Approach to Anemia

Dr Islam Noureldin
ABFM , MRCGP-INT
Specialist & Faculty of Family Medicine

Objectives

Introduction.
Definition of Anemia.
Criteria for Diagnosis of Anemia.
General Clinical Features
Types & Classification of Anemia
Approach and Management
Summary & Take Home Messages

Case

 A 56-year-old female presents for an office evaluation, in

WBHC in November for follow up of her DM , HTN ,
Dyslipidemia.
During the consultation pt complaining of fatigue for 6
months, She reports feeling dizzy on and off for the past
year; the dizziness is associated with weakness that has
been worsening for the past month. She has been feeling
too tired to even walk her regular daily exercise
She occasionally has an alcoholic drink and denies tobacco
or drug use.
She is married and is a retired.

 Her physical exam reveals a well-appearing

female with normal vital signs and no
discernible abnormalities. her blood pressure
is 150/85 mm Hg; her pulse is 98 beats/min;
her respiratory rate is 20 breaths/min; her
temperature is 37.1C;
What is your next step?

 What is the most likely diagnosis?

What is your next step in her evaluation and
why?

Introduction
Anemia is a symptom and not a disease
It is never normal and its cause should always
be sought.
Look for the Primary Cause!
The history, physical examination, and simple
laboratory testing are all useful in evaluating
the anemic patient

Anemia
Definition
a decrease in red blood cell (RBC) mass that
can be detected by hemoglobin (Hb)
concentration, hematocrit (Hct), and RBC
count
adult males: Hb < (13.5 gldL) or Hct <41%
adult femalc:s: Hb < (12 gldL) or Hct <36%

 World Health Organization (WHO) criteria for

anemia in men and women are <13 and
<12 g/dL , respectively.

Clinical Features of any Anemia

History
symptoms of anemia:
fatigue, malaise, weakness, dyspnea, decreased exercise
tolerance,palpitations, headache, dizziness, tinnitus, syncope
acute vs. chronic bleeding.
systemic illness
Diet
Alcohol
family history
Menstural hx: menorrhagia, menometrorrhagia, dysfunctional
uterine bleeding
rule out pancytopenia (recurrent infection, mucosal
bleeding/easy bruisability)

Physical signs
HEENT: pallor in mucous membranes and
conjunctiva
Cardiac: tachycardia, orthostatic hypotension,
systolic flow murmur, wide pulse pressure,
Signsof CHF
Dermatologic: pallor in palmar skin creases
,jaundice (if due to hemolysis)

Can Symptoms & Signs differentiate Cause of

Anemia?

Investigations
CBC with differential ??

Iron Indices??
Blood film
Additional laboratory investigations as
indicated

Differential Dx of Anemia?

Approach to Anemia

Microcytosis

Microcytosis
The condition is defined as a mean corpuscular
volume of less than 80 m3 in adults.
The most common causes of microcytosis are
iron deficiency anemia and thalassemia trait.
Other diagnoses to consider include anemia of
chronic disease, lead toxicity, and sideroblastic
anemia.
Serum ferritin measurement is the first
laboratory test recommended in the evaluation
of microcytosis.
Low ferritin levels suggest iron deficiency.

History and Physical Examination

In addition to general Hx & PE in Anemia:
Important history information includes nutritional
intake (especially whole milk intake in children)
pica or cravings for ice - for IDA
occupational or residential exposure to toxins For
Lead
family history of anemia or ethnicity suggestive of
hemoglobinopathy
systemic symptoms of an underlying chronic
infectious or inflammatory process

 A review of gastrointestinal symptoms,

including abdominal discomfort,
hematochezia, and bright red rectal bleeding,
in adults.
Menstrual history should be obtained in
menstruating women.

How to Differentiate between Causes

of Microcytosis?

Laboratory Tests in the Differentiation of

Microcytosis

CBC
RDW
serum iron levels
serum ferritin levels
TIBC
Transferrin saturation
Reticulocyte blood count
Peripheral blood smears
Hemoglobin electrophoresis

Laboratory Tests in the Differential Diagnosis of

Microcytosis

Iron Deficiency Anemia

IDA is the most common nutritional disorder
worldwide and accounts for approximately
one-half of anemia cases.
IDA result from inadequate iron intake,
decreased iron absorption, increased iron
demand, and increased iron loss.

Etiologies of Iron Deficiency Anemia

Increased iron loss

Inadequate iron intake
Decreased iron absorption
Increased iron demand

Screening?
MEN AND POSTMENOPAUSAL WOMEN
Asymptomatic men and postmenopausal women should not be screened
for iron deficiency anemia.
Testing should be performed in patients with signs and symptoms of
anemia.
All adult men and postmenopausal women with iron deficiency anemia
should be screened for gastrointestinal malignancy.

PREGNANT WOMEN
The American Academy of Family Physicians, U.S. Preventive Services Task
Force, and Centers for Disease Control and Prevention recommend routine
screening of asymptomatic pregnant women for iron deficiency anemia.
The defined values consistent with anemia in pregnancy are hemoglobin
levels less than 11 g in the first or third trimester, or less than 10.5 g in the
second trimester.

CHILDREN
The American Academy of Pediatrics recommends universal hemoglobin
screening and evaluation of risk factors for iron deficiency anemia in all
children at one year of age.

Diagnosis
laboratory-confirmed evidence of anemia, as well
as evidence of low iron stores.
Although IDA is the most common cause of
microcytic anemia, up to 40 percent of patients
with iron deficiency anemia will have normocytic
erythrocytes
IDA should still be considered in all cases of
anemia unless the mean corpuscular volume is
greater than 95 m

Diagnostic approach

 Values consistent with iron deficiency include

a low serum iron leveL , low transferrin
saturation, and a high total iron-binding
capacity

Iron Therapy
Lifestyle Management dietary advice
The dosage of elemental iron required to treat iron deficiency anemia
in adults is 120 200 mg per day for three months
the dosage for children is 3 mg per kg per day, up to 60 mg per day
Monthly CBC for follow up

An increase in hemoglobin of 1 g per dL after one month of treatment

shows an adequate response to treatment and confirms the diagnosis.
In adults, therapy should be continued for three months after the
anemia is corrected (hematocrit and ferritin levels normalize ) to allow
iron stores to become replenished then discontinue oral iron .

 Adherence to oral iron therapy can be a barrier to treatment because of GI

adverse effects such as epigastric discomfort, nausea, diarrhea, and
constipation.

Medication : such as proton pump inhibitors and factors that induce gastric
acid hyposecretion (e.g., chronic atrophic gastritis, recent gastrectomy or
vagotomy) are associated with reduced absorption of dietary iron and iron
tablets

Oral iron replacement is preferred to intravenous (IV) therapy.

It is safer, more cost-effective, and convenient when compared to IV
therapy.
However, intravenous therapy may be substituted when there is:
inadequate iron absorption, continued blood loss, noncompliance or intolerance to
oral iron therapy.

Internal medicine/hematologist consultation is recommended.

Intramuscular (IM) iron therapy is not recommended

except in institutions with facility for treating anaphylactic reactions.
Additional risks of IM iron therapy include unpredictable absorption and local
complications (e.g. pain, staining of the skin, sarcoma formation).

Iron Therapy: Formulations and Dosing

Oral in PHCC: doses according
Other Doses and forms are available in private &
Hamad
Form

Formulation

Elemental iron

Adult dosage

Ferrous fumarate

200-mg tablet

66 mg

One tablet twice - 3

per day

Ferrous gluconate
Not in phcc

300-mg tablet

38 mg

One to three tablets

two or three times
per day

Ferrous sulfate

190-mg tablet

60 mg

One tablet three

times per day

 PARENTERAL IRON THERAPY

Used in patients who cannot tolerate or absorb oral
preparations, such as those who have undergone
gastrectomy, bariatric surgery, or other small bowel
surgeries.
Not Available in PHCC

Interpret lab

Thalassemia
Definition
defects in production of the alpha or beta chains of
hemoglobin
clinical manifestations and treatment depends on specific:
gene and number of alleles affected
Common features:
increasing severity with increasing number of alleles involved
hypochromic microcytic anemia
basophilic stippling, abnormally shaped RBCs on blood film

Pathophysiology:
Defect may be in any of the Hb genes

normally 4 Alpha genes in total

normally 2B genes in total

Fetal hemoglobin, HbF switches to adult forms HbA and HbA2
at 3-6 months of life
HbA constitutes 97% of adult hemoglobin
HbA2 constitutes 3% of adult hemoglobin

Beta-Thalassemia Minor (Thalassemia Trait)

Definition

defect in single allele of beta gene (heterozygous)

common in people of Mediterranean and Asian descent

Investigations
Hb 9-14 gldL , increase RBC ? , MCV<70 much lower levels than with IDA alone ,

normal Fe
peripheral blood film - microcytosis basophilic stippling ,
Hb electrophoresis
specific: HbA2 increased to 3.5-5% (normall.S-3.5%)
Coexisting iron deficiency anemia can lower hemoglobin A2 levels.
iron deficiency anemia must be corrected before Hb electrophoresis results can be
appropriately evaluated.

Treatment

no treatment required
genetic counselling for patient and family

Alpha-Thalassemia
Definition
defect(s) in alpha genes
similar geographic distribution as beta-thalassemia but higher frequency
among Asians and Africans

Investigations
1 defective a gene: silent carrier ; normal Hb, normal MCV
2 defective a genes:alpha-thalassemia trait microcytosis without anemia
3 defective a genes: HbH disease; presents in adults, decreased MCV, decreased
Hb, splenomegaly
4 defective a genes: (hydrops fetalis); not compatible with life

Treatment
depends on degree of anemia
1 or 2 defective a genes: no treatment required

Summary

Normocytic anemia

A 16-year-old male presents to your office with complaints of progressive fatigue

and dyspnea over the last few days. He also has some mild upper
respiratorysymptoms which are being treated with sTMP/SMX,
On examination, you find a well-nourished male in no distress. He is afebrile but
slightly tachycardic. You note mild scleral icterus and pallor of the palmar creases,
but the remainder of the exam is unremarkable. A CBC shows normal WBC count
and platelets, with hemoglobin 10.2 g/dL. On peripheral smear, bite cells and rare
Heinz bodies are reported. The LDH and bilirubin are elevated and the serum
haptoglobin is low, but the other serum chemistries are normal.
Which of the following is the most likely diagnosis?
Which of the following is the most appropriate intervention for this patient
with G6PD deficiency at this point?
A) Admit to the hospital and observe.
B) Admit to the hospital and transfuse 2 units of packed red cell
C) Recommend supportive care and follow-up in a few days.
D) Recommend splenectomy and refer to a general surgeon.

Definition:
The mean RBC volume is normal (ie, MCV between 80
and 100 fL) in patients with normocytic anemia.
The next step in evaluation of normocytic anemia is
determination of the reticulocyte count , this will
differentiate causes.
Anemia with a high RC reflects an increased
erythropoietic response to hemolysis or blood loss.
Anemia with a low or normal RC reflects deficient
production of RBCs (ie, a reduced marrow response to
the anemia)

Normocytic anemia
1) High reticulocyte Count
increased Destruction (retics >2-3%)

Hemolysis
Inherited:
hemoglobinopathy: sickle cell, thalassemia,
Membrane: spherocytic

Acquired:

Immune Coombs positive, drug-related, cold agglutinin

Infection malaria
Microangiopathic hemolytic anemia DIC, TTP, HUS, HELLP
Oxidative / drug-related

Bleeding: Acute vs Chronic

GI, GU, other
With blood loss, reticulocytes should increase 2-3x initially and
then 5-7x over the next week

2) Low reticulocyte count

decreased production (Retics <2%)
a normal reticulocytes in anemia is interpreted as a
sign of reticulocytes production

Pancytopenia

Aplastic anemia, MDS, myelofibrosis, Leukemia

TB
Amyloidosis, sarcoidosis
Drugs chemotherapy

Non-pancytopenia
Anemia of chronic dz
Renal / liver dz

 Dont forget to rule out IDA :

As 40 percent of patients with iron deficiency
anemia will have normocytic erythrocytes

HEMOLYTIC ANEMIAS
Classification:
Hereditary:
abnormal membrane (spherocytosis, elliptocytosis)
abnormal enzymes (pyruvate kinase defictency, G6PD defictency)
abnormal hemoglobin synthesis (thalassemias, hemoglobinopathies)

Acquired:
Immune :hemolytic transfusion reaction, autoimmune HA (AIHA), drugs (e.g. penicillin),
cold agglutinins
non-immune: - (MAHA) , - PNH, hypersplenism , infection (e.g. malaria)

intravascular: G6PD deficiency, TTP, DIC and PNH

extravascular: AIHA and hereditary spherocytosis

Clinical Features Specific to HA

jaundice
dark urine
cholelithiasis (pigment stones)
potential for an aplastic crisis (ie. BM
suppression in overwhelming infection)
iron overload
iron deficiency

laboratory signs
The laboratory signs of hemolytic anemias
include:
1. Increased LDH
2. Increased indirect bilirubin.
3. Increased reticulocyte count
4. Decreased haptoglobin
5. Urine hemosiderin-presence.

Aplastic Anemia
Definition
destruction of hematopoietic cells of the bone marrow leading to
pancytopenia and hypocellular bone marrow
Etiology
Congenital
Acquired :T-cell mediated, drugs , toxins , ionizing radiation ,
post-viral infection , autoimmune
Clinical Features:
can present acutely or insidiously
symptoms of anemia, thrombocytopenia
absence of splenomegaly and lymphadenopathy

Investigations:
CBC
anemia or neutropenia or thrombocytopenia (any
combination) pancytopenia ,
decreased reticulocytes ( < 1% of the total RBC
count)
Bloodfilm
decreased number of normal RBCs
bone marrow
aplasia or hypoplasia of marrow cells with fat
replacement
decreased cellularity

Treatment:
Referral to Emergency for Admission
remove offending agents
supportive care (red cell and platelet transfusions,
antibiotics)
Immunosuppression: anti-thymocyte globulin- 50-60% of
patients respond , cyclosporine
allogenic bone marrow transplant

G6PD Deficiency
Definition : deficiency in glucose-6-phosphate
dehydrogenase ( G6PD) leads to a sensitivity
of RBC to oxidative stress
X-linked recessive
Clinical Features: frequently presents as episodic

hemolysis precipitated by:

oxidative stress
drugs (e.g. sulfonamide, antimalarials, nitrofurantoin)
infection
food (fava beans)

Investigations
neonatal screening
G6PD assay : should not be done in acute
crisis when reticulocyte count is high
(reticulocytes have high G6PD levels)
Blood film

Macrocytosis

61 yrs old female DM controlled on OHA ,

Complaining of Tingling & parathesia in both hands
and feet ?

Next Step

Macrocytosis
Definition
defined as a mean corpuscular volume greater than 100 fL
occurs in approximately 3 percent of the general population
Classified as megaloblastic and nonmegaloblastic
Pathophysiology
Megaloblastic processes are characterized on the peripheral smear by
macro-ovalocytes and hypersegmented neutrophils, which are absent in
nonmegaloblastic.
folate and vitamin B12 deficienciesresult in defective RNAand DNA
syntheses

Macrocytosis
Causes:
1 - Megaloblastic (involving Abnormalities

metabolism

of DNA

B12 and/or folate deficiency in: Atrophic gastritis Enteral

malabsorption
Drugs that impair DNA synthesis (methotrexate, sulfa, chemotherapy)
2 - Non-megaloblastic
Liver dz
hypothyroidism
Alcoholism
Myelodysplasia
Reticulocytosis

Vitamin B12 Deficiency

Vitamin B12 is crucial to normal neurologic
function, red blood cell production, and DNA
synthesis.
Vitamin B12 (cobalamin) deficiency is a common
cause of megaloblastic anemia.

Causes of vitamin B12 deficiency

Decreased ileal absorption

Crohn disease
Ileal resection
Tapeworm infestation
Decreased intrinsic factor
Atrophic gastritis
Pernicious anemia
Postgastrectomy syndrome (includes Roux-en-Y gastric bypass)
Inadequate intake
Alcohol abuse
Older persons
Vegetarians (includes exclusively breastfed children of vegetarian
mothers)
Prolonged medication use
Histamine H blockers
Metformin (Glucophage)
Proton pump inhibitors
2

Suspect Vitamin B12 in the following

Oval macrocytic red blood cells (ie, mean corpuscular volume >100
fL) on the peripheral blood smear, with or without anemia
The presence of hypersegmented neutrophils on the peripheral
blood smear
Unexplained neurologic signs and symptoms, especially dementia
or weakness, sensory ataxia, and paresthesias
High Risk populations, such as older adults, alcoholics, and patients
with malnutrition
Strict vegans are at risk of vitamin B12 deficiency.
Patients who have undergone bariatric surgery are also at risk of
developing folate and vitamin B12 deficiency.
Vitamin B12 and folate deficiency often coexist and are not easily
differentiated on a clinical basis. such patients should be evaluated
for both deficiencies.

Manifestations:
Cutaneous

Hyperpigmentation
Vitiligo
Gastrointestinal
Glossitis
Jaundice
Hematologic
Anemia (macrocytic, megaloblastic)
Thrombocytopenia
Neuropsychiatric
Cognitive impairment
Gait abnormalities
Irritability
Peripheral neuropathy
Weakness

 up to 28 percent of affected patients may have

a normal hemoglobin level, and up to 17
percent may have a normal MCV.
No major medical organizations, including the
U.S. Preventive Services Task Force, have
published guidelines on screening
asymptomatic or low-risk adults for vitamin B12
deficiency, but high-risk patients, such as those
with malabsorptive disorders, prolonged use of
metformin and proton pump inhibitors may
warrant screening.

 The initial laboratory assessment of a patient with

suspected vitamin B12 deficiency should include a CBC
and a serum vitamin B12 level.
Measurements of serum vitamin B12 may not reliably
detect deficiency, and measurement of serum
homocysteine and/or methylmalonic acid should be used
to confirm deficiency in asymptomatic high-risk patients
with low normal levels of vitamin B12.
In patients with clinical symptoms of vitamin B12
deficiency and low levels of serum vitamin B12, no
further confirmatory testing is generally needed

Treatment
IM injection of vitamin B12 at a dosage of
1 mg weekly for eight weeks, followed by 1 mg
monthly for life.
Or
Oral vitamin B12 (1 to 2 mg daily)

Treatment
In a 2005 Cochrane review, patients who received
high dosages of oral vitamin B12 (1 to 2 mg daily)
for 90 to 120 days had an improvement in serum
vitamin B12 similar to patients who received
intramuscular injections of vitamin B12.
These results were consistent in patients
regardless of the etiology of their vitamin B12
deficiency, including malabsorption & states and
pernicious anemia

 Because of the high incidence of vitamin B12

deficiency in patients undergoing gastric
bypass surgery, daily prophylactic
supplementation with 1 mg is recommended.
Never give folate alone to an individual with
megaloblastic anemia because it will mask
B12 deficiency and neurological degeneration
will continue

Summary

Questions
You have prescribed oral iron replacement for a 46year-old female with iron deficiency anemia
related to heavy menses. She wants to be sure that
the iron she takes will be absorbed well.
Which one of the following would you suggest for
improving iron absorption?
A) Calcium
B) Vitamin C
C) Coffee
D) Tea

After you started Iron

Which of the tests will be the first to indicate that
you have instituted appropriate therapy?

How long should you continue iron

supplementation?

 The patient returns to your office in 2 months

but her labs are worse than at first presentation.
The patient swears that she has been taking the
iron faithfully.

Which can lead to a failure of iron therapy for

iron deficiency anemia?

Lab Interpretation

Next Step ?

First Hg electrophoresis report

Second Hg electrophoresis report

Lab Interpretation

The Physician orded Hb electrophoresis

What do you expect the results?

Interpret the Hb electrophoresis?

 A 67-year-old male with moderate macrocytosis

complains of paresthesias of his feet. If the
patient has a borderline low vitamin B12 level,
elevated levels of which one of the following
would suggest vitamin B12 deficiency?
A) Serum gastrin
B) Reticulocytes
C) Methylmalonic acid
D) Serum ferritin
E) Serum folate

Any Questions?

References
AAFP, American Academy of Family Physicians.
Medscape.
Up-to-date.