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  1. 1.   Tauhid Ahmed Bhuiyan, PharmD Pharmacy Practice Resident (PGY-1) King Faisal Specialist Hospital & Research Center
  2. 2.  Explain background, definition, epidemiology, and etiology of iron deficiency anemia (IDA)  Outline diagnostic algorithm of IDA  Identify key laboratory findings to diagnose IDA  Discuss available therapeutic management of IDA
  3. 3.  Anemia is a group of disease characterized by a decrease in either hemoglobin (Hb) or circulating red blood cells (RBCs) o Results in reduced oxygen-carrying capacity of the blood  According to World Health Organization (WHO) o ̴1.6 billion people (1/4 of world’s population ) are anemic  Not an innocent bystander; affects both length and quality of life (QOL)  IDA occurs across all populations and is associated with o Diminished QOL o Physical and cognitive performance, and o Unfavorable clinical outcomes
  4. 4. DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011 Anemia Macrocytic Normocytic Microcytic Megaloblastic Non-megaloblastic IDA Genetic Anomaly 1. Vitamin B12 deficiency 2. Folic acid deficiency 1. Sickle cell 2. Thalassemia 1. Recent blood loss 2. Hemolysis 3. Bone marrow failure 4. Anemia of chronic disease 1. Hepatic disease 2. Drug-induced anemia 3. Hypothyroidism 4. Reticulocytosis
  5. 5.  According to WHO o Anemia is defined as Hb <130 g/L in men or <120 g/L in female  IDA is the result of long-term negative iron balances o Progressive loss of iron stores in the form of hemosiderin and ferritin  IDA is defined as o Anemia with biochemical evidence of iron deficiency based on following laboratory findings • Serum ferritin, total iron binding capacity (TIBC), transferrin saturation, or transferrin receptor DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  6. 6.  IDA is the most common nutritional deficiency in developing and developed countries  IDA is considered to be the leading cause of anemia worldwide, accounting for as many as 50% of cases  Prevalence of IDA greatly varies according to age, gender, physiological, pathological, environmental, and socioeconomic conditions  Data from NHANES*, prevalence of IDA o Young children 1.2% o Women of childbearing age 4.5% *National Health and Nutrition Examination Survey
  7. 7. RBC production DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011 Iron + Hb
  8. 8.  Normal iron content of the body o ̴3-4 g (Hb, myoglobin, and cytochromes)  Iron is best absorb as ferrous (Fe2+) form in the duodenum, and to a smaller extent in jejunum  Daily recommended allowance o Adult males/postmenopausal females: 8 mg o Menstruating female: 18 mg  Iron sources o Heme iron (2-3X more absorbable): meat, fish, and poultry o Non-heme iron: vegetables, fruits, dried beans, nuts, grain products, and dietary supplements  Gastric acid/ascorbic acid increases non-heme iron absorption whereas phytates (in bran), tannins/polyphenols (in tea), and calcium (in dairy product) form insoluble complexes DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  9. 9. ̶ Iron stores are reduced without reducing serum iron levels and can be assessed with serum ferritin measurement ̶ Iron stores can be depleted without causing anemia Iron deficiency occurs; Hb falls just above the lower limit normal Considered as IDA and occurs because of Hb falls to less than normal values Initial Stage Second Stage Third Stage Once iron stores are depleted, there still is adequate iron from daily RBC turnover for Hb synthesis
  10. 10.  IDA results from prolonged negative iron balance  Mainly due to following factors: 1. Inadequate iron intake 2. Decreased iron absorption 3. Increased iron demand or hematopoiesis 4. Increased iron loss Matthew W. et al. Am Fam Physician. 2013;87(2):98-104
  11. 11. Females in the reproductive period of life Menstruation Pregnancy Pathological blood loss Deficient diet Adult males and postmenopausal females Pathological blood loss Infants and children Deficient diet Diminished iron stores at birth Firkin F. Hypochromic anemia. In: de Gruchy’s Clinical Hematology in Medical Practice, 1989 Etiology
  12. 12.  IDA adversely effects o Cognitive performance, behavior, and physical growth of infants, preschool, and school-aged children o The immune status and morbidity from infections of all age groups o The use of energy sources by muscle and thus the physical capacity and work performance of adolescents and adults of all age groups o Increase perinatal risks for mothers and neonates and overall infant mortality during pregnancy
  13. 13.  
  14. 14. Chief Complaints Fatigue, lassitude, palpitation, and generalized weakness History Chronic blood loss, deficient diet Clinical Features 1. Palor skin, nailbed, conjunctiva 2. Koilonychia (brittle, spoon shaped nails) 3. Atrophic glossitis (atrophy of tongue papilla; making the tongue smooth and shiny) 4. Pica (compulsive eating of nonfood items) or pagophagia (compulsive eating of ice) Firkin F. Hypochromic anemia. In: de Gruchy’s Clinical Hematology in Medical Practice, 1989
  15. 15. Symptoms Signs Decreased exercise tolerance Tachycardia Fatigue Pale appearance (most prominent in conjunctiva) Dizziness Decreased mental acuity Irritability Increased intensity of some cardiac valvular murmurs Weakness Palpitations Vertigo Shortness of breath Chest pain DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  16. 16.  Complete blood count (CBC), erythrocyte sedimentation rate (ESR), and peripheral blood film (PBF)  Serum Iron profile  Bone marrow study (if needed)  Investigations to determine other causes of IDA (e.g. fecal occult blood test, colonoscopy, urine examination)
  17. 17. Hematologic Indices Normal Range IDA Hb 70—160 g/L Low Hematocrit (Hct) 0.320—0.47 L/L Low Mean corpuscular volume (MCV) 75—95 fL Low Mean corpuscular hemoglobin (MCH) 24—30 pg Low Mean corpuscular hemoglobin concentration (MCHC) 290—370 g/L Low Red cell distribution width (RDW) 11—15% High (early) DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011c
  18. 18. Lab Exams Comments In IDA Serum Fe (50-100 mcg/dL) 1. It is the concentration bound to transferrin 2. Approximately one-third transferrin bound to iron 3. Levels are decreased by infection and inflammation 4. Best interpreted in conjunction with TIBC Low Serum ferritin (>10-20 mcg/L) 1. Ferritin (storage iron) is proportional to total iron stores 2. Best indicator of iron deficiency or overload 3. Infection or inflammation can increase the concentration, independent of iron status Low Total iron binding capacity (TIBC) (250-410 mcg/dL) 1. Indirect measurement of the iron-binding capacity of serum transferrin (protein) 2. Levels don’t fluctuate over hours or days unlike serum iron High % Saturation of transferrin (>20%) 1. Ratio of serum iron level to TIBC in percentage 2. Reflects the extent to which iron-binding sites are occupied on transferrin and indicates the availability of iron for erythropoiesis 3. Less sensitive and specific for IDA than ferritin Low DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011c
  19. 19. Matthew W. et al. Am Fam Physician. 2013;87(2):98-104
  20. 20.  
  21. 21.  Short term o Resolution of symptoms o Replenish iron stores  Long term o Improve quality of life (QOL) o Prevention of recurrences o Better growth and development (children)
  22. 22.  Pharmacological management o Oral/parenteral iron therapy  Non-pharmacological o Blood transfusion
  23. 23.  
  24. 24. Matthew W. et al. Am Fam Physician. 2013;87(2):98-104
  25. 25.  Recommended dosage requirements o 200 mg elemental iron per day for 3-6 months o 2-3 divided doses to maximize tolerability o Administration should be 1 hour before meals or on empty stomach  Absorption of all oral preparations are similar DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  26. 26. DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  27. 27.  Gastrointestinal (GI) intolerance o Nausea, vomiting, heartburn, and diarrhea or constipation o Slow release or sustained release preparations may be used o Combination products, e.g. Ferro-DDS (ferrous fumarate/docusate), may be advantageous for certain patient population  Cause discoloration of stool DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  28. 28. DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  29. 29.  Indications for therapy o Intolerance to oral route o Malabsorption o Long-term nonadherence o Patient with significant blood loss who refuse transfusion and are intolerant to oral therapy o Chronic kidney disease (CKD)  Currently available formulations include o Dextran, sodium ferric gluconate, iron sucrose, and ferumoxytol  Formulations differ in their molecular size, degradation kinetics, bioavailability, and side effects profile  All preparations carry a risk for anaphylactic reactions but likely to a lesser extent than iron dextran DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011
  30. 30. Formulation Amount of elemental iron (mg/mL) Warning Treatment Common adverse effects Iron Dextran (INFeD) 50 Black Box Warning (BBW): anaphylactic type reactions 10 doses x 100 mg = 1,000 mg Pain and brown staining at injection site, flushing, hypotension, fever, chills, myalgia, anaphylaxis Sodium Ferric Gluconate (Ferrlecit) 62.5 No BBW: Hypersensitivity reaction 8 doses x 125 mg = 1,000 mg Cramps, nausea and vomiting, flushing, hypotension, rash, pruritis Iron Sucrose* (Ferosac®) 20 BBW: anaphylactic type reactions Up to 10 doses x 100 mg = 1,000 mg Leg cramps, hypotension Ferumoxytol (Feraheme) 30 No BBW: Hypersensitivity reaction 2 doses x 510 mg = 1,020 mg Diarrhea, constipation, dizziness, hypotension, peripheral edema DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011 *KFSH&RC Formulary
  31. 31. Hb-iron deficiency (in mg) = body weight (kg) x (normal Hb - actual Hb in g/L) x 0.24 § Above calculation is based on:  A normal Hb 150 g/L for body weights >35 kg and 130 g/L ≤34 kg body weight respectively  The iron-content of hemoglobin (0.34%)  The blood volume (∼7% of the body weight) and the requirements of depot iron (∼15 mg/kg up to a weight of about 34 kg, total of 500 mg >34 kg)  §Factor 0.24 = 0.0034 x 0.07 x 1000 Total iron deficiency in mg = Hb-iron deficiency + depot iron KFSH&RC Formulary *Iron sucrose
  32. 32. • Total vials of iron requirement for SA: • 1508 mg elemental iron / (20 mg/mL) • Total iron sucrose = 75 mL • Iron sucrose (5 mL / ampule) • (75 mL / 5) = 15 ampules  SA, 60 kg woman with a hemoglobin concentration of 80 g/L due to iron deficiency needs parenteral iron replacement, which will be given intravenously in the form of iron sucrose (20 mg iron/mL). Calculate total iron deficiency and amount of iron sucrose (ampules) for SA? [Injection: 5 mL/ampule]  Solution: o Step 1: calculating elemental iron deficiency in Hb of SA • 60 kg X (150 g/L – 80 g/L) X 0.24 = 1008 o Step 2: depot iron • 500 mg (since SA >34 kg) o Step 3: total iron deficiency • Step 1 + Step 2 = 1008 + 500 = 1508 mg elemental iron
  33. 33.  289383
  34. 34.  
  35. 35.  Decision to manage anemia is based on the evaluation of risk and benefit  Transfusion is generally not indicated if Hb >100 g/L whereas transfusion of RBCs should be considered when Hb is <70 to 80 g/L in hospitalized, stable patient  Transfusion of allogeneic blood is indicated in acute situations (e.g. severe blood loss)  Transfusions may also be necessary for patient with cardiac instability DiPiro J. Anemia. In: Pharmacotherapy: A Pathophysiological Approach, 2011 Szczepiorkowski Z. et al. ASH Education Book 2013;1:638-644 or KFSH&RC Transfusion Guideline:
  36. 36.  Positive response in reticulocytosis is seen in few days of oral therapy  Hb should reach to normal level after 2 months  A Hb response of <20 g/L over a 3-week period warrants therapy evaluation  Iron profile should be measure in the first week for oral therapy and 2 weeks after large intravenous doses  Hb and Hct should be measured weekly, and serum iron and ferritin levels should be measured monthly
  37. 37.  Provide education on healthy lifestyle  Identify high risk population for necessary preventative measures  Select appropriate medication therapy based on patient and drug related factors  Provide medication counseling and adherence  Monitor therapeutic outcome and minimize adverse drug reactions
  38. 38.  IDA is the most common form of anemia and is usually the result of prolonged negative iron balance in the body  Four main factors contributing to IDA include o Inadequate iron intake o Decreased iron absorption o Increased iron demand or hematopoiesis o Increased iron loss  Clinical diagnosis of IDA should include complete patient history and physical exams, followed by laboratory investigations  Abnormal laboratory investigations generally include low MCV, serum iron, and ferritin; and high TIBC
  39. 39.  Treatment of IDA usually consists of dietary supplementation and administration of oral iron preparations  General recommendation for oral iron replacement is ̴200 mg elemental iron/day, divided into 2-3 doses to maximize tolerability  Parenteral therapy is usually not indicated unless patient is intolerant to oral therapy, having malabsorption, or in the case of CKD  Anaphylactic reaction should be considered for all parenteral formulation along with strictly monitoring adverse drug reaction
  40. 40.  Decision to manage anemia with blood transfusion is based on the evaluation of the risk and benefit and is only considered when Hb is <70 to 80 g/L  Complete therapeutic response requires iron supplementation for up to 2-6 months, however, symptoms may improve within few days after oral therapy
  41. 41.  Q1: Which of the following is one of the common cause of IDA in young male? A. Deficient diet B. Menstruation C. Pathological blood loss D. None of the above
  42. 42.  Q2: Microcytic hypochromic anemia can be due to the following factor(s): A. Folic Acid B. Vitamin B12 C. Iron deficiency D. Hemolysis
  43. 43.  Q3: Which of the following statement is false regarding iron in our body? A. It is best absorb in ferrous (Fe2+) form in the duodenum B. Heme iron is found in meat, fish, and poultry C. Gastric acid/ascorbic acid increases non-heme iron absorption D. Non-heme iron is 2-3X more absorbable than heme iron
  44. 44.  Q4: Identify the following laboratory investigations for diagnosing IDA as high/low: Hb MCV Serum iron TIBC Serum ferritin Transferrin saturation Low Low Low High Low Low
  45. 45.  Q5: For oral iron products, the following statements are true except: A. Ferrous sulfate tablet contains 65 mg elemental iron B. Administration of oral iron should be 1 hour before meals or on empty stomach preferably C. Can cause GI intolerance and discoloration of stools D. Percent elemental iron of all oral preparations is roughly the same