1. Anemia A Finding, Not Yet a Diagnosis
Herbert L. Muncie, Jr., M.D.

2. Case Finding – Symptoms or Signs
Order CBC if suspect anemia due to:
Symptoms
Fatigue, weakness, blood loss, etc.
Signs on Physical exam
Look for pallor of conjunctivae, face & palms - if all 3 present helps confirm anemia
Absence of pallor does not rule out anemia
Pallor of nail beds/skin creases - of no value in assessing presence or absence of anemia

3. When to order a CBC
CBC is not a screening test for non-pregnant adults
Who should be screened?
Pregnant patients & high risk infants (USPSTF) – (SOR – B)
Asymptomatic infants 6 – 12 months of age – insufficient evidence for or against (SOR – I)
Against is low prevalence, cost & toxicity of Fe

4. Diagnosing Anemia
Diagnosis depends on Hgb/Hct being below a normal value
The “normal” Hgb and Hct changes
Throughout childhood
During pregnancy
Higher for men than women
Normal does not imply optimal
And we do not know what the optimal level is for a patient

5. Normal Adult Red Cell Values
Red Cell Parameter
Adult male
Adult Female
Hemoglobin (g/dL)
Hematocrit (%)
Reticulocytes (%)
Mean corpuscular volume (fl) (MCV)
Red cell distribution width (%) (RDW)

6. Question
52 year old white male, 2 PPD smoker, had a CBC done for mild fatigue & dyspnea on exertion
WBC – 8.7
Hgb – 13.0 g/dL
Hct – 41%
MCV 81 fl
Is this patient anemic?
Yes No
Maybe

7. Adjustments to normal range
Adjust for altitude
> 3,000 feet - lower oxygen tensions, higher values
Adjust for smoking
Smokers have higher values due to carbon monoxide in smoke
Adjust for ethnicity

8. Smoking adjustments for Hgb/Hct
Add this to the normal Hgb/Hct range - e. g.
normal male non-smoker Hct = %
> 2 PPD male smoker normal Hct = %

9. Ethnicity adjustment – Average Normal level

10. Question
52 year old male, 2 PPD smoker, had a CBC done for mild fatigue & dyspnea on exertion
WBC – 8.7
Hgb – 13.0 g/dL
Hct – 41%
MCV 81 fl
Is this patient anemic?
Yes No
Maybe

11. 1st Diagnostic Step after finding anemia
Once you determine the patient is ‘anemic’ then look next at MCV to determine diagnostic tests (if WBC & platelets are normal):
MCV
Anemia category
< 80 fl
Microcytic
80 – 100 fl
Normocytic
> 100 fl
Macrocytic

12. If you suspect blood loss or hemolysis
Order Reticulocyte count (RC)
Normal < 2% - marrow’s response to anemia
Hemolytic anemia usually > 4%
Absolute: RC% X RBC/100
Normal - 25K-75K
> 75K suggests blood loss or hemolysis
Corrected: RCc = RC% X hct/45
Normal RCc = %
> 1% suggests blood loss or hemolysis

13. Anemia - other testing if indicated
Haptoglobin
Low in hemolysis
LDH
High in hemolysis
Hemoglobin electrophoresis
Hemoglobinopathies
Thalassemia

14. Most Common Diagnoses based on MCV
Microcytic
Normocytic
Macrocytic
Iron deficiency*
Chronic disease*
Folate defic.*
Thalassemia*
Blood loss - acute
B12 defic.*
Lead poisoning
Liver disease (alcohol abuse)
Sideroblastic
Hypothyroid
* Discussed in more detail

15. Iron Balance Controlled by absorption, not excretion
Routine loss about 1 mg/day
Menstrual loss averages 30 mg/month or on average 1 mg/day
Normally absorb mg/day
Delicate balance for menstruating females
Pica - Inappropriate consumption of nonnutritive substances (e.g. clay, starch, ice)
Highly characteristic of iron deficiency

16. Microcytic Anemia - Iron Deficiency
Definition: anemia occurs after iron stores are totally depleted
Etiologies: inadequate diet to meet demand, blood loss or both
Children, teens - inadequate diet
Young women – blood loss (menorrhagia) &/or inadequate diet
Older person -
Neoplasm - always exclude cancer
GI loss - may be due to medication (esp. NSAIDs)
Angiodysplasia

17. Iron Sources – Dietary Sources
Heme Iron:
Meat, poultry, fish
Efficiently absorbed & minimally affected by dietary factors
Non-heme Iron:
Green leafy vegetables
Less efficiently absorbed – requires acid digestion
Ascorbic acid increases absorption
Reduced absorption with calcium, tea, coffee

18. Iron Deficiency Anemia (IDA) - consequences
Impaired attention
Learning disabilities
Altered immunity
Reduced work capacity
Pre-term labor
Reduced athletic performance
Reasonable indications for CBC

19. Tests to Diagnose IDA MCV - changes occur late
< 70 fL probably iron deficiency
MCH, MCHC - no clinically useful information
RDW % - reflects anisocytosis
Almost always elevated in IDA – 90%
However, about 50% of patients with thalassemia trait have elevated RDW

20. MCV & iron deficiency anemia (IDA)
Result (fL)
Probability of IDA
< 70
84.3%
70 -74
58.6%
75 -79
30%
80-84
28.1%
85 -89
24.6%
> 90
11.1%

21. Tests for Fe Deficiency
Serum iron - level alone of little value
Low in anemia of chronic disease
Total Iron binding capacity (TIBC) - high in Fe deficiency
Usually low in anemia of chronic disease
Answer to TQ#1

22. Question
38 year old female with type 2 diabetes develops pyelonephritis & is hospitalized
CBC – Hgb 11.0 g/dL, Hct 33%, MCV 79 fl
Ferritin is ordered – result is 115 ng/ml
You wonder if the elevated ferritin is the result of inflammation/infection or does it mean she does not have iron deficiency. What would you order to determine which it is?
Serum iron
Total iron binding capacity
C-reactive protein (CRP)
Transferrin saturation

23. Tests - Ferritin Intracellular iron storage protein
Best single test to assess for Fe deficiency
Levels < 15 µg/L – diagnostic of Fe deficiency
Levels > 100 µG/L - Fe deficiency very unlikely
However, it is an acute phase reactant
Can be elevated in inflammatory, malignant or liver disease & would not reflect Fe stores
If C-reactive protein (CRP) is normal then inflammation is not causing the increased ferritin [Yang 2008]
Answer to TQ#1

24. Ferritin and likelihood IDA
Result
Probability of IDA
< 15 ng/ml
95.7%
ng/ml
79.1%
ng/ml
52.1%
ng/ml
44%
ng/ml
18.8%
> 100 ng/ml
3.3%

25. Additional Tests for Fe Deficiency
Transferrin saturation
Decreased in iron deficiency
Soluble transferrin receptor assay (sTfR)
Excellent for distinguishing between inflammation & iron deficiency
sTfR is not affected by inflammation
sTfR is increased with iron deficiency
Normal with inflammation
However, not available in all labs & expensive

26. Transferrin saturation & iron deficiency
Result
Probability of disease
< 5%
81.8%
5 - 9%
51.7% %
25.8% %
18.2% %
15.6%
> 50% 6%

27. Additional Tests for Fe Deficiency
Bone Marrow
Gold standard - any stainable iron excludes diagnosis
No single biochemical test consistently diagnoses IDA except bone marrow aspirate

28. As tolerated by the patient36
250
21 year old female with fatigue, found to have Hgb/Hct of 9.7/ MCV – 76 Has heavy menses. This patient probably has iron deficiency anemia. How would you tell this patient to take her iron salt?
Once daily (QD)
Twice a day (BID)
Three times a day (TID)
As tolerated by the patient

29. Iron Deficiency - therapy
Do not give iron unless it is iron deficiency anemia & the etiology is determined
Should have a probable etiology
Treat with ferrous salts
Sulfate (325 mg = approximately 60 mg elemental Fe)
Gluconate (325 mg = approximately 36 mg elemental Fe)
Sustained release forms not recommended as initial therapy

30. Iron Deficiency - therapy
Start once daily (QD), may increase to BID or TID with meals if needed & tolerated
QD adequate in children, elderly & pregnancy if not actively bleeding
More GI distress with more frequent doses
Continue for months to replete iron stores
Hgb should increase 1 g/dL every weeks or 2 g/dL within 4 weeks
Serum ferritin > 100 µg/dL indicates appropriate iron stores

31. Iron Deficiency - IV therapy
Indications for IV therapy
Chronic uncorrectable bleeding
Intestinal malabsorption
Intolerance to oral iron
Nonadherence to oral therapy
Hgb < 6.0 g/dL with poor perfusion who would otherwise have received transfusion but refused

32. Iron Deficiency - IV therapy
Iron dextran (Dexferrum®, INFeD®)
mg IM/IV
Risk of anaphylaxis
Ferumoxytol (Feraheme®)
For patients with chronic kidney disease & IDA
510 mg IV x1 & repeat in days

33. Iron Deficiency - IV therapy
Newer agents with less risk of anaphylaxis
Sodium ferric gluconate complex (Ferrlecit® mg IV each HD)
Iron sucrose (Venofer® mg IV each HD)
Primary indications for both drugs are chronic kidney disease or hemodialysis

34. Heart failure & iron deficiency
Patients with heart failure prone to iron deficiency from:
Depletion iron stores – poor nutrition
Defective iron absorption
IV ferric carboxymaltose improved symptoms, functional capacity & QOL with or without anemia [Anker 2009]
Criteria – ferritin < 100 mcg/L or ferritin 100 – 299 & transferrin saturation < 20%
Hgb 9.5 – 13.5 g/dL
Unknown if oral therapy would help

35. Microcytic Anemia – Thalassemia
Hereditary microcytic anemia [Muncie 2009]
Autosomal recessive inheritance
Defect in hemoglobin synthesis
Reduced synthesis of α-globin chains α-thalassemia
Controlled by two genes on each chromosome 16
Reduced synthesis of -globin chains -thalassemia
Controlled by one gene on each chromosome 11

36. α-Thalassemia One of four gene deletions Two of four gene deletions
α-thalassemia silent carrier
Two of four gene deletions
α-thalassemia trait
Three of four gene deletions
α-thalassemia intermedia with significant Hb H (Hb H disease)
Four gene deletions
α-thalassemia major with significant Hb Bart’s

37. α-Thalassemia - diagnosis
No definitive test for α-thalassemia
Hemoglobin electrophoresis normal in adults
In infants if electrophoresis showed:
Hb H – patient has α-thal
Hb Bart’s – usually fatal due to hydrops fetalis

38. α-Thalassemia - treatment
No treatment necessary or helpful
Suggest genetic counseling & possible prenatal diagnostic testing

39. -Thalassemia Two gene defect One gene defect results
-thalassemia trait (minor)
Two gene defect
Mild to moderate decrease in synthesis
-Thalassemia intermedia
Severe decrease in synthesis
-Thalassemia major

40. -Thalassemia Trait - diagnosis
Usually found incidentally when:
Mild microcytic anemia with normal RDW
Normal RDW almost always β-thal trait
RDW can be elevated in 50% patients
If RDW is elevated additional tests are needed
Ferritin to r/o iron deficiency
Lead level to r/o lead poisoning
Finally hemoglobin electrophoresis can help
Reduced or absent Hb A, elevated levels HbA2 (> 3.5%) and elevated Hb F

41. -Thalassemia Trait - treatment
No disease specific treatment available
Adjunctive treatment not needed for most cases
Diagnosis has genetic ramifications
Suggest prenatal screening

42. -Thalassemia intermedia/major
Diagnosed during infancy or early childhood
Will need chronic blood transfusions to survive
With chronic transfusions will get iron overload
Will eventually require iron chelation therapy
Mortality due usually to cardiac iron overload

43. Iron deficiency anemia Anemia of chronic disease Pernicious anemia 35
250
72 y. o. female with diabetes & hyperlipidemia had a CBC for pre-op evaluation for cataract surgery. HGB – 10.1; HCT -30.8, MCV – 89 fl. This patient probably has:?
Iron deficiency anemia
Anemia of chronic disease
Pernicious anemia
Anemia from folate deficiency

44. Anemia of Chronic Disease (ACD)
Most common outpatient etiology of normocytic anemia
Misnomer - can be seen in acute illness
Another name - anemia of chronic inflammation
Occurs in infection/inflammation/neoplasia and unknown other conditions
Anemia can be first clue to disease
Without known disease - pursue further evaluation
Answer to TQ#2

45. Evaluation for occult chronic disease
ESR
TSH
LFTs
BUN & creatinine
If normal PE & lab tests
No further workup is likely to be helpful

46. Associated diseases Acute infections - Chronic infections -
E. g. bacterial, fungal, viral
Chronic infections -
E. g TB, endocarditis, chronic UTI, coccidiomycosis
Inflammatory diseases -
E. g. Osteoarthritis (OA), rheumatoid, collagen-vascular, PMR, hepatitis, decubitus ulcers
Malignancy
Protein-energy malnutrition

47. Anemia of Chronic disease (ACD)
Hematology:
Usually mild anemia (Hct 30 – 34%)
Normochromic/normocytic
May be complicated by true iron deficiency anemia
But would be microcytic or have elevated RDW

48. Pathogenesis of ACD Pathogenesis:
Inflammatory cytokines i.e. interleukin 1, tumor necrosis factor (TNF) mediate etiology
Sequester iron in RE system
Impair proliferation of erythroid progenitor cells
Blunt erythropoietin response

49. Anemia of Chronic disease
Patients have impaired release of Fe from RE cells
Increased Fe stores, not Fe deficiency
Results in
Ferritin level - normal
Serum iron & transferrin saturation - low
True for both ACD & IDA
Transferrin level – normal or decreased
IDA - increased
Low reticulocyte count
Answer to TQ#2

50. Diagnosis of ACD Diagnosis:
Measure transferrin receptor level if unclear
Raised in Fe deficiency
Normal in anemia of chronic disease
Female – mg/L – normal range
Male – mg/L – normal range

51. Anemia of Chronic disease
Treatment:
Anemia resolves if correct underlying disorder
If cannot correct underlying disorder treatment of anemia is not usually indicated
Supplements of Fe, vitamin B12 or folate are of no benefit

52. Anemia of Chronic disease
Treatment: If quality of life is impaired, you can increase the Hgb and Hct with either:
Transfusion
If severe or life-threatening anemia
Erythropoietin
Approved for cancer with chemotherapy; chronic renal disease; HIV infection with myelosuppressive therapy
Good data on short-term outcomes
Little data on effect on course of underlying disease

53. Anemia of Chronic disease
Treatment:
Iron supplements of no benefit unless
Patient has ACD & absolute iron deficiency ferritin < 100 ng/ml
If ferritin > 100 ng/ml supplements associated with adverse outcomes

54. Macrocytic anemia Typically presents with MCV > 110 fL Etiologies
MCV common, often unexplained with no specific diagnosis found
Consider evaluation even if not anemic
Occult B12 deficiency?
Spurious macrocytosis can occur with cold agglutinins, hyperglycemia, leukocytosis
Etiologies
B12 [cyanocobalamin (Cbl)] deficiency
Folate deficiency
Hypothyroidism
Hepatic dysfunction (alcoholism)

55. Macrocytic anemia – Diagnostic Evaluation
Vitamin B12 & folate levels
RBC folate level is more accurate if folate deficiency is suspected [Kaferle 2009]
RBC folate better reflects long-term stores
Nl = ng/ml
Serum folate more easily affected by recent dietary intake
Nl = 2.7 – 17 ng/ml
Consider ordering only a B12 level since if normal could just treat with folate without worrying about complications

56. Macrocytic anemia – Diagnostic Evaluation
Other tests as indicated
TSH; Free T4; Free T3
Liver function tests (LFTs)

57. Folate level with Vitamin B12 Deficiency
Folate level usually increased with B12 deficiency
If both levels are low – is it a mixed deficiency?
Low folate level can cause low B12 level
If both results are low, treat the patient with folic acid & repeat B12 level in 4 weeks
If B12 then is normal, do not need to treat with B12, just continue to give folate
If B12 remains low either treat with B12 or measure MMA level

58. Cbl Deficiency Level < 100 pg/ml confirms deficiency
Levels > 400 pg/ml rules out deficiency
With levels > 100 & < 400 pg/ml
Measure methylmalonic acid (MMA) – normal < 0.4 μmol/L
Elevated only in Cbl deficiency
If MMA normal – points to folate deficiency
Answer to TQ#3

59. Total Homocysteine (tHcy)
tHcy levels are elevated in either vitamin B12 or folate deficiency
tHcy levels may increase % with large protein-rich meal
Samples collected supine are 10% lower
Medications affect levels
Decreased with estrogen, tamoxifen & statins
Increased with L-dopa, fibrates & diuretics
Increased tHcy levels associated with CVD & osteoporosis – nl = < 12 mmol/L

60. Etiologies B12 Deficiency
Inadequate nutritional intake
Unless strict vegetarian, Cbl deficiency implies reduced absorption
Reduced absorption
Loss of intrinsic factor; achlorhydria - Pernicious anemia (PA)
Drugs, gastro-duodenal surgery etc.
Takes 2-5 years to develop deficiency even with severe malabsorption

61. Occult B12 Deficiency Anemia can be absent in early Cbl deficiency
Especially with Cbl level < 350 pg/mL
Consider occult deficiency with new neurologic or psychiatric symptoms
Most common psychiatric symptoms are depression, mania, psychotic symptoms, OCD behavior & cognitive impairment

62. 39
250
72 year old female with H/H 9.2/28.1 & MCV – 112 fl. Diagnosed with pernicious anemia. I would treat this patient with:
Monthly injections of B12 for life
Quarterly injection of B12 for life
Daily oral B12 for life
Monthly injections of B12 for one year

63. Treatment of B12 Deficiency
Oral therapy equal to IM therapy short-term
Oral 2000 µG qd equally effective to IM for hematologic results [Butler 2006] ($100/year)
Passive diffusion accounts for 1-2 % of total absorbed & is unaffected in pernicous anemia or gastro-duodenal resection
Long-term data not available for oral therapy
Cost of medications equal, difference is medical personnel costs
1000 µG IM q month ($70/yr) or 1 mg IM q 3 months

64. Treatment of B12 Deficiency
Nasal vitamin B12 for maintenance after stores repleted & without nervous system involvement (approximately $500/year)
Duration of therapy
Life-long unless reversible cause identified
No evidence of harm associated with elevated B12 levels

65. 39
250
72 year old female with H/H 9.2/28.1 & MCV – 112 fl. Diagnosed with pernicious anemia. I would treat this patient with:
Monthly injections of B12 for life
Quarterly injection of B12 for life
Daily oral B12 for life
Monthly injections of B12 for one year

66. Etiologies Folate Deficiency
Inadequate nutritional intake
Especially with alcohol dependence
Medications
Seizure medications
Chemotherapy
Reduced absorption
Metformin (Glucophage®)
Cholestyramine (Questran®)

67. Treatment of Folate Deficiency
1 mg orally every day
CAUTION - folate may correct anemia of B12 deficiency but not the neurologic sequelae
Before initiating folate therapy verify normal B12 level

68. Key Points - Anemia Order CBC for case finding
Anemia is a finding that requires a diagnosis
MCV helps establish the probable differential diagnosis
Give Fe therapy only for Fe deficiency anemia
Vitamin B12 deficiency can be treated with oral therapy
No specific treatment for the anemia of chronic disease (no supplements)

69. Questions from the Audience?

70. References
Abramson SD. Common uncommon anemias Am Fam Phys 1999;59:851-8.
Anker SD et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:
Brill JR et al. Normocytic anemia. Am Fam Physician 2000;62:
Butler CC et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: asystematic review of randomized controlled trials. Fam Prac 2006;23:
Eussen SJPM et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Int Med 2005;165:
Goodnough LT, et al. Erythropoietin Therapy. N Engl J Med 1997;336:

71. References
Kaferle J et al. Evaluation of macrocytosis. Am Fam Physician 2009;79:
Killip S et al. Iron deficiency anemia. Am Fam Physician 2007;75:671-8.
Muncie HL et al. Alpha and Beta Thalassemia. Am Fam Physician 2009;80:
Yang Z et al. Comparison of plasma ferritin concentration with the ratio of plasma transferrin receptor to ferritin in estimating body iron stores: results of 4 intervention trials. Am J Clin Nutr 2008;87:
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352: