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Year 2 Collin > Haem 4 - The Hb molecule and Thalassaemia > Flashcards

Haem 4 - The Hb molecule and Thalassaemia Flashcards

1
Q

Describe Hb synthesis

A

Occurs during RBC development - begins in pro-erythroblast stage

  • 65% in erythroblast stage (still contains nucleus and mitochondria at this point)
  • 35% reticulocyte stage
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2
Q

Where is haem synthesised

A

In mitochondria

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3
Q

Where is globin synthesised (alpha and beta globin chains)

A

Ribosomes

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4
Q

What is the transporter the body for free iron?

A

Transferrin

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5
Q

Describe the structure and synthesis of haem

A

The same haem is used in all type of haemoglobin

Haem is a combination of a protoporphyrin ring with central iron atom - ferroprotoporyphyrin

Iron usually in Fe2+ form (ferrous form)

-Haem synthesised mainly in mitochondria (which contain delta-ALAS enzyme)

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6
Q

Haem is able to combine …….. with oxygen

A

Reversibly

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7
Q

Various forms of globin can combine with haem - forming different Hb molecules. There are 8 functional globin chains - how are they arranged?

A

8 functional globin chains in 2 clusters

  1. Beta cluster - Beta, gama, delta, epsilon globin genes - short arm of Chr 11
  2. Alpha cluster - alpha and zeta globin genes - short arm of Chr 16
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8
Q

When does zeta and epsilon production stop?

A

In foetal life - taken over by a-globin production.

Hence a-globin defects manifest earlier.

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9
Q

From birth, where is most of the alpha and beta globin made?

A

In the bone marrow - this means beta-thalassaemia usually develops after birth

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10
Q

Describe the tertiary globin structure

A
  1. Approximate sphere
  2. Hydrophilic surface, hydrophobic core (accounting for solubility properties)
  3. Haem pocket
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11
Q

Describe deoxyhaemoglobin

A

It has 2,3-DPG attached - stops O2 binding, has a less stable structure

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12
Q

Describe the primary and secondary globin structure

A

Primary structure = alpha chains have 141 amino acids

Secondary structure has 146 non amino acids

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13
Q

What is the p50 of the Hb-O2 dissociation curve?

A

26.6mmHg

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14
Q

What does the position of the Hb-O2 Dissociation curve depend on

A
  1. 2,3-DPG. If high - shifts curve right
  2. H+ conc - pH. High H+ = shifts curve right (decreased pH)
  3. CO2 conc in RBCs. High CO2 shifts right
  4. Hb structure. HbS shifts right, HbF shifts left
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15
Q

What are the 2 categories of haemoglobinopathies

A
  1. Hb structural variants

2. Defects in globin chain synthesis (thalassaemia)

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16
Q

What is the most common inherited single gene disorder worldwide

A

Thalassaemia

17
Q

How can thalassaemias be classified

A
  1. Globin type affected - most commonly alpha and beta

2. Clinical severity - minor (trait), intermediate, major

18
Q

Describe Beta-Thalassaemia

A

Autosomal recessive (Chr 11)

  1. Deletion/mutation in beta-globin chain –> reduced production of B-globin
  2. Mainly occurs in Mediterranean countries
  3. Carriers = asymptomatic (except microcytic hypo chromic indices)
  4. Variation in severity as varying degree of interference with globin chain synthesis (some mutations = no globin production, some mutations = decreased production)
  • 2x beta(0) genes = major, 2x beta(1) genes = intermediate
19
Q

How are thalassaemias diagnosed

A

Lab diagnoses:

  1. FBC - microcytic hypochromic indices + increased RBCs relative to Hb
  2. Film - increased no. of target cells, poikilocytosis, but no anisocytosis

Hb EPS/HPLC (electrophoresis):

alpha thalassaemia - normal HbA2 and HbF, +/- HbH, not definitive

beta thalassaemia - raised HbA2 and HbF - more straightforward/easy to diagnose

20
Q

What is the gold standard for a-thalassaemia diagnosis

A

Globin chain synthesis/DNA studies

Genetic analysis for B-thalassaemia mutations + Xmnl polymorphism (in B-thalassaemias) _ a-thalassaemia genotype (in all cases)

21
Q

Describe B-thalassaemia major

A
  1. 2 Abnormal copies of B-globin gene
  2. Clinical presentation = after 4-6 months of life
  3. Abnormally shaped RBC
  4. RBC inclusions - alpha chain precipitates
  5. Pappenheimer bodies = excess iron precipitating in granules due to ineffective erythropoiesis - seen using Perls stain
22
Q

What is the clinical presentation of Alpha and beta thalassaemia

A
  1. Extra-medullary haematopoiesis (main cause of presentations)
  2. Severe anaemia (fatal) - presents after 4 months usually
  3. Hepatosplenomegaly - due to extramedullary haematopoiesis
  4. Blood fil shows gross hypochromia - poikilocytosis and many nucleated RBCs
  5. Bone marrow shows erythroid hyperplasia
  6. Bone marrow shows erythroid hyperplasia
23
Q

What are some features of beta thalassaemia

A
  1. Chronic fatigue
  2. Skeletal deformity
  3. Jaundice
  4. Delay in growth an puberty
  5. Splenomegaly
  6. Iron overload

Other complications include - gallstones (cholelithiasis) & biliary sepsis (due to chronic haemolysis), cardiac failure - most deaths from b-thalassaemia (iron overload linked), endocrinopathies, liver failure (iron overload)

24
Q

What are the features of beta-thalassaemia

A
  1. Microcytosis
  2. Hypochromia

(also some cells with basophilic stripping)

25
Q

Which thalassaemia is lethal in utero

A

Alpha-thalassaemia major

26
Q

What is the treatment for thalassaemia major

A
  1. Regular blood transfusions

2. Iron chelation therapy

27
Q

Describe how transfusions are given to treat thalassaemia (major)

A
  1. RBCs are phenotypes/matched
  2. Try to get pre-transfusion conc of 95-100g/L –> this helps to reduce extra-medullary haematopoiesis
  3. Transfusions regularly every 2-4 weeks
  4. If a high requirement, consider splenectomy (+ if splenomegaly).

But splenectomy makes body more susceptible to infection - e.g. Yersinia (loves iron, thrives in this case), other gram negative sepsis, splenectomised patients should have immunisation + antibiotics

28
Q

When is iron chelation therapy done?

A

After 10-12 transfusions or when serum ferritin > 1000mcg/l

AUDIOLOGY and OPHTHALMOLOGY screening done prior to starting (due to retinal side effects)

29
Q

What are the types of iron chelation therapy

A
  1. Desferrioxamine - DFO (deferral). Sc infusion, 5-7 days a week. SEs include: vertebral dysplasia, pseudo-rickets, retinopathy. DON’T use in children. Issues with compliance.
  2. Deferiprone - oral dose. Most effective in reducing myocardial iron. SEs include: hepatic impairment, neutropenia, agranulocytosis. Patients need weekly blood tests to monitor WBCs
  3. Deferasirox - generally well tolerated. 1/day oral dose (20-40mg/kg). SEs include: renal impairment
30
Q

How is iron overload monitored

A
  1. Measure serum ferritin. If over 2500mcg/L, less accurate (associated w greater complications). Ferritin is also an acute phase protein so may be increased during infection/inflammation. Check 3 monthly if transfused patient.
  2. T2 Cardiac and hepatic MRI. Cardiac MRI = relies on contractility of cardiac fibres. If heart relaxation time < 20ms –> stiff fibres –> iron overload —> increased risk of impaired LF function
  3. Liver ferriscan - R2 MRI. Has replaced liver biopsy. Non-invasive quantification of Liver Iron Conc. Unaffected by inflammation or cirrhosis –> more accurate estimation. LIC < 3mg/g normal, >15mg/g associated with cardiac disease. Checked annually or 6-monthly
31
Q

What type of disorder is sickle-beta thalassaemia

A

Sickling disorder - NOT thalassaemia

32
Q

Describe HbE-beta thalassaemia

A

HbE Common in south east Asia - leads to globin chain production.

It has clinically variable expression - but can be as severe as B-thalassaemia major

33
Q

Describe Alpha-thalassaemia and who it affects

A

Deletion/mutation in alpha-globin chains –> reduced/absent production of a-globin chains.

Affects foetus and adult

Severity depends on number of a-globin chains deleted - if all 4 alpha globin chains deleted –> death of foetus

34
Q

What do excess beta and gamma chains form?

A

Tetramers of HbH

35
Q

Describe thalassaemia carrier/minor/trait

A

When person carries single abnormal copy (e.g. of beta-globin chain)

Usually asymptomatic + diagnosed with milid anaemia + microcytosis + hyperchromia

36
Q

Describe Haemoglobin H (HbH) disease

A

3 a-globin chains affected - shows poikilocytosis

37
Q

What are the problems associated with treatment in the developing world

A
  1. Blood availability
  2. Cost and compliance with iron chelation therapy
  3. Availability/cost of bone marrow transplant

Year 2 Collin (114 decks)

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