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 and causes
• Complete anaemia today
• Previous sessions: normocytic and microcytic anaemia
• Duration: 60 mins
• Slides and recordings: app.bitemedicine.com

History and examination

A 49-year-old lady presents to the GP complaining of

• fatigue. She works as a teacher and finds when she

gets back home she has to go straight to bed. Her blood tests reveal she is anaemic: Hb: 98 g/L MCV: 109 fL Vitamin B12: reduced

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Case-based discussion: 1

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A 49-year-old lady presents to the GP complaining of fatigue. She works as a teacher and finds when she gets back home she has to go straight to bed. Her blood tests reveal she is anaemic: Hb: 98 g/L MCV: 109 fL Vitamin B12: reduced What is the most likely cause?

Case history

Poor diet Folate deficiency Pernicious anaemia Crohn’s disease Pregnancy app.bitemedicine.com

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Explanations

app.bitemedicine.com What is the most likely cause? Poor diet Dietary insufficiency is possible, particularly in vegans Folate deficiency The patient is vitamin B12 deficient Pernicious anaemia The most common cause of vitamin B12 deficiency Crohn’s disease Can cause malabsorption but no evidence of disease e.g. loose stools or bloody diarrhoea Pregnancy Can cause vitamin B12 deficiency but no evidence of pregnancy. Also, would be unusual to get pregnant at 49 years of age

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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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Introduction: Macrocytic anaemia

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Introduction: Macrocytic anaemia

Megaloblastic: impaired DNA synthesis Nonmegaloblastic Vitamin B12 deficiency Folate deficiency Liver disease Alcohol Hypothyroidism

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Introduction: Macrocytic anaemia

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Introduction: Macrocytic anaemia

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Introduction: Macrocytic anaemia

Megaloblastic Nonmegaloblastic Causes

• Vitamin B12

deficiency

• Folate deficiency
• Liver disease
• Alcohol
• Hypothyroidism

Pathophysiology Impaired DNA synthesis DNA synthesis not impaired Investigations

• Macrocytic

anaemia

• Megaloblasts
• Hypersegmented

nuclei

• Macrocytic

anaemia

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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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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

Introduction: Vitamin B12 deficiency

Megaloblastic Vitamin B12 deficiency Folate deficiency

Definition: reduced levels of vitamin B12 Epidemiology:

• 6% of people aged under 60 years of age (NICE)
• 20% in those aged above 60
• 11% for those on vegan diets

Risk factors:

• Increasing age
• Gastric surgery
• Malabsorption
• Vegan diet
• Drugs: metformin, antiepileptics

Pathophysiology: Vitamin B12 deficiency

Causes

Decreased intake

• Malnutrition
• Vegan diet

Reduced absorption

• Pernicious anaemia
• Crohn’s disease
• Pancreatic insufficiency
• Gastrectomy
• Fish tapeworm

Increased requirement

• Pregnancy and lactation

Pathophysiology: Pernicious anaemia

Definition: autoimmune process affecting vitamin B12

absorption

Epidemiology:

• Most common cause of vitamin B12 deficiency

Risk factors:

• Females > males
• Autoimmunity: Addison’s disease, vitiligo, T1DM

History and examination

A 49-year-old lady presents to the GP complaining of

• fatigue. She works as a teacher and finds when she

gets back home she has to go straight to bed. Her blood tests reveal she is anaemic: Hb: 98 g/L MCV: 109 fL Vitamin B12: reduced

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Case-based discussion: 1

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Clinical features: Vitamin B12 deficiency

Symptoms/signs

General features of anaemia (see earlier) Glossitis Angular stomatitis Lemon coloured skin in pernicious anaemia

• Pallor
• Jaundice

(1)

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A 49-year-old lady presents to the GP complaining of fatigue. She works as a teacher and finds when she gets back home she has to go straight to bed. Her blood tests reveal she is anaemic: Hb: 98 g/L MCV: 109 fL Vitamin B12: reduced Which of the following is the most specific investigation for pernicious anaemia?

Case history

Antinuclear antibodies Anti-intrinsic factor Anti-parietal cell Anti-glutamic acid decarboxylase Reduced vitamin B12 level app.bitemedicine.com

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Explanations

app.bitemedicine.com Which of the following is the most specific investigation for pernicious anaemia? Antinuclear antibodies Raised in connective tissue disorders e.g. SLE Anti-intrinsic factor High specificity Anti-parietal cell High sensitivity Anti-glutamic acid decarboxylase Raised in T1DM Reduced vitamin B12 level Non-specific. Multiple causes of vitamin B12 deficiency, one of which is pernicious anaemia

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Investigations: Vitamin B12 deficiency

Bloods

• FBC: macrocytic anaemia (MCV >95fL), low reticulocyte count
• Blood film: megaloblasts, hypersegmented nuclei (> 5 lobes)
• Vitamin B12: reduced
• Folic acid

Vit B12 deficiency Folate deficiency Homocysteine Raised Raised Methylmalonic acid Raised Normal

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Investigations: Vitamin B12 deficiency

Vit B12 deficiency Folate deficiency Homocysteine Raised Raised Methylmalonic acid Raised Normal

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Investigations: Vitamin B12 deficiency

• Antibodies
• Intrinsic factor: 50% sensitivity but highly specific
• Parietal cell: 85% sensitive but low specificity

Special tests

• Schilling test: consumption of radiolabelled vitamin B12
• Urinary excretion confirms absorption
• If absorption increases after consumption of intrinsic factor, this suggest pernicious anaemia

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Investigations: Vitamin B12 deficiency

(2)

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Management: Vitamin B12 deficiency

Dietary advice

• Eggs, milk, meat, salmon, cod

Vitamin B12 replacement

• IM hydroxocobalamin: 1g three times a week for 2 weeks (NICE)
• Not diet related: lifelong IM therapy every 2-3 months
• Diet related: oral replacement
• Vegan: may need to continue lifelong
• Non-vegan: can stop once B12 corrected
• In the presence of neurological symptoms, more frequent correction is required

Blood transfusion

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

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Complications: Vitamin B12 deficiency

Complications

Neurological impairment

• Peripheral neuropathy
• Subacute combined degeneration of the spinal

cord

• Dorsal and corticospinal tracts affected
• Dementia

Pancytopaenia Gastric cancer (pernicious anaemia) Congenital malformation

• Neural tube defects

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Complications: Vitamin B12 deficiency

Propionyl CoA replaces acetyl CoA in neuronal membranes

• Demyelination

Folate deficiency Vit B12 deficiency Homocysteine Raised Raised Methylmalonic acid Normal Raised

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Complications: Vitamin B12 deficiency

History and examination

A 60-year-old gentleman presents complaining of fatigue and shortness of breath on exertion. He confesses to drinking 1 bottle of vodka per day and detests green vegetables. Examination reveals conjunctival pallor. Hb: 98 g/L MCV: 109 fL Folate: reduced

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Case-based discussion: 2

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A 60-year-old gentleman presents complaining of fatigue and shortness of breath on exertion. He confesses to drinking 1 bottle of vodka per day and detests green vegetables. Examination reveals conjunctival pallor. Hb: 98 g/L MCV: 109 fL Folate: reduced How does alcohol cause folate deficiency?

Case history

Poor nutrition Inhibits intestinal absorption Inhibits release of folate from the liver All of the above app.bitemedicine.com

Q1 Q2

Increased excretion

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Explanations

app.bitemedicine.com How does alcohol cause folate deficiency? Poor nutrition Alcoholics have poor nutrition Inhibits intestinal absorption Alcohol inhibits monoglutamate absorption Inhibits release of folate from the liver Alcohol prevents folate release from hepatic stores Increased excretion Alcohol increases urinary excretion All of the above Correct

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Introduction: Folate deficiency

Megaloblastic Vitamin B12 deficiency Folate deficiency

Definition: reduced levels of folic acid Epidemiology:

• Prevalence ~ 5% (NICE)

Risk factors:

• Increasing age
• Malabsorption
• Pregnancy
• Alcohol
• Drugs: methotrexate, trimethoprim, antiepileptics

Pathophysiology: Folate deficiency

Causes

Decreased intake

• Malnutrition

Reduced absorption

• Coeliac disease
• Crohn’s disease
• Phenytoin: inhibits conjugase
• OCP: inhibits intestinal absorption
• Alcohol: inhibits intestinal absorption and release
• f folic acid from liver

Drug inhibition

• Methotrexate and trimethoprim: inhibit

dihydrofolate reductase Increased requirement

• Pregnancy and lactation

Pathophysiology: Folate deficiency

Causes

Decreased intake

• Malnutrition

Reduced absorption

• Coeliac disease
• Crohn’s disease
• Phenytoin: inhibits conjugase
• OCP: inhibits intestinal absorption
• Alcohol: inhibits intestinal absorption and release
• f folic acid from liver

Drug inhibition

• Methotrexate and trimethoprim: inhibit

dihydrofolate reductase Increased requirement

• Pregnancy and lactation

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Clinical features: Folate deficiency

Symptoms/signs

General features of anaemia (see earlier) Glossitis Angular stomatitis

(1)

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A 49-year-old lady presents to the GP complaining of fatigue. She works as a teacher and finds when she gets back home she has to go straight to bed. Her blood tests reveal she is anaemic: Hb: 98 g/L MCV: 109 fL Vitamin B12: reduced Which of the following would you expect in folic acid deficiency?

Case history

Raised homocysteine, reduced methylmalonic acid Raised homocysteine, normal methylmalonic acid Raised homocysteine and methylmalonic acid Normal homocysteine, raised methylmalonic acid Reduced homocysteine, raised methylmalonic acid app.bitemedicine.com

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Explanations

app.bitemedicine.com Which of the following would you expect in folic acid deficiency? Raised homocysteine, reduced methylmalonic acid Methylmalonic acid should be normal Raised homocysteine, normal methylmalonic acid Homocysteine cannot be converted to methionine, so it accumulates. Folate is not involved in odd chain fatty acid synthesis and does not affect methylmalonic acid Raised homocysteine and methylmalonic acid This is true of B12 deficiency Normal homocysteine, raised methylmalonic acid Raised homocysteine and normal methylmalonic acid would be expected Reduced homocysteine, raised methylmalonic acid Raised homocysteine and normal methylmalonic acid would be expected

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Investigations: Folate deficiency

Bloods

• FBC: macrocytic anaemia (MCV >95fL)
• Blood film: megaloblasts, hypersegmented nuclei (> 5 lobes)
• Folic acid: reduced
• Vitamin B12

Folate deficiency Vit B12 deficiency Homocysteine Raised Raised Methylmalonic acid Normal Raised

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Investigations: Folate deficiency

(2)

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A 49-year-old lady presents to the GP complaining of fatigue. She works as a teacher and finds when she gets back home she has to go straight to bed. Her blood tests reveal she is anaemic: Hb: 98 g/L MCV: 109 fL Vitamin B12: reduced The patient is noted to also have B12 deficiency. How would you manage them?

Case history

Monitor Commence oral folate Commence IM folate Commence IM hydroxocobalamin Commence IV hydroxocobalamin app.bitemedicine.com

Q1 Q2 Q3

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Explanations

app.bitemedicine.com The patient is noted to also have B12 deficiency. How would you manage them? Monitor The patient has a symptomatic macrocytic anaemia which needs addressing Commence oral folate Never start folate before B12 Commence IM folate Never start folate before B12 Commence IM hydroxocobalamin B12 must be replaced first to prevent neurological symptoms Commence IV hydroxocobalamin Usually given IM

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Management: Folate deficiency

Dietary advice

• Asparagus, broccoli, brown rice, chickpeas, peas

Folic acid replacement

• Oral folic acid: 5mg daily for 4 months
• May need lifelong replacement if the cause is persistent

Vitamin B12 replacement

• If the patient has concomitant B12 deficiency, replace B12 first

Prophylactic folic acid

• Pregnancy: 400mcg folic acid until week 12
• High risk women should be on 5mg

Blood transfusion

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

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Management: Folate deficiency

Vitamin B12 replacement

• If the patient has concomitant B12 deficiency, replace B12 first
• Failure to do so can result in B12 depletion and neurological impairment

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Complications: Folate deficiency

Complications

Exacerbation of B12 deficiency Pancytopaenia Cardiovascular disease

• Raised homocysteine

Congenital malformation

• Neural tube defects

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Introduction: Nonmegaloblastic anaemia

Complications Mechanism

Alcohol

• Toxic effect on RBC progenitors
• Occurs independent of folate and B12 deficiency, or liver disease

Liver disease

• Liver is involved in lipid synthesis which is required for RBC membrane

synthesis Hypothyroidism

• Multifactorial
• Interferes with EPO production
• Clinically:
• No neurological symptoms
• No glossitis or angular stomatitis
• Blood film:
• No hypersegmented neutrophils

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Top-decile question

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Explanations

app.bitemedicine.com Which of the following is NOT an indication to start 5mg folic acid in a lady who is planning to become pregnant? BMI 17 Obesity is an indication Father has a neural tube defect If the mother or father has an NTD, this is an indication The father has a family history of neural tube defect Family history of either partner is an indication Mother has diabetes Diabetes is an indication Mother has thalassaemia Thalassaemia and sickle cell anaemia are indications

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Recap

• Macrocytic
• Megaloblastic
• Nonmegaloblastic

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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Recap

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References

1. Matthew Ferguson 57 / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) 2. Gabriel Caponetti / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)

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

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