1. Seventh International Symposium in Continuing Nursing Education/March, 2014 3/2014 Donald W. McLaren, MD

2. Objectives  To discuss how to evaluate and determine cause of anemia  To discuss Iron deficiency (ID) and Iron Deficiency Anemia (IDA) - causes, evaluation, signs, symptoms, treatment and prevention at different ages  To discuss briefly few other common causes of anemia

4. Burden of anemia globally  24% of world population; 1.62 billion anemic  Greatest burden pregnant women and children < 5  Highest prevalence Africa and SE Asia  In these locations > 65% of children < 5 years are anemic

5. http://www.k4health.org/toolkits/anemia-prevention/anemia-causes-prevalence-impact

6. Definitions  Anemia – reduced # circulating RBCs or decreased circulating hemoglobin as measured by decreased Hgb, Hct or RBC count  Hgb – concentration of hemoglobin (gm/dl)  Hct – % of sample of whole blood (WB) occupied by intact RBCs.  RBC count: # RBCs in specified volume of blood – usually millions of RBC / μL of whole blood (WB)

7.  Indices MCV (mean corpuscular volume) – volume of average RBC measured or calculated as MCV (femtoliters; 10 -15 ) = 10 X Hct ÷ RBC; indication of cell size MCH (Mean Corpuscular Hemoglobin) - mass of Hgb in a RBC MCHC (mean corpuscular hemoglobin concentration) – measure of concentration of hemoglobin in a given volume of packed RBCs

8.  Microcytosis: ↓ MCV; RBC size small  Macrocytosis: ↑ MCV; RBC size large  Normocytosis : MCV WNL; RBC size normal  Hypochromic: paler than normal – ↓Hgb as measured by ↓ MCH, MCHC  Hyperchromic: ↑ Hgb – ↑ MCH, MCHC

9.  RDW (RBC distribution width) – measure of variability of size of RBCs - normal about 11.5-14.5 – increased in nutritional deficiencies (like Fe, B12)  Anisocytosis – when there is a lot of variation of sizes of RBC as seen on microscope - ↑ RDW  Peripheral smear – blood smear stained to be looked at to see cell size, shape, abnormal cells, etc.

10.  Reticulocyte – immature RBC usually released into blood 1 day prior to becoming mature RBC  Reticulocyte count – number of reticulocytes in peripheral blood expressed as % of total RBCs

11. What is included in a CBC  Hgb, Hct  RBC count  Indices – MCV, MCH, MCHC  RDW  WBC and differential or diff indicating how many of each type of WBC is there  Platelet count  Normal values vary with age and sex

12. http://upload.wikimedia.org/wikipedia/en/4/49/CBC_With_Differential.jpg

13. http://www.childrensmn.org/manuals/lab/hematology/018981.asp

16. RBC and appearance in peripheral smear http://en.wikipedia.org/wiki/Reticulocyte_index

17. Reticulocyte unstained and stained http://en.wikipedia.org/wiki/Reticulocyte_index

20. http://www.med-ed.virginia.edu/courses/path/innes/nh/morphology.cfm

21. Define anemia  Hgb, Hct (H/H) > 2 SD below the mean  H/H < 12g/dl or 36% for adult women  H/H < 13.5(14.0) and 41(42)% for men  Higher if live at altitude, smokers, athletes  Consider volume shifts: bleed, pregnancy  African-Americans Hgb 0.5-1.0 g/dl < white  Can drop 15%, be significant drop, still WNL

22. Other basics of erythropoiesis (making of red cells)  EPO (erythropoietin) from kidney ↑ if anemia.  If marrow functioning, raw materials present (iron, B12) EPO stimulates marrow to produce more RBCs – leads to increased reticulocytes.  Reticulocytes released from bone marrow and circulate normally 1 day before becoming mature RBC  Normal RBCs circulate for about 110-120 days before being removed from circulation

23. Some more basics  Ordinarily rate of production = rate of removal  Retics replace about 1% of cells daily so normal retic count around 1% (0.5-1.5%)  If increased RBC destruction (i.e. SCD) must replace more. If cell lifespan 20 days must replace 5% / day  Will now discuss W/U of anemia

24. Causes of Anemia – only 3  Decreased RBC production – bone marrow not keeping up with normal RBC loses (hypoproliferative)  Increased RBC destruction or decreased survival time (hemolysis)  Blood loss (hemorrhage)  Combinations not uncommon

25. Essential Lab for Evaluation of Anemia  CBC  Peripheral smear read by someone who knows what they are looking for  Reticulocyte count  Can classify anemia based on these 3  Other testing depending on results

26. 2 General Approaches to Evaluate Anemia  Kinetic (physiological) approach addresses the mechanism or cause of the anemia. Retic count used to divide into hemolysis or blood loss ( ↓ retic) vs. hypoproliferative ( ↓ retic count)  Morphologic approach – categorizing based on RBC size as determined by MCV and peripheral smear  Will discuss a combination of two

27. Kinetic approach  Low retic = decreased RBC production Lack of nutrients (Fe, B12, folate) Bone marrow disorders or suppression Low EPO level  High retic = increased destruction of RBC or blood loss

28. Morphological Approach to Anemia  Determine RBCs size: small, normal or large based on MCV, peripheral smear  For adults MCV range about 80-96  DDx if microcytic anemia fairly short  Retic count helpful to further sort out normocytic and macrocytic anemias.  Sometimes not straightforward – classic Fe deficiency microcytic, but if mild and early is normocytic

29. Always begin with Hx and Px  Are they stable? Are there S/S of anemia?  Known or obvious bleeding?  Is anemia acute, chronic or subacute  Any chronic illness?  Ethnicity  Alcohol, medications, history transfusions  Good dietary history  Big spleen, liver disease, jaundice, tender bone, H-S megaly, lymphadenopathy

30. Look at rest of CBC/peripheral smear – not just RBCs  Abnormal cells may indicate SCD, spherocytosis, leukemia, and on occasion make the diagnosis for you  Pancytopenia changes the differential diagnosis – likely need hematologist Destruction in peripheral blood Aplastic anemia, hematologic malignancy, B12 deficiency, anorexia, radiation, chemotherapy, myeloproliferative disease

34. Microcytic anemia  Relatively few causes *Fe deficiency anemia (IDA) (early can be normocytic) ○ ↓RBC, ↓Indices, ↑ RDW *Thalassemias ( ↓ globin synthesis) *Lead toxicity ( ↓ heme synthesis) *Anemia of chronic disease (or normocytic) Sideroblastic anemias

36. Macrocytic ( ↑MCV) DDx  *Folate, B12 deficiency (Usual cause of MCV > 115)  Extreme reticulocytosis  Alcoholism, liver disease, hypothyroidism  *HIV antiviral therapy  *Most chemotherapeutic agents  Myelodysplastic disorders  Adults > 65 may have higher MCV than younger – use 100 rather than 96 for ULN

37. Can narrow diagnosis based on peripheral smear and retic count  *Megaloblastic (macro-ovalocytes and hypersegmented neutrophils) or Low retic B12 or folate deficiency HIV meds, Anticonvulsants (folate depletion) (dilantin, valproate), Cancer drugs (+ anemia)  Nonmegaloblastic with round macrocytes and macroreticulocytes – (low retic) Alcohol, thyroid, liver disease (high retic) some hemolytic  Myeloproliferative disorders - bone marrow

39. Normocytic Anemia DDx with reticulocytosis  Huge category – Narrow ddx with retic count  *Blood loss, hypersplenism  *Increased destruction, loss of RBCs (hemolysis) Congenital or intrinsic (Hemoglobinopathy: SS, SC; RBC membrane disorders: spherocytosis; RBC enzyme deficiency (G-6-PD, pyruvate kinase) Acquired (extrinsic): Mechanical, macrovascular, Micro- angiopathic (DIC, HUS, TTP) autoimmune hemolytic anemias, drug related (Aldomet, penicillins, cephalosporins)] PNH  Mixture of micro/macrocytic anemias

40. Normocytic Anemia With Low Retic  Decreased production normal sized cells (*anemia of chronic illness, aplastic anemia, bone marrow infiltration)  *Uncompensated increase in plasma volume (pregnancy)  Low EPO states (CRF, liver or kidney disease, Endocrine deficiency)  Myeloproliferative disorders, dysplasia, fibrosis, marrow replacement  Bone marrow can get dx 90-92% of time

41. Summary (read RPI as retic for now) Microcytic Normocytic Macrocytic ↑ RPI or ARC ↓ RPI or ARC ↓ RPI Or ARC Then it is easy to look up differential for each combination of MCV and Retic. *RPI = Reticulocyte production index; ARC = Absolute retic count

42. Many sites for DDx once anemia classified MCV and RPI  Just Google causes of ____ anemia.  Microcytic anemia or microcytosis http://www.aafp.org/afp/2010/1101/p1117.html  Normocytic anemia or normocytosis http://www.aafp.org/afp/2000/1115/p2255.html  Macrocytic anemia or macrocytosis http://www.aafp.org/afp/2009/0201/p203.html

43. Use of retic count  Normal 0.5-1.5% in adult  Normally keeps up with RBC loss so that Hgb/Hct stable  Can increase significantly to replace lost RBCs in hemolysis, blood loss if a) marrow working, b) sufficient EPO, c) nutrients  How do we know in the face of anemia if elevated retic count is appropriately high vs. insufficient for degree of anemia. If Hct is 25, what should retic be? 3? 7? 15?

44. Most common anemias in U.S. Copyright © 2000-2013 The Cleveland Clinic Foundation. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/anemia/

45. Corrected retic count or RPI (reticulocyte production index)  Can use either absolute retic count (RBC X % retics) or RPI to clarify situation  Reticulocyte count is a %. So, if you decrease RBCs (anemia) with the same number of retics gives falsely elevated %  How many retics being released from bone marrow vs. normal - measure of how many RBCs being made in the bone marrow  1 st of 2 corrections is for low RBC count – to give a “corrected retic count” or “retic index” = Retic count X Hct/45 (normal Hct)

46. 10% retics

47. Retic Count X Hct/normal Hct = 20% X 5/10 = 10%

48. Reticulocyte production index (RPI)  Second correction needed in anemia, retics are released early in a less mature state  Retics normally stay in the blood for 1 day  If released early stay in circulation longer before reaching maturity  Divide previously corrected retic count by maturation factor corrects for early release Hct 36-45: 1.0; Hct 26-35: 1.5 Hct 16-25: 2.0 Hct < 15: 2.5

49. http://faculty.washington.edu/rrichard/anemia.ppt

50. RPI  RPI = retic count X Hct/45 Maturation correction  1-2% is normal in non-anemic individual  In anemia, RPI< 2 means there is an inadequate response to correct anemia and indicates hypoproliferative anemia  In anemia, RPI> 3 appropriate/adequate compensatory response to anemia and represents destruction or decreased survival or loss of red cells

51. http://allaboutblood.com/tag/corrected-reticulocyte-index/

52. Iron (Fe) Deficiency anemia (IDA) in Infants and Young Children  IDA most common cause anemia in world  1-3 years old: 9% in U.S. have ID, 3% IDA  Risk factors: poverty, Black or Hispanic race, obesity, prematurity, immigrants  Fe balance 75% bound in heme proteins Hgb & myoglobin Most rest is storage iron in ferritin, Hemosiderin Tiny amount bound to transferrin for transport 3% in critical enzyme systems

53.  Adults: 5% of daily Fe needs to come from dietary sources: absorption = loss  Children: 30% of daily needs come must from diet due to growth spurt and body muscle mass increases

54. Fe Absorption  Very little normally leaves, enters body daily – little lost in feces, urine. Most recycled by macrophages  Mechanisms affecting intestinal absorption, transport a) body Fe stores, b) rate of erythropoiesis, c) Bioavailability of dietary Fe, d) hepcidin  Absorption increases with ↑ erythropoiesis.

55. Intestinal Fe absorption and need for iron  Bioavailability: Heme sources (meat, poultry, fish) (30%) > than non-heme sources (vegetable) (10%)  Hepcidin: made by liver – inhibits GI Fe absorption and storage Fe release  Healthy term infants have enough Fe stores for 5-6 months if mother has enough Fe. Premies much less.

56. Some Fe sources and infant needs  Breast milk: low Fe; 50% bioavailability  Formulas: 12-36X more Fe; 4-6% bioavailability.  Full term breastfed babies need 1 mg/kg up to 15 mg beginning at age 4 months  Breastfed premies: Need 2-4 mg/kg up to 15 mg starting at age 1 month of age  Age 1-3: 7; 4-8: 10; 9-13: 8 mg/day

57. Causes of IDA  Insufficient Fe intake  Poor Fe absorption (poor dietary sources or other reasons)  Introduction of unmodified cow’s milk at < age 12 months  FOB loss 2 o to cow’s milk protein- induced colitis (6 moa: 30% : 5% FOB + if on Cow’s milk vs. formula in infants)  Breast milk too long – without supplementation

58. Causes of IDA Continued  Giving > 600 ml/day or > 6 breast feeds / day at 8-12 months of age.  Preschool - > 720 cc milk daily (low concentration and bioavailability of Fe + possible ↑ intestinal blood loss increased  Absorbed most from duodenum so decreased absorption with Celiac, Crohn’s, giardia, resection proximal SB, H. pylori.  Blood loss - IBD, cow’s milk protein- induced colitis

59. Prevention  Exclusive breast feeding till age 4-6 mo.  Supplement with Fe at 4 months  With iron fortified cereal after 6 mo  Only Fe fortified formulas (avoid cow’s milk) if not breastfed till age 1 year  After 6 mo > one feeding of foods rich in Vitamin C daily (increase Fe absorption)  After 6 months consider pureed meats  Age 1-5 limit to 24 oz cows milk/day

60. Development of IDA  Use up storage iron first  Iron limited erythropoiesis  IDA (last stage and first to recover)  Initially normocytic / normochromic  Eventually classic microcytic hypochromic hypoproductive anemia

61. Signs/symptoms  Most asymptomatic as develops slowly  Lethargy, irritability, tachypnea, poor feeding  Pallor (not reliable sign till severe), ↑HR  ↓ exercise capacity (even pre-anemic)  Pica (appetite for substances not fit for food - paper, clay, dirt), pagophagia (pica for ice is common and specific for ID) – often precede anemia and resolve early upon treatment  Beeturia (red urine with beets)  Fe deficiency can cause RLS - 9X ↑incidence

62. Complications of IDA and treatment  Neurodevelopmental issues Psychomotor, mental development impairment, cognitive issues even in adolescents Fe supplementation can prevent but may not correct once established. Improvement of attention, concentration and cognitive function with Fe supplementation Auditory and visual dysfunction Decreased work capacity in adults  Immunity – Fe may increase bacterial, malaria infection risk. Transferrin has bacteriostatic effects lost if saturated by Fe

63. Screening  2/3 with ID don’t have IDA (age 1-3 9% ID, 2-3% IDA)  2/3 those anemic have another diagnosis  Anemia risk assessment at ages 4, 15 18, 24, 30 mo then yearly. All premies at risk.  Use focused dietary history Standards already listed < 2 servings of Fe rich foods daily after 6 months or < 3 servings age 1-5 years Intake of sweets, lots of fatty snacks, soft drinks

64. Diagnosis/Lab  Universal lab screening of all 9-12 mo.  Hgb, Hct or CBC  If at risk re-screen at 15-18 months  If high risk of Fe deficiency also check ferritin as one can be ID without IDA  Fe deficiency anemia typically has low MCV, MCH, MCHC and high RDW

66. If IDA suspected  Can treat in this age empirically and test to confirm only if not responding well  If need to prove or if severe check Ferritin best single test – measure of Fe stores. (Acute phase reactant so if another illness can be falsely elevated - ↓ in IDA) Fe ↓ in IDA TIBC (total iron binding capacity) ↑ in IDA Fe/TIBC= Fe, transferrin saturation ↓ in IDA

67. Treatment  If anemic dietary history, correct diet  Lead exposure questionnaire or level  If age > 2 some recommend stool for FOB X 3, retic count, peripheral smear  If in doubt or severe (< 7 Hgb) check Fe, TIBC, ferritin (< 12), transferrin sat along with FOB X 3.

68. Treatment continued  Most cost effective means to tx if consistent diet history and no indication of Pb toxicity is a presumptive trial of iron ($5.00)  3 -6 mg/kg elemental Fe/day up to 150 mg  FeSO 4 daily or BID (FeSO 4 20% elemental Fe)  Continue Fe several (3-4) months after anemia resolved to replace stores  Maximize absorption - give between meals, with juice

69. Iron therapy  Repeat CBC 1 month (sooner if severe) for > 1 gm/dl increase in Hgb – if not re-evaluate  Can use other forms of Fe – i.e. Fe Gluconate  Avoid enteric coated if possible  Rarely causes GI upset at this age (10%)  MUST at same time institute dietary changes  Repeat periodically till normal for age  Once normal continue Fe 3-4 months to replace Fe stores

70. Nonresponders  Check adherence including diet  Intercurrent illness that can lower Hgb?  Check Ferritin, Hgb electrophoresis, Vit B12, RBC folate, Fe, TIBC, ferritin  Fe/TIBC = transferrin saturation  Several stool specimens for occult blood

71. Non-responders continued  Eliminate all cow’s milk protein from diet  R/O Celiac disease  ESR and albumin – to screen for IBD  Consider rare causes, incorrect dx (Thalassemia, Chronic disease)  Rare to need parenteral Fe  Rare to need transfusion even if Hgb 4-5 g/dl unless in distress

72. Adolescents  ↑ risk due to expansion of blood volume, increased muscle mass with growth  Eating patterns (vegetarian, anorexia)  Incidence rises with age in females  ID 11% IDA 3% 16-19 in girl vs. < 1% boys  Obesity, training athletes, periods ↑ risk  Screen ALL at risk, girls q 5 yr beginning at 13, boys once during growth spurt

73. Adolescents  Cutoff Hgb < 11 and cutoff ferritin < 12  For tx least expensive is Fe sulfate 325 Fe Sulfate = 65 mg elemental Fe.  Ca inhibits, ascorbic acid ↑ absorption  If not tolerating iron consider Taking with food + ascorbic acid Feosol 45 mg elemental Fe/5cc better tolerated  More likely not to tolerate, need transfusion (< 7 Hgb + distress, end organ issues)

74. Adults  Main difference in adult – Must look for cause: cause blood loss till proven otherwise. Overt sources of blood loss Severe traumatic hemorrhage Hematemesis, melana, or hematochezia Hemoptysis Severe menorrhagia, pregnancies, lactation Gross hematuria Frequent blood donating Marathon running

75. Occult blood loss – not obvious  Usually GI tract in men and post- menopausal women  Heavy periods in pre-menopausal women  While reduced Fe absorption and deficient diet may be cause, must do GI work-up to avoid missing malignancy  Overall risk of malignancy not high (12%), but much higher than without IDA

76. Evaluation of occult blood loss  First study to do based on history – Colonoscopy vs. EGD  In one study of 100 persons, source found in 62%: 25 with colonoscopy, 36 with EGD, 1 with both; 11 had cancer  For most do colonoscopy first because almost all need even if EGD finds lesion  If cause not found EGD

77. Evaluation of occult blood loss  If no cause found consider SB capsule endoscopy  R/O Celiac disease, H. Pylori, atrophic gastritis esp. if refractory to Fe therapy (100% Celiac, 70% H. Pylori refractory)  Hookworms cause increase losses Can consume 0.3-0.5 ml blood/day Often cause eosinophilia  Consider Foods/meds that interfere with Fe absorption

78.  Other causes Gastric bypass Pulmonary hemosiderosis Intravascular hemolysis leading to urinary loss of Fe Congenital Fe deficiency not responsive to Fe or defects in Fe absorption or utilization

79. Transient erythroblastopenia of childhood  Temporary (always) RBC aplasia occurring at ages 6 mo – 4 yrs  Fairly common but don’t know true incidence as many cases not detected  Normocytic anemia  Cause not known. Viral? Toxic?  Mild neutropenia possible; normal or slightly high platelets

80. TEC  Hgb 6-8 with reticulocytopenia  Normal MCV except during recovery due to retics (distinguishes from congenital pure red cell aplasia – macrocytic anemia)  Lasts 1-2 months then recovery  80% recover within 1 month  Transfusion rarely necessary

81. Thalassemia  Major forms deadly or very sick  Minor and trait look a bit like IDA  Beta thal minor – has elevated Hgb A2, F on Hgb electrophoresis, target cells, low MCV and – W/U for IDA  Alpha more complex  If failed Fe tx important to diagnose to prevent eventual iron overload from increases absorption and repeated tx.

82. B12 (and folate) deficiency  Macrocytic anemia with low retic  Check B12, folate in all with high MCV  B12 variable so if low need repeat  Folate: leafy green veges, fruit, enriched sources  B12 animal products: eggs, meat, fish, milk  (homocysteine, MMA) Both high in B12 and only HC in folate deficiency.

83.  Can effect all 3 hematopoietic cell lines  B12 low from poor intake, gastrectomy, bariatric surgery, H. Pylori, breastfed, fish tapeworm, drugs (PPI), hereditary causes, pernicious anemia, Celiac  Folate – Poor intake, drugs (MTX), increased needs, Celiac  Folate needed in purine synthesis; B12 needed as cofactor in activation of folate  Neurological damage from B12 deficiency which can be permanent

84. S/S/lab in B12 deficiency  B12 – anemia but not always Macrocytosis and oval cells Neuro symptoms Hypersegmented WBC (> 5 nuclei)  B12 signs/symptoms: Glossitis, + anemia, memory loss, irritability, ataxia, dementia, peripheral neuropathy  Danger that neurological symptoms of B12 can be permanent once established

86.  Cobalamin levels — ”Commercial labs use different methods for measuring Cbl. …there are different normal ranges and no "gold standard“ Accordingly, therapeutic trials of Cbl are warranted when testing results are in conflict with the clinical diagnosis.”“  Interpretation of B12 (Cbl) levels :  “●>300 pg/mL (>221 pmol/L) — normal result; Cbl deficiency unlikely (ie, probability of 1 to 5 percent)  ●200 to 300 pg/mL (148 to 221 pmol/L) — borderline result; Cbl deficiency possible  ●<200 pg/mL (<148 pmol/L) — low; consistent with Cbl deficiency (specificity of 95 to 100 percent)”  Schrier SL. “Diagnosis and treatment of vitamin B12 and folate deficiency.” UpToDate accessed on 1/3/2014 http://www.uptodate.com/contents/diagnosis-and-treatment-of-vitamin-b12- and-folate- deficiency?source=search_result&search=vitamin+B12+deficiency&selected Title=1~150 http://www.uptodate.com/contents/diagnosis-and-treatment-of-vitamin-b12- and-folate- deficiency?source=search_result&search=vitamin+B12+deficiency&selected Title=1~150

87. Anemia of chronic disease  Occurs with inflammation (lupus), malignancy, infection (Tb). But even DM, anemia of elderly.  Mechanism Cytokines decrease EPO production (relative decrease) Decreased response to EPO Interference with Fe absorption and trapping by macrophages due to increased hepcidin formation Perhaps some decreased RBC survival  Characteristics Most normocytic normochromic hypoproliferative – (microcytic Fe level, TIBC and transferrin saturation (20% low) decreased but ferritin normal or elevated as acute phase reactant Decreased absolute retic count, RPI Usually mild, non-progressive around 11 - (20% < 8%)

88. Anemia in Malaria  Can cause severe anemia especially in SSA and often on top of chronic anemia  Multiple mechanisms: acute hemolysis, G- 6PD deficiency, extravascular clearance in spleen, intravascular destruction, suppression of erythropoiesis, others  Fe deficiency may be protective against malaria infection – reduced parasitemia, rate of severe malaria by 38%  Especially severe in those with SCD

89. Anemia in Sickle Cell Disease  Chronic hemolysis with Hct 20-30% and 3- 15% reticulocytosis, elevated indirect bili  2 causes of acute severe anemia - present with pallor, weakness, lethargy-can be fatal Splenic sequestration crisis – vaso-occlusion in spleen with rapid increase in size and drop in Hgb of at least 2, low platelets, reticulocytosis. Tend to recur within year Aplastic crisis – Parvovirus B19 – decreased reticulocytes. Often need transfusion though retics return in 2-14 days

90. G6PD glucose-6-phosphate dehydrogenase deficiency  Hemolysis precipitated by certain drugs, infection or occasionally a chronic hemolytic anemia  13 % of black men and 2% black women – different genotype in Mediterranean, Arabic and Asian descent  Primaquine – always check G-6-PD levels prior to giving

91. Summary  While anemia can be quite complex, we presented a fairly simple evaluation of anemia based on the cell size or MCV and mechanism of the anemia based on the retic count of RPI  Anemia is very common with considerable morbidity around the world  We discussed several specific anemias especially IDA, it’s causes, prevention, complications, diagnosis and treatment

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101. Thalassemias  Check for + FH  Ferritin high or normal  RBC proportionately low in Fe deficiency, inappropriately high in thalassemia so > 3 times Hgb  Two types – Alpha and Beta

102. Beta thal (defect in forming beta chain of globin)  Beta Thal major serious illness with severe usually transfusion dependent anemia.  Minor or silent carrier (heterozygote) Hct: usually > 30 Hgb electrophoresis: A2 and F high MCV: < 75 RBC: usually increased Target cells RDW: usually normal Risk: overtreating with Fe when not needed

103. Alpha thal  More complexas there are 4 genes, not 2 – 2 from each parent  4 gene deletion Hgb Barts and fatal early  3 gene deletion Hemoglobin H and severe  2 gene deletion alpha thal minor – hypochromic microcytic anemia  1 gene deletion silent carrier or minimus – usually normal; dx only by DNA analysis  Hgb electrophoresis normal

104. Anemia of Malaria  Major cause of severe malaria especially in sub-Saharan Africa.  Often on top of already existing chronic anemia of various etiologies.  Multiple mechanisms causing hemolysis and bone marrow suppression  Normocytic/normochromic without reticulocytosis

105. Multifactorial  Acute hemolysis in Blackwater fever  G-6PD deficiency and use of Quinine  Extravascular clearance (spleen)  Intravascular destruction of RBC  Clearance of uninfected RBC (10 uninfected cells removed/infected cell  Activation of monocyte/macrophage system  Suppression of erythropoiesis – inadequate EPO, direct inhibition, dyserythropoiesis, cytokine suppression, decreased responsiveness to EPO  Iron deficiency  B12 deficiency may contribute

106.  Fe deficiency may be protective against malaria infection – reduced parasitemia, rate of severe malaria by 38%, all-cause mortality by 60%.  Fe supplementation actually increases malaria morbidity and mortality  Also higher hepcidin – wait till no malaria to treat with Fe  While SS trait is protective, if one has SCD and gets malaria, it tends to be much more severe, deadly than in general population

107. Hemolytic anemias  Often rapid onset, jaundice, bilirubin pigment GB stones, splenomegaly, fragmented cells in peripheral smear  Increased LDH; Reduced haptoglobin 90% specific at diagnosing.  Normal LDH, serum haptoglobin > 25 mg/dl 92% sensitive in ruling out hemolysis in adults  Many kinds beyond scope of talk

108.  CKD, endocrine disorders can present similarly  A few need bone marrow to diagnose  Treat underlying condition unless severe  Treat other complicating factors  Occasionally EPO if very low Hgb  If EPO give iron – may need to be parenteral due to hepcidin blocking absorption

109.  If rate hemolysis > rate of ability of bone marrow to replace destroyed cells develop anemia (AIHA)  CBC, retic, Coombs, urinalysis, blood smear.  AST and LDH up but not ALT  Some types AIHA respond to steroids

110. B12 and folate deficiency  Macrocytic anemia with low retic  All with high MCV should have level B12, folate levels (RBC level better)  B12 variable so if low need two levels  Folate: leafy green veges, fruit and enriched sources  B12 in animal products, eggs, meat, fish, milk  If not sure true deficiency check homocysteine and MMA (methylmalanic acid) – both high if B12 low, homocysteine only if folate deficient

111.  If borderline therapeutic trial reasonable  Can effect all 3 hematopoietic cell lines  B12 low from poor intake, gastrectomy or gastric bypass, bariatric surgery, H. Pylori, breastfed, fish tapeworm, drugs (PPI), Hereditary causes, pernicious anemia  Folate – mainly poor intake and some drugs (MTX), increased needs, Celiac  Danger is neurological damage from B12 deficiency which can be permanent

112.  Folate needed in purine synthesis; B12 needed as cofactor in activation of folate  B12 – anemia but not always Macrocytosis and oval cells Neuro symptoms Hypersegmented WBC (> 5 nuclei)

113.  Folate – only anemia symptoms  B12 – neuro sx can be permanent Glossitis + anemia – but more had MCV > 100 Memory loss Irritability Ataxia Dementia Peripheral neuropathy

114. Mechanisms of anemia in Sickle Cell Disease  All have chronic hemolysis with mild-moderate anemia (Hct 20-30%) and reticulocytosis (3-15%), elevated unconjugated bili, increased LDH and low haptoglobin.  Usually normocytic normochromic  High hemoglobin F  2 causes of acute severe anemia and present with pallor, weakness, lethargy can be fatal Splenic sequestration crisis – vaso-occlusion in spleen so size increases rapidly – up to 30% get prior to splenic fibrosis due to multiple episodes of splenic infarction (splenic enlargement, drop Hgb of at least 2, low platelets, reticulocytosis – can get hypovolemic shock. If get one tend to get recurrence within 12 months

115.  Aplastic crisis – B19 – decreased reticulocytes < 10,000. Often need transfusion though retics return in 2-14 days  Some believe a third crisis and some do not called hyperhemolytic crisis  Teach parents to recognize enlarging spleen

116. Fe deficiency in adults  Fe stores in liver, spleen, bone marrow  Normal 3-4 grams Hgb in circulating cells – 2 grams Iron containing proteins – 400 mg Plasma iron bound to transferrin – 3-7 mg Remainder storage iron in form of ferritin or hemosiderin.

117. Stages of iron deficiency  Loss of stores (20% of menstruating women in U.S. have no stores)  Iron deficient RBC production  After stores gone enough in labile Fe pool to continue till further losses.  Some with very low ferritin without anemia have fatigue and decreased exercise tolerance  Further Fe loss- normocytic anemia with normal absolute retic count (low ferritin, Fe, high TIBC, low transferrin saturation,  Microcytic anemia with low retic count

118.  For adults draw all at once – CBC, ferritin, Fe, TIBC  Test of absorption – 325 mg then repeat Fe 1-4 hours – increase 100 mcg/dL adequate  Nothing else causes low ferritin levels

119.  Best test is ferritin – if known inflammation divide by 3  Sensitivity 59%, specificity 99%  Some recommend using higher cutoff to make more sensitive  Transferrin saturation normal 25-45  High transferrin second in accuracy to ferritin but BCP and pregnancy raise it

120. Symptoms  Asymptomatic  HA, weakness, irritability, fatigue  Impaired exercise tolerance  Pica/Pagophagia  Beeturia – excretion of red urine if eats beets (absorption increased and ferric iron decolorizes  Fe deficiency can cause RLS – in one study of 24%, 9X higher than in general population – may even respond to iron if not iron deficient

121. Iron deficiency adult  The safety of routine iron in places with endemic malaria remains uncertain  Times that intravenous Fe might be considered: if not tolerating oral iron, IBD, chemotherapy induced anemia, unresponsive to oral Fe, if blood loss exceeds amount one can replace, after gastric bypass surgery or subtotal gastric resection

122. Treatment  Not enteric coated  Not with food (inhibit absorption H2 receptor blockers, antacids, PPI, Ca, some antibiotics like tetracycline, fiber, tea, coffee, eggs, milk  Fe ++ best absorbed – give abscorbic acid  If not tolerated: Try one with less iron like Fe gluconate (28-36 mg) Try Ferrous sulfate elixir Give with food  Fe fumarate 106 mg; sulfate 65; gluconate 28-36 mg elemental iron / tablet  Dose 150-200 / day elemental iron  Lower dose for elderly

123. If no response  Incorrect diagnosis  Non-adherence  Coexisting disease interfering  Not absorbed for physical reasons  Iron loss > replacement amount  Malabsorption of iron (Celiac)  Inherited condition

124. Response to treatment  Pagophagia, disappear almost immediately  Better sense well being first few days  7-10 days maximal reticulocytosis  Retic count increases within 3-5 days  Hgb increases after 1-2 weeks by 2 - 3 gm/dl