umped by the heart, blood reaches every part of our bodies and 'feeds' each cell with everything it needs; from oxygen and sugar for energy, to the building blocks for new cells to be built. It also carries the waste products to be cleared away and transports the cells which patrol our bodies and make sure we do not get sick. It is made up of several important parts: a fluid called 'plasma', white blood cells, red blood cells, and platelets. The plasma contains all the nutrients from the things we eat. The platelets make the blood clot if you cut yourself. The white blood cells stop bugs getting into the body and fight infections, such as a cold or sore throat. The red blood cells are what give your blood its colour. They pick up oxygen from your lungs and carry it around your body. These are the cells that are important in your sickle cell anaemia. Red blood cells are able to do this because they carry lots of copies of a special protein called 'haemoglobin'. Blood : F ormed elements (red and white blood cells and platelets) plasma. C omponents of the haemopoietic system Main: blood, bone marrow, lymph nodes and thymus Accessory : spleen, liver and kidneys
A schematic visual model of oxygen binding process, showing all four monomers and hemes, and protein chains only as diagramatic coils, to facilitate visualization into the molecule. Oxygen is not shown in this model, but for each of the iron atoms it binds to the iron (red sphere) in the flat heme. For example, in the upper left of the four hemes shown, oxygen binds at the left of the iron atom shown in the upper left of diagram. This causes the iron atom to move backward into the heme, which holds it, tugging the histidine residue (modeled as a red pentagon on the right of the iron) closer, as it does. This, in turn, pulls on the protein chain holding the histidine.
Classification: hypochromic, microcytic anaemia (small red cells with low haemoglobin; caused by iron deficiency) macrocytic anaemia (large red cells, few in number) normochromic normocytic anaemia (fewer normal-sized red cells, each with a normal haemoglobin content) mixed pictures. Morphological (according to the size and Hb content of the RBCs) Basically, all anaemias can be classified into three groups as per morphology of the RBCs. 1. Microcytic Hypochromic (RBCs are small in size and less haemoglobinised) (a) Iron Deficiency Anaemia (b) Thalassaemia 2. Macrocytic normochromic (RBCs are large in size and normally haemoglobinised) (a) Megaloblastic Anaemia due to Folate/B 12 deficiency 3. Normocytic Normochromic (RBCs are normal in size and normally haemoglobinised) (a) Haemolytic Anaemia (b) Post Haemorrhagic Anaemia Internal Bleeding Malaena (black tarry stool) Haemoptysis Street Accident Bleeding during Operation Post Partum Bleeding (c) Aplastic Anaemia (d) Leukaemia (e) Anaemia due to Renal Failure
Blood corpuscles develop from stem cells through several cell divisions ( n = 17!). Hemoglobin is then synthesized and the cell nucleus is extruded. Erythropoiesis is stimulated by the hormone erythropoietin (a glycoprotein), which is released from the kidneys when renal oxygen tension declines. A nephrogenic anemia can be ameliorated by parenteral administration of recombinant erythropoietin (epoetin alfa) or hyperglycosylated erythropoietin (darbepoetin; longer half-life than epoetin). Even in healthy humans, formation of red blood cells and, hence, the oxygen transport capacity of blood, is augmented by erythropoietin,. This effect is equivalent to high-altitude training and is employed as a doping method by high-performance athletes. Erythropoietin is inactivated by cleavage of sugar residues, with a biological half-life of ~ 5 hours after intravenous injection and a t½ > 20 hours after subcutaneous injection. Given adequate production of erythropoietin, a disturbance of erythropoiesis is due to two principal causes. (1) Cell multiplication is inhibited because DNA synthesis is insuf cient. This occurs in deficiencies of vitamin B12 or folic acid (macrocytic hyperchromic anemia). (2) Hemoglobin synthesis is impaired. This situation arises in iron deficiency, since Fe2+ is a constituent of hemoglobin (microcytic hypochromic anemia).
CAUSES OF ANAEMIA (ETIOLOGY): It is not difficult to understand that anaemia can occur either by diminished formation or excessive destruction of RBCS. A. Diminished Formation (Dyshaemopoietic) 1. Nutritional (a) Iron Deficiency (b) Folic Acid/ Vit B 12 Deficiency (c) Protein Deficiency 2. Decreased Synthesis (a) Aplastic Anaemia (b) Replacement of BM (e.g. Leukaemia) (c) Thalassaemia 3. Chronic Disorder (a) Kidney Disease (b) Advanced Malignancy (c) Chronic Liver Disease B. Excessive Destruction 1. Post Haemorrhage (a) Acute Blood Loss (b) Ghronic Blood Loss 2. Excessive Haemolysis (a) Intracellular Defect (Defective RBC) Thalassaemia Haemoglobinopathies (Hb C/ E) Sickle Cell Anaemia Hereditary Spherocytosis (b) Extracellular Defect Rh Incompatibility Incompatible Blood Transfusion Auto Immune Haemolytic Anaemia Certain Snake Venom
The body of a 70 kg man contains about 4 g of iron, 65% of which circulates in the blood as haemoglobin. About one half of the remainder is stored in the liver, spleen and bone marrow, chiefly as ferritin and haemosiderin . The iron in these molecules is available for fresh haemoglobin synthesis. The rest, which is not available for haemoglobin synthesis, is present in myoglobin, cytochromes and various enzymes
Humans are adapted to absorb iron in the form of haem . Non-haem iron in food is mainly in the ferric state and this needs to be converted to ferrous iron for absorption. Ferric iron, and to a lesser extent ferrous iron, has low solubility at the neutral pH of the intestine; however, in the stomach, iron dissolves and binds to mucoprotein. In the presence of ascorbic acid , fructose and various amino acids , iron is detached from the carrier, forming soluble low-molecular-weight complexes that enable it to remain in soluble form in the intestine. Ascorbic acid stimulates iron absorption partly by forming soluble iron-ascorbate chelates and partly by reducing ferric iron to the more soluble ferrous form. The site of iron absorption is the duodenum and upper jejunum, The stomach plays a role in iron absorption through dissolving iron by HCL and forming soluble complex together with Vitamin C(reducing agent) to aid its reduction into ferrous absorbable form.and absorption is a two-stage process involving first a rapid uptake across the brush border and then transfer into the plasma from the interior of the epithelial cells. The second stage, which is rate limiting, is energy dependent. Haem iron in the diet is absorbed as intact haem and the iron is released in the mucosal cell by the action of haem oxidase. Non-haem iron is absorbed in the ferrous state. Within the cell, ferrous iron is oxidised to ferric iron, which is bound to an intracellular carrier, a transferrin-like protein; the iron is then either held in storage in the mucosal cell as ferritin (if body stores of iron are high) or passed on to the plasma (if iron stores are low). Iron is carried in the plasma bound to transferrin , a β-globulin with two binding sites for ferric iron, which is normally only 30% saturated. Plasma contains 4 mg iron at any one time, but the daily turnover is about 30 mg ( Fig. 21.1 ). Most of the iron that enters the plasma is derived from mononuclear phagocytes, following the degradation of time-expired erythrocytes. Intestinal absorption and mobilisation of iron from storage depots contribute only small amounts. Most of the iron that leaves the plasma each day is used for haemoglobin synthesis by red cell precursors. These cells have receptors that bind transferrin molecules, releasing them after the iron has been taken up. Iron is stored in two forms-soluble ferritin and insoluble haemosiderin . Ferritin is found in all cells, the mononuclear phagocytes of liver, spleen and bone marrow containing especially high concentrations. It is also present in plasma. The precursor of ferritin, apoferritin , is a large protein of molecular weight 450000, composed of 24 identical polypeptide subunits that enclose a cavity in which up to 4500 iron molecules can be stored. Apoferritin takes up ferrous iron, oxidises it and deposits the ferric iron in its core. In this form, it constitutes ferritin, the primary storage form of iron, from which the iron is most readily available. The lifespan of this iron-laden protein is only a few days. Haemosiderin is a degraded form of ferritin in which the iron cores of several ferritin molecules have aggregated, following partial disintegration of the outer protein shells. The ferritin in plasma has virtually no iron associated with it. It is in equilibrium with the storage ferritin in cells and its concentration in plasma provides an estimate of total body iron stores. The body has no means of actively excreting iron . Small amounts leave the body through desquamation (peeling off) of mucosal cells containing ferritin, and even smaller amounts leave in the bile, sweat and urine. A total of about 1 mg is lost daily. Iron balance is, therefore, critically dependent on the active absorption mechanism in the intestinal mucosa. This absorption is influenced by the iron stores in the body, but the precise mechanism of this control is still a matter of debate: the amount of ferritin in the intestinal mucosa may be important, as may the balance between ferritin and the transferrin-like carrier molecule in these cells.
The average diet in the USA contains 10–15 mg of elemental iron daily. A normal individual absorbs 5–10% of this iron, or about 0.5–1 mg daily. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 1–2 mg/d in menstruating women and may be as high as 3–4 mg/d in pregnant women. Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (Figure 33–1). Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferroreductase to ferrous iron (Fe 2+ ) before it can be absorbed by intestinal mucosal cells. ascorbic acid 50 mg increases iron absorption from a meal by 2-3 times. Food reduces iron absorption due to inhibition by phytates, tannates and phosphates. Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron and absorption of iron complexed with heme (Figure 33–1). The divalent metal transporter, DMT1, efficiently transports ferrous iron across the luminal membrane of the intestinal enterocyte. The rate of iron uptake is regulated by mucosal cell iron stores such that more iron is transported when stores are low. Together with iron split from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron (Fe 3+ ) by a ferroxidase. Excess iron can be stored in intestinal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin. In general, when total body iron stores are high and iron requirements by the body are low, newly absorbed iron is diverted into ferritin in the intestinal mucosal cells. When iron stores are low or iron requirements are high, newly absorbed iron is immediately transported from the mucosal cells to the bone marrow to support hemoglobin production.
TRANSPORT Iron is transported in the plasma bound to transferrin, a -globulin that specifically binds two molecules of ferric iron (Figure 33–1). The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptors—integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis. In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cell, where it is funneled into hemoglobin synthesis or stored as ferritin. The transferrin-transferrin receptor complex is recycled to the plasma membrane, where the transferrin dissociates and returns to the plasma. This process provides an efficient mechanism for supplying the iron required by developing red blood cells. Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells. Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin.
STORAGE In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells (Figure 33–1). Apoferritin synthesis is regulated by the levels of free iron. When these levels are low, apoferritin synthesis is inhibited and the balance of iron binding shifts toward transferrin. When free iron levels are high, more apoferritin is produced to sequester more iron and protect organs from the toxic effects of excess free iron. Ferritin is detectable in serum. Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron stores.
ELIMINATION There is no mechanism for excretion of iron. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat. These losses account for no more than 1 mg of iron per day. Because the body's ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron, in response to the body's needs. As noted below, impaired regulation of iron absorption leads to serious pathology.
The normal daily requirement for iron is approximately 5 mg for men, and 15 mg for growing children and for menstruating women. A pregnant woman needs between two and ten times this amount because of the demands of the fetus and increased requirements of the mother.* The average diet in Western Europe provides 15-20 mg of iron daily, mostly in meat. Iron in meat is generally present as haem and about 20-40% of haem iron is available for absorption Humans are adapted to absorb iron in the form of haem. It is thought that one reason why modern humans have problems in maintaining iron balance (there are an estimated 500 million people with iron deficiency in the world) is that the change from hunting to grain cultivation 10 000 years ago led to cereals, which have a relatively small amount of utilisable iron, constituting a significant proportion of the diet. The body of a 70 kg man contains about 4 g of iron, 65% of which circulates in the blood as haemoglobin. About one half of the remainder is stored in the liver, spleen and bone marrow, chiefly as ferritin and haemosiderin . The iron in these molecules is available for fresh haemoglobin synthesis. The rest, which is not available for haemoglobin synthesis, is present in myoglobin, cytochromes and various enzymes Regulation of absorption may involve one or more of: control of mucosal uptake; retention of iron in storage form in the mucosal cell and transfer from the mucosal cell to the plasma. Increased erythropoietic activity also stimulates increased absorption.
Less Intake of Fe, Vitamins and Protein Iron rich foods are Mutton especially liver Chicken, Fish (Tuna fish and sardine) Egg, Spinach, Plantain (unripe banana, Soya bean, Wheat Bran, Brown Bread, Green pea, Milk is a highly nutritious food containing protein, fat, carbohydrate, Vitamin A & D, Calcium, but it is poor in iron content. Diminished Absorption The following factors favour absorbtion: Acidity of gastric juice Vit C Haem bound iron (animal protein) Alcohol consumption Low serum iron level Ferrous iron better than Ferric form Diseases like Chron Disease “&Malabsorbtion Syndrome hamper iron absorbtion. Increased Loss The commonest cause is chronic blood loss from any source: Monthly Menstrual Loss: It is one the commonest cause of anaemia in female of child bearing age. Hook Worm Infestation: Common among villagers who move about barefoot and defaecate in the open field. The hook worm larva enters their body through their feet Bleeding Excessive Demand Pregnancy: The mother has to cater for her requirement as well as of the foetus. It is mandatory that all pregnant women must take iron and folic acid supplement during the 2 nd and 3 rd trimester of pregnancy and continue during lactation. Growth during puberty
Iron therapy is needed in: Iron deficiency due to dietary lack or to chronic blood loss. Pregnancy. The extra iron required by mother and fetus totals 1000 mg, chiefly in the latter half of pregnancy. The fetus takes iron from the mother even if she is iron deficient. Dietary iron is seldom adequate and iron and folic acid (50-100 mg elemental iron plus folic acid 200-500 micrograms/day) should be given to pregnant women from the fourth month. Opinions differ on whether all women should receive prophylaxis or only those who can be identified as needing it. There are numerous formulations. Parents should be particularly warned not to let children get at the tablets. Abnormalities of the gastrointestinal tract in which the proportion of dietary iron absorbed may be reduced, i.e. in malabsorption syndromes such as coeliac disease. Premature babies, since they are born with low iron stores, and in babies weaned late. There is very little iron in human milk and even less in cow's milk. Early treatment of severe pernicious anaemia with hydroxocobalamin, as the iron stores occasionally become exhausted by the surge in red cell formation.
Oral: Several different preparations of ferrous iron salts are available for oral administration. The main one is ferrous sulfate , which has an elemental iron content of 200 μg/mg. Others are ferrous succinate, ferrous gluconate and ferrous fumarate. These are all absorbed to a comparable extent. A small dose may be given at first and increased after a few days. The objective is to give 100-200 mg of elemental iron per day in an adult (3 mg/kg in a child). Iron given on a full stomach causes less gastrointestinal upset but less is absorbed than if given between meals; however, use with food is commonly preferred to improve compliance. A suggested course. Start a patient on ferrous sulphate taken on a full stomach once, then twice, then thrice a day. If gut intolerance occurs, stop the iron and reintroduce it with one week for each step. If this seems to cause gastrointestinal upset, try ferrous gluconate, succinate or fumarate. If simple preparations (above) are unsuccessful, and this is unlikely, then the pharmaceutically sophisticated and expensive sustained-release preparations may be tried. They release iron slowly and only after passing the pylorus, from resins, chelates (sodium iron edetate) or plastic matrices, e.g. Slow-Fe, Ferrograd, Feospan, so that iron is released in the lower rather than the upper small intestine. Patients who cannot tolerate standard forms even when taken with food may get as much iron with fewer unpleasant symptoms if they use a sustained-release formulation. Liquid formulations are available for adults who prefer them and for small children, e.g. Ferrous Sulphate Oral Solution, Paediatric: 5 ml contains 12 mg of elemental iron: but they stain the teeth. Polysaccharide-iron complex (Niferex): 5 ml contains 100 mg of elemental iron. There are numerous other iron preparations which can give satisfactory results. Sustained-release and chelated forms of iron (see above) have the advantage that poisoning is less serious if a mother's supply is consumed by young children, a real hazard. Iron therapy blackens the faeces but does not generally interfere with modern tests for occult blood (commonly needed in investigation of anaemia), though it may give a false positive with some older occult blood tests, e.g. guaiac test. Parenteral: Parenteral iron is rarely given but may be necessary in individuals who are not able to absorb oral iron because of malabsorption syndromes or as a result of surgical procedures or inflammatory conditions involving the gastrointestinal tract. The preparations used are iron-dextran or iron-sorbitol, both given by deep intramuscular injection. Iron-dextran (but not iron-sorbitol ) can be given by slow intravenous infusion, but this method of administration should only be used if absolutely necessary because of the risk of anaphylactoid reactions. oral therapy (at lower dose) should be continued for 3-6 months after the haemoglobin concentration has returned to normal or until the serum ferritin exceeds 50 microgram/1 (or as long as blood loss continues).
Making 25 mg of iron per day available to the bone marrow will allow an iron deficiency anaemia to respond with a rise of 1% of haemoglobin (0.15 g Hb/100 ml) per day; a reticulocyte response occurs between 4 and 12 days. An increase in the haemoglobin of at least 2 g/dl after 3 weeks of therapy is a reasonable criterion of an adequate response. Oral preparations are the treatment of choice for almost all patients due to their effectiveness, safety and low cost. Parenteral preparations should be restricted to the few patients unable to absorb or tolerate oral preparations. Red cell transfusion is necessary only in patients with severe symptomatic anaemia or where chronic blood loss exceeds the possible rate of oral or parenteral replacement. Iron stores are less easily replenished by oral therapy than by injection, and oral therapy (at lower dose) should be continued for 3-6 months after the haemoglobin concentration has returned to normal or until the serum ferritin exceeds 50 microgram/1 (or as long as blood loss continues).
It is illogical to give iron in the anaemia of chronic infection where utilisation of iron stores is impaired; but such patients may als o have true iron deficiency. This may be difficult to diagnose without direct visualisation of stores in a bone marrow aspirate. Iron should not be given in haemolytic anaemias unless there is also haemoglobinuria, for the iron from the lysed cells remains in the body. Moreover the increased erythropoiesis associated with chronic haemolytic states stimulates increased iron absorption and adding to the iron load may cause haemosiderosis.
Acute: . Acute iron toxicity , usually seen in young children who have swallowed attractively coloured iron tablets in mistake for sweets, occurs after ingestion of large quantities of iron salts. This can result in severe necrotising gastritis with vomiting, haemorrhage and diarrhoea, followed by circulatory collapse. Typically acute oral iron poisoning has the following phases: 0.5-1 h after ingestion there is abdominal pain, grey/black vomit, diarrhoea, leucocytosis and hyperglycaemia. Severe cases are indicated by acidosis and cardiovascular collapse which may proceed to coma and death. There follows a period of improvement lastin 6-12 h, which may be sustained or which ma deteriorate to the next stage. Jaundice, hypoglycaemia, bleeding, encephalopathy, metabolic acidosis and convulsions are followed by cardiovascular collapse, coma and sometimes death 48-60 h after ingestion. 1-2 months later, upper gastrointestinal obstruction may result from scarring and stricture Chronic Chronic iron toxicity or iron overload is virtually always caused by conditions other than ingestion of iron salts, for example chronic haemolytic anaemias such as the thalassaemias (a large group of genetic disorders of globin chain synthesis) or repeated blood transfusions. Prolonged heavy excess of iron intake overwhelms the mechanism described and results in haemosiderosis, as there is no physiological mechanism to increase iron excretion in the face of increased absorption. Iron-deficient subjects absorb up to 20 times as much administered iron as those with normal stores. Abnormalities of the small intestine may interfere with either the absorption of iron, as in coeliac disease and other malabsorption syndromes, or possibly with the conversion of iron into a soluble and reduced form, e.g. following loss of acid secretion after a partial gastrectomy Therapy: Raw egg and milk help to bind iron until a chelating agent is available. The first step should be to give desferrioxamine 1-2 g i.m.; the dose is the same in adults and children. Only after this should gastric aspiration or emesis be performed. If lavage is used, the water should contain desferrioxamine 2 g/1. After empty-ing the stomach, desferrioxamine 10 g in 50-100 ml water should be left in the stomach to chelate any remaining iron in the intestinal lumen; it is not absorbed. Subsequently, desferrioxamine should be administered by i.v. infusion not exceeding 15 mg/kg/h (maximum 80 mg/kg/24 h) or further i.m. Injections (2 g in sterile water 10 ml) should be given 12-hourly. Poisoning is severe if the plasma iron concentration exceeds the total iron binding capacity (upper limit 75 mmol/1) or the plasma becomes pink due to the large formation of ferrioxamine (see below). If severe poisoning is suspected i.v. Rather than i.m. administration of desferrioxamine is indicated without waiting for the result of the plasma concentration.
http://www.theironfiles.co.uk/MDS/General/Blood-Transfusions.html When desferrioxamine comes into contact with ferric iron, its straight-chain molecule twines around it and forms a nontoxic complex of great stability (ferrioxamine), which is excreted in the urine giving it a red/orange colour, and in the bile. It is not absorbed from the gut and must be injected for systemic effect. In acute poisoning, as opposed to chronic overload, desferrioxamine 5 g chelates the iron contained in about 10 tablets of ferrous sulphate or gluconate. It has a negligible affinity for other metals in the presence of iron excess
The treatment of acute and chronic iron toxicity involves the use of iron chelators, such as desferrioxamine . This is not absorbed from the gut but is nonetheless given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as intramuscularly and, if necessary, intravenously. In severe poisoning, it is given by slow intravenous infusion. Desferrioxamine forms a complex with ferric iron, and, unlike unbound iron, this is excreted in the urine. A new, orally absorbed iron chelator, deferiprone (L1), was recently licensed in the UK to treat iron overload in patients with thalassaemia major, in whom desferrioxamine is contraindicated or not tolerated. Agranulocytosis and other blood dsyscrasias have been described, so its use requires careful monitoring. Serious adverse effects are uncommon but include rashes and anaphylactic reactions; with chronic use cataract, retinal damage and deafness can occur. Hypotension occurs if desferrioxamine is infused too rapidly and there is danger of (potentially fatal) adult respiratory distress syndrome if infusion proceeds beyond 24 h
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