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 • 2
Case-based discussion: 1 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 3
A 49-year-old lady presents to the GP complaining of fatigue. She works as a Case history 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 Q1 Q2 What is the most likely cause? Poor diet Folate deficiency Pernicious anaemia Crohn’s disease Pregnancy app.bitemedicine.com 4
Explanations Q1 Q2 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 app.bitemedicine.com 5
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 α 2 β 2 90% HbA 2 α 2 δ 2 <2% HbF <2-5% α 2 γ 2 6
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 Alcohol Anaemia of chronic disease Sideroblastic anaemia Liver disease Chronic kidney disease Hypothyroidism Aplastic anaemia 7
Introduction: Macrocytic anaemia 8
Introduction: Macrocytic anaemia Megaloblastic: impaired DNA synthesis Nonmegaloblastic Vitamin B12 deficiency Liver disease Folate deficiency Alcohol Hypothyroidism 9
Introduction: Macrocytic anaemia 10
Introduction: Macrocytic anaemia 11
Introduction: Macrocytic anaemia Megaloblastic Nonmegaloblastic Causes • Vitamin B12 • Liver disease deficiency • Alcohol • Folate deficiency • Hypothyroidism Pathophysiology Impaired DNA DNA synthesis not synthesis impaired Investigations • Macrocytic • Macrocytic anaemia anaemia • Megaloblasts • Hypersegmented nuclei 12
Clinical features: General principles Symptoms Signs Fatigue Tachycardia SOB on exertion Tachypnoea Chest pain Hypotension Palpitations Pallor 13
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 • 14
Introduction: Vitamin B12 deficiency Megaloblastic Definition: reduced levels of vitamin B12 Vitamin B12 deficiency Epidemiology: Folate deficiency 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 •
Case-based discussion: 1 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 18
Clinical features: Vitamin B12 deficiency Symptoms/signs General features of anaemia (see earlier) Glossitis Angular stomatitis Lemon coloured skin in pernicious anaemia (1) • Pallor • Jaundice 19
Case history 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 Q1 Q2 Which of the following is the most specific investigation for pernicious anaemia? Antinuclear antibodies Anti-intrinsic factor Anti-parietal cell Anti-glutamic acid decarboxylase Reduced vitamin B12 level app.bitemedicine.com 20
Explanations Q1 Q2 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 app.bitemedicine.com 21
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 22
Investigations: Vitamin B12 deficiency Vit B12 deficiency Folate deficiency Homocysteine Raised Raised Methylmalonic acid Raised Normal 23
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 • 24
Investigations: Vitamin B12 deficiency (2) 25
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 • 26
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 27
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 28
Complications: Vitamin B12 deficiency 29
Case-based discussion: 2 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 30
A 60-year-old gentleman presents complaining of fatigue and shortness of Case history 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 Q3 Q1 Q2 How does alcohol cause folate deficiency? Poor nutrition Inhibits intestinal absorption Inhibits release of folate from the liver Increased excretion All of the above app.bitemedicine.com 31
Explanations Q1 Q2 Q3 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 app.bitemedicine.com 32
Introduction: Folate deficiency Megaloblastic Definition: reduced levels of folic acid Vitamin B12 deficiency Epidemiology: Folate deficiency Prevalence ~ 5% (NICE) • Risk factors: Increasing age • Malabsorption • Pregnancy • Alcohol • Drugs: methotrexate, trimethoprim, antiepileptics •
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