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My Patient’s Anemic and I’m Not a Hematologist: What Do I Do?

Iron Poor “Tired Blood”. My Patient’s Anemic and I’m Not a Hematologist: What Do I Do?. The Recognition, Diagnosis and Management of Anemia Irwin Gross, M.D. May, 2014. No Disclosures. Prevalence of Anemia. Estimated prevalence of anemia in U.S. is 3.5 million

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My Patient’s Anemic and I’m Not a Hematologist: What Do I Do?

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  1. Iron Poor “Tired Blood” My Patient’s Anemic and I’m Not a Hematologist: What Do I Do? The Recognition, Diagnosis and Management of Anemia Irwin Gross, M.D. May, 2014

  2. No Disclosures

  3. Prevalence of Anemia • Estimated prevalence of anemia in U.S. is 3.5 million • Almost certainly an under-estimate • Previously undiagnosed anemia is common in elective surgical patients • Most common underlying causes include: • Iron deficiency • Vitamin B12 deficiency • Chronic kidney disease • Other chronic inflammatory diseases • Folate deficiency (uncommon in U.S.) • Unexplained Anemia of the Elderly (UAE)

  4. Iron Deficiency in Pediatrics • Prevalence • 9% of 1-3 year olds are iron deficient with 3% IDA • Rates decrease with age until adolescence, then increase when 15% of females are iron deficient • Increased prevalence with decrease in socioeconomic status • Increased prevalence with obesity • Poor intake of iron-rich foods • Obesity is a chronic inflammatory state • Perinatal risk factors • Maternal iron deficiency • Prematurity • Insufficient dietary iron intake in early infancy

  5. Iron Deficiency and Neurocognitive Development • Possible relationship between ID/IDA and neurobehavioral development • Recent RCT in LBW (2,000 – 2,500 gm) neonates • 285 infants randomized to 0, 1, or 2 mg/kg/day of enteric iron supplements from 6 weeks to 6 months of age • Assessed at 3.5 years along with 95 normal BW controls • Results • No difference in IQ between LBW groups or LBW vs. controls • Significant difference in behavioral problems based on Child Behavior Checklist (CBCL) • Scores above the U.S. cutoff: 12.7%, 2.9%, and 2.7% respectively for 0, 1, and 2-mg groups compared with 3.2% in controls Pediatrics 2013; 131:47-55

  6. Gender disparity in anemia prevalence Kassenbaum et al. Blood 2013 doi:10.1182/blood-2013-06-508325

  7. Global prevalence of anemia approximately 30% ! Kassenbaum et al. Blood 2013 doi:10.1182/blood-2013-06-508325

  8. Anemia – It’s an Epidemic! Anemia is a common complication of common diseases • 30-60% of patients with RA have anemia • 30-80% of patients with IBD have anemia • 30-50% of patients with CHF have anemia • 20-40% of diabetics without overt renal failure have anemia • 40-60% of patients with chronic kidney disease have anemia All of these are related to iron absorption and metabolism

  9. Age, Anemia and Iron Deficiency • 17% of adults over the age of 65 have iron deficiency • Of those with iron deficiency anemia, only 50% normalized their hemoglobin with oral iron therapy • 35% of adults over the age of 65 have unexplained anemia (defined as hemoglobin less than 12 g/dl Blood Cells Mol Dis. 2011;46(2):159

  10. Why We Should Care (More) About Anemia? • The value of recognizing and treating anemia goes beyond reducing the risk of transfusion • Effective clinical management of anemia improves patient outcomes in CHF, CKD, IBD, rheumatoid diseases, etc. • Anemia may an indicator of an undiagnosed underlying disease process, e.g. iron deficiency suggesting occult malignancy

  11. Preoperative Anemia and Postoperative Outcomes in Non-cardiac Surgery • ACS NISQIP Database study: 227,425 subjects, > 18 years; major non-cardiac surgery, excluding trauma • 30% of patients were anemic • Patients with even mild anemia (hgb 10 - 12g/dl in women; 10 - 13 g/dl in men) experienced: • Higher 30 day adjusted mortality • Increased morbidity including cardiac, respiratory, urinary tract, wound events, sepsis and thromboembolism • Perioperative transfusion also independently associated with increased morbidity and mortality • Treatment of preoperative anemia should be strongly considered • Transfusion is…”the least favorable option” Musallam Lancet 2011;378:1396-407

  12. Impact of Anemia in Patients with AMI Undergoing PCI: Analysis from the CADILLAC Trial JACC 2004;44(3): 547-553

  13. Iron Deficiency in CHF: An International Pooled Analysis Iron Deficiency (with and without anemia) in 40% of NYHA I and 60% of NYHA IV CHF patients

  14. Iron Deficiency May be More Important than Anemia in CHF

  15. Etiology of Anemia • Common causes of anemia • Iron deficiency • Chronic blood loss • Nutritional deficiency: most common nutritional deficiency worldwide and the most common cause of anemia • Chronic kidney disease (often with iron deficiency) • Chronic heart failure (often with iron deficiency) • Hypothyroidism • Anemia of inflammation, acute or chronic • Most common anemia in hospitalized patients • Often co-exists with iron deficiency • Unexplained anemia of the elderly (UAE)

  16. Etiology of Anemia • Less common causes of anemia • Disorders of hemoglobin synthesis, e.g. thalassemia • Autoimmune hemolytic anemia • Anemia associated with non-hematologic malignancy • Myelodysplasia and other primary clonal abnormalities of the marrow

  17. Unexplained Anemia of the Elderly • Some anemic patients have unexplained anemia of the elderly (UAE) • Usually mild (hgb 11-12 g/dL) but associated with poor outcomes • Approximately 50% have elevated IL-6, CRP, or other markers of inflammation • Low EPO levels • Really a diagnosis of exclusion • If macrocytic, think B12 deficiency, folate deficiency or MDS

  18. A Guide to the Laboratory Diagnosis of Anemia

  19. Laboratory Evaluation of Anemia • Basic evaluation • CBC • Include reticulocyte count • Iron, iron binding capacity, ferritin • Vitamin B12 • Creatinine • Consider as second tier tests • TSH • Folate • DAT • Haptoglobin • LDH

  20. Laboratory Evaluation of Anemia • First review the clinical history, then review the CBC: • Review the red cell indices (will discuss in a moment) • Look for abnormalities in the platelet count • Thrombocytosis: iron deficiency, inflammation or myeloproliferative disease • Thrombocytopenia: many causes, including medications and increases risk of bleeding • Look for abnormalities in number and/or type of white cells • Inflammatory process • Infection • Leukemia, lymphoma, myelodysplasia

  21. Laboratory Evaluation of Anemia • Hemoglobin, hematocrit and red cell count • Hemoglobin reference range: • 14.0 – 17.0 g/dL (male) • 12.0 – 15.0 g/dL (female) – Is Hgb of 12 g/dl truly “normal”? • Hematocrit reference range: • 42 – 51% (male) • 36 – 45% (female) • Red cell count reference range • 4.7 – 6.0 M/µL (male) • 3.9- 5.5 M/µL (female)

  22. Laboratory Evaluation of Anemia • Hemoglobin, hematocrit and red cell count • For purposes of pre-operative anemia screening, we use a hemoglobin less than 13 g/dL as “anemia” for all patients • Hemoglobin < 13 g/dL is “inflection” point for increased risk of transfusion with high blood loss procedures • Recognize that some women with hemoglobin of 12-13 g/dL are normal and that some men with hgb between 13-14 g/dl are not • Hemoglobin is directly measured and is the more “accurate” measure if Hgb and Hct don’t “agree” • Estimated Hct is usually (Hgb value) x 3 • Anemia with elevated red cell count is seen in thalassemia minor

  23. Laboratory Evaluation of AnemiaRed Cell Indices • MCH and MCHC: Mean corpuscular hemoglobin (pg) and corpuscular hemoglobin concentration g/dL (in a given volume of blood) • Of minimal value • MCV: Mean Cell Volume • Most useful of the red cell indices • Measured value in femtoliters (fl) • Reference range 80-100 fl • A primary tool for categorizing anemia • < 80 fl = microcytic • >100 fl = macrocytic

  24. Laboratory Evaluation of AnemiaRed Cell Indices • MCV: Mean Cell Volume • Microcytic anemia (< 80 fl): • Iron deficiency • Thalassemia or other disorders of heme synthesis • Normocytic anemia (80-100 fl) • Anemia of chronic inflammation usually normocytic • Anemia associated with CKD (may be macrocytic) • Anemia associated with hypothyroidism (may be macrocytic) • Iron deficiency anemia and B12 deficiency anemia may also be normocytic

  25. Laboratory Evaluation of AnemiaRed Cell Indices • MCV: Mean Cell Volume • Macrocytic anemia (>100 fl) • Anemia due to B12 or folate deficiency usually macrocytic (but may be normocytic) • Hemolytic anemias are often macrocytic • Anemia secondary to alcohol • Anemia secondary to chronic liver disease • If macrocytosisis associated with ovalocytosis and/or other cytopenias consider possibility of a myelodysplastic syndrome (MDS)

  26. Laboratory Evaluation of AnemiaReticulocytes • Reticulocyte count: • Decreasedin hypoproliferative anemia relative to the degree of anemia (e.g. nutritional deficiency anemia, CKD, ACI, etc.) • “Normal” reticulocyte count in an anemic patient suggests an inadequate marrow response • Increased in hemolytic anemia or blood loss with marrow response and in response to initiation of effective therapy • Best measure is absolute reticulocyte count, not percentage, reticulocyte index or reticulocyte production index • Reference range: 25,000 – 85,000 / microliter

  27. Laboratory Evaluation of AnemiaBeyond the CBC • Labs to evaluate iron status: • Serum iron • Reference range 50 – 150 µg/dL • Decreased in iron deficiency and anemia of acute or chronic inflammation • Diurnal variation with highest levels in the morning • As much as a 30% variation within day and between day due to changes in marrow iron uptake, iron absorption, storage iron outflow, etc. • Fasting sample!

  28. Laboratory Evaluation of AnemiaBeyond the CBC • Labs to evaluate iron status: • Transferrin • The principal plasma protein for transport of iron • Total Iron Binding Capacity (TIBC) is an indirect measure of transferrin concentration and is often used interchangeably with transferrin • TIBC expressed in µg/dL (Reference range: 260-475 µg/dL) • Reference range: 200-400 mg/dL • Increased in iron depletion states • Decreased in inflammatory states including anemia of chronic inflammation and in malnutrition, liver disease, malignancy

  29. Laboratory Evaluation of Anemia Beyond the CBC • Labs to evaluate iron status: • Transferrin saturation (TSAT) • Reference range: 20-45% saturation • < 20% consistent with iron deficiency or functional iron deficiency • > 45% suggests iron overload • Transient increase above 45% typical with I.V. iron Rx • Percent saturation reflects iron available for erythropoiesis • Lower limit of current laboratory reference ranges is too low (in many labs it is < 12-15%)

  30. Laboratory Evaluation of Anemia Beyond the CBC • Labs to evaluate iron status: • Ferritin • Reference range: > 100 ng/mL (upper limit varies with age) • MOST labs use a lower limit of 12-20 ng/mL for females and 30-45 ng/ml for males; this is too low • < 100 ng/ml suggests decreased iron stores • HMW protein consisting of about 20% iron by weight • Found in all cells but especially hepatocytes and macrophages serving as an iron reserve

  31. Laboratory Evaluation of AnemiaBeyond the CBC • Labs to evaluate iron status: • Ferritin (cont’d) • A small amount found in plasma and reflects iron stores in normal individuals • Acute phase reactant - often markedly increased in acute illness regardless of iron status, so increased ferritin does not rule out iron deficiency • Low ferritin is best single laboratory indicator of iron depletion, but a normal or elevated ferritin does NOT rule out iron deficiency

  32. Studies that Assist in Evaluating Iron Deficiency Anemia and Anemia of inflammation

  33. Laboratory Evaluation of AnemiaBeyond the CBC Other labs: • Vitamin B12: • Reference range 200-900 pg/mL • Some patients with B12 between 200-300 pg/mL will also be deficient • If B12 is < 300, consider treatment with B12 or further evaluation with serum methyl malonic acid • If < 200, treat • Up to 15-20% of patients with B12 deficiency will be normocytic, not macrocytic

  34. Laboratory Evaluation of AnemiaBeyond the CBC Other labs: • Folate • Reference range: 5-40 ng/mL serum; 280-900 ng/mL red cell folate • I usually don’t test for folate deficiency • Isolated folate deficiency is uncommon, i.e. there is a low prevalence of folate deficiency in the U.S. • I add oral folate to any treatment regimen for anemia • If you measure folate (e.g. in a patient with macrocytic anemia and a normal B12) • Red cell folate better than serum folate but requires a different blood sample • Serum folate is acceptable IF a fasting sample

  35. Laboratory Evaluation of AnemiaBeyond the CBC Other labs: • Creatinine • Chronic kidney disease (CKD) is a common cause of anemia – 40% of Stage 4 and 5 CKD • Anemia secondary to CKD is, in part, a diagnosis of exclusion • A glomerular filtration rate estimated from the creatinine (eGFR) can be used to qualify patients for anemia treatment with an ESA • CRP • Increased CRP indicates inflammation

  36. Laboratory Evaluation of AnemiaBeyond the CBC Other labs: • Tests for hemolysis • Direct antiglobulin test (positive) • LDH (elevated) • Haptoglobin (decreased) • Bilirubin (elevated, especially indirect) • Reticulocyte count (elevated) • Thyroid Stimulating Hormone (TSH) • Hypothyroidism may be a cause of anemia, usually normocytic

  37. Key Points! • Hemoglobin is directly measured and is the more accurate measure if hgb and hct don’t agree • For purposes of pre-operative anemia management we use a hgb of < 13g/dl as “anemia” (male or female)since that is the inflection point for increased risk of transfusion • Use the absolute reticulocyte count to determine if the anemia is hypoproliferative (thousands/microliter) • Ferritin is an acute phase reactant and does not reflect iron stores in a patient with inflammation

  38. Key Points! • The lower end of published reference ranges for ferritin and transferrin saturation are too low • Ferritin less than 100 ng/ml suggests depleted iron stores • Transferrin saturation less than 20% suggests decreased iron available to the “erythron” for red cell production • Increased ferritin and decreased transferrin saturation is consistent with so-called functional iron deficiency, previously “anemia of chronic disease” or “anemia of chronic inflammation”

  39. Key Points! • Many patients with iron deficient erythropoiesis are not anemic, but still symptomatic from their iron deficiency • Many of the symptoms of iron deficiency anemia are due to iron deficiency, not the anemia • Iron deficiency anemia and B12 deficiency anemia can both be normocytic • Iron deficiency anemia is usually microcytic and B12 deficiency anemia is usually macrocytic, but… • The MCV is normal in 15-20% of patients with B12 deficiency • Many patients with iron deficiency or functional iron deficiency have a normal MCV (not microcytic)

  40. When you’ve done all those tests and you still don’t have a diagnosis • Still no etiology, consider a referral to a hematologist for bone marrow examination and further evaluation • Underlying malignancy • Myelodysplasia • Plasma cell dyscrasia

  41. Iron Deficiency, Functional iron Deficiency and Iron Deficiency Anemia

  42. Iron Deficiency Anemia • Most common cause in U.S. is blood loss • GI lesion • Menstrual or abnormal uterine bleeding • Hematuria • Decreased iron absorption another major cause • Atrophic gastritis, H. pylori, celiac disease, use of PPIs and H2 -antagonists • Gastric bypass surgery • Vegetarian diet • Crohn’s disease, celiac disease, giardiasis • Chronic use of NSAIDs • In pediatrics, cow’s milk at early age

  43. Iron Absorption and Metabolism

  44. How Much Iron? • Elemental iron requirement: 0.27 mg/day for term infants increasing to about 7 mg/day at 7-12 months • 1-2 mg daily in healthy adults • Daily iron requirement • Replace iron lost from epithelial cell sloughing (skin, GU, GI) • Iron for increased blood volume • Iron for increased tissue mass • Iron for stores

  45. Maximum Daily Iron Absorption Maximum daily enteric iron absorption: 5-7 mg

  46. Hepcidin • Most important protein for regulating iron absorption, release and transport • Hepcidin is decreased by anemia, hypoxia, iron deficiency • Decreased hepcidin results in increased iron absorption • Hepcidin is increased by iron loading AND systemic inflammatory response • Systemic inflammation results in iron restricted erythropoiesis (i.e. F.I.D.) due to up-regulation of hepcidin • This is known as “hepcidin blockade”

  47. Iron Absorption and Hemostasis Hepcidin, Inflammation and Iron Metabolism Lysosomal degradation IV Iron IV iron leads to translational and post-translational up - regulation of ferroportin via IRP + IRP’s 1,2 J Am SocNephrol 18: 394-400, 2007 Blood 2005 106: 3979-3984

  48. “Functional” Iron Deficiency • Chronically ill patients often have functional iron deficiency (FID) despite normal or increased ferritin • Include: • Post-operative and trauma patients • Patients with IBD, RA and related diseases, or other chronic inflammatory process • Cardiac patients • Some overlap with Unexplained Anemia of the Elderly (UAE) • Patients with FID: • Are characterized by low iron, low iron binding capacity, and low iron saturation • May have normal or increased ferritin

  49. What all this means about iron absorption and bioavailability • If there is inflammation: • Enteric iron absorption is significantly impaired • Release of iron from storage is significantly impaired • Ferritin may be increased • Transferrin saturation will be decreased • Erythroid (and other) cells will be deprived of adequate iron and become functionally iron deficient • Anemia results • FID is the most common cause of “anemia of chronic disease”

  50. Clinical Manifestations of ID • Signs and symptoms are non-specific • Impaired myocardial function • Increased mortality? • Impaired immune function • Weakness, fatigue, lethargy • Headache • Irritability • Exercise intolerance • Cognitive dysfunction • Pica, especially for ice (pagophagia) • Poor feeding • Restless leg syndrome

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