Microcytichypochromicanaemia 111208111013-phpapp02 (1)
-
Upload
kamani-nagarjun -
Category
Documents
-
view
471 -
download
0
description
Transcript of Microcytichypochromicanaemia 111208111013-phpapp02 (1)
![Page 1: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/1.jpg)
Classification of Anaemia: Microcytic Hypochromic Anaemia
![Page 2: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/2.jpg)
Classification of AnaemiaMicrocytic &
Hypochromic Normochromic & Normocytic Macrocytic
MCV<RRMCH<RR
Defects in haem
synthesis
Defects in globin
synthesis
•Iron deficiency •ACD•Sideroblastic (congenital)
•Thalassaemia•Haemoglobinopathies
MCV within RRMCH within RR
Acute blood lossHaemolysisACDMarrow infiltration
MCV>RR
Megaloblastic Non-megaloblastic
B12/Folate deficiencyLiver diseaseDrug inducedMDS
![Page 3: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/3.jpg)
Iron Regulation
![Page 4: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/4.jpg)
Normal Iron Absorption and Metabolism
![Page 5: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/5.jpg)
Ferritin• Iron storage protein• 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
![Page 6: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/6.jpg)
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
![Page 7: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/7.jpg)
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
![Page 8: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/8.jpg)
Ferroportin
• Transmembrane protein• Found on the surface of most cells:
• Enterocytes • Hepatocytes • RE system
• Regulates iron release from those tissues (iron exporter)
• ‘Hepcidin receptor’
![Page 9: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/9.jpg)
Hepcidin
• Is an antimicrobial 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
![Page 10: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/10.jpg)
![Page 11: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/11.jpg)
Causes of Iron deficiency
Major causes of IDA in Western
Society
Blood loss:•GIT•Urinary
Increased demand:• Growth
• Pregnancy
Inadequate intake• Infants
• vegetarian
Iron sequestration at inaccessible sites (pulmonary haemosiderosis)
Malabsorption
Haemolysis
Major causes of IDA in developing
countries
Parasitic infection
Malnutrition
![Page 12: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/12.jpg)
Symptoms of Iron Deficiency
• 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)
![Page 13: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/13.jpg)
Stages of Iron Deficiency
• 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
![Page 14: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/14.jpg)
• 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
![Page 15: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/15.jpg)
• 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
![Page 16: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/16.jpg)
Diagnosis - FBE
• Hb or borderline• RBC• Hct/PCV • MCV• MCH• MCHC• RDW • +/- thrombocytosis• Elongated cells• Target cells (severe IDA)
![Page 17: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/17.jpg)
![Page 18: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/18.jpg)
Diagnosis- Iron studies
Ferritin Serum Iron
Transferrin Tf Saturation
TIBC TfR
Results in IDA
![Page 19: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/19.jpg)
Differential diagnoses
• Thalassaemias/ Haemoglobinopathies– Not all hbpathies are microcytic and hypochromic
• Anaemia of chronic disease• Congenital sideroblastic anaemia
![Page 20: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/20.jpg)
![Page 21: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/21.jpg)
Treatment of Iron Deficiency
• 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
![Page 22: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/22.jpg)
Anaemia of Chronic Disease
• 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
![Page 23: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/23.jpg)
ACD- Role of Hepcidin
• 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
![Page 24: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/24.jpg)
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 supplementationTx:• Maintaining normal Hb is challenging• EPO administration + IV iron• Anti-inflammatory therapy
![Page 25: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/25.jpg)
Sideroblastic anaemia
• Can either 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
![Page 26: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/26.jpg)
STRUCTURE OF HAEMOGLOBIN
Polypeptides are made up of 2a chains and 2B chains, a2B2. Haem groups bind oxygen.
![Page 27: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/27.jpg)
STRUCTURE OF HAEM
• Haem structure: the iron (Fe)at the centre enables oxygen to bind
![Page 28: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/28.jpg)
Development of Haemoglobin
![Page 29: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/29.jpg)
Stages of Haemoglobin Development
• Embryonic haemoglobin– Hb Gower 1 z2e2
– Hb Portland a2g2
– Hb Gower 2 a2e2
• Foetal Haemoglobin– Hb F a2g2 Foetus 100% Adult <1%
• Adult haemoglobins – Hb A2 a2d2 Adult 1.8-3.6%– Hb A a2b2 Adult 96-98%– The globin genes are arranged on the chromosomes in order of
expression
![Page 30: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/30.jpg)
Inherited defects of globin synthesis
• These are due to:1. Synthesis of an abnormal haemoglobin eg
haemoglobinopathies2. Reduced rate of synthesis of α or β chains:
thalassaemia
![Page 31: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/31.jpg)
Β- Thalassaemia
• Caused by 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
![Page 32: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/32.jpg)
B-thal minor
• Results when 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
![Page 33: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/33.jpg)
B-thal major
• Characterized by severe anaemia first detected in early childhood as σ to β switch takes place
• Patient presents with jaundice, hepatosplenomegaly, marked bone changes (frontal bossing)
![Page 34: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/34.jpg)
α thalassaemia
• Due to 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)
![Page 35: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/35.jpg)
![Page 36: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/36.jpg)
Signs & Symptoms of Thalassaemia
• Severe anaemia first detected in early chilhood
• Jaundice, hepatosplenomegaly, marked bone changes (frontal bossing)
• Microcytic hypochromic anaemia
![Page 37: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/37.jpg)
Laboratory Findings
• Most thalassaemias 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)
![Page 38: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/38.jpg)
Treatment
1. Transfusion2. Iron chelation therapy- desferrioxamine3. BM transplantation4. Hydroxyurea- to increase Hb F levels enough to
eliminate transfusion requirements for patients with thalassaemia major
![Page 39: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/39.jpg)
Hb 107 120-160g/LRCC 5.50 3.80-5.401012/LMCV 61 80-100 fLMCH 19.5 27-32 pgHb A2 5.0 1.8-3.5 %Hb F <0.1 0.0-1.0 %
![Page 40: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/40.jpg)
Comparison of a normal blood film with b-thal major
Normal Blood Film Intermittently transfused b-thal
HbF>90%Bain B. ‘Blood Cells. A practical guide’2006 Free a chains form Heinz bodies and inclusions
Marked haemolysis reticulocytosisBasophilic stippling and Pappenheimer bodies
![Page 41: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/41.jpg)
HbH Disease
![Page 42: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/42.jpg)
Study Questions
• What are 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
![Page 43: Microcytichypochromicanaemia 111208111013-phpapp02 (1)](https://reader034.fdocuments.us/reader034/viewer/2022042700/556ba0e6d8b42a207e8b46c4/html5/thumbnails/43.jpg)
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?