The document discusses iron deficiency anemia (IDA), including its definition, prevalence, diagnostic criteria, and management strategies. It highlights the importance of identifying the underlying causes of iron deficiency, the role of various laboratory tests in diagnosing anemia, and treatment approaches such as dietary changes and iron supplementation. Key factors influencing iron absorption and considerations for special populations, like pregnant women and the elderly, are also addressed.

1. APPROACH TO IRON DEFICIENCY
ANEMIA
Suman Sood, MD, MSCE
Clinical Associate Professor of
Medicine UM Division of
Hematology/Oncology
Director, UM Hemophilia and
Coagulation Disorders Program
39th Annual Internal Medicine
Update July 28, 2023
1

2. Outline
□ General approach to
anemia
□ Iron Deficiency Anemia
(IDA)
□ Diagnosis
□ Workup of etiologies
□ Management
2

3. Approach to
anemia
• Normal red blood cell (RBC)
function
• Definition of anemia
• The CBC
• How to classify anemia
3

4. Normal RBC function
□ RBCs carry
oxygen linked
to hemoglobin
from the lungs
to the tissue
capillaries.
4

5. RBC life cycle
□ Erythropoesis occurs in the bone marrow
□ Erythropoetin (EPO) is the erythroid
specific growth factor.
□ Produced in the kidneys
□ Enhances the growth and
differentiation of erythroid
progenitor cells
■ Helps burst forming units-erythroid (BFU-E)
and colony forming units-erythroid (CFU-E)
become normoblasts.
5

6. RBC life cycle
□ Reticulocyte: formed when a normoblast
extrudes its nucleus to form a mature RBC
□ Circulate for 1 day, and then lose their reticulum
and become mature red blood cells
□ Reticulocyte count is a marker of RBC production
□ Mature RBC: circulates for 110-120 days.
□ Senescent RBCs are removed by macrophages.
Under steady state conditions: 1% of RBCs are
removed by the circulation every day, so 1% of
reticulocytes should be produced every day
6

7. RBC life cycle
7

8. Definition of anemia
□ Reduction in number of circulating red
blood cells (RBC)
□ Affects 25% of the world population
□ WHO estimates (2019):
■ 40% of children 6–59 months of age
■ 37% of pregnant women
■ 30% of women 15–49 years of age worldwide
Biological gender Hemoglobin
(hgb)
Hematocrit
Females <11.9 g/dL <35 percent
Males <13.6 g/dL <40 percent
Global Health Metrics. Anaemia–Level 1 impairment. Lancet. 2019; 393 https://www.healthdata.org/results/gbd_summaries/2019/anemia-level-1-
impairment
8

9. Panel Test Drawn Value Units Range
WBC 00:34 12.6 H THO/uL 4.0-11.0
HEMOGLOBIN
HEMATOCRIT
00:34
00:34
12.1
36
g/dL
%
11.8-15.5
36-46
150-400
0.0-2.0
THO/uL
%
/uL
/uL
/uL
%
%
%
pg
%
fL
%
MIL/uL
%
0.0-8.0
45.0-74.0
20.0-47.0
27-33
31-36
80-100
3.0-11.0
3.80-5.30
11.5-14.5
RBCMORPH
PLATELET Count
% BASOPHILS
Calculated GRANULOCYTES
Calculated LYMPHS
Calculated MONONUCLEARS
% EOSINOPHILS
% GRANULOCYTES
% LYMPHOCYTES
MCH
MCHC
MCV
%
MON
ONUC
LEARS
RBC
RED
Cell
DISTRI
BUTIO
N
MACROCYTES
MICROCYTES
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
00:34
287
0.5
10100
1700
600
1.1
80.3 H
13.7 L
30
34
88
4.3
4.05
17.9 H
SLIGHT *
SLIGHT *
POLYCHROMASIA 00:34 SLIGHT *
RED Blood Cell MORPHOLOGY 00:34 *****
*
HEME
PROFILE +
ELECTRONIC
DIFF
9

10. Hemoglobin
□ Measures the
concentration of the
major oxygen
carrying pigment in
whole blood
□ Values may be
expressed as g/dl
of whole blood
10

11. Hematocrit
□ Percent of a
sample of
whole blood
that is
occupied by
intact red
blood cells
11

12. RBC count
□ Number of red blood cells contained
in a specified volume of whole
blood
□ Expressed as millions of RBCs per
microliter of whole blood
□ Not often used clinically
12

13. RBC Indices
□ *MCV: Mean corpuscular volume ~ size
□ Normal range 80-100 femtoliters
□ MCH: Mean corpuscular hemoglobin ~ color
□ Low in iron deficiency, thalassemia
□ High in macrocytosis
□ MCHC: Mean corpuscular
hemoglobin concentration
□ Low with iron deficiency, thalassemia
□ High in congenital or acquired spherocytosis, or in
other congenital hemolytic anemias
□ RED Cell DISTRIBUTION WIDTH: RDW
□ Increased with reticulocytosis
13

14. Reticulocyte count
□ Can be measured as a percentage of all RBCs, as
an absolute reticulocyte count, or as reticulocyte
production index (takes into account HCT)
□ High: increased erythropoesis--compensation
for hemolytic anemia or blood loss
□ Low (in an anemic patient): impaired RBC
production by the bone marrow
□ With pancytopenia: aplastic anemia, folate or
B12 deficiency, acute leukemia
□ With normal WBC and platelets: pure red cell aplasia
(may be associated with parvovirus B19).
14

15. Nucleated red blood cells
□ Not normally found in circulation
□ May be seen with sickle cell disease,
thalassemia major, various hemolytic
anemias after splenectomy
□ May be seen in patients with a
leukoerythroblastic picture, severe sepsis,
or heart failure
15

16. The peripheral smear
□ It is always important to look at the peripheral blood
smear for clues to the etiology of the anemia
16

17. RBC Morphology
□ MACROCYTES vs MICROCYTES
□ POLYCHROMASIA vs HYPOCHROMIC
□ RED Blood Cell MORPHOLOGY
□ Anisocytosis: variation of RBC size
□ Poikilocytosis: variation of RBC shape
□ Spherocytes: immune mediated hemolysis
□ Schistocytes: red cell fragmentation with
microangiopathic hemolysis
□ Teardrop cells: marrow infiltration
□ Target cells: thalassemia
□ Sickle cells
□ Acanthocytes (spur cells): liver disease
□ Echinocytes (burr cells): renal disease
17

18. Schistocyte
Spherocyte Burr Cell (renal)
Spur Cell (liver) Teardrop Cell Target Cell
18

19. Limitations of the definition
of anemia
□ The “normal” range includes 95% of the
normal population.
□ Therefore 2.5% of normal adults will have values that
are > 2 standard deviations below this range and be
falsely considered anemic
□ The normal ranges are so wide that a patient can
lose up to 15% of their red cell mass and still
have a normal HCT
□ “Normal” values may not apply to
special populations (i.e. high
altitude living, etc.)
19

20. Special populations
□ High altitude: higher Hgb values (less oxygen)
□ Smokers: more likely to have higher Hgb level
due to carbon monoxide exposure
□ Pregnancy
□ Athletes: Hgb can vary depending on
circumstances
□ Dilutional anemia with increased plasma volume, GI
bleeding, intravascular hemolysis (after a marathon),
iron deficiency
□ Polycythemia may occur with dehydration, or the
use of performance enhancing agents such as
androgens and erythropoetin.
20

21. Elderly
□ The elderly generally have lower values
for Hgb and HCT compared to
younger populations
□ However, elderly patients should not be
presumed to have a lower normal range, for
fear of missing a serious underlying disorder.
□ Disorders such as malignancy, peptic
ulcer disease, and infection are
more common in anemic elderly
patients.
21

22. Anemia in the elderly is due to
disease not aging!
□ A number of large studies have shown
increased mortality for elderly anemic
patients.
□ A study of 755 patients older than age 85
showed having a hgb < 13 in men and < 12 in
women (compared to age matched non-anemic
patients):
□ increased mortality 1.6x in men
□ increased mortality 2.3x in women
□ Even without an obvious chronic disease, the mortality
rate in anemic patients was 2x that of non-anemic
patients.
Izaks, et al. JAMA 1999; 281: 1714
22

23. African Americans
□ In both sexes and all ages, values for Hgb
are generally 0.5-1.0 g/dl lower than
in comparable Caucasian
populations.
□ Reason for this is unclear. Some part may
be attributable to an increased
incidence of iron deficiency anemia
and/or alpha thalessemia.
23

24. Volume status
□ Hgb, HCT, and RBC are all concentrations
and depend on the red cell mass as
well as plasma volume
□ Therefore, if red cell mass is decreased or
plasma volume is increased, the patient will
appear anemic
□ i.e.: patients admitted to the hospital dehydrated
may not appear anemic until they are fluid
repleted.
24

25. Anemia: signs and symptoms
□ May result from:
1) decreased oxygen delivery to the tissue
2) hypovolemia with acute bleeding
□ Depends clinically on:
□ time course over which anemia developed
□ degree of anemia
□ oxygen demands of the patient (i.e. at rest versus with exertion)
□ Patients with mild anemia or an anemia that evolved slowly
(mild chronic GI blood loss) will likely be asymptomatic except
with exertion
□ Acute blood loss will lead to marked symptoms of
hypovolemia and tissue ischemia (i.e. chest pain, etc).
25

26. Anemia: signs and symptoms
□ Primary symptoms:
□ Begins with symptoms with exertion:
dyspnea, palpitations, muscle cramps,
decreased exercise tolerance
□ Progresses to symptoms at rest: Dyspnea at
rest, fatigue, weakness, dizziness
□ With underlying disease: worsening CHF,
angina
□ Acute bleeding: hypovolemia:
□ Postural dizziness, lethargy, syncope,
persistent hypotension, shock, death
26

27. Causes of anemia
□ Two methods of classification:
□ Kinetic approach: identify the
mechanism responsible for
anemia
■ Useful for forming a differential diagnosis
□ Morphological approach: categorize the
anemia based on the MCV (mean
corpuscular volume)
■ Useful for further classifying normocytic anemias
27

28. Differential diagnosis
Anemi
a
Decreased
productio
n
Increased
destructio
n
Loss
28

29. Causes of anemia
PRODUCTION DESTRUCTION LOSS
BONE MARROW IMMUNE Blood loss
- Infiltrative: Cancer
- Failure: aplastic
- Radiation, Chemotherapy
Autoimmune
hemolytic anemia
VITAMIN DEFICIENCY
- B12, folate
- Copper
NON-IMMUNE
Microangiopathic
hemolytic anemia
- DIC, TTP, aHUS
- Valve hemolysis
RENAL DISEASE
-Erythropoietin
deficiency
INFLAMMATION
- Acute (sepsis) or chronic
MEDICATIONS
VIRUSES
DIC: Disseminated Intravascular
Coagulation. TTP: thrombotic
thrombocytopenia purpura aHUS: atypical
hemolytic uremic syndrome
29

30. Morphological approach:
□ Macrocytic: MCV > 100 femtoliters
□ Microcytic: MCV < 80 fl
□ Normocytic: MCV 80-100 fl
□ Note: be cautious about interpreting the MCV
after a patient has been transfused
30

31. Underproduction anemias
MICROCYTIC NORMOCYTIC MACROCYTIC
Iron deficiency anemia Anemia of
inflammation, chronic
kidney disease
Megaloblastic
anemia (B12, folate)
Thalassemia,
hemoglobinopath
y
Increased
reticulocyte count
Copper deficiency liver disease
Hypothyroid
Alcohol
MDS, acquired
sideroblastic
anemia
31

32. Microcytic vs macrocytic
anemia
32

33. Microcytic anemia: MCV < 80
□ Iron, iron, iron!
□ Reduced iron availability
□ iron deficiency, anemia of chronic disease,
copper deficiency
□ Reduced globin production
□ thalassemia, hemoglobinopathy
□ Reduced heme synthesis
□ lead poisoning, sideroblastic anemia
(congenital, alcohol)
33

34. Microcytic anemia: in clinical practice
□ Iron deficiency
□ Once diagnosed, essential to determine
the cause of the iron deficient state
□ Anemia of chronic disease
□ Thalassemia minor
□ Alpha thalassemia minor trait is
especially prevalent in African
American populations
□ Diagnosis of exclusion!
34

35. 2010 WHO estimate: ~1.24 billion
individuals are affected by iron deficiency
anemia
IRON DEFICIENCY ANEMIA
Blood. 2019;133(1):30-39
35

36. Iron
□ Crucial to biological functions
□ Respiration, energy production, DNA
synthesis, cell proliferation
■ Hemoglobin, myoglobin
□ Humans are designed to conserve iron
□ Iron is recycled by macrophages after
breakdown of senescent RBCs
□ Iron is retained (no excretion mechanism)
36

37. Iron balance: regulated by
hepcidin
EXCESS IRON
- No physiological excretion mechanism
- TOXIC: hemochromatosis
IRON DEFICIENCY
- Usually from blood loss
-Oral iron absorption
is limited: 1-2 mg/d
-Most iron (25 mg/d) from
iron recycling from old RBCs
Adult: ~3-4g of iron
- 2.5 g in RBC
-1 g stored (bone
marrow, liver, spleen)
37

38. Iron cycle
Only 5-10% of
dietary iron is
absorbed; this
occurs in the distal
duodenum and
proximal jejunum.
38

39. Hepcidin
□ Peptide hormone made in the liver
□ Acute phase reactant
□ Adjusts plasma iron levels
■ Binds/induces degradation of ferroportin
(which exports iron from cells)
□ LOW hepcidin: iron deficiency
□ HIGH hepcidin: in high iron states (or
systemic inflammation/infection)
□ induced by inflammatory cytokines such as IL6 ->
anemia chronic disease
39

40. Hepcidin
Dos Reis Lemos et al. Rev Assoc Med Bras 2010; 56(5)
Ganz et al. BBA 2012; 1823 (9): 1434-43
40

41. NEJM 2015; 372: 1832-43
41

42. Iron deficiency
□ Iron deficiency
□ Precursor to IDA
□ Affects > 2 billion
people worldwide
■ Prevalence twice as
high as IDA
■ 40% in preschool
children
■ 30% in
menstruating
females
■ 38% in pregnant
women
□ Iron deficiency
anemia (IDA)
□ Microcytic
RBCs
□ Top cause of
anemia
worldwide
□ Pica, brittle
fingernails, hair
loss, restless
legs
<- Weakness, fatigue, difficulty concentrating, headaches, irritability, decreased exercise tolerance ->
NEJM 2015; 372: 1832-43
42

43. Blood 2019; 133 (1): 30-
39
43

44. Low iron: must identify the
cause
□ Blood loss
□ Menstruation, pregnancy
□ Chronic GIB
■ Intestinal worm colonization in developing countries
□ Insufficient dietary intake
□ Poor diet
□ Vegan > vegetarian diet
□ Malabsorption
□ Gastric bypass of the duodenum, celiac disease,
H. pylori infection, atrophic gastritis
44

45. Blood Loss: iron deficiency
□ Most common cause of anemia
□ Obvious bleeding: trauma, melena, hematemesis
□ Occult bleeding: slowly bleeding ulcer or
carcinoma
□ Induced bleeding: blood draws for lab
testing, procedures/surgery, excessive
blood donation
□ Pregnancy
□ Menses: 25% of menstruating females have
absent iron stores
In higher income countries, in adult males and post menopausal females,
evaluation of the GI tract (endoscopic or radiographic) finds a cause of IDA
in
Acquired Underproduction Anemias. American Society of Hematology Self Assessment Program 2019; p.
138-160
45

46. Iron deficiency: labs to order
□ CBC
□ TIBC (iron with total binding capacity)
□ Iron level
□ Iron binding capacity (TIBC)
□ % transferrin saturation
□ Ferritin
Patient should not take iron on day of blood draw
46

47. Interpretation of iron stores
Serum
iron
Serum
ferritin
TIBC* %
Transferrin
Saturation
Normal 10-160
ug/dl
40-300 ng/ml
men
20-200 ng/ml
women
228-428
ug/dl
16-45%
Iron
Deficiency
Low Low-
< 10-30
High Low
(often <
9-16%)
Anemia of
Chronic
Disease
Low Normal/
high
Low 10-20%
*TIBC: Total Iron Binding Capacity ~ amount of transferrin
47

48. NEJM 2015; 372: 1832-43
48

49. MANAGEMENT OF IDA
49

50. Iron Deficiency
□ Stepwise approach to treatment
□ Dietary
□ Oral: Ferrous sulfate 325 mg PO qod
■ Take between meals, with orange juice,
for maximal absorption
□ Intravenous (IV) Iron
□ Blood transfusion: 1 unit of blood = 250
mg iron
50

51. Iron
rich
foods
https://www.redcross.org/content/dam/redcrossblood/landing-page-documents/246401_ironrichpyramid_flyer_ms_v02.pdf
□ Red cross: https://www.redcrossblood.org/donate-blood/blood-donation-process/before-during-after/iron-blood-
donation/iron- rich-foods.html
□ Canada: https://carleton.ca/healthy-workplace/wp-content/uploads/Food-Sources-of-Iron.pdf
Heme iron
Red meats, liver,
egg yolk, salmon,
tuna and oysters
Non heme iron
(harder to absorb)
vegetables, fruits
and grains
51

52. Adjunctive iron
□ Other factors that affect dietary iron
absorption
□ INHIBIT absorption: calcium rich foods, tannins in
tea and coffee, phytates in cereals
□ ENHANCE ABSORPTION: ascorbic acid, heme iron,
legumes (removes phytates)
□ Cast iron pans
□ Lucky iron fish
52

53. Oral iron
□ 60 mg elemental
iron every
day- other day
□ Take with vit C
□ Adverse events (AE):
nausea/ vomiting,
constipation,
bloating, darker
stool
□ More iron ->
more AE
Kasthuri et al. Cure HHT website, https://curehht.org/understanding-hht/diagnosis-treatment/hhtguidelines; accessed 5/24/21
53

54. Snook J, Bhala N, Beales ILP, et al. Gut
2021;70:2030–2051.
54

55. Iron every other day (QOD)
□ Excessive dosing is counterproductive
□ Recommend 1 iron pill qod (or MWF)
□ consider take with vit C (no high quality data)
■ Iron generally should not be given with food.
■ Iron should especially be taken separately from calcium-
containing foods and beverages (milk), calcium
supplements, cereals, dietary fiber, tea, coffee, and eggs.
■ Iron should be given two hours before, or four hours after,
ingestion of antacids.
□ AE: N/V, constipation, bloating, darker stool
□ More iron -> more AE
55

56. No point in three times a day
iron….
□ 2015: iron deficient women (n=54): 40-80 mg iron
no more than daily best
□ Higher or more frequent doses of iron raised circulating
hepcidin levels and reduced subsequent fractional
iron absorption.
□ 2017 RCT: women with iron deficiency (n=40).
□ Iron sulfate 60 mg: daily x 14 d vs qod x 28d
□ every-other-day dosing resulted in greater iron absorption
(131 versus 175 mg total), with a trend to less AE
□ Serum hepcidin levels higher with daily dosing
□ RCTs in women with IDA are ongoing
□ DBRCT: 60 mg daily vs 120 mg qod x 8 weeks (n=200 with hgb <
10 and low MCV or ferritin <50); no difference in hgb rise at
week 8 Stoffel et al. Lancet Hematol 2017; 4: 524-33
Pasupathy et al. Sci Rep 2023; 13(1): 1818
56

57. Iron replacement: Time to
response
□ Reticulocytosis: 7-10 days
□ Increased Hgb: 2-4 weeks
□ Resolution of anemia: 4-6 months
□ Continue oral iron replacement for several months
after anemia resolves to replete iron stores.
57

58. What if the patient is not
responding?
□ Adherence, adherence, adherence
□ Ongoing bleeding
□ Celiac disease, atrophic gastritis, H pylori
□ High hepcidin levels
□ Oral iron absorption test:
1. measure baseline fasting serum iron level
2. administer 325 mg PO FeSO4
3. retest serum iron level after 1-2 hrs; should increase by 50-
100
□ If fails to respond -> IV iron

59. When should we use IV iron?
□ Ganzoni equation to calculate iron deficit:
Total iron deficit = weight (kg) x (target Hgb – actual hgb) x 2.4 +
500
Blood 2019; 133 (1): 30-
39
, IBD
59

60. • AE: N/V, pruritus, headache, flushing, myalgias, arthralgias, back pain
• sx resolve within 48 h
Kasthuri et al. Cure HHT website, https://curehht.org/understanding-hht/diagnosis-treatment/hhtguidelines; accessed 5/24/21
60

61. Time to response to IV iron
□ Rapid iron repletion
□ Ferritin peaks 7-9 days after infusion
□ Hemoglobin should rise within 2-3 weeks
□ Remember to continue to monitor CBC and
iron studies every 2-3 months in patients with
ongoing causes of iron deficiency
61

62. Any questions?
Thank you for your
attention!
62