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![• Stage 3
• Microcytic hypochromic anaemia
• Having thoroughly depleted storage iron and
diminished transport iron, developing RBCs
are unable to develop normally
• The result is first smaller cells with adequate
[Hb], although these cannot be filled with Hb
leading to cells becoming microcytic &
hypochromic
• FBE parameters & iron studies all outside RR](https://image.slidesharecdn.com/microcytichypochromicanaemia-111208111013-phpapp021-121117014408-phpapp01/75/Microcytichypochromicanaemia-111208111013-phpapp02-1-15-2048.jpg)
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Microcytichypochromicanaemia 111208111013-phpapp02 (1)
1. Microcytic hypochromic anaemia can be classified based on mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) levels. Defects in iron metabolism, haemoglobin synthesis or blood loss can cause microcytic hypochromic anaemia. 2. Normocytic normochromic anaemia is caused by acute blood loss or bone marrow failure/suppression. Macrocytic anaemia results from vitamin B12 or folate deficiency or liver disease. 3. Diagnosis of the type of anaemia involves a full blood examination and iron studies to measure ferritin, serum iron, transferrin
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Microcytichypochromicanaemia 111208111013-phpapp02 (1)
- 1. Classification of Anaemia: MicrocyticHypochromic Anaemia
- 2. Classification of Anaemia Microcytic & Normochromic Hypochromic & Normocytic Macrocytic MCV<RR MCV within RR MCH within RR MCV>RR MCH<RR Defects in Acute blood loss Megaloblastic Non-megaloblastic Defects in haem globin Haemolysis synthesis synthesis ACD Marrow infiltration •Thalassaemia Liver •Iron •Haemoglobinopathies B12/Folate deficiency disease deficiency •ACD Drug •Sideroblastic induced (congenital) MDS
- 3.
- 4. Normal Iron Absorptionand Metabolism
- 5. Ferritin • Iron storageprotein • Produced by all living organisms including bacteria, algae, & higher plants and animals • In humans, it acts as a buffer against iron deficiency and iron overload • Consists of: • Apoferritin – protein component • Core- ferric, hydroxyl ions and oxygen • Largest amount of ferritin-bound iron is found in: – Liver hepatocytes (majority of the stores) – BM – Spleen • Excess dietary iron induces increased ferritin production • Partially digested ferritin= HAEMOSIDERIN- insoluble and can be detected in tissues (hepatocytes) using Perl’s Prussian blue stain
- 6. Transferrin (Tf) • Transports iron from palsma to erythroblast • Mainly synthesized in the liver • Fe3+ (ferric) couples to Tf • Apotransferrin = Tf without iron • Contains sites for max 2 iron molecules • The amount of diferric Tf changes with iron status – Levels decreased when cellular iron demand is increased – Increased levels lead to increase hepcidin production that decreases iron absorption
- 7. Transferrin Receptor (TfR) •Provides transferrin- bound iron access into cell • Control of TfR synthesis is one of major mechanisms for regulation of iron metabolism • Cells maintain appropriate iron levels by altering TfR expression and synthesis • Increased by iron deficiency • Located on all cells except mature RBC • Can bind up to 2 Tf • apoTf is not recognized by TfR
- 8. Ferroportin • Transmembrane protein •Found on the surface of most cells: • Enterocytes • Hepatocytes • RE system • Regulates iron release from those tissues (iron exporter) • ‘Hepcidin receptor’
- 9. Hepcidin • Is anantimicrobial peptide produced in the liver • Act as a negative regulator of intestinal iron absorption & release from macrophages • Hepcidin binds to the ferroportin receptor & cause degradation of ferroportin, resulting in trapping of iron in the intestinal cells • As a result, iron absorption & mobilization of storage iron from the liver & macrophage are lowered • Increased synthesis of hepcidin occurs when transferrin saturation is high and decreased synthesis when iron saturation is low
- 11. Causes of Irondeficiency Increased demand: •Growth Blood loss: •Pregnancy •GIT •Urinary Inadequate intake •Infants •vegetarian Major causes of IDA in Western Malabsorption Society Iron sequestration at inaccessible sites (pulmonary Haemolysis haemosiderosis) Major causes of IDA Parasitic infection in developing countries Malnutrition
- 12. Symptoms of IronDeficiency • Mainly attributed to anaemia – Fatigue – Pallor – Shortness of breath – Tachycardia – Failure to thrive • More specific features (only apparent in severe IDA ): – Koilonychia – Glossitis – Unusual dietary cravings (pica)
- 13. Stages of IronDeficiency • 3 stages • Stage 1 • Characterized by a progressive loss of storage iron • Body’s reserve iron is sufficient to maintain transport and functional compartments through this phase, so RBC development is normal • No evidence of iron deficiency in peripheral blood and patient experiences no symptoms
- 14. • Stage 2 •Defined by exhaustion of the storage pool of iron • For a time, RBC production is normal relying on the iron available in transport compartment • Anaemia may not be present but Hb level starts to drop • Serum iron, ferritin and Tf saturation decreased • Increased TIBC, Tf and TfR
- 15. • Stage 3 •Microcytic hypochromic anaemia • Having thoroughly depleted storage iron and diminished transport iron, developing RBCs are unable to develop normally • The result is first smaller cells with adequate [Hb], although these cannot be filled with Hb leading to cells becoming microcytic & hypochromic • FBE parameters & iron studies all outside RR
- 16. Diagnosis - FBE • Hb or borderline • RBC • Hct/PCV • MCV • MCH • MCHC • RDW • +/- thrombocytosis • Elongated cells • Target cells (severe IDA)
- 18. Diagnosis- Iron studies Ferritin Serum Transferrin Tf TIBC TfR Iron Saturation Results in IDA
- 19. Differential diagnoses • Thalassaemias/Haemoglobinopathies – Not all hbpathies are microcytic and hypochromic • Anaemia of chronic disease • Congenital sideroblastic anaemia
- 21. Treatment of IronDeficiency • Treatment of underlying cause (ulcers) • Dietary supplementation – Oral supplements • Transfusion – If anaemia is symptomatic and life threatening – No prompt response to treatment • Dimorphic blood film is present in treated IDA – With oral supplements-newly produced cells are normochromic normocytic – Transfused cells are normochromic and normocytic
- 22. Anaemia of ChronicDisease • Anaemia of chronic inflammation • Usually normochromic normocytic; microcytosis & hypochromia develop as the disease progress • Iron stores abundant, but iron is NOT available for erythropoiesis • There are several proposed mechanism for abnormal iron haemostasis in ACD: • Lactoferrin competes with transferrin for iron – RBC don’t have lactoferrin receptors • Ferritin increases • Cytokines inhibit erythropoieis • HEPCIDIN
- 23. ACD- Role ofHepcidin • Increase in hepcidin: – Levels can be increased up to 100 times in ACD – Release from liver after stimulation by IL-6 – Acute phase reactant • Binds to ferroportin – Decreases iron absorption and export from cells
- 24. Diagnosis & Treatment •Identification of the disease • CRP & IL 6 • Measurement of hepcidin levels via ELISA, HPLC or LCMS • Iron studies to distinguish from IDA • Failure to respond to iron supplementation Tx: • Maintaining normal Hb is challenging • EPO administration + IV iron • Anti-inflammatory therapy
- 25. Sideroblastic anaemia • Caneither be inherited or acquired • Rare condition • Most common mutation is in ALA synthase gene (ALAS2) located on X chromosome • Abnormal haem synthesis & presence of ringed sideroblasts in erythroid precursors (visible if stained with Perls Prussian Blue) • Microcytic hypochromic anaemia – Ineffective erythropoiesis – Systemic iron overload
- 26. STRUCTURE OF HAEMOGLOBIN Polypeptidesare made up of 2a chains and 2B chains, a2B2. Haem groups bind oxygen.
- 27. STRUCTURE OF HAEM •Haem structure: the iron (Fe)at the centre enables oxygen to bind
- 28.
- 29. Stages of HaemoglobinDevelopment • Embryonic haemoglobin – Hb Gower 1 2 2 – Hb Portland 2 2 – Hb Gower 2 2 2 • Foetal Haemoglobin – Hb F 2 2 Foetus 100% Adult <1% • Adult haemoglobins – Hb A2 2 2 Adult 1.8-3.6% – Hb A 2 2 Adult 96-98% – The globin genes are arranged on the chromosomes in order of expression
- 30. Inherited defects ofglobin synthesis • These are due to: 1. Synthesis of an abnormal haemoglobin eg haemoglobinopathies 2. Reduced rate of synthesis of α or β chains: thalassaemia
- 31. Β- Thalassaemia • Causedby defective B globin chain synthesis • Due to mutations in the B globin gene • The unpaired α chain precipitate in the developing cells leading to damage to the RBCs surface ~ leading to removal of RBCc by macrophages • Leads to ineffective erythopoiesis • The more α chain in excess, the more haemolysis occurs • Can be divided into B-thal minor and B-thal major
- 32. B-thal minor • Resultswhen 1 of the 2 gene that produces B- chain is defective (heterozygous) • Usually present as a mild asymptomatic anaemia • Hepatomegaly and splenomegaly are seen in some patients
- 33. B-thal major • Characterizedby severe anaemia first detected in early childhood as σ to β switch takes place • Patient presents with jaundice, hepatosplenomegaly, marked bone changes (frontal bossing)
- 34. α thalassaemia • Dueto large deletions in the α globin genes • Notation for the normal α gene complex or haplotype is expressed as α α, signifying 2 normal genes on chr 11 • There are 4 clinical syndromes of α thalassaemias; silent carrier, α-thal minor/trait, HbH disease (due to accumulation of unpaired B chain, homozygous α-thal (hydrops foetalis)
- 36. Signs & Symptomsof Thalassaemia • Severe anaemia first detected in early chilhood • Jaundice, hepatosplenomegaly, marked bone changes (frontal bossing) • Microcytic hypochromic anaemia
- 37. Laboratory Findings • Mostthalassaemias are microcytic & hypochromic • Hb and PCV, MCV • RCC • Poikilocytosis, target cells, elliptocytes, polychromasia, nRBCs, basophilic stippling • Bone marrow – hypercellylar with extreme erythroid hyperplasia • Electrophoresis- decresead % of Hb A • Supravital stain to detect α thalassaemia major (HbH)
- 38. Treatment 1. Transfusion 2. Iron chelation therapy- desferrioxamine 3. BM transplantation 4. Hydroxyurea- to increase Hb F levels enough to eliminate transfusion requirements for patients with thalassaemia major
- 39. Hb 107 120- 160g/L RCC 5.50 3.80- 5.401012/L MCV 61 80-100 fL MCH 19.5 27-32 pg Hb A2 5.0 1.8-3.5 % Hb F <0.1 0.0-1.0 %
- 40. Comparison of anormal blood film with b-thal major Normal Blood Film Intermittently transfused -thal HbF>90% Bain B. ‘Blood Cells. A practical guide’2006 Free chains form Heinz bodies and inclusions Marked haemolysis reticulocytosis Basophilic stippling and Pappenheimer bodies
- 41.
- 42. Study Questions • Whatare the main causes of IDA? • Draw a diagram that explains how iron haemostasis is maintained in the body • Discuss different stages of development of IDA • How would you differentiate between different microcytic and hypochromic anaemia? • Explain the involvement of iron regulatory proteins in ACD
- 43. Study Questions • Describe how you would approach the investigation of a patient who has been diagnosed with mild microcytic hypochromic anaemia. In your answer include the tests, expected results and how they would help you differentiate the disorders to make a final diagnosis. • Are thalassaemias & haemoglobinpathies the same? Why? • Why do patients with iron deficiency and a suspected thalassaemia need to receive iron replacement therapy before Hb electrophoresis and HPLC can be performed? How does iron deficiency influence these tests and the results obtained? • Describing the principle and rationale, explain why Hb electrophoresis and HPLC can be used to diagnose these disorders. Are there any analytical errors that could lead to inaccurate results? • What role does prenatal diagnosis & genetic counseling have in this group of disorders?
Editor's Notes
- #32 The premature death of RBC in the BM leads to ineffective erythropoiesis where the BM is attempting to produce cells, it is not able to release viable cells into the circulation