Seventh International Symposium in Continuing
Nursing Education/March, 2014
3/2014
Donald W. McLaren, MD
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

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

http://www.k4health.org/toolkits/anemia-prevention/anemia-causes-prevalence-impact
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)


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
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

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.

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

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

http://upload.wikimedia.org/wikipedia/en/4/49/CBC_With_Differential.jpg
http://www.childrensmn.org/manuals/lab/hematology/018981.asp
RBC and appearance in
peripheral smear
http://en.wikipedia.org/wiki/Reticulocyte_index
Reticulocyte unstained and
stained
http://en.wikipedia.org/wiki/Reticulocyte_index
http://www.med-ed.virginia.edu/courses/path/innes/nh/morphology.cfm
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

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

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

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

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

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

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
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

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
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
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
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
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
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
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
Summary (read RPI as retic for
now)
Microcytic
Normocytic
↑ RPI
or ARC
↓ RPI
or ARC
Macrocytic
↑ 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
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
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?

Most common anemias in U.S.
Copyright © 2000-2013 The Cleveland Clinic Foundation.
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology-oncology/anemia/
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
 1st of 2 corrections is for low RBC count –
to give a “corrected retic count” or “retic
index” = Retic count X Hct/45 (normal Hct)

10% retics
Retic Count X Hct/normal Hct =
20% X 5/10 = 10%
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 < 15: 2.5
Hct 26-35: 1.5
Hct 16-25: 2.0
http://faculty.washington.edu/rrichard/anemia.ppt
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

http://allaboutblood.com/tag/corrected-reticulocyte-index/
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
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

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.

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.

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

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 2o to cow’s milk proteininduced colitis (6 moa: 30% : 5% FOB +
if on Cow’s milk vs. formula in infants)
Breast milk too long – without
supplementation
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 proteininduced colitis

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

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

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
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
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
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

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
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.

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
FeSO4 daily or BID (FeSO4 20% elemental
Fe)
Continue Fe several (3-4) months after
anemia resolved to replace stores
Maximize absorption - give between meals,
with juice
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
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

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

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
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)
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
Occult blood loss – not obvious
Usually GI tract in men and postmenopausal 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

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

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

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
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

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

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.

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.

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

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







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-b12and-folatedeficiency?source=search_result&search=vitamin+B12+deficiency&selected
Title=1~150
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%)
Anemia in Malaria
Can cause severe anemia especially in
SSA and often on top of chronic anemia
 Multiple mechanisms: acute hemolysis, G6PD 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

Anemia in Sickle Cell Disease
Chronic hemolysis with Hct 20-30% and 315% 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
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

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

Abrams SA. “Iron requirements and iron deficiency in
adolescents.” UpToDate accessed 1/3/2014
http://www.uptodate.com/contents/iron-requirements-andiron-deficiency-inadolescents?source=search_result&search=iron+deficien
cy&selectedTitle=5~150
 Brill JR, Baumgardner DJ. “Normocytic Anemia.”
American Family Physician accessed 1/7/2014
http://www.aafp.org/afp/2000/1115/p2255.html
 Field JJ, Vichinsky EP, DeBaun MR. “Overview of the
management and prognosis of sickle cell disease.
UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/overview-of-themanagement-and-prognosis-of-sickle-celldisease?source=search_result&search=sickle+cell+disea
se&selectedTitle=4~150




Harper JL. “Pediatric megaloblastic anemia.”
Medscape Reference accessed 1/7/2014
http://emedicine.medscape.com/article/959918
-overview
Inoue S. “Pediatric chronic anemia.”
Medscape reference accessed 1/7/2014
http://emedicine.medscape.com/article/954598
-overview
Kaferle J, Strzoda CE. “Evaluation of
Macrocytosis.” American Family Physician
accessed 1/7/2014
http://www.aafp.org/afp/2009/0201/p203.html



Mahoney DH. “Iron deficiency in infants and young
children: screening, clinical manifestations, and diagnosis.
UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/iron-deficiency-ininfants-and-young-children-screening-prevention-clinicalmanifestations-anddiagnosis?source=search_result&search=iron+deficiency&
selectedTitle=3~150
Mahoney DH. “Iron deficiency in infants and young
children: Treatment.” UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/iron-deficiency-ininfants-and-young-childrentreatment?source=search_result&search=iron+deficiency&
selectedTitle=4~150
Patrick A. “Approach to anaemia Iron-B12-Folate.
Accessed 1/7/2014
http://www.macmurray.co.nz/images/userfiles/file/anaemia
%20and%20B12%20-%20Dr%20Alasdair%20Patrick.pdf



Recht M. “Overview of hemolytic anemia in children.
UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/overview-of-hemolyticanemias-inchildren?source=search_result&search=hemolytic&selecte
dTitle=4~150
Roberts DJ. “Anemia in malaria.” UpToDate accessed
1/7/2014 http://www.uptodate.com/contents/anemia-inmalaria?source=search_result&search=anemia+of+malari
a&selectedTitle=1~150
Sandoval C. “Anemia in children due to decreased red
blood cell production. UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/anemia-in-children-dueto-decreased-red-blood-cellproduction?source=search_result&search=anemia+due+to
+reduced+red+cell&selectedTitle=2~150



Sandoval C. “Approach to the child with anemia.”
UpToDate accessed 1/3/2014
http://www.uptodate.com/contents/approach-to-the-childwithanemia?source=search_result&search=anemia&selectedTi
tle=2~150
Schrier SL. “Anemias due to decreased red cell
production. UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/anemias-due-todecreased-red-cellproduction?source=search_result&search=anemia+due+to
+reduced+red+cell&selectedTitle=3~150
Schrier SL, Camaschella C. “Anemia of chronic disease
(anemia of [chronic] inflammation) UpToDate accessed
1/7/2014 http://www.uptodate.com/contents/anemia-ofchronic-disease-anemia-of-chronicinflammation?source=search_result&search=anemia+of+c
hronic&selectedTitle=1~100



Schrier SL. “Approach to the adult patient with anemia.”
UpToDate accessed 1/3/2014
http://www.uptodate.com/contents/approach-to-the-adultpatient-withanemia?source=search_result&search=adult+anemia&sel
ectedTitle=1~150
Schrier SL. “Approach to the diagnosis of hemolytic
anemia in the adult.” UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/approach-to-thediagnosis-of-hemolytic-anemia-in-theadult?source=search_result&search=approach+anemia&s
electedTitle=3~150
Schrier SL. “Causes and diagnosis of iron deficiency
anemia in the adult.” UpToDate accessed 1/3/2014
http://www.uptodate.com/contents/causes-and-diagnosisof-iron-deficiency-anemia-in-theadult?source=search_result&search=approach+to+the+dia
gnosis+of+iron+deficiency+anemia&selectedTitle=1~150



Schrier SL. “Diagnosis and treatment of vitamin B12 and
folate deficiency.” UpToDate accessed on 1/3/2014
http://www.uptodate.com/contents/diagnosis-andtreatment-of-vitamin-b12-and-folatedeficiency?source=search_result&search=vitamin+B12+de
ficiency&selectedTitle=1~150
Schrier SL. “Etiology and clinical manifestations and
clinical manifestations of vitamin B12 and folate deficiency
UpToDate accessed 1/3/2014
http://www.uptodate.com/contents/etiology-and-clinicalmanifestations-of-vitamin-b12-and-folatedeficiency?source=search_result&search=vitamin+B12+de
ficiency&selectedTitle=2~150
Schrier SL. “Mean corpuscular volume.” UpToDate
accessed 1/7/2014
http://www.uptodate.com/contents/mean-corpuscularvolume?source=search_result&search=mean+corpuscular
&selectedTitle=1~150



Schrier SL, Auerbach M. “Treatment of the adult with iron
deficiency anemia.” UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/treatment-of-the-adultwith-iron-deficiencyanemia?source=search_result&search=iron+deficiency+an
emia&selectedTitle=2~150
Vichinsky EP. “Overview of the clinical manifestations of
sickle cell disease.” UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/overview-of-the-clinicalmanifestations-of-sickle-celldisease?source=search_result&search=sickle+cell&select
edTitle=1~150
Vranken MV. “Evaluation of microcytosis.” American
Family Physician accessed 1/7/2014
http://www.aafp.org/afp/2010/1101/p1117.html




Ware RE. “Autoimmune hemolytic anemia in
children.” UpToDate accessed 1/7/2014
http://www.uptodate.com/contents/autoimmunehemolytic-anemia-inchildren?source=search_result&search=hemolytic+
anemia&selectedTitle=4~150
“Evaluation of the anemic patient.” accessed
1/16/2014
www.medicine.wisc.edu/~williams/anemia1.ppt
“The Reticulocyte count.” All about blood.
Accessed 1/7/2014
http://allaboutblood.com/tag/corrected-reticulocyteindex/
“Reticulocyte index.” Wikipedia accessed 1/7/2014
http://en.wikipedia.org/wiki/Reticulocyte_index
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

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
Alpha thal






More complex as 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
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

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
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

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

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

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

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





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
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)
Folate – only anemia symptoms
 B12 – neuro sx can be permanent

 Glossitis
 + anemia – but more had MCV > 100
 Memory loss
 Irritability
 Ataxia
 Dementia
 Peripheral neuropathy
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
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

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.
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
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

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

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





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

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
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

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
