Anemia Beyond the Microcytic, Normocytic and Macrocytic Paradigm

1. AnemiaBeyond the Microcytic, Normocytic and Macrocytic Paradigm Robert C. Oh, MD, MPH MAJ, MC, USA Tripler Army Medical Center

2. Learning Objectives Review the basic pathophysiology of anemias Differentiate between iron deficiency anemia and anemia of chronic disease Recognize the common causes of macrocytosis and differentiating from b12 deficiency

3. Case Intro 33 y/o BF with h/o headaches, lightheadness and fatigue after running. No sig. PMH. Exam unremarkable. Periods are heavy at end, but normal duration and cycles. Currently on cycle. CBC: Hb: 11; HCT 32 MCV 88.8

4. Classification of Anemias Microcytic (< 80 Fl) Iron deficiency Thallesemias Normocytic (80-100 Fl) “Chronic” disease Kidney disease Macrocytic (> 100 Fl) B12/folate deficiency Liver disease; ETOH abuse Myelodysplastic syndrome Hemolytic anemia Normocytic anemia really includes everything in microcytic and macrocytic Normocytic can also include mixed anemiasNormocytic anemia really includes everything in microcytic and macrocytic Normocytic can also include mixed anemias

5. Issues in Primary Care Most are normocytic anemias Iron deficiency overdiagnosed Iron deficiency underdiagnosed Macrocytic anemia not always vitamin deficiency Sometimes they are not anemic!

6. The Normal Red Cell Life Cycle Hormones Kidneys (EPO) G-CSF Bone marrow Iron deposition Reticulocytes Senescence Kidneys detect low oxygen or low circulating blood volume; secretes a hormone, erythyropoeiten (EPO). EPO stimulates the bone marrow to produce RBC’s (reticulocytes) Reticulocytes are released into blood stream, approx 120 days Senescent cells are phagocyotized by spleen and liver Iron recycled by transferrin and stored in liver and RES as ferritinKidneys detect low oxygen or low circulating blood volume; secretes a hormone, erythyropoeiten (EPO). EPO stimulates the bone marrow to produce RBC’s (reticulocytes) Reticulocytes are released into blood stream, approx 120 days Senescent cells are phagocyotized by spleen and liver Iron recycled by transferrin and stored in liver and RES as ferritin

7. Iron Metabolism Dietary iron Circulation Transferrin Incorporation Storage Ferritin Dietary Iron absorbed by duodenum Circulates via plasma transferrin Incorporated within RBCs Storage within RES and Liver via ferritin Dietary Iron absorbed by duodenum Circulates via plasma transferrin Incorporated within RBCs Storage within RES and Liver via ferritin

8. What can go wrong Iron deficiency Increased blood loss Kidney dysfunction Bone marrow disorder Increased destruction (hemolysis)

9. Evaluation CBC Iron TIBC Ferritin Vitamin B12/Folate MMA, HCY Reticulocyte count Peripheral smear TSH Lactate dehydrogenase (LDH) Haptoglobin Coombs test sTR Bone marrow

10. Pitfalls Not using Ferritin Relying on serum iron, TIBC, transferrin saturation alone Not recognizing anemia of chronic dz. Treating with iron Attributing all macrocytic anemia to b12 deficiency Missing hemolytic anemia, myelodysplasia Not following up for resolution

11. Iron Deficiency Anemia Iron loss > dietary iron Malabsorption Blood loss Acute Chronic

12. Total Iron Binding Capacity related to transferrin saturation Transferrin molecule with “seats” for Fe++ High TIBC means more “seats” available for Fe++ (i.e. low iron state) Low TIBC means less “seats” available for Fe++ (i.e. adequate or high iron state) Transferrin sat: iron/TIBC=% saturation TIBC and Transferrin Saturation TIBC inversely related to transferrin saturation. Transferrin “transports” iron in the serum. Think of TIBC as “open seats” on a bus. Transferrin saturation basically is the percentage of “seats” filled with iron. Typically ranges from 200-500TIBC inversely related to transferrin saturation. Transferrin “transports” iron in the serum. Think of TIBC as “open seats” on a bus. Transferrin saturation basically is the percentage of “seats” filled with iron. Typically ranges from 200-500

13. Ferritin Marker of total body iron stores Starts dropping first with iron loss Ferritin is the most sensitive measure for iron deficiency anemia Acute phase reactant? Now that I’ve spent all that time on tibc and transferrin sat, I want you to understand that there is a much better test. If you had 1 test to diagnosis iron deficiency, this is it.Now that I’ve spent all that time on tibc and transferrin sat, I want you to understand that there is a much better test. If you had 1 test to diagnosis iron deficiency, this is it.

14. Ferritin < 15: IDA 15-44: probable IDA 45-100: diagnostic uncertainty > 100: NO IDA

15. Iron Deficiency: Dx

16. Anemia of Chronic Disease 2nd most common anemia Misnomer Disturbance of iron metabolism Inability to utilize iron Iron retention by RES Impaired erythropoiesis

17. ACD: Etiologies Infections (18-95%) Acute Chronic Malignancies (39-77%) Auto-Immune (8-71%) Chronic Kidney Disease (23-50%) Your body is smart. If you have infections (both acute and chronic) or cancer or autoimmune disease which is trying to utilize the iron to feed the illness, your body is going to hide it. Where? Ferritin. I don’t know who perpetuated the myth that ferritin is not a useful test in chronic or acute illness b/c it’s an acute phase reactant.Your body is smart. If you have infections (both acute and chronic) or cancer or autoimmune disease which is trying to utilize the iron to feed the illness, your body is going to hide it. Where? Ferritin. I don’t know who perpetuated the myth that ferritin is not a useful test in chronic or acute illness b/c it’s an acute phase reactant.

18. Diagnosing ACD Low to normal Iron Low to normal TIBC Normocytic (may be microcytic) High ferritin* Ferritin > 100 diagnostic of ACD

19. Case Intro 33 y/o BF with h/o headaches and lightheadness and fatigue after running. No sig. PMH. Exam unremarkable. Periods are heavy at end, but normal duration and cycles. Currently on cycle. CBC: Hb: 11; HCT 32 MCV 88.8

20. Case Intro You decide to check an iron panel, TSH, b12 and folic acid level B12: 464 (247-911) Folate: 10.1 (<5.4) TSH: 1.95 (0.35-5.10) Iron: 57 (50-170) TIBC: 362 (250-450) Trans sat: 16 (15-50%) Ferritin: 14 (10-291)

21. Macrocytic Anemias MCV> 100 FL Etiologies Alcohol Chronic liver disease Vitamin b12/folate Myelodysplasia Hemolysis Reticulocytosis

22. Acute Macrocytic Anemia Rule out hemolysis, reticulocytosis Reticulocyte count Peripheral smear Haptoglobin LDH Coombs test

23. Vitamin B12 deficiency Serum B12 not accurate Methylmalonic acid (MMA) Homocysteine (HCY) Macrocytic anemia Invariably with low serum b12

24. Pitfalls Not using Ferritin Relying on serum iron, TIBC, transferrin saturation alone Not recognizing anemia of chronic dz. Treating with iron Attributing all macrocytic anemia to b12 deficiency Missing hemolytic anemia, myelodysplasia Not following up for resolution

25. Cases

26. Case: “MT” Microcytosis

27. Case: “MT” 39 y/o WM for routine physical, seen in the Family Medicine clinic. Otherwise healthy, but is c/o fatigue. No significant PMH, PSH, no meds

28. Labs WBC: 5.5 HGB: 12.2 HCT: 37.0 (40.0-53.1) MCV: 78.6 (80-100) PLT: 255 (150-440) RDW: 14.9 (11.5-14.5) TSH: 13.864 (0.35-5.10) FT4: 0.9 (.89-1.76) Retic %: 2.0 (0.5-2.3)

29. “MT”: 39 y/o AD Male WBC: 5.5 HGB: 12.2 HCT: 37.0 (40.0-53.1) MCV: 78.6 (80-100) PLT: 255 (150-440) RDW: 14.9 (11.5-14.5) TSH: 13.864 (0.35-5.10) FT4: 0.9 (.89-1.76) Retic %: 2.0 (0.5-2.3)

30. What is your diagnosis? Iron: 147 (50-170) TIBC: 389 (250-450) Trans sat: 38 (15-50) Ferritin 6 (22-322) B12: 808 Folate: 9.8 Started on iron supplementation

31. Case: “JL” Normocytic anemia

32. Case: “JL” 83 y/o M otherwise healthy, with PMH sig for HLD and HTN. Has been recently been treated for chronic otitis media. Presents to you with c/o fatigue more than usual.

33. Case: “JL” Initial labs WBC: 8.9 HGB: 11.0 HCT: 32.1 (40.0-53.1) MCV: 92.1 (80-100) PLT: 298 Iron: 42 (50-170) TIBC: 272 (250-450) Trans sat: 16 (15-50) Ferritin: 294 (22-322) B12: 369 (247-911)

34. “JL”: 83 y/o WM with fatigue Initial labs WBC: 8.9 HGB: 11.0 HCT: 32.1 (40.0-53.1) MCV: 92.1 (80-100) PLT: 298 Iron: 42 (50-170) TIBC: 272 (250-450) Trans sat: 16 (15-50) Ferritin: 294 (22-322) B12: 369 (247-911)

35. Case: “JL” Started on iron sulfate Colonoscopy= negative EGD=negative ESR=60 After tx ? Hb/Hct: 13.8/38.9

36. Case: “AG” Macrocytosis

37. Case: “AG” 79 y/o M here for routine exam, new visit. On reviewing his PMH/PSH, he states that he has had a partial gastrectomy for an “ulcer” approx. 25 years ago. No medications, no supplementation CBC, B12/folate, iron panel ordered to r/o vitamin b12 and iron deficiency

38. Labs WBC: 4.2 HBG: 13.6 (13.3-17.7) HCT: 39.9 (40.0-53.1) MCV: 102.6 (80-100) PLT: 351 (150-440) Iron: 178 (50-170) TIBC 339 (250-450) Tran sat: 52 (15-50) Ferritin: 23 (22-322) B12: 312 (247-911) Folate: 17.3 (>5.4)

39. Further History After further questioning, he does admit to drinking approx 6-8 beers a day. CAGE negative. He also states that he has been “losing his voice” x 1month. He is a chronic smoker, approx 1ppd x 60 years

40. 79 y/o with partial gastrectomy WBC: 4.2 HBG: 13.6 (13.3-17.7) HCT: 39.9 (40.0-53.1) MCV: 102.6 (80-100) PLT: 351 (150-440) Iron: 178 (50-170) TIBC 339 (250-450) Tran sat: 52 (15-50) Ferritin: 23 (22-322) B12: 312 (247-911) Folate: 17.3 (>5.4)

41. Follow-up Was started on b12 supplementation 500 mcg qd Was started on iron supplementation 325 mg qd ENT consult for hoarseness GI consult for c-scope

42. Follow up ENT: found invasive SCCA of vocal cords C-scope negative 2 months later labs: WBC 4.1 HGB: 13.7 HCT: 40.2 (40.0-53.1) MCV: 102.2 (80-100) Serum B12: 769

43. Case: “HR” Normocytic

44. Case: “HR” 84 y/o WM who presents to the ER with fatigue and SOB. Dx’d with mild CHF, admitted to hospital. Recently returned from 1 wk trip to Arizona. PMH: HTN, HLD, COPD Hospital labs CBC: H/H: 11.6/25.9 MCV 97.4 CBC: H/H 14.8/43.6 MCV 95.2 (1 yr prior)

45. Case “HR” CBC WBC: 10.2 HB: 7.6 HCT: 23.2 MCV: 91.7 PLT: 426

46. Case: “HR” Corrected Retic%= 1.57 (normal) Peripheral smear: unremarkable Iron 10 (50-170) TIBC 201 (250-450) Trans sat: 5 (15-50) Ferritin: 1278 TSH: 2.9

47. Questions?

48. Case: “KS” Normocytic

49. Case: “KS” 89 y/o M with pmh sig for HTN, BPH, osteoporosis with mild complaints of fatigue. Otherwise healthy; colon screen UTD. Initial CBC WBC: 7.4 (3.9-10.6) Hbg: 12.5 (13.3-17.7) Hct: 36.4 (40.0-53.1) MCV: 90.8 (80-100) Plt 154 (150-440)

50. Case: “KS” Iron: 49 (50-170) TIBC: 246 (250-450) Trans sat: 20 (15-50) Ferritin: 695 (22-322) B12: 227 (247-911) Folate: 13.9 (>5.4)

51. Case: “KS” Treated w/ oral b12 500 mcg qd Recheck 3 months later B12: 1006 CBC: Hgb: 12.5 HCT: 36.8 MCV: 87.7 PLT: 130

52. Case: “KS” Repeat labs Ferritin 352 (22-322) Occult blood x 3 negative 15 months later… Hbg: 10.4 --iron 36 (50-170) Hct: 30.5 --Ferritin 43 (22-322) MCV 82.2 (80-100)

53. Case: “JR” Normocytic

54. Case: “JR” 28 y/o WF dependant with no sig. PMH with c/o dysuria, frequency and urgency x 1 week. Now has developed fevers/chills and severe nausea, vomiting and flank pain Exam: 102.7F, +CVA T Labs: U/A c/w UTI (neg HCG) Admitted for + N/V and inability to take PO fluids.

55. Case: “JR” Initial CBC WBC: 18.9 HGB: 12.7 (11.7-15.7) HCT: 37.5 (35.1-47.1) MCV: 84.6 (80-100) PLT: 235 HD#2 WBC: 14.9 HGB: 11.6 HCT: 33.7 MCV: 87 PLT: 200

56. What’s going on?

57. Key Points Ferritin is BEST marker for iron deficiency Ferritin can help you dx Anemia of Chronic disease Acute illnesses can cause chronic disease Macrocytic anemia not always b12 deficiency Look for other cause if b12 level normal and MCV still > 100

58. Questions?