Anemia basic and approach

Breif presentation on basics of anemia and its causes, approach.

1. ANEMIA DR HASEEB AHMED BHATTI MBBS, MD (USA)

2. Definition Anemia is a condition in which the number of RBCs or their oxygen-carrying capacity(Hb content) is insufficient to meet physiologic needs, which vary by age, sex, altitude, smoking, and pregnancy status For diagnosis and further evaluation Hb values: • <13 g/dL in adult males. • <12.0 g/ dL in adult females. Hgb = expression of amount (g/dL). Hct = expression of volume (% or decimal fraction). RBC = expression of number (#/mm 3 ). WHO recommendations

3. Anemia: Special Populations Higher Hb/HCT: Patients living at high altitudes Smokers and patients living in air pollution areas Endurance athletes have increased HCT Lower Hb/HCT: African-Americans have 0.5 to 1 g/dl lower Hb than do Caucasians Elderly (slowed erythropoiesis) Pregnant women (hemodilution)

4. Normal erythropoiesis © Dr. Haseeb Ahmed Bhatti

5. © Dr. Haseeb Ahmed Bhatti

6. Normal Iron cycle © Dr. Haseeb Ahmed Bhatti

7. Mechanism of anemia Any process that can disrupt the normal life span of a red blood cell may cause anemia. Normal life span of a red blood cell is typically around 120 days. Red blood cells are made in the bone marrow. Anemia is caused essentially through two basic pathways. Anemia is caused by either: 1. a decrease in production of red blood cells or hemoglobin, or an increase in loss or destruction of red blood cells.

8. Pathophysiologic Classification I. Anemia due to blood loss a. Acute post haemorrhagic anemia b. Anemia due to chronic blood loss II. Anemia due to impaired red cell formation a. Cytoplasmic maturation defects - Deficient haem synthesis : Iron deficiency anemia -Deficient globin synthesis : Thalassaemic syndromes b. Nuclear maturation defects Vitamin B12 & /or Folic acid deficiency : Megaloblastic anemia 6 © Dr. Haseeb Ahmed Bhatti

9. Pathophysiologic Classification c. Defect in stem cell proliferation & differentiation Aplastic anemia Pure red cell aplasia d. Bone marrow failure due to systemic diseases (anemia of chronic disorders) Anemia of inflammation/infections, disseminated malignancy. Anemia in renal disease Anemia due to endocrine & Nutritional deficiences Anemia in liver disease © Dr. Haseeb Ahmed Bhatti

10. Pathophysiologic Classification e. Bone marrow infiltration Leukaemias lymphomas Multiple myeloma f. Congenital anemia Sideroblastic anemia Congenital dyserythropoietic anemia. III. Anemia due to increased red cell destruction (hemolytic anemias) Intracorpuscular defect (erythrocyte defects- membrane abnormalities, metabolic disturbances, disorders of hemoglobin) Extracorpuscular defect (abnormal elements in vascular bed that “attack” RBCs) © Dr. Haseeb Ahmed Bhatti

11. Morphology Classification Microcytic (MCV <80 µ 3 ): Iron deficiency, thalassemia, chronic disease/inflammation, sideroblastic anemia, lead poisoning. Normocytic (MCV 80-100 µ 3 ): Acute blood loss, chronic disease, hypersplenism, bone marrow failure, hemolysis. Macrocytic (MCV >100 µ 3 ): B12 or folate deficiency, hemolysis with reticulocytosis, chemotherapy, hypothyroidism, MDS.

12. Copyright ©2002 American Society of Hematology. Copyright restrictions may apply. Schrier, S. ASH Image Bank 2002;2002:100325 Figure 1. Note the profound central pallor of the hypochromic and microcytic RBC

13. CLINICAL FEATURES © Dr. Haseeb Ahmed Bhatti

14. Physical examination Pallor (may be jaundiced– think hemolytic) Tachycardia, bounding pulses Systolic flow murmur Glossitis Angular cheilosis Decreased vibratory sense/ joint position sense (B12 deficiency, w/ or w/o hematologic changes) Ataxia, positive Romberg sign (severe B12/folate deficiency)

15. Preliminary investigations: Complete blood count (CBC), red cell indices, white blood cell count, and differential, and platelet count Absolute reticulocyte count Serum ferritin level Serum transferrin saturation (TSAT) Serum vitamin B12 and folate levels © Dr. Haseeb Ahmed Bhatti

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17. Fe ++ deficiency anemia Most commonly due to chronic bleeding and erythropoiesis limited by iron stores that have been depleted May be dietary (pica, lack of meat/ vegetables, other) Iron balance is very close in menstruating women, so Fe ++ deficiency is not uncommon with no other source of bleeding Determine the underlying cause

18. Labs Iron and ferritin will be low TIBC (total iron binding capacity) will be high, since iron stores are not saturating their binding sites on transferrin Reduced RBC counts (definition of anemia) Microcytosis & hypochromia are hallmarks, but early Fe ++ may be normocytic (± hypochromic) Usually, MCH and MCHC will both be low (whereas in macrocytic anemia, the MCH may be normal while the MCHC is low, because of the larger cell size)

19. Lab Test for DDx of Common Microcytic Hypochromic Anemias Iron Deficiency Thalassemia Minor Chronic Disease Scrum Iron  N or   TIBC  N or  N or  % Iron Saturation  (< 10%) N or   Serum Feritin   

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21. Treatment Iron, oral in most cases, parenteral in cases of malabsorption All forms of iron are constipating; the amount of constipation directly relates to the amount of elemental iron delivered If intolerant of FeSO 4 (cheapest), reduce the dose, rather than switching form Start 325 mg QD, increase slowly to TID Grey/black iron stools vs tarry stools Avoid tea with iron, encourage citrus fruits Follow up the cause of the iron deficiency!

22. Anemia of chronic disease Normocytic anemia with ineffective erythropoiesis (reduced reticulocyte count) May be normochromic or hypochromic Results from Chronic inflammation (e.g. rheumatologic disease): Cytokines released by inflammatory cells cause macrophages to accumulate iron and not transfer it to plasma or developing red cells (iron block anemia) Renal failure (erythropoietin from kidneys) Endocrine (e.g. hypothyroid) Hepatic disease Bone marrow suppression (EPO is elevated)

23. Treatment Correct or manage underlying disease when possible May need EPO injection ($$$$) EPO is the treatment of choice for anemia of renal failure In bone marrow deficiency/malignancy, treat if possible, remove precipitating drugs, may require BMT

24. Macrocytic anemia with ineffective erythropoiesis Low/normal reticulocyte count, macrocytosis Most common is folate/B12 deficiency Dietary: folate far more common, B12 may occur in strict vegans Pernicious anemia: lack of B12 protection in stomach and gut Poor uptake in terminal ileum (e.g. in Crohn’s disease) B12 and folate are essential for cell maturation and DNA synthesis, erythrocytes end up large, usually normochromic, since iron is not lacking Other: drugs, toxins, myelodysplasia

25. MCV > 115 fl DDX Folate or B12 Deficiency Folic Acid Deficiency B 12 Deficiency Peripheral smear & BM morphology Same Same Dietary Cause Common, in 3-4 months Rare, except pure vegans, 3-4 yrs Drugs interfering with absorbtion Dilantin, oral contraceptives Omeprazole (Prilosec) Neurologic findings No May be present Methylmalonic acid level Normal Elevated Schilling test Useful for etiology Obtain after Rx

26. Folate deficiency Folate intake is usually dietary, and may be deficient with low fresh fruit & vegetable intake Folate supplementation of bread prevents neural tube defects in pregnancy PE may include neurological effects if severe deficiency

27. Copyright ©2001 American Society of Hematology. Copyright restrictions may apply. Schrier, S. ASH Image Bank 2001;2001:100231 Figure 2. Note the hypersegmented neutrophil (7-8 lobes)

28. B12 deficiency Less common, usually caused by absorption problems, rather than dietary deficiency B12 needs Intrinsic Factor for protection from degradation in gut Produced by parietal cells of stomach, protects through gut for uptake at terminal ileum Pernicious anemia from immune attack of IF production EtOH-related gastritis can affect IF production, and liver disease may also contribute to macrocytosis

29. Neurological effects Deficiency results in damage to dorsal columns (sensory) and lateral columns (motor) of spinal cord Decreased vibration sense and position sense of joints detectable, and may affect gait, etc. May have positive Romberg’s test Severe effects may include ataxia and dementia

30. Labs Folate and B12 levels Schilling test may be useful to establish etiology of B12 deficiency Assesses radioactive B12 absorption with and without exogenous IF Other tests if pernicious anemia is suspected Anti- parietal cell antibodies, anti-IF antibodies Secondary causes of poor absorption should be sought (gastritis, ileal problems, ETOH, etc.)

31. Treatment– supplementation Do NOT correct folate levels unless B12 is OK Correction of folate deficiency will correct hematologic abnormalities without correcting neurological abnormalities Check B12 and correct first B12 usually 1000 mg I.M. q month B12 stores take a long time to deplete; missed doses are not usually a problem Oral supplementation is gaining support; usually effective in pernicious anemia (1-2 mg PO QD) Reticulocyte count should respond in 1 wk

32. Normochromic, normocytic anemia with effective erythropoiesis INCREASED reticulocyte count Acute blood loss Very acutely, with hypovolemia, may have normal blood counts, will become anemic with volume replenishment Hemolytic anemia Increased reticulocyte production cannot keep pace with loss of RBCs peripherally

33. Hemolytic Anemia Intrinsic RBC causes Membranopathies : hereditary spherocytosis Enzymopathies: G6PD Hemoglobinopathies: Sickle cell disease Extrinsic causes Immune mediated: Autoimmune (drug, virus, lymphoid malignance) vs Alloimmune (transfusion reaction) Microangiopathic (TTP) Infection (Malaria) Chemical agents (spider venom) © Dr. Haseeb Ahmed Bhatti Inadequate number of RBCs caused by premature destruction of RBCs

34. Immune hemolytic anemia IgG or IgM labeled as “warm” or “cold” Antibodies on RBC result in hemolysis Usually acute, often with jaundice May be drug-induced Cold hemolytic anemia often post-infectious, generally not severe, worsens with exposure of periphery to cold temperatures

35. Diagnosis of Hemolysis Symptoms depend on degree of anemia ( ie , rate of destruction) Clinical features: anemia, jaundice, reticulocytosis , high MCV & RDW, elevated indirect bili , elevated LDH, low haptoglobin, positive DAT/ Coomb’s (AIHA) Acute intravascular hemolysis: fever, chills, low back pain, hemoglobinuria Smear: polychromatophilia, spherocytosis & autoagglutination

36. Copyright ©2001 American Society of Hematology. Copyright restrictions may apply. Schrier, S. ASH Image Bank 2001;2001:100214 Figure 1. Note the dense microspherocytes and the macrocytes with polychromasia

37. Special cases of hemolytic anemia Glucose-6 Phosphate Dehydrogenate deficiency More common in African and Mediterranean populations Lack of RBC enzyme makes cells very sensitive to oxidative stress (infection, certain drugs eg. penicillin, quinidine, quinine, rifampin) Treatment: avoid triggers if possible, especially inciting drugs

38. Sickle cell disease African background, Autosomal recessive Abnormal hemoglobin (HBS) causes change in RBC shape(sickle or crescent), resulting in constant RBC destruction by the spleen, functional asplenia, susceptible to infection Arterial occlusion leads to infarcts, pain crises, acute chest syndrome, stroke, MI Keep hydrated, treat pain, take infection seriously

39. © Dr. Haseeb Ahmed Bhatti

40. Thalassemias Decreased production of normal hemoglobin polypeptide chains. Classified according to hemoglobin chain that is affected ( α , β , γ , δ ) Common, variable severity of hemolysis Characterized by hypochromic microcytic red cells (MCV markedly decreased while MCHC only slightly decreased) Beta Thalassemia most common in this country and can be suspected if electrophoresis shows a compensatory increase in Hb A2 and/or F (fetal). (Note: Hb A2 generally does not increase above 10%)

41. Case Studies

42. Anemia Case Study #1 A 72 year old male has the CBC findings shown. Peripheral RBCs are hypochromic & microcytic.

43. Anemia Case Study #1 What test would you order for this patient? A-Hemoglobin Electrophoresis B-Retic count C-Stool for occult blood D-B12 Assay E-Bone marrow biopsy

44. Anemia Case Study #1 Two questions: What is your diagnosis? What is the next step for this patient?

45. Anemia Case Study #1 Answers Question 1 Likely Iron Deficiency Anemia Question 2 Colonoscopy

46. Anemia Case Study #2 A 48 year old male has become progressively more fatigued at the end of the day. This has been going on for months. In the past month he has noted paresthesias with numbness in his feet. A CBC demonstrates the findings shown.

47. Anemia Case Study #2 A peripheral blood smear (the slide is representative of this condition) shows red blood cells displaying macro- ovalocytosis and neutrophils with hypersegmentation.

48. Anemia Case Study #2 Which of the following tests would be most useful to determine the etiology? A. Hemoglobin electrophoresis B. Reticulocyte count C. Stool for occult blood D. Vitamin B12 assay E. Bone marrow biopsy

49. Anemia Case Study #2 Questions: What is the diagnosis from these findings? How do you explain the neurologic findings?

50. Anemia Case Study #2 Answers: Question 1 This is a macrocytic (megaloblastic) anemia. The neurologic findings suggest vitamin B12 deficiency (pernicious anemia). Question 2 The B12 deficiency leads to degeneration in the spinal cord (posterior and lateral columns).

51. Thank you © Dr. Haseeb Ahmed Bhatti An approach to diagnosis of anemia https://youtu.be/aupUH6ONmQg