayed DNA synthesis - these are megaloblasts, they are large (i.e. high MCV) and have no nuclei
Anaemia: What do you do in practice?
Thorough history and examination FBC+film Reticulocyte count U/Es, LFTs, TSH B12, Folate, Ferritin
How would you investigate B12 deficiency
IF antibodies
Schilling test
Coeliac antibodies
Causes of macrocytic anemia
*B12/folate deficiency (megaloblastic) Alcohol excess/liver disease Hypothyroid HAEMATOLOGICAL: -Antimetabolite therapy -Haemolysis -Bone marrow failure -Bone marrow infiltration
What type of anaemia is iron deficiency anaemia
Microcytic
**What type of anaemia is pernicious anaemia
Macrocytic
Megaloblastic
What is pernicious anaemia
Lack of RBCs due to a lack of B12
Clinical presentation of pernicious anaemia
Anaemia: Fatigue, Lethargy, Dyspnoea, Faintness, Palpitations, Headache
B12 deficiency: neurological problems:
-Symmetrical paresthesia (burning or prickling pain, tingling) in fingers and
toes
- Early loss of vibration sense and proprioception
- Progressive weakness and ataxia
Pathophysiology of pernicious anaemia
Absorption of B12 occurs in the terminal ileum and requires Intrinsic factor for transport across intestinal mucosa.
IF is deficient in pernicious anaemia.
Causes megaloblastic anaemia.
Parietal cell antibodies in serum in 90% of patients. IF antibodies found inonly 50%.
Achlorhydria (reduced HCl production) possible.
Parietal cells of stomach are attacked due to autoimmunity causing atrophic gastritis
Where is intrinsic factor release
Gastric parietal cells
Aetiology of pernicious anaemia
Autoimmune destruction of parietal cells/Intrinsic factor
Also malabsorption or diet (vegan) may contribute
Epidemiology of pernicious anaemia
1/10,000 in N europe
Peak age of 60
Diagnostic tests of pernicious anaemia
Blood film: macrocytic RBC
Autoantibody: IF (intrinsic factor) antibodies
Serum B12 is low
Hb is low
Reticulocyte count is low
(serum bilirubin may be raised)
Treatment of pernicious anaemia
IM Hydroxocobalamin (Replenish stores of Vitamin B12) If neuro involvement then refer to haemaologist. Do NOT give Folic acid instead of B12, this leads to fulminant neurological deficit
Risk factors of pernicious anaemia
Elderly Female Fair-haired, blue eyes Blood group A Thyroid and Addisons disease
Where do you find vitamin B12
Meat
Fish
Dairy products
(not plants)
How long do stores of vitamin B12 last?
4 years
How is B12 absorbed
By binding to intrinsic factor produced by gastric parietal cells, then being absorbed in the terminal ileum of small intestines.
What is vitamin B12 used for?
Thymidine and DNA synthesis
What types of anaemia is folate deficiency
Megaloblastic macrocytic anaemia
Where in diet do you get folate
Green vegetables e.g. spinach, broccoli, nuts, yeast, liver
How long do stores of folate last?
4 months
Risk factors of folate deficiency anaemia
Elderly Poverty Alcoholic Pregnant Crohn's or Coeliac disease
Clinical presentation of folate deficiency
Anaemia: Fatigue, lethargy, dyspnoea, faintness, palpitations, headache
Folate deficiency: Develops over 4 months of deficiency (due to bodily reserves). Possibly depression. Glossitis.
(may be asymptomatic)
Pathophysiology of folate deficiency
Folate is essential for DNA synthesis. Therefore in folate deficiency, there is impairment of DNA synthesis.
Results in delayed nuclear maturation, resulting in large RBCs as well as decreased RBC production in the bone marrow.
Folate also essential for fetal development
Why is folate important for fetal development?
Deficiency can result in neural tube defects
Main cause of folate deficiency anaemia
- Main cause is poor intake due to dietary deficiency e.g. poverty, alcoholics and elderly.
- Increased demand e.g. pregnancy or increased cell turnover i.e. haemolysis, malignancy, inflammatory disease and renal dialysis
- Malabsorption e.g. coeliac disease or Crohn’s disease
- Antifolate drugs e.g. methotrexate and trimethoprim
How can you differentiate between folate and B12 deficiency
No neuropathy in folate deficiency - unlike B12
Diagnosis of folate deficiency
Blood film: macrocytic
Erythrocyte folate levels: indicated reduced body stores (serum folate also low)
Treatment of folate deficiency
Folic acid supplement.
Treat underlying cause.
Advise regarding folate deficiency in pregnancy
Complications from untreated B12 deficiency
HF, angina, foetus development
What type of anaemia is haemolytic anaemia
Normocytic
can be macrocytic if there are many young RBCs - which are larger and excessive destruction of older RBCs
Where does haemolytic anaemia occur
Circulation (intravascular)
Reticuloendothelial system i.e. by macrophages of liver, spleen (espcially spleen) and bone marrow (extravascular)
When RBC in circulation are destroyed, what is the Hb initially bound to?
Haptoglobulin
But soon these become saturated leading to excess free plasma Hb
What happens to excess plasma Hb that is not bound to haptoglobulin
Filtered by the renal glomerulus and enters the urine, although small amounts are reabsorbed by the renal tubules.
In renal tubular cells, Hb is broken down and becomes deposited in cells as Haemosiderin
What colour do reticulocytes stain on peripheral blood film?
with a light BLUE tinge
What is larger out of reticulocytes and mature RBCs
Reticulocytes
Consequences of haemolysis
Shortened RBC survival:
- compensatory increase in RBC production by the bone marrow (can have Compensated haemolytic diseases)
- BM can increase its output by 6-8 times by increasing the proportion of cells committed to erythropoiesis and by expanding the volume of active marrow
By what process are RBCs made
Erythropoiesis
**Main causes of haemolytic anaemia
RBC membrane defects - Hereditary spherocytosis
Enzyme defects - Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Haemoglobinopathies: B or A Thalassaemia, Sickle cell disease
Autoimmune haemolytic anaemia
Haemolytic anaemia clinical presentation
Anaemia: Fatigue, lethargy, dyspnoea, faintness, palpitations, headache
Haemolytic:
Jaundice, gall stones, leg ulcers, signs of underlying cause
Features of Haemolytic anaemia
- High serum UNCONJUGATED BILIRUBIN
- High urinary UROBILINOGEN
- High faecal STERCOBILINOGEN
- Splenomegaly
- Bone marrow expansion
- Reticulocytosis - increased reticulocytes
What is the most common inherited haemolytic anaemia in Northern Europeans
Hereditary Spherocytosis
Autosomal dominant
Deficiency in SPECTRIN structural protein -> surface to volume ratio decreases and cells become spherocytic (more rigid and less deformable)
Pathophysiology of haemolytic anaemia
RBCs are destroyed before usual 120 day lifespan.
BM provides compensatory reticulocytes.
RBC destruction can be extra or intra vascular.
Mostly extravascular, where cells are removed from the circulation by macrophages, particularly in the spleen.
Aetiology of haemolytic anaemia
Inherited:
Red cell membrane defect (spherocytosis); Haemoglobin abnormalities; Metabolic defects
Acquired:
Autoimmune; Mechanical destruction; Secondary to systemic disease (liver failure); Infections (malaria)
Epidemiology of haemolytic anaemia
Depends on underlying cause
Sickle cell mainly African people
Autoimmune is slightly more common in females
Diagnostic tests of haemolytic anaemia
Reduced haemoglobin
Raised serum bilirubin and urinary urobilinogen
Spherocytes, Increased reticulocytosis (Blood film, blood count)
Increased MCV
Direct antiglobulin (Coombs test) to rule out an AI haemolytic anaemia if negative
Treatment of haemolytic anaemia
Folate and iron supplement;
Immunosuppressive if autoimmune;
Splenectomy if hereditary spherocytosis or other approaches fail
Complications of haemolytic anaemia
Cardiac failure
What are spherocytes
Spherical RBCs
What is ‘Aplastic’ anaemia
Lack of haemopoiesis as a result of bone marrow failure
Clinical presentation of aplastic anaemia
Anaemia: Fatigue, lethargy, dyspnoea, faintness, palpitations, headache.
BM failure: Increased susceptibility to infection and bleeding
Pathophysiology of aplastic anaemia
Reduction in the number of pluripotential stem cells along with a fault in those remaining or an immune response against them - meaning they are unable to repopulate.
Can occur in only one cell line, leading to isolated deficiencies
Aetiology of aplastic anaemia
Congenital
Acquired (mostly)
Cytotoxic drugs
Infections
Epidemiology of aplastic anaemia
2/1000000
More common in Asia
Diagnostic tests of aplastic anaemia
FBC: Pancytopenia with low reticulocytes
BM biopsy: hypocellular marrow with increased fat spaces
Treatment of aplastic anaemia
Removal of causative agent.
Cautious blood and platelet transfusion.
If not spontaneous recovery: BMTransplant or immunosuppressive therapy
Complications of aplastic anaemia
Increased infection and bleeding
What is the most common metabolic RBC disorder
Glucose-6-Phosphate dehydrogenase deficiency
What is the importance of G6PD
Enzyme in the pentose monophosphate shunt that maintains glutathione in the reduced state.
AKA it’s vital for a reaction that is necessary for RBC’s by providing a NADPH which is used with glutathione to PROTECT the RBC from OXIDATIVE DAMAGE from compounds such as hydrogen peroxide
Pathophysiology of G6PD deficiency
G6PD is an enzyme in the pentose monophosphate shunt that maintains glutathione in the reduced state.
This protects against oxidant injury in the RBC. Therefore lack of G6PD causes increased haemolysis.
Inheritance pattern of G6PD deficiency
X-linked recessive
Clinical presentation of G6PD deficiency
Neonatal jaundice, (chronic) Haemolytic anaemia Acute haemolysis (precipitated by fava beans)
Diagnosis of G6PD deficiency
Direct measurement of enzymes in RBC:
e.g. G6PD enzyme levels (will be low)
Treatment of G6PD deficiency
Avoid fava beans
Transfusion if necessary
What makes up normal haemoglobin (HbA)
Haem
2 alpha chains
2 beta chains
What makes up foetal haemoglobin (HbF)
Haem
2 alpha chains
2 gamma chains
What makes up Haemoglobin delta (HbA2)
Haem
2 alpha chains
2 delta chains
In an adult what % of RBCs are:
HbA (normal)
HbA2 (delta)
HbF (foetal)
HbA (normal) - 97%
HbA2 (delta) - 2%
HbF (foetal) - 1%
What is Thalassaemia
Defective subunit of the haemoglobin complex
Clinical presentation of thalassaemia
Variable
Alpha generally presents in utero; Beta in infancy
Can be asymptomatic if heterozygote
Homozygote may have severe anaemia, with failure to thrive and bone deformities due to hypertrophy of ineffective marrow)
What type of anaemia is thalassaemia
Microcytic
Types of thalassaemia
Beta Thalassaemia = Reduced B chain synthesis
Alpha Thalassaemia = Reduced A chain synthesis
Pathophysiology of Beta thalassaemia
- Little or no B chain production resulting in EXCESS ALPHA CHAINS
- These excess alpha chains combine with whatever delta and gamma chains
are produced - Resulting in increased HbA2 (Hb delta) and HbF (Hb gamma)
- Defects are normally point mutations instead of gene deletions.
- Mutations result in defects in transcription, RNA splicing and modification, translation via frame shifts and nonsense codons, producing highly unstable B-globin that cant be utilised.
Different clinical presentations of Beta thalassaemia
Minor - heterozygous, asymptomatic, mild anaemia possible, RBCs are hypochromic and microcytic with a low MCV
Intermedia - symptomatic with moderate anaemia
Major - homozygous
Minor beta-thalassaemia presentation and iron deficiency can be confused - how can you tell difference between the two
Serum ferritin and iron stores are normal in beta-thalassaemia
Diagnosis of beta thalassaemia
Homozygous: Blood count and film
• Hypochromic microcytic anaemia
• Raised reticulocyte count
• Nucleated RBC in peripheral circulation
Haemoglobin electrophoresis shows increase HbF (gamma) and absent or less HbA (normal)
Treatment of Thalassaemia
Homozygotes:
Blood transfusion to try and avoid complications.
Iron chelating agent for iron overload e.g. SC Desferrioxamine
Ascorbic acid increases iron excretion in urine, helps offset iron overload
More severe = BMT
Example of an iron chelating agent
Desferrioxamine (SC)
Diagnosis of thalassaemia
Either genetic testing or Hb electrophoresis (after identifying microcytosis)
What can be given to increase iron excretion in urine
Ascorbic acid
Epidemiology of thalassaemia
1% carriers of beta
5% carriers of alpha
Pathophysiology of alpha thalassaemia
- In contrast to beta-thalassaemia, alpha-thalassaemia is often caused by gene deletions
- The gene for alpha-globin chains is duplicated on both chromosomes 16
- The deletion of one alpha chain or both alpha-chain genes on each chromosome 16 may occur (deletion of one alpha chain is most common)
Can you keep going?
Yes you fukin nutter
Symptoms of Anaemia
Fatigue Lethargy Dyspnoea Palpitations Headache
Signs of Anaemia
Pale skin
Pale mucous membranes
Tachycardia (compensatory to meet demand)
Side effects of Iron deficiency anaemia treatments
Black stools Constipation Diarrhoea Nausea Epigastric abdo pain
Signs of iron deficiency anaemia
Brittle hair and nails
Atrophic glossitis (inflamed/smooth tongue)
Kolionychia (spoon shaped nails)
Angular stomatitis (inflammation of corners of mouth)
B12 and Folate deficiency anaemia can be referred to as megaloblastic anaemias. What does megaloblastic mean?
There has been an inhibition of DNA synthesis.
Means RBCs keep growing without division (no mitosis) => macrocytosis
*Symptom of Haemolytic anaemia
Gallstones
Signs of Haemolytic anaemia
Jaundice
Leg Ulcers
Splenomegaly
Signs of underlying disease (SLE Malar rash)