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CASE REPORT
Presenter : Sasikala S Balakrishnan
Yeoh Shu TIng
Day/Date : Wednesday, 28th of August 2013
Supervisor : dr. Tina Christina. L. Tobing , Sp.A(K)
CHAPTER I
INTRODUCTION
1.1. BACKGROUND
The term thalassemia is derived from the Greek words Thalassa (sea)
and Haema (blood) and refers to disorders associated with defective synthesis of
alpha- or beta-globin subunits of hemoglobin (Hb)A(alpha2; beta2), inherited as
pathologic alleles of one or more of the globin genes located on chromosomes 11
(beta) and 16 (alpha). More than 200 deletions or point mutations that impair
transcription, processing, or translation of alpha- or beta-globin mRNA have been
identified. The clinical manifestations are diverse, ranging from absence of
symptoms to profound fatal anemias in utero, or, if untreated, in early childhood.
Thalassemias are genetic disorders in globin chain production, inherited
autosomal recessive blood disease. In thalassemia, the genetic defect results in
reduced rate of synthesis of one of the globin chains that make up hemoglobin.
Reduced synthesis of one of the globin chains causes the formation of abnormal
hemoglobin molecules, and this in turn causes the anemia which is the
characteristic presenting symptom of the thalassemias.1,2Thalassemia was first defined in 1925 when Dr. Thomas B. Cooley
described five young children with severe anemia, splenomegaly, and unusual
bone abnormalities and called the disorder erythroblastic or Mediterranean anemia
because of circulating nucleated red blood cells and because all of his patients
were of Italian or Greek ethnicity. In 1932 Whipple and Bradford coined the term
thalassemia from the Greek word thalassa, which means the sea (Mediterranean)
to describe this entity. Somewhat later, a mild microcytic anemia was described in
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families of Cooley anemia patients, and it was soon realized that this disorder was
caused by heterozygous inheritance of abnormal genes that, when homozygous,
produced severe Cooley anemia.2,3
In Europe, Riette described Italian children with unexplained mild
hypochromic and microcytic anemia in the same year Cooley reported the severe
form of anemia later named after him. In addition, Wintrobe and coworkers in the
United States reported a mild anemia in both parents of a child with Cooley
anemia. This anemia was similar to the one that Riette described in Italy. Only
then was Cooley's severe anemia recognized as the homozygous form of the mild
hypochromic and microcytic anemia that Riette and Wintrobe described. This
severe form was then labeled as thalassemia major and the mild form as
thalassemia minor. These initial patients are now recognized to have been
afflicted with thalassemia. In the following few years, different types of
thalassemia that involved polypeptide chains other than chains were recognized
and described in detail. In recent years, the molecular biology and genetics of the
thalassemia syndromes have been described in detail, revealing the wide range of
mutations encountered in each type of thalassemia.2,4
Pericardial effusion is a common finding in everyday clinical practice. The
first challenge to the clinician is to try to establish an etiologic diagnosis.
Sometimes, the pericardial effusion can be easily related to a known underlying
disease, such as acute myocardial infarction, cardiac surgery, end-stage renal
disease or widespread metastatic neoplasm. When no obvious cause is apparent,
some clinical findings can be useful to establish a diagnosis of probability.
The presence of acute inflammatory signs (chest pain, fever, pericardial
friction rub) is predictive for acute idiopathic pericarditis irrespective of the size
of the effusion or the presence or absence of tamponade. Severe effusion with
absence of inflammatory signs and absence of tamponade is predictive for chronic
idiopathic pericardial effusion, and tamponade without inflammatory signs for
neoplastic pericardial effusion. Epidemiologic considerations are very important,
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as in developed countries acute idiopathic pericarditis and idiopathic pericardial
effusion are the most common etiologies, but in some underdeveloped geographic
areas tuberculous pericarditis is the leading cause of pericardial effusion. The
second point is the evaluation of the hemodynamic compromise caused by
pericardial fluid. Cardiac tamponade is not an all or none phenomenon, but a
syndrome with a continuum of severity ranging from an asymptomatic elevation
of intrapericardial pressure detectable only through hemodynamic methods to a
clinical tamponade recognized by the presence of dyspnea, tachycardia, jugular
venous distension, pulsus paradoxus and in the more severe cases arterial
hypotension and shock. In the middle, echocardiographic tamponade is
recognized by the presence of cardiac chamber collapses and characteristic
alterations in respiratory variations of mitral and tricuspid flow. Medical treatment
of pericardial effusion is mainly dictated by the presence of inflammatory signs
and by the underlying disease if present. Pericardial drainage is mandatory when
clinical tamponade is present. In the absence of clinical tamponade, examination
of the pericardial fluid is indicated when there is a clinical suspicion of purulent
pericarditis and in patients with underlying neoplasia. Patients with chronic
massive idiopathic pericardial effusion should also be submitted to pericardial
drainage because of the risk of developing unexpected tamponade. The selection
of the pericardial drainage procedure depends on the etiology of the effusion.
Simple pericardiocentesis is usually sufficient in patients with acute idiopathic or
viral pericarditis. Purulent pericarditis should be drained surgically, usually
through subxiphoid pericardiotomy. Neoplastic pericardial effusion constitutes a
more difficult challenge because reaccumulation of pericardial fluid is a concern.
The therapeutic possibilities include extended indwelling pericardial catheter,
percutaneous pericardiostomy and intrapericardial instillation of antineoplastic
and sclerosing agents. Massive chronic idiopathic pericardial effusions do not
respond to medical treatment and tend to recur after pericardiocentesis, so wide
anterior pericardiectomy is finally necessary in many cases. 5
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CHAPTER II
LITERATURE REVIEW
2.1. THALASSEMIA
2.1.1. DEFINITION
Thalassemia syndromes are inherited genetic diseases caused by mutation
of alpha or beta globin genes, which result in abnormal hemoglobin synthesis. The
patho-physiologic mechanisms can be divided into decreased production of par-
ticular types of hemoglobin (Thalassemias) and production of abnormal structure
of hemoglobin types (Hemoglobinopathies). These lead to not only abnormal
morphologic of erythrocytes (red blood cells), but also shorten life span of
erythrocytes due to increased in vivo fragility and extra-vascular red cell
destruction (hemolysis) along with ineffective erythropoiesis (bizarre, dys-
functional marrow production). Thalassemia gene is an autosomal inheritance,
which implies that both parents of the affected child must have a silent carrier
state, so called thalassemia trait or hetero- zygote, while they are both
asymptomatic.
2.1.2. EPIDEMIOLOGY
Certain types of thalassemia are more common in specific parts of the
world. thalassemia is much more common in Mediterranean countries such as
Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus,
Sardinia, and Malta, have a significantly high incidence of severe thalassemia,
constituting a major public health problem. For instance, in Cyprus, 1 in 7
individuals carries the gene, which translates into 1 in 49 marriages between
carriers and 1 in 158 newborns expected to have b thalassemia major. As a result,
preventive measures established and enforced by public health authorities have
been very effective in decreasing the incidence among their populations. B
thalassemia is also common in North Africa, the Middle East, India, and Eastern
Europe.
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Conversely, thalassemia is more common in Southeast Asia, India, the
Middle East, and Africa. Worldwide, 15 million people have clinically apparent
thalassemic disorders. Reportedly, disorders worldwide, and people who carry
thalassemia in India alone number approximately 30 million. These facts confirm
that thalassemias are among the most common genetic disorders in humans; they
are encountered among all ethnic groups and in almost every country around the
world.2,4,5
Although -thalassemia has >200 mutations, most are rare. Approximately
20 common alleles constitute 80% of the known thalassemias worldwide; 3% of
the world's population carries genes for -thalassemia, and in Southeast Asia, 5
10% of the population carries genes for -thalassemia. In a particular area there
are fewer common alleles. In the U.S., an estimated 2,000 individuals have -
thalassemia.1
2.1.3. AETIOLOGY
Thalassemia syndromes are characterized by varying degrees of ineffective
hematopoiesis and increased hemolysis. Clinical syndromes are divided into -
and -thalassemias, each with varying numbers of their respective globin genes
mutated. There is a wide array of genetic defects and a corresponding diversity of
clinical syndromes. Most -thalassemias are due to point mutations in one or both
of the two -globin genes (chromosome 11), which can affect every step in the
pathway of -globin expression from initiation of transcription to messenger RNA
synthesis to translation and post translation modification. Picture below shows the
organization of the genes (i.e., and , which are active in embryonic and fetal
life, respectively) and activation of the genes in the locus control region (LCR),
which promote transcription of the -globin gene. There are four genes for -
globin synthesis (two on each chromosome 16). Most -thalassemia syndromes
are due to deletion of one or more of the -globin genes rather than to point
mutations. Mutations of -globin genes occur predominantly in children of
Mediterranean, Southern, and Southeast Asian ancestry. Those of -globin are
most common in those of Southeast Asian and African ancestry.6
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(source:Manual of Pediatric Hematology and Oncology)
Major deletions in thalassemia are unusual (in contrast to thalassemia),
and most of the encountered mutations are single base changes, small deletions, or
insertions of 1-2 bases at a critical site along the gene, as in the image below.
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(source: Thalassemia, Emedicine Multimedia)
2.1.4. CLASSIFICATION
The thalassemias can be defined as a heterogeneous group of genetic
disorders of hemoglobin synthesis, all of which result from a reduced rate of
production of one or more of the globin chains of hemoglobin. This basic defect
results in imbalanced globin chain synthesis, which is the hallmark of all forms of
thalassemia. The thalassemias can be classified at different levels. Clinically, it is
useful to divide them into three groups: the severe transfusion-dependent (major)
varieties; the symptomless carrier states (minor) varieties; and a group of
conditions of intermediate severity that fall under the loose heading thalassemia
intermedia. This classification is retained because it has implications for both
diagnosis and management.4
-THALASSEMIA2,8
The -thalassemia syndromes are caused by abnormalities of the b-gene
complex on chromosome 11. More than 150 different mutations have been
described, and most of these are small nucleotide substitutions within the b gene
complex. Deletions and mutations that result in abnormal cleavage or splicing of
-globin RNA may also result in thalassemia characterized by absent (0) or
reduced (+) production of -globin chains.2,7
THALASSEMIA MINOR (THALASSEMIA TRAIT)
Heterozygosity for a b-thalassemia gene results in a mild reduction of b-
chain synthesis and, therefore, a reduction in HbA and mild anemia. Hemoglobin
levels are 10 to 20 g/L lower than that of normal persons of the same age and
gender, but the anemia may worsen during pregnancy. This mild anemia usually
produces no symptoms, and longevity is normal. Thalassemia trait is almost
always accompanied by familial microcytosis and hypochromia of the red blood
cells. Target cells, elliptocytes, and basophilic stippling are seen on the peripheral
blood smear. Almost all individuals with b-thalassemia trait have MCVs less than
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75 fL, and mean MCV is 68 fL. In thalassemia trait the MCV is disproportionately
low for the degree of anemia because of a red blood cell count that is normal or
increased. The RDW is normal in thalassemia trait. The ratio of MCV/RBC
(Mentzer index) is 12 in iron deficiency. Iron studies
are normal. In an individual with microcytic red blood cells, a diagnosis of b-
thalassemia trait is confirmed by an elevated HbA2 (22) level. The normal level
of HbA2 is 1.5 to 3.4%, and HbA2 >3.5% is diagnostic of the most common form
of -thalassemia trait. Levels of HbF (22) are normal (
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ineffective erythropoiesis that are a consequence of unbalanced globin chain
synthesis. In homozygous -thalassemia, -globin chains are produced in normal
amounts and accumulate, denature, and precipitate in the RBC precursors in the
bone marrow and circulating RBC. These precipitated -globin chains damage the
RBC membrane, resulting in destruction within the bone marrow (ineffective
erythropoiesis) and in the peripheral blood.
The fetus and the newborn infant with homozygous -thalassemia are
clinically and hematologically normal. In vitro measurements demonstrate
reduced or absent -chain synthesis. Increasingly, homozygous -thalassemia is
being diagnosed in the United States by neonatal electrophoretic hemoglobin
screening that shows only HbF and no HbA Symptoms of -thalassemia major
develop gradually in the first 6 to 12 months after birth, when the normal
postnatal switchover from -chains to -chains results in a decreased level of
HbF). By the age of 6 to 12 months, most affected infants show pallor, irritability,
growth retardation, jaundice, and hepatosplenomegaly as a result of
extramedullary hematopoiesis. By 2 years of age, 90% of infants are symptomatic,
and progressive changes in the facial and cranial bones develop. The hemoglobin
level may be as low as 30 to 50 g/L at the time of diagnosis.
Other varian of -thalassemia are:6
Silent carrier thalassemia: Similar to patients who silently carry
thalassemia, these patients have no symptoms, except for possible low
RBC indices. The mutation that causes the thalassemia is very mild and
represents a + thalassemia.
Thalassemia intermedia: This condition is usually due to a compound
heterozygous state, resulting in anemia of intermediate severity, which
typically does not require regular blood transfusions.
thalassemia associated with chain structural variants: The most
significant condition in this group of thalassemic syndromes is the Hb E/
thalassemia, which may vary in its clinical severity from as mild as
thalassemia intermedia to as severe as thalassemia major.
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-THALASSEMIA2,9
The a-thalassemia syndromes are prevalent in people from Southeast Asia
and usually result from deletion of one or more of the four -globin genes on
chromosome 16. In general, the severity is proportional to the number of -globin
genes deleted which can be quantitated by DNA analysis.1,6
SILENT CARRIER (2-THALASSEMIA TRAIT, - /)
Individuals with a single -globin gene deletion are clinically and
hematologically normal, but they may be identified at birth by the presence of
small amounts (1-3%) of the fast-migrating Barts hemoglobin (4) by neonatal
hemoglobin electrophoresis. In later life, the diagnosis can be established only by
determining the number of a-globin genes by DNA analysis.
1-THALASSEMIA TRAIT (-/- OR --/)
Individuals in whom two of four -globin genes are deleted have mild
microcytic anemia. At birth, relative microcytosis with 5 to 8% of HbBarts is
present. Barts hemoglobin disappears by 3 to 6 months of age, and the
hemoglobin electrophoresis becomes normal. After the newborn period, a
definitive diagnosis may be impractical in this mild disorder, and the diagnosis is
usually suspected when other causes of microcytic anemia, such as -thalassemia
trait or iron deficiency, are ruled out.
1-Thalassemia trait can occur in two ways: a cis-deletion in which the two
deleted a genes are on the same chromosome 16, and a trans-deletion in which
one a-gene is deleted from each of the 16 chromosomes. The cis-deletion is usual
in Southeast Asian populations, whereas the trans-deletions are usual in people of
African ethnicity. Thus, although -thalassemia commonly occurs in African
people, a maximum of only two genes can be deleted in any individual because of
the trans-configuration. Consequently, the more severe -thalassemia syndromes
associated with three and four -deletions are not seen.
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HEMOGLOBIN H DISEASE (--/-)
Three -globin gene deletions result in hemoglobin H disease, which is
associated with a marked imbalance between a- and -globin chain synthesis.
Excess free chains accumulate and combine to form an abnormal hemoglobin, a
tetramer of chains (4) called HbH. HbH is unstable and precipitates within red
blood cells, leading to chronic microcytic, hemolytic anemia. Laboratory findings
include a moderately severe microcytosic anemia (Hb 60-100 g/L with evidence
of hemolysis). Precipitated HbH can be demonstrated in the red blood cells with
supravital stains. On hemoglobin electrophoresis, HbH has a fast mobility and
accounts for 10 to 15% of the total hemoglobin.
FETAL HYDROPS SYNDROME (--/--)
Deletion of all four a-globin genes results in a syndrome of hydrops fetalis
with stillbirth or immediate postnatal death. In the absence of -chain synthesis,
such fetuses are incapable of synthesizing embryonic hemoglobins. At birth,
hemoglobin electrophoresis shows predominantly Barts hemoglobin (4) and small
amounts hemoglobin H (4) as well as embryonic hemoglobins. The high oxygen
affinity of Barts hemoglobin makes it oxygen transport ineffective, leading to the
intrauterine manifestations of severe hypoxia, out of proportion to the degree of
anemia. A number of infants with this syndrome who have been identified
prenatally and treated with intrauterine and postnatal transfusions have survived.
These infants are transfusion dependent, but some are developing normally. As in
thalassemia major, the only curative therapy is bone marrow transplantation.
Termination of the pregnancy is often recommended because of a high frequency
of severe maternal toxemia associated with a hydropic fetus.
Thalassemias can also be classified at the genetic level into the , , or
thalassemias, according to which globin chain is produced in reduced
amounts. In some thalassemias, no globin chain is synthesized at all, and hence
they are called 0 or 0 thalassemias, whereas in others some globin chain is
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produced but at a reduced rate; these are designated + or + thalassemias. The
thalassemias, in which there is defective and chain synthesis, can be
subdivided in the same way, i.e., into ()+ and ()0 varieties.4
(source:Pediatric Hematology)
2.1.5. PATHOGENESIS
The basic defect in all types of thalassemia is imbalanced globin chain
synthesis. However, the consequences of accumulation of the excessive globin
chains in the various types of thalassemia are different. In thalassemia,
excessive chains, unable to form Hb tetramers, precipitate in the RBC
precursors and, in one way or another, produce most of the manifestations
encountered in all of the thalassemia syndromes; this is not the situation in
thalassemia.
The excessive chains in thalassemia are chains earlier in life and chains
later in life. Because such chains are relatively soluble, they are able to form
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homotetramers that, although relatively unstable, nevertheless remain viable and
able to produce soluble Hb molecules such as Hb Bart (4 chains) and Hb H (4
chains). These basic differences in the 2 main types of thalassemia are responsible
for the major differences in their clinical manifestations and severity.
chains that accumulate in the RBC precursors are insoluble, precipitate in
the cell, interact with the membrane (causing significant damage), and interfere
with cell division. This leads to excessive intramedullary destruction of the RBC
precursors. In addition, the surviving cells that arrive in the peripheral blood with
intracellular inclusion bodies (excess chains) are subject to hemolysis; this means
that both hemolysis and ineffective erythropoiesis cause anemia in the person with
thalassemia.
The ability of some RBCs to maintain the production of chains, which are
capable of pairing with some of the excessive chains to produce Hb F, is
advantageous. Binding some of the excess a chains undoubtedly reduces the
symptoms of the disease and provides additional Hb with oxygen-carrying ability.
Furthermore, increased production of Hb F, in response to severe anemia,
adds another mechanism to protect the RBCs in persons with thalassemia. The
elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together
with the profound anemia, stimulates the production of erythropoietin. As a result,
severe expansion of the ineffective erythroid mass leads to severe bone expansion
and deformities. Both iron absorption and metabolic rate increase, adding more
symptoms to the clinical and laboratory manifestations of the disease. The large
numbers of abnormal RBCs processed by the spleen, together with its
hematopoietic response to the anemia if untreated, results in massive
splenomegaly, leading to manifestations of hypersplenism.
If the chronic anemia in these patients is corrected with regular blood
transfusions, the severe expansion of the ineffective marrow is reversed. Adding a
second source of iron would theoretically result in more harm to the patient.
However, this is not the case because iron absorption is regulated by 2 major
factors: ineffective erythropoiesis and iron status in the patient.
Ineffective erythropoiesis results in increased absorption of iron because of
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downregulation of the HAMP gene, which produces a liver hormone called
hepcidin. Hepcidin regulates dietary iron absorption, plasma iron concentration,
and tissue iron distribution and is the major regulator of iron. It acts by causing
degradation of its receptor, the cellular iron exporter ferroportin. When ferroportin
is degraded, it decreases iron flow into the plasma from the gut, from
macrophages, and from hepatocytes, leading to a low plasma iron concentration.
In severe hepcidin deficiency, iron absorption is increased and macrophages are
usually iron depleted, such as is observed in patients with thalassemia intermedia.
Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of
different anemias, such as is seen in thalassemia, anemia of inflammation, and
chronic renal diseases. Improvement and availability of hepcidin assays facilitates
diagnosis of such conditions. The development of hepcidin agonists and
antagonists may enhance the treatment of such anemias.
By administering blood transfusions, the ineffective erythropoiesis is
reversed, and the hepcidin level is increased; thus, iron absorption is decreased
and macrophages retain iron.
Iron status is another important factor that influences iron absorption. In
patients with iron overload (eg, hemochromatosis), the iron absorption decreases
because of an increased hepcidin level. However, this is not the case in patients
with severe thalassemia because a putative plasma factor overrides such
mechanisms and prevents the production of hepcidin. Thus, iron absorption
continues despite the iron overload status.
As mentioned above, the effect of hepcidin on iron recycling is carried
through its receptor "ferroportin," which exports iron from enterocytes and
macrophages to the plasma and exports iron from the placenta to the fetus.
Ferroportin is upregulated by iron stores and downregulated by hepcidin. This
relationship may also explain why patients with thalassemia who have similar
iron loads have different ferritin levels based on whether or not they receive
regular blood transfusions.
For example, patients with thalassemia intermedia who are not receiving
blood transfusions have lower ferritin levels than those with thalassemia major
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who are receiving regular transfusion regimens, despite a similar iron overload. In
the latter group, hepcidin allows recycling of the iron from the macrophages,
releasing high amounts of ferritin. In patients with thalassemia intermedia, in
whom the macrophages are depleted despite iron overload, lower amounts of
ferritin are released, resulting in a lower ferritin level.
Most nonheme iron in healthy individuals is bound tightly to its carrier
protein, transferrin. In iron overload conditions, such as severe thalassemia, the
transferrin becomes saturated, and free iron is found in the plasma. This iron is
harmful since it provides the material for the production of hydroxyl radicals and
additionally accumulates in various organs, such as the heart, endocrine glands,
and liver, resulting in significant damage to these organs.
2.1.6. CLINICAL MANIFESTATIONS
History
Thalassemia minor usually presents as an asymptomatic mild microcytic
anemia and is detected through routine blood tests. Thalassemia major is a severe
anemia that presents during the first few months after birth. Thalassemia minor
(beta thalassemia trait) usually is asymptomatic, and it typically is identified
during routine blood count evaluation. Thalassemia major (homozygous beta
thalassemia) is detected during the first few months of life, when the patient's
level of fetal Hb decreases.
Physical Examination
Patients with the beta thalassemia trait generally have no unusual physical
findings. The physical findings are related to severe anemia, ineffective
erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from
transfusion and increased iron absorption. Skin may show pallor from anemia and
jaundice from hyperbilirubinemia. The skull and other bones may be deformed
secondary to erythroid hyperplasia with intramedullary expansion and cortical
bone thinning. Heart examination may reveal findings of cardiac failure and
arrhythmia, related to either severe anemia or iron overload. Abdominal
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examination may reveal changes in the liver, gall bladder, and spleen.1,2,5
Hepatomegaly related to significant extramedullary hematopoiesis typically
is observed. Patients who have received blood transfusions may have
hepatomegaly or chronic hepatitis due to iron overload; transfusion-associated
viral hepatitis resulting in cirrhosis or portal hypertension also may be seen. The
gall bladder may contain bilirubin stones formed as a result of the patient's life-
long hemolytic state. Splenomegaly typically is observed as part of the
extramedullary hematopoiesis or as a hypertrophic response related to the
extravascular hemolysis. Extremities may demonstrate skin ulceration. Iron
overload also may cause endocrine dysfunction, especially affecting the pancreas,
testes, and thyroid.11
2.1.7. DIAGNOSIS
1.History
The history in patients with thalassemia widely varies, depending on the severity
of the condition and the age at the time of diagnosis.
In most patients with thalassemia traits, no unusual signs or symptoms are
encountered.
Some patients, especially those with somewhat more severe forms of the
disease, manifest some pallor and slight icteric discoloration of the sclerae with
splenomegaly, leading to slight enlargement of the abdomen. An affected child's
parents or caregivers may report these symptoms. However, some rare types of
thalassemia trait are caused by a unique mutation, resulting in truncated or
elongated chains, which combine abnormally with chains, producing
insoluble dimers or tetramers. The outcome of such insoluble products is a
severe hemolytic process that needs to be managed like thalassemia intermedia
or, in some cases, thalassemia major.
The diagnosis is usually suspected in children with an unexplained
hypochromic and microcytic picture, especially those who belong to one of the
ethnic groups at risk. For this reason, physicians should always inquire about the
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patient's ethnic background, family history of hematologic disorders, and dietary
history.
Thalassemia should be considered in any child with hypochromic
microcytic anemia that does not respond to iron supplementation.
In more severe forms, such as thalassemia major, the symptoms vary
from extremely debilitating in patients who are not receiving transfusions to
mild and almost asymptomatic in those receiving regular transfusion regimens
and closely monitored chelation therapy.
Children with thalassemia major usually demonstrate none of the initial
symptoms until the later part of the first year of life (when chains are needed
to pair with chains to form hemoglobin (Hb) A, after chains production is
turned off). However, in occasional children younger than 3-5 years, the
condition may not be recognized because of the delay in cessation of Hb F
production.
Patients with Hb E/ thalassemia may present with severe symptoms and a
clinical course identical to that of patients with thalassemia major.
Alternatively, patients with Hb E/ thalassemia may run a mild course similar to
that of patients with thalassemia intermedia or minor. This difference in severity
has been described among siblings from the same parents. Some of the variation
in severity can be explained based on the different genotypes, such as the type of
thalassemia gene present (ie, + or -0), the co-inheritance of an thalassemia
gene, the high level of Hb F, or the presence of a modifying gene These changes
are caused by massive expansion of the bone due to the ineffective erythroid
production.
The ineffective erythropoiesis also creates a state of hypermetabolism
associated with fever and failure to thrive.
Occasionally, gout due to hyperuricemia, as well as kidney stones, are
seen more frequently as patients with thalassemia major are living longer.
Chronic anemia and exposure to chelating agents were thought to be blamed for
this complication.
Iron overload is one of the major causes of morbidity in all patients with
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severe forms of thalassemia, regardless of whether they are regularly transfused.
o In transfused patients, heavy iron turnover from transfused blood is
usually the cause; in nontransfused patients, this complication is usually
deferred until puberty (if the patient survives to that age).
o Increased iron absorption is the cause in nontransfused patients, but
the reason behind this phenomenon is not clear. Many believe that, despite the
iron overload state in these patients and the increased iron deposits in the bone
marrow, the requirement for iron to supply the overwhelming production of
ineffective erythrocytes is tremendous, causing significant increases in GI
absorption of iron.
o Bleeding tendency, increased susceptibility to infection, and organ
dysfunction are all associated with iron overload.
Poor growth in patients with thalassemia is due to multiple factors and
affects patients with well-controlled disease as well as those with uncontrolled
disease.
Patients may develop symptoms that suggest diabetes, thyroid disorder, or
other endocrinopathy; these are rarely the presenting reports.Patients with
thalassemia minor rarely demonstrate any physical abnormalities. Because the
anemia is never severe and, in most instances, the Hb level is not less than 9-10
g/dL, pallor and splenomegaly are rarely observed.
In patients with severe forms of thalassemia, the findings upon physical
examination widely vary, depending on how well the disease is controlled.
Findings include the following:
Children who are not receiving transfusions have a physical appearance so
characteristic that an expert examiner can often make a spot diagnosis.
In Cooley's original 4 patients, the stigmata of severe untreated
thalassemia major included the following:
o Severe anemia, with an Hb level of 3-7g/dL
o Massive hepatosplenomegaly
o Severe growth retardation
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o Bony deformities
These stigmata are typically not observed; instead, patients look healthy.
Any complication they develop is usually due to adverse effects of the treatment
(transfusion or chelation).
Bony abnormalities, such as frontal bossing, prominent facial bones, and
dental malocclusion, are usually striking.
Severe pallor, slight to moderately severe jaundice, and marked
hepatosplenomegaly are almost always present.Complications of severe anemia
are manifested as intolerance to exercise, heart murmur, or even signs of heart
failure. Growth retardation is a common finding, even in patients whose disease
is well controlled by chelation therapy. Patients with signs of iron overload may
also demonstrate signs of endocrinopathy caused by iron deposits. Diabetes and
thyroid or adrenal disorders have been described in these patients. In patients
with severe anemia who are not receiving transfusion therapy, neuropathy or
paralysis may result from compression of the spine or peripheral nerves by large
extramedullary hematopoietic masses.
2. Laboratory studies in thalassemia include the following:
The CBC count and peripheral blood film examination results are usually
sufficient to suspect the diagnosis. Hemoglobin (Hb) evaluation confirms the
diagnosis in thalassemia, Hb H disease, and Hb E/ thalassemia.
o In the severe forms of thalassemia, the Hb level ranges from 2-8
g/dL.
o Mean corpuscular volume (MCV) and mean corpuscular Hb
(MCH) are significantly low, but, unlike thalassemia trait, thalassemia major is
associated with a markedly elevated RDW, reflecting the extreme anisocytosis.
o The WBC count is usually elevated in thalassemia major; this is
due, in part, to miscounting the many nucleated RBCs as leukocytes.
Leukocytosis is usually present, even after excluding the nucleated RBCs. A
shift to the left is also encountered, reflecting the hemolytic process.
o Platelet count is usually normal, unless the spleen is markedly
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enlarged.
o Peripheral blood film examination reveals marked hypochromasia
and microcytosis, hypochromic macrocytes that represent the
polychromatophilic cells, nucleated RBCs, basophilic stippling, and occasional
immature leukocytes, as shown below.
o
Peripheral blood film in Cooley anemia.
o Contrast this with the abnormalities associated with Hb H, an
thalassemia, shownbelow.
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Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball
appearance).
o Hb electrophoresis usually reveals an elevated Hb F fraction,
which is distributed heterogeneously in the RBCs of patients with
thalassemia, Hb H in patients with Hb H disease, and Hb Bart in newborns
with thalassemia trait. In -0 thalassemia, no Hb A is usually present; only
Hb A2 and Hb F are found.
Iron studies are as follows:
o Serum iron level is elevated, with saturation reaching as high as
80%.
o The serum ferritin level, which is frequently used to monitor the
status of iron overload, is also elevated. However, an assessment using serum
ferritin levels may underestimate the iron concentration in the liver of a
transfusion-independent patient with thalassemia.
Complete RBC phenotype, hepatitis screen, folic acid level, and human
leukocyte antigen (HLA) typing are recommended before initiation of blood
transfusion therapy.9
3.Imaging Studies
Skeletal survey and other imaging studies reveal classic changes of the bones that
are usually encountered in patients who are not regularly transfused.
The striking expansion of the erythroid marrow widens the marrow spaces,
thinning the cortex and causing osteoporosis. These changes, which result from
the expanding marrow spaces, usually disappear when marrow activity is halted
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by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in
patients whose conditions are well-controlled.
In addition to the classic "hair on end" appearance of the skull, shown
below, which results from widening of the diploic spaces and observed on plain
radiographs, the maxilla may overgrow, which results in maxillary overbite,
prominence of the upper incisors, and separation of the orbit. These changes
contribute to the classic "chipmunk facies observed in patients with thalassemia
major
The classic "hair on end" appearance on plain skull radiographs of a patient with
Cooley anemia.
Other bony structures, such as ribs, long bones, and flat bones, may also
be sites of major deformities. Plain radiographs of the long bones may reveal a
lacy trabecular pattern. Changes in the pelvis, skull, and spine become more
evident during the second decade of life, when the marrow in the peripheral bones
becomes inactive while more activity occurs in the central bones.
Compression fractures and paravertebral expansion of extramedullary
masses, which could behave clinically like tumors, more frequently occur during
the second decade of life. In a recent study from Thailand, investigating
unrecognized vertebral fractures in adolescents and young adults with thalassemia
syndrome, 13% of the patients studied were found to have fractures and 30% of
them had multiple vertebral fractures. Those who were thought to be older had
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more severe disease, were splenectomized, and had been on chelation therapy for
a longer time.
MRI and CT scanning are usually used in diagnosing such complications.
Chest radiography is used to evaluate cardiac size and shape. MRI and CT
scanning can be used as noninvasive means to evaluate the amount of iron in the
liver in patients receiving chelation therapy.
A newer non invasive procedure involves measuring the cardiac T2* with
cardiac magnetic resonance (CMR). This procedure has shown decreased values
in cardiac T2* due to iron deposit in the heart. Unlike liver MRI, which usually
correlates very well with the iron concentration in the liver measured using
percutaneous liver biopsy samples and the serum ferritin level, CMR does not
correlate well with the ferritin level, the liver iron level, or echocardiography
findings. This suggests that cardiac iron overload cannot be estimated with these
surrogate measurements. This is also true in measuring the response to chelation
therapy in patients with iron overload. The liver is clear of iron loading much
earlier than the heart, which also suggests that deciding when to stop or reduce
treatment based on liver iron levels is misleading.
The relationship between hepatic and myocardial iron concentration was
assessed by T2-MRI in patients receiving chronic transfusion. A poor correlation
was noted, and approximately 14% of patients with cardiac iron overload were
identified who had no matched degree of hepatic hemosiderosis. Left ventricular
ejection fraction (LVEF) was insensitive for detecting high myocardial iron. For
this reason, cardiac evaluation should be addressed separately.
T2* MRI technique (T2* is the time needed for the organ to lose two
thirds of its signal, and it is measured in milliseconds (ms); when iron concentrate
increases, T2* shortens). R2* is the reciprocal of T2* and equals 1000/T2* and is
measured in a unit of inverse seconds. This technique has been recently validated
and is used for evaluation of cardiac and liver iron load. A shortening of
myocardial T2* to shorter than 20 ms is associated with an increased likelihood of
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decreased LVEF, whereas patients with T2 value of longer than 20 ms have a very
low likelihood of decreased LVEF; values from 10-20 ms indicate a 10% chance
of decreased LVEF, 8-10 ms an 18% chance, 6 ms a 38% chance, and 4 ms a 70%
chance of decreased LVEF.[2]
This T2* MRI technique. is not readily available in many parts of the
world. For this reason, the need for simpler and more available procedure was
addressed in a study conducted recently in Italy, where serial echocardiographic
LVEF measurements were proved to be very accurate and reproducible. The study
suggested that a reduction in of LVEF greater than 7% , over time, as determined
by 2-dimensional echocardiography, may be considered a strong predictive tool
for the detection of thalassemia major patients with increased risk of cardiac
death.
Hepatic iron content (HIC) obtained by liver biopsy, cardiac function tests
obtained by echocardiography measurements, and multiple-gated acquisition scan
(MUGA) findings were compared with the results of iron measurements on R2-
MRI in the liver and heart.
Various iron overload patients were involved in the study, which revealed
that R2-MRI was strongly associated with HIC (weakly but significantly with
ferritin level) and represents an excellent noninvasive method to evaluate iron
overload in the liver and heart and to monitor response to chelation therapy. T2*
and R2* MRI are preferred by many, however, because they allow measurements
of both liver and cardiac iron at the same time.
HIC should be measured annually if possible in all patients on long-term
blood transfusion therapy. Normal HIC values are up to 1.8 mg Fe/g dry weight
levels, while a level of up to 7 mg/g/dry weight seen in carriers of
hemochromatosis was shown to be asymptomatic and without any adverse effects.
High levels of greater than 15 mg/g/dry weight is consistent with significant iron
deposition and is associated with progression to liver fibrosis. Nontransferrin-
bound iron (NTBI) is usually elevated in the plasma at this level.
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4. The following tests may be indicated:
ECG and echocardiography are performed to monitor cardiac function.
HLA typing is performed for patients for whom bone marrow
transplantation is considered.
Eye examinations, hearing tests, renal function tests, and frequent blood
counts are required to monitor the effects of deferoxamine (DFO) therapy and
the administration of other chelating agents
5.Procedures
Bone marrow aspiration is needed in certain patients at the time of the
initial diagnosis to exclude other conditions that may manifest as thalassemia
major.
Liver biopsy is used to assess iron deposition and the degree of
hemochromatosis. However, using liver iron content as a surrogate for evaluation
of cardiac iron is misleading. Many studies have shown very poor correlation
between the two; hence, cardiac evaluation for the presence of iron overload needs
to be addressed separately.
Measurement of urinary excretion of iron after a challenge test of DFO is
used to evaluate the need to initiate chelation therapy and reflects the amount of
iron overload
6.Histologic Findings
All severe forms of thalassemia exhibit hyperactive marrow with erythroid
hyperplasia and increased iron stores in marrow, liver, and other organs. In the
untreated person with severe disease, extramedullary hematopoiesis in unusual
anatomic sites is one of the known complications.
Erythroid hyperplasia is observed in bone marrow specimens. Increased
iron deposition is usually present in marrow, as depicted in the image below, liver,
heart, and other tissues.
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Excessive iron in a bone marrow preparation.
7.Staging
Some use a relevant staging system based on the cumulative numbers of
blood transfusions given to the patient to grade cardiac-related symptoms and
determine when to start chelation therapy in patients with thalassemia major or
intermedia. In this system, patients are divided into 3 groups.
The first group contains those who have received fewer than 100 units of
packed RBCs (PRBCs) and are considered to have stage I disease. These patients
are usually asymptomatic; their echocardiograms reveal only slight left ventricular
wall thickening, and both the radionuclide cineangiogram and the 24-hour ECG
findings are normal.
Patients in the second group (stage II patients) have received 100-400 units of
blood and may report slight fatigue. Their echocardiograms may demonstrate left
ventricular wall thickening and dilatation but normal ejection fraction. The
radionuclide cineangiogram findings are normal at rest but show no increase or
fall in ejection fraction during exercise. Atrial and ventricular beats are usually
noticed on the 24-hour ECG.
Finally, in stage III patients, symptoms range from palpitation to
congestive heart failure, decreased ejection fraction on echocardiogram, and
normal cineangiogram results or decreased ejection fraction at rest, which falls
during exercise. The 24-hour ECG reveals atrial and ventricular premature beats,
often in pairs or in runs.
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A second classification, introduced by Lucarelli, is used for patients with
severe disease who are candidates forhematopoietic stem cell transplantation
(HSCT).This classification is used to assess risk factors that predict outcome and
prognosis and addresses 3 elements: (1) degree of hepatomegaly, (2) presence of
portal fibrosis in liver biopsy sample, and (3) effectiveness of chelation therapy
prior to transplantation.
If one of these elements is unfavorable prior to HSCT, the chance of event-free
survival is significantly poorer than in patients who have neither hepatomegaly
nor fibrosis and whose condition responds well to chelation (class 1 patients). The
event-free survival rate after allogeneic HSCT for class 1 patients is 90%,
compared with 56% for those with hepatomegaly and fibrosis and whose
condition responds poorly to chelation (class 3).10
2.1.8. DIFFERENTIAL DIAGNOSIS
Iron-deficiency anaemia also produces a hypochromic, microcytic anaemia
but Fe and ferritin are low whilst iron-binding capacity is high. Acute leukaemia may require bone marrow aspiration to differentiate.
Rhesus incompatibility is rare now and postmortem Hb electrophoresis
should differentiate in cases of hydrops fetalis.
Diamond-Blackfan syndrome is a rare congenital cause of erythroid
aplasia. It causes a severe normochromic, macrocytic anaemia usually in
infancy and is often associated with craniofacial or upper limb anomalies. 11
2.1.9. TREATMENT
Person with thalassemia trait require no treatment or long term monitoring.
They usually do not have iron deficiency, so iron supplements will not improve
their anemia. Accordingly, iron therapy should only be administered if iron
deficiency occurs.
Blood transfusions
Person with beta thalassemia major require periodic and lifelong blood
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transfusions to maintain a haemoglobin level higher than 9.5g per dl (95g per L)
and sustain normal growth. The need for blood transfusions may begin as early as
six months age. For persons with beta thalassemia intermedia, the decision to
transfuse is a more subjective clinical assessment. Transfusion requirements are
episodic and become necessary when the persons haemoglobin is inadequate for
a normal life or when the anemia impairs growth and development.
Chelation
Transfusion- dependent patients develop iron overload because they have
no physiologic process to remove excess iron from multiple transfusions.
Therefore they require treatment with an iron chelator starting between five and
eight years of age. Deferoxamine, subcutaneously or intravenously, has been the
treatment of choice. Although this therapy is relatively nontoxic, it is cumbersome
and expensive. The U.S Food and Drug Administration recently approved oral
deferasirox(Exjade) as an alternative treatment. Adverse effects of deferasirox
were transient and gastrointestinal in nature,, and no cases of agranulocytosis were
reported.
Bone Marrow Transplant
Bone marrow transplantation in childhood is the only curative therapy for
beta thalassemia major. Hematopoietic stem cell transplantation generally results
in an excellent outcome in low-risk persons, defined as those with no
hepatomegaly, no portal fibrosis on liver biopsy, and regular chelation therapy, or
at most, two of these abnormalities.
Management of Specific Conditions
Hypersplenism
If hypersplenism causes a marked increase in transfusion requirements,
splenectomy may be needed. Surgery is usually delayed until at least four years of
age because of the spleens role in clearing bacteria and preventing sepsis. At least
one month before surgery, patient should receive the pneumococcal
polysaccharide vaccine. Children should also receive the pneumococcal conjugate
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vaccine series. Antibiotic prophylaxis with penicillin, 250mg orally twice a day, is
recommended for all persons during the first two years after surgery and for
children younger than 16 years.
Cardiac
Serum ferritin has been used as a marker of iron storage to predict cardiac
complications. Ferritin levels less than 2500ng per ml are associated with
improved survival. However, ferritin levels are unrealiable when liver disease is
present.9
2.1.10. COMPLICATIONS
Iron overload is one of the major causes of morbidity in severe forms of
thalassaemia. Iron overload can occur even without transfusions as
absorption is increased by 2-5 g per year and this increases with regular
transfusions to an excess of over 10 g of iron per year. Excess iron is
deposited in body organs, especially the pancreas, liver, pituitary and heart,
causing fibrosis and eventual organ failure. Bleeding tendency and
susceptibility to infection are also related to iron overload. Endocrine
dysfunction secondary to iron overload is common in multiply transfused
patients, manifesting ashypogonadotrophic hypogonadism, short stature,
acquired hypothyroidism, hypoparathyroidism and diabetes mellitus.
Repeated transfusions increase the risk of blood-borne diseases,
including hepatitis Band C, although all blood is screened for known blood-
borne infections. Infection with rare opportunistic organisms may causepyrexia and enteritis in patients with iron overload. Yersinia
enterocolitica thrives with the abundant iron. Unexplained fever, especially
with diarrhoea, should be treated with gentamicin and co-trimoxazole, even
when cultures are negative.
Severe anaemia may cause high-output cardiac failure.
Osteoporosis is common and apparently multifactorial in aetiology but
alendronate or pamidronate is an effective treatment.
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The long-term increased red-cell turnover causes hyperbilirubinaemia
and gallstones.
Hyperuricaemia may lead to gout.
With increasing length of survival, hepatocellular carcinoma is becoming
an increasing problem.
Desferrioxamine can cause toxicity:
Local reaction at the site of injection can be severe.
High-frequency hearing loss has been reported in 30-40% of patients.
Colour andnight blindness can occur. These complications may be reversible.
Eye and hearing examinations should be performed every 6-12 months in
patients on chelation therapy.7
2.1.11. PROGNOSIS
The prognosis depends on the severity of the disease and adherence to
treatment.
thalassaemia:
The prognosis is excellent for asymptomatic carriers.
The overall survival for HbH disease is good overall but
variable. Many patients survive into adulthood, but some patients
have a more complicated course.
Hydrops fetalis is incompatible with life.
thalassaemia:
Thalassaemia minor (thalassaemia trait) usually causes
mild, asymptomatic microcytic anaemia, with no effect on
mortality or significant morbidity.
Severe thalassaemia major (also called Cooley's anaemia)
has traditionally had a poor prognosis with 80% dying from
complications of the disease in the first five years of life.
Until recently, patients who received transfusions only did
not survive beyond adolescence because of cardiac complications
caused by iron toxicity. The introduction of chelating agents to
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remove excessive iron has increased life expectancy dramatically.
The overall survival following stem cell transplantation has
been shown to be 90% with a disease-free survival of 86% over a
mean follow-up period of 15 years.13
2.2. PERICARDIAL EFFUSION
2.2.1. DEFINITION
The normal pericardium is a fibro elastic sac surrounding the heart that
contains a thin layer of fluid. Pericardial effusion is the presence of an abnormal
amount of fluid and/or an abnormal character to fluid in the pericardial space. It
can be caused by a variety of local and systemic disorders, or it may be
idiopathic.6
2.2.2. AETIOLOGY
Inflammation of the pericardium (pericarditis) is a response to disease,
injury or an inflammatory disorder that affects the pericardium. Pericardial
effusion is often a sign of this inflammatory response.
Pericardial effusion may also occur when the flow of pericardial fluids is
blocked or when blood accumulates within the pericardium. It's not clear how
some diseases contribute to pericardial effusion, and sometimes the cause can't be
determined.
Specific causes of pericardial effusion may include:
Viral, bacterial, fungal or parasitic infections
Inflammation of the pericardium due to unknown cause (idiopathic
pericarditis)
Inflammation of the pericardium following heart surgery or a heart attack
(Dressler's syndrome)
Autoimmune disorders, such as rheumatoid arthritis or lupus
Waste products in the blood due to kidney failure (uremia)
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Underactive thyroid (hypothyroidism))
Spread of cancer (metastasis), particularly lung cancer, breast cancer,melanoma, leukemia, non-Hodgkin's lymphoma or Hodgkin's disease
Cancer of the pericardium or heart
Radiation therapy for cancer if the heart was within the field of radiation
Chemotherapy treatment for cancer, such as doxorubicin (Doxil) and
cyclophosphamide (Cytoxan)
Trauma or puncture wound near the heart
Certain prescription drugs, including hydralazine, a medication for high
blood pressure; isoniazid, a tuberculosis drug; and phenytoin (Dilantin,
Phenytek, others), a medication for epileptic seizures 7
2.2.3. CLINICAL MANIFESTATION
The 1st symptom of pericardial disease is often precordial pain. The major
complaint is a sharp, stabbing sensation over the precordium and often the left
shoulder and back; the pain may be exaggerated by lying supine and relieved by
sitting, especially leaning forward. Because of the absence of sensory innervation
of the pericardium, the pain is probably referred pain from diaphragmatic and
pleural irritation. Cough, dyspnea, abdominal pain, vomiting, and fever may also
occur. The presence of symptoms or signs associated with other organs depends
on the cause of the pericarditis.
Many of the findings on physical examination are related to the degree of
fluid accumulation in the pericardial sac. The presence of a friction rub is helpful
but is a variable sign in acute pericarditis; it usually becomes apparent when the
effusion is small. When the effusion is larger, muffled heart sounds may be the
only auscultatory finding. Narrow pulses, tachycardia, neck vein distention, and
increased pulsus paradoxus suggest significant fluid accumulation.
Pulsus paradoxus is caused by the normal slight decrease in systolic
arterial pressure during inspiration. With cardiac tamponade, this normal
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phenomenon is exaggerated, probably because of decreased filling of the left side
of the heart with the inspiratory phase of respiration. The degree of pulsus
paradoxus is determined with a mercury manometer. The patient is told to breathe
normally without exaggeration. By allowing the manometer to fall slowly, the 1st
Korotkoff sound will initially be heard intermittently (varying with respirations).
This 1st point is noted, and the manometer is then allowed to fall until the 1st
Korotkoff sound is heard continuously. The difference between these two systolic
pressures is the pulsus paradoxus. A pulsus paradoxus greater than 20 mm Hg in a
child with pericarditis is an indicator of the presence of cardiac tamponade; a 10
20 mm Hg change is equivocal. Increased pulsus paradoxus may also be seen in
patients with severe dyspnea of any cause, in patients with pulmonary disease
(emphysema or asthma), in obese individuals, or in patients being ventilated with
a positive pressure respirator. In these patients, the paradoxical pulse is due to a
marked increase in intrathoracic pressure. The cause of a paradoxical pulse in a
child maintained on a ventilator after heart surgery may therefore be difficult to
assess.8
2.2.4.PATHOPHYSIOLOGY
The pericardium consists of 2 layers, the visceral pericardium
(epicardium) and the parietal pericardium, which enclose a potential space (ie, the
pericardial cavity) between them. This cavity is normally lubricated by a very
small amount of serous fluid (< 30 mL in adults). Inflammation of the pericardium
or obstruction of lymphatic drainage from the pericardium of any etiology causes
an increase in fluid volume, referred to as a pericardial effusion.
Pericardial inflammation results in an accumulation of fluid in the
pericardial space. The fluid varies according to the cause of the pericarditis and
may be serous, fibrinous, purulent, or hemorrhagic. Cardiac tamponade occurs
when the amount of pericardial fluid reaches a level that compromises cardiac
function. In a healthy child, 1015 mL of fluid is normally found in the pericardial
space, whereas in an adolescent with pericarditis, fluid in excess of 1,000 mL may
accumulate. For every small increment of fluid, pericardial pressure rises slowly;
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once a critical level is reached, pressure rises rapidly and culminates in severe
cardiac compression. Inhibition of ventricular filling during diastole, elevated
systemic and pulmonary venous pressure, and if untreated, eventual compromised
cardiac output and shock occur.
Malignant involvement of the pericardium may be primary (less common)
or secondary (spreading from a nearby or distant focus of malignancy). Secondary
neoplasms can involve the pericardium by contiguous extension from a
mediastinal mass, nodular tumor deposits from hematogenous or lymphatic
spread, and diffuse pericardial thickening from tumor infiltration (with or without
effusion). In diffuse pericardial thickening, the heart may be encased by
an effusive-constrictive pericarditis.
Other rare mechanisms include chronic myelomonocytic leukemia and
intrapericardial extramedullary hematopoiesis with preleukemic conditions or
during blast crisis in chronic myeloid leukemia. Obstruction of lymphatic
drainage by mediastinal tumors, either benign or malignant, can also give rise to
pericardial effusion, which can be chylous. These mechanisms may act
independently or jointly in any particular child with malignancy. The underlying
myocardium is not involved in most patients.6
2.2.5. DIAGNOSIS AND LABORATORY STUDIES
The extent to which pericardial effusions should be evaluated with fluid
analysis remains an area of some debate. Initially, in a patient with a new
pericardial effusion, the likelihood of myocarditis or pericarditis should beassessed, and the initial diagnostic evaluation should be directed toward these
conditions. In general, all patients with pericardial tamponade, suspected purulent
effusion, or poor prognostic indicators in the setting of pericarditis should
undergodiagnosticpericardiocentesis.
The following lab studies may be performed in patients with suspected pericardial
effusion.
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Electrolytes - Metabolic abnormalities (eg, renal failure)
CBC count with differential - Leukocytosis for evidence of infection, as
well as cytopenias, as signs of underlying chronic disease (eg, cancer,
HIV)
Cardiac enzymes: Troponin level is frequently minimally elevated in acute
pericarditis, usually in the absence of an elevated total creatine kinase
level. Presumably, this is due to some involvement of the epicardium by
the inflammatory process. Although the elevated troponin may lead to the
misdiagnosis of acute pericarditis as a myocardial infarction, most patients
with an elevated troponin and acute pericarditis have normal coronary
angiograms. An elevated troponin level in acute pericarditis typically
returns to normal within 1-2 weeks and is not associated with a worse
prognosis.
Thyroid-stimulating hormone - Thyroid-stimulating hormone screen for
hypothyroidism
Rickettsial antibodies - If high index of suspicion of tick-borne disease
Rheumatoid factor, immunoglobulin complexes, antinuclear antibody test
(ANA), and complement levels (which would be diminished) - In
suspected rheumatologic causes
PPD and controls
Pericardial fluid analysis - Routine tests (these should be considered part
of the standard pericardial fluid analysis)
o Lactic (acid) dehydrogenase (LDH), total protein - The Light
criteria (for exudative pleural effusion) found to be as reliable in
distinguishing between exudative and transudative effusions
Total protein fluid-to-serum ratio >0.5
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LDH fluid-to-serum ratio >0.6
LDH fluid level exceeds two thirds of upper-limit of
normal serum level
o Other indicators suggestive of exudate - Specific gravity >1.015,
total protein >3.0 mg/dL, LDH >300 U/dL, glucose fluid-to-serum
ratio 10,000) with neutrophil
predominance suggests bacterial or rheumatic cause, although
unreliable
o Gram stain - Specific but insensitive indicator of bacterial infection
o Cultures - Signals and identifies infectious etiology
o Fluid hematocrit for bloody aspirates - Hemorrhagic fluid
hematocrits usually significantly less than simultaneous peripheral
blood hematocrits
Pericardial fluid - Special tests (these should be considered individually
based on the pretest probability of the coexisting condition under concern)
o Viral cultures
o Adenosine deaminase; polymerase chain reaction (PCR); culture
for tuberculosis; smear for acid-fast bacilli in suspected
tuberculosis infection, especially in patients with HIV
o A definite diagnosis of tuberculous pericarditis is based on the
demonstration of tubercle bacilli in pericardial fluid or on a
histological section of the pericardium. Probable tuberculous
pericarditis is based on the proof of tuberculosis elsewhere in a
patient with otherwise unexplained pericarditis, a lymphocytic
pericardial exudate with elevated adenosine deaminase levels,
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and/or appropriate response to a trial of antituberculosis
chemotherapy.
Tumor markers: Elevated carcinoembryonic antigen (CEA) levels in
pericardial fluid have a high specificity for malignant effusions.
Imaging Studies
Chest radiography
Findings include enlarged cardiac silhouette (so-called water-bottle heart)
and pericardial fat stripe.
Image is from a patient with malignant pericardial effusion. Note the
"water-bottle" appearance of the cardiac silhouette in the
anteroposterior (AP) chest film.
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A third of patients have a coexisting pleural effusion.
Radiography is unreliable in establishing or refuting diagnosis of
pericardial effusion.
Echocardiography
Echocardiography is the imaging modality of choice for the diagnosis of
pericardial effusion, as the test can be performed rapidly and in unstable patients.
Most importantly, the contribution of pericardial effusion to overall cardiac
enlargement and the relative roles of tamponade and myocardial dysfunction to
altered hemodynamics can be evaluated with echocardiography.9
Echocardiogram (parasternal, long axis) of a patient with a moderate
pericardial effusion.
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Subcostal view of an echocardiogram that shows a moderate-to-large amount
of pericardial effusion.
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This echocardiogram shows a large amount of pericardial effusion (identified
by the white arrows).
2-D echocardiography
o Pericardial effusion appears as an echo-free space between the
visceral and parietal pericardium. Early effusions tend to
accumulate posteriorly owing to expandable posterior/lateral
pericardium. Large effusions are characterized by excessive motion
within the pericardial sac. Small effusions have an echo-free space
of less than 10 mm, and are generally seen posteriorly. Moderate-
sized effusions range from 10-20 mm and are circumferential, and
greater than 20 mm indicates a large effusion. Fluid adjacent to the
right atrium is an early sign of pericardial effusion. [10 ]
o Severe cases may be accompanied by diastolic collapse of the right
atrium and right ventricle (and in hypovolemic patients, the left
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atrium and left ventricle), signaling the onset of pericardial
tamponade (see Cardiac Tamponade).
o
This image is from a patient with malignant pericardial
effusion. The effusion is seen as an echo-free region to the right
of the left ventricle (LV).
M-mode echocardiography
o
M-mode is adjunctive to 2D imaging for the detection ofpericardial effusion. Effusions can be classified using M-mode
according to a system proposed by Horowitz, et al.[11 ]
Type A: No effusion
Type B: Separation of epicardium and pericardium
Type C1: Systolic and diastolic separation of pericardium
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Type C2: Systolic and diastolic separation of pericardium,
attenuated pericardial motion
Type D: Pronounced separation of pericardium and
epicardium with large echo-free space
o In the parasternal long-axis view, discordant changes in right and
left ventricular cavity size can suggest pronounced interventricular
dependence.
Doppler echocardiography
o Transmitral and transtricuspid inflow velocities should be
interrogated to assess for respiratory variation. Decreases in flow
during inspiration (transmitral) or expiration (transtricuspid) should
raise the suspicion of clinically significant interventricular
dependence and tamponade physiology.
o
Pulmonic vein inflow may show a decrease in early diastolic flowwith hemodynamically significant effusions. Hepatic vein diastolic
flow reversal may also be seen.
False-positive echocardiograms can occur in pleural effusions, pericardial
thickening, increased epicardial fat tissue, atelectasis, and mediastinal lesions.
Epicardial fat tissue is more prominent anteriorly but may appear
circumferentially, thus mimicking effusion. Fat is slightly echogenic and tends tomove in concert with the heart, 2 characteristics that help distinguish it from an
effusion, which is generally echolucent and motionless.
In addition to its mimicry, pericardial fat accumulation is a source of
bioactive molecules, is significantly associated with obesity-related insulin
resistance, and may be a coronary risk factor.12
In patients with pericardial effusion, imaging from low to midposterior
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thorax can provide additional diagnostic echocardiographic images and should be
used in patients in whom conventional images are technically difficult or require
additional information.
Transesophageal echocardiography (TEE)
TEE maintains all of the advantages of transthoracic echocardiography
and is useful in characterizing loculated effusions. However, this may be difficult
to perform in patients with symptomatic effusions due to hemodynamic
instability, making the required sedation more difficult.
Intracardiac echocardiography (ICE)
ICE is generally reserved for the assessment of pericardial effusion in the
setting of percutaneous interventional or electrophysiology procedure. Phased
array ICE systems can perform both 2-D and Doppler interrogations.
Computed tomography
CT can potentially determine composition of fluid and may detect as little
as 50 mL of fluid.
CT can detect pericardial calcifications, which can be indicative of
constrictive pericarditis.
CT results in fewer false-positive results than echocardiography.
CT can be problematic in patients who are unstable given the time
required to transport to and from the scanner and perform the test.
Magnetic resonance imaging
MRI can detect as little as 30 mL of pericardial fluid.
May be able to distinguish hemorrhagic and no hemorrhagic fluids, as
hemorrhagic fluids have a high signal intensity on T-1 weighted images,
whereas no hemorrhagic fluids have a low signal intensity.
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Nodularity or irregularity of the pericardium seen on MRI may be
indicative of a malignant effusion.
MRI is more difficult to perform than CT scan acutely, given the length of
time the patient must remain in the scanner.
Both MRI and CT scan may be superior to echocardiography in detecting
loculated pericardial effusions, especially when located anteriorly. Also, these
modalities allow for greater visualization of the thoracic cavity and adjacent
structures, and therefore may identify other abnormalities relating to the cause of
the effusion.12
Other Tests
Electrocardiography
Early in the course of acute pericarditis, the ECG typically displays diffuse
ST elevation in association with PR depression. The ST elevation is
usually present in all leads except for aVR, but postmyocardial infarction
pericarditis, the changes may be more localized. Classically, the ECG
changes of acute pericarditis evolve through 4 progressive stages:
o Stage I - Diffuse ST-segment elevation and PR-segment depression
o Stage II - Normalization of the ST and PR segments
o Stage III - Widespread T-wave inversions
o
Stage IV - Normalization of the T waves
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This electrocardiogram (ECG) is from a patient with malignant
pericardial effusion. The ECG shows diffuse low voltage, with a
suggestion of electrical alternans in the precordial leads.
Patients with uremic pericarditis frequently do not have the typical ECG
abnormalities.
2.2.6. DIFFERENTIAL DIAGNOSIS
Cardiac Tamponade Pericarditis, Constrictive-Effusive
Cardiomyopathy, Dilated Pericarditis, Uremic
Myocardial Infarction Pulmonary Edema, Cardiogenic
Pericarditis, Acute Pulmonary Embolism
Pericarditis, Constrictive
2.2.7. TREATMENT
Medical Care
Initially, medical care of pericardial effusion is focused on determination
of the underlying etiology.
Aspirin/nonsteroidal anti-inflammatory agents (NSAIDs)
o Most acute idiopathic or viral pericarditis occurrences are self-
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limited and respond to treatment with aspirin (650 mg q6h) or
another NSAID.
o Aspirin may be the preferred nonsteroidal agent to treat pericarditis
after myocardial infarction because other NSAIDs may interfere
with myocardial healing.
o Indomethacin should be avoided in patients who may have
coronary artery disease.
o Meurin et al performed a multicenter, randomized, double-blind
trial on the effect of the NSAID diclofenac in reducing
postoperative pericardial effusion volume. Diclofenac, 50 mg, or
placebo twice daily for 14 days was given to 196 patients at high
risk for tamponade because of pericardial effusion more than 7
days after cardiac surgery. The authors found that diclofenac was
not effective at reducing the size of the effusion or preventing late
cardiac tamponade.[15 ]
Colchicine: The routine use of colchicine is supported by results from the
COlchicine for acute PEricarditis (COPE) trial. In this trial, 120 patients
with a first episode of acute pericarditis (idiopathic, acute,
postpericardiotomy syndrome, and connective tissue disease) entered a
randomized, open-label trial comparing aspirin treatment alone with
aspirin plus colchicine (1-2 mg for the first day followed by 0.5-1 mg/d for
3 mo). Colchicine reduced symptoms at 72 hours (11.7% vs
36.7%;P=0.03) and reduced recurrence at 18 months (10.7% vs
36.7%;P=0.004; 5 needed treatment). Colchicine was discontinued in 5
patients because of diarrhea. No other adverse events were noted.
Importantly, none of the 120 patients developed cardiac tamponade or
progressed to pericardial constriction.12
Steroids
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o Steroid administration early in the course of acute pericarditis
appears to be associated with an increased incidence of relapse
after tapering the steroids.
o In the COPE trial, steroid use was an independent risk factor for
recurrence (odds ratio=4.3). Also, an observational study strongly
suggests that the use of steroids increases the probability of relapse
in patients treated with colchicine.[16 ]
o Systemic steroids should be considered only in patients with
recurrent pericarditis unresponsive to NSAIDs and colchicine or as
needed for treatment of an underlying inflammatory disease. If
steroids are to be used, an effective dose (1-1.5 mg/kg of
prednisone) should be given, and it should be continued for at least
1 month before slow tapering.
o The intrapericardial administration of steroids has been reported to
be effective in acute pericarditis without producing the frequentreoccurrence of pericarditis that complicates the use of systemic
steroids, but the invasive nature of this procedure limits its use.
Hemodynamic support
o Patients who have effusions with actual or threatened tamponade
should be considered to have a true or potential emergency. Most
patients require pericardiocentesis to treat or prevent tamponade.
However, treatment should be carefully individualized.
o Hemodynamic monitoring with a balloon flotation pulmonary
artery catheter is useful, especially in those with threatened or mild
tamponade in whom a decision is made to defer pericardiocentesis.
Hemodynamic monitoring is also helpful after pericardiocentesis to
assess both reaccumulation and the presence of underlying
constrictive disease. However, insertion of a pulmonary artery
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catheter should not be allowed to delay definitive therapy in
critically ill patients.
o Intravenous fluid resuscitation may be helpful in cases of
hemodynamic compromise.
o In patients with tamponade who are critically ill, intravenous
positive inotropes (dobutamine, dopamine) can be used but are of
limited use and should not be allowed to substitute for or delay
pericardiocentesis.
Antibiotics
o In patients with purulent pericarditis, urgent pericardial drainage
combined with intravenous antibacterial therapy (eg, vancomycin 1
g bid, ceftriaxone 1-2 g bid, and ciprofloxacin 400 mg/d) is
mandatory. Irrigation with urokinase or streptokinase, using large
catheters, may liquify the purulent exudate, but open surgical
drainage is preferable.
o The initial treatment of tuberculous pericarditis should include
isoniazid 300 mg/day, rifampin 600 mg/day, pyrazinamide 15-30
mg/kg/day, and ethambutol 15-25 mg/kg/day. Prednisone 1-2
mg/kg/day is given for 5-7 days and progressively reduced to
discontinuation in 6-8 weeks. Drug sensitivity testing is essential.
Uncertainty remains whether adjunctive corticosteroids are
effective in reducing mortality or progression to constriction.
Surgical resection of the pericardium remains the appropriate
treatment for constrictive pericarditis. The timing of surgical
intervention is controversial, but many experts recommend a trial
of medical therapy for noncalcific pericardial constriction and
pericardiectomy in nonresponders after 4-8 weeks of
antituberculosis chemotherapy.
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Antineoplastic therapy (eg, systemic chemotherapy, radiation) in
conjunction with pericardiocentesis has been shown to be effective in
reducing recurrences of malignant effusions.
Corticosteroids and NSAIDs are helpful in patients with autoimmune
conditions.12
Surgical Care
Surgical care of pericardial effusion includes the following:
Subxiphoid pericardial window with pericardiostomy
o This procedure is associated with low morbidity, mortality, and
recurrence rates, and can be considered as a reasonable alternative
diagnostic or treatment modality to pericardiocentesis in selected
patients.
o It can be performed under local anesthesia. This is advantageous
because general anesthesia often leads to decreased sympathetic
tone, resulting in hemodynamic collapse in patients with
pericardial tamponade and shock.
o It may be less effective when effusion is loculated.
o One study indicated it may be safer and more effective at reducing
recurrence rates than pericardiocentesis. However, only patients
who were hemodynamically unstable underwentpericardiocentesis, and no change in overall survival rate was
observed.
Thoracotomy
o This should be reserved for patients in whom conservative
approaches have failed.
o Thoracotomy allows for creation of a pleuropericardial window,
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which provides greater visualization of pericardium.
o Thoracotomy requires general anesthesia and thus has higher
morbidity and mortality rates than the subxiphoid approach.
Video-assisted thoracic surgery
o Video-assisted thoracic surgery (VATS) enables resection of a
wider area of pericardium than the subxiphoid approach without
the morbidity of thoracotomy.
o The surgeon is able to create a pleuropericardial window and
address concomitant pleural pathology, which is especially
common in patients with malignant effusions.
o One disadvantage of VATS is that it requires general anesthesia
with single lung ventilation, which may be difficult in otherwise
seriously ill patients.
Median sternotomy
o This procedure is reserved for patients with constrictive
pericarditis.
o Operative mortality rate is high (5-15%).
Consultations
A cardiologist should be involved in the care of patients with pericardial
effusion.
Cardiothoracic surgery may be required for recurrent or complicated cases
(see Surgical Care).
2.2.8. COMPLICATIONS
Pericardial tamponade
o Can lead to severe hemodynamic compromise and death.
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o Heralded by equalization of diastolic filling pressures.
o Treat with expansion of intravascular volume (small amounts of