Anemia
A Finding, Not Yet a Diagnosis
Herbert L. Muncie, Jr., M.D.
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

When to order a CBC

CBC is not a screening test for nonpregnant adults

Who should be screened?
 Pregnant
patients & high risk infants
(USPSTF) – (SOR – B)
infants 6 – 12 months of age
– insufficient evidence for or against (SOR
– I)
 Asymptomatic

Against is low prevalence, cost & toxicity of Fe
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
Normal Adult Red Cell Values
Red Cell Parameter
Adult male
Adult Female
Hemoglobin (g/dL)
13.0 - 17.2
11.6 - 15.1
Hematocrit (%)
41 - 50
36 - 44
Reticulocytes (%)
0.5 - 2.0
0.5 - 2.0
Mean corpuscular
volume (fl) (MCV)
80 - 100
80 - 100
11.5 - 14.5
11.5 - 14.5
Red cell distribution
width (%) (RDW)
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?
a)
b)
c)
Yes
No
Maybe
Adjustments to normal range

Adjust for altitude


Adjust for smoking


> 3,000 feet - lower oxygen tensions, higher
values
Smokers have higher values due to carbon
monoxide in smoke
Adjust for ethnicity
Smoking adjustments for Hgb/Hct
Characteristic
Hct (%)
Non-smoker
Hgb
(g/dL)
0.0
All smokers
+0.3
+1.0
1/2 - 1 pk/d
1 - 2 pks/d
> 2 pks/d
+0.3
+0.5
+0.7
+1.0
+1.5
+2.0
0.0
Add this to the normal Hgb/Hct range - e. g.
• normal male non-smoker Hct = 41 - 50%
• > 2 PPD male smoker normal Hct = 43 - 52%
Ethnicity adjustment – Average Normal
level
14
13.5
13
White Men
13.7
African American
Men
White Women
13.2
12.9
12.7
12.5
12.2
12.2
12
11.5
11.5
11.5
11
Men Age
20 - 59
Men Age
Women
60+
Age 20 - 49
Women
Age 60+
African American
Women
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?
a)
b)
c)
Yes
No
Maybe
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
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 = 0.5 - 1%

> 1% suggests blood loss or hemolysis
Anemia - other testing if indicated
 Haptoglobin

Low in hemolysis
 LDH

High in hemolysis
 Hemoglobin
electrophoresis

Hemoglobinopathies

Thalassemia
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
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 1.5 - 3.0 mg/day


Delicate balance for menstruating females
Pica - Inappropriate consumption of
nonnutritive substances (e.g. clay, starch,
ice)

Highly characteristic of iron deficiency
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
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
Iron Deficiency Anemia (IDA) consequences
Impaired attention
 Learning disabilities
 Altered immunity
 Reduced work capacity
 Pre-term labor
 Reduced athletic performance
 Reasonable indications for CBC

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
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%
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
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?
a)
b)
c)
d)
Serum iron
Total iron binding capacity
C-reactive protein (CRP)
Transferrin saturation
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]
Ferritin and likelihood IDA
Result
Probability of IDA
< 15 ng/ml
95.7%
15 - 24 ng/ml
79.1%
23 - 34 ng/ml
52.1%
35 - 44 ng/ml
44%
45 - 100 ng/ml
18.8%
> 100 ng/ml
3.3%
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 increased with iron deficiency


sTfR is not affected by inflammation
Normal with inflammation
However, not available in all labs & expensive
Transferrin saturation & iron deficiency
Result
Probability of disease
< 5%
81.8%
5 - 9%
51.7%
10 - 19%
25.8%
20 - 29%
18.2%
30 - 49%
15.6%
> 50%
6%
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
21 year old female with fatigue, found to have
Hgb/Hct of 9.7/30.6. MCV – 76 Has heavy
menses. This patient probably has iron deficiency
anemia. How would you tell this patient to take
her iron salt?
a)
b)
c)
d)
Once daily (QD)
Twice a day (BID)
Three times a day (TID)
As tolerated by the patient
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
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 6 - 12 months to replete iron stores


Hgb should increase 1 g/dL every 2 - 3 weeks or 2 g/dL
within 4 weeks
Serum ferritin > 100 µg/dL indicates appropriate iron
stores
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
Iron Deficiency - IV therapy

Iron dextran (Dexferrum®, INFeD®)
25 - 100 mg IM/IV
 Risk of anaphylaxis


Ferumoxytol (Feraheme®)
For patients with chronic kidney disease & IDA
 510 mg IV x1 & repeat in 3 - 8 days

Iron Deficiency - IV therapy


Newer agents with less risk of anaphylaxis

Sodium ferric gluconate complex (Ferrlecit® 125 mg IV each HD)

Iron sucrose (Venofer® - 100 mg IV each HD)
Primary indications for both drugs are chronic
kidney disease or hemodialysis
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
Microcytic Anemia – Thalassemia

Hereditary microcytic anemia [Muncie 2009]

Autosomal recessive inheritance

Defect in hemoglobin synthesis
synthesis of α-globin chains α-thalassemia
 Reduced

Controlled by two genes on each chromosome 16
synthesis of -globin chains -thalassemia
 Reduced

Controlled by one gene on each chromosome 11
α-Thalassemia

One of four gene deletions


Two of four gene deletions


α-thalassemia trait
Three of four gene deletions


α-thalassemia silent carrier
α-thalassemia intermedia with significant Hb H
(Hb H disease)
Four gene deletions

α-thalassemia major with significant Hb Bart’s
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
α-Thalassemia - treatment
 No
treatment necessary or helpful
 Suggest
genetic counseling & possible
prenatal diagnostic testing
-Thalassemia

One gene defect results
 -thalassemia
 Two

trait (minor)
gene defect
Mild to moderate decrease in synthesis
 -Thalassemia

intermedia
Severe decrease in synthesis
 -Thalassemia
major
-Thalassemia Trait - diagnosis
 Usually
 Mild
found incidentally when:
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
-Thalassemia Trait - treatment
No disease specific treatment available
 Adjunctive treatment not needed for most
cases
 Diagnosis has genetic ramifications


Suggest prenatal screening
-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
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:?
a)
b)
c)
d)
Iron deficiency anemia
Anemia of chronic disease
Pernicious anemia
Anemia from folate deficiency
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
Evaluation for occult chronic disease
ESR
 TSH
 LFTs
 BUN & creatinine
 If normal PE & lab tests


No further workup is likely to be helpful
Associated diseases

Acute infections 

Chronic infections 


E. g TB, endocarditis, chronic UTI,
coccidiomycosis
Inflammatory diseases 

E. g. bacterial, fungal, viral
E. g. Osteoarthritis (OA), rheumatoid, collagenvascular, PMR, hepatitis, decubitus ulcers
Malignancy
Protein-energy malnutrition
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
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
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


Transferrin level – normal or decreased


True for both ACD & IDA
IDA - increased
Low reticulocyte count
Diagnosis of ACD
Diagnosis:
 Measure transferrin receptor level if unclear
Raised in Fe deficiency
 Normal in anemia of chronic disease
 Female – 1.9 - 4.4 mg/L – normal range
 Male – 2.2 - 5 mg/L – normal range

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
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
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

Macrocytic anemia

Typically presents with MCV > 110 fL




MCV 100-110 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)
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 = 160-700 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
Macrocytic anemia – Diagnostic Evaluation

Other tests as indicated

TSH; Free T4; Free T3

Liver function tests (LFTs)
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
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

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
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
72 year old female with H/H 9.2/28.1 &
MCV – 112 fl. Diagnosed with pernicious
anemia. I would treat this patient with:
a) Monthly injections of B12 for life
b) Quarterly injection of B12 for life
c) Daily oral B12 for life
d) Monthly injections of B12 for one year
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
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
72 year old female with H/H 9.2/28.1 &
MCV – 112 fl. Diagnosed with pernicious
anemia. I would treat this patient with:
a) Monthly injections of B12 for life
b) Quarterly injection of B12 for life
c) Daily oral B12 for life
d) Monthly injections of B12 for one year
Etiologies Folate Deficiency

Inadequate nutritional intake



Especially with alcohol dependence
Medications

Seizure medications

Chemotherapy
Reduced absorption

Metformin (Glucophage®)

Cholestyramine (Questran®)
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
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)
Questions from the Audience?