Aims and objectives Why is haematology so difficult? - - PowerPoint PPT Presentation

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Aims and objectives

• Why is haematology so difficult?
• Classification of anaemias
• Duration: 70 mins
• Slides and recordings: app.bitemedicine.com

History and examination

A 20-year-old lady presents to the GP with lethargy. She is a medical student and complains of intense fatigue, struggling to stay awake during lectures. As soon as she gets home, she goes straight to bed. She reveals that she often has heavy periods.

Observations

HR 80, BP 118/77, RR 18, SpO2 98%, Temp 37.0

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Case-based discussion: 1

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A 20-year-old lady presents to the GP with lethargy. She is a medical student and complains of intense fatigue, struggling to stay awake during lectures. As soon as she gets home, she goes straight to bed. She reveals that she often has heavy periods. Observations: HR 80, BP 118/77, RR 18, SpO2 98%, Temp 37.0 Which of the following is the most likely type of anaemia?

Question 1

Microcytic Normocytic Macrocytic Megaloblastic Aplastic app.bitemedicine.com

Q3 Q4 Q5 Q1 Q2

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Explanations

app.bitemedicine.com Which of the following is the most likely type of anaemia? Microcytic Chronic blood loss, e.g. menstrual bleeding, leads to iron deficiency and is the commonest cause

• f anaemia worldwide

Normocytic Iron deficiency is microcytic Macrocytic Iron deficiency is microcytic Megaloblastic This is a subtype of macrocytic anaemia Aplastic This is a cause of a normocytic anaemia and may occur secondary to infection e.g. parvovirus B19

Q3 Q4 Q5 Q1 Q2

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Introduction: Anaemia

Structure of haemoglobin

• 4 polypeptide ‘globin’ chains
• Each chain is complexed to a haem molecule
• Haem is an iron containing compound

Anaemia: reduction of haem and/or globin Normal Hb variants Structure Proportion in adults HbA α2β2 90% HbA2 α2δ2 <2% HbF α2γ2 <2-5%

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Introduction: Anaemia

Anaemia

• Men: Hb <130g/L
• Women: Hb <120g/L
• Classified based on mean corpuscular volume (MCV)

Microcytic (MCV < 80fL) Normocytic (MCV 80-95fL) Macrocytic (MCV >95fL) Iron deficiency Acute blood loss B12 deficiency Thalassaemia Haemolytic anaemia Folate deficiency Anaemia of chronic disease Anaemia of chronic disease Alcohol Sideroblastic anaemia Chronic kidney disease Liver disease Aplastic anaemia Hypothyroidism

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Clinical features: General principles

Symptoms Signs

Fatigue Tachycardia SOB on exertion Tachypnoea Chest pain Hypotension Palpitations Pallor

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History taking: General principles

History of presenting complaint

• Symptoms of anaemia e.g. SOB
• Screen for areas of blood loss: GI, resp, urinary tract, menstrual
• Alarm symptoms: weight loss, loss of appetite, night sweats, lymphadenopathy
• Dietary habit

Past medical history

• Chronic disease
• Trauma

Family history

• Inherited disorders e.g. haemoglobinopathies

Drug history, social history

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Investigations: General principles

Bedside

• Full set of observations

Bloods

• FBC: reduced Hb. Assess MCV
• Blood film
• Iron studies
• B12 and folate levels
• Haemolysis screen: bilirubin, haptoglobin, Coombs test
• U&Es: CKD
• TFTs: hypothyroidism
• LFTs: chronic liver disease

Imaging

• Assess for site of blood loss

Special tests

• Bone marrow biopsy

Iron deficiency anaemia

Microcytic anaemia Iron deficiency Thalassaemia Anaemia of chronic disease Sideroblastic anaemia Definition: reduced intake, increased requirement, or increased loss of iron, leading to anaemia

Epidemiology:

• Most common cause of anaemia and affects ~ 500 million

people worldwide (NICE)

• 3% of men and 8% of women in the UK

Pathophysiology: Iron deficiency anaemia

Aetiology: Iron deficiency anaemia

Age group Cause Infants

• Malnutrition
• Breast feeding

Children

• Malnutrition
• Malabsorption
• E.g. Coeliac disease

Adults

• Peptic ulcer disease
• Menorrhagia
• Malabsorption
• E.g. Coeliac disease

Elderly

• Colon cancer

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You confirm a microcytic anaemia. Which of the following tests should be conducted next if you suspect iron deficiency?

Question 2

Serum iron Transferrin Ferritin Total iron binding capacity Urinary iron app.bitemedicine.com

Q3 Q4 Q5 Q2 Q1

A 20-year-old lady presents to the GP with lethargy. She is a medical student and complains of intense fatigue, struggling to stay awake during lectures. As soon as she gets home, she goes straight to bed. She reveals that she often has heavy periods. Observations: HR 80, BP 118/77, RR 18, SpO2 98%, Temp 37.0

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Explanations

app.bitemedicine.com You confirm a microcytic anaemia. Which of the following tests should be conducted next if you suspect iron deficiency? Serum iron Can be unreliable due to diurnal variation and can vary between labs Transferrin NICE advise measuring ferritin Ferritin NICE advises measuring this first-line. Low in iron deficiency Total iron binding capacity NICE advise measuring ferritin Urinary iron This is not measured

Q3 Q4 Q5 Q2 Q1

Aetiology: Iron deficiency anaemia

Cause Reduced intake

• Malnutrition
• Breastfeeding
• Malabsorption
• Coeliac disease

Increased requirement

• Pregnancy

Increased loss

• Chronic bleeding
• Colon cancer
• Menorrhagia
• Peptic ulcer disease

Clinical features: Iron deficiency anaemia

Features

Glossitis Angular stomatitis/chelitis Koilonychia Pica

(1) (2)

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Q2

Which of the following is true for a patient with iron deficiency anaemia?

Question 3

Treat with blood transfusion Treat with intravenous iron Arrange urgent upper GI endoscopy if ≥50 Arrange urgent colonoscopy if ≥60 Arrange urgent colonoscopy if ≥65 app.bitemedicine.com

Q3 Q1 Q4 Q5

A 20-year-old lady presents to the GP with lethargy. She is a medical student and complains of intense fatigue, struggling to stay awake during lectures. As soon as she gets home, she goes straight to bed. She reveals that she often has heavy periods. Observations: HR 80, BP 118/77, RR 18, SpO2 98%, Temp 37.0

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Explanations

app.bitemedicine.com Which of the following is true for a patient with iron deficiency anaemia? Treat with blood transfusion Oral iron is first line Treat with intravenous iron Oral iron is first line. IV iron can be used if oral therapy not tolerated Arrange urgent upper GI endoscopy if ≥50 Not indicated unless suspecting an upper GI bleed in any age group Arrange urgent colonoscopy if ≥60 As per NICE guidelines Arrange urgent colonoscopy if ≥65 NICE suggest ≥60

Q2 Q3 Q1 Q4 Q5

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Investigations: Iron deficiency anaemia

Bloods

• FBC: microcytic anaemia (MCV <80fL)
• Blood film: hypochromic red cells, target cells
• Iron studies
• Ferritin: reduced
• Serum iron: reduced
• TIBC: increased
• Transferrin saturation: decreased

Imaging

• Endoscopy
• Suspecting upper GI bleed
• ≥60 years old with iron deficiency anaemia

Special tests

• Coeliac serology

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Management: Iron deficiency anaemia

Address the underlying cause Oral iron replacement

• Ferrous sulphate or ferrous fumarate
• Monitor Hb 2-4 weeks after starting and then at 2-4 months
• Treatment should continue for 3 months after anaemia corrected

Intravenous iron replacement

• Not responding or intolerant to oral therapy
• Malabsorption
• Renal failure

Blood transfusion

• Hb <70g/L or
• Hb <80g/L and cardiac co-morbidity

History and examination

A 1-year-old child is brought to the GP as his mother is concerned he is not gaining weight. He is dropping

• ff the centiles on his growth chart.

On examination he appears pale and has evidence of

• hepatosplenomegaly. His forehead looks prominent.

Further investigations reveal a diagnosis of beta thalassaemia major.

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Case-based discussion: 2

(3)

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Which of the following would you expect to see on haemoglobin electrophoresis in this patient?

Question 1

Raised HbH Raised HbA Raised HbA2 Reduced HbF HbS app.bitemedicine.com A 1-year-old child is brought to the GP as his mother is concerned he is not gaining weight. He is dropping off the centiles on his growth chart. On examination he appears pale and has evidence of hepatosplenomegaly. His forehead looks prominent. Further investigations reveal a diagnosis of beta Thalassaemia major.

Q1 Q2

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Question 1

app.bitemedicine.com Which of the following would you expect to see on haemoglobin electrophoresis? Raised HbH Associated with alpha thalassaemia Raised HbA Reduced in beta thalassaemia Raised HbA2 Raised along with HbF Reduced HbF Should be raised HbS Associated with sickle cell disease

Q1 Q2

Introduction: Thalassaemia

Microcytic anaemia Iron deficiency Thalassaemia Anaemia of chronic disease Sideroblastic anaemia

Definition: autosomal recessive haemoglobinopathy

• Impaired globin chain synthesis

Epidemiology:

• Prevalent in areas of malaria
• Alpha thalassaemia: Asian and African
• Beta thalassaemia: Asian, Mediterranean and Middle Eastern

Pathophysiology: Thalassaemia

Normal Hb Structure Proportion in adults HbA α2β2 90% HbA2 α2δ2 <2% HbF α2γ2 <2-5% Alpha thalassaemia Beta thalassaemia Reduced Reduced Reduced Increased Reduced Increased

Pathophysiology: Alpha Thalassaemia

Impaired synthesis of alpha globin

• 4 alleles on chromosome 16 are responsible for alpha globin production
• Gene deletions

Disease

• No. of

deletions HbA (α2β2) HbA2 (α2δ2) HbF (α2γ2) Features Silent carrier 1 N N N Asymptomatic Trait 2 ↓ ↓ ↓ Mild anaemia HbH 3 ↓↓ ↓↓ ↓↓ Beta chains form tetramers Marked anaemia Hb Barts 4 Absent Absent Absent Gamma chains form tetramers Hydrops fetalis Death in utero

Pathophysiology: Beta Thalassaemia

Impaired synthesis of beta globin

• 2 alleles on chromosome 11 are responsible for beta globin production
• Gene mutations
• Reduced production (β+)
• Absent production (β0)

Disease Genetics HbA (α2β2) HbA2 (α2δ2) HbF (α2γ2) Features Trait β/β+ ↓ ↑ ↑ Asymptomatic or mild symptoms Intermedia β+/β+ β+/β0 Variable Variable Variable Variable Major β0/β0 Absent ↑↑ ↑↑ Marked anaemia

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Which of the following is the cause of his prominent forehead?

Question 2

Trauma Cortical thickening Normal variant Bone marrow expansion Osteomyelitis app.bitemedicine.com A 1-year-old child is brought to the GP as his mother is concerned he is not gaining weight. He is dropping off the centiles on his growth chart. On examination he appears pale and has evidence of hepatosplenomegaly. His forehead looks prominent. Further investigations reveal a diagnosis of beta Thalassaemia major.

Q2 Q1

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Explanations

app.bitemedicine.com Which of the following is the cause of his prominent forehead? Trauma No evidence of trauma Cortical thickening It’s an issue with the marrow, not the cortex Normal variant Not normal as the patient has thalassaemia Bone marrow expansion Compensatory bone marrow expansion in sites away from the long bones occurs, causing frontal bossing and prominent zygomatic bones Osteomyelitis We would not expect this in thalassaemia, nor would we expect it to occur in the frontal bone

Q2 Q1

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Clinical features: Thalassaemia

Signs

Neonatal jaundice Hepatosplenomegaly Failure to thrive Chipmunk facies

(3)

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Investigations: Thalassaemia

Bloods

• FBC: microcytic anaemia (MCV <80fL)
• Blood film: hypochromic red cells, target cells, Howell Jolly bodies
• Hb electrophoresis

Imaging

• Skull X-ray: hair-on-end appearance

(4) (5)

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Management: Thalassaemia

Alpha and Beta thalassaemia trait

• No intervention required

HbH and beta thalassaemia major

• Regular blood transfusions
• Folate supplementation: haemolysis leads to folate deficiency
• Iron chelation: desferrioxamine reduces the risk of iron overload
• Splenectomy
• Patients develop splenomegaly due to extramedullary haematopoiesis
• Leads to hypersplenism and increased haemolysis
• Stem cell transplant: only curative option

Introduction: Anaemia of chronic disease

Microcytic anaemia Iron deficiency Thalassaemia Anaemia of chronic disease Sideroblastic anaemia

Definition: anaemia due to inflammation mediated reduction in

RBC production

• Microcytic or normocytic anaemia

Epidemiology:

• Second most common anaemia worldwide
• Multiple causes
• E.g. prevalence of ACD in rheumatoid arthritis ~ 30-40%

Introduction: Anaemia of chronic disease

Aetiology

• Autoimmune disorders e.g. rheumatoid arthritis
• Chronic infection
• Chronic disease e.g. CKD, heart failure
• Malignancy
• Major trauma

Pathophysiology: Anaemia of chronic disease

Functional iron deficiency

Investigations: Anaemia of chronic disease

Bloods

• Iron studies
• Ferritin: raised
• Serum iron: reduced
• Transferrin saturation: reduced
• TIBC: reduced
• Inflammatory markers: raised

Chronic disease Iron deficiency Hb Reduced Reduced Serum Fe Reduced Reduced Ferritin Raised Reduced Transferrin saturation Reduced Reduced TIBC Reduced Raised Inflammatory markers Raised Reduced

Management: Anaemia of chronic disease

Treat the underlying cause

• Anaemia is frequently mild and the below is may not be required

Iron supplementation

• Oral or intravenous

Erythropoietin Blood transfusion

• Not usually required

Introduction: Sideroblastic anaemia

Microcytic anaemia Iron-deficiency Thalassaemia Anaemia of chronic disease Sideroblastic anaemia

Definition: Anaemia due to defective haem synthesis within the

mitochondria

Aetiology:

• Congenital: X-linked recessive enzyme deficiency
• Vitamin B6 deficiency
• Lead poisoning
• Chronic alcoholism

Pathophysiology: Sideroblastic anaemia

Glycine + succinal CoA δ-aminolevulinic acid Porphobilinogen Hydroxymethylbilane Uroporphyrinogen III Coproporphyrinogen III Protoporphyrin + Fe Haem

ALA synthase ALA dehydrogenase Ferrochelatase

• Congenital: ALA synthetase
• Lead: ALA dehydrogenase and

ferrochelatase

• Vitamin B6: cofactor for ALA synthase
• Alcohol: mitochondrial poison

MITOCHONDRIA

Pathophysiology: Sideroblastic anaemia

• Iron becomes trapped in the mitochondria and forms a ring around the nucleus of the

erythroblast

• Ringed sideroblast

(6)

Investigations: Sideroblastic anaemia

Bloods

• FBC: microcytic anaemia (MCV <80fL)
• Blood film: ringed sideroblasts
• Iron studies
• Ferrtin: increased
• Serum iron: increased
• Transferrin saturation: increased
• TIBC: reduced

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Top-decile question

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Explanations

app.bitemedicine.com Which of the following is most associated with choriocarcinoma? Iron deficiency Not associated Anaemia of chronic disease Not associated Sideroblastic anaemia Not associated Alpha thalassaemia Increased spontaneous abortion in Hb Barts disease Beta thalassaemia Not associated

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Recap

• Microcytic
• Iron deficiency: most common
• Chronic disease: second most common
• Thalassaemia
• Sideroblastic anaemia

Microcytic (MCV < 80fL) Normocytic (MCV 80-95fL) Macrocytic (MCV >95fL) Iron deficiency Acute blood loss B12 deficiency Thalassaemia Haemolytic anaemia Folate deficiency Anaemia of chronic disease Anaemia of chronic disease Alcohol Sideroblastic anaemia Chronic kidney disease Liver disease Aplastic anaemia Hypothyroidism

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References

1. Matthew Ferguson 57 / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) 2. CHeitz / CC BY (https://creativecommons.org/licenses/by/2.0) 3. US Federal Government / Public domain 4. Paulo Henrique Orlandi Mourao and Mikael Häggström / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) 5. Dr Graham Beards / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) 6. Paulo Henrique Orlandi Mourao / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)

All other images were made by BiteMedicine or under basic license from Shutterstock and not suitable for redistribution.

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