RBC INDICES,IRON METABOLISM, ANEMIAS &POLYCYTHEMIA
LECTURE FIRST YEAR MBBS
LECTURE 03 AND 04
BONE MARROW MICRO ENVIRONMENT
• Fat cells
• Fibroblast
• Reticulum cells
• Endothelial cells
• Macrophages
• Collagen
• Fibronectin
ANAEMIAReduction In Oxygen
Carrying
Capacity Of Blood
Or
Reduction In
Haemoglobin
Level Below Lower Limit
Of Normal For That Age
And Sex
Classification of AnaemiaAccording to Cause
• Blood Loss
• Increased Destruction of RBCs
• Impaired Production of RBCs
BLOOD LOSS
Acute : Trauma
Chronic : Lesions Of
G.I.Tract
Gynecological
Losses
Increased Rate Of Destruction
Of RBCs (HEMOLYTIC ANEMIAS)
Intra Corpuscular Defects
Hereditary:
Red Cell Membrane Disorders
Spherocytosis, Elliptocytosis
Red Cell Enzyme DeficienciesPyruvate kinase deficiency
Hexo kinase deficiency
G6PD deficiency
Increased Rate Of Destruction
Of RBCs (HEMOLYTIC ANEMIAS)
Disorders Of Hemoglobin Synthesis
Deficient Globin Synthesis:
Thalassemia Syndromes
Structurally Abnormal Globin Synthesis
Haemoglobinopathies:
Sickle Cell Anemia
Unstable Haemoglobins
Increased Rate Of Destruction
Of RBCs (HEMOLYTIC ANEMIAS)
Acquired
Membrane Defect:Paroxysmal Nocturnal Hemoglobinuria
INCREASED RATE OF DESTRUCTION
OF RBCs (HEMOLYTIC ANEMIAS)
• Extra Corpuscular Defects• Antibody mediated• Infections• Malaria
Impaired Red Cell Production
Disturbance Of Proliferation And
Differentiation Of Stem Cells:
Aplastic Anemia
Anemia Of Renal Failure
Disturbance Of Proliferation And Maturation
Of Erythroblasts
Defective DNA Synthesis :Deficiency Or Impaired Utilization Of Vit B12 And Folic Acid
(Megaloblastic Anemias)
Defective Hemoglobin Synthesis:
Deficient Heme Synthesis e.g. Iron Deficiency
Deficient Globin Synthesis e.g. Thalassemias
Disturbance Of Proliferation And Maturation Of
Erythroblasts
Unknown Or Multiple Mechanisms:
Sideroblastic Anemia
Anemia Of Chronic Infections
Myelophthisic Anemias Due To Marrow
Infiltration
ABSOLUTE VALUES
Red Cell Indices
MCV: Mean Corpuscular Volume
MCH: Mean Corpuscular Haemoglobin
MCHC: Mean Corpuscular Haemoglobin
Concentration
Based On Following Parameters
Red Cell Count
Haemoglobin Level
Packed Cell Volume
MCV= PCV
RED CELL COUNT = 90 fl
MCH= HB
RED CELL COUNT = 30 pg
MCHC= HB
PCV = 333 g/l
Morphological Classification(Based On RBC Morphology & Absolute Values)
Hypochromic Microytic
(MCV<76 fl, MCH< 27 pg)
• Iron Deficiency Anemia
• Thalassemia
• Anaemia Of Chronic Disorders
• Siderobastic Anemia
• Lead Poisoning
Morphological Classification(Based On RBC Morphology & Absolute Values)
Normochromic Normocytic
(MCV & MCH Within Normal Range)
• Acute Blood Loss
• Mixed Deficiences
• Haemolytic Anaemias
• Bone Marrow Failure e.g. Post Chemotherapy
• Bone Marrow Infiltration e.g. Carcinoma
• Renal Disease
Morphological Classification(Based On Rbc Morphology & Absolute Values)
Macrocytic
MCV > 96fl
• Megaloblastic Marrow
• Vitamin B12 Deficiency
• Folate Deficiency
IRON METABOLISM
Iron Metabolism
Body Iron Distribution
Total Iron 2-5g
Haemoglobin Contains 2/3 (1.7 -- 2.4g)
Storage Iron 1/3 (0.5 - 1.5g)
Myoglobin 200 - 300mg
Enzymes Traces
Iron Metabolism
Dietary Iron
10 - 15mg In Western Diet
5 To 10% Is Absorbed
Food
Meat, Liver
Vegetable, Fruits, Eggs,
Dairy Products
Iron Metabolism
Storage Iron
Ferritin Water Soluble
Haemosiderin Insoluble
Iron Absorption
DUODENUM
MUCOSAL CELL(APOFERRITIN)
TRANSFERRIN
STORES TISSUES
Dietary
iron
ABSORPTION OF IRON
TRANSPORT AND STORAGE
IRON ABSORPTION
• Iron is absorbed mainly from the small intestine.
• It is absorbed through the intestinal cells (enterocytes)by pinocytosis and transported into the blood.
• Bile is essential for the absorption of iron.
• Iron is present mostly in ferric (Fe3+) form. It isconverted into ferrous form (Fe2+) which is absorbed intothe blood.
• Hydrochloric acid from gastric juice makesthe ferrous iron soluble so that it could be convertedinto ferric iron by the enzyme ferric reductase fromenterocytes.
• From enterocytes, ferric iron is transported into blood by a protein called ferroportin.
• In the blood, ferric iron is converted into ferrous iron and transported
Iron Absorption
FactorsSite : Duodenum
Form : Haem > Non Haem
Factors:
Favouring Absorption Reducing Absorption
Ferrous Form Ferric Form
Acids – HCL,VITC. Alkali – Antacid
Iron Deficiency Iron Excess
Increased Decreased
Erythropoiesis Erythropoiesis
Pregnancy Desferrioxamine
Tea, Phytate
IRON TRANSPORT
• Immediately after absorption into blood, iron combines with a β-globulin called apotransferrin secreted by liverthrough bile resulting in the formation of transferrin.
• And iron is transported in blood in the form of transferrin.Iron combines loosely with globin and can be released easily at any region of the body.„
Iron Transport
Beta Globulin
Transferrin (Liver)
I Molecule Binds 02 Atoms Of Iron
1/3 Is Saturated
Receptor Mediated
STORAGE OF IRON
• Iron is stored in large quantities in reticuloendothelial cells and liver hepatocytes.
• In other cells also it is stored in small quantities.
• In the cytoplasm of the cell, iron isstored as ferritin in large amount. Small quantity of iron is also stored as hemosiderin
REGULATION OF TOTAL IRON IN THE BODY
• Absorption and excretion of iron are maintained almost equally under normal physiological conditions.
• When the iron storage is saturated in the body, it automatically reduces the further absorption of iron from the gastrointestinal tract by feedback mechanism.
REGULATION OF TOTAL IRON IN THE BODY
• Factors which reduce the absorption of iron:1. Stoppage of apotransferrin formation in the liver, so that the iron cannot be absorbed from the intestine.2. Reduction in the release of iron from the transferrin, so that transferrin is completely saturated with iron and further absorption is prevented
CAUSES OF IRON DEFICIENCY
Chronic Blood Loss:Uterine
GI Loss
Urinary
Rarely Other Sites
Increased Demands:Growing Age
Prematurity
Pregnancy
Lactation
Malabsorption:Gastrectomy
Coeliac Disease
Poor Diet:Under Developed Countries
Old Age
D/D OF HYPOCHROMIC MICROCYTIC
ANAEMIA
1. Iron Deficiency Anaemia
2. Anaemia Of Chronic Disorder
3. Thalasemia (Alpha Or Beta) Trait
4. Sideroblastic Anaemia
DIAGNOSIS OF IRON DEFICIENCY
Detailed History & Physical Examination
Blood Picture
Red Cell Indices
Biochemical Tests
Bone Marrow Iron
Hb Electrophoresis
LABORATORY FINDINGS
HAEMOGLOBIN:
RED CELL INDICES:
MCV MCH MCHC
RED CELL MORPHOLOGY:
Hypochromic Microcytic
BONE MARROW ASPIRATION:
Erythroid Hyperplasia
Iron Absent
LABORATORY FINDINGS
• RDW (Red Cell Distribution Width)
• Degree of variation in size of RBC
Low MCV Iron deficiency
High RDW
Low MCV β Thalassemia minor
Normal RDW
LABORATORY FINDINGS
SERUM FERRITIN: <15ug/l
SERUM IRON
TOTAL IRON BINDING CAPACITY
SATURATION OF TRANSFERRIN
Free erythrocyte protoporphyrin
Soluble transferrin receptor
INVESTIGATION OF CAUSE OF IRON
DEFICENCY
Careful History Taking
Stool For Occult Blood/ Ova Of Hook Worm
GI Endoscopy
MEGALOBLASTIC
ANAEMIA
Vitamin B12 (Cyanocobalamin)
• Vitamin B12, intrinsic factor and folic acid are necessary for the maturation of RBCs.
• Vitamin B12 is the maturation factor necessary for erythropoiesis.SourceVitamin B12 is called extrinsic factor since it is obtained mostly from diet. Its absorption from intestine requires the presence of intrinsic factor of Castle.
Vitamin B12
• Vitamin B12 is stored mostly in liver and in small quantity in muscle.
• When necessary, it is transported to the bone marrow to promote maturation of RBCs.
• It is also produced in thelarge intestine by the intestinal flora.
Vitamin B12
• Essential for synthesis of DNA in RBCs.
• Its defciency leads to failure in maturation of the cell and reduction in the cell division.
• Cells are larger with fragile and weak cell membrane resulting in macrocytic anemia.
• Defciency of vitamin B12 causes pernicious anemia. So, vitamin B12 is called antipernicious factor
Intrinsic Factor of Castle
• Intrinsic factor of castle is produced in gastric mucosa by the parietal cells of the gastric glands. It is essentialfor the absorption of vitamin B12 from intestine.
• In the absence of intrinsic factor, vitamin B12 is not absorbed from intestine.
Defciency of intrinsic factor
• This leads to pernicious anemia.
• DEFICIENCY occurs in:i. Severe gastritisii. Ulceriii. Gastrectomy.
VITAMIN B12 FOLATE NUTRITIONAL
ASPECTS
VIT B12 FOLATE
NORMAL DAILY
DIETARY INTAKE
7 – 30ug 200 – 250 ug
MAIN FOODS ANIMAL PRODUCE
ONLY
MOST FOODS, LIVER
GREENS & YEAST
COOKING LITTLE EFECT EASILY DESTROYED
MINIMAL ADULT
DAILY REQUIREMENT
1 – 2 ug 150 ug
BODY STORES 2 – 3 mg
(SUFFICIENT FOR 2
– 4 Yrs)
10 – 12 mg(SUFFICIENT
FOR 4 MONTHS)
ABSORPTIO SITE ILIEUM DUODENUM &
JEJUNUM
MECHANISM INTRINSIC FACTOR CONVERSION TO
MONO GLUTAMATE
FORM
LIMIT 2 – 3 ug DAILY 50 – 80 % OF DIETARY
CONTENT
ENTERO HEPATIC 5 – 10 ug DAILY 90 ug DAY
TRANSPORT IN
PLASMA
MOST BOUND TO TC,
I, TC II ESSENTIAL
FOR CELL UPTAKE
WEAKLY BOUND TO
ALBUMIN
MAJOR
INTRACELLULAR
FORMS
METHYL & DEOXY –
ADENOSYL
COBALAMIN
REDUCED
POLYGLUTAMATE
DERIVATIVES
USUAL THERAPEUTIC
FORM
HYDROXYCOBALAM
IN
FOLIC ACID
CLINICAL FEATURES
1. Insidious Onset/Asymptomatic Initially
2. Progressive Signs & Symptoms Of Anaemia
3. Mild Jaundice
4. Glossitis and Angular Stomatitis
5. Loose Motions/Nausea/Weight Loss
6. Purpura (Rarely)
7. Skin Pigmentation (Rarely)
8. CNS Symptoms
Peripheral Neuropathy. Tingling, Numbness,
Subacute Combined Degeneration Of Cord Due To Demyelination Of Dorsal And Dorsolateral Columns
9. Sterility
DEFINITE EFFECTS OF VIT B12 OR
FOLATE DEFICIENCY
Megaloblastic Anaemia
Macrocytosis Of Epithelial Cells
Neuropathy ( B12 Only)
Neural Tube Defects (Folate)
Sterility
LABORATORY FINDINGS
1. Blood Counts Pancytopenia
2. RBCs Morphology Macrocytosis
MCV > 96 Fl
Oval Macrocytosis,aniso Poikilocytosis
3. WBC Morphology Hypersegmented Neutrophils . (Six Or More Lobes)
4.
Bone Marrow Hypercellular Megaloblastic Erythropoesis.
Giant Metamyelocytes
5. Increased Unconjugated Bilirubin
6. Increased Serum LDH
DIAGNOSIS OF B12 OR FOLATE
DEFICIENCY
1. Estimation Of B12 And Folate Level
2. Therapeutic Trial.
1ug B12 100ug Folic Acid
Response - Increased Retics (in disease rectics
decrease)
Increased Haemoglobin
PERNICIOUS ANAEMIA
Autoimmune Origin
If Deficiency Due To Atrophic Gastritis
Affects Females More Often – Old Age, Familial
Association With Other Autoimmune Diseases
e.g Vitiligo, Myxedema, Thyrotoxicosis,
Increased Incidence Of Gastric Carcinoma.
Congenital Lack Of Intrinsic factor
DIAGNOSIS – ANTIBODIES IN SERUM
Pernicious anemia
• Pernicious anemia is the anemia due to deficiency of vitamin B12.
• It is also called Addison’s anemia. It is dueto atrophy of the gastric mucosa because of autoimmune destruction of parietal cells.
• The gastric atrophy results in decreased production of intrinsic factor and poorabsorption of vitamin B12, which is the maturation factor for RBC.
• RBCs are larger and immature with almostnormal or slightly low hemoglobin level. Synthesis of hemoglobin is almost normal in this type of anemia. So, cells are macrocytic and normochromic/hypochromic.
HAEMOLYTIC
ANAEMIA
CLASSIFICATION OF HAEMOLYTIC ANAEMIA
• HEREDITARY • MEMBRANE
– Hereditary spherocytosis– Hereditary elliptocytosis
• METABOLISM– G6PD deficiency– Pyruvate kinase deficiency
• HAEMOGLOBIN– Abnormal (Hb S, Hb C, Unstable Hb)– Deficient (Thalassemia)
CLASSIFICATION CONTINUED
• ACQUIRED
– IMMUNE
• AUTO IMMUNE
• ALLO IMMUNE
• Drug associated
• Sepsis
• DIC
CLINICAL FEATURES
Pallor – Anaemia
Jaundice – Fluctuating
Splenomegaly
Hepatomegaly
Gall Stones – Pigment
Color Of Urine – I/V Haemolysis
LABORATORY FINDINGS
DIVIDED INTO THREE GROUPS
1. FEATURES OF INCREASED RED CELLS
BREAKDOWN
a. serum bilirubin raised, unconjugated and bound to albumin
b. urine urobilinogen increased
c. Faecal Stercobilinogen Increased
LABORATORY INVESTIGATIONS
• Features Of Increased Red Cell Production
– Reticulocytosis
– Bone Marrow Erythroid Hyperplasia
LABORATORY FINDINGS
• Evidence Of Damaged Red Cells
– Morphology
– Osmotic Fragility
CAUSES OF INTRAVASCULAR
HAEMOLYSIS
1. Mismatched Blood Transfusion (Usually ABO)
2. G6PD Deficiency With Oxidant Stress
3. Some Autoimmune Haemolytic Anemias
4. Some Drug And Infection – Induced Haemolytic Anemias
CONSEQUENCES OF
INTRAVASCULAR HEMOLYSIS
Intravascular Haemolysis
Free Haemoglobin In Plasma
Bound To Haptoglobin
Removed By Liver (macrophages)
Decreased Haptoglobin
CONTINUED
Free Haemoglobin In Plasma
Filtered By Glomeruli
Reabsorbed By Renal Tubules
Renal Tubules Saturated
Free Haemoglobin In Urine
CONTINUED
Haemoglobin Breakdown In Tubular
Epithelium
Iron Converted To Haemosiderin
Shed With Cells In Urine
LABORATORY FEATURES
• Haemoglobinemia
• Haemoglobinuria
• Haemosidrinuria
• Methaemalbuminaemia
G6PD DEFICIENCY
DEFICIENCY OR FUNCTIONAL INADEQUACY LEADS
TO IMPAIRED REDUCTION OF GLUTATHIONE
OXIDANT STRESS
(DRUGS, INFECTIONS)
SEX LINKED MALES AFFECTTED
FEMALES ARE CARRIERS
G6PD DEFICIENCY
CLINICAL FEATURES
1. Acute Haemolytic Anaemia
2. Chronic Haemolytic Anaemia
3. Neonatal Jaundice
DIAGNOSIS:
Blood Film – Bite Cells
Reticulocyte, Heinz Bodies
Screening Tests
Enzyme Assays, On Red Cells
SICKLE CELL ANAEMIA
Hbs Crystalises At Low O2
Substitution Of Valine For Glutamic Acid In Position 6
Homozygous – Disease
Variable Clincal Expression
Severe Haemolytic Anaemia
Painful Vascular – Occlusive Crisis
Precipated By Infection , Acidosis
Deoxygenation ( Allitude, Operation – GA)
Heterozygous – Trait
No Anaemia , Normal RBC Morphology
Crisis May Be Caused By Anoxia/ Infection
HEREDITARY SPHEROCYTOSIS
Defect Or Deficiency Of Spectrin
(Memb Structural Protein) In RBC Membrane
Autosomal Dominant Usually
Anaemia
Jaundice - Pigment Gall Stones
Splenomegaly
Aplastic Crisis
HEREDITARY
SPHEROCYTOSIS• Pathogenesis
– Defective gene
– Abnormal or decreased spectrin
– RBC Membrane defect• Spherocytosis
• Increased osmotic fragility
• Increased glucose requirement
• Decreased deformity of RBCs
• Diagnosis– History and clinical examination
– Blood film examination
– Osmotic fragility test
Thalassaemia
Structure Of Haemoglobin
Sites Of Gobin Chain Synthesis
Types Of Haemoglobin In Adults
Hb A: Alpha2 Beta2 97%
Hb A2: Alpha2 Delta2 2-3%
Hb F: Alpha2 Gama2 < 1%
Disorders of Haemoglobin
Qualitative Haemoglobinopathies
Quantitative – Thalassaemias
Thalassaemias - Classification
On Genetic basis
• α –Thalassaemia
• β –Thalassaemia
–β 0 - Thalassaemia
–β+ Thalassaemia
Clinical Classification
Thal Minor –trait, asymptomatic
Thal Major –transfusion dependent
Thal Intermedia – transfusion not required
Hydrops Fetalis –death in utero,
α –Thalassaemia
Clinical Features
Anaemia
Hepato Splenomegaly
Skeletal Changes
Iron Overload
Growth Retardation
Lab Diagnosis
Blood CP
Hb Electrophoresis
Alpha/Beta Chain Analysis
DNA Analysis
Prenatal Diagnosis
Prevention
Blood Picture
1. Blood Counts
Haemoglobin Moderate to severe Anaemia
TLC Normal or Raised
Platelets Normal or Low
2. RBCs Morphology
Hypochoromic Microcytic
Anisopoikilocytosis
Nucleated RBCs
2. Reticulocyte Count Raised
Haemoglobin Electrophoresis
Thalassemia Trait
Increased Hemoglobin A2
Thalassemia Major
Increased Haemoglobin Hb F
APLASTIC ANAEMIA
PANCYTOPENIA
• Reduction in blood counts of all major cell lines.
- Red cells
- White cells
- Platelets
CAUSES PANCYTOPENIA- Decreased Marrow Function
- Aplasia
- Acute leukaemia, Myelodysplasia
- Infiltration with lymphoma, solid
tumours, tuberculosis
- Megaloblastic anaemia
- Paroxysmal nocturnal hemoglobinuria
- Myelofibrosis. (rare)
- Haemophagocytic syndrome
- Increased peripheral destruction
splenomegaly
APLASTIC ANAEMIA
• Aplastic (hypoplastic) anemia is defined as pancytopenia resulting from aplasia of bone marrow
CAUSES OF APLASTIC ANAEMIA
- Primary
- Congental Fanconi’s Anaemia
- Acquired Idiopathic
- Secondary
- Ionizing Radiations
- Chemicals
- Drugs
- Infections
PATHOGENESIS• Reduction in number of haemopoetic stem cells
in bone marrow.
- Defective stem cells
- Defective haemopoetic
microenvironment
- Deficiency of factors stimulating
haemopoetic
• Immunologicl Mechanisms
Causing inhibition of haemopoesis.
CLINICAL FEATURES
• Onset at any age – young adults usually
• Acute or insidious
• Signs and symptoms of anemia
• Fever – Neutropenia
• Bleeding – thrombocytopenia
• NO ORGANOMEGALY
LABORATORY FINDINGS
• Blood CP
- Haemoglobin – decreased
- TLC. Low – neutropenia
- Platelet count. low
• Reticulocyte Count
- Very low
LABORATORY FINDINGS
• Bone Marrow
- Hypoplasia. Loss of haemopoetic tissue and replacement by fat
• Bone marrow trephine
- Essential
- Hypoplastic
PURE RED CELL APLASIA
• Chronic Form
- Rare condition characterized by anemia with normal leucocytes and platelets and grossly reduced or absent erythroblasts in bone marrow
• Congenital Form
- Diamond Blackfan Syndrome
• Acute Form
- Parvo virus B19 infection
POLYCYTHEMIA
• Increase in circulating red blood cells above normal.
• May be associated with a real increase or only apparent because of decrease in plasma volume.
SECONDORY POLYCYTHEMIA
• Most common
• Also called physiological as in high altitude
• Due to Tissue hypoxia (cardiac and pulmonary diseases)
POLYCYTHEMIA VERA
• Polycythemia vera is caused by a genetic aberration in the hemocytoblastic cells that produce the blood cells.
• Negative feed back for regulation of RBC production is lost
EFFECT OF POLYCYTHEMIA ON CIRCULATORY SYSTEM
• Greatly increased viscosity of the blood
• decreases the rate of venous return to the heart
BUT
• blood volume is greatly increased in polycythemia,which tends to increase venous return
THANK YOU
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