Diagnosis and Iron Deficiency Anemias.pptx

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1. Iron Deficiency Anemia DR. KHAWJA FAQIRULLAH SEDIQI, MD, PGY2

2. Anemia Anemia: Hb <13.6 g/ dL in males Hb <12 g/ dL in females Or Hematocrit below 41% in males Hematocrit below 36% in females Hematocrit levels are less useful than hemoglobin levels in assessing anemia because they are calculated rather than measured directly

3. Classification of anemia Marrow production defects ( hypoproliferation ) low reticulocyte production index together little or no change in red cell morphology (a normocytic, normochromic anemia) red cell maturation defects ( ineffective erythropoiesis ) slight to moderately elevated reticulocyte production index either macrocytic Or microcytic decreased red cell survival ( blood loss/hemolysis ).

4. Hypoproliferative anemias are the most common anemias, and in the clinic, iron deficiency anemia is the most common of these followed by the anemia of inflammation. The anemia of inflammation, similar to iron deficiency, is related in part to abnormal iron metabolism IDA is normocytic normochromic early and then microcytic hypochromic lately.

5. RPI<2.5% RPI<2.5% RPI > 2.5% RPI < 2.5% RPI: Reticulocyte production index 1. Blood loss 2. Intravascular hemolysis

6. Iron Metabolism Role of iron: carry O 2, as a part of HB, myoglobin in muscle, cytochrome system in mitochondria Iron Content, mg Adult Male, 80 kg Adult Female, 60 kg Hemoglobin Myoglobin /enzymes Transferrin iron Iron stores 2500 500 3 600–1000 1700 300 3 0–300

7. The Iron Cycle in Humans Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin transferrin as Mono ferric or diferric The turnover (half-clearance time) of transferrin-bound iron is very rapid—typically 60–90 min The clearance time of transferrin-bound iron from the circulation is affected Plasma iron level Erythroid marrow activity

8. Iron cycle transferrin receptors—the cell having the greatest number of receptors (300,000–400,000/cell) is the developing erythroblast the average red cell life span is 120 days. Thus , 0.8–1% of red cells are replaced each day. At the end of its life span , the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system , and the red cell undergoes phagocytosis. Once within the RE cell, the ingested hemoglobin is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin via the iron export channel, ferroportin . It is the efficient and highly conserved recycling of iron from senescent red cells that supports steady-state (and even accelerated) erythropoiesis

9. Cont… Each milliliter of red cells contains 1 mg of elemental iron Daily need of a young man is 1mg iron Daily need of child bearing age female is 1,4 mg With markedly stimulated erythropoiesis , demands for iron are increased by as much as six- to eightfold

10. Iron absorption 10% of dietary iron is absorbed Absorption depends on: -dietary iron content - bioavailability ( heme vs. non- heme ) - mucosal cell receptor number Main absorption occurs in duodenum .

11. Nutritional Iron Balance Iron excretory pathway is: Blood loss Loss of epithelial cells from the skin, gut, and genitourinary tract Iron comes into the body from: Absorption from food From medicinal. Through red-cell transfusions Injection of iron complexes The average iron intake in an adult male is 15 mg/d with 6% absorption; for the average female, the daily intake is 11 mg/d with 12% absorption one-third of the female population in the United States has virtually no iron stores

12. Cont… When ionizable iron salts are given together with food, the amount of iron absorbed is reduced. When the percentage of iron absorbed from individual food items is compared with the percentage for an equivalent amount of ferrous salt, iron in vegetables is only about one-twentieth as available, egg iron one-eighth, liver iron one-half, and heme iron one-half to two-thirds

13. During the last two trimesters of pregnancy, daily iron requirements increase to 5–6 mg, and iron supplements are strongly recommended for pregnant women in developed countries Iron absorption takes place largely in the proximal small intestine For absorption, iron must be taken up by the luminal cell. That process is facilitated by the acidic contents of the stomach, which maintains the iron in solution. At the brush border of the absorptive cell, the ferric iron is converted to the ferrous form by a ferrireductase

14. Iron absorption cont … DMT-1 is a general cation transporter. Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin . The function of ferroportin is negatively regulated by hepcidin , the principal iron regulatory hormone. In the process of release, iron interacts with another ferroxidase, hephaestin , which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin , the copper-carrying protein

15. Iron absorption is influenced by a number of physiologic states: Erythroid hyperplasia Hepcidin Anemias Inflammatory states

16. Iron: too much is bad Generates free radicals Causes oxidative damage to cells Protective mechanisms Intracellular and intravascular iron bound to carrier proteins- transferrin, ferritin, hemoglobin, etc. Iron absorption tightly regulated .

17. Iron deficiency anemia

18. General aspects Iron deficiency is one of the most prevalent forms of malnutrition. Globally , 50% of anemia is attributable to iron deficiency and accounts for approximately nearly a million deaths annually worldwide. Africa and parts of Asia bear 71% of the global mortality burden; North America represents only 1.4% of the total morbidity and mortality associated with iron deficiency

19. Stages of Iron Deficiency :

20. Negative iron balance : demands for (or losses of) iron exceed the body’s ability to absorb iron from the diet. results from a number of physiologic mechanisms: including blood loss pregnancy (in which the demands for red cell production by the fetus outstrip the mother’s ability to provide iron) rapid growth spurts in the adolescent, or inadequate dietary iron intake. Blood loss in excess of 10–20 mL of red cells per day is greater than the amount of iron that the gut can absorb from a normal diet . Under these circumstances, the iron deficit must be made up by mobilization of iron from RE storage sites . During this period, iron stores—reflected by the serum ferritin level or the appearance of stainable iron on bone marrow aspirations—decrease.

21. Negative iron balance As long as iron stores are present and can be mobilized, the serum iron, total iron-binding capacity (TIBC), and red cell protoporphyrin levels remain within normal limits. At this stage, red cell morphology and indices are normal

22. Iron deficient erythropoeisis When iron stores become depleted, the serum iron begins to fall. Gradually , the TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron stores are absent when the serum ferritin level is <15 μg /L. As long as the serum iron remains within the normal range , hemoglobin synthesis is unaffected despite the dwindling iron stores . Once the transferrin saturation falls to 15–20%, hemoglobin synthesis becomes impaired. This is a period of iron-deficient erythropoiesis . Careful evaluation of the peripheral blood smear reveals the first appearance of microcytic cells, and if the laboratory technology is available, one finds hypochromic reticulocytes in circulation. Gradually, the hemoglobin begins to fall, reflecting iron-deficiency anemia . The transferrin saturation at this point is <10–15%

23. Iron deficiency anemia moderate anemia is present (hemoglobin 10–13 g/ dL ), the bone marrow remains hypoproliferative . With more severe anemia (hemoglobin 7–8 g/ dL ), hypochromia and microcytosis become more prominent , target cells and misshapen red cells ( poikilocytes ) appear on the blood smear as cigar- or pencil-shaped forms, and the erythroid marrow becomes increasingly ineffective. Consequently , with severe prolonged iron-deficiency anemia, erythroid hyperplasia of the marrow develops, rather than hypoproliferation

24. Causes of Iron Deficiency Increased Demand for Iron     Rapid growth in infancy or adolescence   Pregnancy   Erythropoietin therapy Increased Iron Loss     Chronic blood loss   Menses   Acute blood loss   Blood donation   Phlebotomy as treatment for polycythemia vera Decreased Iron Intake or Absorption     Inadequate diet    Malabsorption from disease ( sprue , Crohn's disease)    Malabsorption from surgery ( postgastrectomy )   Acute or chronic inflammation

25. Clinical Presentation of Iron Deficiency Certain clinical conditions. Pregnancy Adolescence Periods of rapid growth Intermittent history of blood loss of any kind A cardinal rule is that the appearance of iron deficiency in an adult male or postmenopausal female means gastrointestinal blood loss until proven otherwise

26. anemia itself (easy fatigability, tachycardia, palpitations , and dyspnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue , brittle nails, spooning of nails ( koilonychia ), and cheilosis . Dysphagia due to the formation of esophageal webs (Plummer-Vinson syndrome) may occur in severe iron deficiency. Many iron-deficient patients develop pica, craving for specific foods (ice chips, etc ) often not rich in iron

27. PICA and iron deficiency Compulsive ingestion of usually a single non-nutritive substance Behavior cured with therapeutic iron therapy Typical ingested substances Carpet Dirt Hair Clothing Clay

28. Signs and symptoms Restless leg syndrome is a common but a nonspecific finding in patients with iron deficiency anemia

29. Laboratory Iron Studies Serum Iron and Total Iron-Binding Capacity: The serum iron level represents the amount of circulating iron bound to transferrin Normal: 50–150 microg / dL The TIBC is an indirect measure of the circulating transferrin. Normal: 300–360microg/ dL Transferrin saturation, which is normally 25–50 %, is obtained by the following formula: serum iron × 100 ÷ TIBC

30. Iron-deficiency states are associated with saturation levels <20 %. There is a diurnal variation in the serum iron. A transferrin saturation >50 % indicates that a disproportionate amount of the iron bound to transferrin is being delivered to nonerythroid tissues. If this persists for an extended time, tissue iron overload may occur

31. Serum Ferritin : Free iron is toxic to cells Within cells, iron is stored complexed to protein as ferritin or hemosiderin the serum ferritin level correlates with total body iron stores Adult males 100micro g/L , adult female30 g/L As iron stores are depleted, the serum ferritin falls to <15 μg /L. Such levels are diagnostic of absent body iron stores

32. Bone Marrow Iron Stores Ferritin levels Bone marrow stain Bone marrow biopsy for evaluation of iron stores is rarely performed. If the biopsy is done, it shows the absence of iron in erythroid progenitor cells by Prussian blue staining. The platelet count is commonly increased, but it usually remains under 800,000/ mcL (800 × 109/L )

33. Red Cell Protoporphyrin Levels Protoporphyrin is an intermediate in the pathway to heme synthesis. Under conditions in which heme synthesis is impaired, protoporphyrin accumulates within the red cell. This reflects an inadequate iron supply to erythroid precursors to support hemoglobin synthesis. Normal values are <30 μg / dL of red cells . In iron deficiency, values >100 μg / dL are seen. The most common causes of increased red cell protoporphyrin levels are absolute or relative iron deficiency and lead poisoning

34. Serum Levels of Transferrin Receptor Protein Because erythroid cells have the highest numbers of transferrin receptors of any cell in the body, and because transferrin receptor protein (TRP) is released by cells into the circulation, serum levels of TRP reflect the total erythroid marrow mass . Another condition in which TRP levels are elevated is absolute iron deficiency. Normal values are 4–9 μg /L determined by immunoassay . This laboratory test is becoming increasingly available and, along with the serum ferritin, has been proposed to distinguish between iron deficiency and the anemia of inflammation

35. Differential Diagnosis Tests Iron Deficiency Inflammation Thalassemia Sideroblastic Anemia Smear Micro/hypo Normal/ Micro/hypo Micro/hypo with targeting Variable Serum iron (μ g/ dL ) <30 <50 Normal to high Normal to high TIBC (μ g/ dL ) >360 <300 Normal Normal Percent saturation <10 10-20 30-80 30-80 Ferritin ( microg /L) <15 30-200 50-300 50-300 Hemoglobin pattern on electrophoresis Normal Normal Abnormal with   thalassemia ; can be normal with thalassemia Normal

36. Treatment

37. Severity and cause of iron-deficiency anemia will determine the appropriate approach to treatment. As an example, symptomatic elderly patients with severe iron-deficiency anemia and cardiovascular instability may require red cell transfusions. Younger individuals who have compensated for their anemia can be treated more conservatively with iron replacement. For the majority of cases of iron deficiency (pregnant women, growing children and adolescents, patients with infrequent episodes of bleeding, and those with inadequate dietary intake of iron), oral iron therapy will suffice. For patients with unusual blood loss or malabsorption , specific diagnostic tests and appropriate therapy take priority. Once the diagnosis of iron-deficiency anemia and its cause is made, there are three major therapeutic approaches

38. Red Cell Transfusion In those: symptoms of anemia, cardiovascular instability, continued and excessive blood loss from whatever source Correct the anemia Source of iron for reutilization Transfusion therapy will stabilize the patient while other options are reviewed

39. Oral iron therapy In the asymptomatic patient with established iron-deficiency anemia and an intact gastrointestinal tract, treatment with oral iron is usually adequate Factors that enhance iron absorption : Oral Iron Preparations Daily treatment dosage 100-200 element iron Goal : repair the anemia, and also provide stores of at least 0.5–1 g of iron Duration of treatment period of 6–12 months Side effect

40. Complications of oral iron therapy : gastrointestinal distress is the most prominent and is seen in at least 15–20% of patients . Abdominal pain, nausea, vomiting, or constipation may lead to noncompliance. Although small doses of iron or iron preparations with delayed release may help somewhat, the gastrointestinal side effects are a major impediment to the effective treatment of a number of patients

41. Diet Encouraging dietary intake of iron-rich foods is also useful. Such foods include oysters, kidney beans, beef liver, tofu, beef (chuck roast, lean ground beef), turkey leg, whole-wheat bread, tuna , eggs, shrimp, peanut butter, leg of lamb, brown rice, raisin bran (whole grain–enriched cereals), lentils, and beans. Ideally, oral iron preparations should be taken on an empty stomach, since food may inhibit iron absorption

42. Cont … Generic Name Tablet (Iron Content), mg Elixir (Iron Content), mg in 5 mL Ferrous sulfate 325(65) 195(39) 300(60) 90(18) Extended release 525(105) Ferrous fumarate 325(107) 195(64) 100(33) Ferrous gluconate 325(39) 300(35) Polysaccharide iron 150(150) 50(50) 100(100)

43. Response to Oral Iron therapy depending on the EPO stimulus and the rate of absorption. Typically , the reticulocyte count should begin to increase within 4–7 days after initiation of therapy and peak at 1–1½ weeks. The absence of a response may be due to poor absorption, noncompliance (which is common), or a confounding diagnosis Continue iron therapy for at least 3-4 months, possibly longer

44. A useful test in the clinic to determine the patient’s ability to absorb iron is the iron tolerance test . Two iron tablets are given to the patient on an empty stomach, and the serum iron is measured serially over the subsequent 2–3 h. Normal absorption will result in an increase in the serum iron of at least 100 μg / dL . If iron deficiency persists despite adequate treatment, it may be necessary to switch to parenteral iron therapy

45. Causes for poor response to oral iron -Non-compliance *** -Incorrect administration*** -Incorrect diagnosis -Incorrect dosing -Ongoing blood loss - Malabsorption

46. Parentral iron therapy Not tolerate iron therapy Need is relatively acute Iron deficiency not responding to oral iron therapy -Poor compliance -Adverse effects - Malabsorption * -Ongoing hemorrhage * .

47. Parenteral iron is used in two ways: Administer the total dose of iron Repeated small doses over time Amount of iron needed: Body weight (kg) x 2.3 x (15–patient's hemoglobin, g/ dL ) + 500 or 1000 mg (for stores). Side effect: anaphylaxis , Generalized symptoms appearing several days after the infusion of a large dose of iron can include arthralgias , skin rash, and low-grade fever Although a test dose (25 mg) of parenteral iron dextran is recommended Early in the infusion of iron, if chest pain , wheezing, a fall in blood pressure, or other systemic symptoms occur , the infusion of iron should be stopped immediately

48. IV iron therapy Preparations : Iron dextran (HMW and LMW) Ferric gluconate Iron sucrose Side effects : Anaphylaxis (2-3% with iron dextran) Chills, back pain, body aches .