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8.2 b-Thalassemia Major (Cooley’s Anemia) 293
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8.2
b -Thalassemia Major (Cooley’s Anemia)
b -thalassemia major is a hereditary hemolytic anemia,
characterized by defi ciency in the hemoglobin beta chain
synthesis. Patients with b -thalassemia major are prone to
repeated attacks of intravascular hemolysis that requires
repeated hospitalization and blood transfusions.
Patients with b -thalassemia major present with
microcystic hypochromic anemia with signs of fatigue
and cardiac tachycardia.
Repeated blood transfusion predisposes to hemosiderosis and tissue iron burden, which is the most severe
complication of this disease. Hemosiderosis causes
cardiomyopathy, hepatic failure, hypogonadism (pituitary siderosis), and endocrinal abnormalities. Bronze
diabetes is a term used to describe diabetes mellitus
induced in a patient with thalassemia due to pancreatic
hemosiderosis. The term “bronze” refers to skin darkening and hyperpigmentation that is seen in patients
with chronic thalassemia, due to deposition of hemosiderin in the subcutaneous tissues. Hypoparathyroidism is one of the most important endocrinal
complications of thalassemia.
Extramedullary hematopoiesis is commonly observed
in these patients due to increased body demands.
Extramedullary hematopoiesis can be appreciated on
plain radiographs as abnormally widened, fl at bones.
Within the past few years, MRI has emerged as a
powerful diagnostic tool to detect hemosiderosis
through the body. Techniques for tissue iron burden
quantifi cation are well-established for the liver and the
heart. Early treatment with chelating agents (e.g.,
Desferrioxamine) reduces the severity of the iron burden complication. MRI iron burden quantifi cation
helps in monitoring chelation therapy.
Square-shaped metacarpals and thin cortex, due to bone
marrow proliferation (Fig. 8.2.2 ).
Dilated ribs due to extramedullary hematopoiesis (Fig. 8.2.3 ).
Splaying of the femoral metaphysis (erlenmeyer fl ask
deformity).
Fig. 8.2.1. A plain radiograph of the lateral skull of a patient
with thalassemia shows hair-on-end-appearance
Signs on Skeletal Radiograph
Skull hair-on-end appearance : increase of the trabeculae
within the skull bones, due to extramedullary hematopoiesis
that widens the clavarial fl at bones (Fig. 8.2.1 ).
Fig. 8.2.2. A plain radiograph of the hand shows squaring and
expansion of the phalanges due to extrameduallry hematopoiesis
in a young patient with thalassemia
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Fig. 8.2.3. AP plain radiograph shows expansion of the ribs due
to extrameduallry hematopoiesis ( arrowheads )
causes of nonenhanced CT high-density liver are Wilson’s
disease due to copper deposition, and hepatic iodine
deposition, rarely seen in amiodarone toxicity.
Hepatosplenomegaly often occurs due to extramedullary
hematopoiesis (Fig. 8.2.5 ).
Thoracic paraspinal masses and enlarged lymph nodes
may be seen due to extramedullary hematopoiesis
(Fig. 8.2.6 ).
Cerebral calcification may be seen due to hypoparathy-
roidism in thalassemia patients. Patients may uncommonly
show bilateral symmetrical basal ganglia calcifications
(Fig. 8.2.7 ).
Fig. 8.2.4. Axial nonenhanced CT of the abdomen shows highdensity liver
Signs on CT
Hepatic hemosiderosis is one of the main causes of
high-density liver on nonenhanced CT images (Fig. 8.2.4 ). The
liver density will show high HU diff erence compared to the
muscles and the spleen, with a range of 80–140 HU. Other
Fig. 8.2.5. Axial nonenhanced CT of the abdomen shows
hepatomegaly with left liver lobe hypertrophy
Fig. 8.2.6. Axial nonenhanced CT illustration of the thorax
shows bilateral paraspinal masses due to extramedullary
hematopoiesis ( arrowheads ). These masses can be easily mis-
taken for tumors. Other signs of extramedullary hematopoiesis
support the diagnosis
8.2 b-Thalassemia Major (Cooley’s Anemia) 295
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Signs on MRI
Iron burden quantifi cation is done with the use of T2*
sequences (Fig. 8.2.8 ). The supraparamagnetic properties of
the iron deposited within the tissues cause decreased signal
intensity of the tissues containing iron. As a result, hepatic
parenchyma, splenic parenchyma, and cardiac muscles with
siderosis appear hypointense compared to normal parenchyma.
In mild liver siderosis, the liver appears hypointense only on T2*
images, compared to muscles. In moderate to severe cases, the
liver appears hypointense to spleen and muscles in all sequences.
The spleen shows almost the same picture as the liver, due to
iron deposition. In primary hemochromatosis, only the liver
shows decreased signal intensity, while the spleen is spared.
In the heart, iron overload appears as a dark ring on T1W,
T2W, and T2* images.
In bronze diabetes, the pancreas and sometimes the adrenals
show low signal intensity due to iron deposition.
In hypogonadism and signs of pituitary failure, the anterior
pituitary shows low signal intensity on T1W, T2W, and T2*
Fig. 8.2.7. Axial nonenhanced brain CT shows bilateral, almost
symmetrical, basal ganglia calcifi cations
images, refl ecting severe iron deposition.
Fig. 8.2.8. Axial abdomen
section in different sequences
illustrates the method of liver
iron burden quantifi cation in
the liver and the paraspinal
muscles
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8.2
For Further Reading
1 . Papakonstantinou O et al MR imaging of spleen in beta-
thalassemia major. Abdom Imaging. 2006. doi: 10.1007/
s00261.006.9138–4
2. Lal A et al Focal splenic lesions as a cause of extramedul-
lary hematopoiesis in a case of thalassemia. Eur J Radiol
Extra. 2008;68:e125–7
3. Karimi M et al Hypoparathyroidism and intracerebral cal-
cifi cation in patients with beta-thalassemia major. Eur J
Radiol. 2008. doi: 10.1016/j.ejrad.2008.02.003
4. Drakonaski E et al Adrenal glands in beta-thalassemia
major: magnetic resonance (MR) imaging features and
correlation with iron store. Eur Radiol. 2005;15:2462–68
5. Louis CK Low grow th of children with b -thalassemia major.
Indian J Pediatr. 2005;72:159–64
6. Mavrogeni S et al Magnetic resonance evaluation of liver
and myocardium iron deposition in thalassemia intermedia and b -thalassemia major. Int J Cardiovasc Imaging
2008;24:849–54
7. Karimi M et al Prevalence of hepatosplenomegaly in beta
thalassemia minor subjects in Iran. Eur J Radiol. 2007. doi:
10.1016/j.ejrad.2007.09.027
8. Argyropoulou MI et al MRI evaluation of tissue iron burden in patients with b -thalassemia major. Pediatr Radiol.
2007;37:1191–200
9. Positano V et al Improved T2* assessment in liver iron
overload by magnetic resonance imaging. Magn Reson
Imaging. 2008. doi:10.1016/j.mri.2008.06.004
8.3 Sickle Cell Disease 297
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8.3
Sickle Cell Disease
Sickle cell disease (SCD) is an autosomal recessive
genetic disorder, characterized by episodic attacks of
hemolytic anemia and vaso-occlusive attacks due to
“sickeling” of the red blood cells (RBCs) under certain
body conditions that include dehydration, metabolic
acidosis, and low oxygen saturation.
SCD results from abnormal production of hemoglobin (Hb-S). Sickle cell patients are homozygous (HbSS),
while heterozygous patients have “sickle cell trait”.
SCD can also arise when Hb-S is combined with abnormal hemoglobin (e.g., Hb-S-thalassemia). Hb-S differs
from the normal Hb-A only in the substitution of valine
for glutamic acid in the sixth position of the b chain.
In SCD, the normal, discoid RBCs shape is transform into a sickle-shaped, sticky mass during deoxygenation. These sickle cells can stick together, forming
a hard mass that may lead to emoblization and arterial
infarction in different parts of the body.
Approximately 50% of patients with SCD experience painful crises by the age of 5 years. Patients with
sickle cell disease have natural protection against
malaria; the reasons are unknown.
The Lungs in SCD
Patients with SCD have greater susceptibility to pneumonia (100 times more than other children), due to
impaired immune status. The infective agents are commonly Streptococcus pneumoniae, Hemophilus infl u-
enzae, and Salmonella . Acute chest syndrome (ACS) is
a term used to describe newly developed pulmonary
consolidation. accompanied by fever, chest pain, dyspnea, and cough. The underlying cause is known, and
presumably due to fat emboli. ACS is the second most
common cause for hospital admissions in children with
SCD, after painful crises. ACS is also seen in up to
10% of SCD patients after general anesthesia.
The Skeletal System in SCD
Skeletal manifestations in SCD range between vasoocclusive crises, extramedullary hematopoiesis, osteomyelitis, and vertebral changes. Bone infarction is the
most common cause of pain crises in SCD. However,
silent infarctions do exist in patients with SCD. There
are four zones seen in bone infarction by histology: the
zone of cell death located in the center, the zone of
ischemic tissue, the zone of hyperemia, and the outer
zone of normal bony tissue.
Osteomyelitis means infl ammation of the bone
and the bone marrow. Osteomyelitis is commonly
caused by Salmonella infection in sickle cell
patients. In nonsickle cell patients, the most common cause of osteomyelitis is Staphylococcus
aureus .
Diff erential Diagnoses and Related Diseases
Hand - foot syndrome is an uncommon disease seen in
sickle cell patients in up to 20% of cases, characterized by bilateral infl ammation and swelling of the fi ngers and toes (dactylitis). Patients present with fever,
bilateral digital swelling in the hands and feet, leucocytosis, and pain. It can be mistaken for osteomyelitis
in the initial presentation. Osteomyelitis is uncommonly known to cause bilateral infection in the hands
and feet simultaneously. Also, osteomyelitis often
involves the long bones, not the small bones of the
hands and feet. Most patients experience this syndrome before 4 years of age, and the disease has not
been reported beyond 7 years. The condition is selflimiting, with a duration that varies from a week to a
month.
What is the difference between osteonecrosis, avas-
cular necrosis, and bone infarction?
Osteonecrosis is ischemic death of the bone and
bone marrow.
Avascular necrosis is osteonecrosis that occurs in
the epiphyses.
Bone infarction is osteonecrosis that occurs in the
metaphyses or diaphyses.
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8.3
The Brain in SCD
In SCD, the brain may be damaged due to infarction
from sickle cell emboli, or from vasculitis. Up to 25%
of patients with SCD will have a neurological complication over their lifetime; 11% of these complications
will occur by the age of 20 years. Silent infarction is
defi ned as MRI manifestation of cerebral infarction in
the absence of clinical symptoms, and occurs in up to
22% of patients with SCD.
The Spleen in SCD
Multiple spleen infarctions due to vaso-occlusive crises are a very common feature in SCD. With time, the
spleen is replaced by fi brous tissue and by calcium and
hemosiderin deposition (called autosplenectomy ). Up
to 94% of patients are asplenic by the age of 5 years.
Patients with splenectomy are susceptible to infection with Staphylococcus pneumoniae, Salmonella,
and Haemophilus infl uenzae . Pneumococcal vaccine is
often started between 2 and 5 years of age.
Sequestration syndrome is another condition that
commonly occurs in SCD patients, characterized by
rapid pooling of the blood within the spleen, resulting in
intravascular volume depletion and dropping hematocrite levels. When the sequestration is severe, patients
present with abdominal fullness, thirst, tachycardia, and
tachypnea that may rapidly progresses into circulatory
collapse. Up to 30% of patients experience sequestration
syndrome between the ages of 6 months and 3 years.
the appearance of dense bone within the aff ected bone
(bone-in-bone appearance).
H-shaped vertebra : there is central end plate depression, with
sparing of the anterior and posterior margins due to previous
infarctions of vertebral bodies. An H-shaped vertebra is a
characteristic sign of SCD (Fig. 8.3.2 ).
Expansion of the diploic medullary spaces of the skull due to
increased hematopoietic demands (hair-on-end appearance).
Osteomyelitis : the early changes seen radiographically are
soft-tissue swelling or a mass, occasionally gas, periosteal
reaction, and (later) cortical destruction. There are usually no
signs on plain radiograph in the fi rst 2 weeks of infection. The
cortical destruction fi rst appears as small lucent holes
(permeative destruction), followed later by larger coalescent
lesions (moth-eating destruction). Osteomyelitis can be
diffi cult to diff erentiate from infarction.
Hand-foot syndrome : the typical signs of dactylitis include
soft-tissue swelling of the digits, cortical thinning, multiple
intramedullary radiolucent deposits, and thick periosteal new
bone formation (Fig. 8.3.3 ). The radiological manifestations
are completely reversible after 8 months.
Protrusio acetabuli may occur in SCD in up to 20% of cases.
Signs on Chest Radiograph
Pneumonia is seen as areas of patchy lung infi ltration with air
bronchogram. The airspace disease may be lobar or diff use.
Acute chest syndrome is seen as single or multiple patchy areas of
airspace disease, often confi ned to the middle and lower lobes.
Up to 60% of patients with ACS show normal chest radiograph.
Signs on Skeletal Radiograph
Bone infarction : seen as a radiolucent area surrounded by the
sclerotic rim, typically in the epiphyses and the medullary
cavity (Fig. 8.3.1 ). Later, sclerosis of the infarcted areas causes
Fig. 8.3.1. Plain radiograph of the distal femur metaphysis
shows radiolucent areas surrounded by sclerotic rims ( arrow-
heads ) due to old bone infarction in a patient with sickle cell
disease (SCD)
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Signs on Chest CT
Extramedullar hematopoiesis may be found as bilateral or unilateral,
smooth or lobulated paraspinal masses in the lower thoracic spine,
without vertebral erosions. History of hematological disease is
the key diagnosis to diff erentiate these masses from tumors.
Signs on Abdominal CT
Spleen infarction is seen on noncontrast enhanced images as a
hypodense, wedge-shaped area, which typically starts from
the periphery toward the center, with no contrast enhancement (Fig. 8.3.4 ).
Sequestration syndrome is seen as splenomegaly with
hypodense peripheral areas.
Signs on Skeletal MRI
Fig. 8.3.2. Lateral vertebral plain radiograph of a patient with
SCD shows H-shaped thoracic vertebra
Fig. 8.3.3. Plain radiograph
of both hands in a sickle-cell
patient shows thick periosteal
new bone formation affecting
the fi fth and fourth right
metacarpal bones and the
fi fth left metacarpal bone
( arrowheads ), changes
indicating hand-foot
syndrome
MRI is important in the early detection of bone infarction. On
T2W images, there is an area surrounded by a hyperintense
line and an outer hypointense line ( Double-line sign ). The
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8.3
Fig. 8.3.4. Axial abdominal postcontrast CT shows multiple
hypodense wedge-shaped areas within the spleen, due to multiple areas of infarction
high-intensity line represents the zone of hyperemia.
Double-line sign is found in up to 80% of cases of bone
infarction.
The yellow marrow is made of 80% fat, 15% water, and 5%
proteins. On MRI, it gives high signal in T1W images. In
contrast, the red marrow is made of 40% fat, 40% water, and
20% proteins. This high water content gives low signal in both
T1W and T2W images. Extracellular hematopoiesis, especially
within the vertebrae, can be suggested by observation of the
intervertebral disc signal. Normally, the vertebral bodies have
higher signals than the intervertebral discs on T1W images,
due to the fatty marrow. In extracellular hematopoiesis, the
yellow marrow is reconverted into red marrow due to the
hematpoietic demands, resulting in low signal intensity of the
vertebral bodies compared to the intervertebral discs on T1W
images ( high- density disc sign ). This sign is observed in any
disease with bone marrow infi ltration.
Signs on Brain MRI
Silent infarction is detected as a high signal intensity lesion
within the white matter on T2W or FLAIR images.
Moyamoya disease is detected by its classical “puff of smoke”
appearance on MR-angiography, and occlusion of the
ipsilateral internal carotid artery.
For Further Reading
1. Lonergan GJ et al Sickle cell anemia. RadioGraphics. 2001;
21:971–94
2. Ejindu VG et al Musculoskeletal manifestations of sickle
cell disease. RadioGraphics. 2007;27:1005–21
3. Schatz J et al Sickle cell disease as a neurodevelopmental
disorder. Ment Retard Dev Disabil Res Rev. 2006;12:200–7
4. John N. Lukens. Sickle cell disease. Dis Mon. 1981;27:1–56
5. Babhulkar SS et al The hand-foot syndrome in sickle-cell
haemoglobinopathy. J Bone Joint Surg (Br). 1995;77-B:310–2
6. Janet Watson R et al The hand-foot syndrome in sickle-cell
disease in young children. Pediatrics. 1963;31;975–82
7. John N. Lukens. Sickle cell disease. Dis Mon. 1981;27:1–56
8.4 Pernicious Anemia 301
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8.4
Pernicious Anemia
Pernicious anemia (PA) is a disease characterized by
the development of megaloblastic anemia due to
destruction of the gastric parietal cells. Megaloblastic
anemias are a subgroup of macrocystic anemias (large
volume red blood cells), which most commonly arise
due to vitamin B 12 and folate defi ciencies.
Normally, the parietal cells in the gastric mucosa
secret an intrinsic factor, which is important for absorption of vitamin B
fundus of the stomach contains parietal cells, the body
contains the cells responsible for the secretion of pepsin and hydrochloric acid, and the antrum contains G
cells. Patients with PA develop antigastric parietal cells
(GPC) and anti-intrinsic factor antibodies (gastric parietal cells antibodies, or AGPA), which attack the parietal cells and cause autoimmune gastritis. Destruction
of the gastric parietal cells leads to gastric mucosal
atrophy, and compromises the production of the intrinsic factor. Moreover, the atrophic gastritis also compromises the gastric acid pump, leading to defi ciency
in the secretion of gastric acids (hypo- or achlorhydria). Loss off vitamin B 12 causes defective synthesis
of the bone marrow cellular activities, leading to the
development of megaloblastic erythropoiesis and macrocytic anemia.
Chronic gastritis induces enterochormaffi n-like cell
hyperplasia, which may result in the development of
gastric carcinoid tumors. Compared to the general
population, gastric adenocarcinoma is 3–5 times more
frequent among patients with PA. The activity of natural killer cells, which participate in immunosurveillance against tumor dissemination, is believed to be
compromised in patients with PA.
Atrophic gastritis is divided into two types. Atrophic
gastritis type (a) is characterized by mucosal atrophy
affecting the fundus and the body of the stomach, with
antral sparing. In contrast, atrophic gastritis type (b) is
characterized by antral mucosal atrophy, with limited
involvement of the fundus and body.
AGPAs are found in 20% of patients with diabetes
mellitus type 1 (DMT1). Researchers suggest that
patients with DMT1 should be regularly screened for
from the gastrointestinal tract. The
12
atrophic gastritis. PA is rare found in the general population, with an incidence of 0.1–2% of the population.
On the other hand, patients with DMT1 have a threefold increased incidence of PA, with a prevalence of
2.5–4%.
Diagnosis is confi rmed by detecting AGPA levels in
the serum by the Schilling test.
Signs on Barium Meal
In a normal double-contrast barium meal examination, the
stomach mucosal folds (rugae) are observed arranged in an
irregular fashion through the fundus, body, and antrum
Fig. 8.4.1 ). At the lesser curvature near the pylorus, the
(
mucosal folds become longitudinal and are known as
magenustrass. Area gastrica is an area of nodular mucosal
elevation located near the antrum (Fig. 8.4.2 ).
In PA, there is tubular-shaped fundus <8 cm in diameter
absent or reduced amount of the normal gastric rugae in the
fundus of the body (bald fundus), and small or absent area
gastrica (Fig. 8.4.3 ).
Fig. 8.4.1 Double-contrast barium meal shows the normal confi guration of the stomach with the mucosal folds (rugae) nicely
demonstrated
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8.4
Fig. 8.4.2 Double-contrast barium meal shows area gastrica,
seen as an area with nodular mucosal pattern
For Further Reading
1. Levine MS et al Atrophic gastritic in pernicious anemia:
diagnosis by double-contrast radiography. Gastrointest
Radiol. 1989;14:215–19
2. Varis K et al An Appraisal of tests for severe atrophic gastritis in relatives of patients with pernicious anemia. Dig Dis
Sci. 1979;24:187–91
Fig. 8.4.3 Double-contrast barium meal of a patient with pernicious anemia demonstrates severe atrophic gastritis with loss of
the normal mucosal folds. Compare this image with
3. Wickramasinghe SN. Diagnosis of megaloblastic anemias.
Blood Rev. 2006;20:299–318
4. Vargas JA et al Natural killer cell activity in patients with
pernicious anemia. Dig Dis Sci. 1995;40:1538–41
5. Tzellos TG et al Pernicious anemia in a patient with type 1
diabetes mellitus and alopecia areata universalis. J Diabet
Complicat. doi:10.1016/j.jdiacomp.2008.o5.003
Fig. 8.4.1
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