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ESA 2 - MEH > 5. Causes of anaemia > Flashcards

5. Causes of anaemia Flashcards

1
Q

What is anaemia and why is this a problem?

A

Anaemia = Hb conc. lower than the normal range.

Causes inability to deliver enough O2 to tissues.

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2
Q

What is the normal Hb range in the adult male and female?

A 
Male = 130-180 g/L
Female = 115-165 g/L
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3
Q

What are the symptoms and clinical signs of anaemia?

A

Symptoms:

i) fatigue
ii) dyspnoea
iii) palpitations
iv) headache
v) angina and intermittent claudication (older Ps)

Clinical signs:

i) pallor
ii) tachycardia
iii) systolic murmur

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4
Q

Why are the symptoms of chronic anaemia less severe than those of acute-onset anaemia?

A

If anaemia develops slowly, body has time to adjust to lower conc. of Hb by:
1- increasing cardiac stroke volume to increase blood supply to tissues
2- increasing conc. of 2,3-BPG in RBCs to promote O2 dissociation

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5
Q

What are the different types of causes of anaemia?

A
  1. Bone marrow
    - abnormal erythropoiesis
    - abnormal Hb synthesis
  2. Peripheral RBCs
    - abnormal function
    - abnormal structure
    - abnormal metabolism
  3. RBC removal
    - excessive blood loss
    - abnormal function of reticuloendothelial system
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6
Q

What are the main causes of reduced erythropoiesis (dyserythropoiesis)?

A
  1. aplastic anaemia = absence of haemopoietic progenitors
    i) e.g. from chemotherapy, ionising radiation, infection with parovirus, autoimmune disease
    ii) BM infiltrated by cancer cells or fibrous tissue (myelofibrosis) - means normal haemopoietic cells are reduced
  2. myelodysplastic syndromes = abnormal blood cells and precursors
  3. chronic kidney disease… insufficent EPO production to stimulate normal levels of erythropoiesis
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7
Q

What is aplastic anaemia and what does condition does this lead to?

A

Inability of haematopoietic stem cells to generate mature blood cells.

Results in pancytopenia:

  • lack of RBCs (anaemia)
  • lacks of WBCs (leucopenia)
  • lack of platelets (thrombocytopenia)
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8
Q

What are myelodysplastic syndromes (MDS)?

A

Usually occur in elderly but can occur earlier in life

Production of abnormal clones of BM stem cells … large, defective RBCs prematurely destroyed by the RES (=macrocytic anaemia)… dev of progressive anaemia or pancytopenia (and acute leukaemia in a high proportion of cases).

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9
Q

How are myelodysplastic syndromes diagnosed?

A

i) genetic change detected by looking at BM cells chromosomes
ii) microscopy of blood and BM cells: RBCs are defective and large

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10
Q

How is anaemia in myelodysplastic syndromes treated?

A
  • chronic transfusion of RBCs in many Ps

- chemotherapy followed by stem cell transplantation can be curative in a minority (young and fit)

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11
Q

What are the main causes of anaemia caused by haemoglobin abnormalities?

A
  1. lack of iron
    - iron deficiency anaemia
    - anaemia of chronic disease (lack of functional iron)
  2. deficiency in building blocks for DNA synthesis
    - vitB12
    - folate
  3. mutations in globin genes
    - thalassaemia
    - sickle cell disease
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12
Q

Suggest causes for iron deficiency.

A

1- inadequate dietary supply
2- increased requirements (growth spurts, pregnancy, lactation)
3- decreased absorption (gastrectomy, coeliac disease)
4- increased blood loss from bleeding (uterine, GI, renal tract, nose, lungs…)

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13
Q

What is anaemia of chronic disease?

A

Associated with chronic inflammatory conditions such as rheumatoid arthritis, chronic infections (e.g. TB) and malignancy.

i) increased activity of macrophages reduces lifespan of RBCs
ii) iron stored in macrophages not released for use in BM
iii) BM shows lack of response to EPO - blunted EPO receptor
iv) chronic release of cytokines such as IL-6… increased hepcidin production by liver… decreased iron absorption

Anaemia may be microcytic, normocytic or macrocytic.

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14
Q

What clinical sign indicates anaemia of chronic disease?

A

increased CRP and ferritin

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15
Q

What changes are caused by iron deficiency anaemia?

A

Changes to:

  1. epithelial tissues
  2. nails (koilonychia)
  3. mouth (angular cheilitis)
  4. oesophagus (Plummer-Vinson syndrome)
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16
Q

Which 2 diseases occur as a result of mutations in Hb globin genes?

A
  1. thalassaemias = reduced rate of synthesis of normal alpha- or beta- globin chains
  2. sickle cell disease = synthesis of abnormal haemoglobin
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17
Q

What is the genetic and cellular basis of sickle cell disease?

A
  1. point mutation (A to T) causes substitution of glutamic acid by valine in position 6 in beta-globin chain…
  2. formation of HbS with a “sticky” hydrophobic pocket in beta globin protein - allows deoxygenated haemoglobin to polymerise…
  3. promotes cell sickling under low O2 tension…
  4. repeated episodes of sickling causes damage to cell membrane - loses elasticity…
  5. RBCs unable to deform as they pass through narrow capillaries…
  6. vessel occlusion and ischaemia
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18
Q

What are the symptoms of anaemia usually mild in sickle cell disease?

A

well tolerated as HbS readily gives up O2 in comparison to HbA

but clinical pattern of disease very variable between individuals

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19
Q

What possible clinical problems are associated with sickle cell disease?

A

Thrombosis of small blood vessels:

  1. eyes: retinopathy, blindness
  2. brain: stroke
  3. lungs: pneumonia, infarcts, acute chest syndrome
  4. iron overload in heart and liver
  5. spleen: atrophy (due to multiple infarcts)
  6. kidney: decreased concentrating ability, infarcts
  7. gallbladder: pigment gallstones
  8. bone: osteomyelitis, avascular necrosis of femoral head
  9. skin ulcers
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20
Q

In which ethnic groups are thalassaemias prevalent?

A

beta-T: S. Asian and Mediterranean

alpha-T: Far East

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21
Q

What is thalassaemia and what are the different types?

A

decreased or absent alpha or beta globin chain production resulting in imbalance in composition of alpha2beta2 tetramer.

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22
Q

What are the 4 main effects of globin chain imbalances in thalassaemias?

A
  1. hypochromic microcytic RBCs - due to low levels of intracellular haemoglobin
  2. low RBC count
    - whichever chain remains in excess precipitates… premature cell death prior to release from BM
    - RBCs that do enter circulation are susceptible to oxidative damage of membrane due to precipitated globin chains… haemolysis (excessive destruction in spleen)
  3. extramedullary haemopoiesis - attempt to compensate but results in splenomegaly, hepatomegaly and haemopoiesis expansion into bone cortex… impairs growth and causes skeletal abnormalities. EPO stimulation further contributes to haemopoiesis drive.
  4. iron overload (major cause of premature death)
    - excessive absorption of dietary iron due to ineffective haemopoiesis
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23
Q

Which treatments are required in thalassaemia?

A
  1. repeated blood transfusions (to treat anaemia)
  2. iron chelation
  3. folic acid (to prevent secondary deficiency)
  4. immunisation
  5. holistic care - cardiology, endocrine, psychological
  6. stem cell transplantation in come (to try and promote normal RBC production)
24
Q

What are the 3 different types of beta-thalassaemia?

A
  1. beta-thalassaemia minor
    - heterozygous: one normal gene
    - usually asymptomatic with mild anaemia
  2. beta-thalassaemia intermedia
    - genetically heterogenous: mild variants of homozygous, severe variants of heterozygous…
    - severe anaemia, but not enough to require regular blood transfusions
  3. beta-thalassaemia major
    - homozygous
    - severe transfusion-dependent anaemia that manifests 6-9 months after birth as synthesis switches from HbF to HbA
25
Q

What are the 4 different types of alpha-thalassaemia?

A
  1. silent carrier state
    - deletion of single alpha-globin gene
    - asymptomatic, without anaemia
  2. alpha-thalassaemia trait
    - deletion of 2 alpha-globin genes (both genes on 1 chromo or 1 gene on each chromo)
    - minimal or no anaemia and no physical signs
  3. haemoglobin H (HbH) disease
    - deletion of 3 alpha-globin genes
    - beta-globin tetramers (HbH) are formed
    - moderately severe anaemia
  4. hydrops fetalis
    - deletion of all 4 alpha-globin genes
    - in foetus, excess of y-globin chain form tetramers (Hb Bart) that are unable to deliver O2 to tissues - usually intrauterine death
26
Q

What does microscopy of blood cells in thalassaemia show?

A

1) alpha-thalassaemia trait and beta-thalassaemia minor:
- microcytosis
- hypochromia

2) HbH disease and beta-thalassaemia intermedia:
- microcytosis
- hypochromia
- anisopoikilocytosis
- target cells
- Heinz bodies
- circulating nucleated RBCs

27
Q

Deficiency in what components leads to megaloblastic anaemia? Explain why.

A
  • VitB12 and folate = DNA synthesis building blocks necessary for nuclear divisions and nuclear maturation.
  • If deficient, nuclear maturation and cell divisions lag behind cytoplasm development… large, partially replicated RBC precursors, with inappropriately large nuclei and open chromatin, are released into blood = megaloblastic anaemia.
28
Q

How do we acquire vitB12?

A

Food of animal origin, synthesised by microorganisms

29
Q

Describe the absorption of B12.

A
  1. In the stomach, free B12 and B12 released from proteins by proteases form complex with haptocorrin protein…
  2. complex digested by pancreatic proteases in small intestine, releasing B12…
  3. binds to glycoprotein intrinsic factor (IF) produced by stomach parietal cells….
  4. IF-B12 complex internalised by binding to receptors in ileum…
  5. internalised B12 forms complex with transcobalamin II….
  6. released into portal bloodstream and delivered to tissues possessing transcobalamin II-B12 receptors, e.g.
    - bone marrow
    - liver takes up ~50% dietary B12 released into circulation
30
Q

Why does it take several years to become B12 deficient?

A

liver stores B12 - sufficient to supply B12 requirements for ~3-6yrs

31
Q

Why is vitB12 required by the body?

A

2 metabolic reactions:

  • transfers methyl group from L-methylmalonyl-CoA to form succinyl-CoA
  • transfers methyl group from FH4 to homocysteine to form methionine
32
Q

Why can lack of vitB12 lead to folate deficiency?

A

VitB12 required to transfer methyl group from FH4 to homocysteine to form methionine - so lack of B12 ‘traps’ folate in stable methyl-FH4 form… prevents its use in other reactions such as nucleotide synthesis.
= functional folate deficiency

33
Q

Name 4 reasons for vitB12 deficiency.

A
  1. VitB12 dietary deficiency, e.g. vegan/poor diet
  2. Pernicious anaemia = autoimmune disease targeting gastric parietal cells… intrinsic factor (IF) deficiency (can also be caused by gastrectomy)… B12 not internalised.
  3. Diseases of terminal ileum, e.g. Crohn’s disease, ileal resection, tropical spure - IF-B12 complex cannot bind to ileum.
  4. Congenital transcobalamin deficiency… B12 not delivered to tissues.
34
Q

How do we acquire folate?

A

Synthesised in bacteria and plants - present in variety of animal and vegetable food sources, esp. green leafy vegetables.

35
Q

Describe the absorption of folate.

A
  1. Taken up in duodenum and jejenum…
  2. converted to tetrahydrofolate (FH4) by intestinal cells…
  3. enters poral circulation and much taken up by liver which acts as store (but not very long).
36
Q

What is the role of tetrahydrofolate in metabolism?

A
  • Acts as 1C carrier, accepting C units from sources such as serine, glycine, histidine and formate.
  • Once attached to FH4, these C can be oxidised or reduced and used to provide C for other processes, e.g. synthesis of thymidine, adenine and guanine, and transfer of methyl groups to VitB12.
37
Q

How can folate deficiency occur?

A
  1. dietary deficiency
  2. increased demands in pregnancy and lactation, increased erythropoiesis (e.g. haemolytic anaemia), severe skin disease (psoriasis, exfoliative dermatitis)
  3. proximal small bowel (duodenum and jejenum) disease, e.g. Coeliac disease
  4. alcoholism (inadequate intake and intestinal cell damage)
  5. Crohn’s disease drugs (e.g. methotrexate) - inhibit dihydrofolate reductase enzyme
38
Q

What can folate deficiency during pregnancy cause?

A

Neural tube defects in developing foetus due to deterimental effect on DNA synthesis

39
Q

What can vitB12 deficiency cause as well as anaemia?

A
  • neurological disease - focal demyelination affecting spinal cord, peripheral nerves and optic nerves
  • depression and dementia can also develop
40
Q

Name 4 inherited anaemias involving abnormalities in RBC membrane proteins.

A
  1. hereditary spherocytosis
  2. hereditary elliptocytosis
  3. hereditary pyropoikilocytosis
  4. hereditary stomatocytosis
41
Q

Describe the appearance of spherocytes, elliptocytes, acanthocytes and target cells.

A
  • spherocytes - sphere-shaped rather than biconcave disc
  • elliptocytes - cigar-shaped
  • acanthocytes - irregularly contracted
  • target cells (codocytes) - central aggregation of Hb
42
Q

How can damage to RBC membranes be acquired?

A
  1. mechanical damage
    - heart valves
    - inflammation and fibrosis of small BVs due to vasculitis, microangiopathies or disseminated intravascular coagulopathy (damaged by fibrin strands)
  2. heat damage (burns)
  3. osmotic change (drowning)

Cause schistocyte formation and consequent anaemia.

43
Q

What is glucose-6-phosphate dehydrogenase deficiency?

A

G6PDH deficiency = X-linked recessive mutation in G6PDH, the rate limiting enzyme of the pentose phosphate pathway - supplies reducing energy by maintaining NADPH levels.

44
Q

Why does G6PDH deficiency cause haemolytic anaemia and jaundice?

A

Pentose phosphate pathway is only source of reduced glutathione (required for protection against oxidative stress) in RBCs.

G6PDH deficiency thus increases risk of haemolytic anaemia in states of oxidative stress (e.g. infection, exposure to certain chemical/drugs) as oxidative stress causes:
- RBC membrane damage through lipid peroxidation - lack of flexibility leads to mechanical stress
- protein damage: aggregates of cross-linked haemoglobin (Heinz bodies)
and so leads to increased haemolysis in the spleen.

Metabolism of the excessive Hb to bilirubin can lead to jaundice.

45
Q

Why does pyruvate kinase deficiency lead to haemolytic anaemia?

A
  • Pyruvate kinase catalyses the final step in glycolysis, transferring phosphate from phosphoenol pyruvate to ADP to form ATP.
  • Since RBCs lack MT, pyruvate kinase deficiency blocks only metabolic pathway that can supply ATP for cellular processes… Na/K ATPase pump stops working… cells lose K+ to plasma… water moves down conc gradient out of cell… cell shrinks and dies.
46
Q

What is autoimmune haemolytic anaemia and what are the 2 types?

A

Autoantibodies produced against RBC membrane proteins.
Broadly classified as:
- warm autoimmune haemolytic anaemia (IgG, maximally active at 37 degrees)
- cold autoimmune haemolytic anaemia (IgM, maximally active at 4 degrees)

47
Q

Describe some key laboratory features of autoimmune haemolytic anaemia.

A
  1. increased reticulocytes (as BM tries to compenate)
  2. increased bilirubin (haem breakdown)
  3. increased LDH (RBCs are rich in this enzyme)
48
Q

What is the mode of inheritance of hereditary spherocytosis?

A

mostly autosomal dominant (some cases of autosomal recessive)

49
Q

What causes hereditary spherocytosis?

A

Mutation in genes coding for RBC membrane proteins, e.g.

  • ankyrin (most common)
  • spectrin (alpha and beta)
  • band 3 protein
  • protein 4.2
50
Q

What is the function of the RBC membrane proteins involved in hereditary spherocytosis?

A

Maintain normal, biconcave shape of a RBC

  • spectrin: actin crosslinking and molecular scaffold protein that links the PM to the cytoskeleton
  • ankyrin: links integral membrane proteins to the underlying spectrin-actin cytoskeleton
  • band 3: facilitates chloride and bicarbonate exchange across the PM; physical linkage of PM to cytoskeleton (via binding with ankyrin and 4.2)
  • protein 4.2: ATP-binding protein, may regulate association of band 3 with ankyrin
51
Q

How does mutation of the RBC membrane proteins in hereditary spherocytosis change spherocyte shape?

A

Protein mutation causes membrane loss through release of microvesicles and decreased surface to volume ratio (round rather than biconcave), leading to loss of deformability.

52
Q

Why do hereditary spherocytosis patients present with splenomegaly, anaemia and jaundice?

A

reduced flexibility (due to decreased surface:volume ratio)… RBCs trapped in microvasculature… trapped in spleen sinusoids… increased phagocytosis - extravascular haemolysis… splenomegaly, anaemia and jaundice.

53
Q

Why is the reticulocyte count increased in hereditary spherocytosis patients?

A
  • Reticulocytes = immature red blood cells (usually circulate in bloodstream for 1 day before differentiating)
  • Increased in attempt to compensate for haemolysis and anaemia
54
Q

What are the 4 main complications that can occur in hereditary spherocytosis?

A
  1. haemolytic crisis (2ary to viral infection): accelerated RBC haemolysis… more pronounced anaemia and jaundice.
  2. aplastic crisis (2ary to viral infection): dramatic fall in Hb level and reticulocyte count due to temporary RBC maturation arrest… more pronounced anaemia
  3. folate deficiency: due to increased BM requirements… megaloblastic anaemia (from decreased cellular division - requires folate)
  4. gallstones: increased RBC haemolysis… increased bilirubin from haem breakdown, which must be excreted in bile by liver… formation of pigmented gallstones composed of calcium bilirubinate.
55
Q

What is the main treatment option for severe hereditary spherocytosis?

A

splenectomy

ESA 2 - MEH (42 decks)

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