Failure of red cell production Dr Dupe Elebute
Failure of red cell production Dr Dupe Elebute Consultant Haematologist
Aim n n To revise the process and control of normal erythropoiesis To discuss the mechanisms of failure of red cell production
Overview n n Origin and control of red cell production Role of iron in haemoglobin structure and function Role of vitamin B 12 and folic acid in red cell production Other causes of failure of red cell production
Erythropoiesis n n Erythropoiesis is the process of red blood cell production Erythrocytes are derived from the division and differentiation of a common stem cell precursor
Erythropoiesis: earliest stages BFU-E (day 3), CFU-E (day 7), immature erythroblast (day 11) and mature erythroblast (day 15). Romanowsky stain.
Erythropoietin n n n Haemopoietic growth factor Main control of rbc production Produced in the kidney Released by low O 2 tension (hypoxia, anaemia) Reacts with Epo receptors on red cell precursors to increase rbc production Recombinant Epo available (anaemia due to renal failure)
Haematinics n n n Dietary substances Essential for production of red blood cells and Hb Most important: n n n Iron Vitamin B 12 Folic acid
Anaemia n n n Reduced haemoglobin level Normal range depends on age and gender Subclassified by red cell indices n n n Microcytic, hypochromic Normocytic, normochromic Macrocytic
Microcytic, hypochromic anaemia Definition: n Caused by defective synthesis of Hb, resulting in red cells that are smaller than normal (microcytic) and contain reduced amounts of haemoglobin (hypochromic). Differential diagnosis: n Iron deficiency anaemia n Thalassaemia n Sideroblastic anaemia
Iron n Function Ø Ø n Major role in several metabolic processes Combines with protoporphyrin ring to form haem Four haem groups to each tetramer of Hb 1 g of Hb can combine with 1. 34 ml of O 2 Dietary source Ø Ø Present in food as ferric hydroxide Red meat best source
Iron Daily dietary iron requirements per 24 hours: Male 1 mg Adolescence 2 -3 mg Female (reproductive age) Pregnancy 2 -3 mg 3 -4 mg Infancy 1 mg Maximum bioavailability from normal diet about 4 mg
Iron n Absorption Ø Ø Ø n Occurs in duodenum and jejunum Enhanced by acid and reducing agents 1 -2 mg (5 -10%) absorbed daily Transport Ø Ø Ø In plasma combined with transferrin Combined with apoferritin in RES Stored as ferritin
Iron deficiency anaemia (IDA) n inadequate intake of iron Ø Ø n increased loss of iron Ø Ø Ø n dietary deficiency Malabsorption menorrhagia gastro-intestinal bleeding haematuria increased need for iron Ø Pregnancy and lactation Barium meal showing hiatus hernia causing IDA
IDA: signs and symptoms n n n Rapidly progressive anaemia usually causes more symptoms Some people with severe anaemia have no symptoms at all Common symptoms of anaemia include: Ø Ø Ø Tiredness; Fatigue Pale appearance Irritability; Headache Reduced exercise capacity Palpitations
IDA: signs and symptoms (2) n Ø Ø Severe and prolonged deficiency may produce the following symptoms: Painless glossitis (tongue smooth and red) Curling and softening of the nails (spooning; koilonychia) Brittle hair Pica ( unusual dietary cravings) Nail changes in iron deficiency anaemia (koilonychia)
IDA: diagnosis n Blood tests (FBC): Low Hb, MCV and MCH n Blood film: n n the red blood cells are smaller (microcytic) than usual and paler in colour (hypochromic). Some of the red cells may have an abnormal shape (poikilocytosis; pencil cells) Platelet count may be raised
Normal blood film Hypochromic, microcytic picture with marked anisocytosis and poikilocytosis
IDA: diagnosis (2) n Iron studies n n Serum iron: low Total iron binding capacity: high Transferrin saturation: low Serum Ferritin level: low (10 -30μmol/l) (50 -70μmol/l) (>16%) (12 -150μg/l) best indicator of body iron status; when <12μg/l, indicates iron deficiency!
n Iron stores in the bone marrow: The marrow smear is treated with potassium ferricyanide (Prussian blue) which stains the iron within the reticuloendothelial cells blue. Reduced iron stores Normal iron stores
Differential diagnosis of a hypochromic anaemia IDA Anaemia of chronic disorder Thalassaemia trait All Low normal All in relation to anaemia or mild reduction Very low for degree of anaemia Serum iron N TIBC N N Serum ferritin N/ N BM iron stores Absent Present MCV, MCHC Sideroblastic anaemia congenital Acquired
IDA: further investigations n Dietary history n Drug history: Aspirin, other anti-inflammatory Menstrual history n Exclude GI tract malignancy n Ø Ø Ø faecal occult blood (checks faeces for microscopic amounts of blood) colonoscopy (tube test to look at the large bowel); gastroscopy. (tube test to look at gullet and stomach)
IDA: treatment n Treat underlying cause n Oral iron: Ferrous sulphate n n n (67 mg per 200 mg tablet) Cheap! Treat for up 4 -6 months to correct anaemia and replenish stores Hb rise of about 2 g/dl every 3 weeks S/E include nausea, diarrhoea, constipation Reduce dose or use preparation with lower iron content. e. g. Ferrous gluconate (37 mg per 300 mg tablet Ferrous succinate, lactate, fumarate: more expensive
IDA: treatment n Parenteral iron rarely used as allergic reactions, anaphylaxis quite common Ø Ø n Preparations of iron dextran or iron-sorbitolcitrate given intramuscularly (I. M) or intravenously (I. V) Iron dextran can be given I. V in total dose infusion NB: Blood transfusion is rarely indicated and may be dangerous
Macrocytic anaemia Definition: n Rise in the mean cell volume of the red cells above the normal range (adults 80 -95 fl) Differential diagnosis: n Reticulocytosis (acute bleeding) n Vitamin B 12 or folate deficiency n Alcoholic liver disease n Hypothyroidism n Myelodysplasia (MDS)
Macrocytic anaemia: investigation Clinical n Dietary history n GI symptoms n Alcohol consumption n Hypothyroidism (lethargy, weight gain)
Macrocytic anaemia: investigation n Blood film n n n Hypersegmented neutrophils (B 12 def) Target cells, stomatocytes (liver disease) Abnormal morphology (MDS)
Normal blood film Blood film in vitamin B 12 deficiency showing macrocytic red cells and a hypersegmented neutrophil.
Macrocytic anaemia: investigation n n Reticulocyte count Liver and thyroid function tests Serum B 12 and folate assays Bone marrow aspirate n n Megaloblastic features Alternative diagnosis (MDS, AA)
High power view of a normal bone marrow aspirate Megaloblastic features in BMA Megaloblastic BM: giant metamyelocytes
Vitamin B 12 n Source: n n Only produced by micro-organisms Mainly from animal produce Stable to cooking Absorption: n n Mainly through the ileum Combines with intrinsic factor (IF) IF produced by gastric parietal cells Complex combines with IF receptors in terminal ileum ―› B 12 absorbed
Vitamin B 12 deficiency n n Minimum daily requirement: 1 -2μg Body stores: 2 -3 mg (lasts for 2 -4 yrs) Deficiency caused by: n Malabsorption n Dietary lack (vegans) n Pernicious anaemia (antibodies directed against IF) n Blind-loop syndrome
Vitamin B 12 deficiency (2) Symptoms and signs: n n Macrocytic, megaloblastic anaemia Neurological symptoms – subacute combined degeneration of the cord Glossitis due to Vitamin B 12 deficiency
B 12 deficiency: investigation n Radioactive vitamin B 12 absorption with and without intrinsic factor (Schilling test) Serum gastric parietal and intrinsic factor antibodies Endoscopy–gastric biopsy (vitamin B 12 deficiency), duodenal biopsy (folate deficiency)
B 12 deficiency: treatment n n n Hydroxycobalamin: parenteral preparation only Initial/loading dose of 1 mg every 3 -4 days for up to 6 doses Maintenance dose of 1 mg every 3 months
Folic Acid n n Source: n Most foods esp meat (liver), vegetables, yeasts n Natural folates largely in the polyglutamate form n Easily destroyed by cooking Absorption: n Polyglutamates deconjugated and converted to monoglutamate 5 -methyltetrahydrofolate n Absorbed through duodenum and jejunum
Folic Acid n n n Normal dietary intake 600 -1000 g Daily requirement 100 -200 g Body stores 10 -12 mg (enough for 4 months) Deficiency caused by: n Inadequate dietary intake (lack of fresh veg!) n Malabsorption: coeliac disease, tropical sprue n Increased demands: pregnancy, proliferative disorders e. g. chronic haemolytic anaemia
Folate deficiency Symptoms and signs: n Megaloblastic anaemia n Neural tube defects in fetus n n No clear relation between maternal folate levels and defects but… Folic acid supplements in early pregnancy shown to reduce incidence of spina bifida, anencephaly, cleft palate and hare lip
Folate deficiency Treatment: n B 12 deficiency must be excluded first to prevent development/exacerbation of neurological disease n n Oral folic acid: 5 mg daily Prophylaxis in pregnancy: 400 g from time of conception
Bone marrow failure syndromes n n n Acquired/Idiopathic Ø Aplastic anaemia Ø Red cell aplasia Acquired/Infection Ø Parvovirus B 19 Congenital Ø Fanconi anaemia Ø Diamond Blackfan anaemia
Bone marrow trephine biopsy showing normal ratio of haemopoietic cells and fat spaces Hypoplastic bone marrow Aplastic bone marrow
More Information from: n n n Essential Haematology: Hoffbrand & Pettit Lecture notes on Haematology: Hughes. Jones & Wickramasingh ABC of clinical haematology: Provan
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