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blood and are detected [3]. A transferrin saturation level of
less than 16% indicates an iron supply that is insufficient to
support normal erythropoiesis [3].
The most frequent causes of iron-deficiency anemia are:
• Chronic GI bleeding, often subclinical, due to gastric
ulcerations, GI malignancies.
• Decreased iron absorption: malnutrition, vegan diet, celiac
sprue, inflammatory bowel disease (Crohn’s), gastrec-
tomy/bariatric surgery, increased gastric pH, or use of
chronic gastric acid suppressants.
• States with increased iron demand, i.e., pregnancy, rare
iron refractory genetic disorders.
Treatment
Replacing iron and correcting the underlying etiology are the
cornerstones of therapy. After 1 week of treatment, reticulocyto-
sis should begin. In 3 weeks, Hgb should be 2 g/dL higher.
Iron supplementation should continue not only until Hgb
level is normalized, but until iron stores are repleted, typi-
cally after 6 months of therapy. Repletion can be confirmed
when serum ferritin normalizes.
Oral supplementation is preferred; however, IV iron
preparations can be given to patients with high Fe require-
ments, inability to absorb Fe from GI tract, or intolerance to
oral iron preparations.
Preferred oral iron replacement:
• Ferrous sulfate 325 mg orally: For best absorption and
tolerability, take 30 min before meals. Can start with 1 tab/
day and increase up to three times per day. If unable to
take three times per day, 1–2 times per day may be suffi-
cient as long as the Hgb is recovering.
• Adverse effects: bloating, change in bowel habits, black
stools.
Refractoriness to treatment should raise the concern of
compliance issues, poor absorption, and possibly incorrect
diagnosis (e.g., thalassemia, anemia of chronic inflammation).
N.K. Shenoy and H.J. Cordero
289
Normocytic Anemia
There is an overlapping of some anemias with normal MCV
which might be either hypoproliferative or hyperprolifera-
tive, but could also present as normocytic, microcytic, or mac-
rocytic. This category includes acute blood loss/hemorrhagic
anemia, anemia of renal disease, hypothyroidism, early stages
of iron deficiency, anemia of chronic inflammation, sickle cell
anemia, pure red cell aplasia as seen in thymomas, chronic
lymphocytic leukemia, and parvovirus infection.
Anemia of Chronic Inflammation (ACI)
Previously known as anemia of chronic disease, this is the
second most common form of anemia after iron deficiency.
Classically, it was thought to be caused only by inflammatory,
infectious, or malignant processes; however, diabetes and
severe trauma have also been proposed etiologies. Major
causes include malignancy, HIV infection, rheumatologic dis-
orders, inflammatory bowel disease (Crohn’s), heart failure,
renal insufficiency, and chronic obstructive pulmonary
disease.
The underlying process is multifactorial. It involves
increased pro-hepcidin, an acute-phase reactant, causing
decreased intestinal absorption of iron and trapping of iron
in the macrophages resulting in decreased availability for
heme synthesis. Also, there is an inability to increase erythro-
poiesis, relative decrease in erythropoietin (EPO) produc-
tion, and RBC survival. These changes are mediated by
inflammatory cytokines, TNF-alpha, IL-1, IL-6, INF-b, and
INF-g.
Patients with anemia of chronic disease and concomitant
iron-deficiency anemia more frequently have microcytes, and
their anemia tends to be more severe. The ratio of the con-
centration of soluble transferrin receptors to the log of the
ferritin level of less than 1 suggests anemia of chronic disease,
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290
whereas a ratio of more than 2 suggests absolute iron defi-
ciency coexisting with anemia of chronic disease [3].
The primary treatment of ACI is correction of the underly-
ing disorder. Blood transfusions are only indicated in the
setting of severe symptomatic anemia Hgb < 6.5 mg/dL or
acute bleeding. Transfusion affords some benefit in survival
for patients with myocardial infarction.
Iron supplementation might be beneficial if ferritin or
TIBC saturation is low or low normal.
EPO can be administered if EPO level is < 500 mU/mL
and Hgb <10 g/dL for cancer or chemo-related ACI.
Macrocytic Anemia
Macrocytic anemia is defined by an MCV > 100, and can be
categorized as megaloblastic or non-megaloblastic depending
on the presence of hypersegmented neutrophils in addition
to macrocytic RBCs in the peripheral smear [4].
Megaloblastic Anemia
Resulting from impaired DNA synthesis, megaloblastic
anemia is usually caused by folate or vitamin B12 (cobala-
min) deficiency, which in turn could be due to chemothera-
peutic agents that impair absorption or block enzymes during
DNA synthesis.
Vitamin B12 Deficiency
Always establish a cause of vitamin B12 deficiency. Major
causes include pernicious anemia, atrophic gastritis, bacterial
overgrowth, pancreatic insufficiency, ileal resection or
Crohn’s disease involving the ileum, chronic proton pump
inhibitor or histamine 2-blocker use, HIV, Helicobacter
N.K. Shenoy and H.J. Cordero
291
pylori, and Diphyllobothrium latum (fish tapeworm)
infections.
Common signs and symptoms of B12 deficiency include
general symptoms of anemia, beefy tongue, and neurologic
symptoms due to degeneration of the lateral and dorsal col-
umns of the spinal cord known as subacute combined degen-
eration (SCD). Symptoms of SCD include paresthesias from
axonal degeneration, cerebellar ataxia, proprioceptive deficit,
and dementia.
Laboratory findings include low serum B12 level (<200
very suggestive, 200–400 borderline), along with elevated
methylmalonic acid (MMA) and homocysteine levels, mac-
rocytosis, pancytopenia, and hypersegmented neutrophils. If
MMA is normal, significant B12 deficiency is unlikely.
Treatment of severe cases is supplementation of B12 by
injection of 1000 mcg daily for 5 days, then monthly. Oral B12,
dosed at 500–1000 mcg daily, is usually absorbed well enough
even in patients with atrophic gastritis, gastric resection, or
pernicious anemia.
Folate Deficiency
Folate deficiency is most commonly caused by poor dietary
ingestion. Other causes are malabsorption (sprue), and
hemolytic anemia.
In B12 deficiency neurologic abnormalities can be present
and MMA is elevated.
However, in folate deficiency neurologic abnormalities are
absent and MMA is normal, and homocysteine is increased.
RBC folate levels rather than serum folate levels are more
accurate for diagnosing deficiency.
Treatment is to give folate 1 mg/day even if deficiency is
caused by malabsorption.
Non-megaloblastic anemia: Other causes of macrocytic
anemias without megaloblastosis include:
17. A nemi a
292
• Liver disease
• Alcohol abuse (even in the absence of vitamin B12 or
folate deficiency)
• Hypothyroidism
• Smoking
• Drugs (hydroxyurea, antiretrovirals, 5-FU, azathioprine,
etc.)
• Primary bone marrow disorders
• Reticulocytosis
Hyperproliferative Anemias
Hyperproliferative anemias are the result of acute blood loss
or increased RBC destruction such as in hemolysis, which
may be due to congenital or acquired causes. Aside from
blood loss, hyperproliferative anemias warrant a referral to a
hematologist given the complexity of management.
Defects in Red Cell Membrane
Hereditary spherocytosis is characterized by osmotically frag-
ile spherical red blood cells due to a deficiency of one of the
membrane proteins. Spherocytes have diminished deform-
ability, predisposing them to entrapment and destruction in
the spleen.
Patients present with evidence of hemolysis (anemia, jaun-
dice, reticulocytosis, gallstones, splenomegaly) with spherocy-
tosis (spherocytes on the peripheral smear and increased
osmotic fragility) and a positive family history.
Peripheral smears usually show easily identifiable sphero-
cytes lacking central pallor.
Treatment includes folic acid supplementation (1 mg/day)
and splenectomy for moderate to severe cases. Ultrasound
should be carried out before splenectomy to exclude the
presence of gallstones. If present, cholecystectomy is also
indicated [5].
N.K. Shenoy and H.J. Cordero
293
Defects in Red Blood Cell Metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
diminishes the reductive energy of the red cell affecting red
cell integrity when exposed to certain drugs, infections, chem-
icals, and fava beans, resulting in hemolysis.
Oxidized hemoglobin precipitates to form Heinz bodies
which are plucked out of the red cell leading to hemolysis and
“bite cell” and “blister cell” morphology [6].
Patients require education about foods (e.g., fava beans)
and drugs (e.g., quinolones, sulfa, and certain antimalarials)
that should be avoided. Patients should be aware of the
signs of hemolytic crisis (orange/dark urine, lethargy, fatigue,
jaundice) and be hypervigilant during acute infections.
Patients should be transfused with packed red blood cells if
Hb level is below 7 g/dl or if hemoglobinuria persists and
Hb is below 9 g/dL [7].
Hemoglobinopathies
Sickle Cell Disease
Sickle cell disease is the most commonly observed hemoglo-
binopathy in the United States, affecting 1:500 African-
American births and 1:36,000 Hispanic-American births.
The defect is a Glu → Val substitution in the sixth amino
acid of the β-globin gene producing mutant β-globins that
form hemoglobin S which polymerizes resulting in deformed
RBCs. Sickle cells are prematurely destroyed or hemolyzed
which reduces nitric oxide (NO) bioavailability contributing
to vasoconstriction and platelet activation. This cascade of
events causes endothelial damage, production of inflamma-
tory mediators, and overexpression of adhesion molecules
producing vaso-occlusion and stasis [8].
Always be aware of the three main types of complications
of sickle cell anemia:
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294
• Hemolysis associated: severe anemia, cholelithiasis, acute
aplastic episodes (parvovirus B19 infection), pulmonary
hypertension
• Infectious complications: Streptococcus pneumoniae, E.
coli sepsis, osteomyelitis (Salmonella)
• Vaso-occlusive: painful crises, acute chest syndrome,
splenic sequestration/infarcts, stroke, osteonecrosis of the
bone, priapism, leg ulcers, spontaneous abortion, renal
insufficiency
Management of Common Acute Complications
Vaso-occlusive crisis (VOC): In patients with mild-to-moder-
ate pain who report relief with NSAIDS, continue the same
treatment in the absence of contraindications. In severe pain,
hospitalization for pain control is indicated.
Fever: If temperature ≥101.3 °F (38.5 °C), evaluate with
H&P, CBC with differential, reticulocyte count, blood cul-
ture, and urine culture when urinary tract infection is
suspected [9].
Hospitalize if acute chest syndrome (acute onset of lower
respiratory tract disease with cough, shortness of breath,
tachypnea, retractions, or wheezing with or without fever),
stroke, priapism lasting >4 h, acute pain requiring parenteral
opiates, or fever with temperature ≥103.1 °F (39.5 °C).
Chronic complications include chronic pain, leg ulcers,
avascular necrosis, pulmonary hypertension, and renal and
ophthalmologic complications [9].
Outpatient treatment focuses on prevention of acute and
chronic complications of sickle cell anemia.
Patients should be treated with hydroxyurea under the fol-
lowing conditions: three or more sickle cell severe pain crises
in a 12-month period; pain that interferes with daily activities
and quality of life, severe and/or recurrent ACS; or severe
symptomatic chronic anemia. Hydroxyurea should be discon-
tinued if the patient becomes pregnant or is breastfeeding.
The starting dosage for adults (500 mg capsules) is 15 mg/
kg/day. The dosage should be reduced to 5–10 mg/kg/day if
the patient has chronic kidney disease [9].
N.K. Shenoy and H.J. Cordero
295
Health maintenance includes vaccination against
Streptococcus pneumoniae and regular screening for hyperten-
sion, proteinuria, and retinopathy [9].
Thalassemias
In this type of anemia, there is decreased synthesis of struc-
turally normal globin proteins, characterized by low Hgb and
unusually small and fragile RBCs (microcytosis), although
the RBC count may be normal. In thalassemia minor, the
RBC count is usually high and the Hgb and RDW will be
normal or slightly abnormal. Subtypes of thalassemia involve
imbalances in the four chains of amino acids that comprise
hemoglobin (alpha- and beta-globins). This causes instability
in the globin chains, which precipitate in RBC precursors in
the bone marrow, leading to ineffective erythropoiesis and
microcytic anemia:
• Decreased α synthesis = α thal → relative excess of β
globins
• Decreased β synthesis = β thal → relative excess of α
globins
Although thalassemia major is a serious disease, in adult
medicine we see thalassemia minor, which requires no
treatment:
• Beta thalassemia minor: generally asymptomatic; mild
microcytic anemia
• Alpha thalassemia minor: lifelong mild microcytic anemia,
microcytosis out of proportion to the degree of anemia,
high RBC count [10]
Hemolytic Anemia
The reticulocyte index will be >2% (see algorithm). Based on
the underlying pathophysiologic process, hemolytic anemias
can be classified as immune and non-immune mediated:
17. A nemi a
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• Immune mediated (Coombs positive)
• In addition to recent history of blood transfusions or spe-
cific drug use, further workup needs to be done to deter-
mine the following:
1. Autoimmune (warm or cold).
2. Alloimmune (acute or delayed transfusion reaction).
3. Drug induced (e.g., quinidine, phenacetin, INH,
hydralazine, sulfa drugs, penicillin, methyldopa,
dapsone, nitrites, rifampin). Patients with G6PD
deficiency are particularly prone.
• Non-immune mediated (Coombs negative)—intravascular
hemolysis due to:
1. Microangiopathic hemolytic anemia
2. Defects in RBC membrane/enzymes
3. Infections (bacterial, viral, or fungal)
Usually hemolytic anemia is normocytic, but can be mac-
rocytic if there is significant reticulocytosis. Testing includes
LDH, indirect bilirubin, haptoglobin, urinary-free hemoglobin
(if brisk intravascular hemolysis, positive dipstick, but no
RBC on urine analysis), and Coombs (direct antiglobulin test
or DAT) test.
Microangiopathic hemolysis produces schistocytes on
smear due to mechanical intravascular disruption of RBCs.
Always send a preliminary panel of hemolysis labs for any
unexplained normocytic anemia (or macrocytic with high
reticulocyte count). Without a high index of suspicion, subtle
hemolysis can be missed.
Clinical Pearls
Categorize anemia based on reticulocyte index and cell size.
Anemia can have more than one etiology in the same
patient.
Acute treatment of anemia should be based on symptoms,
not Hgb level.
N.K. Shenoy and H.J. Cordero
297
Don’t Miss This!
Test for gastrointestinal cancer in all patients older than
50 years of age with microcytic anemia.
Think of hemolysis with unexplained normocytic anemia.
B12 deficiency is a reversible cause of dementia.
Acknowledgment The authors would like to acknowledge Dr. Naseema
Gangat’s valuable input and edits. Dr. Gangat is a staff hematologist at
Mayo Clinic, Rochester, in charge of the hematology education curricu-
lum for the Internal medicine residents at Mayo Clinic.
References
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2014;371:1324–31. https://doi.org/10.1056/NEJMra1215361.
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pop.2016.07.006.
3. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl
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4. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am
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S1876-3553(09)60005-3.
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