Approach to Anemia and Iron Deficiency Anemia PDF

Presenting problems in blood disease  Learning objectives 1-Definition ,types and classification causes of anemia 2-Clinical presentation of Anaemia 3-Investigation and approach to anemia 4-IDA causes approach to investigation and diagnosis 5-Mechanism of Iron absorption & r...

Presenting problems in blood disease  Learning objectives 1-Definition ,types and classification causes of anemia 2-Clinical presentation of Anaemia 3-Investigation and approach to anemia 4-IDA causes approach to investigation and diagnosis 5-Mechanism of Iron absorption & regulation & Distribution of Body Iron 6-DDX and treatment of IDA  Anaemia Anaemia refers to a state in which the level of hemoglobin in the blood is below the normal range appropriate for age and sex. Other factors, including pregnancy and altitude, also affect haemoglobin levels and must be taken into account when considering whether an individual is anaemic. The clinical features of anaemia reflect diminished oxygen supply to the tissue and depend upon the 1-degree of anaemia, 2-the rapidity of its development and 3- the presence of cardiorespiratory disease. A rapid onset of anaemia (e.g. due to blood loss) will cause more profound symptoms than a gradually developing anaemia. Individuals with cardiorespiratory disease will have symptoms of anaemia at higher haemoglobin levels than those with normal cardiorespiratory function. The diagnosis of anaemia not only includes the assessment of its clinical severity but must also define the underlying cause. This rests on the clinical history and examination, assessment of the full blood count and blood film, and further appropriate investigations. History: 1. Iron deficiency anaemia is the most common type of anaemia world-wide. A thorough gastrointestinal history is important, looking in particular for symptoms indicating blood loss. 2. Menorrhagia is a common cause of anaemia in females still menstruating, so women should always be asked about their periods. 3. A dietary history should assess the intake of iron and folate which may become deficient in comparison to needs (e.g. in pregnancy or during periods of rapid growth).  Past medical history: may reveal a disease which is known to be associated with anaemia, such as rheumatoid arthritis (the anaemia of chronic disease), or previous surgery (e.g. resection of the stomach or small bowel which may lead to malabsorption of iron and/or vitamin B12). Family history : ethnic background of the patient are important. Haemolytic anaemias such as the haemoglobinopathies and hereditary spherocytosis may be suspected from the family history. Pernicious anaemia may also be familial. A drug history: may reveal the ingestion of drugs which can be associated with blood loss (e.g. aspirin and anti-inflammatory drugs) or drugs that may cause haemolysis or aplasia.  Physical examination As well as the general physical findings of anaemia, there may be specific findings related to the aetiology of the anaemia; for example, a patient may be found to have a right iliac fossa mass due to an underlying caecal carcinoma. Haemolytic anaemias can cause jaundice. Vitamin B12 deficiency may be associated with neurological signs including peripheral neuropathy, dementia and signs of subacute combined degeneration of the cord. Sickle-cell anaemia may result in leg ulcers. Anaemia may be multifactorial and the lack of specific symptoms and signs does not rule out silent pathology. Causes of anaemia 1-Decreased or ineffective marrow production Lack of iron, vitamin B12 or folate Hypoplasia Invasion by malignant cells Renal failure Anaemia of chronic disease 2-Peripheral causes Blood loss Haemolysis Hypersplenism Schemes for the investigation of anaemias are often based on the size of the red cells, which is most accurately indicated by the mean cell volume (MCV) in the FBC. Commonly, in the presence of anaemia: A normal MCV (normocytic anaemia) suggests either acute blood loss or the anaemia of chronic disease (ACD) A low MCV (microcytic anaemia) suggests iron deficiency or thalassaemia A high MCV (macrocytic anaemia) suggests vitamin B12 or folate deficiency  The reticulocyte count allows the critical distinction between anemia arising from a primary failure of red cell production and that resulting from increased red cell destruction. Erythrocytes newly released from the marrow still contain small amounts of RNA; these are termed reticulocytes, and can be detected by staining the peripheral blood smear with methylene blue or other supravital stains. In response to the stress of anemia, erythropoietin (EPO) production increases and promotes the production and release of increased numbers of reticulocytes. The number of reticulocytes in the peripheral blood therefore reflects the response of the bone marrow to anemia. Around 30% of the total world population is anaemic and half of these, some 600 million people, have iron deficiency. The classification of anaemia by the size of the red cells (MCV) indicates the likely cause. Red cells in the bone marrow must acquire a minimum level of haemoglobin before being released into the blood stream. Whilst in the marrow compartment red cell precursors undergo cell division driven by erythropoietin. If red cells cannot acquire haemoglobin at a normal rate they will undergo more divisions than normal and will have a low MCV when finally released into the blood. The MCV is low because component parts of the haemoglobin molecule are not fully available: that is, iron in iron deficiency, globin chains in thalassaemia, haem ring in congenital sideroblastic anaemia and, occasionally, poor iron utilisation in the anaemia of chronic disease. In megaloblastic anaemia the biochemical consequence of vitamin B12 or folate deficiency is an inability to synthesise new bases to make DNA. A similar defect of cell division is seen in the presence of cytotoxic drugs or haematological disease in the marrow such as myelodysplasia. In these states, cells haemoglobinise normally but undergo fewer cell divisions, resulting in circulating red cells with a raised MCV. The red cell membrane is composed of a lipid bilayer which will freely exchange with the plasma pool of lipid. Conditions such as liver disease, hypothyroidism, hyperlipidaemia and pregnancy are associated with raised lipids and may cause a raised MCV. Iron Deficiency Anemia  Prevalence of IDA: Around 30% of the total world population is anaemic and half of these, some 600 million people, have iron deficiency. It is more common in developing countries like ours.  Why is Iron so Important !? Iron is required for a large variety of fundamental processes transport of oxygen and electrons and respiration. One of the most important iron containing proteins are heme proteins, which include Hemoglobin , myoglobin, cytochromes, peroxidases and catalase. Nearly half of enzymes and co-factors of Kreb cycle , either contain iron or require its presence.  Iron absorption : Normal mixed diet contains about 10-20 mg of iron /day. This present in inorganic or organic forms. Dietary sources include : meats especially liver and kidney, egg yolk, some green vegetables like Peas, lentil and beans. Milk has low iron content generally. Usually only 5-10% of ingested iron is absorbed. After ingestion of iron containing foods, Iron is released from protein complexes by acid and proteolytic enzymes in stomach and SI, and then is maximally absorbed in duodenum and less so Jejunum.  Iron absorption regulation The intestinal mucosal cells play the key role in physiological regulation of body intake of iron. The body iron stores are reflected in the cytoplasmic iron content of mucosal intestinal cells. And if : 1. Body stores are high, so is mucosal cell iron : iron absorption from intestinal lumen is prevented, and mucosal cells with their iron are shed into lumen (physiological) 2. Body stores are low, so is mucosal cell iron : the mucosal cells permit absorption.  Mucosal Intestinal cell Blood lumen stream 1. If iron stores Iron are depleted 2. If iron stores are Iron overloaded ferritin shed  Absorption Dietary Iron Epithelial cells in duodenum and Jejunum absorption SIMPLIFIED DIAGRAM OF IRON Plasma as Metabolism transferrin bound Iron Iron released RBC destroyed at the end of their life Iron Developing Hemoglobin incorporated in in the RBC Erythroblasts haem of Hb In marrow  Excretion of Iron : There is no physiological mechanism for excretion of Iron, and losses of iron occur through: 1. Shedding of intestinal cells and macrophages in stool. 2. Urine. 3. Nails, hair and desquamated skin cells. 4. Menstruation in females. Total losses of Iron/day ~ 1 mg is counterbalanced by a daily absorption of ~ 1 mg from diet.  Distribution of Body Iron : Total body iron in an adult is ranges from 3.5 –2.5g ; higher in males than in females. Most body iron is present in Hemoglobin of the blood (~ 65-70%). Storage Iron is present in forms of Ferritin and hemosidrin, in reticuloendothelial system (in bone marrow, spleen and liver), and paranchymal liver cells (gaining their Iron from plasma transferrin) (~25-29%). Tissue Iron : in iron-containing enzymes and Myoglobin of muscles(~4%). Plasma Iron is carried by Iron transporting protein transferrin, constitutes only a tiny portion of body Iron (~0.1%).  Distribution of Body Iron Plasma (transferrin) (~0.1%) Myoglobin (~4%) Storage iron (~25-29%) Hemoglobin (~65 -70% Iron deficiency anaemia Blood loss The most common explanation in men and post- menopausal women is gastrointestinal blood loss. This may result from occult gastric or colorectal malignancy, gastritis, peptic ulceration, inflammatory bowel disease, diverticulitis, polyps and angiodysplastic lesions. On a world-wide basis, hookworm and schistosomiasis are the most prevalent causes of gut blood loss. Gastrointestinal blood loss may be exacerbated by the chronic use of aspirin or NSAIDs, which cause intestinal erosions and impair platelet function. In women of child-bearing age, menstrual blood loss, pregnancy and breastfeeding contribute to iron deficiency by depleting iron stores; in developed countries one-third of women in this age bracket have low iron stores but only 3% display iron- deficient haematopoiesis. Rarely, chronic haemoptysis or haematuria may cause iron deficiency. Malabsorption A dietary assessment should be made in all patients to ascertain their iron intake. Gastric acid is required to release iron from food and helps to keep iron in the soluble ferrous state. Hypochlorhydria in the elderly or that due to drugs such as proton pump inhibitors may contribute to the lack of iron availability from the diet, as may previous gastric surgery. Iron is absorbed actively in the upper small intestine and hence can be affected by coeliac disease. Anyone with features of malabsorption or recurrent deficiency in the absence of other explanations, young men with normal diet or young women with normal menstruation and diet in association with iron deficiency, should be screened for coeliac disease. Physiological demands At times of rapid growth such as infancy and puberty, iron demands increase and may outstrip absorption. This may be exacerbated by prematurity and breastfeeding in infants or menstruation in girls. In pregnancy, iron is diverted to the fetus, the placenta and the increased maternal red cell mass, and is lost with bleeding at parturition. There is no consensus about the routine use of iron supplementation in pregnancy but if women with a poor dietary history or previous heavy menstrual losses become pregnant and the side-effects are acceptable, it is a justifiable practice.  Causes of Iron Deficiency: 1. Blood Loss : Most common cause in developed countries; Most likely from the gastrointestinal tract (hookworm infestation, Duodenal ulcer, Ca stomach or colon, crohn’s , ulcerative colitis, hemorrhoids, salicylates). In females bleeding from genital tract is also quite common. 2. Nutritional : Quite common cause of Iron deficiency in developing and underdeveloped countries, especially if inadequate intake is coupled with increased demand (e.g infancy and pregnancy and adolescence). 3. Inadequate absorption : Malabsorption syndromes e.g. Celiac disease. Investigations A-Confirmation of iron deficiency 1-Plasma ferritin is a measure of iron stores and the best single test to confirm iron deficiency. It is a very specific test; a subnormal level is due to iron deficiency, hypothyroidism or vitamin C deficiency. Levels can be raised by liver disease and in an acute phase response; in these conditions a ferritin level of up to 100 μg/l may still be associated with absent bone marrow iron stores. 2-Plasma iron and total iron binding capacity (TIBC) are measures of iron availability, hence are affected by many factors besides iron stores. 3-Plasma iron has a marked diurnal and day-to-day variation and becomes very low during an acute phase response but is raised in liver disease and haemolysis. 4-Transferrin levels are lowered by malnutrition, liver disease, an acute phase response and nephrotic syndrome but raised by pregnancy or the oral contraceptive pill. 5-A transferrin saturation of less than 16% (i.e. S.iron/TIBC × 100)is consistent with iron deficiency but is less specific than a ferritin measurement. All proliferating cells express membrane transferrin receptors to acquire iron; a small amount of this receptor is shed into blood and found in a free soluble form there. At times of poor iron stores, cells up-regulate transferrin receptor expression; hence the levels of 6-soluble plasma transferrin receptor increase. This can now be measured by immunoassay and used to distinguish storage iron depletion in the presence of an acute phase response or liver disease where a raised level indicates iron deficiency. In difficult cases it may still be necessary to examine a 7-bone marrow aspirate for iron stores. B-Investigation of the cause This will depend upon the age and sex of the patient as well as the history and clinical findings. In men over the age of 40 years and in post- menopausal women with a normal diet, the upper and lower gastrointestinal tract should be investigated by endoscopy or barium studies. If coeliac disease is suspected, serum antigliadin and anti-endomysium antibodies and duodenal biopsy are indicated. In the tropics stool and urine should be examined for parasites.  Clinical Findings : Clinical features related to underlying pathology, if any. Early stages : no significant findings. As anaemia progresses : A-Signs and Symptoms of anaemia : Pallor, Fatigue, decrease exercise capacity, shortness of breath. B-Mucosal changes in severe IDA: 1. Mouth soreness (glossitis, smooth red tongue). 2. Spooning of nails (koilonychia) C-Pica (craving to eat unusual substances like dirt, Clay, ice, salt hair or cardboard). D-No Organomegaly relevant to IDA, is expected. Pallor Glossitis Koilonychia (Spooning of the nails)  Blood Picture in IDA: 1. Hemoglobin : reduced 2. PCV : reduced. 3. MCH, MCV, MCHC all reduced 4. Leucocytes and platelets usually normal. 5. Red cells on film : Hypochromic, microcytic. 6. Bone marrow aspirate : Non-specific changes. Depleted Iron stores on Staining the marrow with a stain for iron (Diagnostic).  Blood Film findings in IDA: Normochromic, normocytic NORMAL Hypochromic, Microcytic IDA  Diagnosis of IDA : 1. Hematological findings. 2. Serum Iron and TIBC : Serum Iron reduced. Total Iron binding capacity increased S. Iron/TIBC : Transferrin saturation reduced (< 15%). 3. S. Ferritin : reflects storage iron and is classically reduced in IDA(< 15ug/L). 4. Bone marrow Iron : as determined by Prussian blue stain for marrow Iron is depleted. (Diagnostic). Iron stain on marrow Iron is represented by blue granules Normal Marrow Iron deficient marrow Normal storage Iron Absent storage iron  Differential diagnosis of IDA (from other causes of hypochromic Anaemia): 1. Thalassaemia : Clinical features, Iron studies and Hb electrophoresis. 2. Sideroblastic Anaemia. Clinical features, Iron studies, bone marrow iron stain. 3. Lead poisoning: History, blood film, Iron steady, urine lead. 4. Anaemia of Chronic disorders: History, Iron studies. Management Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron supplementation is appropriate. Ferrous sulphate 200 mg 8-hourly (120 mg of elemental iron per day) is more than adequate and should be continued for 3-6 months to replete iron stores. The occasional patient is intolerant of ferrous sulphate, with dyspepsia and altered bowel habit. In this case a reduction in dose to 200 mg 12-hourly or a switch to ferrous gluconate 300 mg 12-hourly (70 mg of elemental iron per day) should be made. Delayed-release preparations are not useful since they release iron beyond the upper small intestine where it cannot be absorbed. The haemoglobin should rise by 10 g/l every 7-10 days and a reticulocyte response will be evident by 1 week. A failure to respond adequately may be due to non- compliance, continued blood loss, malabsorption or an incorrect diagnosis. The occasional patient with malabsorption or chronic gut disease may need parenteral iron with deep intramuscular injection of iron sorbitol (1.5 mg of iron per kg body weight). This will produce a haematological response and rapidly replete iron stores. Patients should be warned that a brown skin discoloration like a tattoo is likely to develop at the sites of administratio. Previously, iron dextran or iron sucrose was used, but new preparations of iron isomaltose and iron carboxymaltose have fewer allergic effects and are preferred.  Management of IDA: 1. Check and exclude causes of Iron deficiency especially pathological blood loss. 2. Oral Iron therapy: is the treatment of choice. 3. Paraenteral Iron : is only indicated if there is malabsorption or intolerence to oral iron. Body weight (kg) x 2.3 × (15-patient's hemoglobin, g/dL) + 500 or 1000 mg (for stores). Thank you