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review article
Edward W. Campion, M.D., Editor
Microcytic Anemia
Thomas G. DeLoughery, M.D.
T
From the Hematology Section, Knight Can- he microcytic anemias are those characterized by the produc-
cer Institute; and the Departments of Med- tion of red cells that are smaller than normal. The small size of these cells is
icine, Pathology, and Pediatrics, Oregon
Health and Science University, Portland. due to decreased production of hemoglobin, the predominant constituent of
Address reprint requests to Dr. DeLough- red cells (Fig. 1). The causes of microcytic anemia are a lack of globin product (thal-
ery at the Division of HematologyMedi- assemia), restricted iron delivery to the heme group of hemoglobin (anemia of in-
cal Oncology, Oregon Health and Science
University, 3181 S.W. Sam Jackson Park Rd., flammation), a lack of iron delivery to the heme group (iron-deficiency anemia),
Portland, OR 97239, or at delought@ and defects in the synthesis of the heme group (sideroblastic anemias). This review
ohsu.edu. highlights new aspects of the most common microcytic anemias: thalassemia,
N Engl J Med 2014;371:1324-31. anemia of inflammation, and iron-deficiency anemia.
DOI: 10.1056/NEJMra1215361
Copyright 2014 Massachusetts Medical Society.
Th a l a sse mi a
Thalassemias are diseases of hemoglobin synthesis, with subtypes named after the
hemoglobin chain involved (Table 1). Given that each chromosome 16 carries two
copies of the gene encoding the chain, there are four types of -thalassemia:
trait 1, trait 2, hemoglobin H disease, and hemoglobin Barts. Patients with the trait
thalassemias present with no or very mild anemia and variable microcytosis
both more pronounced in patients with the trait-2 form. Deletion of or mutations
in three -chain genes lead to hemoglobin H disease, which is marked by more
prominent anemia, often with a hemolytic component. Hemoglobin Barts is char-
acterized by a lack of -chain production, resulting in hydrops fetalis due to the
lack of fetal and adult hemoglobin production.
The main geographic locations where -thalassemia is found are Africa, the
Mediterranean area, and Southeast Asia, but the more severe forms hemoglobin
H disease and hemoglobin Barts are seen only in the Mediterranean area and
Southeast Asia.1 The reason for this geographic association with severity concerns
the two molecular forms of -thalassemia trait 2 one in which one copy of the
gene is mutated on each chromosome (trans) and the other in which one chromo-
some has both genes mutated (cis). The predominant genotype of thalassemia trait
in Africa is trans, but the cis form is found in other areas, which can lead to he-
moglobin H disease and hemoglobin Barts.
-Thalassemia is common in the Mediterranean area and Southeast Asia. Be-
cause there is one copy of the hemoglobin chain on chromosome 11, patients can
be either heterozygous (thalassemia minor) or homozygous (thalassemia major)
for the defective hemoglobin chain. Some patients are homozygous for -chain
mutations but still have residual -chain synthesis, resulting in an intermediate
phenotype (thalassemia intermedia). Patients with thalassemia minor present with
mild microcytic anemia. Thalassemia major is manifested soon after birth as se-
vere transfusion-dependent anemia. As the name implies, thalassemia intermedia
can range in presentation from transfusion-dependent anemia to anemia that is
slightly more severe than that in patients with thalassemia minor.
Also common in Southeast Asia is hemoglobin E disease, in which lysine is
substituted for glutamine at position 26 of the chain. This mutation also activates
Iron deficiency
Anemia of inflammation
Iron
Heme
Hemoglobin
Protoporphyrin
Globin
Sideroblastic
anemia
Thalassemia
ME
an alternative messenger RNA (mRNA) splice site, Iron Deficienc
DE y
Campion
leading to a marked reduction in protein synthesis. Artist N Koscal
People who are heterozygous for hemoglobin E The most common anemiaFigure isAUTHOR
iron-deficiency
has been redrawn and type has beenane-
PLEASE NOTE:
reset
Please check carefully
have microcytosis with target cells, and those who mia. Besides playing a crucial
Issue date role
10/2/2014as an oxygen
are homozygous have only mild anemia. However, carrier in the heme group of hemoglobin, iron is
children with one copy each of the -thalassemia found in many key proteins in the cells, such as
gene and the hemoglobin E gene will have a se- cytochromes and myoglobin, so it is not unexpect-
vere phenotype, resulting in a transfusion-depen- ed that a lack of iron has effects other than ane-
dent anemia. mia. Three studies have focused on nonanemic
iron deficiency leading to fatigue. Two studies
A nemi a of Infl a m m at ion showed that oral iron supplementation reduces
fatigue, with no significant change in hemoglobin
Inflammatory states are often accompanied by levels, in women with a ferritin level of less than
microcytic anemia. The cause of this anemia is 50 ng per milliliter,4,5 and a third study showed a
twofold.2 First, renal production of erythropoietin lessening of fatigue with parenteral iron admin-
is suppressed by inflammatory cytokines, resulting istration in women with a ferritin level of 15 ng
in decreased red-cell production. Second, lack of per milliliter or less or an iron saturation of 20%
iron availability for developing red cells can lead or less.6
to microcytosis. The lack of iron is largely due to Owing to obligate iron loss through menses,
the protein hepcidin,3 an acute-phase reactant that women are at greater risk for iron deficiency than
leads to both reduced iron absorption and re- men. Iron loss in all women averages 1 to 3 mg
duced release of iron from body stores. The pro- per day, and dietary intake is often inadequate to
tein ferroportin mediates cellular efflux of iron. maintain a positive iron balance.7,8 A 1967 study
Hepcidin binds to and down-regulates ferropor- showed that 25% of healthy, college-age women
tin, thereby blocking iron absorbed by enterocytes had no bone marrow iron stores and that another
from entering the circulation and also preventing 33% had low stores.9 Pregnancy adds to demands
the release of iron from its body stores to develop- for iron, with requirements increasing to 6 mg per
ing red cells (Fig. 2). day by the end of pregnancy.10
Mean
Corpuscular Findings on
Type Volume Hemoglobin Electrophoresis Other Features
fl g/dl
-Thalassemia
Major 5075 <7 Increased hemoglobin A2 Severe anemia
Intermedia 5075 <9 Increased hemoglobin A2 Target cells on smear
Minor 6575 910 Increased hemoglobin A2 Target cells on smear
-Thalassemia
Trait 1 ( /) 8085 1214 Normal
Trait 2 (/) or ( /) 6575 1213 Normal
Hemoglobin H disease (/) 6069 98 Hemoglobin H Hemolysis,
splenomegaly
Hemoglobin Barts ( /) Hemoglobin H, hemoglobin Hydrops fetalis
Barts
Hemoglobin E disease
Heterozygous 8085 12 Hemoglobin E present Rare target cells on smear
Homozygous 7079 1112 Hemoglobin E predominant Target cells on smear
* The normal range for mean corpuscular volume is 80 to 100 fl. The normal range for hemoglobin level is 13.5 to 17.5 g
per deciliter in men and 12 to 16 g per deciliter in women.
Athletes are another group at risk for iron defi- reduced can be a clue to etiologic factors, because
ciency.11 Gastrointestinal tract blood is the a value of less than 70 fl is rare in patients with
source of iron loss, and exercise-induced hemoly- anemia of inflammation. There have been a vari-
sis leads to urinary iron losses.12 Decreased ab- ety of proposed prediction rules with the use of
sorption of iron has also been implicated as a blood indexes to differentiate between thalassemia
cause of iron deficiency, because levels of hepci- and iron deficiency, but these have limited pre-
din are often elevated in athletes owing to dictive power; therefore, specific testing is required.
training-induced inflammation.11 Although it is On the blood smear, microcytic cells can be
clear that frank anemia can affect exercise per- recognized because they are smaller than a lym-
formance, evidence is increasing that nonanemic phocyte nucleus. Hypochromia an increase in
iron deficiency may also be detrimental.13 the size of the central pallor of red cells can
An interactive Obesity and its surgical treatment are also risk also be observed. In iron-deficiency anemia and
graphic showing
blood smears
factors for iron deficiency. Obese patients are of- anemia of inflammation, microcytic cells pre-
is available ten iron-deficient, with increased hepcidin levels dominate, but in -thalassemia and hemoglobin
at NEJM.org being implicated in decreased absorption.14 After
bariatric surgery, the incidence of iron deficiency
can be as high as 50%.15 Because the main site Figure 2 (facing page). Mechanism of Anemia
of Inflammation.
of iron absorption is the duodenum, surgeries
Normally, iron is absorbed in the gastrointestinal tract
that involve bypassing this part of the bowel are and is delivered to transferrin for transport to the de-
associated with an increased incidence of iron veloping red cells, with any excess stored in hepato-
deficiency. However, iron deficiency is seen as a cytes. In inflammatory states, decreased absorption of
sequela of most types of bariatric surgery.16 iron leads to reduced saturation of transferrin and im-
paired release of iron from storage, resulting in a lack
of iron delivery to the developing red cells. These
Di agnosis changes are mediated by hepcidin, which binds and in-
hibits ferroportin, the main iron-export protein. DMT1
In a patient who presents with microcytosis, the denotes divalent metal transporter 1.
extent to which the mean corpuscular volume is
Gut lumen
Gut Fe2+
lumen
DMT1
Enterocyte
Enterocyte
Enterocyte
cytoplasm
Transferrin Transferrin
Fe2+ Fe2+
Desaturated transferrin
Iron is transferred to supplies less iron to
developing red cells developing red cells
Hepatocytes
COLOR FIGURE
Low-molecular-weight iron 25 mg as test dose; if no adverse reaction within 1 hr, then 975 mg over 46 hr for
dextran total dose of 1000 mg
Ferric gluconate 125 mg over 1 hr; repeat in seven subsequent sessions for total dose of 1000 mg
Iron sucrose 200 mg over 1560 min, 300 mg over 1.5 hr, or 500 mg over 4 hr; repeat in one to
four subsequent sessions for total dose of 1000 mg
Ferumoxytol 510 mg over 17 sec; repeat in 38 days for total dose of 1020 mg
Ferric carboxymaltose 750 mg over 1530 min; repeat in 7 days for total dose of 1500 mg
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