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IRON METABOLISM & MICROCYTIC HYPOCHROMIC ANAEMIAS.pptx

Abigail was diagnosed with iron deficiency anaemia (IDA) at KNUST Hospital. On her follow up visit after 3 months of iron fersolate treatment, her iron profile results are expected to show: 1. Increased serum iron and transferrin saturation levels as the treatment replenishes her iron stores. 2. Normal serum ferritin levels as the treatment addresses the iron deficiency. 3. Potentially normal or increased sTFR-1 levels depending on whether her increased iron levels meet erythropoietic demand, since sTFR-1 reflects iron availability for red blood cell production. The treatment is expected to correct the iron deficiency underlying Abigail's IDA

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MICROCYTIC HYPOCHROMIC ANAEMIAS Iron deficiency anaemia Anaemia of chronic diseases Thalassaemias Dr. Benedict Sackey Dept. of Med. Diagnostics KNUST
Outline • Iron metabolism – Dietary sources & daily requirement of iron – Absorption of iron – Assessment of body iron stores – Excretion of iron – Iron overload, causes and effect. • Anaemia – Causes, signs and symptoms of anaemia – Adaptive response to anaemia • Microcytic hypochromic anaemia – Development of Iron Deficiency Anaemia (IDA) – Development of anaemia of chronic diseases – Thalassaemia • Lab Diagnosis of Microcytic Hypochromic Anaemia • Treatment of IDA
Introduction Iron is the most abundant trace element in the body. It’s a necessary element for organisms due to the role it plays in vital processes such as:  Transport and storage of oxygen eg: Hb, myoglobin  cofactor in numerous enzymatic reactions in the tissues responsible for oxidation eg: cytochromes, catalases, flavoproteins etc.  Electron transport chain  Hb contains the largest compartment of iron in the body and hemosiderin and ferritin are the two major iron storage forms in the body (BM, liver, spleen, kidney). Minor storage include myoglobin, enzymes involved in oxidation processes in tissues & transferrin.
Intro - conti • The body`s iron is recycled over and over again for use in the erythropoietic cycle. • Thus, quantity of body iron is carefully controlled because both deficiency and excess is detrimental to the body.
Clinical relevance of iron • Deficiency of iron is associated with signs & symptoms : fatigue, dizziness, headache, irritability, palpitations, pallor, glossitis, spoon shaped nails (koilonychia), hair loss, dysphagia (plummer-vinson syndrome) blue sclerae, pica (apetite for non-food substances such as an ice, clay, starch). • Excess free iron can be very toxic cells and organs. • Free iron participates in Fenton’s reaction which results in free radicals capable of oxidizing lipids, cleaving proteins and denaturing DNA and RNA. • Organisms have evolved to maintain proper iron homeostasis
Distribution of body`s iron • The avg total iron conc. in the body is 2-4g. ~2/3 of the body`s iron is contained in RBC making ~ 2g of iron. • Remaining 1/3 is sequestrated predominantly in ferritin. • An avg of 20-30 mg of iron is required per day for erythropoiesis. 20-25 mg of this is obtained from recycling of destroyed RBCs and ~2mg is absorbed from the diet per day • 1ml whole blood contains 0.5mg of iron. Thus, 2800mg of iron in the peripheral blood • Storage iron (500mg in women, 1000mg in men) • 500mg in iron containing proteins
Body`s Iron Requirement • Total daily iron requirement is approx. • 1mg/day for men/infant & postmenopausal women, • 2mg/day for menstruating female • 3-4mg/day for pregnant female • A normal individual absorbs 5-10% of ingested iron. This can increase to 20% or more if body`s iron store is low. • Heme iron in food such as meat is better absorbed than inorganic iron salts such as ferrous sulphate, gluconate, fumarate or succinate. • Iron is absorbed over the length of the small intestine but more efficiently at the duodenum.
Iron transport through the enterocytes • Fe2+ from inorganic sources and that released from heme by heme oxygenase-1 are transported within the enterocytes by Ferroportin-1. • The amount of iron transported to transferrin (Tf) is controlled by hepcidin, a protein synthesized by the liver which mediates proteolytic degradation of ferroportin-1 • Iron only combines with transferrin at its Fe3+ state, thus, caeruloplasmin oxidizes Fe2+ to Fe3+ • Transferrin, then transport iron to needed sites such as red cells, brain endothelia cells, hepatocytes etc which express transferrin receptors (TfR). DMT1 – divalent metal transporter- 1 Fe2+ - ferrous iron Fe3+ - ferric iron
Iron uptake by cells • Iron uptake from transferrin requires transferrin receptor. Tf is coded for by a gene (TFRC) on chromosome 3. • Two types of TfR, TfR1 and TfR2 are expressed in human. TfR1 and TfR2 share 66% resemblance in their ectodomain. • TfR1 is expressed in many tissues whereas TfR2 expression is only limited to hepatocytes and erythropoietic progenitors. • TfR2 has 25-fold less binding affinity for Tf and acts as a sensor of serum iron level whereas TfR1 regulates cellular iron uptake. • Transferrin has a very high affinity for iron at neutral pH. Transferrin binds to the receptor, and the complex is then internalized and iron is released when the pH of the internal vesicles is reduced to about 5.5 • After iron release, apotransferrin returns to the circulation and can undertake further cycles of iron uptake and delivery. • The number of transferrin receptors on a cell reflects the iron requirement of the cell. NRBC in the marrow thus express the highest numbers of TfR. • Transferrin receptors are proteolytically cleaved at the cell membrane and circulates bound to transferrin as sTfR. • sTfR level increases in IDA and increased rate of erythropoiesis thus measurements of circulating sTfR are used as an indicator of iron deficiency • sTfR conc are similar in healthy males and females, unlike serum ferritin (sFn) conc.
• Cells that express TfRs such as liver, intestine and some immune cells also have homeostatic iron regulator gene (HFE) which produces HFE protein. • HFE protein interact with other proteins such as TfR1 and TfR2 on cell surface to determine amount of iron in the body. • Thus HFE protein competes with Tf for binding sites on TfR1 due to overlapping binding sites Hepcidin regulation • Hepcidin is a primary regulator of total body iron homeostasis and disease-causing TfR2 mutations cause Hereditary Hemochromatosis through a reduction in hepcidin production • The transcription of hepcidin is regulated by iron, bone morphogenetic proteins (BMPs), inflammation, hypoxia, and erythropoietic activity
FACTORS INFLUENCING IRON ABSORPTION Increased absorption • Alcohol • Anaemia • Ascorbic acid eg. fruits • Depletion of iron stores • HCL • Liver disease • Increased erythropoiesis • Hypoxia • High altitude Decreased absorption • Antacids eg: Magnesium tri-silicate • Certain clays • Mal-absorption syndrome • Phytates. eg; cereals & legumes • Fibers eg; cereals & legumes • Heavy metals (Ca, Zn, Mg, Pb) • Tetracycline • Polyphenolics in plant foods • Tannins in teas & coffees • Low altitude Vitamin-C counteract absorption inhibitory effect thus vegetarians must consume plants Foods rich in vitamin-C and iron such as legumes, whole grain cereals, brown rice, Nuts, seeds, fruits.
Hemoglobin synthesis in RBC • Iron is incorporated into protoporphyrin- IX to form heme in the mitochondria by ferrochelatase. • Heme released from mitochondria combines with globin synthesized in cytosol by ribosomes to form haemoglobin. • The level of intracellular free heme regulates normoblasts uptake of iron. • Impairment of heme synthesis results in excess iron accumulate in the mitochondria of the normoblast forming ringed sideroblast demonstrable in sideroblastic anaemia with Prussian blue stain.
Demonstration of ringed sideroblast Deposition of iron granules demonstrable with Prussian blue stain
Distribution of iron in the body A. Metabolically Active Iron • Haemoglobin • “Serum” iron bound to the transport protein transferrin in blood. • Tissue Iron: found in cytochromes and enzymes • Myoglobin: iron involved in oxygen reserve in muscles B. Storage Iron: • Ferritin: found in blood, tissue fluids, and cells (hepatocytes) • Hemosiderin: found in macrophages and BM
Measurement of Body Iron status This can be determined by estimating: • Serum Iron level (Transferrin bound iron). • Total iron binding capacity (TIBC): measurement of transferrin (total # of binding sites for iron atoms on transferrin). • % transferrin saturation: (Serum iron/TIBC x100). This measures % of true binding sites on all transferrin molecule that are occupied by iron. • Serum ferritin : Levels correlate with body iron stores. • Hemosiderin: assesses iron stores in bone marrow. • Hepcidin levels • sTFR-1 levels
Abigail reported at KNUST Hospital and was diagnosed with IDA. Based on Abigail’s review FBC results performed 3months. After starting iron fersolate hematinic treatment predict her iron profile result on the review date using Low, normal or increased to depict your expectation. Justify your answers.
EXCRETION OF IRON • Small loss of iron each day in urine, faeces. • Skin and nails • Exfoliated GIT epithelial cells • Menstruating females • Bile – This however account for only about 1-2 mg daily. • Certain medications eg. Desferrioxamine • Blood donation - to reduce excessively high level of iron.
IRON OVERLOAD
Overview Iron overload is accumulation of excess amount of total body iron. The most notable organs with iron deposition include liver, heart and the endocrine glands. Primarily, iron overload is often inherited. Secondary iron overload could be cased by chronic transfusion, hemolysis, excessive parenteral/dietary consumption of iron. Two causes of pathologic iron overload –hemochromatosis and hemosiderosis are known. • Hereditary Hemochromatosis (HH) Genetic mutations that lead to reduced hepcidin expression leads to iron overload. • 4 types of HH are reported and 3 are as a result of low levels of hepcidin expression. – Type I, (HFE mutation) - a single amino acid HFE mutation and prevalent throughout Europe – Type II a and b [hemojuvelin (HJV) and hepcidin mutations respectively] – most severe – Type III (TfR2 mutation) -TfR2 HH is far rarer and is the result of various mutations – Type IV is mutations in Ferropoietin • Untreated, HH leads to iron accumulation in the liver, heart, pancreas, and joints leading to cirrhosis, arrhythmias, diabetes, and arthritis. •
• Mutation in HFE gene (C282Y) and H63D resulting in excessive absorption of iron • Excess accumulation of Fe can progress to involve widespread deposition of iron in parenchymal tissue with resulting organ injury. • Iron deposits in hepatocytes, cardiac cells, endocrine cells, and other parenchymal cells can interfere with the their normal function and may lead to death. • HFE gene is located on the short arm of chrom. 6 Diagnosis of HH • Diagnosed with blood test, genetic test, MRI and liver biopsy • Serum ferritin >300 ng/mL in men and 200 ng/mL in women • Transferrin saturation > 45% suggest HH • Transferrin saturation > 62% predicts homozygous HH in 92% cases • Transferrin saturation < 20% indicate iron deficiency
Causes Of Iron Overload • Multiple transfusions • Liver disease • Prolonged use of medicinal iron • Ineffective erythropoiesis
Hemosiderosis This is an iron overload disorder resulting in accumulation of hemosiderin in the tissues. Hemosiderosis is unassociated with tissue damage bcos vast majority of iron is contained in macrophages.
Effects Of Iron Overload Non-transferrin-bound iron (NTBI) circulates in the plasma Excess iron promotes the generation of free hydroxyl radicals, propagators of oxygen- related tissue damage Liver cirrhosis/ fibrosis/cancer Insoluble iron complexes are deposited in body tissues and end-organ toxicity occurs Diabetes mellitus Growth failure Capacity of serum transferrin to bind iron is exceeded Iron overload Cardiac failure Infertility HSC senescence (Fenton Reaction) O2- + H2O2 O2 + OH- + HO
When Is Iron Conc. a Problem? • Normal total body iron is 2.5 – 4.0g. • Tissue damage occurs when total body iron is 7 – 15 g. • The liver iron closely reflects total body iron (total body iron stores in mg per kg of body weight = 10.6 x hepatic iron conc in mg per gram of liver, dry weight A SECTION OF THE LIVER SHOWING CIRRHOSIS
Management of iron overload • The goal of iron chelation therapy is to decrease tissue iron to concentrations where iron-mediated toxicity cannot occur. • This is achieved by chelating iron and detoxifying iron using appropriate chelators • The metabolism and pharmacokinetics of iron chelators are critical determinant to their therapeutic success. • Only a small fraction of body iron is available for chelation at any given time, as the majority of storage iron is not effectively chelated at clinically achievable chelator concentrations. • Achievement of safe tissue iron levels therefore takes many months or years with current chelation regimens. • Various tissues in the body have different safe iron levels. Cardiac toxicity is the most common cause of death in transfusional iron overload but the level of iron in the heart is a little fraction of that in the liver, despite prognosis of cardiac toxicity inferred from association of iron level/dry weight of liver tissue.
Major target of iron chelators Intracellular labile iron pool • This is the iron derived mainly from lysosomal catabolism of ferritin and also from iron uptake of transferrin or non-transferrin bound iron into cells. Since the liver is a key organ for iron storage as ferritin, the liver is therefore a key target for chelation therapy. Iron from RBC catabolism in macrophages • In a healthy individual, 20 mg of iron is released by macrophages in liver, spleen, and marrow every day. Transit iron released from macrophages is the major source of urinary iron achieved with DFO therapy Iron chelators can be harmful • The toxicity of iron chelators may result: either from the 1. excessive chelation of iron or other metals eg; zinc needed for essential metabolic functions 2. toxicity of unstable iron-chelate complexes 3. Iron chelators are cytotoxic to dividing cells at concentrations of 1-10 µM depending on the cell type involved and the duration of exposure to chelators
• Deferoxamine • Deferiprone • most clinical manifestations of iron loading do not appear until the second decade of life but liver biopsies in young patients reveal that the deleterious effects of iron starts much earlier.
ANAEMIA • Anaemia is a condition where Hb conc is below the reference value for the age and sex of the individual. • Anaemia generally occurs when RBC loss or destruction exceeds it production. • Being common clinical & laboratory finding, anaemia is not in itself a clinical diagnosis but rather, a manifestation of a disease. • Hb is the primary molecule for gaseous transport in the body, thus anaemia, results in inadequate supply of oxygen to the tissues, a condition called hypoxia.
SIGNS & SYMPTOMS OF ANAEMIA • Pallor • Fatigue • Rapid pulse • Shortness of breath • Irritability, (difficulty in concentrating) • Headache • Dizziness • Bleeding • Nausea and decreased appetite • Menstrual irregularities • Loss of libido or potency • Heart murmurs • Angenia pectoris (chest pain with exertion) • Heart failure • Coma • Sore tongues • Brittle nails
Clinical features • Mild - Mild dyspnea (difficult respiration) on exertion, palpitation. • Moderate - Mild dyspnea on exertion, palpitation and excessive fatigue. • Severe - Dyspnea at rest, tachycardia with pounding pulse, weakness, dizziness, syncope (spontaneous loss of consciousness), headache, insomnia (inability to sleep).
Causes of Anaemia General mechanism • Increased blood loss – acute or chronic eg. GIT ulcerations, piles, coagulopathies, haemorrhage etc. • Decreased Hbproduction. Eg; thalasaemias. • Increased destruction of RBC resulting in decreased RBC life-span – Acquired -malaria,effectofcertainmedications – Congenital-SCD,hereditary spherocytosis, G6PDdeficiency. • Impairment of RBC formation (insufficientandineffective erythropoiesis) -leukaemia,aplastic/hypoplastic,parvo-virus, marrowsuppressivedrugs.
ADAPTIVE RESPONSE TO ANAEMIA • If tissue oxygenation is inadequate due to anaemia, compensatory mechanisms come into play to ensure survival. These include:  Increased pulse rate, stroke volume, cardiac output.  Increased erythropoietin production  Decreased affinity of Hb for oxygen (↑2,3 DPG)  Diversion of blood to more vital organs eg: brain.
MICROCYTIC HYPOCHROMIC ANAEMIAS • These are group of anaemic conditions where the RBCs are smaller in sizes (microcytic) and contain lesser Hb content (hypochromia) than normal. • Main causes of this anaemia are; o Defective heme - either iron or porphyrin deficiency o Decreased globin production eg. Thalassaemias. Types of microcytic hypochromic anaemias o Iron deficiency anaemia o Anaemia of chronic diseases o Thalassaemias
IRON DEFICIENCY ANAEMIA • This is the condition where depleted level of iron in the body leads to synthesis of fewer RBC which do not contain adequate amount of Hb. • Etiology: • Chronic Bleeding • Menorrhagia (prolonged menstruation) • Peptic Ulcer • Stomach Cancer • Ulcerative Colitis • Intestinal Cancer • Haemorrhoids • Decreased Iron Intake • Increased Iron Requirment (Juvenile Age, Pregnancy, Lactation).
Stages Of Iron Deficiency Anaemia • Pre-latent – reduction in iron stores without reduced serum iron levels • Hb (N), MCV (N), transferrin saturation (N), iron absorption (), serum ferritin (), marrow iron () • Latent – iron stores are exhausted, but the blood haemoglobin level remains normal • Hb (N), MCV (N), TIBC (), serum ferritin (), transferrin saturation (), marrow iron (absent) • Iron deficiency anaemia – blood Hb conc, falls below the lower limit of normal • Hb (), MCV (), TIBC (), serum ferritin (), transferrin saturation (), marrow iron (absent)
Lab. Diagnosis Of Iron Deficiency Anaemia Complete blood count (CBC) and serum iron profile Evaluation of blood smear with RBC indices Retics count. • Low Hb /PCV - indicates anaemia. • Low MCV - abnormally smaller sizes RBCs (microcytic) • Low MCH & MCHC - reflecting decreased content of RBC haemoglobinization (hypochromia). • An increased red cell distribution width (RDW) - reflecting an increased variability in the sizes of RBC (anisocytosis). In evaluation of anaemia, MCV should always be interpreted with the RDW.
CBC of IDA patient Showing marked RBC Microcytosis with hypochromia
IDA after treatment Dimorphic RBC pop. Of microcytic hypochromic & normocytic normochromic
Diagnosis of IDA- Peripheral Blood Smear • Examination of blood smear reveals, RBC microcytosis with hypochromia, target cells, elliptical & tear drop shaped (poikilocytosis - meaning variation in shapes). • Reduced/ absence of polychromatic cells and retic count/RPI shows very low (< 1.0%) or absence of retics. • The more severe the anaemia, the greater the abnormalities of RBCs. • Platelet may be normal, decreased or increased. • In severe IDA, the peripheral blood smear may show mild thrombocytosis.
BLOOD FILM FROM IRON DEFICIENT PATIENT Lymphocyte
BLOOD FILM FROM IRON DEFICIENT PATIENT-moderate
Blood Film Showing severe Iron Deficiency Anaemia
Biochemical Tests For IDA • A low serum iron level (< 50µg/dl). • High Total Iron Binding Capacity (TIBC) (> 400µg/dl) • Low Transferrin Saturation (< 15%) • Low Serum ferritin ( normal range, 30-300mg/dL) • Serum transferrin receptor – increased (normal range, 1.8 - 4.6 mg/L) Note: Low serum ferritin is the most sensitive indicator of IDA. Normal and high serum ferritin could be caused by chronic diseases & inflammation conditions. • Serum iron level measures iron bound to transferrin which is not part of haemoglobin. It is also a negative acute phase reactant.
BONE MARROW TEST FOR IRON STORE- HAEMOSIDERIN STAINED WITH PRUSSIAN BLUE STAIN
BM in IDA showing absence of stainable iron
Treatment of IDA • Elemental iron 4-6 mg/kg/day or Iron sulfate (ferrous sulfate) 325 mg three times a day. Stool softener recommended at first sign of constipation. • Reticulocyte count will rise in 4-5 days • Hb starts to rise at 1 week. Expect 6-8 weeks to normalize hemoglobin. • Once normalized, continue Fe therapy 1-2 months to replace Fe stores in marrow. Continue daily dose of iron intake for 6 months after correction of anaemia. Do not expect ferritin levels to normalize until then.
Anaemia of Chronic Disease • ACD is a common type of anaemia seen in patients with infectious, inflammatory, or neoplastic diseases that persist for more than a month. • It does not include anaemias caused by marrow replacement, blood loss, haemolysis, renal insufficiency, hepatic disease, or endocrinopathy, even when these disorders are chronic. • The ACD is the commonest cause of anaemia in hospitalized patients.
Pathogenesis • ACD is associated with iron retention in the RES. • Macrophages in RES fail to release iron to circulating transferrin but rather mop up available iron for storage as ferritin in hepatocytes. Macrophages can also secrete hepcidin in response to inflammation through TLR-4 pathway to inhibit iron absorption from GIT and iron-recycling macrophages • Again, there is decreased pdtn of transferrin and it`s increased sequestration in the spleen and in the foci of inflammation resulting in reduced concentration of transferrin in circulation • Shortened red cell life span to 60-90 days. • Erythropoiesis failure due to growth inhibition of erythroid progenitors by cytokines released from inflammatory cells such as (TNF- , IL-1 & 6, IFN- ) and erythropoietin under-pdtn.
Lab diagnosis • The anaemia is usually mild - moderate ( Hb 7-11g/dl). • The anaemia is initially normochromic and normocytic (MCHC and MCV are normal) but eventually become microcytic hypoc. - ESR/ C-reactive protein is high reflecting inflammation • Reticulocytes - normal or decreased. • Serum Iron - decreased • TIBC - reduced • Transferrin saturation (TS) - moderately decreased • Serum Ferritin- increased or normal Note; ferritin is an acute-phase reactant protein & its level can increase even in IDA if there is inflammation. • Serum Transferrin Receptor (sTR) – Low/Normal
Advantages of ACD • Withdrawal of iron by increased storage of the metal within the reticulo-endothelial system acts to limit the availability of iron to microorganisms or tumor cells and thereby inhibit their growth and proliferation. • Decreased Hb reduces the oxygen transport capacity of the blood and decreases the overall oxygen supply, which may primarily affect rapid proliferating (malignant) tissues and micro-organism. Note: • The greatest risk for harm is mistaking ACD for IDA thus subjecting patient to iron pills (hematinic) which will cause iron overload and multiple organ toxicity.
Microcytic hypochromic anaemia due to Thalassaemias • Thalassemias are a heterogeneous group of inherited disorders caused by gene mutations that reduce or completely preclude the synthesis of one or more of the globin chains of the haemoglobin. • They are classified as alpha () or beta (β) depending on which pair of globin chains is synthesized inefficiently. • 2 β- genes on chromosome 11, produce the β-globin chain and 4 - genes on chromosome 16 produce the - globin chain.
Development of thalassaemia • Deletion of one β-gene (β+) or both β-gene (β0) result in reduced or absence of β- globin chain. • Likewise, deletion of 1, 2, 3, or all 4 -  globin genes results in either varied levels of reduced globin pdtn or complete absence of - globin. • These affect the amount of Hb formed and the sizes of the RBC resulting in varied severity of microcytic hypochromic anaemia.
Unbalance in pdtn of globin chains Unbalance between  and β chains
β-Thalassaemia trait Target cells RBC microcytic hypochromic
β-Thal. major (homozygous β-thal)
Peripheral blood smear in  -thal (Hb H disease) Micro-anisocytosis, poikilocytosis with target cells and bizarre shaped RBC, showing marked hypochromia.
Lab. Techniques for thalassaemia diagnosis • This can be done by: 1. Hb electrophoresis by acid & alkaline pH and subsequent Hb variant quantification. 2. Iso-electric focusing (IEF) with iso-scan quantification 3. Hb high performance liquid chromatography (HPLC) 4. DNA analysis with sequencing.
DIFFERENTIAL DIAGNOSIS: IRON DEFICIENCY ANAEMIA

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IRON METABOLISM & MICROCYTIC HYPOCHROMIC ANAEMIAS.pptx

  • 1.
    MICROCYTIC HYPOCHROMIC ANAEMIAS Iron deficiencyanaemia Anaemia of chronic diseases Thalassaemias Dr. Benedict Sackey Dept. of Med. Diagnostics KNUST
  • 2.
    Outline • Iron metabolism –Dietary sources & daily requirement of iron – Absorption of iron – Assessment of body iron stores – Excretion of iron – Iron overload, causes and effect. • Anaemia – Causes, signs and symptoms of anaemia – Adaptive response to anaemia • Microcytic hypochromic anaemia – Development of Iron Deficiency Anaemia (IDA) – Development of anaemia of chronic diseases – Thalassaemia • Lab Diagnosis of Microcytic Hypochromic Anaemia • Treatment of IDA
  • 3.
    Introduction Iron is themost abundant trace element in the body. It’s a necessary element for organisms due to the role it plays in vital processes such as:  Transport and storage of oxygen eg: Hb, myoglobin  cofactor in numerous enzymatic reactions in the tissues responsible for oxidation eg: cytochromes, catalases, flavoproteins etc.  Electron transport chain  Hb contains the largest compartment of iron in the body and hemosiderin and ferritin are the two major iron storage forms in the body (BM, liver, spleen, kidney). Minor storage include myoglobin, enzymes involved in oxidation processes in tissues & transferrin.
  • 4.
    Intro - conti •The body`s iron is recycled over and over again for use in the erythropoietic cycle. • Thus, quantity of body iron is carefully controlled because both deficiency and excess is detrimental to the body.
  • 5.
    Clinical relevance ofiron • Deficiency of iron is associated with signs & symptoms : fatigue, dizziness, headache, irritability, palpitations, pallor, glossitis, spoon shaped nails (koilonychia), hair loss, dysphagia (plummer-vinson syndrome) blue sclerae, pica (apetite for non-food substances such as an ice, clay, starch). • Excess free iron can be very toxic cells and organs. • Free iron participates in Fenton’s reaction which results in free radicals capable of oxidizing lipids, cleaving proteins and denaturing DNA and RNA. • Organisms have evolved to maintain proper iron homeostasis
  • 6.
    Distribution of body`siron • The avg total iron conc. in the body is 2-4g. ~2/3 of the body`s iron is contained in RBC making ~ 2g of iron. • Remaining 1/3 is sequestrated predominantly in ferritin. • An avg of 20-30 mg of iron is required per day for erythropoiesis. 20-25 mg of this is obtained from recycling of destroyed RBCs and ~2mg is absorbed from the diet per day • 1ml whole blood contains 0.5mg of iron. Thus, 2800mg of iron in the peripheral blood • Storage iron (500mg in women, 1000mg in men) • 500mg in iron containing proteins
  • 7.
    Body`s Iron Requirement •Total daily iron requirement is approx. • 1mg/day for men/infant & postmenopausal women, • 2mg/day for menstruating female • 3-4mg/day for pregnant female • A normal individual absorbs 5-10% of ingested iron. This can increase to 20% or more if body`s iron store is low. • Heme iron in food such as meat is better absorbed than inorganic iron salts such as ferrous sulphate, gluconate, fumarate or succinate. • Iron is absorbed over the length of the small intestine but more efficiently at the duodenum.
  • 8.
    Iron transport throughthe enterocytes • Fe2+ from inorganic sources and that released from heme by heme oxygenase-1 are transported within the enterocytes by Ferroportin-1. • The amount of iron transported to transferrin (Tf) is controlled by hepcidin, a protein synthesized by the liver which mediates proteolytic degradation of ferroportin-1 • Iron only combines with transferrin at its Fe3+ state, thus, caeruloplasmin oxidizes Fe2+ to Fe3+ • Transferrin, then transport iron to needed sites such as red cells, brain endothelia cells, hepatocytes etc which express transferrin receptors (TfR). DMT1 – divalent metal transporter- 1 Fe2+ - ferrous iron Fe3+ - ferric iron
  • 9.
    Iron uptake bycells • Iron uptake from transferrin requires transferrin receptor. Tf is coded for by a gene (TFRC) on chromosome 3. • Two types of TfR, TfR1 and TfR2 are expressed in human. TfR1 and TfR2 share 66% resemblance in their ectodomain. • TfR1 is expressed in many tissues whereas TfR2 expression is only limited to hepatocytes and erythropoietic progenitors. • TfR2 has 25-fold less binding affinity for Tf and acts as a sensor of serum iron level whereas TfR1 regulates cellular iron uptake. • Transferrin has a very high affinity for iron at neutral pH. Transferrin binds to the receptor, and the complex is then internalized and iron is released when the pH of the internal vesicles is reduced to about 5.5 • After iron release, apotransferrin returns to the circulation and can undertake further cycles of iron uptake and delivery. • The number of transferrin receptors on a cell reflects the iron requirement of the cell. NRBC in the marrow thus express the highest numbers of TfR. • Transferrin receptors are proteolytically cleaved at the cell membrane and circulates bound to transferrin as sTfR. • sTfR level increases in IDA and increased rate of erythropoiesis thus measurements of circulating sTfR are used as an indicator of iron deficiency • sTfR conc are similar in healthy males and females, unlike serum ferritin (sFn) conc.
  • 10.
    • Cells thatexpress TfRs such as liver, intestine and some immune cells also have homeostatic iron regulator gene (HFE) which produces HFE protein. • HFE protein interact with other proteins such as TfR1 and TfR2 on cell surface to determine amount of iron in the body. • Thus HFE protein competes with Tf for binding sites on TfR1 due to overlapping binding sites Hepcidin regulation • Hepcidin is a primary regulator of total body iron homeostasis and disease-causing TfR2 mutations cause Hereditary Hemochromatosis through a reduction in hepcidin production • The transcription of hepcidin is regulated by iron, bone morphogenetic proteins (BMPs), inflammation, hypoxia, and erythropoietic activity
  • 11.
    FACTORS INFLUENCING IRONABSORPTION Increased absorption • Alcohol • Anaemia • Ascorbic acid eg. fruits • Depletion of iron stores • HCL • Liver disease • Increased erythropoiesis • Hypoxia • High altitude Decreased absorption • Antacids eg: Magnesium tri-silicate • Certain clays • Mal-absorption syndrome • Phytates. eg; cereals & legumes • Fibers eg; cereals & legumes • Heavy metals (Ca, Zn, Mg, Pb) • Tetracycline • Polyphenolics in plant foods • Tannins in teas & coffees • Low altitude Vitamin-C counteract absorption inhibitory effect thus vegetarians must consume plants Foods rich in vitamin-C and iron such as legumes, whole grain cereals, brown rice, Nuts, seeds, fruits.
  • 12.
    Hemoglobin synthesis inRBC • Iron is incorporated into protoporphyrin- IX to form heme in the mitochondria by ferrochelatase. • Heme released from mitochondria combines with globin synthesized in cytosol by ribosomes to form haemoglobin. • The level of intracellular free heme regulates normoblasts uptake of iron. • Impairment of heme synthesis results in excess iron accumulate in the mitochondria of the normoblast forming ringed sideroblast demonstrable in sideroblastic anaemia with Prussian blue stain.
  • 13.
    Demonstration of ringedsideroblast Deposition of iron granules demonstrable with Prussian blue stain
  • 14.
    Distribution of ironin the body A. Metabolically Active Iron • Haemoglobin • “Serum” iron bound to the transport protein transferrin in blood. • Tissue Iron: found in cytochromes and enzymes • Myoglobin: iron involved in oxygen reserve in muscles B. Storage Iron: • Ferritin: found in blood, tissue fluids, and cells (hepatocytes) • Hemosiderin: found in macrophages and BM
  • 15.
    Measurement of BodyIron status This can be determined by estimating: • Serum Iron level (Transferrin bound iron). • Total iron binding capacity (TIBC): measurement of transferrin (total # of binding sites for iron atoms on transferrin). • % transferrin saturation: (Serum iron/TIBC x100). This measures % of true binding sites on all transferrin molecule that are occupied by iron. • Serum ferritin : Levels correlate with body iron stores. • Hemosiderin: assesses iron stores in bone marrow. • Hepcidin levels • sTFR-1 levels
  • 16.
    Abigail reported atKNUST Hospital and was diagnosed with IDA. Based on Abigail’s review FBC results performed 3months. After starting iron fersolate hematinic treatment predict her iron profile result on the review date using Low, normal or increased to depict your expectation. Justify your answers.
  • 17.
    EXCRETION OF IRON •Small loss of iron each day in urine, faeces. • Skin and nails • Exfoliated GIT epithelial cells • Menstruating females • Bile – This however account for only about 1-2 mg daily. • Certain medications eg. Desferrioxamine • Blood donation - to reduce excessively high level of iron.
  • 18.
  • 19.
    Overview Iron overload isaccumulation of excess amount of total body iron. The most notable organs with iron deposition include liver, heart and the endocrine glands. Primarily, iron overload is often inherited. Secondary iron overload could be cased by chronic transfusion, hemolysis, excessive parenteral/dietary consumption of iron. Two causes of pathologic iron overload –hemochromatosis and hemosiderosis are known. • Hereditary Hemochromatosis (HH) Genetic mutations that lead to reduced hepcidin expression leads to iron overload. • 4 types of HH are reported and 3 are as a result of low levels of hepcidin expression. – Type I, (HFE mutation) - a single amino acid HFE mutation and prevalent throughout Europe – Type II a and b [hemojuvelin (HJV) and hepcidin mutations respectively] – most severe – Type III (TfR2 mutation) -TfR2 HH is far rarer and is the result of various mutations – Type IV is mutations in Ferropoietin • Untreated, HH leads to iron accumulation in the liver, heart, pancreas, and joints leading to cirrhosis, arrhythmias, diabetes, and arthritis. •
  • 20.
    • Mutation inHFE gene (C282Y) and H63D resulting in excessive absorption of iron • Excess accumulation of Fe can progress to involve widespread deposition of iron in parenchymal tissue with resulting organ injury. • Iron deposits in hepatocytes, cardiac cells, endocrine cells, and other parenchymal cells can interfere with the their normal function and may lead to death. • HFE gene is located on the short arm of chrom. 6 Diagnosis of HH • Diagnosed with blood test, genetic test, MRI and liver biopsy • Serum ferritin >300 ng/mL in men and 200 ng/mL in women • Transferrin saturation > 45% suggest HH • Transferrin saturation > 62% predicts homozygous HH in 92% cases • Transferrin saturation < 20% indicate iron deficiency
  • 21.
    Causes Of IronOverload • Multiple transfusions • Liver disease • Prolonged use of medicinal iron • Ineffective erythropoiesis
  • 22.
    Hemosiderosis This is aniron overload disorder resulting in accumulation of hemosiderin in the tissues. Hemosiderosis is unassociated with tissue damage bcos vast majority of iron is contained in macrophages.
  • 23.
    Effects Of IronOverload Non-transferrin-bound iron (NTBI) circulates in the plasma Excess iron promotes the generation of free hydroxyl radicals, propagators of oxygen- related tissue damage Liver cirrhosis/ fibrosis/cancer Insoluble iron complexes are deposited in body tissues and end-organ toxicity occurs Diabetes mellitus Growth failure Capacity of serum transferrin to bind iron is exceeded Iron overload Cardiac failure Infertility HSC senescence (Fenton Reaction) O2- + H2O2 O2 + OH- + HO
  • 24.
    When Is IronConc. a Problem? • Normal total body iron is 2.5 – 4.0g. • Tissue damage occurs when total body iron is 7 – 15 g. • The liver iron closely reflects total body iron (total body iron stores in mg per kg of body weight = 10.6 x hepatic iron conc in mg per gram of liver, dry weight A SECTION OF THE LIVER SHOWING CIRRHOSIS
  • 25.
    Management of ironoverload • The goal of iron chelation therapy is to decrease tissue iron to concentrations where iron-mediated toxicity cannot occur. • This is achieved by chelating iron and detoxifying iron using appropriate chelators • The metabolism and pharmacokinetics of iron chelators are critical determinant to their therapeutic success. • Only a small fraction of body iron is available for chelation at any given time, as the majority of storage iron is not effectively chelated at clinically achievable chelator concentrations. • Achievement of safe tissue iron levels therefore takes many months or years with current chelation regimens. • Various tissues in the body have different safe iron levels. Cardiac toxicity is the most common cause of death in transfusional iron overload but the level of iron in the heart is a little fraction of that in the liver, despite prognosis of cardiac toxicity inferred from association of iron level/dry weight of liver tissue.
  • 26.
    Major target ofiron chelators Intracellular labile iron pool • This is the iron derived mainly from lysosomal catabolism of ferritin and also from iron uptake of transferrin or non-transferrin bound iron into cells. Since the liver is a key organ for iron storage as ferritin, the liver is therefore a key target for chelation therapy. Iron from RBC catabolism in macrophages • In a healthy individual, 20 mg of iron is released by macrophages in liver, spleen, and marrow every day. Transit iron released from macrophages is the major source of urinary iron achieved with DFO therapy Iron chelators can be harmful • The toxicity of iron chelators may result: either from the 1. excessive chelation of iron or other metals eg; zinc needed for essential metabolic functions 2. toxicity of unstable iron-chelate complexes 3. Iron chelators are cytotoxic to dividing cells at concentrations of 1-10 µM depending on the cell type involved and the duration of exposure to chelators
  • 27.
    • Deferoxamine • Deferiprone •most clinical manifestations of iron loading do not appear until the second decade of life but liver biopsies in young patients reveal that the deleterious effects of iron starts much earlier.
  • 28.
    ANAEMIA • Anaemia isa condition where Hb conc is below the reference value for the age and sex of the individual. • Anaemia generally occurs when RBC loss or destruction exceeds it production. • Being common clinical & laboratory finding, anaemia is not in itself a clinical diagnosis but rather, a manifestation of a disease. • Hb is the primary molecule for gaseous transport in the body, thus anaemia, results in inadequate supply of oxygen to the tissues, a condition called hypoxia.
  • 30.
    SIGNS & SYMPTOMSOF ANAEMIA • Pallor • Fatigue • Rapid pulse • Shortness of breath • Irritability, (difficulty in concentrating) • Headache • Dizziness • Bleeding • Nausea and decreased appetite • Menstrual irregularities • Loss of libido or potency • Heart murmurs • Angenia pectoris (chest pain with exertion) • Heart failure • Coma • Sore tongues • Brittle nails
  • 31.
    Clinical features • Mild- Mild dyspnea (difficult respiration) on exertion, palpitation. • Moderate - Mild dyspnea on exertion, palpitation and excessive fatigue. • Severe - Dyspnea at rest, tachycardia with pounding pulse, weakness, dizziness, syncope (spontaneous loss of consciousness), headache, insomnia (inability to sleep).
  • 32.
    Causes of Anaemia Generalmechanism • Increased blood loss – acute or chronic eg. GIT ulcerations, piles, coagulopathies, haemorrhage etc. • Decreased Hbproduction. Eg; thalasaemias. • Increased destruction of RBC resulting in decreased RBC life-span – Acquired -malaria,effectofcertainmedications – Congenital-SCD,hereditary spherocytosis, G6PDdeficiency. • Impairment of RBC formation (insufficientandineffective erythropoiesis) -leukaemia,aplastic/hypoplastic,parvo-virus, marrowsuppressivedrugs.
  • 33.
    ADAPTIVE RESPONSE TOANAEMIA • If tissue oxygenation is inadequate due to anaemia, compensatory mechanisms come into play to ensure survival. These include:  Increased pulse rate, stroke volume, cardiac output.  Increased erythropoietin production  Decreased affinity of Hb for oxygen (↑2,3 DPG)  Diversion of blood to more vital organs eg: brain.
  • 34.
    MICROCYTIC HYPOCHROMIC ANAEMIAS •These are group of anaemic conditions where the RBCs are smaller in sizes (microcytic) and contain lesser Hb content (hypochromia) than normal. • Main causes of this anaemia are; o Defective heme - either iron or porphyrin deficiency o Decreased globin production eg. Thalassaemias. Types of microcytic hypochromic anaemias o Iron deficiency anaemia o Anaemia of chronic diseases o Thalassaemias
  • 35.
    IRON DEFICIENCY ANAEMIA •This is the condition where depleted level of iron in the body leads to synthesis of fewer RBC which do not contain adequate amount of Hb. • Etiology: • Chronic Bleeding • Menorrhagia (prolonged menstruation) • Peptic Ulcer • Stomach Cancer • Ulcerative Colitis • Intestinal Cancer • Haemorrhoids • Decreased Iron Intake • Increased Iron Requirment (Juvenile Age, Pregnancy, Lactation).
  • 36.
    Stages Of IronDeficiency Anaemia • Pre-latent – reduction in iron stores without reduced serum iron levels • Hb (N), MCV (N), transferrin saturation (N), iron absorption (), serum ferritin (), marrow iron () • Latent – iron stores are exhausted, but the blood haemoglobin level remains normal • Hb (N), MCV (N), TIBC (), serum ferritin (), transferrin saturation (), marrow iron (absent) • Iron deficiency anaemia – blood Hb conc, falls below the lower limit of normal • Hb (), MCV (), TIBC (), serum ferritin (), transferrin saturation (), marrow iron (absent)
  • 37.
    Lab. Diagnosis OfIron Deficiency Anaemia Complete blood count (CBC) and serum iron profile Evaluation of blood smear with RBC indices Retics count. • Low Hb /PCV - indicates anaemia. • Low MCV - abnormally smaller sizes RBCs (microcytic) • Low MCH & MCHC - reflecting decreased content of RBC haemoglobinization (hypochromia). • An increased red cell distribution width (RDW) - reflecting an increased variability in the sizes of RBC (anisocytosis). In evaluation of anaemia, MCV should always be interpreted with the RDW.
  • 38.
    CBC of IDApatient Showing marked RBC Microcytosis with hypochromia
  • 40.
    IDA after treatment DimorphicRBC pop. Of microcytic hypochromic & normocytic normochromic
  • 41.
    Diagnosis of IDA-Peripheral Blood Smear • Examination of blood smear reveals, RBC microcytosis with hypochromia, target cells, elliptical & tear drop shaped (poikilocytosis - meaning variation in shapes). • Reduced/ absence of polychromatic cells and retic count/RPI shows very low (< 1.0%) or absence of retics. • The more severe the anaemia, the greater the abnormalities of RBCs. • Platelet may be normal, decreased or increased. • In severe IDA, the peripheral blood smear may show mild thrombocytosis.
  • 42.
    BLOOD FILM FROMIRON DEFICIENT PATIENT Lymphocyte
  • 43.
    BLOOD FILM FROMIRON DEFICIENT PATIENT-moderate
  • 44.
    Blood Film Showingsevere Iron Deficiency Anaemia
  • 45.
    Biochemical Tests ForIDA • A low serum iron level (< 50µg/dl). • High Total Iron Binding Capacity (TIBC) (> 400µg/dl) • Low Transferrin Saturation (< 15%) • Low Serum ferritin ( normal range, 30-300mg/dL) • Serum transferrin receptor – increased (normal range, 1.8 - 4.6 mg/L) Note: Low serum ferritin is the most sensitive indicator of IDA. Normal and high serum ferritin could be caused by chronic diseases & inflammation conditions. • Serum iron level measures iron bound to transferrin which is not part of haemoglobin. It is also a negative acute phase reactant.
  • 46.
    BONE MARROW TESTFOR IRON STORE- HAEMOSIDERIN STAINED WITH PRUSSIAN BLUE STAIN
  • 47.
    BM in IDAshowing absence of stainable iron
  • 48.
    Treatment of IDA •Elemental iron 4-6 mg/kg/day or Iron sulfate (ferrous sulfate) 325 mg three times a day. Stool softener recommended at first sign of constipation. • Reticulocyte count will rise in 4-5 days • Hb starts to rise at 1 week. Expect 6-8 weeks to normalize hemoglobin. • Once normalized, continue Fe therapy 1-2 months to replace Fe stores in marrow. Continue daily dose of iron intake for 6 months after correction of anaemia. Do not expect ferritin levels to normalize until then.
  • 49.
    Anaemia of ChronicDisease • ACD is a common type of anaemia seen in patients with infectious, inflammatory, or neoplastic diseases that persist for more than a month. • It does not include anaemias caused by marrow replacement, blood loss, haemolysis, renal insufficiency, hepatic disease, or endocrinopathy, even when these disorders are chronic. • The ACD is the commonest cause of anaemia in hospitalized patients.
  • 50.
    Pathogenesis • ACD isassociated with iron retention in the RES. • Macrophages in RES fail to release iron to circulating transferrin but rather mop up available iron for storage as ferritin in hepatocytes. Macrophages can also secrete hepcidin in response to inflammation through TLR-4 pathway to inhibit iron absorption from GIT and iron-recycling macrophages • Again, there is decreased pdtn of transferrin and it`s increased sequestration in the spleen and in the foci of inflammation resulting in reduced concentration of transferrin in circulation • Shortened red cell life span to 60-90 days. • Erythropoiesis failure due to growth inhibition of erythroid progenitors by cytokines released from inflammatory cells such as (TNF- , IL-1 & 6, IFN- ) and erythropoietin under-pdtn.
  • 51.
    Lab diagnosis • Theanaemia is usually mild - moderate ( Hb 7-11g/dl). • The anaemia is initially normochromic and normocytic (MCHC and MCV are normal) but eventually become microcytic hypoc. - ESR/ C-reactive protein is high reflecting inflammation • Reticulocytes - normal or decreased. • Serum Iron - decreased • TIBC - reduced • Transferrin saturation (TS) - moderately decreased • Serum Ferritin- increased or normal Note; ferritin is an acute-phase reactant protein & its level can increase even in IDA if there is inflammation. • Serum Transferrin Receptor (sTR) – Low/Normal
  • 52.
    Advantages of ACD •Withdrawal of iron by increased storage of the metal within the reticulo-endothelial system acts to limit the availability of iron to microorganisms or tumor cells and thereby inhibit their growth and proliferation. • Decreased Hb reduces the oxygen transport capacity of the blood and decreases the overall oxygen supply, which may primarily affect rapid proliferating (malignant) tissues and micro-organism. Note: • The greatest risk for harm is mistaking ACD for IDA thus subjecting patient to iron pills (hematinic) which will cause iron overload and multiple organ toxicity.
  • 53.
    Microcytic hypochromic anaemiadue to Thalassaemias • Thalassemias are a heterogeneous group of inherited disorders caused by gene mutations that reduce or completely preclude the synthesis of one or more of the globin chains of the haemoglobin. • They are classified as alpha () or beta (β) depending on which pair of globin chains is synthesized inefficiently. • 2 β- genes on chromosome 11, produce the β-globin chain and 4 - genes on chromosome 16 produce the - globin chain.
  • 54.
    Development of thalassaemia •Deletion of one β-gene (β+) or both β-gene (β0) result in reduced or absence of β- globin chain. • Likewise, deletion of 1, 2, 3, or all 4 -  globin genes results in either varied levels of reduced globin pdtn or complete absence of - globin. • These affect the amount of Hb formed and the sizes of the RBC resulting in varied severity of microcytic hypochromic anaemia.
  • 55.
    Unbalance in pdtnof globin chains Unbalance between  and β chains
  • 56.
    β-Thalassaemia trait Target cellsRBC microcytic hypochromic
  • 57.
  • 58.
    Peripheral blood smearin  -thal (Hb H disease) Micro-anisocytosis, poikilocytosis with target cells and bizarre shaped RBC, showing marked hypochromia.
  • 59.
    Lab. Techniques forthalassaemia diagnosis • This can be done by: 1. Hb electrophoresis by acid & alkaline pH and subsequent Hb variant quantification. 2. Iso-electric focusing (IEF) with iso-scan quantification 3. Hb high performance liquid chromatography (HPLC) 4. DNA analysis with sequencing.
  • 60.
    DIFFERENTIAL DIAGNOSIS: IRONDEFICIENCY ANAEMIA